Table of contents

Contributors

xii

Preface

xvii

Get more from this Handbook

xviii

List of abbreviations

xxix

Chapter 1 - Structure and function of the respiratory system

Anatomy and development of the respiratory system

Robert Dinwiddie

Applied respiratory physiology

Caroline Beardsmore and Monika Gappa

Immunology and defence mechanisms

Diana Rädler and Bianca Schaub

Environmental determinants of childhood respiratory health

and disease

Erik Melén and Matthew S. Perzanowski

Chapter 2 - Respiratory signs and symptoms

History and physical examination

Michael B. Anthracopoulos, Kostas Douros and Kostas N. Priftis

Cough

Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang

Tachypnoea, dyspnoea, respiratory distress and chest pain

Josef Riedler

Snoring, hoarseness, stridor and wheezing

Kostas N. Priftis, Kostas Douros and Michael B. Anthracopoulos

Exercise intolerance

Kai-Håkon Carlsen

Chapter 3 - Pulmonary function testing and other diagnostic tests

Static and dynamic lung volumes

Oliver Fuchs

Respiratory mechanics

Oliver Fuchs

Reversibility, bronchial provocation testing and exercise testing

Kai-Håkon Carlsen

Blood gas assessment and oximetry

Paola Papoff, Fabio Midulla and Corrado Moretti

Exhaled nitric oxide, induced sputum and exhaled breath analysis

100

Johan C. de Jongste

Pulmonary function testing in infants and preschool children

107

Enrico Lombardi, Graham L. Hall and Claudia Calogero

Single- and multiple-breath washout techniques

113

Sophie Yammine and Philipp Latzin

Forced oscillation techniques

118

Shannon J. Simpson and Graham L. Hall

Polysomnography

122

Sedat Oktem and Refika Ersu

Chapter 4 - Airway endoscopy

Flexible bronchoscopy

132

Jacques de Blic

Bronchoalveolar lavage

140

Fabio Midulla, Raffaella Nenna and Ernst Eber

Bronchial brushing and bronchial and transbronchial biopsies

146

Petr Pohunek and Tamara Svobodová

Rigid and interventional endoscopy

151

Thomas Nicolai

General anaesthesia, conscious sedation and local anaesthesia

156

Jacques de Blic and Caroline Telion

Chapter 5 - Lung imaging

Conventional radiography

161

Meinrad Beer

Computed tomography

166

Harm A.W.M. Tiddens, Marcel van Straten and Pierluigi Ciet

Magnetic resonance imaging

176

Lucia Manganaro and Silvia Bernardo

Ultrasonography

183

Carolina Casini, Vincenzo Basile, Mariano Manzionna and

Roberto Copetti

Isotope imaging methods

189

Georg Berding

Interventional radiology

193

Efthymia Alexopoulou, Argyro Mazioti and Dimitrios Filippiadis

Chapter 6 - Inhalation therapy

Aerosol therapy

198

Hettie M. Janssens

Chapter 7 - Acute and chronic lung infections

Epidemiology

207

Steve Turner

Microbiology testing and interpretation

214

Elpis Hatziagorou, Emmanuel Roilides and John Tsanakas

Immunisation against respiratory pathogens

221

Horst von Bernuth and Philippe Stock

Upper respiratory tract infections

227

Rossa Brugha, Chinedu Nwokoro and Jonathan Grigg

Community-acquired pneumonia

233

Mark L. Everard, Vanessa Craven and Patricia Fenton

Hospital-acquired pneumonia

242

Vanessa Craven, Patricia Fenton and Mark L. Everard

Lung involvement in immunodeficiency disorders

248

Rifat Chaudry and Paul Aurora

Non-CF bronchiectasis

253

Elif Dagli

Pleural infection, necrotising pneumonia and lung abscess

258

Fernando M. de Benedictis, Chiara Azzari and Filippo Bernardi

Bacterial bronchitis with chronic wet lung

266

Petr Pohunek and Tamara Svobodová

Chapter 8 - Tuberculosis

Pulmonary TB, latent TB, and in vivo and in vitro tests

270

Zorica Zivkovic and James Paton

Extrapulmonary TB and TB in the immunocompromised host

284

Toyin Togun, Uzor Egere and Beate Kampmann

Chapter 9 - Bronchial asthma and wheezing disorders

Epidemiology and phenotypes of bronchial asthma and

293

wheezing disorders

Franca Rusconi, Ben D. Spycher and Claudia E. Kuehni

Genetic and environmental factors in bronchial asthma and

298

wheezing disorders

Oliver Fuchs and Erika von Mutius

Acute viral bronchiolitis

305

Fabio Midulla, Ambra Nicolai and Corrado Moretti

Preschool wheezing

310

Paul L.P. Brand, Annemie M. Boehmer, Anja A.P.H. Vaessen-Verberne

Bronchial asthma

316

Mariëlle Pijnenburg and Karin C. Lødrup Carlsen

Emerging therapeutic strategies

328

Giorgio Piacentini and Laura Tenero

Differential diagnosis of bronchial asthma

334

Giorgio Piacentini and Laura Tenero

Chapter 10 - Allergic disorders

Pathophysiology and epidemiology of allergic disorders

339

Karin C. Lødrup Carlsen

In vivo and in vitro diagnostic tests in allergic disorders

345

Gunilla Hedlin

Anaphylaxis

349

Antonella Muraro

Allergic rhinitis

354

Michele Miraglia Del Giudice, Francesca Galdo and Salvatore Leonardi

Atopic dermatitis

363

Paolo Meglio, Elena Galli and Nunzia Maiello

Food allergy

370

Alessandro Fiocchi, Lamia Dahdah and Luigi Terracciano

Allergic bronchopulmonary aspergillosis

376

Andrew Bush

Specific immunotherapy, prevention measures and alternative treatment

383

Susanne Halken and Gunilla Hedlin

Chapter 11 - Cystic fibrosis

Genetics, pathophysiology and epidemiology of CF

390

Sabina Gallati

Screening and diagnosis of CF

397

Jürg Barben and Kevin Southern

CF lung disease

402

Nicolas Regamey and Jürg Barben

Extrapulmonary manifestations of CF

410

Anne Munck, Manfred Ballmann and Anders Lindblad

Emerging treatment strategies in CF

421

Melinda Solomon and Felix Ratjen

Prognosis, management and indications for lung transplantation in CF

427

Helen Spencer and Andrew Bush

Chapter 12 - Congenital malformations

Airway malformations

435

Ernst Eber and Andreas Pfleger

Thoracic malformations

445

Ashok Daya Ram, Jennifer Calvert and Sailesh Kotecha

Vascular malformations

452

Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera,

Chiara Gardella, Silvia Rosina, Michele Ghezzi and Francesca Rizzo

Chapter 13 - Bronchopulmonary dysplasia and chronic lung disease

Aetiology, pathogenesis, prevention and evidence-based

461

medical management

Robert I. Ross-Russell

Nutritional care

466

Kajsa Bohlin

Neurodevelopmental assessment and outcomes

469

Charles C. Roehr, Lex W. Doyle and Peter G. Davis

Long-term respiratory outcomes

472

Manuela Fortuna, Marco Filippone and Eugenio Baraldi

Chapter 14 - Pleural, mediastinal and chest wall diseases

Pleural effusion, chylothorax, haemothorax and mediastinitis

477

Juan Antón-Pacheco, Carmen Lucas-Paredes and

Antonio Martinez-Gimeno

Pneumothorax and pneumomediastinum

485

Nicolaus Schwerk, Folke Brinkmann and Hartmut Grasemann

Neuromuscular disorders

492

Anita K. Simonds

Chest wall disorders

497

Daniel Trachsel, Carol-Claudius Hasler and Jürg Hammer

Chapter 15 - Sleep-related disorders

Physiology and pathophysiology of sleep

503

Sedat Oktem and Refika Ersu

OSAS and upper respiratory airway resistance syndrome

514

Maria Pia Villa and Silvia Miano

Central sleep apnoea and hypoventilation syndromes

521

Malin Rohdin and Hugo Lagercrantz

Impact of obesity on respiratory function

528

Andrea Bon, Martina Tubaro and Mario Canciani

Chapter 16 - Lung injury and respiratory failure

Lung injury

533

Andreas Schibler

Acute and chronic respiratory failure

538

Robert I. Ross-Russell and Colin Wallis

Home oxygen therapy, invasive ventilation and NIV, and home

545

ventilatory support

Brigitte Fauroux, Adriana Ramirez and Sonia Khirani

Chapter 17 - Other respiratory diseases

Primary ciliary dyskinesia

551

Deborah Snijders, Serena Calgaro, Massimo Pifferi, Giovanni Rossi

and Angelo Barbato

Gastro-oesophageal reflux-associated lung disease and

559

aspiration syndrome

Osvaldo Borelli, Efstratios Saliakellis, Fernanda Cristofori and

Keith J. Lindley

Foreign body aspiration

566

Iolo Doull

Bronchiolitis obliterans

570

Francesca Santamaria, Silvia Montella and Salvatore Cazzato

Plastic bronchitis

577

Bruce K. Rubin and William B. Moskowitz

Haemangiomas, lymphangiomas and papillomatosis

582

Thomas Nicolai

Interstitial lung diseases

587

Annick Clement, Guillaume Thouvenin, Harriet Corvol and Nadia Nathan

Surfactant dysfunction and alveolar proteinosis

596

Armin Irnstetter, Carolin Kröner, Ralf Zarbock and Matthias Griese

Pulmonary vascular disorders

601

Andrea McKee and Andrew Bush

Eosinophilic lung diseases and hypersensitivity pneumonitis

610

Carlo Capristo, Giuseppina Campana, Francesca Galdo, Emilia Alterio

and Laura Perrone

Pulmonary haemorrhage

619

Robert Dinwiddie

Sickle cell disease

625

Tobias Ankermann

Lung and mediastinal tumours

630

Amalia Schiavetti

Systemic disorders with lung involvement

636

Andrew Bush

Lung transplantation and management of post-lung transplant patients

647

Paul Robinson and Paul Aurora

Contributors

Chief Editors

Ernst Eber

Fabio Midulla

Respiratory and Allergic Disease Division,Department of Paediatrics,

Department of Paediatrics

“Sapienza” University of Rome,

and Adolescence, Medical University

Rome, Italy.

of Graz, Graz, Austria.

midulla@uniroma1.it

ernst.eber@medunigraz.at

Authors

Emilia Alterio

Paul Aurora

Department of Pediatrics, Second

Great Ormond Street Hospital for

University of Naples, Naples, Italy.

Children, London, UK.

p.aurora@ucl.ac.uk

Efthtymia Alexopoulou

2nd Department of Radiology,

Chiara Azzari

University Hospital ATTIKON,

Department of Pediatrics, University

Athens, Greece.

of Florence, Mayer Children’s

ealex64@hotmail.com

Hospital, Florence, Italy.

c.azzari@meyer.it

Tobias Ankermann

Klinik für Allgemeine Pädiatrie

Manfred Ballmann

Universitätsklinikum Schleswig-

Department of Pediatric

Holstein (UKSH), Kiel, Germany.

Pulmonology, Ruhr-University

ankermann@pediatrics.uni-kiel.de

Bochum, Bochum, Germany.

m.ballmann@klinikum-bochum.de

Michael B. Anthracopoulos

Respiratory Unit, Department of

Eugenio Baraldi

Paediatrics, University of Patras,

Pediatric Pneumonolgy, University of

Patras, Greece.

Padova, Padova, Italy.

manthra@otenet.gr

baraldi@pediatria.unipd.it

Roberta Antona

Angelo Barbato

Consiglio Nazionale delle Ricerche,

Department of Pediatrics, University

Istituto di Biomedicina e Immunolo-

of Padova, Italy.

gia Molecolare, Palermo, Italy.

barbato@pediatria.unipd.it

roberta.antona@ibim.cnr.it

Jürg Barben

Juan L. Antón-Pacheco

Division of Respiratory Medicine,

Pediatric Surgery, Hospital Universi-

Children’s Hospital St. Gallen,

tario 12 de Octubre, Madrid, Spain.

St Gallen, Switzerland.

janton.hdoc@salud.madrid.org

juerg.barben@kispisg.ch

xii

Vincenzo Basile

Kajsa Bohlin

Pediatric Department, Monopoli

Neonatal intensive Care,

Hospital, Bari, Italy.

Karolinska Institutet, Karolinska

vinbasile67@libero.it

University Hospital

Huddinge, Stockholm, Sweden.

Caroline Beardsmore

kajsa.bohlin@ki.se

Department of Infection, Immunity

and Inflammation (Child Health),

Andrea Bon

University of Leicester, Leicester, UK.

Pediatric Department, University of

csb@le.ac.uk

Udine, Udine, Italy.

gandale@gmail.com

Meinrad Beer

Department of Pediatric

Osvaldo Borrelli

Radiology, Medical University Graz,

Department of Paediatric

Graz, Austria.

Gastroenterology, Division of

meinrad.beer@medunigraz.at

Neurogastroenterology and Motility,

Great Ormond Street Hospital for

Georg Berding

Children, ICH University College of

Department of Nuclear Medicine,

London, London, UK.

Hannover Medical School, Hannover,

osvaldo.borrelli@gosh.nhs.uk

Germany.

berding.georg@mh-hannover.de

Paul L.P. Brand

Princess Amalia Children’s Clinic,

Filippo Bernardi

Isala Klinieken, Zwolle,

Department of Pediatrics, University

The Netherlands.

of Bologna, S. Orsola-Malpighi

p.l.p.brand@isala.nl

Hospital, Bologna, Italy.

filippo.bernardi@unibo.it

Folke Brinkmann

Department of Pediatrics, Pediatric

Silvia Bernardo

Pneumology, Allergology and

Radiological Oncological and

Neonatology, Hannover Medical

Pathological Sciences, Umberto I

School, Hannover, Germany.

Hospital, “Sapienza” University of

brinkmann.folke@mh-hannover.de

Rome, Rome, Italy.

silviabernardo@live.it

Rossa Brugha

Centre for Paediatrics, Blizard

Annemie M. Boehmer

Institute, Barts and the London

Department of Paediatrics, Maasstad

School of Medicine and Dentistry,

Hospital, Rotterdam,

Queen Mary University of London,

The Netherlands.

London, UK.

BoehmerA@maasstadziekenhuis.nl

r.brugha@qmul.ac.uk

xiii

Andrew Bush

Fabio Cardinale

Department of Paediatric Respiratory

Department of Pediatric Allergy and

Medicine, Royal Brompton Hospital,

Pulmonology, Paediatric Hospital

London, UK.

Giovanni XXIII, University of Bari,

A.Bush@rbht.nhs.uk

Bari, Italy.

fabiocardinale@libero.it

Claudia Calogero

Respiratory Medicine, Anna Meyer,

Kai-Håkon Carlsen

University Hospital for Children,

Institute of Clinical Medicine,

Florence, Italy.

University of Oslo, Oslo, Norway.

c.calogero@meyer.it

k.h.carlsen@medisin.uio.no

Serena Calgaro

Carolina Casini

Department of Pediatrics, University

Pediatric Department, Sant’Andrea

of Padova, Padova, Italy.

Hospital, Rome, Italy.

serena.calgaro@studenti.unipd.it

carolinacasini@libero.it

Jennifer Calvert

Salvatore Cazzato

Department of Neonatal Medicine,

Dept of Pediatrics, University of

University Hospital of Wales, Cardiff

Bologna, S. Orsola-Malpighi

and Vale LHB, Cardiff, UK.

Hospital, Bologna, Italy.

salvatore_cazzato@aosp.bo.it

Giuseppina Campana

Department of Pediatrics, Second

Anne B. Chang

University of Naples, Naples, Italy.

Respiratory Medicine, Royal

Children’s Hospital, Brisbane,

Mario Canciani

Australia.

Pediatric Department, Azienda

annechang@ausdoctors.net

Ospedaliero, Universitaria di Udine,

Udine, Italy.

Rifat Chaudry

canciani.mario@aoud.sanita.fvg.it

Great Ormond Street Hospital for

Children, London, UK.

Carlo Capristo

r.chaudry@gosh.nhs.uk

Department of Pediatrics, Second

University of Naples, Naples, Italy.

Pierluigi Ciet

carlo.capristo@unina2.it

Radiology and Pediatric

Pulmonology, Erasmus Medical

Center, Sophia Children’s Hospital,

Rotterdam, The Netherlands.

p.ciet@erasmusmc.nl

xiv

Annick Clement

Peter G. Davis

Paediatric Pulmonary Department,

Department of Newborn Research,

Reference Centre for Rare Lung

The Royal Women’s Hospital,

Diseases, AP-HP, Hôpital Trousseau,

Melbourne, Australia.

INSERM UMR S-938, Université

pgd@unimelb.edu.au

Pierre et Marie Curie, Paris, France.

annick.clement@trs.aphp.fr

Ashok Daya Ram

Department of Paediatric Surgery,

Roberto Copetti

Birmingham Children’s Hospital,

Latisana General Hospital, Latisana,

Birmingham, UK.

Italy.

ashokdram@hotmail.com

robcopet@tin.it

Fernando M. de Benedictis

Harriet Corvol

Department of Mother and Child

Paediatric Pulmonary Department,

Health, Salesi University Children’s

Reference Centre for Rare Lung

Hospital, Ancona, Italy.

Diseases, AP-HP, Hôpital Trousseau,

debenedictis@ospedaliriuniti.

INSERM UMR S-938, Université

marche.it

Pierre et Marie Curie, Paris, France.

harriet.corvol@trs.aphp.fr

Jacques de Blic

Université Paris Descartes,

Vanessa Craven

Assistance Publique des Hôpitaux

Department of Respiratory Medicine

de Paris, Hôpital Necker Enfants

and Microbiology, Sheffield

Malades, Service de Pneumologie

Children’s Hospital, Sheffield, UK.

et Allergologie Pédiatriques Paris,

valgar@doctors.org.uk

France.

j.deblic@nck.aphp.fr

Fernanda Cristofori

Pediatrics Department, University of

Giovanna De Castro

Bari, Bari, Italy.

Department of Paediatrics,

fernandacristofori@gmail.com

“Sapienza” University of Rome,

Rome, Italy.

Elif Dagli

giovanna.decastro@uniroma1.it

Pediatric Pulmonology, Marmara

University, Istanbul, Turkey.

Johan C. de Jongste

elifzdagli@gmail.com

Dept of Pediatrics/Respiratory

Medicine, Erasmus Medical Center,

Lamia Dahdah

Sophia Childrens’ Hospital,

Division of Allergy, Department

Rotterdam, The Netherlands.

of Pediatrics, Pediatric Hospital

j.c.dejongste@erasmusmc.nl

Bambino Gesù, Rome, Italy.

lamia.dahdah@opbg.net

Robert Dinwiddie

Brigitte Fauroux

Portex Unit, Institute of Child Health,

AP-HP, Hopital Armand Trousseau,

London, UK.

Pediatric Pulmonary Department,

rdinwiddie@doctors.org.uk

INSERM U 955, Université Pierre et

Marie Curie, Paris, France.

Iolo Doull

brigitte.fauroux@trs.aphp.fr

Department of Paediatric Respiratory

Medicine, Children’s Hospital for

Patricia Fenton

Wales, Cardiff, UK.

Department of Respiratory Medicine

doullij@cf.ac.uk

and Microbiology, Sheffield

Children’s Hospital, Sheffield, UK.

Kostas Douros

patricia.fenton@sch.nhs.uk

Respiratory Unit, 3rd Department of

Paediatrics, “Attikon” Hospital,

Giuliana Ferrante

University of Athens, Athens, Greece.

Consiglio Nazionale delle Ricerche,

costasdouros@gmail.com

Dipartimento di Scienze per la

Promozione della Salute e Materno

Lex W. Doyle

Infantile, University of Palermo,

Department of Obstetrics and

Palermo, Italy.

Gynaecology, The University of

giuliana.ferrante@unipa.it

Melbourne, Melbourne, Australia.

lwd@unimelb.edu.au

Dimitrios Filippiadis

2nd Deaprtment of Radiology,

Uzor Egere

University Hospital ATTIKON,

Vaccinology Theme, Medical

Athens, Greece.

Research Council (MRC) Unit, The

dfilippiadis@yahoo.gr

Gambia, Africa.

uegere@mrc.gm

Marco Filippone

Department of Pediatrics, University

Refika Ersu

of Padova, Padova, Italy.

Division of Pediatric Pulmonology,

filippone@pediatria.unipd.it

Marmara University, Istanbul, Turkey.

rersu@yahoo.com

Alessandro Fiocchi

Division of Allergy, Dept of

Mark L. Everard

Pediatrics, Pediatric Hospital

School of Paediatrics and Child

Bambino Gesù, Rome, Italy.

Health, University of Western

allerg@tin.it

Australia, Princess Margaret

Hospital, Subiaco, Australia.

mark.everard@uwa.edu.au

xvi

Manuela Fortuna

Chiara Gardella

Pediatric Pneumonolgy, University of

Dept of Pulmonary Disease, G.

Padova, Padova, Italy.

Gaslini Institute, Genoa, Italy.

fortuna.manuela@alice.it

chiaragardella@hotmail.com

Oliver Fuchs

Michele Ghezzi

Division of Paediatric Allergology,

Pulmonary Disease Department,

University Children’s Hospital,

G. Gaslini Institute, Genoa, Italy.

Ludwig-Maximilians-University,

Munich, Germany.

Hartmut Grasemann

oliver.fuchs@med.lmu.de

Division of Respiratory Medicine,

Department of Pediatrics, The

Francesca Galdo

Hospital for Sick Children, Toronto,

Department of Pediatrics, Second

Canada.

University of Naples, Naples, Italy.

hartmut.grasemann@sickkids.ca

Sabina Gallati

Matthias Griese

Division of Human Genetics,

Hauner Childrens’ Hospital,

Departments of Paediatrics and

University of Munich, Germany.

Clinical Research, Inselspital,

matthias.griese@med.uni-

University of Bern, Bern, Switzerland.

muenchen.de

sabina.gallati@insel.ch

Jonathan Grigg

Elena Galli

Paediatric Respiratory and

Department of Pediatric Allergy,

Environmental Medicine Blizard

Research Centre, San Pietro Hospital

Institute, Barts and the London

- Fatebenefratelli, Rome, Italy.

School of Medicine and Dentistry,

galli.elena@fbfrm.it

Queen Mary University of London,

London, UK.

Monica Gappa

j.grigg@qmul.ac.uk

Children’s Hospital and Research

Insitute for the Prevention of

Susanne Halken

Allergies and Respiratory Diseases in

Hans Christian Andersen Children’s

Children, Marien-Hospital Wesel

Hospital, Odense University

GmbH, Wesel, Germany.

Hospital, Odense,

Monika.gappa@prohomine.de

Denmark.

Susanne.Halken@rsyd.dk

xvii

Graham L. Hall

Hettie M. Janssens

Paediatric Respiratory Physiology ,

Department of Paediatric Respiratory

Telethon Institute for Child Health

Medicine, Erasmus Medical Center,

Research, Perth, Australia.

Sophia Children’s Hospital,

grahamh@ichr.uwa.edu.au

Rotterdam, The Netherlands.

H.Janssens@erasmusmc.nl

Jürg Hammer

Paediatric Intensive Care and

Andreas Jung

Pulmonology, University-Children’s

Children`s University Hospital

Hospital Basel, Basel, Germany.

Zurich, Division of Respiratory

juerg.hammer@unibas.ch

Medicine, Zurich, Switzerland.

andreas.jung@kipsi.uzh.ch

Carol-Claudius Hasler

Paediatric Orthopaedics, University

Beate Kampmann

Children’s Hospital UKBB, Basel,

Vaccinology Theme, Medical

Switzerland.

Research Council (MRC) Unit, The

carolclaudius.hasler@ukbb.ch

Gambia, Africa.

bkampmann@mrc.gm

Elpis Hatziagorou

Peadiatric Respiratory Unit, 3rd

Ahmad Kantar

Paediatric Dept, Aristotle University

Department of Paediatrics, Institutes

of Thessaloniki, Hippokration

of Bergamo Hospitals, Bergamo,

Hospital, Thessaloniki, Greece.

Italy.

elpcon@otenet.gr

kantar@tin.it

Gunilla Hedlin

Sonia Khirani

Astrid Lindgren Children’s

A.A.O. Ospedali Riuniti di Bergamo,

Hospital, Department of Women’s

U.S.C. Pneumologia, Bergamo, Italy.

and Children’s Health and Centre for

sonia_khirani@yahoo.fr

Allergy Research, Karolinska

Institutet, Stockholm, Sweden.

Sailesh Kotecha

Gunilla.Hedlin@ki.se

Department of Child Health, School

of Medicine, Cardiff University,

Armin Irnstetter

University Hospital of Wales, Cardiff,

Pneumology Dept, University of

UK.

Munich, Dr. von Haunersches

kotechas@cardiff.ac.uk

Kinderspital, Munich, Germany.

armin.irnstetter@med.uni-

Carolin Kröner

muenchen.de

Pediatrics Dept, University of

Munich, Munich, Germany.

Carolin.Kroener@med.uni-

muenchen.de

xviii

Claudia E. Kuehni

Keith J. Lindley

Division of International and

Great Ormond Street Hospital,

Environmental Health, Institute of

London, UK.

Social and Preventive Medicine,

k.lindley@ucl.ac.uk

University of Bern, Switzerland.

kuehni@ispm.unibe.ch

Karin C. Lødrup Carlsen

Department of Paediatrics, Women

Stefania La Grutta

and Children’s Division, Oslo

Consiglio Nazionale delle Ricerche,

University Hospital, Oslo, Norway.

Istituto di Biomedicina e

k.c.l.carlsen@medisin.uio.no

Immunologia Molecolare, Palermo,

Italy.

Enrico Lombardi

stefania.lagrutta@ibim.cnr.it

Paediatric Pulmonary Unit, Anna

Meyer Paediatric University Hospital,

Hugo Lagercrantz

Florence, Italy.

Neonatal Research Unit, Department

e.lombardi@meyer.it

of Woman and Child Health,

Karolinska Institutet, Astrid Lindgren

Carmen Luna-Paredes

Children’s Hospital, Karolinska

Hospital Universitario 12 de Octubre,

University Hospital, Stockholm,

Madrid, Spain.

Sweden.

lunalavin1@yahoo.es

hugo.lagercrantz@ki.se

Nunzia Maiello

Philipp Latzin

Department of Women, Children

Division of Respiratory Medicine,

and General and Specialized Surgery,

Department of Paediatrics, University

Second University of Naples, Naples,

Children’s Hospital of Bern, Bern,

Italy.

Switzerland.

nunzia.maiello@unina2.it

philipp.latzin@insel.ch

Velia Malizia

Salvatore Leonardi

Consiglio Nazionale delle Ricerche,

Department of Pediatrics, University

Istituto di Biomedicina e

of Catania, Catania, Italy.

Immunologia Molecolare, Palermo,

leonardi@unict.it

Italy.

velia.malizia@ibim.cnr.it

Anders Lindblad

Dept of Pediatrics, Queen Silvias

Lucia Manganaro

Hospital, Gothenburg University,

Department of Radiological Sciences,

Gothenburg, Sweden.

Umberto I Hospital, “Sapienza”

anders.lindblad@vgregion.se

University of Rome, Rome, Italy.

lucia.manganaro@uniroma1.it

xix

Mariano Manzionna

Silvia Montella

Pediatric Department, Monopoli

Department of Pediatrics, Federico II

Hospital, Bari, Italy.

University, Naples, Italy.

mariano.manzionna@alice.it

amina2004@virgilio.it

Antonio Martinez-Gimeno

Corrado Moretti

Division of Respiratory Medicine,

Department of Paediatrics Emer-

Hospital Universitario 12 de Octubre,

gency and Intensive Care, “Sapienza”

Madrid, Spain.

University of Rome, Rome, Italy.

amgimeno@gmail.com

corrado.moretti@uniroma1.it

Argyro Mazioti

William B. Moskowitz

Department of Radiology, General

Department of Pediatrics, The

Hospital of Larissa, Larissa, Greece.

Children’s Hospital of Richmond at

argyromazioti@yahoo.gr

VCU, Richmond, VA, USA.

moskowit@hsc.vcu.edu

Andrea Mckee

Paediatric Respiratory Medicine,

Anne Munck

Royal Brompton Hospital, London,

Paediatric CF Centre Gastrointesti-

UK.

nal and Pulmonology Department,

a.mckee@rbht.nhs.uk

Robert Debré University Hospital,

Paris-Diderot AP-HP, Paris, France.

Paolo Meglio

anne.munck@rdb.ap-hop-paris.fr

Department of Pediatric Allergy,

Research Centre, San Pietro Hospital

Antonella Muraro

- Fatebenefratelli, Rome, Italy.

Food Allergy Centre, Department of

paolo.meglio@tiscali.it

Women and Child Health, University

of Padua, Padua, Italy.

Erik Melén

muraro@pediatria.unipd.it

Institute of Environmental Medicine,

Karolinska Institutet, Stockholm,

Nadia Nathan

Sweden.

Paediatric Pulmonary Department,

erik.melen@ki.se

Reference Centre for Rare Lung

Diseases, AP-HP, Hôpital Trousseau,

Silvia Miano

INSERM UMR S-938, Université

“Sapienza” University of Rome,

Pierre et Marie Curie, Paris, France.

Rome, Italy.

nadia.nathan@trs.aphp.fr

silvia.miano@gmail.com

Raffaella Nenna

Michele Miraglia del Giudice

Department of Paediatrics,

Department of Pediatrics, Second

“Sapienza” University of Rome,

University of Naples, Naples, Italy.

Rome, Italy.

michele.miraglia@unina2.it

raffaella.nenna@uniroma1.it

Ambra Nicolai

Paola Papoff

Department of Paediatrics, University

PICU, Policlinico Umberto I,

of Rome, Rome, Italy.

“Sapienza” University of Rome,

ambra10.nic@gmail.com

Rome, Italy.

p.papoff@libero.it

Thomas Nicolai

University Kinderklinik, Munich,

James Paton

Germany.

Royal Hospital for Sick Children,

tnicolai@med.uni-muenchen.de

Glasgow, UK.

james.paton@glasgow.ac.uk

Chinedu Nwokoro

Centre for Paediatrics, Blizard

Laura Perrone

Institute, Barts and the London

Department of Pediatrics, Second

School of Medicine and Dentistry,

University of Naples, Naples, Italy.

Queen Mary University of London,

laura.perrone@unina2.it

London, UK.

c.nwokoro@qmul.ac.uk

Matthew S. Perzanowski

Department of Environmental Health

Beatrice Oberwaldner

Sciences, Mailman School of Public

Klinische Abteilung für

Health, Columbia University, New

Pulmonologie und Allergologie,Univ.

York, NY, USA.

Klinik für Kinder-und

mp2217@columbia.edu

Jugendheilkunde, Graz, Austria.

beatrice.oberwaldner@klinikum-

Andreas Pfleger

graz.at

Respiratory and Allergic Disease

Division, Department of Paediatrics

Sedat Oktem

and Adolescence Medicine, Medical

Istanbul Medipol University, Division

University of Graz, Graz, Austria.

of Pediatric Pulmonology, Istanbul,

andreas.pfleger@meduni-graz.at

Turkey.

sedatoktem@hotmail.com

Maria Pia Villa

Dept of Pediatrics, University

Serena Panigada

Hospital, Rome, Italy.

Pediatric Pulmonary and Allergy Unit,

mariapia.villa@uniroma1.it

Istituto Giannina Gaslini, Genoa,

Italy.

Giorgio Piacentini

serenapanigada@ospedale-gaslini.

Department of Pediatrics, University

ge.it

of Verona, Verona, Italy.

giorgio.piacentini@univr.it

xxi

Massimo Pifferi

Nicolas Regamey

Department of Pediatrics, University

Division of Respiratory Medicine,

of Pisa, Pisa, Italy.

Department of Paediatrics, Inselspital

m.pifferi@med.unipi.it

and University of Bern, Bern,

Switzerland

Mariëlle Pijnenburg

Nicolas.Regamey@insel.ch

Department of Paediatrics/Paediatric

Respiratory Medicine, Rotterdam

Elena Ribera

The Netherlands.

Pulmonary Disease Department,

m.pijnenburg@erasmusmc.nl

G. Galini Institute, Genoa, Italy.

Petr Pohunek

Josef Riedler

Paediatric Pulmonology,

Children’s Hospital Schwarzach,

University Hospital Motol, Prague,

Salzburg, Austria.

Czech Republic.

josef.riedler@kh-schwarzach.at

petr.pohunek@LFMotol.cuni.cz

Francesca Rizzo

Kostas N. Priftis

Pulmonary Disease Department,

Respiratory Unit, 3rd Department of

G. Galini Institute, Genoa, Italy.

Paediatrics, “Attikon” Hospital,

University of Athens, Athens, Greece.

Paul Robinson

kpriftis@otenet.gr

Dept of Respiratory Medicine,

Children’s Hospital at Westmead,

Diana Rädler

Westmead, Australia.

Pulmonary Dept, University Children´s

paul.robinson1@health.nsw.gov.au

Hospital, Munich,

Germany.

Charles C. Roehr

diana.raedler@med.uni-muenchen.de

Dept of Neonatology, Charité Berlin,

Berlin, Germany.

Adriana Ramirez

christoph.roehr@charite.de

ADEP ASSISTANCE, Suresnes, France.

a.ramirez@adepassistance.fr

Malin Rohdin

Neonatal Research Unit, Department

Felix Ratjen

of Woman and Child Health,

Hospital for Sick Children, Toronto,

Karolinska Institutet, Astrid Lindgren

Canada.

Children’s Hospital, Karolinska

felix.ratjen@sickkids.ca

University Hospital, Stockholm,

Sweden.

malin.rohdin@ki.se

xxii

Emmanuel Roilides

Francesca Santamaria

Peadiatric Respiratory Unit, 3rd

Department of Paediatrics, Federico

Paediatric Dept, Aristotle University of

II University, Naples, Italy.

Thessaloniki, Hippokration

santamar@unina.it

Hospital, Thessaloniki, Greece.

roilides@gmail.com

Bianca Schaub

Silvia Rosina

University Children’s Hospital

Munich, Munich, Germany.

Giovanni Rossi

Bianca.Schaub@med.uni-muenchen.de

Pulmonary and Allergy Units,

Giannina Gaslini Institute, Genova,

Amalia Schiavetti

Italy.

Department of Paediatrics,

giovannirossi@ospedale-gaslini.ge.it

“Sapienza” University of Rome,

Rome, Italy.

Robert I. Ross-Russell

amalia.schiavetti@uniroma1.it

Department of Paediatrics,

Addenbrooke’s Hospital, Cambridge,

Andreas Schibler

UK.

Paediatric Critical Care Research

robert.ross-russell@addenbrookes.

Group, Paediatric Intensive Care

nhs.uk

Unit, Mater Children’s Hospital,

Brisbane, Australia.

Bruce K. Rubin

andreas.schibler@mater.org.au

Children’s Hospital of Richmond at

VCU, Richmond, VA, USA.

Nicolaus Schwerk

brubin@vcu.edu

Department of Pediatrics , Pediatric

Pneumology, Allergology and

Franca Rusconi

Neonatology, Hannover Medical

Epidemiology Unit, Anna Meyer,

School, Hannover, Germany.

Children’s Hospital, Florence, Italy.

schwerk.nicolaus@mh-hannover.de

f.rusconi@meyer.it

Mary Sharp

Oliviero Sacco

Neonatology Clinical Care Unit,

Pulmonary Disease Department,

King Edward Memorial Hospital for

G. Gaslini Institute, Genoa, Italy.

Women, Perth, Australia.

olivierosacco@ospedale-gaslini.ge.it

Mary.Sharp@health.wa.gov.au

Efstratios Saliakellis

Michael Shields

Great Ormond Street Hospital,

Department of Child Health, Queen’s

London, UK.

University of Belfast, Belfast, UK.

efstratios.saliakellis@gosh.nhs.uk

m.shields@qub.ac.uk

xxiii

Anita K. Simonds

Ben D. Spycher

NIHR Respiratory Biomedical

Division of International and

Research Unit, Royal Brompton &

Environmental Health, Institute of

Harefield NHS Foundation Trust,

Social and Preventive Medicine,

London UK.

University of Bern, Bern, Switzerland.

A.Simonds@rbht.nhs.uk

bspycher@ispm.unibe.ch

Shannon J. Simpson

Philippe Stock

Paediatric Respiratory Physiology,

Charité Kinderklinik mit Schwerpunkt

Telethon Institute for Child Health

Pneumologie und Immunologie

Research, University of Western

Labor Berlin - Fachbereich

Australia, Perth, Australia.

Allergologie, Berlin, Germany.

shannons@ichr.uwa.edu.au

philippe.stock@charite.de

Deborah Snijders

Tamara Svobodová

Department of Pediatrics, University

Paediatric Respiratory Division,

of Padova, Padova, Italy.

University Hospital Motol, Prague,

olanda76@gmail.com

Czech Republic.

tamara.svobodova@lfmotol.cuni.cz

Nicoletta Solari

Pulmonary Disease Department,

Giancarlo Tancredi

G. Gaslini Institute, Genoa, Italy.

Department of Paediatrics,

“Sapienza” University of Rome,

Rome, Italy.

Melinda Solomon

giancarlo.tancredi@uniroma1.it

Hospital for Sick Children, Toronto,

Canada.

Caroline Telion

melinda.solomon@sickkids.ca

Département d’anesthesie,

Assistance Publique des Hôpitaux de

Kevin Southern

Paris, Hôpital Universitaire Necker

Institute of Child Health, University

Enfants Malades, Paris, France.

of Liverpool, Alder Hey Children’s

caroline.telion@nck.aphp.fr

NHS Foundation Trust, Liverpool,

UK.

Laura Tenero

kwsouth@liverpool.ac.uk

Clinica Pediatrica,

Pediatria Verona, Verona, Italy.

Helen Spencer

lauratenero@hotmail.com

Great Ormond Street Hospital,

London, UK.

Luigi Terracciano

helen.spencer@gosh.nhs.uk

Melloni Paediatria, Melloni University

Hospital, Milan, Italy. terrycom1957@

gmail.com

xxiv

Guillaume Thouvenin

Steve Turner

Paediatric Pulmonary Department,

Child Health, Royal Aberdeen

Reference Centre for Rare Lung

Children’s Hospital, Aberdeen, UK.

Diseases, AP-HP, Hôpital Trousseau,

s.w.turner@abdn.ac.uk

INSERM UMR S-938, Université

Pierre et Marie Curie, Paris, France.

Anja A.P.H. Vaessen-Verberne

guillaume.thouvenin@trs.aphp.fr

Department of Paediatrics, Amphia

Hospital, Breda, The Netherlands.

Harm A.W.M. Tiddens

AVaessen-Verberne@amphia.nl

Pediatric pulmonology, Erasmus

Medical Center, Sophia Children’s

Horst von Bernuth

Hospital, Rotterdam,

Pediatric Pneumology and

The Netherlands.

Immunology, Charité Berlin, Berlin,

h.tiddens@erasmusmc.nl

Germany.

Horst.von-Bernuth@charite.de

Toyin Togun

Vaccinology Theme, Medical

Marcel van Straten

Research Council (MRC) Unit, The

Department of Radiology, Erasmus

Gambia, Africa.

MC, Rotterdam, The Netherlands.

ttogun@mrc.gm

marcel.vanstraten@erasmusmc.nl

Daniel Trachsel

Erika von Mutius

Paediatric Intensive Care and

University Children’s Hospital,

Pulmonology, University-Children’s

Ludwig Maximilians-University,

Hospital Basel, Basel, Switzerland.

Munich, Germany.

daniel.trachsel@ukbb.ch

erika.von.mutius@med.uni-

muenchen.de

JohnTsanakas

Peadiatric Respiratory Unit, 3rd

Colin Wallis

Paediatric Dept, Aristotle University

Respiratory Unit, Great Ormond

of Thessaloniki, Hippokration

Street Hospital, London, UK.

Hospital, Thessaloniki, Greece.

Colin.Wallis@gosh.nhs.uk

tsanakasj@ath.forhnet.gr

Sophie Yammine

Martina Tubaro

Pediatric Pulmonology Dept,

Pediatric Department, University of

University of Bern, Bern, Switzerland.

Trieste, Trieste, Italy.

sophie.yammine@insel.ch

martina.tubaro@gmail.com

xxv

Preface

“Tell me and I forget.

Teach me and I remember.

Involve me and I learn.”

Benjamin Franklin

The dissemination of knowledge, and medical and public education constitute a

fundamental objective of the ERS mission; and the ERS School aims to provide

excellence in respiratory medicine education. In 2005, the ERS School started

the very ambitious HERMES (Harmonised Education in Respiratory Medicine

for European Specialists) project. Since then, seven HERMES Task Forces

have formed to standardise training and education within different specialties

of respiratory medicine. To support the implementation of various educational

activities, the ERS has produced a series of Handbooks as educational tools, with

the ERS Handbook of Respiratory Medicine being the first textbook to be launched

in 2010.

Starting in 2007, the Paediatric Respiratory Medicine Task Force, using a formal

consensus process and working with numerous experts throughout Europe,

developed a HERMES syllabus (description of the competencies required) and

a HERMES curriculum (description of how competencies should be taught,

learned and assessed), as well as a voluntary European examination in paediatric

respiratory medicine. With the paediatric HERMES project now well underway,

it is an opportune time to publish an ERS Handbook of Paediatric Respiratory

Medicine to provide a comprehensive update for specialists within this field of

respiratory medicine. The content of this Handbook follows the HERMES syllabus

and curriculum to provide a compact, state-of-the-art textbook, with each of the

sections prepared by senior specialists and clinical experts in the field.

We hope that this Handbook will not only inform our trainees but also provide an

easily accessible and comprehensive update for colleagues at all levels of seniority

across paediatric respiratory medicine. Thus, this educational tool is intended

to make a significant contribution to increasing the standards of training in

paediatric respiratory medicine throughout Europe and, ultimately, to improving

the care of children with respiratory disease.

We are indebted to the ERS School Committee and to the ERS staff who so

thoroughly and thoughtfully curated this Handbook, and last, but not least, to

all the contributors who have shared their knowledge and experience with the

readers.

Ernst Eber and Fabio Midulla

Chief Editors

xxvii

Get more from this Handbook

By buying the ERS Handbook of Paediatric Medicine, you also gain access to the

electronic version of the book, as well as an accredited online CME test.

To log in, simply visit www.ersnet.org/handbook and enter the unique code

printed on the inside of the front cover. Once logged in, you’ll be able to

download the entire book in PDF or EPUB format, to read on your computer or

mobile device.

You’ll also be able to take the online CME test. This Handbook has been

accredited by the European Board for Accreditation in Pneumology

(EBAP) for 18 CME credits.

Also available from the ERS

NUMBER 56 / JUNE 2012

Paediatric Asthma

Edited by Kai-Håkon Carlsen and

Jorrit Gerritsen

European Respiratory Monograph 56:

European Respiratory Monograph

Paediatric Asthma covers all aspects of

47: Paediatric Lung Function offers

paediatric asthma from birth through

a comprehensive review of the lung

to the start of adulthood. It considers

function techniques that are currently

diagnostic problems in relation to the

available in paediatric pulmonology.

many phenotypes of asthma, covers the

This field is developing rapidly and

treatment of both mild-to-moderate and

equipment and software can tell us

severe asthma, and discusses asthma

more than ever about respiratory

exacerbations as well as exercise-

physiology in health and disease in

induced asthma. The issue provides

children with various lung disorders.

an update on the pathophysiology

The issue provides a state-of-the-art

of asthma, the role of bacterial and

review of the techniques, with a special

viral infections, and the impact of

focus on the clinical applications and

environmental factors, allergy, genetics

usefulness in diagnosing and treating

and epigenetics.

children with chronic lung disease.

Go to erm.erjsournals.com to view the table of contents for each Monograph

To buy a copy of these Monographs please visit ersbookshop.com

xxviii

List of abbreviations

(C)HF

(Congestive) heart failure

AHI

Apnoea-hypopnoea index

AIDS

Acquired immunodeficiency syndrome

BMI

Body mass index

Cystic fibrosis

COPD

Chronic obstructive pulmonary disease

CPAP

Continuous positive airway pressure

Computed tomography

ECG

Electrocardiogram

ENT

Ear, nose and throat

FEV1

Forced expiratory volume in 1 s

FVC

Forced vital capacity

Haemoglobin

HIV

Human immunodeficiency virus

HRCT

High-resolution computed tomography

KCO

Transfer coefficient of the lung for carbon monoxide

MRI

Magnetic resonance imaging

NIV

Noninvasive ventilation

OSA(S)

Obstructive sleep apnoea (syndrome)

PaCO2

Arterial carbon dioxide tension

PaO2

Arterial oxygen tension

PCR

Polymerase chain reaction

PtcCO

Transcutaneous carbon dioxide tension

SaO2

Arterial oxygen saturation

SpO2

Arterial oxygen saturation measured by pulse oximetry

Tuberculosis

TLC

Total lung capacity

TLCO

Transfer factor for the lung for carbon monoxide

V'E

Minute ventilation

xxix

Anatomy and development

of the respiratory system

Robert Dinwiddie

Anatomy of the lower respiratory tract

Larynx The larynx can be divided into three

areas (fig. 1):

The lower respiratory tract consists of the

trachea, hila of the lungs, large bronchial

N supraglottis,

airways, small airways and alveoli. The larynx

N glottis,

lies at the junction of the upper and lower

N subglottis.

respiratory tract and since it is a frequent

source of pathology in children its anatomy

It extends from the tip of the epiglottis to the

will also be described. The mediastinum

lower border of the cricoid cartilage. In the

contains the heart and its related cardiac

neonatal period it lies at the level of cervical

structures:

vertebrae C2-C3 and in adults at the level of

C3-C6. It contains major cartilaginous

N thymus,

structures including the epiglottic, thyroid

N trachea,

and cricoid cartilages, and the paired

N thoracic lymph nodes,

arytenoid cartilages. The vocal apparatus is

N thoracic duct,

muscular and consists of the false vocal

N vagus nerves,

cords (vestibular folds) and the true vocal

N recurrent laryngeal nerves,

cords (folds). The true vocal cords are drawn

together by adduction of the arytenoid

N autonomic nerve plexus.

cartilages. The larynx is bounded on each

Another important structure which passes

side by the aryepiglottic folds. These lie

through the thorax via the mediastinum is

between the lateral borders of the epiglottis

the oesophagus.

anteriorly and the upper edge of the

arytenoid cartilages, which join posteriorly

to form the interarytenoid cartilage. The

larynx is chiefly innervated by branches of

Key points

the vagus nerves. The subglottic area is

supplied by the recurrent laryngeal nerves

N The anatomy of the thorax can be

which also arise from the vagal nervous

divided into the lungs, heart,

system. These supply the vocal cords and

mediastinum, pleura, diaphragm and

damage to them can result in unilateral or

chest wall.

bilateral vocal cord paralysis.

The lungs can be further subdivided

Hila Each hilum forms the root of the lung

into the trachea, bronchi, hila, lobes

joining it to the heart and the trachea.

and preacinar and acinar regions.

Structures that pass through this area on

The mediastinum contains the

each side include the major bronchus,

thymus, the heart and its associated

pulmonary artery, superior and inferior

structures, thoracic lymphatics,

pulmonary veins, bronchial artery and vein,

sympathetic and parasympathetic

vagus nerves, pulmonary autonomic nerves

nerves and the oesophagus.

and lymphatic vessels. Lymph nodes within

each hilum are often directly involved in

ERS Handbook: Paediatric Respiratory Medicine

become bronchioles before finally

Epiglottis

becoming a terminal bronchiole (table 1).

Vocal cord (fold)

The portion of the respiratory tree from the

Vestibular fold

trachea down to the terminal bronchioles is

(false cord)

known as the preacinar region. The acinar

Aryepiglottic fold

region comprises the gas exchanging units

Trachea

and includes seven further branches of the

distal lung made up of the respiratory

Interarytenoid

bronchioles, alveolar ducts and the

cartilage

alveolar sacs.

Figure 1. Laryngeal anatomy as seen from above.

The blood supply to the trachea and

bronchi is principally via the bronchial

disease processes spreading systemically

arteries and the intercostal arteries, which

from the lung parenchyme.

arise via the systemic circulation from the

aorta. The upper trachea is supplied by

Trachea and bronchi The trachea is made up

branches of the inferior thyroid arteries.

of anterolateral cartilaginous rings and a

The venous drainage from the trachea

fibro-muscular posterior wall. The trachea

returns via the inferior thyroid venous

divides into the right and left main bronchi

plexus. The tracheal nerve supply is via

(fig. 2). The right main bronchus is more

the vagus nerves, the recurrent laryngeal

vertically orientated than the left resulting in

nerves, supplying parasympathetic

a greater percentage of inhaled foreign

fibres and sympathetic nerves arising

bodies entering that side. The right main

from the upper ganglia of the

bronchus gives off the right upper lobe

sympathetic trunks.

bronchus and continues as the bronchus

intermedius. This divides into the right

middle and lower lobe bronchi. The right

upper lobe bronchus divides into three

segmental bronchi: apical, posterior and

anterior. The right middle lobe bronchus

divides into two: the medial and lateral

segments of the middle lobe. The right lower

lobe bronchus gives off a superior

segmental branch and then medial, lateral,

anterior and posterior segments. Segmental

bronchi are particularly important to

recognise during bronchoscopy. The left

main bronchus divides into the left upper

and lower lobe bronchi. The left upper lobe

bronchus gives off the superior division

supplying the apical, anterior and posterior

branches of the left upper lobe. The inferior

division of the left upper lobe supplies the

superior and inferior segments of the lingua.

The left lower lobe bronchus then descends

laterally to give off a posteriorly located

apical segment of the left lower lobe and

then the antero-medial, lateral and posterior

basal segmental bronchi. After dividing into

segmental bronchi the airways further

subdivide into subsegmental bronchi and

then, from generation seventeen onwards,

Figure

2. The trachea and bronchi.

P.L. Shah.

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Anatomical subdivisions of the lung

Trachea

Right main bronchus

Left main bronchus

Segmental bronchi right

Segmental bronchi left

Right upper lobe:

Left upper lobe:

Apical

Posterior

Right middle lobe:

Left middle lobe:

Lateral

Superior

Medial

Inferior

Right lower lobe:

Left lower lobe:

Superior (apical)

Apical

Medial basal

Antero-medial basal

Anterior basal

Lateral basal

Posterior basal

Pulmonary vasculature and lymphatic

aorta, subsequently crossing to the left side

drainage The pulmonary artery carries

and runs alongside the oesophagus. It ends

deoxygenated blood to the lungs, thereafter

in the neck where it enters the left internal

subdividing and eventually becoming

jugular vein. The right bronchomediastinal

alveolar capillaries. Oxygenated blood then

lymphatic trunk joins the right lymphatic

returns via the pulmonary capillary and

duct and enters the venous circulation at the

venous circulation to the left atrium. The

junction of the subclavian and internal

pulmonary arteries lie anterior to the carina

jugular veins. Leakage of fluid from the

and main bronchi. Each artery then enters

thoracic duct is the primary cause of

the lung via the hilum. There are two

chylothorax in the paediatric age group.

pulmonary veins on each side (superior and

Mediastinum The mediastinum is divided

inferior) that pass in front of and below the

into superior, anterior, middle and posterior

adjacent pulmonary artery and major

portions. It contains the thymus, which

bronchus.

develops from the third branchial pouch and

The lymphatic drainage of the lungs, pleurae

has two lobes located in the superior and

and mediastinum is via visceral lymph

anterior mediastinum. Its principle function

nodes. These are arranged along the

is the programming of thymocytes.

bifurcation of the trachea, major bronchi

Thymocytes, which originate from bone

and peripheral bronchi. Further nodes are

marrow, mature into T-lymphocytes and

situated in the mediastinum. The output of

have major immune functions, especially in

most of these vessels is into a

relation to resistance to infection and the

bronchomediastinal trunk on each side of

development of atopic status and allergy. T-

the trachea. Another major lymphatic vessel

helper (Th)-1 lymphocytes form part of the

in the chest is the thoracic duct. This starts

cellular immune system and are principally

in the abdomen and enters the chest on the

involved in the response to infection. Th-2

right side through the aortic hiatus of the

lymphocytes are part of the humoral

diaphragm. It then ascends close to the

immune system mainly involved in allergic

ERS Handbook: Paediatric Respiratory Medicine

responses resulting in atopy and allergy-

especially in preterm infants. Intercostal

related diseases including anaphylaxis,

muscles are also less active during rapid eye

asthma and allergic rhinitis.

movement (REM) sleep which lasts twice as

long in infancy as in later life. As the child

The thymus gland is proportionately largest

matures and spends more time awake and

in infancy and early childhood; by

in the vertical position, gravity acts on the

adolescence it has begun to atrophy and

ribs and intercostal muscles pulling them

greatly decreases in size.

downwards. The chest also becomes less

circular in shape and more ovoid,

Mediastinal lymph nodes are located in the

particularly in the preschool years. The rib

pre-tracheal, paratracheal and subcarinal

cage becomes increasingly calcified with age

areas, as well as adjacent to the

and consequently stiffer which improves its

oesophagus.

mechanical efficiency.

Diaphragm The diaphragm is the principal

Development of the lungs

muscle of respiration in childhood. It

consists of a fibro-muscular sheet of tissue

Lung development starts very early in fetal

that separates the thorax from the abdomen.

life, just before 28 days of gestation, as an

It is comprised of a central membranous

endodermal outgrowth of the fetal gut called

tendon to which the muscles of the

the ventral diverticulum. Although almost all

diaphragm are attached. These comprise

of the lung structure is in place by the time

muscles arising from the xiphoid process of

of birth the process continues throughout

the lower sternum, the lower six costal

childhood into adolescence.

cartilages and the upper two to three lumbar

Intrauterine lung development Lung

vertebrae. Diaphragmatic muscles are more

development in utero is divided into four

easily fatigued in infancy because they

periods.

contain a smaller proportion of fatigue-

resistant muscle fibres than in later life. The

N Embryonic: 3rd to 7th week of gestation.

diaphragm is perforated by a number of

N Pseudoglandular: 7th to 17th week.

hiatal openings through which important

N Canalicular: 17th to 27th week.

structures pass from the thorax to the

N Alveolar period: from 27th week to term.

abdomen. These include the oesophagus

Embryonic period (3-7 weeks): During this

(oesophageal hiatus), the aorta (aortic

period the initial lung bud develops as an

hiatus) and the inferior vena cava (vena

endodermal groove from the fetal foregut

caval hiatus). The diaphragm is supplied by

(respiratory diverticulum). The lining of the

the right and left phrenic nerves arising

larynx, trachea, major airways and alveoli is

through the cervical vertebrae C3, C4 and C5.

endodermal in origin. The thyroid, cricoid

Chest wall The chest wall includes the ribs

and arytenoid cartilages and their associated

and the intercostal muscles. The ribs initially

muscles, originating from the mesoderm of

develop as cartilage. The chest wall

the fourth and sixth branchial arches, also

functions as a pump which performs the

develop during this period. The developing

respiratory movements driving respiration

tracheobronchial tree then subdivides into

itself. In the fetus the ribs are almost at right

the major bronchi, lobar bronchi and

angles to the vertebral column and the

peripheral airways. Other locally developing

muscles of the diaphragm are arranged

mesodermal tissues influence this

more horizontally than in later life. Chest

branching pattern. At the end of this period

movements are therefore less efficient in

the major subdivisions of lung anatomy

early life than later life when the child adopts

have already formed and although the

a more upright posture. The cartilaginous

associated blood supply is not fully

nature of the ribs also makes the chest wall

developed each lung bud is supplied via the

less stiff, thus, resulting in the potential for

pulmonary trunk, which appears at 5 weeks

paradoxical movements and indrawing of

gestation from the sixth bronchial arch and

the thoracic cage during inspiration,

divides into right and left branches. Each

ERS Handbook: Paediatric Respiratory Medicine

Trachea Major

Segmental/

Bronchioli

Alveoli

bronchi

subsegmental

Terminal Respiratory

Ducts

Sac

Airway

bronchi

generations

10-15

8-10

Preacinus^#

Acinus¶

Figure 3. Anatomy of the tracheobronchial tree.^#: this region comprises the conducting portion including

trachea, bronchi and bronchioli to terminal bronchioles;^": this region comprises a gas exchanging unit

(with alveoli) and includes respiratory bronchioli, alveolar ducts and alveolar sacs. Reproduced from

Dinwiddie (1997), with permission from the publisher.

lung bud is also connected to the evolving

as the arterial duct (ductus arteriosus) and

left atrium by a pulmonary vein. The

remains patent until the early period of

associated capillaries begin their

adaptation to post-natal life. Bronchial

development in the adjacent mesenchyme.

arteries also develop directly from the aorta.

The more distal preacinar arteries develop

Pseudoglandular period (7-17 weeks): During

and are fully present by 16 weeks.

this period there is further rapid branching

of the airways. By 16 weeks the terminal

Canalicular period (17-27 weeks): At this

stage the lungs develop their distal

bronchioles have developed and airway

architecture. The peripheral airways elongate

columnar and cuboidal lining cells have

and the epithelial lining cells become

appeared. Fetal lung fluid develops and is

cuboidal in shape in the lower airway

propelled through the airways by fetal

generations. Mesodermal tissue thins out

breathing movements first seen at around

and the pulmonary microcirculation

10 weeks of gestation with important

matures. Terminal bronchioles, respiratory

consequences for volume expansion of the

bronchioles and distal alveolar sacs develop

fluid-filled lungs. Other specialised tissues

rapidly. The acinus, which forms the distal

develop including the cilia from 6 weeks,

gas exchange unit of the lung, develops its

which becomes fully developed, including in

final structure by 24 weeks; immediately

the trachea, by 18 weeks. Cartilage and

before this time thin-walled saccules appear

lymph vessels develop from 10 weeks

to develop into individual alveoli. The most

onwards. These spread peripherally through

peripheral pulmonary vascular structures

the developing lungs. Goblet cells, mucus

develop as intimately associated alveolar

glands and airway muscles also first appear

capillary units to form a blood-gas barrier

at this time and continue their development

sufficient to maintain extrauterine life even

throughout prenatal and post-natal life. The

at this gestation (fig. 3).

main pulmonary arteries and veins develop

further; the right pulmonary artery arises

The alveolar lining cells subdivide into two

from the proximal part of the sixth right

types: Type I and Type II. Each is

branchial arch following which the distal

histologically distinguished by 24 weeks

part degenerates. The left pulmonary artery

gestation. Type I (gas exchanging) cells

arises from the sixth left aortic arch which

occupy 95% of the alveolar lining. Primary

gives off the main artery and then continues

surfactant production occurs in Type II cells.

ERS Handbook: Paediatric Respiratory Medicine

Signalling pathways Overall, lung

Table 2. Components of surfactant

morphogenesis is under the control of a

Phospholipids

78%

number of signalling pathways. These are

primarily controlled by genetic factors,

Dipalmitoylphosphatidylcholine

66%

especially for the development of lung

Phosphatidylglycerol

lobulation and the first 16 airway

Phosphatidylethanol

generations. These activities are mediated

through a number of peptide growth factors

Sphingomyelin

and more distally by similar substances

Cholesterol, glycerides and

12%

modified by local physical factors that

fatty acids

regulate distal airway branching,

Surfactant proteins A, B, C and D

10%

development of the pulmonary vasculature

and, ultimately, the alveoli. A number of

polypeptides are known to be involved in

soluble and acts mainly by decreasing

this process including transforming growth

protein-related inhibition of surfactant

factor (TGF)-b, bone morphogenic protein

activity. It also has an important role in lung

(BMP)-4, fibroblast growth factors (FGFs),

inflammation where it acts as part of the

platelet-derived growth factor (PDGF),

host defence mechanism. SP-A levels are

epidermal growth factors (EGF)/TGFs, sonic

responsive to pre-natal corticosteroid

hedgehog (SHH), vascular endothelial

therapy. SP-B, which is hydrophobic, is an

growth factor (VEGF), insulin-like growth

important component of lamellar bodies. It

factors (IGFs) and granulocyte-macrophage

facilitates the reduction of alveolar surface

colony-stimulating factor (GM-CSF), as well

tension when alveolar volume is reduced

as thyroid transcription factor (TTF)-1

during expiration. SP-C, also hydrophobic, is

protein.

another important protein component of

lamellar bodies. It appears to function

Surfactant

closely with SP-B in the spreading of

Surfactant is produced in the Type II alveolar

surfactant onto the alveolar surface, thus,

lining cells. It has a number of important

facilitating its surface tension reducing

functions. The primary role of surfactant is

properties. SP-D is water soluble and not

to promote and maintain lung volume and

directly associated with the function of

prevent alveolar collapse during expiration.

surfactant phospholipids. Its principal role

Thus, surfactant decreases the mechanical

appears to be as an innate immune system

work and energy expenditure of breathing,

protein that acts as part of the host defence

especially at birth. Surfactant also has an

against infections, e.g. with common

important role in host defence of the lungs

respiratory tract bacteria and viruses.

against infection and in their response to

ABCA3 is another important substance

tissue insults, such as barotrauma during

related to surfactant function. It is an ATP

treatment. Genetic defects in surfactant

production are now known to be major

binding cassette protein. Its precise function

aetiological factors in several chronic and

is not yet fully known but it has been shown

potentially lethal lung diseases of infancy

to be widely present in Type II alveolar

and childhood (table 2).

epithelial lining cells. Its most likely action is

in the inward transport of lipids for

Type II alveolar lining cells are principally

surfactant production.

involved in the production, storage,

Surfactant secretion occurs by a process in

secretion and recirculation of surfactant

which lamellar bodies are released from

through the intracellular lamellar bodies.

The principal surface active lipid in

Type II lining cells within the alveoli.

surfactant is phosphatidylcholine.

Phospholipids combine with SP-A, SP-B and

SP-C. Secretion is stimulated by stretching

Four surfactant proteins have been

of the lung parenchyma, as well as by

identified. Surfactant protein (SP)-A is water

extrinsically administered b-adrenergic

ERS Handbook: Paediatric Respiratory Medicine

agonists. Surfactant lasts for approximately

stimulates neutrophilic destruction of

5 h before being broken down.

bacteria, including Staphylococcus aureus,

Approximately 50% of active surfactant is

Streptococcus pneumoniae and Escherichia coli.

recycled through the lamellar bodies before

Exogenous surfactant is not only used in the

being reused. When secreted into the alveoli

treatment of preterm infants but also in a

and distal small airways, mature surfactant

variety of diseases in older children.

forms a structure (tubular myelin) that,

along with other compounds, lines the

During this pseudoglandular period the

alveolar surface. Fully functional surfactant

lungs reach a liquid-filled volume similar to

secreted in normal amounts into the alveoli

the air filled FRC after birth of ,25-

results in decreasing surface tension as the

30 mL?kg^-1. Fetal breathing movements at

alveoli shrink in volume, preventing their

this gestation are especially important in the

collapse at the end of expiration. On

maintenance of the developing lung

inspiration surface tension rises.

volumes.

At birth, even in the presence of surfactant,

In summary:

an initial opening pressure is required to

establish a stable functional residual

N Surfactant is predominantly composed of

capacity (FRC) of ,30 mL?kg^-1. This is in the

phospholipids, principally

order of 15 cmH₂O. In the surfactant-

phosphatidylcholine.

deficient pre-term infant, pressures twice as

N Surfactant contains four proteins A, B, C,

great may be needed just to initially open

and D.

the alveoli with a tendency for recurrent

N Surfactant proteins have important

collapse at end expiration. The presence of

surface tension lowering functions and

adequate amounts of active surfactant also

innate immune modulating properties.

results in the achievement of significantly

N Genetic deficiencies of surfactant

greater lung volumes at full inspiration.

proteins cause serious, and potentially

lethal, lung disease in neonates and

Several potentially severe conditions occur

infants.

in young infants and children if

abnormalities exist in the surfactant

Alveolar sac period (27 weeks to term)

production or breakdown pathways. These

include potentially lethal or severe lung

This is the final stage of fetal lung

disease in early life if there are genetic

development. It is at this stage of fetal life

mutations of SP-B, SP-C, ABCA3 and TTF-1.

that the lungs are able to sustain

These conditions are important causes of

independent breathing. The epithelial lining

respiratory distress syndrome in full term,

cells further differentiate and establish their

otherwise normal, babies. Another condition

intimate inter-relationship with the epithelial

of variable severity, alveolar proteinosis,

lining surface of the alveoli. Distal lung

occurs in older children and adults when

growth continues as the respiratory

there is deficiency of GM-CSF, a substance

bronchioles subdivide into saccules, which

which is vital for the breakdown of

then form their final specialised structure

surfactant.

becoming alveoli. Alveoli are lined by two

distinct types of cell. Type I alveolar lining

Surfactant proteins have important

cells cover 95% of the alveolar surface and

immunological functions. SP-A increases

have a thickness of 0.1-0.01 mm. Type II

macrophage activity in the lung. It also

alveolar lining cells are thicker, with a

facilitates the destruction of various

diameter of 10 mm. Although covering only

microorganisms by other immune-

5% of the alveolar surface, they play a vital

modulated cells within the lung. The roles of

role in surfactant production and

SP-B and SP-C in lung inflammation have not

metabolism.

yet been fully evaluated. SP-D stimulates

the phagocytosis of several types of micro-

During this period the pulmonary

organisms by alveolar macrophages. It also

vasculature develops rapidly. The arterial

ERS Handbook: Paediatric Respiratory Medicine

Length from

Age

TB to pleura

Pleura

16 weeks

0.1 mm

gestation

0.1 mm

RB₃

19 weeks

0.2 mm

gestation

RB₁

RB₃

S₃

28 weeks

0.6 mm

S₂

gestation

RB₁

S₃

Birth

1.1 mm

RB₁

S₁

S₂

2 months

1.75 mm

RB₁

AD₆

AD₂

7 years

4 mm

RB₁

RB₃

Figure 4. Development of the acinus. Stages of acinar development in fetal and post-natal life. TB:

terminal bronchiole, RB: respiratory bronchiole; TD: terminal duct; S: saccule; AD: alveolar duct; At:

atrium; AS: alveolar sac. Reproduced from Hislop (1974) with permission from the publisher.

muscle coat is proportionately thicker than

childhood. This is covered in detail in this

in later life. This allows for intense

Handbook in the Sleep-related Disorders

vasoconstriction during periods of

section. Important reflexes that originate in

intrauterine hypoxia but is a major

the chest wall are the Hering-Breuer reflex

contributory factor to persistent pulmonary

and the Head’s paradoxical reflex. The

hypertension in the neonatal period (fig. 4).

Hering-Breuer reflex is an inspiratory

inhibitory response mediated through the

Control of breathing

vagal nerves. It is particularly active in the

The development of control of breathing is a

control of the rate and depth of breathing in

complex process beginning early in fetal life

the neonatal period and during the first

and is continuously changing throughout

2 months of life. The Head’s paradoxical

ERS Handbook: Paediatric Respiratory Medicine

reflex is initiated by rapid lung inflation and

Table 3 Factors affecting lung growth and development

precipitates an increase in respiratory effort.

Abnormal embryonic and fetal development

The increased compliance of the ribcage in

the neonatal period can lead to distortion

Genetics

during REM sleep, resulting in respiratory

Hormones

irregularity and, in some cases, apnoea.

Maternal and fetal malnutrition

Post-natal lung development

Reduced fetal breathing movements

After birth the alveoli become multilocular

Reduced fetal lung fluid volumes

and progressively increase in size and

Inadequate size of thoracic cage

numbers with further out budding of the

Impaired adaptation to post-natal life

alveolar saccules. By term, approximately

one-third to one half of the adult alveolar

Preterm birth and its treatment

numbers is present. Thereafter, alveoli

Maternal smoking in pregnancy

continue to increase in number, especially

Pre- and post-natal infection

during the first 2 years of life reaching

100-250 million by the end of this period.

Adult numbers of alveoli, 300-400 million,

are already present by the age of 2-3 years.

malformations, e.g. diaphragmatic hernia,

Boys have more alveoli than girls. Alveolar

can have profound effects on the growth and

multiplication continues at a reduced rate

development of both the affected and also

and is finally completed by 8-10 years of

the contralateral lung, especially if it arises

age. After this there is a continuing increase

during the pseudoglandular period when

in diameter of the large airways and further

airway generation is occurring at its

remodelling of the alveoli until physical

maximum rate. Reduced alveolarisation is

growth is complete. The peripheral airways

another associated complication. Genetic

increase in relative size and proportion

factors are particularly important and play a

compared to the central airways until the

significant role in controlling various

age of 5 years. Lung volumes increase

hormone-related influences, including

throughout childhood. A final growth spurt

thyroid hormones (TTF-1), FGF, PDGF,

occurs in adolescence associated with a

IGF-1 and TGF-b, as well as steroid

parallel increase in lung volumes which lasts

hormones, specifically oestrogen a and b

longer in boys than in girls. TLC at birth in a

and androgen receptor hormones which are

3-kg newborn infant is, on average, 150 mL

expressed in developing lung tissue.

(50 mL?kg^-1) increasing to 6.0 L

Maternal malnutrition results in low birth-

(75 mL?kg^-1) in adult males and 4.2 L

weight babies as does placental

(60 mL?kg^-1) in adult females. During the

insufficiency. These factors can lead to

first 10 years of life the rib cage gradually

reduced lung growth for gestation. Severe

changes from a horizontal orientation to the

maternal malnutrition, studied at the end of

downward (caudal) slope of the adult.

World War II, has been shown to result in an

Ossification of the ribs also progresses

increase in COPD in adult life in affected

throughout childhood into early adult life

offspring. Fetal breathing movements are

reaching completion in the early 20s.

first seen at 10 weeks gestation and are

important for lung growth because of their

Factors affecting lung growth and

role in the development and maintenance of

development

lung volume. Lung cell proliferation is

inhibited if fetal breathing movements are

A number of factors can adversely affect

diminished. Absence of fetal breathing

lung growth and development throughout

results in pulmonary hypoplasia including a

both fetal and post-natal life; these are

decrease in distal lung airspaces.

shown in table 3.

Hypoplastic lungs secondary to reduced

Abnormalities of embryonic and fetal

fetal breathing movements have impaired

development, including congenital

synthesis and secretion of pulmonary

ERS Handbook: Paediatric Respiratory Medicine

surfactants resulting in abnormal lung

Thus, the growth and development of the

mechanics at birth. Reduced amniotic fluid

lungs is a continuous process from early

volumes during pregnancy due to early

fetal life, throughout childhood and into

rupture of the membranes or secondary to

early adulthood. The most important

abnormal renal function, which results in

changes occur before birth and in early

oligohydramnios, can result in pulmonary

childhood. It is at these times that other

hypoplasia. Intrauterine pleural effusions,

adverse events, such as severe intercurrent

such as congenital chylothorax, can result in

infections, are most likely to have profound

effects on future structure and function.

inhibition of lung growth. Syndromes

involving reduced thoracic cage

development, for example Jeune’s

Further reading

asphyxiating thoracic dystrophy, are

associated with pulmonary hypoplasia and

Dinwiddie R. Development of the Lungs.

In: Dinwiddie R, ed. Diagnosis and

impaired surfactant secretion. Another

Management of Paediatric Respiratory

cause of pulmonary hypoplasia relates to

Disease. 2nd Edn. Edinburgh, Churchill

respiratory muscle weakness, such as

Livingstone, 1997; pp. 1-8.

occurs in congenital myopathies and

Gaultier C. Developmental Anatomy and

neuropathies. Impaired adaptation to

Physiology of the Respiratory System. In:

extrauterine life leading to chronic hypoxia

Taussig LM, et al., eds. Pediatric

or treatment-induced hyperoxia, with or

Respiratory Medicine. 1st Edn. St Louis,

without long-term ventilation resulting in

Mosby, 1999; pp. 18-37.

barotrauma-induced lung injury, can also

Hislop A, et al. (1974). Development of

impair age-related lung growth and

the acinus in the human lung. Thorax; 29:

90-94.

development. Maternal smoking in

Inanlou MR, et al. (2005). The role of fetal

pregnancy is a well-described cause of

breathing-like movements in lung orga-

impairment of small airway development

nogenesis. Histol Histopathol; 20: 1261-

with immediate and long-term

1266.

consequences on small airway development

LeVine AM, et al. The Surfactant System.

and resultant hyperresponsiveness. Severe

In: Chernick V, et al., eds. Kendig’s

infections in early life, such as with

Disorders of the Respiratory Tract in

adenovirus, can lead to obliterative

Children.

7th

Edn.

Philadelphia,

bronchiolitis and impaired post-natal lung

Saunders Elsevier, 2006; pp. 17-22.

development.

ERS Handbook: Paediatric Respiratory Medicine

Applied respiratory

physiology

Caroline Beardsmore and Monika Gappa

Knowledge of respiratory physiology is

considering the applications of these

essential for understanding the pathological

measurements in a clinical context the

changes in disease, and the application and

underlying principles of the most

interpretation of respiratory function tests.

commonly used measurements will be

Pathological changes in lung physiology will

summarised.

vary according to disease or condition, but

Spirometry and the flow-volume loop

common patterns can be observed

according to whether the condition is

Spirometry is the means of recording the

primarily obstructive or restrictive in nature.

volumes of inspired and expired air, and the

This dichotomy may be overly simplistic for

maximum flows during the respiratory

describing some of the conditions that the

manoeuvres.

respiratory paediatrician will have to

Equipment and procedure The original

manage, but can serve as a useful starting

spirometers used from the inception of the

point (fig. 1). Whatever condition is under

technique until the 1980s were mechanical

consideration, spirometry remains a

devices with a chamber from which the

cornerstone of assessment, and

subject breathed in and out. The chamber

measurement of lung volume is also vital

incorporated a low-resistance movable

for interpretation. This section will briefly

section that accommodated the change in

summarise the underlying measurement

volume without any appreciable pressure

principles and discuss how to approach

change, and the movement was translated

clinical questions by applying available

into a recording, either directly via a pen on

respiratory function tests. Before

a chart or via a transformer into a digital

recording (fig. 2). These mechanical

spirometers measured changes in volume

Key points

directly, and flow was calculated secondarily.

The historical devices have been superseded

Distinguishing obstructive and

by electronic spirometers which have the

restrictive disorders is simplistic but a

advantages of portability, simplicity of

helpful starting point.

cleaning and ease of use. The electronic

spirometers usually incorporate a

N A combination of spirometry and body

pneumotachograph or an ultrasonic flow-

plethysmography is most useful.

meter to measure flow, with volume

N Visual inspection of the flow-volume

subsequently being obtained by

loop, including the inspiratory limb, is

differentiation.

essential.

Children who are able to cooperate with

Assessment of inflammation is

testing will be asked to make an airtight seal

becoming increasingly recognised as

around the mouthpiece, breathe steadily

an important part of the overall

and then make maximum inspiratory and

evaluation.

expiratory manoeuvres. The recordings of

volume change showing tidal breathing and

ERS Handbook: Paediatric Respiratory Medicine

a maximum (slow) respiratory manoeuvre

Measurements of lung volume

are shown in figure 2. In addition to a slow

manoeuvre, a full forced manoeuvre is

The principal means of measuring absolute

generally recorded. The derivation of a flow-

lung volumes are gas dilution (usually

helium dilution), plethysmography and

volume loop from the volume-time

nitrogen washout, all of which measure

recording (the spirogram) is shown (fig. 3).

functional residual capacity (FRC) and

The manoeuvres are repeated several times

derived lung volumes (refer to the

in order to achieve the best (highest) values

Pulmonary function testing and other

and assess repeatability. Internationally

diagnostic tests section in this Handbook).

accepted guidelines exist for the technical

The underlying principle for

specifications and performance of

plethysmography differs from the gas

spirometers, the conduct of the test, and

dilution or washout techniques, and this

quality control. Some modifications may be

may be utilised to characterise the

necessary for children, and the use of

pathophysiology in different disease states.

incentive spirometry may be particularly

helpful in younger children.

Equipment and procedure Whole body

plethysmography is used to measure

(intra)thoracic gas volume. The principle of

Restrictive conditions:

Obstructive conditions:

the measurement is such that it includes the

lnterstitial lung disease,

e.g. asthma, including

volume of all the air in the chest, whether in

neuromuscular disease

extrathoracic airway

communication with the airway and

(e.g. Duchennne’s

obstruction

muscular dystrophy)and

ventilated, or not. In contrast, FRC is

skeletal abnormalities

generally taken to include the volume of the

(e.g. scoliosis)

lungs in free communication with the airway

opening and therefore ventilated.

Nevertheless, the abbreviation FRCp (FRC by

Spirometry (principally

The pattern of the

VC) shows the

flow-volume loop obtained

plethysmography) has gained popularity and

extent of restriction and

through spirometry can

will be used hereafter. The measurement of

is helpful for regular

indicate the site of

FRCp is based on Boyle’s law. The subject is

monitoring.

obstruction (intrathoracic

enclosed in a cabin, which is almost airtight,

Lung volume

or extrathoracic) and

measurements will

whether it is fixed or

and breathes through a pneumotachograph

show the extent of the

variable.

that measures airflow. A shutter is closed in

deficit at either end of

Changes in FEV1,FVC and

the device through which the subject is

the VC range.

expiratory flows can

breathing, transiently occluding the external

Measurements of

quantify the extent of

compliance and gas

intrathoracic obstruction,

transfer may be helpful

and perform a similar

where the underlying

function for extrathoracic

condition is pulmonary

obstruction.

4.0

in origin.

Lung volume

3.0

TLC

Tests of respiratory

measurements can show

muscle strength can

the extent of any

2.0

help in the evaluation

hyperinflation or gas

of neuromuscular

trapping.

1.0

disease.

Other investigations (e.g.

FRC

gas mixing) may show

0.0

abnormal function before

spirometry becomes

abnormal and may be

helpful in monitoring

Time h

individuals and in research.

Figure 2. a) Original type of mechanical

Figure 1. Consideration of abnormalities as either

spirometer and b) associated recording of changes

restrictive or obstructive in nature. These are not

in volume. The recording shows three tidal breaths

mutually exclusive and individuals frequently show

at FRC followed by inspiration to TLC, and

elements of both.

expiration of VC to RV.

ERS Handbook: Paediatric Respiratory Medicine

is switched to breathe 100% oxygen from

3.0

TLC

3.0

either a reservoir or a bias flow. The expired

PEF

nitrogen is quantified and the lung volume

1.5

FEF50

calculated. In simple terms, if the alveolar

50% VC

concentration of nitrogen was 80% and 2 L

0.0

of nitrogen was exhaled during the test, the

FEV1

lung volume would be 26100/80 L, or 2.5 L.

FEV

The measurement is usually continued until

-1.5

the expired nitrogen is ,2.5%; continuation

2 3 4

beyond this point results in significant

Time s

Flow L.s^-1

amounts of nitrogen dissolved in the blood

coming out of solution in the lungs and

Figure 3. Relationship between a) spirogram and

resulting in an artefactually high estimation

b) expiratory flow-volume curve, showing

of lung volume.

inspiration to TLC followed by forced expiration to

RV. PEF occurs early in the manoeuvre, followed

The principle behind the test is not

by smooth decline in flow to RV. Note that FEV

restricted to nitrogen, and it is possible to

can only be derived from the spirogram.

use other tracer gases. These are first

‘‘washed in’’ to the lungs by giving the

airway. The subject makes a respiratory

subject a pre-set concentration of inert,

effort against the shutter and the alveolar

nonsoluble gas to breathe until alveolar

pressure change is measured directly from

(end-tidal) concentration is equal to the

the mouthpiece. The change in thoracic

inspired concentration. One advantage of

volume as the subject compresses or

other gases can be the avoidance of

expands the chest is measured indirectly

breathing 100% oxygen, which can have

from the cabin pressure and used in the

undesired effects on pulmonary blood flow

calculation.

in certain patients (see chapter 3).

Once FRCp has been measured during the

Helium dilution Measurement of lung

transient period of airway occlusion the

volume by helium dilution requires a

subject continues to breathe through the

mechanical spirometer which, at the start of

mouthpiece and, after one or two breaths,

the measurement, is set to a known volume

makes a full inspiration and expiration so

and contains a known concentration of

that the TLC and residual volume (RV) can

helium (typically 10%). The subject is

be determined (refer to the Pulmonary

connected to breathe tidally from the

function testing and other diagnostic tests

spirometer, with carbon dioxide being

section in this Handbook).

absorbed in order not to provoke

hyperventilation. Oxygen is titrated into the

Nitrogen washout The principle behind this

system in order to maintain a stable

technique is to quantify the volume of

baseline volume and prevent onset of

nitrogen within the lungs and then, knowing

hypoxia. As the air in the lungs mixes and

the alveolar concentration of nitrogen,

equilibrates with that in the spirometer, a

calculate lung volume. Therefore, the

new, lower concentration of helium is

equipment combines a means of measuring

established. When this is stable, the FRC can

volume, usually a pneumotachograph, and a

be calculated as follows:

nitrogen analyser or equivalent. The

technical issues associated with nitrogen

V1C15V2C2

analysers mean that nitrogen is usually

where C1 and C2 are the initial and final

measured either by mass spectrometry or by

concentrations of helium, V1 is the starting

quantification of other gases (oxygen and

volume of the spirometer and V2 is the final

carbon dioxide) and subtracting these from

volume, i.e. spirometer and lung volume

100%. The procedure requires the subject to

combined. Rearranging:

breathe through a mouthpiece and, when

steady respiration is established, the subject

V25V1C1/C2

ERS Handbook: Paediatric Respiratory Medicine

and

early changes within the small airways than

parameters obtained using full forced

FRC5V2-V1

expiratory manoeuvres.

The calculated value of FRC is likely to need

Assessment of obstruction

some small adjustment for the dead space of

the mouthpiece and any connections to the

Patients with obstructive disorders form the

spirometer. The spirometer will be at room

largest component of the workload of the

temperature, but (by convention) lung

respiratory paediatrician, with diseases

volume is expressed at BTPS (body

involving the small airways (mainly asthma

temperature, ambient pressure, saturated

and CF) being the most common.

with water vapour). Most modern equipment

Spirometry continues to be an essential part

will have the corrections within the software

of assessment and monitoring,

so that the measurement shown will be

demonstrating deviation from predicted

accurate. Usually three determinations are

values and changes over time or in response

made and a mean value reported.

to treatment. The typical patient with

obstructive respiratory disease will have an

Which measurement of lung volume is most

expiratory flow-volume loop that shows a

appropriate? The measurement of choice

distinct concave shape, such that flows at

will depend on why the measurement is

high lung volumes (peak expiratory flow

being taken, i.e. what is the question to be

(PEF) and forced expiratory flow at 25% of

answered. Measurements based on dilution

FVC (FEF25)) will be relatively spared and

or washout measure the volume of lung that

those at lower lung volumes (FEF50 and

is being ventilated, i.e. functional, available

FEF75) will show a greater reduction. Visual

for gas exchange. Trapped gas will not be

inspection of the flow-volume loop is an

included. Plethysmography measures

essential part of the evaluation. During the

trapped gas in addition to the ventilated

course of expiration, the site of flow

portions of the lung, because all the air in

limitation moves progressively down the

the thorax (whether trapped or not) is

bronchial tree into ever smaller airways,

subjected to changes in pressure and

where the extent of any airway narrowing

volume that are used in the calculation. In

(e.g. caused by oedema of the airway

healthy individuals the differences in FRC

epithelium mucosa) has a greater effect.

may be slight but in others they can differ

considerably, and the size of the difference

When FEV1 and FVC are compared with

may be informative. Therefore, in some

predicted values both indices may be within

patients with complex conditions, it may be

normal limits, but in obstructive airway

helpful to include different methods to

disease the FEV1/FVC ratio is usually

assess lung volumes in the evaluation.

reduced and this can be helpful in

Measurements based on dilution or

interpreting spirometry. However, FEV1/FVC

washouts have the advantage that the time

should not be considered in isolation,

taken to complete the measurements can be

because it cannot convey whether either or

informative. Where pulmonary function is

both component parts are within normal

good, equilibration of gas or the ease with

limits or not. For example, when assessing

which a gas is washed out is rapid. More

response to bronchodilator in an asthmatic

accurately, the amount of ventilation

patient, there may be a significant

required to achieve equilibration or washout

improvement in both FEV1 and FVC, but

is less in a healthy individual than in a

little change in FEV1/FVC. When assessing

subject with deranged function, and

changes in response to treatment it is

assessment of this adds valuable

helpful to take account of changes in the

information. This change in ventilation can

shape of the flow-volume curve, since it is

be quantified by parameters of ventilation

not uncommon to measure a significant

inhomogeneity such as the Lung Clearance

improvement in FEV1 (usually an increase of

Index (LCI) and other indices which have

o12%), but for the patient to still have a

been shown to be much more sensitive to

significant degree of obstruction so that the

ERS Handbook: Paediatric Respiratory Medicine

expiratory flow-volume curve continues to

dilate the extrathoracic airway, so the

show marked concavity. Vice versa, a change

abnormality will not be evident. During

in the flow-volume loop from concave to

inspiration the pressure gradient will be

linear or convex may be the sole indicator of

reversed and the tendency may be for

bronchial reversibility in patients with

unstable regions of the extrathoracic airway

asthma, even if the parameters are within

to be sucked inwards. The inspiratory flow

the normal range.

will be low and may be variable. During

performance of the test it may be noticeable

The shape of the flow-volume loop can also

that the patient takes a long time to inspire

help with the diagnosis of obstruction in the

fully to TLC; a technician or physiologist with

large airways. With a fixed obstruction, such

experience of observing and coaching

as a subglottic stenosis, the maximum flow

children can confirm whether the test is

that can be achieved will be determined by

indicative of extrathoracic obstruction or not.

the physical dimensions of the airway at its

narrowest point. Depending on the

In cases where there is severe obstruction of

underlying cause of the obstruction, this

the small airways (e.g. an exacerbation of

may change little as the child grows, so that

asthma or advanced CF), the distribution of

the absolute peak inspiratory and expiratory

lung volumes may become abnormal.

flows remain fairly constant from one year

During the course of expiration the airways

to the next, with progressive worsening of

become narrower as lung volume decreases,

the flows as related to predicted values. The

and when the airways are abnormally

flow-volume curve will appear flattened on

narrowed (e.g. due to oedema, excessive

both the inspiratory and expiratory limbs,

mucus or contraction of the smooth

with a loss of a well-defined peak flow and

muscles within the airway wall) they may

no significant response to bronchodilator

close completely at an early stage in the

(fig. 4).

manoeuvre. When this happens, RV is

increased and vital capacity (VC) is reduced.

Where there is an extrathoracic variable

Since the range of prediction for RV is fairly

obstruction, the abnormality will be evident

wide, the RV/TLC ratio is a useful indicator

on the inspiratory limb of the flow-volume

of early airway closure. If airway narrowing

loop (fig. 4), and expiration may be

becomes more marked, so that airway

unaffected. During expiration the positive-

closure begins within the normal tidal

pressure gradient extending from the lung

breathing range, the patient will adopt a

down to the airway opening will tend to

pattern of breathing which involves

breathing at an elevated FRC in order to

maintain airway patency. If this becomes a

Baseline

Predicted

frequent or extended event, such that the

inspiratory muscles become trained, it is

possible that the TLC (which is dependent,

in part, on respiratory muscle strength) may

increase. A reduction in VC should be an

indicator for measurement of absolute lung

volumes in such patients. The technique of

choice for this should be plethysmography,

Volume L

since this technique can quantify trapped

gas. In the most extreme cases, where

Figure 4. a) Fixed obstruction (tracheal stenosis),

patients have extensive airflow obstruction

with flattening of both inspiratory and expiratory

curves. On expiration, flow is reduced primarily at

and uneven distribution of pressure changes

high lung volume, with normal flow in the last

within the chest, the assumptions

quarter of VC. b) Variable upper airway

underpinning plethysmography may no

obstruction (laryngeal polyp), illustrating reduced

longer be valid but in these individuals there

flow through inspiration but normal pattern to

is usually clear clinical evidence of

expiratory curve.

hyperinflation.

ERS Handbook: Paediatric Respiratory Medicine

Assessment of restriction

predicted loop, and almost invariably the

loops will be aligned at TLC (fig. 5). To the

Restrictive diseases are characterised by a

uninitiated, this will give the erroneous

reduction in TLC, leading to restriction in

impression that the reduction in VC occurs

lung expansion. Usually, reduced VC in the

due to elevation of RV and not by a

forced expiratory manoeuvre will prompt

reduction in TLC. Flows at high lung

further assessment of lung function to

volumes (PEF and FEF25) are reduced in

diagnose or exclude true restrictive

restrictive disease, not because of airway

respiratory disease. The subject may report

obstruction but because the volumes at

shortness of breath on exertion with poor

which they are measured are constrained.

exercise tolerance, or in severe cases

Alignment of the recorded flow-volume loop

shortness of breath on mild exertion or at

with the predicted loop at TLC will further

rest. Where the underlying condition is

compound the impression that flows are

known, such as a skeletal or neuromuscular

reduced; alignment at RV may be helpful in

disorder, spirometry will be part of the

these cases.

assessment, usually on a regular basis. A

single assessment is usually of limited

Measurement of absolute lung volumes will

value, since the range of predicted value is

confirm whether the deficit in VC is

wide. Serial measurements are more

exclusively at the upper end (i.e. reduction in

informative, for example in the early stages

TLC only) or whether RV is also increased,

of Guillain-Barré syndrome as a pointer to

as may happen in skeletal abnormalities. RV

probable need for mechanical ventilation, or

may also be elevated in severe obstructive

to monitor the progression of scoliosis.

disease, but changes in spirometry will

usually distinguish between the two.

The shape of the expiratory flow-volume

Measurements of absolute lung volumes are

loop in pure restrictive disorders in children

all based on determination of FRC, which

will generally show a linear or even a convex

may be influenced by the posture of the

descending portion, in contrast to that

subject. The number of individual

observed in obstructive disorders. Most

measurements performed may also affect

spirometers will display the flow-volume

the accuracy, and is generally higher for

loop together with a schematic of the

plethysmography than other techniques

where a maximum of three determinations

is usual. In contrast, the within-test

Predicted

repeatability of spirometry is generally good,

making VC the index of choice for

monitoring changes in restrictive disease.

Where the restriction is due to a

neuromuscular condition, spirometry may

be more variable and the flow-volume loop

can give the impression of inconsistency of

Volume L

effort; in these cases the operator must be

alert to the tiring effect of repeated forced

Figure 5. Flow-volume loop from a child with

manoeuvres and avoid too many

restrictive disorder, including a schematic of the

unnecessary and fruitless attempts at

predicted expiratory flow-volume loop with a VC

achieving higher values of VC.

of 3.0 L predicted. a) The actual flow-volume loop

aligned with the schematic at TLC. It appears as if

When the restrictive pattern results from a

the expiratory flows are substantially below the

muscular condition, such as muscular

predicted flows. b) The actual flow-volume loop

dystrophy, if the diaphragm is involved the

aligned at RV, showing that measured expiratory

flows coincide with predicted flows over much of

VC may be further reduced when the

the VC. Note that the precise positioning of the

patient lies supine when compared to an

actual loop on the schematic requires

upright posture. If the diaphragm is weak

measurement of absolute lung volumes.

or incompetent, the abdominal contents

ERS Handbook: Paediatric Respiratory Medicine

move up into the thorax when the patient

oximetry at rest and during exercise is easy

lies down, whereas when the subject is

to apply and informative when abnormal; a

upright the gravitational force prevents this

finding of normal saturation is reassuring

from happening. Assessing the posture-

but can disguise the presence of significant

related change may therefore be relevant if

lung disease.

surgery is contemplated. Although

Assessment of inflammation

sequential measurements of VC are

undoubtedly helpful in monitoring changes

Applied respiratory physiology has

in the function of patients with muscle

historically been mainly limited to studies of

disease, it may be difficult to interpret

pulmonary mechanics and gas exchange,

them if it is impossible to make an

but should properly be extended to

accurate measurement of body height, as is

peripheral lung function. In the clinical

often the case in nonambulant patients

setting this should include an assessment of

who may also have developed scoliosis. A

the degree of inflammation, particularly in

measurement of VC may have increased in

asthma. The most common means of

absolute terms from one annual review to

assessment is measurement of the exhaled

the next, but the net effect may yet be

nitric oxide fraction (FeNO). Measurement of

deterioration if the increase in VC has not

nitric oxide is also relevant in screening for

kept up with linear growth. An alternative

primary ciliary dyskinesia, because levels of

approach is to measure maximum

nasal FeNO are lower than in healthy

inspiratory and expiratory pressures

individuals. Equipment for measuring FeNO

directly, which has the advantage that

ranges from laboratory-based analysers

predicted values can be related to age

using a chemiluminescence technique to

rather than height.

hand-held, portable devices that incorporate

an electrochemical sensor. The

Interstitial lung diseases are rare in children

measurement of FeNO requires that the

but also result in a restrictive pattern with a

subject maintains a steady expiratory flow

reduction in TLC, although FRC and RV may

for a minimum period of 4 s, which is

be normal. In these children the ability of

usually achieved by having the subject

gases to diffuse from the alveoli into the

breathe out against a resistance, with the

blood may be reduced, a situation that can

value of FeNO (expressed in parts per billion)

also arise in children treated with certain

being available within approximately 2 min.

medications for cancer. Assessment of

A detailed review of the technical aspects

TLCO, from its components KCO and alveolar

and clinical applications is available (see

volume (VA), can be informative in children

chapter 3). The measurement of FeNO may

able to perform the necessary manoeuvre.

contribute to confirming a diagnosis of

The most common technique is the single-

asthma, but has a greater role in assessing

breath method. In brief, the subject breathes

response to steroids. Failure of high levels of

out to RV, then takes a full inspiration of a

FeNO to respond to steroids may alert the

gas mix that includes 0.3% carbon

clinician to poor adherence on the part of

monoxide and a proportion of an inert,

the child with asthma or the parents.

insoluble gas (usually helium or neon),

followed by a 10-s breath-hold and a slow,

Measurement of FeNO can be considered a

steady exhalation. The rate at which carbon

marker of inflammation, but in this regard it

monoxide is transferred out of the lungs and

may be of most help in asthma. In CF

into the blood can be calculated and related

(where airway inflammation is a feature)

to the volume of the lungs, determined from

values of FeNO are normal or even low. In

the dilution of the inert gas. The cooperation

situations where FeNO may not be useful,

required for successful measurements

looking at the profile of inflammatory cells

means that the transfer factor cannot be

or other biomarkers in sputum may be

measured in very young children, but it may

informative (see chapter 3) but the value of

be possible in some as young as 6 years of

various biomarkers is still being evaluated.

age. From a practical perspective, pulse

Sputum may be produced spontaneously,

ERS Handbook: Paediatric Respiratory Medicine

particularly in patients with CF, but can be

Horstman M, et al.

(2005). Transfer

otherwise obtained by sputum induction

factor for carbon monoxide. Eur Respir

with hypertonic saline. In children where this

Monogr; 31: 127-145.

is not possible, bronchoalveolar lavage can

Miller MR, et al. (2005). Standardisation

be used to obtain the sample in those

of spirometry. Eur Respir J; 26: 319-338.

Quanjer PH, et al. (2012). Multi-ethnic

individuals where the importance of the

reference values for spirometry for the 3-

sample merits the invasiveness of the

95-yr age range: the global lung function

procedure.

2012 equations. Eur Respir J; 40: 1324-

1343.

Further reading

Quanjer PH, et al. (1994). [Lung volumes

and forced ventilatory flows. Work Group

Beydon N, et al.

(2007). An official

on Standardization of Respiratory

American Thoracic Society/European

Function Tests. European Community

Respiratory Society statement: pulmonary

for Coal and Steel. Official position of

function testing in preschool children.

the European Respiratory Society]. Rev

Am J Respir Crit Care Med; 175: 1304-1345.

Mal Respir; 11: Suppl. 3, 5-40.

Goldman MD, et al. (2005). Whole-body

Troosters T, et al.

(2005). Respiratory

plethysmography. Eur Respir Monogr; 31:

muscle assessment. Eur Respir Monogr;

15-43.

31: 57-71.

ERS Handbook: Paediatric Respiratory Medicine

Immunology and defence

mechanisms

Diana Rädler and Bianca Schaub

The immune system is a system of

itself, but also in closely connected

interdependent cell types that collectively

regulation with the adaptive system.

protect the body from various diseases with

Innate defence mechanisms

increasing specificity of immune regulation.

In general, it is composed of two major

Innate immunity of the lung The lung is

parts of immune defence, namely the innate

exposed to a multitude of airborne

and the adaptive immune system, also

pathogens while only very few cause

designated as the first- and second-line of

respiratory infections. This observation is

defence, respectively. In order to keep a

proof of the efficiency of the lungs’ defence

healthy immune balance, the innate defence

system. The innate immune system is

system needs to be regulated efficiently by

composed of a mechanical, physical and

chemical barrier, which act together in the

defence against invading microorganisms

(fig. 1).

Key points

The first defence mechanism of the lung is

Innate immune mechanisms

an initial mechanical barrier to avoid the

comprise a mechanical, physical and

invasion of particles .5 mm into the upper

chemical barrier, which act together in

airways. This barrier comprises the:

the defence against invading

microorganisms.

N nasal hairs,

N nasopharynx channels,

The airway epithelium forms a

N glottis,

physical barrier against inhaled

N trachea,

substances and contributes to host

N small branches of the bronchi and

defence by producing mediators of

bronchioles.

the chemical barrier, including

chemokines, cytokines, antimicrobial

The surface of the airways is covered with

peptides, proteinase inhibitors and

mucins and glycoproteins which trap

surfactant proteins.

microorganisms. This complex is then

Adaptive immune mechanisms

cleared by cilliary movement of the mucus to

include T-cell-mediated responses of

the oropharynx.

different subpopulations and

Cell types participating in innate immunity

components of the humoral and

Several cell types participate in initiating and

mucosal immune system.

maintaining the innate immune response

Interaction of innate and adaptive

and link the innate and adaptive part of the

immune regulation is required for

immune defence (fig. 1). Macrophages

specific defence against respiratory

engulf and digest pathogens by

diseases, involving prenatal and post-

phagocytosis and initiate the adaptive

natal factors.

immune system. Dendritic cells are a link

between the innate and adaptive immunity,

ERS Handbook: Paediatric Respiratory Medicine

Allergens, microorganisms, pollutants

Mucins

Recognition of pathogens

Chemical barrier

Mechanical barrier

Glycoproteins

Collections

AMPs (defensins, LL-37)

Cilia

NOD1 and NOD2

Lysozyme

TLRs

Lactoferrin

Physical barrier

Innate

Airway epithelium

Adaptive

IL-10

Mast cell

γδ T-cell

CD4⁺

Naïve

IL-12

Prostaglandins

Th9 cell Th22 cell

IL-17

CD8⁺

IFN-γ

T-cell

G-CSFHistamine

CD8⁺

TNF-α

IL-9

IL-8

IL-22

MHC II

Th17 cell

Macrophage

CTL

TCR

IFN-γ

Cytotoxins

Granulocytes

NK cell

B-cell

Th0 cell

Th1 cell

Basophil Eosinophil Neutrophil (PMN)

TLR

IL-4

IL-13

IFN-γ

Th2 cell

TNF-α

Treg

Chloramines

Histamine

Toxic granule proteins

TGF-β

Leukotrienes

IL-10

Plasma cell

Prostaglandin derivates

Respiratory diseases

Figure 1. Overview of the initiation and interaction of the innate and adaptive immune system. LL-37:

cathelicidin; IL: interleukin; G-CSF: granulocyte colony-stimulating factor; DC: dendritic cell; NK: natural

killer cell; Th: T-helper cell; TGF-b: transforming growth factor-b; CTL: cytotoxic T-cell.

as they ingest, process and present antigens

histocompatibility complexes (MHCs) on

to further cell types of the immune system.

their surface. The cdT-cells are a small

Granulocytes are a group of white blood

subset of T-cells which have a T-cell receptor

cells containing cytoplasmatic granules.

(TCR) composed of a c- and d-chain instead

They are divided into three types, namely

of the more frequent occurring a- and b-

neutrophils, eosinophils and basophils.

chain. These cells are thought to play an

Neutrophils participate in phagocytosis and

important role in the recognition of lipid

immediate killing of microorganisms,

antigens. Due to their complex biology, i.e.

independent of previous exposure, whereas

exhibiting characteristics of the innate and

basophils are highly specialised in the

the adaptive immune system, they are

synthesis and secretion of several

thought to be involved in both systems.

pharmacologically active products such as

Mast cells participate in inflammatory

histamine, proteases, leukotrienes or

processes by releasing characteristic

prostaglandin derivates. Eosinophils are

granules and hormonal mediators upon

recruited to the site of inflammation during

activation. For example, they produce

a T-helper (Th)-2 type immune response,

histamine and prostaglandins.

where they produce a variety of cytokines

and lipid mediators and release their toxic

Thrombocytes primarily act in blood clotting

granule proteins.

but also initiate innate immune functions by

secretion of pro-inflammatory molecules.

Additionally, natural killer cells are a type of

cytotoxic lymphocyte, which are involved in

Recognition of pathogens by the airway

a fast immune reaction and killing of cells in

epithelium The airway epithelium is the

the absence of antibodies and major

point of contact for smaller inhaled

ERS Handbook: Paediatric Respiratory Medicine

substances like allergens, microorganisms

adequate response following microbial

or pollutants. It presents the interface

exposure, and are involved in the regulation

between external environment and internal

of cytokine, chemokine and AMP expression

milieu. This epithelium forms a physical

and the production of reactive oxygen

barrier and, moreover, contributes to the

species (ROS). The different TLRs can detect

host defence in several ways, including

a variety of bacterial, viral and fungal

production of chemokines, cytokines and

products, as well as damage-associated

antimicrobial peptides (AMPs), as well as

molecular patterns (DAMPs) that are

proteinase inhibitors and surfactant proteins

released by cells undergoing necrosis. The

as chemical barrier.

TLR signalling pathway is divided into two

main signalling cascades, the myeloid

As a response to pathogenic exposure, the

differentiation primary response gene 88

innate immune system releases

(MyD88)-dependent and -independent

antimicrobial peptides into the lumen of the

pathways. In the MyD88-dependent

airways and chemokines, as well as

pathway, all TLRs except TLR3 recruit the

cytokines into the submucosa. These

adaptor molecule MyD88 upon stimulation

mediators initiate inflammatory reactions

and induce nuclear factor (NF)-kB and

accompanied by the recruitment of

mitogen-activated protein kinase (MAPK)

phagocytes, dendritic cells and lymphocytes,

through interleukin (IL)-1 receptor-associated

which in turn help to initiate adaptive

kinases (IRAK)1 and IRAK4 and the tumour

immune responses. In order to introduce

necrosis factor (TNF) receptor-associated

the aforementioned cascade,

factor (TRAF)-6. This leads to activation of

microorganisms need to be recognised first.

NF-kB and MAPK (JNK and p38), followed by

Microorganisms have characteristic

the translocation of NF-kB and activator

conserved molecules on their surface, the

protein 1 to the nucleus and the upregulation

pathogen-associated molecular patterns

of proinflammatory genes. Additionally, TLR2

(PAMPs), which can be recognised by

and TLR4 require the adaptor molecule

pattern recognition receptors (PRR). These

TIRAP (TIR domain-containing adaptor

receptors comprise soluble forms, such as

protein), which acts as a bridging molecule

collectins. Eight collectins have been

between the receptor and MyD88.

identified so far, including the mannan-

binding lectin (MBL) or the surfactant

The MyD88-independent signalling pathway,

proteins (SP)-A and SP-D. Collectins play a

which depends on the adaptor molecule

key role in the first line of defence by binding

TRIF (TIR domain-containing adaptor

to invading microorganisms and thereby

inducing interferon (IFN)-c), is utilised by

enhancing phagocytosis by macrophages.

TLR3 and TLR4. TRIF forms a complex with

The other groups of PRRs are the

TRAF-3 and subsequently activates the

intracellular nucleotide-binding

interferon regulatory factors (IRF)-3 and

oligomerisation domain (NOD) proteins

IRF7, which locate to the nucleus and

NOD1 and NOD2, which are involved in

activate IFN-inducible genes. The adaptor

peptidoglycan recognition, and the

molecule TRAM (TRIF-related adaptor

transmembrane molecules, such as Toll-like

molecule) is solely involved in TLR4 MyD88-

receptors (TLRs), which directly mediate a

independent signalling, where it recruits

cellular response after microbial exposure.

TRIF to the TLR4 complex.

The TLR signalling cascade is shown in

TLRs can also form homo- or heterodimers,

figure 2. TLRs are the homolog to the Toll

such as TLR2 with TLR1 and TLR6,

receptor in Drosophila flies. In total, 13 TLRs

respectively. The dimers have different

have been identified in mammals so far and

10 of these have been shown to be

ligand specificity. Moreover, additional co-

expressed in humans.

receptor molecules increase ligand

sensitivity. Four different adaptor molecules

TLRs are abundant on nearly all cells of the

exist: MyD88, TIRAP, TRIF and TRAM. This

body. They are responsible for initiating an

variety of adaptor molecules might allow

ERS Handbook: Paediatric Respiratory Medicine

Triacyl

Diacyl

Bacterial

Flagellin

lipopeptide

CpG DNA

MD-2

Bacteria

Viral

LPS

ssRNA

Viral

dsRNA

MyD88

TIRAP

Cytoplasm

FADD

IRAK

Endosome

CASP8

TRAF6

Apoptosis

MAPK

NF-κB

IRAK

IFN-α

TRAF3

IFN-β

Nucleus

IL-β

IKKε

IL-6

IRF7

IRF3

IRF7

IL-12

TBK1

IL-8

TNF-α

IRF3

AP-1

RANTES

CD40

NF-κB

CD80

CD86

T-cell

Inflammation

stimulation

Antiviral

immune response

Figure

2. TLR signalling cascade. The myeloid differentiation primary response gene 88 (MyD88)-

dependent pathway can be used by all TLRs except TLR3 (black arrows). The MyD88-independent

pathway is utilised by TLR3 and TLR4 (blue arrows). RANTES: regulated on activation, normal T-Cell

expressed and secreted; IRF: interferon regulatory factors; AP-1: activator protein-1; MAPK: mitogen-

activated protein kinase; IKKe: IkB kinase-e; TBK: TANK-binding kinase; FADD: Fas-associated death

domain; CASP: caspase 8, apoptosis-related cysteine peptidase.

them to recruit different transducers,

in TLRs, such as TLR2 and TLR4, have been

resulting in specific downstream signalling.

shown to play an important role in the

For TLR4 signalling, CD14 faciliates the

development of immune-mediated lung

presentation of lipopolysaccharide (LPS) to

diseases in childhood.

MD-2, a co-receptor required for LPS

Antimicrobial factors Airway epithelial cells

recognition by TLR4.

secrete large numbers of different

The most studied TLR, TLR4, is the central

molecules, which are involved in

component in response to LPS, a unit of the

inflammatory processes. These molecules

outer membrane of Gram-negative bacteria.

kill microorganisms, induce wound healing

TLR2 recognises a wide array of bacterial

and angiogenesis, and orchestrate the

and fungal substances. Recently, TLR2 was

adaptive immune response (fig. 1). The term

described to also be expressed on regulatory

AMP summarises a class of innate effector

T-cells (Tregs), a type of T-cell that

molecules of the lung, with a broad

suppresses the activity of pathogenic T-cells

spectrum of activity against bacteria, fungi

and prevents the development of

and enveloped viruses. AMPs are classified

autoimmune responses and allergic lung

according to their size, predominant amino

diseases. TLR2 stimulation is thought to

acids or conformational structure, whereas

reduce the suppressive function of Tregs.

defensins and cathelicidins are the principal

Moreover, single-nucleotide polymorphisms

families found in the respiratory tract.

ERS Handbook: Paediatric Respiratory Medicine

Defensins are highly structured compact

The communication of alveolar

peptides, classified into a- and b- subgroups

macrophages with other immune cells is of

depending on their folding. The a-defensin

great importance in order to launch an

human neutrophil peptides (HNP)-1 to

efficient immune response (fig. 1).

HNP4 are present on neutrophils and have a

Cytokines play a major role in pulmonary

non-oxidative microbicidal activity. The b-

host defence, especially IL-10, IL-12, IFN-c,

defensins are widely expressed throughout

granulocyte colony-stimulating factor (G-

the epithelia in order to avoid microbial

CSF) and TNF-a, the key mediator in

colonisation. In general, defensins induce

recruiting polymorphonuclear leukocytes

proliferation of the airway epithelial cells and

(PMLs) into the lung. Microorganisms that

are involved in wound repair. Cathelicidin,

are resistant to the microbicidal activity

also called LL-37, displays a similar activity

require cell-mediated immunity associated

as defensins and attracts neutrophils,

with the recruitment of large numbers of

monocytes, activated mast cells and CD4⁺

PMLs into the alveolar space by generating

T-cells. These AMPs also show a synergistic

mediators, such as the arachidonic acid

activity with other host defence molecules,

metabolite leukotriene B₄, and complement

such as the large antimicrobial proteins

or chemotactic peptides, such as IL-8.

lysozyme and lactoferrin, which are present

Neutrophil recruitment and enhancement of

in airway fluids. Lysozyme acts as a lytic to

phagocytic defence The PMLs represent the

bacterial membranes whereas the

largest population of intravascular

antibacterial activity of lactoferrin is

phagocytes with greater phagocytic activity

mediated by their iron-binding property. It

than alveolar macrophages. In response to

holds iron, an element necessary for growth,

inflammatory stimuli like tissue-released

away from the bacterial metabolism. The

mediators and microbial-derived

function of these antimicrobial substances

compounds, they migrate into the infected

in host defence has been proven in several

tissue site. Following phagocytosis, fusion

animal experiments. For example, mice

of the phagosome and lysosome and add-on

deleted in the LL-37 homologue CRAMP

fusion of azurophil granules with the

(cathelicidin antimicrobial peptide) showed

phagolysosome generates highly toxic

an impaired defence against invasive

antimicrobial compounds like chloramines

bacterial infections. Moreover, AMPs play an

and defensins, lysozyme and other

important role in several lung diseases, such

proteases. During pulmonary infection and

as pneumonia, chronic bronchitis or CF. In

inflammation, PMLs also participate in the

CF patients, AMPs might become

regulation of local host responses by

inactivated as a result of the high salt

secreting TNF-a, IL-1b, IL-6 and macrophage

concentration in the epithelial lining fluid.

inflammatory protein (MIP)-2.

Moreover, AMPs show a concentration-

dependent toxicity towards eukaryotic cells.

In summary, the innate immune system is

In high concentrations, which have been

crucial for an immediate defence against

described in CF and chronic bronchitis

infection. However, this part of the immune

patients, AMPs contribute to exuberant

system does not contain an immunological

inflammation, potentially through lysis of

memory, which allows a fast and specific

lung epithelial cells, induction of IL-8

response in the case of a reinfection with

production and restriction of defensin-

familiar agents. This immunological

induced cytotoxicity.

memory is a key feature of the second,

Alveolar macrophages represent the first-line

adaptive, part of the immune defence.

of phagocytic defence against particles that

Adaptive defence mechanisms

evade the mechanical defence. These cells

combine important phagocytic, microbicidal

Basic principles of adaptive immune defence

and secretory functions and initiate

The adaptive immune system requires a

inflammation and further immune

couple of days for an efficient, specific

responses.

immune defence. This system gets switched

ERS Handbook: Paediatric Respiratory Medicine

on when the innate defence mechanisms are

anti-parasitic and allergic immune

not sufficient. The adaptive immune system

responses.

is induced by different cellular processes

and activation of the innate immune

Tregs are relevant for keeping the balance of

response. While some infections can be

different T-cell populations (Th1/Th2) and,

controlled through activation of the innate

thus, for a healthy immune balance. Th17

immune system, the adaptive immune

and Th22 cells operate in a pro-

system is essential for several respiratory

inflammatory fashion, as far as hitherto

tract infections. Besides T-cell mediated

known, and are essential for acute

immune responses, the humoral and the

inflammatory processes through activating

mucosal immune system play a prominent

or recruiting neutrophils to the local

role in the adaptive immune defence.

infection. Th9 cells, previously grouped in

the Th2 subpopulation, constitute a new

T-cell mediated immune response After T-cell

subpopulation and produce the cytokine

development in the thymus, T-cells reach

IL-9. The different T-cell populations secrete

the blood circulation, migrate through

a more or less specific cytokine pattern

peripheral lymphatic tissue, circulate

(fig. 1). The cytotoxic CD8 T-cells recognise

through the blood and tissue and return via

and eliminate virus-infected cells by

the lymphatic system to the blood

secreting cytotoxins such as perforin,

circulation. Migration is supported by CCR7,

granulysin and granzymes.

a chemokine receptor, which binds CCL21

(ligand) and is produced by stroma cells in

The humoral immune system response to

the T-cell zone of the peripheral lymphoid

infections consists of production of

organs. After rolling of T-cells, adhesion,

antibodies through plasma cells, which

diapedesis and migration into the T-cell

derive from B-lymphocytes, binding of the

zone, antigen presentation takes place.

antibody to the pathogen and elimination

through phagocytosis and molecules of the

To complete the adaptive immune response,

humoral immune system. For production of

naïve T-cells need contact with a specific

the antibodies, antigen-specific Th cells are

antigen. After presenting the processed

important. B-cell proliferation and

antigen peptides via MHCII (to the TCR),

differentiation takes place in the T-/B-cell

the co-stimulatory cascade is initiated,

periphery in the secondary lymphatic tissue,

which consists of complex interactions of

followed by the T-cell periphery and the

several T-cells and antigen-presenting cells

germinal centre. IgM is produced by mature

(APCs). The most potent APCs are dendritic

B-cells. IgM in the blood circulation is

cells; their interaction with T-cells is a key

essential for protection against infections,

factor for the induction of efficient immune

whereas the IgG-isotype diffuses into the

responses. Subsequently, T-cell

tissue. Overall, the humoral defence system

differentiation into effector T-cells and

operates through the production of specific

proliferation takes place. These effector cells

antibodies. Effector cell mechanisms are

operate with other cells, not with the

determined through the ‘‘heavy chains’’ of

pathogen itself.

the isotype and antibody classes.

T-cells can be roughly classified into the

subpopulations of CD4⁺ and CD8⁺ T-cells.

The secretory Ig, i.e. IgA and IgM, are

The CD4⁺ T-cells consists of Th1, Th2, Tregs

secreted by epithelial cells of the mucus

and the recently described subgroups Th17,

gland into the lumen, while IgG and IgE

Th22 and Th9 (fig. 1). Th1 effector cells

diffuse passively. During an immune

support activation of macrophages and

response, different functions and amounts

express cytokines, which induce a class

of Ig can be detected. Newborns already

switching to specific antibody classes. Th2

have a large amount of secretory (s)IgM and

cells express B-cell activating effector

sIgA, directed against bacterial and viral

proteins and secrete cytokines, regulating

pathogens and also against antigens, e.g. for

the class-switching which is responsible for

anti-casein.

ERS Handbook: Paediatric Respiratory Medicine

This antigen sensitisation takes place during

the breast during lactation. Due to its

intrauterine development, as there is no

physiological function (e.g. gas exchange in

passage over the placenta. sIgA is the main

the lungs), surfaces are thin and barriers are

Ig in the respiratory tract, while sIgM

permeable. Its main role is an efficient

decreases during maturation. While IgM can

defence against invading infectious agents.

efficiently agglutinate particulated antigens

Thus, it is not surprising that the majority of

and make microbes more susceptible to

severe infections worldwide are caused by

phagocytosis, IgA is essential for binding of

invasion of pathogens through the mucosa.

antigens without activating an inflammatory

Approximately 4 million people worldwide

response. IgA (two subclasses: IgA1 (80% in

die of acute respiratory infections every year.

the respiratory tract) and IgA2) protects

Besides pathogens, foreign, non-pathogenic

against viruses and bacteria by inhibiting

antigens can invade, e.g. food proteins in the

bacterial adherence, blocking toxins and

gastrointestinal tract.

neutralising viruses. The former is sensitive

The mucosal immune system probably

to bacterial proteases (Streptococcus

contains 75% of all lymphocytes of the body

pneumoniae, Haemophilus influenzae and

and produces the majority of Ig in healthy

Neisseria meningitidis). By binding IgA to

individuals. Specific features of the mucosal

antigens before transcytosis, it can

immune systems are as follows.

additionally activate cells through binding to

the Fc receptors. Two major mechanisms of

N Anatomical: the interaction between

IgA response exist, an innate, T cell-

mucosa-epithelium and lymphatic tissue,

independent mechanism, which provides a

particularly components of the lymphatic

first line of protection, and a T cell-

tissue.

dependent adaptive response, which takes

N Modulated effector-cell mechanisms:

longer to develop the high affinity

activated or memory-cells exist also

antibodies. IgG is locally produced, binds

without prior infection and nonspecific

subephithelial antigens and leads to local

natural effector T-cells and Tregs are

inflammation after complement fixation. It

present.

also exists in the bronchial lumen.

N Immune regulation: an actively

downregulated immune response,

The adaptive immune response requires at

inhibitory macrophages and tolerance-

least 96-100 h to establish antigen contact

inducing dendritic cells are present.

for T- and B-cells and differentiation and

proliferation of effector cells. After activation

Some immune responses to antigen

of adaptive immune responses, antibodies

overload occur in the mucosa, induced by

and effector T-cells are distributed via the

particular compartments of the mucosal

circulation and recruited to the relevant

immune system. Antigen intake and

tissue, in this case the lung. An effective

presentation, Microfold cells and especially

adaptive immune response is characterised

dendritic cells are involved, while special

through protection and immunological

‘‘homing receptors’’ are relevant.

memory. This manifests itself via an

improved chance to react against familiar

Pathogenic microorganisms use different

pathogens and to eliminate them

strategies to invade the body, e.g. inclusion

successfully. Memory T- and B-cells are

of antibodies, inflammatory mechanisms

developed. This protection can be generated

and modulation of different components of

artificially by vaccination.

the immune system. The immune system of

the mucosa has to distinguish between

The mucosal immune system is of

potentially harmful and harmless antigens.

considerable size and includes the

Accordingly, it can induce an efficient

gastrointestinal tract, the lower respiratory

effector response to pathogens and will not

tract, the genitourinary tract and other

respond to colonisation of common airway

exocrine glands such as the pancreas,

microorganisms. As bacterial colonisation

conjunctiva, eye glands, salivary gland and

generally exerts a positive effect on humans,

ERS Handbook: Paediatric Respiratory Medicine

there has to be ‘‘coexisting, non-harmful’’

chronic airway diseases. This seems to

immune regulation. In the mucosal immune

depend on the specific pathogen. Exposure

system, antigen presentation to the T-cell is

to environmental pollution during

the main component for the decision

pregnancy is an example of an exogenous

between tolerance and defence. In the

risk factor that changes structural processes

absence of inflammation, antigen

of the lung and has an impact on early

presentation occurs without complete co-

immune maturation. This multifaceted field

stimulation. Mostly, differentiation of Tregs

of research demonstrates that many

occurs, which guarantees a healthy immune

complex interactions of innate and adaptive

regulation. If pathogens invade, an

immune regulation are required to induce

inflammatory response is induced,

an effective immune response.

activation of antigen presentation and co-

Development of defence mechanism Defence

stimulation occurs and a protective T-cell

against potentially harmful substances and

response is initiated.

pathogens is crucial for healthy

Relevance of interaction of innate and adaptive

development. As the development of the

immune regulation for specific defence against

immune system occurs during the prenatal

respiratory diseases While exogenous and

stage, the specific defence mechanisms of

environmental factors can influence

the lung are most probably already

susceptibility to pulmonary diseases,

developed.

modulation and interaction of innate and

Prenatal period Prenatal immune regulation

adaptive immune responses play a

is complex and it is probable that ‘‘immune

prominent role in the defence and regulation

programming’’ occurs at this early stage.

of a ‘‘healthy immune response’’.

Various studies suggest that exposure to

For asthma, one of the most common

different components of the environment

chronic diseases in childhood, a close

can interfere with early programming. These

interaction of the innate and the adaptive

include infections, smoke exposure or

immune system early in life, often in the first

certain maternal dietary habits. Bidirectional

year or during intrauterine development, is

interactions between the mother and the

responsible for whether a child develops

fetus seem to be key for post-natal immune

asthma or transient wheezing or stays

maturation; however, this field of research is

healthy.

still evolving. Besides genetic factors, in

particular epigenetics, the environment and

The most convincing results originate from

their interactions seem to influence this

epidemiological studies. Multiple cross-

early immune response.

sectional and longitudinal studies have

replicated the finding that prenatal exposure

Regarding modulatory mechanisms of

(during pregnancy) to an environment rich

intrauterine immune regulation, there may

in microbial substances can decrease the

be different explanations. Potential exposure

risk for asthma, hay fever and atopy for the

of fetal cells to allergens can occur through

offspring. It has been shown that activation

the transfer of amniotic fluid via the

of the innate immune system via TLRs

placental tissue starting at 20 weeks of

modulates the adaptive immune response,

gestational age. Furthermore, indirect

which can subsequently be protective

modulation through influences on the

against the development of Th2-mediated

maternal immune system is likely, as the

immune diseases such as asthma. Besides

fetal-placental transfer occurs via an active

activation of the innate TLR-receptors,

mother-child regulation. Immune cells in

activation of Tregs seems to be essential as

decidual tissue of the mother (e.g.

an important adaptive defence mechanism.

macrophages, CD8⁺ and cd-T-cells and large

granulated lymphocytes) can induce

A further example is respiratory infections

rejection of paternal histocompatibility

early in life, which can lead to subsequent

antigens. Additionally, novel data indicate

protection or, conversely, a higher risk for

that maternal-fetal tolerance to paternal

ERS Handbook: Paediatric Respiratory Medicine

allo-antigens is an active process in which

which local part of the airway (upper/lower

peripheral Tregs specifically respond to

respiratory tract) are relevant besides

paternal antigens to induce tolerance.

genetics, epigenetics and other

Overall, maturation of the infant adaptive

environmental triggers.

immune system probably starts between the

A multifaceted influence on early immune

15th and 20th week of gestation and can be

development of a child is most likely critical

antigen specific.

for the development of allergic airway

Post-natal period During this period, similar

disease or, vice versa, for potential protection

influences as during the prenatal period are

against childhood asthma, for example. All

present in addition to ongoing immune

these influences can occur prenatally and

maturation. Contact with environmental

are the key for later immune and, potentially,

factors such as smoke exposure or

disease development.

respiratory pathogens probably directly

Taken together, the innate and adaptive

change the development of immune

immune system need to work efficiently

regulation in the airways. Airway APCs seem

individually, being closely connected to each

to be important during the late phase of

other in order to provide successful defence

inflammation. They are most likely involved

against invading pathogens or inflammation

in the local damage during inflammatory

in general. In the case of default regulation

processes of the airways and are, therefore,

in any part of the system, either partial or

also important for programming of T-cell

absent defence can result in different forms

responses after their migration in the lymph

of immune-mediated disease such as

nodes.

infections or more chronic diseases like

allergies.

Regarding dendritic cells, age-dependent

immaturity is associated with a decreased

ability to react to inflammatory conditions.

Further reading

In children during the first year of life, no

dendritic cells are present in the airways if

Akira S, et al. (2004). Toll-like receptor

no inflammation occurs. In the case of

signalling. Nat Rev Immunol; 4: 499-511.

Braun-Fahrlander C, et al.

(2002).

severe respiratory infection, some mature

Environmental exposure to endotoxin

dendritic cells are present. Thus, local

and its relation to asthma in school-age

impacts on lung structures, such as

children. N Engl J Med; 347: 869-877.

infectious processes, seem to affect

Huh JC, et al.

(2003). Bidirectional

dendritic cell maturation and, subsequently,

interactions between antigen-bearing

T-cell activation.

respiratory tract dendritic cells

(DCs)

and T cells precede the late phase

Early infections of the respiratory tract, e.g.

reaction in experimental asthma: DC

rhinovirus, are associated with allergic

activation occurs in the airway mucosa

inflammation later in childhood. However,

but not in the lung parenchyma. J Exp

this early ‘‘priming’’ of the airways seems to

Med; 198: 19-30.

occur depending on the type of infection, as

Lauener RP, et al. (2002). Expression of

other infections are rather protective against

CD14 and Toll-like receptor 2 in farmers’

development of allergic airway

and non-farmers’ children. Lancet; 360:

inflammation.

465-466.

Liu J, et al. (2011). TLR2 polymorphisms

In summary, early exposure to infections

influence neonatal regulatory T cells

seems to influence maturation of local

depending on maternal atopy. Allergy;

immune networks, which can switch on Th1-

66: 1020-1029.

mediated immune responses and are, in

Nizet V, et al. (2001). Innate antimicro-

turn, relevant for efficient defence, while

bial peptide protects the skin from

Th2-related immune responses are most

invasive bacterial infection. Nature; 414:

likely decreased. However, more studies are

454-457.

needed to elucidate which infections at

ERS Handbook: Paediatric Respiratory Medicine

Nyirenda MH, et al. (2011). TLR2 stimula-

Schaub B, et al. (2009). Maternal farm

tion drives human naive and effector

exposure modulates neonatal immune

regulatory T cells into a Th17-like pheno-

mechanisms through regulatory T cells.

type with reduced suppressive function. J

J Allergy Clin Immunol; 123: 774-782.

Immunol; 187: 2278-2290.

Strachan DP (1989). Hay fever, hygiene,

Riedler J, et al.

(2001). Exposure to

and household size. BMJ; 299: 1259-1260.

farming in early life and development of

Tschernig T, et al. (2001). Dendritic cells

asthma and allergy: a cross-sectional

in the mucosa of the human trachea are

survey. Lancet; 358: 1129-1133.

not regularly found in the first year of life.

Schaub B, et al. (2006). Immunology and

Thorax; 56: 427-431.

defence mechanism of the developing

Williams Z (2012). Inducing tolerance to

lung. Eur Respir Monogr; 37: 60-78.

pregnancy. N Engl J Med; 367: 1159-1161.

ERS Handbook: Paediatric Respiratory Medicine

Environmental determinants

of childhood respiratory

health and disease

Erik Melén and Matthew S. Perzanowski

Worldwide, exposure to second-hand smoke

environmental factors have also been

is one of the most common indoor

identified, such as farming and rural

pollutants and as many as 40% of children

environments. Large individual variability in

are regularly exposed. Adverse effects of

response to environmental factors exists,

long-term exposure to anthropogenic

especially for allergen exposure, and genetic

ambient air pollution on children’s

susceptibility may partly account for this

respiratory health are also well described,

(termed gene-environment interaction).

particularly in relation to asthma and lung

This chapter will discuss the role of these

function. In developing countries, biomass

major environmental determinants of

smoke from domestic fires for cooking and

respiratory health in children.

warmth constitutes a major source of air

Adverse effects of environmental exposures

pollutants. Children are known to be more

susceptible to hazardous airborne

Environmental tobacco smoke (ETS) There is

substances compared to adults, possibly

ample evidence from both epidemiological

because of their growing organs and tissues.

and experimental studies that ETS has many

In addition, children have higher ventilation

negative effects on several organs in the

per minute in relation to body size and often

body, including the respiratory system,

have higher physical activity compared to

through induction of oxidative stress,

adults, which leads to relatively higher

inflammation and tissue damage. If a child’s

exposure. However, protective

mother smokes during pregnancy, the fetus

is exposed to nicotine, carcinogens and

other toxic substances that pass the

Key points

placental barrier. Solely prenatal exposure,

without subsequent post-natal exposure, is

Exposure to ETS, ambient air

associated with a 60-70% increased risk of

pollutants and biomass smoke

asthma in pre-school children, which under-

increases the risk of respiratory

lines the importance of targeted preventive

disease (e.g. asthma and pneumonia)

efforts. Post-natal ETS exposure has been

in children.

convincingly associated with asthma and

lung function deterioration in many

N Protective effects of certain exposures,

studies.

such as farming lifestyle and some

microbes, on asthma and allergy have

Data from the World Health Organization

been observed.

(WHO) show that, on average, 40% of

Genetic susceptibility and

children aged 0-14 years are regularly

co-exposure to several environmental

exposed to ETS, with the lowest exposure in

factors contribute to an overall

central and southern Africa (12%) and

complex relationship between

highest exposure in East Asia (67%).

inhalant allergens and disease

Children are considered to be at increased

development.

vulnerability to ETS-related health effects

relative to adults because of heavy exposure

ERS Handbook: Paediatric Respiratory Medicine

in the home by family members that is

children living .1500 m from the motorway.

difficult to avoid. The global disease burden

Whether this growth deficit persists into

of ETS exposure in children is immense and

later adulthood is not known. Exposure in

the importance of preventive measures to

utero and during infancy appears particularly

reduce this exposure cannot be stressed

harmful and studies report negative effects

enough. It has been estimated that 165 000

on lung function in infants, as well as in

children aged ,5 years die every year from

school-age children. Also in areas with

lower respiratory infections caused by ETS

relatively low air pollution levels such as

exposure.

Stockholm, Sweden, remarkably strong

effects are seen in that children with the

Anthropogenic air pollution Combustion of

highest exposure during the first year of life

fossil fuels contributes both particulate

are four to five times more likely to have

matter (PM) (e.g. soot, non-volatile

poor lung function at school-age compared

polycyclic aromatic hydrocarbons (PAHs))

to low-exposed children, further supporting

and gases (primarily NO, NO₂, CO₂, SO₂,

the relevance of air pollution to impaired

ozone, volatile PAHs) to indoor and outdoor

lung development.

air. PM10 and PM2.5 (particles with a 50%

cut-off aerodynamic diameter of 10 and

Biomass smoke Open domestic fires for

2.5 mm, respectively) constitute inhalable

biomass burning (wood, charcoal, crop

particulates and these are commonly

residues, etc.) for cooking and heating are

measured in studies on respiratory effects

main sources of air pollutants in certain

from pollutants. Automobile exhaust (gases

parts of the world (fig. 1). More than 2

in particular), combustion processes and

billion people live in households in which

road dust (particulates) are the main

biomass fuels are used regularly. Several

sources of pollutants of interest for the

studies show positive associations between

respiratory system. Other chemical agents,

asthma prevalence and biomass cooking

such as phthalates commonly used in

indoors, but a recent meta-analysis did not

consumer products, can evaporate into food

provide reliable evidence of overall increased

or the air and exposure to these agents has

risk of asthma in children. However, many

also been associated with respiratory

studies on biomass smoke effects suffer

symptoms.

from limitations in study design,

Similar to ETS, ambient air pollutants may

confounding control and low power, and

induce airway inflammation, increased

further research in this area is warranted.

airway responsiveness and lung damage,

partly due to oxidative stress mechanisms.

Both short- and long-term exposure has

been associated with an increasing range of

adverse respiratory outcomes, and air

pollutants are well-known triggers for

asthma exacerbations. Exposure to particles

from diesel exhaust have also been linked to

atopy, and experimental data support

adjuvant effects of particles on IgE

synthesis. However, conflicting evidence for

air pollution being causative in the

development of asthma and allergy persists.

There is evidence that adverse long-term

effects of air pollution occur on lung

function growth. A US study from California

Figure 1. Open domestic fire for cooking and

showed that children who lived within

heating (image courtesy of J. Thacher, Institute of

500 m of a motorway had ,3% lower lung

Environmental Medicine, Karolinska Institutet,

function, measured as FEV1, compared to

Stockholm, Sweden; personal communication).

ERS Handbook: Paediatric Respiratory Medicine

In contrast to effects on asthma, there is

Presence of older siblings in the home, day

rather strong evidence that exposure to

care attendance and certain infections (e.g.

indoor air pollutants from cooking or heating

herpes or Epstein-Barr virus) early in life

is associated with pneumonia and acute

were reported to protect against the

lower respiratory infections in young

development of asthma in school-age

children. A recent WHO meta-analysis

children. From an immunological point of

concluded that indoor exposure increased

view, reduced activity of T-regulatory cells,

the risk of pneumonia almost two-fold. From

which may lead to reduced immune

a population point of view, this is of utmost

suppression, has been emphasised as a

importance since pneumonias can be

basis for the mechanisms behind the

attributed to around half of all deaths occurr-

hypothesis. As of today, recent data

ing worldwide in children ,5 years of age.

indicate, however, that the hygiene

hypothesis only partly holds true, and that

Allergens The role of inhalant allergen

aetiological mechanisms are, after all,

exposure in the aetiology of asthma and

rather unclear.

allergic sensitisation is complex, and our

understanding of these processes has

Farming lifestyle One key component of the

changed markedly during the last 30 years.

hygiene hypothesis, farming lifestyle, has

It is now acknowledged that asthma and

consistently been associated with low

allergy are heterogeneous diseases and that

prevalence of asthma and allergy in both

overall, wide-spread generalisation about

low-income and high-income countries.

allergen exposure and disease development

Early animal contact at the farm and

cannot be made. It is likely that genetics,

consumption of unpasteurised milk seem to

phenotype diversity and large variations in

be particularly important for the protective

the intensity and pattern of allergen

effect. In addition, children living on farms

exposure contribute to this complex picture.

are exposed to a greater variety of

Nevertheless, sensitisation remains an

environmental microorganisms (certain

important risk factor for asthma

bacteria and fungi) compared to non-

exacerbations and development of severe

farming children and this diversity is

symptoms. In combination with an upper

inversely related to the risk of asthma.

respiratory infection, exposure to a certain

Visible mould and dampness in the home

allergen in sensitised individuals may have

are, however, associated with increased

detrimental effects. Asthma is rather

risks of asthma and allergy.

common in urban, low socioeconomic

The link between environmental exposure

families, and for ‘‘inner-city asthma’’,

and genetic factors

exposure to cockroach and dust mite

allergens have more convincingly been

Although smoking and exposure to certain

associated with disease. A recent trial of

air pollutants are established risk factors for

anti-IgE among inner-city children in the

respiratory diseases, not all individuals who

USA found a decrease in seasonal

are highly exposed develop diseases such as

exacerbation peaks (autumn and winter)

asthma. Thus, large individual variability in

typically associated with viruses, suggesting

response to environmental factors exists,

a complex relationship between allergic

and genetic susceptibility (and epigenetics)

sensitisation, viruses and asthma

may partly account for this. In this context,

exacerbations.

genes involved in the anti-oxidative system,

inflammation and innate immunity have

Role of protective environmental factors

been a particular focus in studies of

The hygiene hypothesis Almost 25 years ago,

respiratory diseases. Variants in IL13, GSTP1

the so called ‘‘hygiene hypothesis’’ was

and TNF have been shown to modulate the

introduced suggesting that the decrease in

adverse effects of ETS on asthma risk and

infectious burden and microbial exposure

pulmonary function, and CD14 variants are

during early life may have led to increased

related to the risk for allergy related to

predisposition to allergy and asthma.

domestic dust mite allergen exposure.

ERS Handbook: Paediatric Respiratory Medicine

In addition, gene-environment interactions

Dherani M, et al.

(2008). Indoor air

have been reported with both protective and

pollution from unprocessed solid fuel

adverse effects observed. For example, the

use and pneumonia risk in children aged

dose-response to developing sensitisation

under five years: a systematic review and

to cockroach with increasing cockroach

meta-analysis. Bull World Health Organ;

allergen exposure was observed to be

86: 390-398.

Ege MJ, et al.

(2011). Exposure to

greatest among children exposed to higher

environmental microorganisms and

levels of PAHs and those with a deletion of

childhood asthma. N Engl J Med; 364:

GSTM1 (involved in detoxification of PAH).

701-709.

However, convincing and reproducible

Gauderman WJ, et al. (2007). Effect of

interaction effects have been difficult to

exposure to traffic on lung development

identify in large, well-characterised data sets,

from 10 to 18 years of age: a cohort study.

especially if genome-wide association study

Lancet; 369: 571-577.

(GWAS) data were used. Further research is

Laumbach RJ, et al. (2012). Respiratory

warranted in this area before we better

health effects of air pollution: update on

understand the complex interplay between

biomass smoke and traffic pollution.

genes and the environment and certainly

J Allergy Clin Immunol; 129: 3-11.

before clinical applications can be

Melén, E., et al. (2012). Pathophysiology

implemented.

of asthma: lessons from genetic research

with particular focus on severe asthma.

Conclusion

J Intern Med; 272: 108-120.

Neuman A, et al. (2012). Maternal smok-

There is good evidence that exposure to

ing in pregnancy and asthma in preschool

pollutants such as ETS, ambient air

children: a pooled analysis of eight birth

pollutants and biomass smoke increase the

cohorts. Am J Respir Crit Care Med; 186:

risk of respiratory disease in children.

1037-1043.

Protective effects of certain exposures, such

Oberg M, et al. (2011). Worldwide burden

as farming lifestyle and microbes, on

of disease from exposure to second-hand

smoke: a retrospective analysis of data

asthma and allergy are also well described.

from 192 countries. Lancet; 377: 139-146.

Genetic susceptibility and co-exposure to

Olmedo O, et al. (2011). Neighborhood

several environmental factors contribute to

differences in exposure and sensitization

an overall complex relationship between

to cockroach, mouse, dust mite, cat, and

inhalant allergen exposure and disease

dog allergens in New York City. J Allergy

development.

Clin Immunol; 128: 284-292.

Perzanowski MS, et al. (2013). Early-life

cockroach allergen and polycyclic aro-

Further reading

matic hydrocarbon exposures predict

Brooks C, et al.

(2013). The hygiene

cockroach sensitization among inner-city

hypothesis in allergy and asthma: an

children. J Allergy Clin Immunol; 131: 886-

update. Curr Opin Allergy Clin Immunol;

893.

13: 70-77.

Schultz, ES., et al. (2012). Traffic-related

Bruin, JE., et al. (2010). Long-term con-

air pollution and lung function in children

sequences of fetal and neonatal nicotine

at 8 years of age: a birth cohort study. Am

exposure: a critical review. Toxicol Sci; 116:

J Respir Crit Care Med; 186: 1286-1291.

364-374.

Strachan DP. (1989). Hay fever, hygiene,

Busse WW, et al. (2011). Randomized trial

and household size. BMJ;

299:

1259-

of omalizumab (anti-IgE) for asthma in

1260.

inner-city children. N Engl J Med;

364:

Tischer C, et al.

(2011). Association

1005-1015.

between domestic mould and mould

Carlsten C, et al.

(2012). Air pollution,

components, and asthma and allergy in

genetics, and allergy: an update. Curr

children: a systematic review. Eur Respir J;

Opin Allergy Clin Immunol; 12: 455-461.

38: 812-824.

ERS Handbook: Paediatric Respiratory Medicine

History and physical

examination

Michael B. Anthracopoulos, Kostas Douros and Kostas N. Priftis

Respiratory medicine, particularly in young

children, relies much more on clinical

Key points

information than on precise laboratory

results. Even in today’s world of technological

Patient history is focused on the

wonders, there is no substitute for a proper

respiratory system and is adapted to

history and physical examination. This

patient circumstances (emergency

section discusses basic issues of paediatric

situation, chief complaint, chronic

medical history and physical examination of

problem, age, etc.); however, other

the respiratory system, and briefly addresses

pertinent organ systems should not

the pathogenesis of physical findings. Lung

be neglected and structure is

sounds and specific signs and symptoms are

important in order to avoid missing

addressed in separate sections of this

helpful clues.

chapter.

Respiratory physical examination of

the chest includes inspection,

Medical history

palpation, percussion and

Patient history in respiratory consultation is

auscultation. Nomenclature of lung

governed by the same principles as any

sounds is a subject of considerable

other medical history. The child’s parents

confusion.

are the primary source or, at the very least,

A structured physical examination of

important contributors to the history.

the chest, applied with flexibility in

However, when obtained by proxy, the

paediatric patients, including the

subjective nature of the information can be

upper respiratory system, evaluation

further obscured. The chaotic use of terms

of cyanosis, the digits and other

for respiratory signs and symptoms, such as

pertinent organ systems, is

‘‘wheezing’’, adds to the confusion.

fundamental to the evaluation of the

Nevertheless, useful information may be

respiratory patient.

obtained from children as young as 3 years

of age and from the age of 8 years, the child

should be the principal source of the history.

and a chronological description of the

Privacy of older children and adolescents

problem. Clarification of its onset,

must be respected (Bickley et al., 2013).

frequency, timing, duration and severity,

The physician should ask open-ended

relation to specific circumstances, and

questions and, depending on the complaint,

response to medication already used should

further questioning will focus on and expand

be sought. Other relevant signs and

specific points. Still, a general structure of

symptoms need to be investigated and

the required information needs to be kept in

previous assessments and laboratory results

mind in order to cover all the issues relevant

reviewed. Past medical history, especially

to the presenting illness. Such structure

that of the respiratory system, is important.

should include the major concern that

Recurring or persistent respiratory

prompted consultation (chief complaint)

problems, emergency visits,

ERS Handbook: Paediatric Respiratory Medicine

hospitalisations, surgery, vaccination status,

(coryza) or a sudden episode of choking

and pre-, peri- and neonatal circumstances

while eating or playing with small objects,

including prematurity, mode of delivery,

thus suggestive of aspiration?

birth weight, etc. need to be assessed.

Viral infections in young children are the

Family and social history are not to be

most common cause/trigger of such

neglected, and review of other organ

symptoms; six to eight colds per year,

systems is no less important in paediatric

mostly during the colder months, are not

patients than it is in adults. The all too

unusual at a young age. However, an

common presentation of a young child who

excessive number of severe infections,

appears ‘‘chesty all the time’’ and

recalcitrant nappy rash and oral candidiasis

‘‘continuously coughing and wheezing’’

exemplifies the aforementioned issues.

beyond 6-12 months of age may indicate

immunodeficiency.

Chief complaint and past medical history It is

important to discern from the beginning

Careful questioning should attempt to

what a parent means by ‘‘wheezing’’: is it a

discern whether the current episode is

‘‘whistling’’ expiratory sound or is it

actually different from previous ones and, if

reminiscent of ‘‘rattling’’ of the chest? The

so, in what respect. In addition, what is its

proverbial expression ‘‘not all that wheezes

duration and that of similar previous

is asthma’’ holds true, but then again, ‘‘not

episodes? Are they only triggered by colds

all that wheezes is a wheeze’’. Regarding

(viral wheeze) or are there other triggers

cough, it is important to clarify whether it is

such as laughter, exercise, strong odours,

dry and irritating, or whether it sounds wet

aeroallergens, etc. (multiple-trigger

(or productive, if the child can produce

wheeze)?

sputum); also, if it is often accompanied by

Cough and wheeze after exercise are

wheeze. Cough-variant asthma, if existent, is

associated with airway hyperresponsiveness;

unusual and chronic (.4 weeks duration)

intolerance to exercise, poor feeding and

wet cough is the most common

oedema are consistent with CHF.

presentation of persistent (protracted)

bacterial bronchitis, an ‘‘out-of-fashion

Do the episodes occur during night sleep

paediatric diagnosis revisited’’ that may

and, if so, do they wake up the child?

require more extensive investigation.

Seasonality of symptoms (viral or pollen

season) and evidence of eczema, allergic

In the case of diagnosed asthma, a

rhinitis and/or allergic sensitisation should

questionnaire-based clinical scoring system

be addressed.

such as the Children’s Asthma Control Test

(C-ACT), which has been validated for

Does the child vomit and does vomiting

children aged 4-11 years, is useful in the

always come after coughing, or is it related

evaluation of asthma control. C-ACT uses

to meals and the recumbent position (i.e.

information from the child (four questions,

reminiscent of gastro-oesophageal reflux)?

including a visual scale) and the parents

(three questions); the score is based on

Have inhaled medications been used and

daytime asthma symptoms such as cough

does any medical (or other) intervention

and wheeze (also during exercise and play),

appear helpful? If the patient is already on

night awakenings due to asthma, and

medications, their compliance should be

parental report of disease activity during the

evaluated. History of hospitalisations or

last 4 weeks.

emergency department visits and

physicians’ diagnoses should be obtained.

If a diagnosis of asthma cannot be made

with reasonable certainty, further probing

What was the age of onset of symptoms? If

may be in order. What was the reason that

close to birth, congenital malformations or

prompted specialist consultation? Was the

genetic inheritance should be considered.

onset of wheeze and/or cough acute or

Weight and height graphs need to be

progressive? Was it related to viral cold

reviewed and adequate growth ascertained;

ERS Handbook: Paediatric Respiratory Medicine

if the weight lags behind these, information

management choices and compliance

on stool consistency should be sought and

expectations.

the diagnosis of CF considered.

Physical examination

Knowledge of the duration of pregnancy is

Upper airways The upper respiratory tract

important, as are the circumstances at birth

should be examined and facial (e.g.

(including birth weight and Apgar scores)

micrognathia, retrognathia, asymmetry or

and during the neonatal period. History of

depressed nasal bridge) or buccal (e.g. cleft

prematurity, intubation, mechanical

lip and/or palate, bifid or long uvula, texture

ventilation, or prolonged oxygen

of the oropharynx, and presence and size of

dependence and corrected oesophageal

tonsils) deformities should be noted.

atresia with or without a tracheo-

Examination of the nasal passages can be

oesophageal fistula is crucial for interpreting

performed with a nasal or a large ear

the child’s respiratory symptoms in later

speculum. It may reveal mucosa that is

years; the diagnoses of chronic lung disease

acutely inflamed and bright red (consistent

of prematurity, subglottic stenosis,

with infectious rhinitis), or pale and boggy

tracheomalacia and gastro-oesophageal

(consistent with allergic rhinitis). The

reflux need to be considered accordingly.

History and duration of breastfeeding,

presence of nasal polyps before age 12 years

gastro-oesophageal reflux, and problems of

should prompt investigation for CF, while in

poor feeding or failure to thrive should be

older adolescents, they are often the result

addressed.

of allergic rhinitis or chronic sinusitis.

Chief complaints such as cyanotic episodes,

The issue of allergy often arises in the

hoarseness, stridor, snoring and/or apnoea,

presence of airway disease (e.g. asthma).

haemoptysis, chest pain, etc. will require

The frequent upward rubbing of the nose

further specific probing by the respiratory

due to itching (allergic salute) and the

specialist (see the relevant sections of this

resultant crease across the front of the nose

chapter).

are signs of allergic rhinitis. The patient may

use the facial muscles in order to relieve

Family, environmental and social history

nasal itching (‘‘rabbit nose’’ or the

Family history of asthma, allergies or CF is

‘‘Bewitched’’ sign). Skin creases on the

very helpful. It is important to investigate for

lower eyelids are also consistent with allergy

consanguinity of parents, miscarriages and

(allergic crease). Erythematous, itchy

childhood deaths (including sudden infant

conjunctivae and nasal symptoms are

death of a sibling) in the family, as well as

characteristic of hay fever. The classic signs

history of HIV positivity or TB.

of dark circles under the eyes, a constantly

Environmental history can be quite

open mouth - often associated with a

revealing. Exposure to indoor tobacco

history of snoring and, in more severe cases,

smoke, wood stove heating or gas cooking

with sleep apnoea - and a high arched

can trigger asthma exacerbations and

palate identify children with upper airway

predispose to poor respiratory health.

obstruction (rhinitis and enlarged lymphoid

Questions should address exposure to other

tissue) but not necessarily of allergic

inhaled irritants and the presence of pets

aetiology. Evidence or history of eczema is

and indoor plants. Wall-to-wall carpets, an

also helpful.

aged dwelling environment or renovation

Chest The patient’s chest should be exposed

may be important contributors to the child’s

and inspected for congenital or acquired

symptoms. This also holds true for exposure

deformities (e.g. pectus excavatum, pectus

to outdoor air pollution.

carinatum, kyphoscoliosis). During

Social history may help to determine the

inspection - indeed, throughout the entire

quality of historical information and the

physical examination - the two sides of the

patients’ household circumstances, and aids

chest are compared. Hyperinflation of the

the physician in forming realistic

thorax (e.g. air trapping due to asthma or

ERS Handbook: Paediatric Respiratory Medicine

chronic lung disease) or asymmetry of the

difficult to realise in children due to the

two hemithoraces (e.g. due to

higher frequency of their voice. Low-pitch,

pneumothorax or cardiomegaly) should be

high-amplitude sounds, such as repeating

sought; asymmetrical excursion of the

‘‘ninety-nine’’ or ‘‘one-one-one’’ (equivalent

hemithoraces due to paralysis of the

vocalisations should be used in other

hemidiaphragm may also occur.

languages), rather loudly will result in

increased tactile fremitus in the case of

Chest expansion, respiratory rate and

parenchymal consolidation (e.g.

pattern of breathing should be noted, and

pneumonia) and attenuation of the tactile

increased work of breathing - as evidenced

fremitus in the case of pneumothorax and

by tachypnoea, retractions, use of accessory

pulmonary distension (air trapping). Pleural

respiratory muscles and paradoxical

friction rubs may also be noted.

respiration - should be assessed (see

Tachypnoea, dyspnoea, respiratory distress

Since its initial description two and a half

and chest pain). In chronic obstruction, the

centuries ago, dedicated teachers have

Hoover sign may be observed. It consists of

taught the art of percussion to medical

(untoward) indrawing of the lateral chest

students. The method is based on the match

during inspiration at the level where the

(or mismatch) of the vibratory

diaphragm attaches to the ribcage. It is

characteristics of adjoining materials such

associated with an outward movement of

as tissues. Thus, by interpreting the acoustic

the lateral ribs caudally to this level and is

result of an impulse, one can draw

caused by the reduction of the zone of

conclusions about the bordering tissues.

diaphragm-chest wall apposition. It may be

When there is great mismatch (e.g. chest

associated with the loss of the bucket-

wall overlying a pneumothorax), there will be

handle movement of the ribs of the barrel-

resonance and the sound is perceived as

shaped chest and with the exaggeration of

tympanic. Conversely, when there is small

pump-handle movement about the

acoustic difference between the bordering

longitudinal axis of the body. However, it

tissues (e.g. pleural fluid underneath the

does not reliably reflect the degree of

chest wall), the energy of the impulse

obstruction.

propagates quickly and the sound is dull.

Between these two extremes are the

Palpation of the chest usually follows that of

characteristics of the sound produced by

the head and neck. It is mainly used to

chest percussion over normal lung

confirm the findings of inspection. Areas of

parenchyma. Most paediatricians use the

tenderness and masses (e.g. lymph nodes)

indirect method of percussion, whereby they

may be identified. The position of the

tap lightly, vertical to the surface, with the

trachea, i.e. the tracheal ‘‘tug’’, is more

long finger of one hand (plexor), two or

easily felt than observed.

three times in each position, on the terminal

Chest excursion can be evaluated and

phalanx of the middle finger of their other

asymmetrical movement can be identified

hand (pleximeter), which is placed over an

by placing the palms of both (warm) hands

intercostal space. The chest is percussed

in a manner ‘‘wrapping’’ the child’s chest

symmetrically.

symmetrically, with the thumbs placed

Since the respiratory system is the most

posteriorly and the rest of the fingers

frequently affected organ system in

anterior. The physician ‘‘follows’’ the chest

paediatric practice, respiratory sounds heard

excursions during breathing with his hands,

at a distance or auscultated over the chest

comparing the two sides by observing the

may provide valuable clues. The stethoscope

movement of the thumbs away from the

has practical and symbolic value for the

midline.

general physician and the pulmonologist

Vibrations generated by the voice and felt

alike. Auscultation provides the most

with the palm of the hands or the base of the

detailed information of the entire physical

fingers, i.e. tactile fremitus, are more

examination. The binaural stethoscope is

ERS Handbook: Paediatric Respiratory Medicine

favoured by most physicians and can

over the chest during inspiration and

adequately serve the specialist. The

hardly audible during normal expiration.

diaphragm of the head piece, when pressed

N Bronchial sound is auscultated over the

firmly on the skin, filters out the lower

upper anterior chest wall, of higher

frequencies and allows for better perception

frequency and intensity than vesicular

of the high-pitched sounds. Conversely, the

sound and of approximately equal

bell should be applied lightly (to avoid

duration in inspiration and expiration.

stretching the skin) in order to select for

lower frequencies. Appropriately sized chest

Normal breath sounds are characterised by

pieces for different chest sizes should be

a broad frequency spectrum that ranges

selected.

according to the location of auscultation.

Tracheal sounds are heard over the

To have infants assume a straight position

extrathoracic trachea. They are broad-

and young children cooperate for proper

spectrum noises with frequency spectra

auscultation is an art; still, it may not always

from ,100 to .1500 Hz and a rapid power

be possible to listen adequately over all lung

decrease at ,800 Hz. They have a short

segments. The upper lobes are best

inspiratory and long expiratory duration.

auscultated over the upper anterior chest,

Muscle sounds are low-frequency (,20 Hz),

lower lobe sounds are best heard over the

low-intensity sounds related to the

posterior lower chest, and the middle lobe

contraction force of thoracic skeletal

and lingula are best represented on the

muscles that mesh into the normal breath

respective sides of the lower third of the

sound spectrum. Often, the terms

sternum. Over the lateral chest, in the

‘‘respiratory sounds’’, ‘‘breath sounds’’ and

axillae, all lobes can be auscultated.

‘‘lung sounds’’ are used interchangeably.

This is also the case with the terms

To date there is no definitive nomenclature

‘‘vesicular sound’’ and ‘‘normal breath

of lung sounds. In this section, the

sound’’, and with the terms ‘‘bronchial

terminology of the CORSA (Computerized

sound’’ and ‘‘tracheal sound’’. In fact, the

Respiratory Sound Analysis) guidelines is

sound described here as ‘‘bronchial’’ is

adopted (Sovijärvi et al., 2000); terms used

termed ‘‘bronchovesicular’’ (intermediate

by other authorities or popular among

between tracheal and vesicular) in certain

physicians are also mentioned.

textbooks (Brown et al. 2008; Bickley et al.,

Respiratory sounds are related to chest air

2013), while the terms ‘‘tracheal sound’’ and

movement, either normal or adventitious,

‘‘bronchial sound’’ are used

heard at the mouth, the trachea and the

interchangeably.

chest; they include sounds produced by

Adventitious sounds are additional sounds

cough, snoring, sneezing or respiratory

superimposed on normal breath sounds;

muscle contraction, but exclude voiced

they are usually associated with pulmonary

sounds. Lung sounds are the respiratory

disorders. Adventitious sounds are primarily

sounds heard (or otherwise detected) over

divided into continuous (musical or

the chest.

wheezes) and discontinuous (nonmusical or

(Normal) breath sounds are respiratory

crackle) sounds.

sounds that arise from breathing, excluding

Wheeze is the respiratory sound term most

adventitious sounds. They consist of the

widely used by physicians and the general

following.

public, albeit with dismal specificity. It is

N Vesicular breath sound (a misnomer, as

characterised by periodic waveforms

it does not originate in vesicles, i.e. the

(continuous, of musical quality) with a

alveoli) is a quiet, low-frequency,

dominant frequency .100 Hz (range ,100

nonmusical sound. Its energy peaks

to .1000 Hz) and duration o100 ms.

below 100 Hz and decreases rapidly

However, the term usually implies a

between 100 and 200 Hz, but is still

dominant frequency of .300 to 400 Hz.

audible above 1000 Hz. It is auscultated

Lower-frequency wheezes have different

ERS Handbook: Paediatric Respiratory Medicine

pathogenesis and are often termed rhonchi

or bubbling sounds’’ originating in the large

(see later). In general, wheezes are louder

airways (i.e. what most authorities would

than breath sounds and may be audible at

term ‘‘coarse expiratory crackles’’, see

the patient’s mouth or at a distance. They

below).

are better transmitted through the airways

rather than through the lung to the thoracic

Crackles (other terms in use are

surface and their higher frequencies

‘‘crepitations’’ or ‘‘rales’’) are adventitious,

(approximately .700 Hz) are better or

discontinuous (nonmusical) sounds, usually

solely transmitted over the trachea. Wheeze

auscultated during inspiration, that

is of great clinical value as it is usually

represent local phenomena. Crackles are

associated with airway obstruction

classified according to their waveform,

due to various mechanisms (e.g.

duration and timing in the respiratory cycle.

bronchoconstriction, airway wall oedema,

Fine crackles (subcrepitant crackles) are

intraluminal obstruction such as a foreign

characterised by high pitch, low intensity

body, external compression or dynamic

and short duration (two-cycle duration

airway collapse). Prediction models (the

(2CD) ,10 ms). They are caused by the

fluid dynamic flutter theory) have shown

explosive opening of small airways collapsed

that expiratory wheeze always signifies flow

by surface forces (increased elastic lung

limitation, while its absence does not

recoil pressure or inflammation/oedema in

preclude flow limitation (Grotberg et al.,

the lung); they are gravity dependent and the

1989). Healthy subjects can wheeze during

sound is rarely transmitted to the mouth.

forced expiration, probably due to the

Fine, late inspiratory crackles are typical of

aforementioned mechanism. However, the

interstitial/fibrotic lung disease. However,

mechanism of generation of inspiratory

they may also be present in normal subjects

wheezes, which are often associated with

who inhale slowly from their residual lung

more pronounced obstruction, is not clear.

volume, which can be explained by the

In addition, wheeze may be produced by

mechanism already described. Coarse

turbulent flow-induced airway wall vibration,

crackles (crepitant crackles) are low-pitched,

without flow limitation (Pasterkamp et al.,

higher intensity and longer duration sounds

1997). Notably, there is a loose correlation

(2CD .10 ms); they are more scant, gravity

between the proportion of wheeze detected

independent and usually audible at the

throughout the respiratory cycle and the

mouth. They are generated by a different

severity of obstruction, but there is no

mechanism to that of fine crackles, i.e.

correlation between wheeze intensity and

movement of thin secretions in the bronchi

the degree of obstruction. It should be

or the bronchioles. They start early and

remembered that wheezing is not a

continue until mid-inspiration but may be

parameter of the clinical scores of asthma,

heard during expiration. A typical example of

croup or bronchiolitis. The classification of

coarse crackles can be heard in

wheeze into mono- and polyphonic is

bronchiectasis and chronic airway

addressed in a separate section of this

obstruction (e.g. CF). Similar auscultatory

chapter, as is stridor, which is a loud, usually

findings can be found focally early in

inspiratory, continuous sound that, other

pneumonia but shift into more end-

than being heard at the mouth or at a

inspiratory crackles of variable duration that

distance, can be auscultated over the chest

progress to fine crackles during recovery.

wall.

Acoustic analysis has characterised the

crackles of cardiac failure as coarse, of long

Rhonchus (plural: rhonchi) is a low-pitched,

duration during inspiration and appearing

continuous (musical) sound that consists of

late in the course of the disease (Brown et

rapidly dampened sinusoids (frequency

al., 2008; Pasterkamp et al., 2012).

,300 Hz, duration .100 ms). Rhonchi are

generated by intraluminal secretions and

Other adventitious sounds are squawk and

collapse of large airways. However, the term

the pleural friction sound. A squawk

has also been used for expiratory ‘‘gurgling

(sometimes classified as a type of wheeze)

ERS Handbook: Paediatric Respiratory Medicine

is a ‘‘composite’’, short (50-400 ms),

environment. The peripheral perfusion of

inspiratory adventitious sound with a

the patient should be taken into account.

musical character (short inspiratory wheeze)

The detection of cyanosis is influenced by

that is preceded by a crackle. It is not

various factors such as type and intensity of

associated with airway obstruction but

light, skin pigmentation, and ambient

rather with pulmonary fibrosing (restrictive)

temperature. Central cyanosis is sought at

disease. It is thought to result from the

the ear lobes, the mucous membranes

vibrations set in motion by the sudden

(buccal, tongue and nasal) and the retina. It

opening of a collapsed airway. Pleural

is considered to be reliable evidence of

friction sound (or friction rub) is coarse

hypoxaemia. Peripheral cyanosis or

crackles (often described as ‘‘leathery’’)

acrocyanosis (circumoral, or in the distal

produced by inflamed parietal and visceral

phalanges of fingers and toes) is more

pleura that cause vibration of the chest wall

common and, especially in case of cold

and local pulmonary parenchyma. It can be

extremities, does not necessarily imply

auscultated during inspiration or in both

hypoxaemia. Tissues with increased oxygen

phases of breathing. Pleural friction

consumption or reduced blood flow

precedes pleural effusion and disappears

(increased arteriovenous oxygen difference)

when fluid is formed. The ‘‘rub’’ is

are prone to high concentrations of reduced

synchronous with breathing and does not

Hb; hence, the poor clinical value of

disappear with cough, but is modified by the

peripheral cyanosis in evaluating arterial

breathing pattern and posture (Brown et al.,

oxygen content (Stack, 2005).

2008; Bickley et al., 2013).

The value of reduced Hb in the capillary bed

Voice transmission is filtered by normal lung

required for cyanosis is 4-6 g?dL^-1, which

parenchyma so that speech becomes

corresponds to 3 g?dL^-1 of reduced Hb in

indistinct (i.e. perceived as an

arterial blood. Capillary blood oxygen

incomprehensible mumble) when

content is postulated to be halfway between

auscultating the chest. When there is

the arterial and the venous values.

underlying consolidation or compression,

Depending on the Hb content, cyanosis will

higher frequencies are effectively

occur at different levels of SaO₂: for Hb 8

transmitted. Thus, normally spoken syllables

(anaemia), 14 (normal) and 20 g?dL^-1

become distinct during auscultation; this is

(polycythaemia), the respective SaO₂ that is

termed bronchophony. Aegophony is a

necessary for cyanosis is 65%, 78% and

similar change in transmission but has a

85%. In the newborn, fetal Hb (HbF) shifts

nasal quality with a change of ‘‘E’’ sounds to

the oxygen dissociation curve to the left,

‘‘A’’. Whispered pectoriloquy is an unusually

thus preventing cyanosis in the neonate. The

clear transmission of whispered sounds

opposite is true for sickle Hb (HbS) in sickle

during auscultation in the case of severe

cell disease (West, 2008). Differential

consolidation or compression.

cyanosis may be observed in congenital

Cyanosis and clubbing Examination of organ

heart disease (e.g. cyanosis of the lower part

systems beyond the respiratory system

of the body in preductal coarctation of the

should be performed as deemed necessary.

aorta, and of the upper part of the body in

Inspection of the skin and mucosa for

transposition of the great arteries).

cyanosis is obviously important, and the

The sensitivity of cyanosis in the evaluation

fingers should be evaluated for digital

of hypoxaemia is poor. Therefore,

clubbing.

hypoxaemia should be assessed by

Cyanosis is the bluish-purple discoloration

measuring PaO₂ or, more readily, SpO₂. Pulse

of the skin or the mucosa caused by high

oximetry is an invaluable clinical tool,

concentrations of reduced Hb in the

considered by some as the fifth vital sign.

capillary bed and the subcapillary venous

Nevertheless, the possibility of abnormal Hb

plexus. Ideally, cyanosis should be evaluated

(e.g. carboxyhaemoglobin or

in daylight in a comfortably warm

methaemoglobin) should be taken into

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Differential diagnosis of cyanosis

Severe decrease of air entry

Congenital malformations (may present as

Choanal atresia

emergencies in the neonate)

Supraglottic fusion of the larynx

‘‘Complete’’ laryngeal web

Laryngeal cyst

Cricoid ring dysplasia

Vocal cord paralysis

Vascular ring (usually presents later)

Mediastinal cyst/mass

Oesophageal atresia ¡ tracheo-oesophageal

fistula

Large bronchogenic cyst

Congenital cyst adenomatoid malformation

Congenital lobar emphysema

Lung hypoplasia/agenesis

Pneumothorax (due to rupture of cyst)

Lymphangiectasia/chylothorax

Congenital diaphragmatic hernia

Severe thoracic dysplasia

Airway obstruction

Severe croup

Foreign body

Angio-oedema

Retro-, parapharyngeal abscess

Neck mass

Asthma

Bronchiolitis

Chronic lung disease of prematurity

Severe aspiration

Lung compression

Large pneumothorax (especial under tension)

Pneumomediastinum

Haemothorax

Large space occupying lesion (congenital or

acquired)

Pleural effusion

Prominent abdominal distention

Anatomical or functional abnormalities of

Severe chest wall deformity

the thoracic cage

Flail chest

Diaphragmatic paralysis

Neuromuscular disease (Guillain-Barré

syndrome, botulism, poliomyelitis,

diaphragmatic paralysis)

Myopathy (muscular dystrophy, myasthenia

gravis, Werding-Hoffman)

Hypokalaemia

Organophosphate poisoning

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Continued

Disorders of gas exchange (V9/Q9 mismatch,

dead space ventilation, alveolar-capillary block)

Peripheral airway obstruction

Bronchitis

Bronchiolitis

Pneumonia

Chronic lung disease of prematurity

Exacerbation of severe bronchiectasis

ARDS

Aspiration (from above or below)

Gastro-oesophageal reflux

Swallowing dysfunction

Congenital anomalies (laryngeal cleft, tracheo-

oesophageal fistula)

Meconium aspiration

Atelectasis

Interstitial lung disease/pulmonary fibrosis

Pulmonary oedema

CHF

Smoke inhalation

Chemical pneumonia

High altitude

Idiopathic pulmonary haemosiderosis/

Heiner syndrome

Pulmonary embolus

Rare in children (dyspnoea/respiratory distress

and hypoxaemia are disproportionately

severe to the auscultatory and chest

radiography findings)

Cardiovascular disorders

Cyanotic congenital heart disease

Transposition of the great arteries (variations)

Tetralogy of Fallot

Pulmonary atresia with ventricular septal

defect

Double-outlet right ventricle (variations)

Total anomalous pulmonary venous return

Tricuspid atresia

Ebstein anomaly of the tricuspid valve

Truncus arteriosus

CHF (cardiogenic shock)

Cardiovascular pump failure (myocarditis,

arrhythmia, post-operative complication,

metabolic disorder, drugs)

Right heart failure/pulmonary hypertension/

PPHN

Restrictive pericarditis/myocarditis/

Pneumo- and haemopericardium (tamponade)

endocardial fibroelastosis/atrial myxoma

are emergent situations

Inefficient tissue oxygenation

Polycythaemia/HbF

Favour cyanosis

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Continued

Methaemoglobinaemia

Hereditary (HbM, Hb reductase deficiency)

Acquired (aniline dyes, nitrites, nitrates, drugs:

dapsone, nitroglycerine, benzocain,

sulfonamides, etc.)

Shock

Haemorrhage

Sepsis

Cardiogenic

Adrenal insufficiency

CNS irritation or depression

Seizures

Meningitis/encephalitis

Cerebral oedema

Haemorrhage

Intracerebral

Subdural

Subarachnoid

Drugs/toxins

Anaesthetics

Narcotics

Sedatives

Spasmolytics

Peripheral cyanosis

Vasoconstriction

Exposure to cold

Drugs

Autonomic nervous system disturbances

(Raynaud phenomenon etc.)

Hypoperfusion

Clot

Post-traumatic

Vasculitis

DIC

Venous blood stasis

Skin colour

Blue hues

Blue-tinged skin lesions

Extended ectasia of the subcapillary

venous bed

Venous stasis

Blood extravasation

Drugs

Amiodarone

Silver toxicity

Other causes

Breath hold

Infants and young children

Cry

Hypoglycaemia

Infants

Familial dysautonomia

V9: ventilation; Q9: perfusion; ARDS: acute respiratory distress syndrome; PPHN: primary pulmonary

hypertension of the newborn; CNS: central nervous system; DIC: diffuse intravascular coagulation.

ERS Handbook: Paediatric Respiratory Medicine

account in the interpretation of the pulse

Further reading

oximetry reading (Fouzas et al., 2011).

Bickley LS, et al. Bates’ Guide to Physical

Table 1 presents the differential diagnosis of

Examination and History Taking.

11th

cyanosis/hypoxaemia.

Edn. Philadelphia, Wolters Kluwer

Clubbing is the thickening of the connective

Health/Lippincott Williams & Wilkins,

tissue in the distal phalanges of the fingers

2013.

and toes. It can be detected clinically in

Brown MA, et al. Clinical assessment and

diagnostic approach to common pro-

three ways (Pasterkamp, 2012):

blems. In: Taussig LM, et al., eds.

N the Schamroth sign, which is the

Pediat-ric Respiratory Medicine.

2nd

obliteration of the diamond shaped

Edn. Philadelphia, Mosby-Elsevier, 2008;

opening at the base of the nail beds that

pp. 101-133.

is normally created by precisely opposing

DeGowin EL, ed. Bedside Diagnostic

Examination: a Comprehensive Pocket

the dorsal surface of the distal phalanges

Textbook.

5th

Edn. New York,

of similar (right-left) fingers;

Macmillan, 1987.

N the inversion of the phalangeal depth

Fouzas S, et al. (2011). Pulse oximetry in

ratio, i.e. the ratio of the distal phalangeal

pediatric practice. Pediatrics;

128:

740-

diameter (measured most accurately by

752.

calliper at the level of the eruption of the

Grotberg JB, et al.

(1989). Flutter in

nail) over the interphalangeal diameter

collapsible tubes: a theoretical model of

(measured at the crease between the two

wheezes. J Appl Physiol; 66: 2262-2273.

distal phalanges) is .1 in clubbing

Pasterkamp H, et al. (1997). Respiratory

instead of the normal ,1 ratio;

sounds. Advances beyond the stetho-

N the increase of the hyponychial angle

scope. Am J Respir Crit Care Med; 156:

(defined by the plane of the nail and that

974-987.

of the adjacent skin at the eruption of the

Pasterkamp H. The history and physical

nail) to .180u as compared to the normal

examination. In: Wilmott RW, et al., eds.

,180u value.

Kendig & Chernick’s Disorders of the

Respiratory Tract in Children.

8th Edn.

Clubbing is an important indicator of lung

Philadelphia, Saunders Elsevier,

2012;

disease more commonly seen in CF and

pp. 110-130.

non-CF bronchiectasis, empyema, or lung

Sovijärvi AR, et al. (2000). Definition of

abscess, but it may also occur in association

terms for applications of respiratory

with heart (congenital or endocarditis), liver

sounds. Eur Respir Rev; 10: 597-610.

or other gastrointestinal disease. It may

Stack AM. Cyanosis. In: Davis MA, et al,

reflect the course of disease over time. It

eds. Signs and Symptoms in Pediatrics.

may be associated with (usually painful)

Urgent and Emergent Care. Philadelphia,

periostosis in the context of hypertrophic

Elsevier-Mosby, 2005; pp. 58-65.

osteoarthropathy.

ERS Handbook: Paediatric Respiratory Medicine

Cough

Ahmad Kantar, Michael Shields, Fabio Cardinale and Anne B. Chang

Cough is the most common symptom of

atelectasis or collapse from retained

airway lung disease. It is also a frequent

secretions and recurrent pneumonia occur

reason for which medical advice is sought.

frequently. As a symptom, it is nonspecific

Cough is an important physiological

and many of the potential causes in children

protective reflex that clears airways of

are different from those in adults (Gibson et

secretions and inhaled or aspirated material.

al., 2010; Chang et al., 2007).

The importance of cough in maintaining

The cough reflex pathway involves cough

respiratory health is evident in clinical

receptors, mediators of sensory nerves and

situations where the cough is ineffective

an afferent pathway, the vagus nerve, the

(e.g. generalised muscular weakness,

cough centre, an efferent pathway, and the

tracheobronchomalacia and laryngeal

effectors. Cough has three defining features:

disorders). When these conditions exist,

N an initial deep breath,

N a brief, powerful expiratory effort against

Key points

a closed glottis, and

N opening of the glottis with closure of the

Cough has different major

nasopharynx and vigorous expiration

overlapping constructs based on

through the mouth.

duration, inflammation type,

Within this definition, there are several

phenotype or clinical syndromes.

variants. The act may be: a single deep

It is not logical to try to suppress a

inspiration followed by a single glottic

cough that has a protective role.

closure interrupting an almost complete

expiration near to residual volume; the same

It is important to try to make a

as this but with multiple glottic closures

diagnosis and treat the underlying

during the single expiration; or a ‘‘bout’’ of

cause of cough. Potential causes in

coughing, with each expiratory effort either

children are different from those in

completed or partial. Other acts, such as the

adults.

‘‘huff’’ of clearing the throat and the

There is little evidence that either

expiratory effort with glottis closure due to

nonspecific isolated cough or post-

touching the vocal folds or trachea (the

infectious coughing respond to any

‘‘expiration reflex’’) are, by definition, not

currently available treatment.

cough but may be fragments of a cough

(Widdicombe, 2003).

There is good evidence that children

with protracted (persistent)

Cough can be initiated from the larynx,

productive (moist or wet) cough

including its supraglottal part, from the

benefit from treatment with

trachea and from the larger bronchi.

antibiotics to cover the organisms

Irritation of the smaller bronchi, the

associated with protracted bacterial

bronchioles and the alveoli does not seem to

bronchitis.

cause effective cough because the luminal

airflows and velocities would be too low to

ERS Handbook: Paediatric Respiratory Medicine

have shear forces adequate to clear airway

many factors including the duration of cough

mucus and debris. Cough sound is due to

(acute versus chronic), the setting (e.g.

vibration of larger airways and laryngeal

affluent versus less developed), selection

structures during turbulent flow in

criteria of the children studied (e.g. general

expiration. Rheological properties of mucus

practice versus specialist clinics), follow-up

and shearing of the secretions from the

rate, depth of clinical history, examination

airways influence cough sound.

and investigations performed (Chang, 2011).

For example, bronchiectasis (a condition

Causes

causing susceptibility to airway infection) is

Cough has different major overlapping

more common in places like Turkey than in

constructs based on:

Italy, and a child with bronchiectasis may be

not correctly diagnosed unless followed up

N duration (acute, subacute or chronic),

with a chest CT scan.

N inflammation type (neutrophilic,

The common causes of acute and chronic

eosinophilic, lymphocytic or neurogenic)

cough in children are presented in tables 1

and 2. In addition to the many aetiologies of

N clinical syndromes (e.g. acute bronchitis,

cough, there are also exacerbation factors,

laryngotracheobronchitis, protracted

such as air pollution. The ascribed possible

bacterial bronchitis or aspiration

underlying aetiologies of chronic cough have

bronchitis).

a very wide spectrum that ranges from acute

Although the inflammation classification

cough related to a viral infection, to chronic

may be useful in defining treatment

cough from nonspecific cough (that is more

(especially in eosinophilic bronchitis),

likely to resolve spontaneously), to serious

phenotypic descriptions and clinical

causes such as foreign bodies in the airways

syndromes are usually used in the clinical

and bronchiectasis. Not surprisingly,

arena. The characterisation of these clinical

different centres report highly variable

syndromes related to cough is dependent on

aetiologies (Chang, 2008) that are probably

Table 1. Common causes of acute cough (,2 weeks duration)

Associations or characteristic

Additional comments

Infection related

Upper respiratory dominant

A large number of viruses can cause acute bronchitis

May be associated with common cold, otitis media,

sinusitis or pharyngitis

Croup

Stridor

Pertussis

Usually paroxysmal ¡ post-tussive vomiting

In younger children, whoop may be present

Pneumonia

Tachypnoea ¡ dyspnoea and fever

Environmental

Acute exposure to toxicants

For example, exposure to burning debris and other

chemical pollutants

Others

Foreign body inhalation

History of choking

Acute asthma

History and symptoms of asthma

This is not an exhaustive list. Any pathogen that infects the respiratory tract can cause bronchitis and this includes

opportunistic pathogens, fungi and helminths. All the causes of chronic cough in table 2 can present as acute

cough. Nonpulmonary conditions (e.g. acute leukaemia or cardiac failure) can also present with acute cough.

ERS Handbook: Paediatric Respiratory Medicine

Table 2. Common causes of chronic cough (.4 weeks duration)

Associations or characteristic

Additional comments

Conditions where other symptoms and signs

are mostly absent (nonspecific cough)

Mycoplasma

Pertussis

In the acute phase, cough is usually

paroxysmal ¡ post-tussive vomiting

In younger children, whoop may be present

Post-infectious cough

Cough that naturally resolves without

treatment

Habitual tic (psychological)

Early phase of specific cough

Wet or productive cough

Protracted bacterial bronchitis

Chest radiographs usually show only

peribronchial thickening

Tracheomalacia may co-exist especially if

recurrent

Chronic suppurative lung disease or

bronchiectasis

Recurrent small volume aspiration

Many children have a neurodevelopmental

problem as well but its absence does not

indicate absence of recurrent aspiration

Other conditions where other symptoms and

signs are mostly present (specific cough)

Asthma

Dyspnoea with exertion

Wheeze

Foreign body inhalation

History of choking

This is not an exhaustive list. Other less common conditions include the entire spectrum of lung disease,

such as interstitial lung disease and plastic bronchitis, and other conditions external to the respiratory tract,

such as cardiac disease, ear disease, gastro-oesophageal reflux and OSA; in the last two conditions, debates

still exist as to cause and effect. Both the US (Chang et al., 2006b) and Australia/New Zealand (Chang et al.,

2006a) guidelines classify chronic cough as duration .4 weeks but the British Thoracic Society (Shields et al.

2008) uses a duration of .8 weeks. The duration used in other European countries varies. For example, the

Belgian guideline defines prolonged cough as a daily cough lasting for .3 weeks (Leconte et al., 2008).

(at least in part) related to inherent

as well as indirectly, such as through the

difficulties in studying chronic cough (Chang,

immune system and neural pathways.

2011). Some of these are outlined here.

However, irrespective of exposure, cough

should not be simply ascribed to pollutants

The most clinically important air pollutant in

such as environmental tobacco smoke (ETS)

childhood bronchitis is tobacco smoke.

exposure. Cohort studies on children with

Systematic reviews have described the link

chronic cough have shown that cough

between cough and air pollution, both

resolution was still achieved in children

indoors and outdoors (Laumbach, 2010). It

exposed to ETS (including a cohort with

is increasingly appreciated, in human and

high exposure rates (56%)) (Asilsoy et al.,

animal studies, that environmental

2008; Marchant et al., 2006b). This

pollutants may have additive effects and

suggests that, while ETS is undoubtedly

influence the respiratory apparatus directly

associated with increased coughing

ERS Handbook: Paediatric Respiratory Medicine

illnesses and an important contributing

more than 2-3 weeks in 10% of normal

factor, ETS alone is not the sole aetiology.

children. Provided the child is otherwise well

with no pyrexia, tachypnoea or crackles, it is

Defining causes and ascribing aetiologies In

likely best to wait for resolution as aetiology

the interpretation of studies that describe

is most often viral. There is limited evidence

cough aetiology, clinicians need to be

that any therapy is beneficial.

cognisant of several key points. Firstly,

clinicians should be aware of the ‘‘time-

N Erythromycin is useful for early pertussis

period’’ effect. The time-period effect,

cases.

described Evald et al. (1989), refers to the

N Honey medications and vapour rub may

spontaneous resolution of cough with time.

reduce the severity of acute cough.

Secondly, the placebo effect is as high as

N Antibiotics may be beneficial for acute

80% in cough studies (Eccles, 2002).

bacterial bronchitis but most bacterial

Hutton et al. (1991) described that ‘‘parents

cases resolve naturally anyway.

who wanted medicine at the initial visit

reported more improvement at follow-up,

An inhaled foreign body is a possibility when

regardless of whether the child received

there is a sudden onset of cough with no

drug, placebo, or no treatment’’. Thus, in

upper respiratory tract infection or after a

non-randomised controlled trial cough

choking episode; bronchoscopy is needed to

studies, the time factor and a priori

remove the foreign body. In allergic rhinitis

definition of what constitutes an

and post-nasal drip syndrome (throat-

improvement in cough needs to be

clearing type cough), intranasal steroids

predetermined. Studies that do not

and/or antihistamines may be beneficial.

predefine these have limited validity. Just by

10% of normal children with acute cough due

seeing a doctor who takes an interest in the

to upper respiratory tract infections are still

child’s cough, the cough score and quality of

coughing 3-4 weeks later. Some children with

life improves before treatment (Marchant et

a ‘‘post-infectious cough’’ (prolonged acute

al., 2006a). Thirdly, studies that do not use

coughing after an obvious upper respiratory

validated outcome measures for cough

infection) cough for much longer and this is

research require scrutiny in light of the

especially true for those with pertussis (Hay

above. A small reduction in cough scores in

et al., 2005). Providing the child is otherwise

association with a medication given does

well, waiting for a period of time allows

not mean that the treatment for the

natural resolution of post-infectious

assumed aetiology is the true cause of the

coughing and pertussis to occur.

cough. The small change may be related to

the variability of the test itself. Also,

Do not use a wait-and-see approach if there

paediatric cough-related issues, like most

is:

other conditions, particularly in young

children, share similarities but also have

N weight loss,

substantial important differences when

N night sweats,

compared to adults. Thus, publications on

N haemoptysis,

clinical issues of cough in adults may not be

N sudden-onset cough or cough after a

applicable in children (Chang, 2011).

choking episode,

N coughing is relentlessly progressive (e.g.

Management

TB, expanding intrathoracic mass,

retained foreign body, collapsed lobe or

It is not logical to try to suppress a cough

pertussis), or

that has a protective role (see earlier). It is

N the child has a clinical history of

important to try to make a diagnosis and

symptoms or signs (or are at risk) of

treat the underlying cause (e.g. asthma, CF

underlying chronic lung disease (e.g.

and non-CF bronchiectasis).

finger clubbing, barrel-shaped chest,

Acute cough In upper respiratory tract

Harrison’s sulci, recurrent pneumonia

infection with bronchitis, cough usually lasts

and immunodeficiency).

ERS Handbook: Paediatric Respiratory Medicine

Chronic cough The underlying principle for

appropriate antibiotic and the child

the management of chronic cough is to

returning to completely good health

make the correct diagnosis and manage the

confirms the diagnosis. Failure to respond

underlying condition. Remove child from

or other features of chronic disease should

ETS or other pollutant exposure. Children

trigger further investigations as to an

started on ACE inhibitors may have a dry

underlying cause, such as:

cough, which stops with medication

withdrawal.

N persistent bacterial bronchitis,

N CF,

Chronic cough is very common and often

N immune deficiencies,

there are no pointers to a specific diagnosis

N primary ciliary disorders,

(e.g. normal chest radiograph, normal lung

N recurrent pulmonary aspiration, or

function and dry isolated cough in otherwise

N retained inhaled foreign body.

well child). In such cases often a ‘‘trial of

treatment’’ is used to confirm a diagnosis as

Care needs to be taken, especially in

it is neither feasible nor desirable to

children with neurological or neuromuscular

extensively investigate all such children.

disabilities, to ensure dysfunction of

However, it is important to realise that

swallowing and gastro-oesophageal reflux is

natural resolution typically occurs with the

treated to prevent recurrent pulmonary

passage of time and, therefore, a response

aspiration.

to treatment must not be taken as

confirming a diagnosis. Children responding

Psychogenic or habit coughing can be

to a trial of therapy should have the

difficult to treat if there is some secondary

treatment stopped and only a second clear-

gain associated with an underlying stressor

cut response should be used to suggest a

and psychotherapy may be needed. More

diagnosis.

often behavioural therapies can be

employed to empower the child to be able to

There is little evidence that either

resist the urge to cough on his/her own (e.g.

nonspecific isolated cough or post-

the child takes a sip of hot lemon drink with

infectious coughing responds to any

each urge to cough)

currently available treatment (inhaled

corticosteroids (ICS), b₂-agonists,

Conclusion

leukotriene antagonists, anti-gastro-

The approach to a child with problem

oesophageal reflux therapy, cromones and

coughing involves firstly trying to arrive at a

environmental modification). Most of these

specific diagnosis (after taking history,

coughs resolve naturally but over a

examination and performing relevant tests)

considerable period of time. Ultra-high-dose

and using targeted treatments. Nonspecific

ICS may have a small benefit but the side-

isolated coughing in an otherwise well child

effects seem to outweigh the benefits.

may not need treating if natural resolution is

There is good evidence that children with

occurring. In some, a trial of antiasthma

protracted or persistent productive (moist

therapy may help diagnose cough-

or wet) cough benefit from treatment with

predominant asthma but it is important to

antibiotics to cover the organisms

keep at the back of one’s mind that the

associated with protracted bacterial

response to a trial of treatment may simply

bronchitis (e.g. Haemophilus influenzae,

be natural resolution. Chronic wet cough

Pneumococcus and Moraxella), such as co-

suggests excessive mucus in the airways

amoxiclav (Chang et al., 2008). It is

and may indicate potentially a serious lung

important that a full 14-day course is given

condition. Protracted bacterial bronchitis

and, sometimes, a prolonged course is

seems to be the most common cause, which

needed for 4-6 weeks along with intensive

responds by definition to a full course of

physiotherapy before the persistent

antibiotics. Care needs to be taken because

endobronchial infection is eradicated. A

these children, if not adequately treated,

positive response to a full course of an

may develop bronchiectasis.

ERS Handbook: Paediatric Respiratory Medicine

Further reading

Gibson PG, et al. (2010). CICADA: Cough in

children and adults: diagnosis and assess-

Asilsoy S, et al.

(2008). Evaluation of

ment. Australian Cough Guidelines sum-

chronic cough in children. Chest;

134:

mary statement. Med J Aust; 192: 265-271.

1122-1128.

Hay AD, et al. (2005). The natural history

Chang AB (2008). ACCP cough guidelines

of acute cough in children aged 0-4 years

for children: can its use improve out-

in primary care: a systematic review. Br J

comes? Chest; 134: 1111-1112.

Gen Pract; 52: 401-409.

Chang AB (2011). Therapy for cough:

Hutton N, et al. (1991). Effectiveness of

where does it fall short? Expert Rev

an antihistamine-decongestant combina-

Respir Med; 5: 503-513.

tion for young children with the common

Chang AB, et al. (2006a). The Thoracic

cold: a randomized, controlled clinical

Society of Australia and New Zealand.

trial. J Pediatr; 118: 125-130.

Position statement. Cough in children:

Laumbach RJ (2010). Outdoor air pollu-

definitions and clinical evaluation. Med J

tants and patient health. Am Fam

Aust; 184: 398-403.

Physician; 81: 175-180.

Chang AB, et al. (2006b). Guidelines for

Leconte S, et al. (2008). Prolonged cough

evaluating chronic cough in pediatrics:

in children: a summary of the Belgian

ACCP evidence-based clinical practice

primary care clinical guideline. Prim Care

guidelines. Chest; 129: 260S-283S.

Respir J; 17: 206-211.

Chang AB, et al. (2007). Cough through-

Marchant JM, et al. (2006a). Utility of

out life: children, adults and the senile.

signs and symptoms of chronic cough in

Pulm Pharmacol Ther; 20: 371-382.

predicting specific cause in children.

Chang AB, et al.

(2008). Chronic wet

Thorax; 61: 694-698.

cough: protracted bronchitis, chronic

Marchant JM, et al. (2006b). Evaluation

suppurative lung disease and bronchiec-

and outcome of young children with

tasis. Pediatr Pulmonol; 43: 519-531.

chronic cough. Chest; 129: 1132-1141.

Chang AB, et al. (2012). A multi-centre

Shields MD, et al.

(2008). British

study on chronic cough in children:

Thoracic Society Guidelines recommen-

burden and etiologies based on a stan-

dations for the assessment and manage-

dardized management pathway. Chest;

ment of cough in children. Thorax; 63:

142: 943-950.

Suppl. 3, iii1-iii15.

Eccles R (2002). The powerful placebo in

Weir K, et al.

(2011). Oropharyngeal

cough studies? Pulm Pharmacol Ther; 15:

aspiration and silent aspiration in chil-

303-308.

dren. Chest; 140: 589-597.

Evald T, et al.

(1989). Chronic non-

Widdicombe JG. A brief review of the

asthmatic cough is not affected by

mechanisms of cough. In: Chung KF, et

inhaled beclomethasone dipropionate. A

al., eds. Cough: Causes, Mechanisms and

controlled double blind clinical trial.

Therapy. Oxford, Blackwell Publishing

Allergy; 44: 510-514.

Ltd, 2003; pp. 17-23.

ERS Handbook: Paediatric Respiratory Medicine

Tachypnoea, dyspnoea,

respiratory distress and

chest pain

Josef Riedler

Definition

sternocleidomastoid muscle, head bobbing

and a seesaw type of thoracoabdominal

Tachypnoea describes abnormally high

movements. Various diseases of the

breathing frequencies and often

airways, lung parenchyma, rib cage and

accompanies dyspnoea. The normal

diaphragm, as well other organs, can cause

respiratory rate decreases with age and can

dyspnoea and respiratory distress (table 1).

be quite variable, particularly in newborns

and young infants. The mean values range

The following are abnormal patterns of

from 25 to 35 breaths?min^-1 in the first years

breathing with changes in breathing

of life and decrease to 15 to 20 breaths?min^-1

frequency, rhythm or respiratory effort.

in the adolescent. Tachypnoea without

Apnoea: no breathing (central apnoea or

dyspnoea is seen in young infants with a

obstructive apnoea).

compliant rib cage and in children with

fever, anaemia and intoxication, and as a

Hypopnoea: shallow breathing without

the production of hypercarbia.

result of psychogenic causes.

Hyperpnoea: deep breathing without the

The term dyspnoea refers to an abnormal

production of hypocarbia.

breathing pattern usually with increased

Bradypnoea: slow respiratory rate

respiratory effort. Dyspnoea can be caused

(metabolic alkalosis, increased brain

by different objective factors and is a very

pressure and respiratory muscle fatigue).

subjective feeling of difficult or painful

Tachypnoea: high respiratory rate.

breathing and often ‘‘air hunger’’. Objective

Hypoventilation: decreased alveolar

signs of respiratory distress are

ventilation, which usually leads to

suprasternal, intercostal or subcostal chest

hypercarbia.

wall retractions, flaring of the alae nasi, use

Hyperventilation: increased alveolar

of accessory muscles such as the

ventilation, which usually leads to

hypocarbia.

Biot breathing: irregular respiration at

Key points

variable tidal volumes interrupted by

apnoea (sign of brain damage).

N Dyspnoea can be caused by

Cheyne-Stokes breathing: cycles of

respiratory, cardiac, metabolic,

increasing and decreasing tidal volumes

neuromuscular or psychogenic

interrupted by apnoea (sign of brain

conditions.

damage).

N History taking and physical examination

Kussmaul breathing: deep respiration

are cornerstones of a proper

(metabolic acidosis).

assessment of a child with dyspnoea,

Chest pain is rather common in children.

tachypnoea or respiratory distress.

Whereas the most likely cause is

N A clear diagnosis is mandatory for

musculoskeletal, functional or psychogenic,

correct treatment.

benign and self-limited in older children,

serious conditions have to be excluded,

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Causes of dyspnoea

Respiratory

Extrathoracic obstruction (croup, epiglottitis, laryngospasm and foreign body)

Intrathoracic obstruction (asthma, obstructive bronchitis, bronchiolitis, foreign body

aspiration and tracheomalacia)

Pneumonia, atelectasis, pneumothorax, pleural effusion, trauma, pulmonary embolus,

pulmonary hypertension

Cardiac

Myocarditis, acute myocardial infarction, CHF, acute pulmonary oedema

Cardiac arrhythmias

Metabolic

Metabolic acidosis (diabetes mellitus, inborn error of metabolism)

Metabolic alkalosis (CF, hypertrophic stenosis of pylorus)

Neuromuscular and central

Defects or dysfunction of diaphragm

Myopathy and neuropathy

Poisoning, drugs, trauma and anaemia

Psychogenic

Hyperventilation

Anxiety and trauma

Vocal cord dysfunction

particularly in younger children (table 2). A

the child increases the respiratory effort to

thorough history often helps to find the

overcome the narrowing. This leads to an

cause and avoids unnecessary diagnostic

increase of the negative intratracheal/

steps. The following aspects of pain should

intrabronchial pressure distal to the

be assessed:

obstructive site during inspiration which

often results in airway collapse. At the same

N intermittent versus persistent pain,

time the intrapleural pressure becomes more

N short lasting (hours or days) versus longer

negative (up to -40 cmH₂O) leading to

lasting (months),

retraction of the compliant parts of the chest

N localised, sharp, superficial versus diffuse,

wall and of suprasternal and substernal

deep, visceral,

tissue. This can be seen particularly in infants

N occurrence of cough, dyspnoea or fever,

with floppy airways and the more quadratic

N prevalent during sleep,

shape of the thorax with horizontally lined

N related to swallowing or heart burn,

ribs. Nasal flaring may be present and helps

N association with posture, motion and

to reduce upper airway resistance and to

exercise.

stabilise the upper airways by reducing the

negative pharyngeal pressure. Flaring of the

In most situations a multidisciplinary

alae can also help reduce the inhalation time

approach including a paediatric

and respiratory muscle activities in situations

pulmonologist, cardiologist, orthopaedics

of chest or abdominal pain.

and psychologist should be attempted.

In normal inspiration, the diaphragm

Pathophysiology

contracts and moves downwards leading to

In case of obstruction or dynamic

outward motion of the thorax and the

compression of the extrathoracic airways,

abdomen. Paradoxical breathing refers to

ERS Handbook: Paediatric Respiratory Medicine

Table 2. Causes of chest pain

Musculoskeletal disorders (myositis, myalgia, costochondritis, Tietze syndrome and deformities

of vertebral column)

Trauma

Herpes zoster

Mastitis and gynaecomastia

Pulmonary infarction

Sickle cell anaemia

Pneumothorax, pleuritis, atelectasis and foreign body aspiration

Mediastinitis

Chemical pneumonitis

Gastro-oesophageal reflux, hiatus hernia and diaphragmatic irritation

Pericarditis, myocarditits, coronary disease, idiopathic hypertrophic subaortic stenosis and

arrhythmia

Pancreatitis and cholecystitis

Psychogenic

inward movement of the chest wall during

case, the time course of the symptoms, i.e.

inspiration, mostly due to paralysis of the

sudden onset or longer lasting, is essential.

intercostal muscles or the diaphragm. This

A past history of asthma or recurrent

breathing pattern with seesaw type of

obstructive bronchitis helps in determining

thoracoabdominal motion can also be seen

the cause of acute intrathoracic airway

in preterm babies and newborns with a very

obstruction. Possible foreign body

compliant thorax. In older children, however,

inhalation needs to be excluded in a young

the most likely cause is respiratory muscle

child with unilateral wheezing or diminished

fatigue and impending respiratory failure.

breath sounds on one side of the thorax.

Risk factors such as known allergies, a

The more distal the obstruction, the more

positive family history, underlying

effort is needed to get the air out of the lung.

cardiovascular conditions, psychological

The elastic ‘‘recoil pressure’’ of the lung

disorders, drugs or recent infections should

tissue is no longer sufficient as a driving

be assessed. In patients with long lasting or

force in expiration and this usually passive

recurrent episodes of dyspnoea, normal

process becomes an active one. In this

growth and normal physical fitness point

situation, the usually negative intrapleural

towards a more benign course. Dyspnoea

pressure becomes positive during expiration

due to functional or psychological

leading to bulging of intercostal spaces.

conditions usually disappear during sleep

(fig. 1).

Physiological triggers in the various causes of

dyspnoea are changes in carbon dioxide and

Inspection Correct observation is one of the

oxygen tension (PCO₂ and PO₂, respectively)

most important parts of the physical

and in blood pH, as well as irritation of pain

examination in a child with dyspnoea.

and thermo receptors and direct damage of

Tachypnoea at rest, particularly during

neuronal receptors of breathing.

sleep, is suggestive of increased effort in

breathing. In a child with pneumonia,

Assessment of the patient and differential

respiratory rate increases to improve

diagnosis

oxygenation. Thus, visible tachypnoea is one

History In a patient with severe respiratory

of the most sensitive signs of restrictive lung

distress, history taking will be limited. In any

disease, such as pneumonia, atelectasis,

ERS Handbook: Paediatric Respiratory Medicine

Acute dyspnoea,

respiratory rate or

Inspection,

auscultation,

percussion

No intra- or extrathoracic

obstruction, crackles or

No intra- or extrathoracic

Normal inspiration, expiratory

Inspiratory stridor, normal or

diminished lung sounds

obstruction, normal lung

wheeze (one or both sides)

obstructive expiration

present

sounds

Intrathoracic

Respiratory: blood

Metabolic: blood gases,

obstruction: blood gases,

Extrathoracic

gases, ultrasound,

electrolytes, blood

bronchodilator test

obstruction: blood

chest radiograph,

glucose

(both sides), fluoroscopy

gases

thoracic CT

(one-sided)

Neuromuscular or

Cardiac: blood gases,

central: blood gases,

ECG, Echo, chest

fluoroscopy, brain

radiograph

imaging, liquor puncture

electromyogram

Psychogenic or

functional

Figure 1. Assessment of acute dyspnoea.

alveolitis, or pleural effusion and

trachea usually can be heard without a

pneumothorax. In airway obstruction of the

stethoscope. The noise either comes from

younger child, indrawing of the suprasternal

vibrations of the aryepiglottic folds or vocal

fossa or subcostal and intercostal tissue and

cords (vocal cord dysfunction) or from

nasal flaring is usually present. In unilateral

dynamic compression of the extrathoracic

diseases of the lungs, the rib cage or

part of the trachea just below the

diaphragm are seen as asymmetric

obstruction of the subglottic or proximal

breathing motion. Chronic airway

trachea (subglottic stenosis or croup). The

obstruction may result in a barrel-shaped

sound may vary in pitch and intensity due to

chest with increased anteroposterior

the site of obstruction. A more coarse

diameter. A bilateral skin fold below and a

character indicates pharygolaryngeal site

bluish coloration of the lower eyelid may be

(epiglottitis), whereas a sharp high-pitched

seen in atopy. Digital clubbing may

tone may come from the subglottic region

accompany long lasting respiratory disease

(croup). An additional expiratory stridor

like CF, and can be found rarely in lung

suggests involvement of the intrathoracic

abscess and empyema. Peripheral or central

part of the trachea. Stridor of a baby that

cyanosis occurs when the absolute

diminishes or even disappears in the prone

concentration of reduced haemoglobin in

position is very suggestive of a benign

the arterial blood exceeds 3 g per100 mL.

infantile floppy larynx.

Auscultation and percussion Inspiratory

Wheeze due to intrathoracic airway

stridor indicating narrowing of the larynx or

obstruction refers to polyphonic continuous

ERS Handbook: Paediatric Respiratory Medicine

musical lung sounds, in some languages

children with hypothermia and peripheral

called ‘‘asthma concert’’ and is present in

vasoconstriction, pulse oximetry cannot be

expiration and sometimes inspiration.

relied on. In these situations arterial blood

Narrowing of a single central bronchus

gas tests are mandatory. Besides this

results in a unilateral monophonic wheeze

indication, assessing blood gases is crucial

often heard in a foreign body aspiration into

for information on PCO₂ and acid/base

a main bronchus. Crackles are non-musical,

constellation. In a dyspnoeic child the rapid

discontinuous sounds indicating air

increase in PCO₂ (.5 mmHg per hour) is of

movements through secretions (bronchitis)

great concern because this can be the first

or sudden opening or closing of airways or

sign of impending respiratory failure and the

alveoli (pneumonia). They are coarse when

need for ventilation. Hypocarbia and

they come from the bronchi and fine from

respiratory alkalosis is indicative of

bronchioli or alveoli. A dyspnoeic child with

hyperventilation seen in psychogenic

unilateral fine crackles most probably suffers

disorders or hyperventilation tetany.

from pneumonia, whereas bilateral fine

Hypocarbia and respiratory alkalosis also

crackles might be indicative of alveolitis,

occur as compensation for metabolic

bronchiolitis or lung oedema. In

acidosis. In ventilated children PCO₂ values

pneumonia, the normally present

are assessed and are necessary for

bronchovesicular breath sounds are

monitoring ventilation parameters. PCO₂

replaced by bronchial sounds because the

measurement is essential for evaluating

bronchioli and alveoli component is lacking

chronic lung disease (CF, chronic neonatal

due to congestion and secretions.

lung disease or severe restrictive lung

Unilaterally diminished lung sounds with

disease) and assessment of possible long-

dull percussion notes suggests atelectasis,

term oxygen supplementation.

tumour or pleural effusion. Less breath

Respiratory imaging A very thorough and

sounds and hypersonic/tympanic

skilled physical examination with proper

percussion on one side of the thorax might

auscultation and percussion often leads to a

be a sign of pneumothorax.

definitive diagnosis without the need for

Pulse oximetry and blood gases Pulse

further imaging in a child with dyspnoea.

oximetry is a noninvasive means for

This is the case in most patients with

measuring the body’s SaO₂. A slight decrease

obstruction due to asthma or typical viral

in oxygen saturation cannot readily be

bronchiolitis. A chest radiograph helps to

detected by simple inspection of the skin or

rule out pneumonia, atelectasis or

the mucous membranes. Pulse oximetry is

pneumothorax. Children with lung TB are

an essential tool in any child with dyspnoea

rarely dyspnoeic or in respiratory distress,

or respiratory distress. Causes for

only in the case of miliary TB.

desaturation are similar to those for

cyanosis. By far the most likely cause is

Usually, a radiograph sufficiently detects

ventilation/perfusion mismatch (V9/Q9) due

lung bleeding in haemosiderosis or chest

to viral or bacterial infections of the lung.

trauma. However, in the work-up of lung,

Sepsis, inhalation of toxic fumes, acute

mediastinal or rib cage tumours, CT or MRI

respiratory distress syndrome (ARDS) or

will be necessary. CT is diagnostic in

pulmonary oedema may lead to oxygen

bronchiectasis and mandatory in suspected

diffusion impairment. In preterm babies,

interstitial lung disease. Chest radiographs

respiratory distress syndrome is caused by

are hardly ever useful in the assessment of

insufficient production of surfactant. Target

dyspnoea due to upper respiratory tract

values for oxygen saturation in these babies

pathology. In preterm babies a chest

are in the range of 84-88% to avoid

radiograph confirms clinical respiratory

detrimental effects of oxygen on the eyes.

distress syndrome due to surfactant

Later in life, 92% is the lower limit of

deficiency or suggests different pathology,

normal. In severe dyspnoeic children with

such as lobar emphysema, cysts or other

signs of cardiorespiratory failure or in

causes of congenital airway malformation.

ERS Handbook: Paediatric Respiratory Medicine

In these cases CT or MRI will follow. In a

patients and parents of the non-organic, and

dyspnoeic child with pleural effusion,

usually benign, course of the disease. In

sonography can be used to monitor the

vocal cord dysfunction, the inspiratory and

amount and consistency of the fluid and to

expiratory part of the flow-volume loop

guide tapping. Many centres now use

often shows saw-tooth like changes. In

interventional radiologists to insert chest

patients with neuromuscular or skeletal

drains under ultrasonic guidance.

problems, lung function measurement is

helpful in predicting potential limitations for

Lung function measurement In most patients

surgery and anaesthesia.

with acute dyspnoea, history taking, physical

examinations, lab tests and imaging lead to

Bronchoscopy and bronchoalveolar lavage In

diagnosis and lung function measurements

an acutely dyspnoeic child with unilateral

are not necessary. Response to an anti-

diminished lung sounds and a possible

obstructive treatment of lower or upper

history of foreign body aspiration, rigid

airways is assessed clinically. However, in

bronchoscopy should be performed. Apart

case of reported episodes of dyspnoea or

from removal of a foreign body there is

limitations in physical activities and

virtually no indication for rigid

uneventful actual physical examination, lung

bronchoscopy. However, the use of flexible

function measurements may confirm or rule

bronchoscopy has substantially increased

out obstructive or restrictive airway disease.

in the last 20 years and one of the most

In the diagnosis of obstruction, spirometry

prevalent indications is dyspnoea with

and flow-volume loop are essential whereas

inspiratory stridor. Infantile larynx,

in suspected restriction vital capacity and

congenital or acquired subglottic stenosis,

TLC need to be assessed. Carbon monoxide

subglottic haemangioma, or a vascular

diffusion is measured when an impairment

ring can be found. Bronchoalveolar lavage

of the alveolar-capillary diffusion capacity is

is warranted in a child in whom lung

suspected as a cause for dyspnoea.

bleeding, gastric content aspiration,

Impairment of diffusion can also be

surfactant deficiency or certain infections

investigated by the means of pulse oximetry

(Pneumocystis jirovecii, Aspergillus,

under physical stress. Standardised

Cytomegalovirus), particularly in

protocols for treadmill tests and bicycle

immunosuppression, are thought to cause

ergometry are available. A drop in FEV1 of

dyspnoea. The role of transbronchial or

.10% after standardised physical activity

open lung biopsies is particularly in

suggests exercise-induced

severely sick patients with longer lasting or

bronchoconstriction. In functional or

chronic dyspnoea in whom no diagnosis

psychogenic dyspnoea, a normal lung

could have been made by investigations

function may be useful for reassuring

so far.

Acute

dyspnoea

Intrathoracic

Potential

Respiratory rate

Diffusion impairment

Extrathoracic

Psychogenic or

, PCO

,PO

obstruction

foreign body

(respiratory or cardiac)

obstruction

functional

(both sides)

(one-sided)

O2 saturation

Repeated β₂-

O_2, diuretics,

Rule out

Psychogenical

Rule out epiglottitis,

O_2,

intensive care,

possibly

intervention,

agonists,

pneumothorax

steroids orally or

ventilation

corticosteroid i.v.

catecholamines,

or effusion

biofeedback

i.v. inhalation of

possibly antibiotics

adrenalin

Rigid

bronchoscopy and

removal, no

β₂-agonists

Figure 2. Management of acute dyspnoea. PCO₂: carbon dioxide tension; PO₂: oxygen tension.

ERS Handbook: Paediatric Respiratory Medicine

Evaluation of non-respiratory causes of

administered intravenously. Inadequate

dyspnoea As seen in table 1, conditions

release of antidiuretic hormone often

other than respiratory ones also need to be

accompanies severe respiratory distress and

considered in a child with dyspnoea. If a

warrants reduction in fluid administration.

respiratory cause is unlikely, a cardiac

In a toxic dyspnoeic child with typical

assessment including electrocardiogram

symptoms of epiglottitis, rapid intubation

and echocardiography should be performed.

and administration of antibiotics is

Abnormalities in blood gases, blood

necessary. Systemically applied steroids

glucose, lactate, pyruvate or ammonia

and, in selected cases, inhalation of

suggest defects in metabolism. In some

adrenaline are cornerstones of the treatment

cases a detailed neurologic or psychological

of a child with inspiratory stridor and

evaluation will be necessary.

suspected croup. 400-1000 mg of

General management

salbutamol is inhaled in airway obstruction

due to asthma or obstructive bronchitis. In

A clear diagnosis is essential before

these diseases the obstruction is reversible

management can start in a dyspnoeic

and wheezing and respiratory distress will

patient. Figure 2 depicts the different

diminish after application. If this is not the

diagnostic paths and corresponding

case, irreversible airway obstruction due to a

treatment modalities. However, some

foreign body or mechanical narrowing must

general management steps apply for most

be suspected. The later situation warrants

situations. Cardiopulmonary resuscitation is

bronchoscopy and further evaluation or

obligatory in any unconscious child with

treatment.

cardiac or respiratory arrest. As a general

rule, children in respiratory distress should

not be investigated or transported in a lying

Further reading

position but with upper body elevated. To

Pasterkamp H. The history and physical

find out whether oxygen needs to be

examination. In: Chernick V, et al., eds.

supplemented, pulse oximetry has to be

Kendig’s Disorders of the Respiratory

performed. Repeated checks of blood gases

Tract in Children. 7th Edn. Philadelphia,

help to detect increases in PCO₂ and

Saunders Elsevier, 2006; pp. 75-93.

potential impending respiratory failure with

Riedler J. Symptome häufiger respirator-

the need of invasive or noninvasive

ischer Krankheiten. In: Lentze MJ, et al.,

ventilation. Nasogastric tubes should be

eds. Pädiatrie Grundlagen und Praxis. 3.

avoided, particularly in infants with

Auflage. Heidelberg, Springer,

2007;

respiratory distress, because they

pp. 1041-1045.

substantially increase airway resistance and

Thomas P

(2005). I can’t breathe.

respiratory work load. Usually, enteral

Assessment and emergency management

feeding is reduced to ,50% in these infants

of acute dyspnoea. Aust Fam Physician;

to avoid compression of lungs by abdominal

34: 523-529.

distension. The necessary fluids are

ERS Handbook: Paediatric Respiratory Medicine

Snoring, hoarseness, stridor

and wheezing

Kostas N. Priftis, Kostas Douros and Michael B. Anthracopoulos

Wheezing, stridor and snoring are common

Key points

causes of noisy breathing, particularly in

infants and young children, and their

Wheeze is a continuous, usually high-

presence indicates a degree of airway

pitched whistling sound that is

obstruction. The term ‘‘noisy breathing’’ is

accompanied by prolongation of the

used to describe respiratory sounds that are

expiratory phase; it is believed to

audible to the ‘‘naked ear’’ without the use

originate from oscillation of large

of a stethoscope. Although the evaluation of

airways in response to turbulent

noisy breathing is not always

airflow in partially blocked

straightforward, the proper identification of

intrathoracic airways.

these noises is of major clinical importance,

as it can assist in localising the site of an

Stridor is a musical, monophonic,

obstruction and, thus, in the differential

high-pitched sound that can be heard

diagnosis of the potential underlying causes

without a stethoscope, and it is

(table 1).

caused by narrowed large,

extrathoracic airways; its presence

The cause is often obvious from the history

suggests significant obstruction of

and clinical examination, and the final

airflow in the larynx and proximal

diagnosis can be reached with a minimum

trachea.

of diagnostic procedures. However, an

Snoring is produced during sleep

interventional approach may sometimes be

and is due to obstructed air

necessary to effectively diagnose the cause,

movement in the naso- and

especially if a lower airway lesion is

oropharynx; children who snore tend

suspected.

to have more collapsible airways and/

The difficulty in correctly recognising these

or increased size of adenotonsillar

abnormal sounds arises from the different

tissue.

types that may be present in the same

Rattle is created by the movement of

patient at the same time or at different

excessive secretions during normal

points in time, and from the fact that they

airflow in the central and extrathoracic

are frequently intermittent and not heard

airways; it has a ‘‘rattling’’,

during the clinical examination, making the

noncontinuous quality, but quite

clinician rely only on the parent’s

commonly is mislabelled by parents

description. Parent’s descriptions are often

as wheezing.

inaccurate, and their use of terms to

describe a noise can be quite misleading;

Hoarseness (or dysphonia) is a

this can also be the case among physicians,

disorder of phonation and is used to

as there is still ambiguity in the terminology

describe a change in the quality of the

used for respiratory noises in the medical

voice; it is not usually associated with

literature, highlighting the need for a

airway obstruction.

common nomenclature in each language.

Nevertheless, a detailed history by the

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Different kinds of noisy breathing, site of origin and usual potential causes

Noise

Site of origin

Common causes

Wheezing

Intrathoracic airways

Asthma

(wheeze)

(primarily expiratory)

Viral wheeze

Bronchiolitis

Foreign body

Protracted bacterial bronchitis

Tracheo/bronchomalacia

Stridor

Extrathoracic airways

Croup

(primarily inspiratory)

Epiglottitis

Laryngomalacia

Tracheomalacia

Vocal cord paralysis

VCD

Snoring

Oro/nasopharyngeal airway

Collapsible airways with increased size of

adenotonsillar tissue

Obesity

Craniofacial disorders

Rattle

Intra- and extrathoracic

Acute viral bronchitis

airways

Protracted bacterial bronchitis

Neurologic disorders with swallowing

dysfunction and/or chronic aspiration

Grunting

Glottis

Respiratory distress syndrome (neonates)

Pneumonia

Bacterial infection

Snuffles

Blocked nasal passages

Upper respiratory tract infections

Allergic rhinitis

parents on the exact nature of the

In this section, wheezing, stridor and

respiratory noise, with special attention to

snoring will be discussed, and there will be a

whether it occurs during inspiration,

brief reference to some other quite common

expiration or both, whether it is low or high

types of noisy breathing, namely rattle,

pitched, or has a musical quality and is

grunting and snuffle. Hoarseness (or

accompanied by vibrations of the chest wall,

dysphonia), which is a disorder of phonation

and perhaps the imitation of the various

and is not usually associated with airway

sounds by the physician, will undoubtedly

obstruction, will also be discussed.

assist in differentiating between the various

noises.

Wheezing

Computerised acoustic analysis technology

Wheeze is a continuous, usually high-

has been used to evaluate the properties of

pitched whistling sound with a musical

sounds and, in the future, may provide an

quality. It can be heard throughout the

objective clinical tool for correctly

respiratory cycle but is more common

characterising respiratory sounds and

during expiration and is accompanied by

assessing disease activity through the serial

prolongation of the expiratory phase. It

recording and quantification of these

originates from turbulent airflow, caused by

sounds. However, for the time being, this

partially blocked intrathoracic airways, that

technology is used only for research

oscillates the airway wall and gives rise to

purposes.

the sound.

ERS Handbook: Paediatric Respiratory Medicine

Although, in theory, wheezing can arise from

The absence of a choking event is not

throughout the conducting airways, it requires

reassuring, as ,15% of cases are not

sufficient airflow that, practically, it is

associated with a clear history of a choking

restricted to the large and medium-sized

episode. Monophonic progressive wheeze

airways. Still, it is common experience that

implies either a focal endobronchial lesion

wheezing is audible in cases of extensive small

(endobronchial TB or adenoma) or

airway narrowing, as is the case with asthma

extraluminal compression of central airways

and with bronchiolitis. This could be due to air

by a growing lymph node or other mass and

trapping in the lung periphery and the higher

should always prompt further investigation.

pleural pressures required to overcome the

In general, monophonic wheeze needs a

narrowing. Thus, the wheeze is thought to be

thorough investigation with chest

produced by the resultant external

radiography, flexible bronchoscopy and/or

compression of the larger airways, especially

CT. If foreign body aspiration is a strong

during infancy when the walls of the more

possibility, urgent rigid bronchoscopy

central bronchi are more collapsible. Since the

should be carried out, while mere suspicion

noise is produced by a multitude of airways

should prompt investigation of the airways

throughout the lungs the wheeze consists of a

with a flexible bronchoscope.

multitude of distinct harmonics (differing

Stridor

acoustic characteristics) and is therefore

‘‘polyphonic’’. Conversely, when the sound is

Stridor is a musical, monophonic, high-

generated by one (e.g. stenosis, foreign body)

pitched sound, albeit much more harsh

or few, at the most, large airways, it consists of

(oligophonic) than wheeze, which can be

a much more limited number of harmonics

heard without a stethoscope, especially

and is termed ‘‘monophonic’’ (perhaps more

during inspiration. It is caused by

precisely, ‘‘oligophonic’’). The ‘‘focal’’ nature

oscillations of narrowed large, extrathoracic

of the generation of the monophonic wheeze

airways, and its presence suggests

may explain the decrease of its loudness with

significant obstruction of airflow in the

the increase in the distance of the site of

larynx and extrathoracic trachea. The

auscultation from the sound source

generation of stridor can be explained by the

(obstruction).

dynamics of inspiration-expiration

(particularly when forced) and Bernoulli’s

Assessment The most common cause of

principle, which, simply put, states that the

intermittent episodes of polyphonic wheeze

pressure (dynamic energy) exerted by a

in children is asthma. A prompt response of

wheeze to a trial of bronchodilator is of great

moving fluid (or gas) on a surface decreases

importance, as it strongly supports the

as the velocity (kinetic energy) of the fluid

diagnosis of asthma. In infants, especially if

increases. Inhalation generates negative

crepitations predominate on auscultation

(relative to that of the atmosphere)

intrapleural pressure, which, in turn, is

and particularly if it is the first episode of

applied to the trachea. In normal

diffuse airway obstruction, bronchiolitis is

individuals, this results in minimal collapse,

the most likely diagnosis, although asthma

which is not clinically relevant. However, if

cannot be excluded. The response to

the airway is partially obstructed, there is a

bronchodilators, the presence and/or a

family history of atopy may all help to

disproportionally large drop in the

differentiate bronchiolitis or viral wheeze

intraluminal pressure, which is created by

from asthma. Although simple

the respiratory muscles in order to

overcome the obstruction. This pressure

noninterventional studies like chest

drop is further augmented by the turbulent

radiography, allergy testing and spirometry

flow through the ‘‘constricted’’ laryngeal/

may be useful in older children, more

tracheal tube due to Bernoulli’s principle,

elaborate studies are usually not necessary.

which further deteriorates the narrowing (a

Acute onset of monophonic wheeze raises

floppy extrathoracic airway will deteriorate

the possibility of foreign body aspiration.

the collapse even further). The Bernoulli

ERS Handbook: Paediatric Respiratory Medicine

effect, which creates high-frequency

.90% of all cases of stridor in children. It is

fluctuations of intraluminal pressure, is also

unlikely to occur before 6 months of age.

probably primarily responsible for the

Most episodes are mild and only a minority

vibrations of the airway wall that are

of children need hospital admission. The

responsible for the creation of stridor.

obstruction is due to subglottic oedema

Conversely, exhalation induces a positive

and, in most cases, stridor occurs during

intraluminal pressure of the extrathoracic

inspiration, although it can be biphasic in

airway, which tends to distend the

severe disease. Other quite exceptional

extrathoracic trachea, alleviate the tracheal

infectious causes of acute stridor are

obstruction and reduce expiratory flow

epiglottitis, and bacterial tracheitis.

resistance. These mechanisms explain why

Foreign body aspiration should always be

stridor is predominantly inspiratory,

suspected whenever the beginning of stridor

although it can also be present during

is abrupt and accompanied by severe

expiration if the obstruction is severe

respiratory distress. Rigid bronchoscopy

enough (fig. 1).

constitutes the definitive procedure in this

Assessment The history and physical

case, as it not only allows for the

examination provides information on the

visualisation of the airways but also for the

persistence of stridor (chronic versus acute),

removal of the foreign body.

acuity of onset (abrupt versus gradual),

timing during the respiratory cycle

The most common cause of chronic stridor

(inspiratory, expiratory or biphasic),

in infancy is laryngomalacia. It usually

accompanying symptoms (fever or coryza),

manifests days or weeks after birth and

hoarse and/or weak cry, cyanotic episodes,

symptoms usually resolve by 12-18 months.

positional differences in the intensity of

The noise varies in intensity depending on

noise, interval symptoms between episodes

the respiratory effort and varies with the

and severity of respiratory distress.

position of the patient. The obstruction is

due to prolapse of the epiglottis or the loose

The most common cause of acute stridor is

mucosal tissue overlying the arytenoid

viral croup, which is quite common and

cartilages into the laryngeal inlet. Laryngeal

presents with stridor accompanied by

walls collapse due to the subatmospheric

hoarseness, dry barking cough and

pressure generated during inspiration. On

respiratory distress. Croup is usually

expiration, the positive luminal pressure

preceded by coryzal symptoms and

overcomes the obstruction, thus keeping the

improves within a few days. It accounts for

airway open; therefore, if there is expiratory

Extrathoracic airway

C₇

T₁

Intrathoracic airway

Inspiratory phase

Expiratory phase

Figure 1. During inhalation, a negative (relative to that of the atmosphere) intrapleural pressure in

extrathoracic airways is generated, which in turn is applied to the trachea. This results in minimal collapse,

which, in normal individuals, is not clinically relevant. Exhalation induces a positive intraluminal pressure

of the extrathoracic airway, which tends to distend the extrathoracic trachea.

ERS Handbook: Paediatric Respiratory Medicine

stridor, an alternative diagnosis needs to be

can be set only with direct visualisation of

sought.

the cords with laryngoscopy, during an

episode.

Intermittent, sudden-onset, daytime

episodes of stridor in school-aged children

Snoring

or adolescents may indicate vocal cord

dysfunction (VCD). In this condition, which

Snoring is a sound that is produced during

may coexist with asthma, the vocal cords are

sleep from the increase in resistance to the

held in a paradoxical adducted position.

airflow in the upper airways and, more

Patients present with significant inspiratory

specifically, in the region of the naso- and

stridor and respiratory distress. Symptoms

oropharynx. Children who snore tend to

usually appear during exercise, especially in

have more collapsible airways and increased

highly competitive young athletes, but may

size of adenotonsillar tissue. During rapid

also appear without any identifiable cause.

eye movement (REM) sleep, the tone in

pharyngeal muscles is reduced, resulting in

Rare causes of chronic stridor include vocal

an increase in the frequency and severity of

cord paralysis (congenital or acquired),

obstruction. Snoring is more pronounced on

laryngeal clefts, subglottic stenosis

inspiration but it can also be audible during

(congenital or acquired), haemangiomas,

expiration. It is considered to be common in

laryngeal cysts and laryngeal webs.

children, with the reported prevalence

ranging from 5% to 20%. Its severity ranges

For acute episodes of stridor that are typical

from the so-called primary snoring with no

of croup, there is no need for investigations

evidence of ventilation abnormalities to

other than clinical evaluation. However,

severe OSAS. The latter is characterised by

children who have unusually prolonged or

episodes of complete or partial upper airway

recurrent episodes, or are not completely

obstruction leading to hypoxaemia and/or

asymptomatic between episodes, and

hypercapnia, and frequent nocturnal

children ,6 months of age require

arousals. The spectrum of disorders from

endoscopic evaluation.

primary snoring to OSAS is characterised as

In infants with chronic inspiratory stridor

sleep disordered breathing (SDB).

who are thriving and do not have significant

Assessment The main concern in the

respiratory distress, cyanotic episodes,

evaluation of snoring is to define the

chronic cough, hoarseness or weak cry, the

children who may suffer health

most likely diagnosis is laryngomalacia and

consequences related to the pathology

there is no need for further investigations.

underlying this breath sound; this may prove

However, if any of the above characteristics

to be difficult. OSAS cannot be diagnosed

are present, a more thorough investigation

simply on the grounds of a history of

is in order. If an endoscopic evaluation is

decided upon, it is preferable to perform

snoring since not all children who snore

both rigid laryngotracheoscopy and flexible

have OSAS, nor is the absence of snoring is

bronchoscopy. Rigid instruments allow a

sufficient to exclude OSAS, as parents may

much better view of the posterior aspect of

not have noticed the snoring of their child.

the larynx and upper trachea, whereas

Furthermore, there is some evidence

flexible bronchoscopy is superior in

suggesting that primary snoring may not be

evaluating airway dynamics. The entire

completely benign.

airway should always be examined, despite

A detailed history is helpful. Children who

the finding of a lesion in the larynx that can

suffer from OSAS snore almost every night,

explain the stridor, since in ,15% of

snoring usually persists throughout the

patients, an additional lesion will coexist in

night and there are frequent apnoeic

the lower airways.

episodes followed by loud snorts and

If VCD is suspected, spirometry may show

changes in position. They may suffer from

‘‘truncated’’ inspiratory and expiratory flow-

daytime tiredness, poor concentration and

volume loops. However, definite diagnosis

enuresis. Behaviour and learning problems

ERS Handbook: Paediatric Respiratory Medicine

(including attention deficit hyperactivity

created by excessive secretions which are

disorder) are not unusual. Clinical

moving during normal airflow in the central

examination may reveal adenoidal facies,

and extrathoracic airways. The mislabelling

enlarged tonsils or hyponasal speech.

of a rattle as wheeze may result in

Obesity, prematurity, family history and

overdiagnosis (and overtreatment) of

craniofacial anomalies are all well-known

asthma in children.

risk factors for OSAS. However, history and

clinical examination are not sufficient to

The most common cause of rattle is acute

reliably identify OSAS and the definitive

viral bronchitis and, in preschoolers, upper

diagnosis has to rely on polysomnography

airway viral infections. A rattle can be heard

(PSG), which is considered the gold

for a few days or weeks and subsides after

standard for evaluating children for SDB.

the removal of secretions from cough and

Still, this method is complex, expensive and

mucociliary clearance. Chronic rattling

time-consuming; these drawbacks restrict

sound is often related to chronic aspiration

its usefulness to a limited number of

in children with various neurological

specialised centres. A simplified alternative

conditions.

method is the continuous recording of

Grunting

oxygen saturations overnight with pulse

oximetry. Furthermore, there are a number

Grunting is a short, hoarse, moaning or

of other devices that monitor pulse oximetry

crying-like expiratory sound that occurs

with a combination of one or more

when a partially closed glottis halts the

parameters, like chest wall movement, body

expiratory flow of air. This mechanism may

movement and airflow. Due to their low

be considered as a self-administered form of

cost, simplicity and portability, they can be

peak end-expiratory pressure, since the

used for unattended studies at home. In

slowing of expiratory flow increases the

general, these methods have high positive

functional residual capacity and alveolar

and low negative predictive values, which

pressure, and prevents alveolar collapse.

imply that patients with negative results

However, the underlying pathophysiology is

require a full PSG for definitive diagnosis.

not yet fully elucidated. In neonates, the

noise is commonly associated with

Adenotonsillectomy is the treatment of

respiratory distress syndrome. In older,

choice for the vast majority of children with

previously healthy children, it is a sign of

OSAS. When surgery is not an option or if

pneumonia, whereas in children with

resolution of symptoms is not achieved

underlying chronic disease, it is considered

following surgery, nasal CPAP is usually

as a sign of serious bacterial infection.

effective.

Snuffles

Rattle

The term snuffles (or snorts) is used to

Parents tend to use ‘‘wheeze’’ as a generic

describe noisy breathing coming from

term to describe a variety of abnormal

blocked nasal passages. It is also used to

respiratory sounds. One of the commonest

describe the common cold or simply a runny

errors is the misuse of the word ‘‘wheeze’’ to

nose. The noise is audible throughout the

describe a coarse respiratory sound known

respiratory cycle and is associated with

as rattle. Rattle is characterised by a much

visible secretions from the nares. Apart from

lower pitch than wheeze, it has a ‘‘rattling’’,

upper respiratory tract infections, snuffles

noncontinuous quality, is usually

may also indicate allergic rhinitis or, on rare

accompanied by chest wall vibrations that

occasions, primary ciliary dyskinesia and

are easily detectable by parents, and it can

nasal polyps as in CF.

be heard during both inspiration and

expiration. It is found quite often in infants

Hoarseness

and toddlers and, although there is a paucity

of data in the literature regarding the

The term hoarseness (or dysphonia) is used to

underlying mechanism, it is believed to be

describe a change in the quality of the voice.

ERS Handbook: Paediatric Respiratory Medicine

It can be caused by any pathological or

Vocal cord paralysis is rare in children. It can

behavioural condition that affects the

be bilateral or unilateral. The former is

function or the structure of the larynx. The

mostly caused by central nervous system

problem appears to be common in children,

anomalies like Arnold-Chiari malformation,

with a reported incidence ranging from 6% to

whereas the latter mainly results from

23%. However, these numbers are derived

damage to the left recurrent laryngeal nerve

from small epidemiological studies that have

because of birth trauma, heart anomalies or

used a variety of definitions for dysphonia/

cardiac surgery. However, bilateral and

hoarseness or no definition at all.

unilateral vocal cord palsy can be idiopathic

without any identifiable cause. In bilateral

Hoarseness usually evolves gradually, which

palsy, there is almost always severe airways

may result in delayed diagnosis and

obstruction and stridor, whereas in

treatment. Fortunately, in most children, it is

unilateral stridor, it may be absent and the

due to benign or self-limited causes that

lesion may manifest as a husky, weak cry.

require no intervention or can be managed

Bilateral vocal cord paralysis is a

with voice therapy techniques.

predisposing cause of chronic or recurrent

aspiration pneumonitis. About half of these

Assessment A detailed history and clinical

palsies recover spontaneously, largely

examination are essential for the evaluation

irrespective of their cause.

of hoarseness. The persistence and

evolution of hoarseness, i.e. if it is acute

In general, history and physical examination

versus chronic, or intermittent versus

may help to distinguish between many of the

continuous progressive, is of pivotal

pathological conditions causing hoarseness.

importance. Acute hoarseness is usually due

However, direct inspection of the larynx by

to injury of the mucosa overlying the vocal

laryngoscopy is usually necessary for a

chords after ‘‘vocal abuse’’ but may also

definitive diagnosis. If the hoarseness is

result from infectious or inflammatory

rapidly progressive and/or is accompanied

processes. Chronic problems typically

by stridor or respiratory distress,

indicate structural abnormalities. If

laryngoscopy is mandatory.

hoarseness is intermittent and worsens in

Conclusion

the morning, then gastro-oesophageal reflux

is a distinct possibility. Conversely, if it is

Distinguishing the various respiratory

worse in the evening following prolonged

noises can, at times, be quite challenging.

use of the voice, it may be related to

The terminology is confusing and there is no

anatomical problems such as vocal nodules.

gold standard for the definition of the

Persistent, progressive dysphonia that

different sounds. Things are more

fluctuates from day to day may suggest the

complicated when the clinician has to rely

presence of papillomatosis. The presence of

only on the parents’ description and

stridor or any other form of noisy breathing

interpret their terms for the breathing noise

and/or respiratory distress indicates a

that they are referring to. Acoustic analysis

serious and potentially life-threatening

of respiratory sounds may improve

condition that must be evaluated and

communication among clinicians and

treated promptly. The presence of dysphagia

audio-video recordings demonstrating the

implies either a neurological problem

various sounds may prove quite useful in

affecting both the laryngeal and

order to improve the accuracy of the

hypopharyngeal area, or a mass lesion

information that is obtained.

affecting both swallowing and vocalisation.

It is imperative to ask whether there are

The clinical usefulness of respiratory noises

potential iatrogenic causes, including

could be improved by technology, such as

previous endotracheal intubation or

video recording and sound analysis, but

nasogastric tube insertion, that may have

although these techniques would clearly

contributed to the emergence of the

improve uncertainty regarding the

problem.

estimation of each specific noise, they are

ERS Handbook: Paediatric Respiratory Medicine

not suitable for everyday clinical practice

Elphick HE, et al.

(2004). Validity and

and their use remains confined to research

reliability of acoustic analysis of respira-

projects.

tory sounds in infants. Arch Dis Child; 89:

1059-1063.

Fakhoury K. Approach to wheezing in

Further reading

children.

www.uptodate.com/contents/

approach-to-wheezing-in-children.

Au CT, et al. (2009). Obstructive sleep

McMurray JS (2003). Disorders of phona-

breathing disorders. Pediatr Clin North

tion in children. Pediatr Clin North Am;

Am; 56: 243-259.

50: 363-380.

Bilavsky E, et al.

(2008). Are grunting

Mellis C (2009). Respiratory noises: how

respirations a sign of serious bacterial

useful are they clinically? Pediatr Clin

infection in children? Acta Paediatr; 97:

North Am; 56: 1-17.

1086-1089.

Witmans M, et al.

(2011). Update on

Boudewyns A, et al.

(2010). Clinical

pediatric sleep-disordered breathing.

practice: an approach to stridor in infants

Pediatr Clin North Am; 58: 571-589.

and children. Eur J Pediatr; 169: 135-141.

Zalvan C, et al. Etiology and management

Chang JI, et al.

(2012). Evidence-based

of hoarseness in children. www.uptodate.

practice: management of hoarseness/

com/contents/etiology-and-management-

dysphonia. Otolaryngol Clin North Am;

of-hoarseness-in-children.

45: 1109-1126.

Elphick HE, et al.

(2001). Survey of

Further listening

respiratory sounds in infants. Arch Dis

Child; 84: 35-39.

The R.A.L.E. Repository. www.rale.ca.

ERS Handbook: Paediatric Respiratory Medicine

Exercise intolerance

Kai-Ha˚ kon Carlsen

Exercise intolerance or the lack of ability to

participate in physical activity and exercise

Key points

together with peers may have many causes.

Some of the most common causes of

N Participating in and mastering physical

exercise intolerance are of respiratory origin

exercise is extremely important in

and will be briefly dealt with here (table 1).

children and adolescents.

N Participation in physical activity

Participating in physical activity is important

improves quality of life, fitness and life

for children, for their growth, their long-term

expectancy in many respiratory

development and future health. In asthmatic

disorders.

children, physical fitness has been

associated with psychological functioning.

N Treatment of childhood asthma

should aim at mastering physical

One of the most common respiratory causes

activity and exercise-induced asthma.

of exercise intolerance is exercise-induced

asthma (EIA), a frequent manifestation of

N Several chronic respiratory disorders

childhood and adolescent asthma. In the

of childhood may influence the ability

Oslo birth cohort, the Environment and

to participate in physical activity.

Childhood Asthma study, exercise-induced

Assessment of the ability to

bronchoconstriction (EIB) was found in

participate in physical activity and

8.6% of all 10-year-old children and in 36.7%

setting up therapeutic procedures to

of children with current asthma, whereas in

counteract exercise intolerance should

be part of the diagnostic assessment

a Danish population-based study of 494

of children with respiratory disease.

children aged 7-16 years, EIB with a o10%

reduction in FEV1 after exercise was found in

16% of the subjects.

programme in children and adolescents

When participating in systematic physical

(mean age 13.4 years), but they found a

training, the fitness and quality of life of an

reduction in total IgE and specific IgE to

asthmatic adolescent or child improves, as

house dust mite in the actively training

confirmed by a Cochrane-based meta-

group. Fanelli et al. (2007) conducted a 16-

analysis of eight training studies including

week training programme of 90 min twice a

226 asthmatics aged o6 years of age.

week in two groups (index and control) of

Similar results were also reported when later

children with moderate-to-severe persistent

studies were also included. Counil et al.

asthma. In the training group they found

(2003) confirmed improvement in aerobic

improved fitness (peak oxygen uptake

and anaerobic fitness in asthmatic

(V9O₂peak), work rate and oxygen pulse

adolescents (mean age 13 years), but no

during submaximal and maximal work),

improvement in lung function after 6 weeks

improved quality of life, reduction in exercise

of training with high-intensive bouts.

bronchoconstriction and reduced dose of

Moreira et al. (2008) found no changes in

inhaled steroids in 11 out of 21 subjects in the

asthma control after a 3-month training

training group compared to four out of 17

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Causes of exercise intolerance in children and adolescents

Cause of exercise

Clinical characteristics

Diagnostic procedure

intolerance

EIA

Expiratory dyspnoea occurring

Exercise test for exercise-

shortly after end maximal or

induced bronchoconstriction

sub-maximal exercise

Clinical airways obstruction

EIVCD

Inspiratory stridor occurring

Continuous laryngoscopic

during maximal exercise

exercise test

Exercise-induced

Anaphylaxis occurring during

Food allergy evaluation

anaphylaxis

or immediately after exercise,

Simultaneous food provocation

most often with food intake

and exercise test under safe

(allergenic) within the last 2 h

emergency precautions

prior to exercise

Other chronic respiratory

Chronic respiratory disorder,

CPET with recording of breath to

disorders with reduced

which can be of different kind

breath V9O₂max and

baseline lung function

(CF, primary ciliary dyskinesia

simultaneous tidal flow-

and bronchiectasis)

volume loops every minute

Reduced baseline lung function

Detection of flow limitation and

measure EELV

Dysfunctional breathing in

Chronic or recurrent changes in

Nijmegen questionnaire

asthma

breathing patterns causing

respiratory (and non-

respiratory) complaints

Symptoms include dyspnoea

with normal lung function,

deep sighing, chest pain, chest

tightness, frequent yawning,

hyperventilation and

breathlessness during exercise

Poor physical fitness

Breathlessness during exercise

CPET (maximum work capacity

before ordinarily anticipated

and/or V9O2max)

Muscle stiffness

Obesity

As for poor physical fitness

Other chronic disabling

Varying clinical picture

Clinical assessment

disorders

CPET: cardiopulmonary exercise test; EELV; end-expiratory lung volume; V9O2max: maximal oxygen uptake.

in the control group. Thus, the training

physically active as healthy children, whereas

subjects improved their exercise tolerance

other studies have demonstrated that

through physical training.

physical activity and fitness are related to

asthma control and improve with optimal

Subjects with higher physical activity levels

treatment and asthma control. Therefore, to

were found in a review of longitudinal studies

master EIA is considered one of the main

to have a lower incidence of asthma (OR

objectives of treating childhood asthma.

0.87, 95% CI 0.77-0.99), thus indicating a

potential for protection of developing asthma

Exercise-induced vocal cord dysfunction

by being physically active.

Exercise-induced vocal cord dysfunction

Some studies demonstrate that asthmatic

(EIVCD) is caused by airways obstruction

children are as physically fit and as

during exercise due to airflow limitation in

ERS Handbook: Paediatric Respiratory Medicine

the laryngeal area. This was first described in

specific IgE to tri V-gliadin. Other food

1983. This condition occurs frequently

allergens may also be responsible. Usually,

during adolescence, and is almost as

it is sufficient to secure removal of the

frequent as EIB, especially among girls

causative food allergen from the food, with

active in sport with high fitness levels. The

the patient then tolerating exercise.

symptoms consist of inspiratory stridor as

However, as a precaution the patient should

the exercise load increases. When reaching a

still carry an Epi-pen. Diagnosis may be

submaximal or maximal level, stridor usually

secured by simultaneous administration of

appears. The laryngeal area represents the

the suspected food allergen and an exercise

smallest orifice for the air to pass through

test with safe emergency precautions being

during inspiration, and in well-trained

taken.

youths, especially girls, the orifice becomes

Chronic lung diseases other than asthma

too small to allow entry of the required

amount of air without the appearance of

These may also cause exercise intolerance,

stridor and reduction of V9O₂peak. Several

but through other mechanisms. Whereas

laryngeal structures can participate in the

baseline lung function is usually normal or

airflow limitation, and the treatment may vary

close to normal in asthma, exercise causes

depending on this. Treatment may be

bronchoconstriction, which limits the ability

surgical or conservative. Lung function

of participating in physical exercise. In other

during exercise will, in many cases, be

chronic lung disorders, exercise usually does

characterised by reduced inspiratory flow.

not cause bronchoconstriction, but reduced

This condition has often been misinterpreted

baseline lung function may represent a

as EIA, but with no effect of asthma

pulmonary limitation for participating in

treatment. Inspiratory stridor during maximal

physical exercise similar to other children.

exercise may be observed during testing for

This includes CF, primary ciliary dyskinesia,

EIB, but an exact diagnosis requires a

other causes of bronchiectasis, secondary

continuous laryngoscopic exercise test.

lung disease to immunodeficiency and other

chronic lung diseases with reduced baseline

Exercise-induced anaphylaxis

lung function. The reduced lung function

will represent a flow limitation during

Exercise-induced anaphylaxis is a condition

exercise, which limits the possibility of

with anaphylaxis provoked by physical

increasing oxygen uptake with the increasing

exercise. This is a rare, but dramatic

demands for oxygen during exercise, thus

disorder in which the anaphylaxis occurs

giving rise to an anaerobic metabolism. The

during or immediately after exercise. It may

resulting dyspnoea is due to reaching the

be life threatening and is most often food

limits of airflow and not due to obstruction

dependent (food-dependent exercise-

of the airways due to the exercise, as in

induced anaphylaxis (FDEIA)), but may also

asthma. The patient will have an anaerobic

be due to exercise alone. Usually there is an

metabolism during exercise at a much

associated food allergy, but this may be

earlier time-point (fig. 1).

unknown to the patient as food allergy

symptoms may not occur without

Some other causes of exercise intolerance

simultaneous exercise. Most often both

are specific for athletes, such as exercise-

exercise and the specific food are

induced arterial hypoxaemia and swimming-

independently tolerated in FDEIA,

induced pulmonary oedema; therefore,

simultaneous exposure to both are usually

these are only mentioned for completeness.

required for the symptoms of anaphylaxis to

occur. Wheat proteins have often been

One condition that has received little focus

found to be the causative food in FDEIA,

in children is dysfunctional breathing. This

most often due to the major component

condition is defined by chronic or recurrent

allergen, tri V-gliadin. One should be aware

changes in breathing patterns. Symptoms

that, in some cases, negative specific IgE

include dyspnoea with normal lung function,

may be found to wheat even with increased

deep sighing, chest pain, chest tightness,

ERS Handbook: Paediatric Respiratory Medicine

Early exercise

Mid exercise

End exercise

Figure 1. Tidal breathing during exercise in a) a patient with asthma and b) a patient with chronic lung

disease (bronchiectasis). The patient with asthma demonstrated normal baseline lung function at early,

mid and end exercise. The patient with chronic lung disease had reduced baseline lung function during

early, mid and end exercise, demonstrating flow limitation and increased end-expiratory lung volume.

There was no flow limitation in the patient with asthma.

frequent yawning, hyperventilation and

the opposite, to focus on mastering of

breathlessness during exercise. A diagnosis is

physical activity and training, would

based on the Nijmegen questionnaire. A

represent a positive starting point. The

recent study demonstrated that this condition

patients presenting with exercise

occurred in 5.7% of asthmatic children

intolerance should be encouraged to

followed at a hospital outpatient clinic.

participate in exercise to improve physical

fitness and muscular strength. Physical

There are other non-respiratory causes of

training has been shown to prolong life

exercise intolerance that are not included in

expectancy in patients with CF, and

the above review. These often appear with

systematic training in children with and

breathlessness and muscular weakness as

without pulmonary disorders will improve

the most prominent symptoms. These

fitness, quality of life and life expectancy.

include general physical illnesses such as

In children with chronic lung disease focus

cardiac disease and other general disabling

should be on optimal treatment of their

diseases. Other causes are poor physical

respiratory disease in combination with a

fitness, when the physical activity level does

systematic training programme focusing

not meet expectations in the absence of any

on upper girdle muscles and fitness in

illness, and obesity with its limitations to

order to enable them to master physical

physical activity (table 1).

activity and to participate on an equal level

To focus on exercise intolerance may

with their peers in sports and outdoor

represent a negative point of view. Rather,

living.

ERS Handbook: Paediatric Respiratory Medicine

Further reading

Ram FS, et al. (2000). Effects of physical

training in asthma: a systematic review.

Backer V, et al. (1992). Bronchial respon-

Br J Sports Med; 34: 162-167.

siveness to exercise in a random sample of

Ram FS, et al. (2005). Physical training

494

children and adolescents from

for asthma. Cochrane Database Syst Rev;

Copenhagen. Clin Exp Allergy; 22: 741-747.

4: CD001116.

Berntsen S, et al.

(2009). Norwegian

Refsum HE, et al. Exercise-associated

adolescents with asthma are physical

ventilatory insufficiency in adolescent

active and fit. Allergy; 64: 421-426.

athletes. In: Oseid S, et al. The

Counil FP, et al.

(2003). Training of

Asthmatic Child in Play And Sports.

aerobic and anaerobic fitness in children

London, Pitmann Books Limited, 1983;

with asthma. J Pediatr; 142: 179-184.

pp. 128-139.

de Groot EP, et al. (2013). Dysfunctional

Roksund OD, et al.

(2009). Exercise

breathing in children with asthma: a rare

induced dyspnea in the young. Larynx as

but relevant comorbidity. Eur Respir J; 41:

the bottleneck of the airways. Respir Med;

1068-1073.

103: 1911-1918.

Del Giacco SR, et al. (2012). Allergy and

Scheett TP, et al. (2002). The effect of

sports in children. Pediatr Allergy Immunol;

endurance-type exercise training on

23: 11-20.

growth mediators and inflammatory

Eijkemans M, et al.

(2012). Physical

cytokines in pre-pubertal and early

activity and asthma: a systematic review

and meta-analysis. PLoS One; 7: e50775.

pubertal males. Pediatr Res;

52:

491-

497.

Fanelli A, et al. (2007). Exercise training

on disease control and quality of life in

Stanghelle JK, et al. (1992). . Eight-year

follow-up of pulmonary function and

asthmatic children. Med Sci Sports Exerc;

39: 1474-1480.

oxygen uptake during exercise in 16-year-

Lee TH, et al. (1985). Heterogeneity of

old males with cystic fibrosis. Acta

mechanisms in exercise-induced asthma.

Paediatrica; 81: 527-531.

Thorax; 40: 481-487.

Strunk RC, et al. (1989). Cardiovascular

Lodrup Carlsen KC, et al. (2006). Asthma

fitness in children with asthma correlates

in every fifth child in Oslo, Norway: a 10-

with psychologic functioning of the child.

year follow up of a birth cohort study.

Pediatrics; 84: 460-464.

Allergy; 61: 454-460.

Vahlkvist S, et al. (2010). Effect of asthma

Maat RC, et al. (2007). Surgical treatment

treatment on fitness, daily activity and

of exercise-induced laryngeal dysfunction.

body composition in children with

Eur Arch Otorhinolaryngol; 264: 401-407.

asthma. Allergy; 65: 1464-1471.

Moreira A, et al. (2008). Physical training

Varjonen E, et al. (1997). Life-threatening,

does not increase allergic inflammation

recurrent anaphylaxis caused by allergy to

in asthmatic children. Eur Respir J;

32:

gliadin and exercise. Clin Exp Allergy; 27:

1570-1575.

162-166.

ERS Handbook: Paediatric Respiratory Medicine

Static and dynamic lung

volumes

Oliver Fuchs

This section begins with a short review on

measured with ‘‘slow’’ breathing

static and dynamic lung volumes. Then,

manoeuvres: tidal volume (VT), inspiratory

physiological principles underlying forced

reserve volume (IRV), expiratory reserve

expiration and especially flow limitation will

volume (ERV), inspiratory capacity (IC), and

be highlighted. Lastly, the reader will be

vital capacity (VC), the latter being the

introduced to the field of lung function, and

volume exhaled from full inspiration to full

relevant literature in relation to current

expiration, or inhaled from full expiration to

guidelines for those measurements in

full inspiration. This explains the limitations

children as well as normative data will be

especially of a VC manoeuvre in unco-

pointed out.

operative subjects, particularly during early

childhood and preschool age.

Static lung volumes

Using additional techniques such as body

Lung volumes that are not affected by air

plethysmography and gas dilution

flow are termed static lung volumes and

techniques, it is also possible to measure

consist of specific volumes and capacities

the residual volume (RV), which is

(sums of specific volumes). All static

important for maintaining continuous gas

volumes are age-dependent and increase

exchange during profound expiration. It

with age during childhood. In contrast to a

cannot be exhaled and has thus to be

forced expiration (see later), the following

measured indirectly. With these

static lung volumes can be directly

measurements, it is also possible to

calculate the TLC and the functional residual

capacity (FRC). The FRC is the volume of air

Key points

in the lung after a normal expiration during

tidal breathing. It is dependent on standing

Lung volumes that are not affected by

height, age, posture, compliance and tone of

air flow are termed static lung

the diaphragm and represents the volume at

volumes and consist of volumes and

which the elastic recoil pressures of the lung

capacities (sum of specific volumes).

and of the chest wall are in balance. Static

lung volumes that can be measured either

N The total lung capacity and the

directly or indirectly as well as capacities

functional residual capacity include a

are displayed in the table 1 and figure 1

volume of gas that cannot be exhaled

together with their respective

(residual volume) and which is

important for maintaining continuous

acronyms.

gas exchange during profound

Dynamic lung volumes

expiration.

Lung volumes that are affected by air flow,

N Lung volumes that are affected by air

are termed dynamic lung volumes and they

flow are termed dynamic lung

are measured during spirometry with a

volumes and are measured during

forced expiration. Dynamic lung volumes, as

forced expiration.

well as expiratory flows that can be

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Static lung volumes

Parameter

Acronym

Explanation

Volumes

Tidal volume

Normal volume of air moved between in- and

expiration during quiet tidal breathing when no

additional effort is applied

Inspiratory

IRV

Volume of air that can additionally be inhaled in

reserve volume

maximal inspiration

Expiratory

ERV

Volume of air that can additionally be exhaled in

reserve volume

maximal expiration

Residual volume

Volume of air that remains in the lung after

maximal expiration

Capacities:

Functional

FRC

RV + ERV: volume of air that remains in the lung

sums of

residual capacity

after normal expiration during quiet tidal

volumes

breathing when no additional effort is applied

Inspiratory

VT + IRV: volume of air that can be inhaled in

capacity

maximal inspiration

Vital capacity

ERV + VT + IRV: volume of air moved between

combined maximal in- and expiration

Total lung

TLC

RV + ERV + VT + IRV: maximal total volume of air

capacity

in the lung including volume of air moved

between combined maximal in- and expiration

and volume of air that remains in the lung after

maximal expiration

Volumes

Capacities

IRV

Inspiration

TLC

ERV

Expiration

FRC

Time

Figure 1. Spirogram with lung volumes (left) and capacities (right) and with expiratory (left) and

inspiratory (right) vital capacity manoeuvres.

ERS Handbook: Paediatric Respiratory Medicine

measured during spirometry, are displayed

needs to be familiar with the mechanics of

in table 2 and figures 2 and 3 together with

the airways and also with respiratory

their respective acronyms. Forced expiration

mechanics, as well as the physiological

rarely occurs under physiological conditions

principles underlying forced expiration in

in everyday life, and it requires collaboration

spirometry.

with inhalation to TLC and then exhalation

down to the RV, both as long and as quickly

As described elsewhere in this Handbook,

as possible, thus provoking flow limitation

the airways are interconnected by sur-

without any further effort dependence. This

rounding lung tissue leading to pulmonary

measurement displays limitations in non-

tethering. During inspiration, the lung

cooperative subjects, which is why a forced

expands and the airway calibres increase

expiratory manoeuvre is usually possible

due to this tissue network. During

only from late preschool age onward. In

expiration, the lung deflates and the airway

order to better understand the performance

diameter decreases concurrently, reflecting

of such a manoeuvre, and its results, one

breathing-dependent changes in airway

Table 2. Dynamic lung volumes and expiratory flows that can be measured during spirometry

Parameter

Acronym

Explanation

Volumes

Forced vital capacity

FVC

Volume of air that can be exhaled during

forced expiration after maximal

inspiration to TLC

Forced expiratory

FEV1

Volume of air that can be exhaled during

volume in 1 s

1 s in forced expiration after maximal

inspiration to TLC

Forced expiratory

FEVx

Volume of air that can be exhaled during

volume in x second(s)

x second(s) in forced expiration after

maximal inspiration to TLC. Preschool

children may not be able to expire for

1 s. Here, FEV0.5 or FEV0.75 are useful

parameters.

Tiffeneau index

FEV1/FVC

Ratio of volume of air that can be

exhaled during 1 s in forced expiration

after maximal inspiration to TLC over

total volume of air that can be exhaled

during forced expiration after maximal

inspiration to TLC.

Flows

Peak expiratory flow

PEF

Maximal expiratory flow during forced

expiration

Forced expiratory flow

FEFx

Maximal expiratory flow at 75%, 50% or

at x% of FVC (already

(FEF75, FEF50,

25% of FVC already exhaled, primarily

exhaled)

FEF25)

used in English language

Maximal expiratory

MEFx

Maximal expiratory flow at 25%, 50% or

flow at x% of FVC (to

(MEF75, MEF50,

75% of FVC to be exhaled, primarily used

be exhaled)

MEF25)

in German language

Maximal midexpiratory

MMEF or

Maximal mean expiratory flow between

flow

FEF25-75 or

25% and 75% of FVC expired (FEF25-75)

MEF25-75

or, equally, 75% and 25% of FVC to be

expired (MEF25-75), is highly correlated

with, but not equal to, FEF50 or MEF50,

respectively

ERS Handbook: Paediatric Respiratory Medicine

Volume

1 s

TLC

FEV1

Time

Figure 2. Volume-time relationship during forced expiration. The solid line represents measurement in a

healthy subject; the broken line represents measurement in a subject with obstruction and a lower value of

FEV1.

resistance. Thus, the airways do not

The consequent driving force of expiratory

resemble a system of rigid, but - still an

flow (the resulting pressure drop from the

oversimplification - of compliant and

alveoli along the airways to the airway

moreover also compressible tubes building

opening) the transairway pressure (Pta) can

up resistance to air flow. This air flow results

be calculated as:

from a pressure difference between the ends

Pta 5 Palv - Pm

(1)

of the tube system, the airway opening

(mouth), usually the barometric pressure

where Palv is the sum of pure static (volume

(Pm) and the pressure in the alveoli (Palv),

dependent) pressure made up by elastic

with the latter being below Pm during

recoil (Pst) and of the additional positive

inspiration and above Pm during expiration.

pressure in the pleural space (Ppl)

While expiration during quiet tidal breathing

usually happens passively, this is not the

Palv 5 Pst + Ppl

(2)

case during forced expiration which is

This results in expiratory flow (V9) which can

additionally supported by active muscular

be calculated as:

contraction. Active expiration results in a

reduced transversal and sagittal diameter of

V9 5 Pta / RAW 5 [(Pst + Ppl) - Pm] / RAW (3)

the thorax (due to activity of the internal

intercostal muscles), elevation of the

Hence, any change in V9 is dependent on

diaphragm and, as the main contributor of

both resulting pressure Pta and resulting

the expiratory driving force, increased

resistance RAW. By measuring flow during

intraabdominal pressure (activity of rectus

spirometry, one cannot know whether any

abdominis, transversus abdominis and

change in flow is due to a change in

external as well as internal oblique muscles).

pressure or in resistance. Under the

ERS Handbook: Paediatric Respiratory Medicine

Flow

PEF

Expiration

FEF25 = MEF75

FEF50 = MEF50

FEF75 = MEF25

Volume

FVC

Inspiration

Figure 3. Flow-volume loops before and during forced expiration. Flow-volume loops during inspiration

(below) and expiration (above) before (dotted line, light grey) and during forced expiration. The solid line

represents measurement in a healthy subject and the broken line represents measurement in a subject with

obstruction.

point in the airway tree where intrabronchial

condition of flow limitation with maximal

and extrabronchial pressures are equal, i.e.

muscular activity, however, flow is

where Pintrabronch5Ppl. This point is termed

independent of any further increase in

the equal pressure point (EPP). According to

driving force and thus representative of

equation (4), the pressure drop along the

airway calibre. The following section depicts

airway equals Pst at the site of EPP, with Pst

why this is the case during forced expiration.

- as highlighted above - being volume-

Dynamic airway compression As highlighted

dependent. This has an important

above, inhaling deeply and then exhaling

implication. During expiration, lung volume

with maximum effort increases Ppl and Palv

decreases and consequently so does Pst.

well above Pm, thus creating the driving

Hence, the EPP will be closer to the alveoli

force for airflow in forced expiration. The

with small lung volumes (e.g. towards the

positive Ppl results in pressure on the whole

end of expiration) as compared to the start

lung tissue and importantly, also on airways.

of forced expiration, where it is located near

Accordingly, not only Palv but also pressure

the upper thoracic aperture. One can

in the airway lumen (Pintrabronch) increase as

imagine the EPP entering the trachea during

a result of Pst and positive Ppl.

expiration and then splitting up into several

EPPs in segmental, more compliant bronchi

Pintrabronch 5 Pst + Ppl

(4)

making up an EPP wave front.

Pintrabronch slowly decreases from the alveoli

The movement of the EPP during forced

(5Palv) towards the airway opening (5Pm).

expiration is the reason why this airway

Under the condition of maximum forced

compression is called dynamic. Upstream of

expiration and flow limitation, there will be a

the EPP, towards the alveoli, airways are not

ERS Handbook: Paediatric Respiratory Medicine

compressed as Pintrabronch . Ppl.

than Ppl at this position before reaching the

Downstream, however, there will be airway

above anatomical impediment. This results

compression, creating a check valve, the

in airway closure and increased residual

flow through which is effort-independent.

volume resembling hyperinflation.

Why is this so? If one pictures the airway as

Measurement of static and dynamic lung

a compressible tube, airway compression

volumes

results in an increased resistance to flow.

Likewise, the intraluminal gas pressure

As highlighted above, the static lung

upstream of the compressed airway is

volumes VT, IRV, ERV, IC, and VC can be

increased. Despite this, the speed of air

directly measured during spirometry, while

through this airway segment can never

others (RV, FRC and TLC) require body

exceed the velocity by which a pressure wave

plethysmography or gas dilution techniques

propagates through the wall of this airway

such as multiple-breath washouts (MBW).

segment (this is called wave-speed

Importantly, body plethysmography and

limitation). This is alike to a loud sound

MBW do not measure exactly the same. In

which cannot travel any faster than a quiet

short, body plethysmography is a measure

sound, the speed of both being limited to

of compressibility of thoracic gas volume

that of sound in air.

based on Boyle’s law. The measured volume

includes non- or poorly ventilated lung

Limiting maximum expiratory flow in

regions. This in contrast to the

addition to increased airway resistance,

measurement of FRC by MBW (FRC-MBW),

airway compression at the site of the check

which reflects a volume that communicates

valve depends on several factors: airway wall

with larger airways. FRC-MBW can be

thickness and tone of bronchial muscles.

computed by either mass spectrometry or

This has important implications. More

devices based on ultrasonic flow meters

compliant airways will give rise to lower flow

which are also able to measure molar mass

rates than stiffer airways in the case of

of gas. Here, FRC-MBW is calculated on the

airway compression. Consequently,

basis of conservation of mass. This means

maximum expiratory flow is smaller at low

that any amount of gas within the lung may

than at high lung volume, explaining the

be computed after measuring the con-

descending portion of the flow-volume

centration of this gas in expired air as well as

curve during forced expiration. Moreover, in

the total volume of expired air if one washes

the case of both abnormally compliant

this gas out of the lung, such as by inhaling

airways (e.g. in the case of bronchomalacia)

pure oxygen to measure washout of

and of airways with increased resistance

nitrogen. With MBW it is also possible to

such as in asthmatic airway obstruction, the

calculate parameters that allow assessment

EPP and the site of airway compression will

of ventilation homogeneity, such as the lung

be located more downstream (towards the

clearance index (LCI), which is important in

larger airways). In a healthy subject, all these

small airway diseases such as CF but also in

EPPs can be pictured at the same relative

asthma.

position at the same time and the same

airway generation. In case of airway

Detailing all the guidelines for lung function

obstruction, however, the EPP front

measurements in children would be clearly

becomes inhomogeneous, the EPPs attain

beyond the scope of this chapter.

different relative positions and the flow-

Measurements during quiet tidal breathing

volume curve becomes concave instead of a

are possible even in infants, and if sedation

straight downward line (fig. 3). The end of

is used also in toddlers. Due to lack of

the forced expiratory manoeuvre results

cooperation, early childhood may impose

from the thoracic structure itself, which

difficulties for any lung function

imposes an insurmountable impediment to

measurements. From preschool age on,

any further expiration, resulting in the RV. In

measurements during tidal breathing and

case of airway obstruction with a more

especially those requiring either forced

downstream EPP, Pintrabronch will be smaller

expiration or a VC manoeuvre are once again

ERS Handbook: Paediatric Respiratory Medicine

feasible, especially in experienced

Hammer J, et al., eds (2005). Paediatric

paediatric centres. For guidelines and

Pulmonary Function Testing. Progr Respir

recommendations as well as peculiarities

Res. Basel, Karger.

of paediatric lung function testing across

Hyatt RE (1983). Expiratory flow limita-

age groups, the interested reader is

tion. J Appl Physiol; 55: 1-7.

referred to the respective chapters in this

Mead J, et al. (1967). Significance of the

Handbook and to the relevant literature.

relationship between lung recoil and

maximum expiratory flow. J Appl Physiol;

For recent advances relating to normative

22: 95-108.

data for spirometry covering large age

Quanjer P, et al.

(2012). Multi-ethnic

ranges and also early childhood, the author

reference values for spirometry for the 3-

would also like to refer to the relevant

95 year age range: the global lung function

literature (Stanojevic et al., 2007; Quanjer

2012 equations. Eur Respir J; 40: 1324-1343.

et al., 2012) as well as to www.

Stanojevic S, et al.

(2007). Reference

growinglungs.org.uk.

ranges for spirometry across all ages: a

new approach. Am J Respir Crit Care Med;

177: 253-260.

Further reading

West JB, ed. Pulmonary Pathophysio-

Dawson SV, et al. (1977). Wave speed

logy.

The Essentials. Philadelphia,

limitation of expiratory flow - a unifying

Lipincott Williams & Wilkins, 2008.

concept. J Appl Physiol; 43: 498-515.

West JB, ed. Respiratory Physiology.

Frey U, et al., eds. Paediatric Lung

The Essentials. Philadelphia, Lippincott

Function. Eur Respir Monogr 2010; 4.

Williams & Wilkins, 2008.

ERS Handbook: Paediatric Respiratory Medicine

Respiratory mechanics

Oliver Fuchs

Breathing is the movement of air along

overcome elastic or static forces and is

pressure differences in the lung and airways.

stored as potential energy. Any force

A simple model of the respiratory tract is

necessary to overcome resistance is lost as

that of a stiff tube (airways) connected in

heat due to friction; its contribution to

series to an elastic balloon (lung). The

physical work is very small.

following formula describes how much

In the healthy subject, expiration happens

pressure (P) is needed for a certain volume

passively along elastic retraction forces.

(V), dependent on the compliance (C), the

During inspiration, however, a negative

resistance (R) related to a certain flow (V9),

intrapleural (Ppleur) and secondly intra-

and the acceleration (V99) necessary to

alveolar pressure (PA) is created by

overcome the system’s inertia to changes in

respiratory muscles in relation to the

flow (impedance; I):

surrounding atmospheric pressure (Patm).

PA and Ppleur can be used to calculate the

P 5 V/C + RV9 + IV99

resulting transpulmonary pressure

Respiratory mechanics are determined by

(Ptranspulm):

elastic properties of the respiratory system

Ptranspulm 5 PA - Ppleur

(C), reflecting changes in volume without

any change in flow (static forces). Another

Strain and static properties of the respiratory

factor is represented by non-elastic forces

system change constantly during pulmonary

(RV9), which are dynamic forces due to their

development. During breathing, PA equals

dependency on flow. The third factor,

Patm at the end of inspiration and expiration.

impedance, plays only a minor role. The

For Ppleur, this is only the case during

major part of physical work is necessary to

infancy. Even earlier, i.e. during the first

breaths after birth and then again from

childhood when elastic retraction forces

Key points

increase during growth, Ppleur is always

negative in relation to Patm both during

Respiratory mechanics are helpful in

inspiration and expiration.

understanding the cyclic changes in

airflow due to pressure differences

Elastic properties of the respiratory system:

during breathing and the influence of

compliance

elastic (compliance) and dynamic

Elastic properties of thorax and lungs act in

properties of the respiratory system

opposite directions. While the thorax is

(resistance).

predisposed to expand due to its structure,

Both compliance and resistance are

lungs tend to collapse because of their

volume dependent and display

content of elastic fibres and surface tension

influence of age due to growth and

at the alveolar gas-water interface.

development from infancy throughout

Adhesion forces in the pleural space, which

childhood to adulthood.

make the lung tissue follow any change in

thoracic diameter during inspiration and

ERS Handbook: Paediatric Respiratory Medicine

expiration, prevent lung collapse. Pulmonary

Depending on where pressure changes are

tethering transmits these forces throughout

measured at zero flow at the end of

the lung tissue; pressure differences (PA-

inspiration and expiration, it is possible to

Patm) are built up and enable airflow

calculate CCW (Ppleur-Patm), CL

towards alveoli.

(PA-Ppleur5Ptranspulm) or CRS (PA-Patm).

Ppleur and its relative changes are measured

Law of Laplace, alveolar gas-water phases and

using an oesophageal pressure probe.

surfactant Alveolar physical properties can

be compared to those of soap bubbles.

Compliance is volume dependent There is a

Surface tension minimises the area between

direct relationship between compliance and

the gas-water phases. Resulting forces

the ratio of volume over pressure gradients.

follow the law of Laplace, describing the

Accordingly, compliance is volume

pressure (P) in relation to surface tension

dependent, visualised in a pressure-volume

(T) and radius (r):

curve (fig. 1). The pressure-volume curve

for CRS has a characteristic S-shape with

P 5 2T/r

inflection points. The slope reflects CRS,

which is largest in the steep middle part of

The higher the surface tension and the

the curve. Thus, the physical work needed

smaller the radius, the higher the resulting

for inflation during inspiration is lowest in

pressure and the more probable alveolar

this range. Beyond inflection points physical

collapse is. Surfactant (surface active agent)

work is increasing and respiration becomes

reduces surface tension directly proportional

less efficacious. The lower part of the curve

to its alveolar concentration. Thus, reducing

results from closure of smaller airways and

surface tension becomes more efficacious in

alveoli below a specific lung volume, the so-

case of smaller radii and concomitant

called closing volume. The upper part

increases in concentration, the opposite

results from exhaustion of elastic properties

being the case during pulmonary

in the lung structure due to distension of

hyperinflation. As a net effect, alveolar

elastic fibres, thorax and alveolar septa.

radius is stabilised and the coexistence of

Thus, mechanical ventilation beyond the

neighbouring smaller and larger alveoli is

upper inflection point may carry the risk of

possible. Without surfactant, smaller alveoli

volutrauma or barotrauma. As the

would collapse and empty into larger alveoli

compliance is volume dependent, its value

in direct contact.

is standardised by relating it to a certain

lung volume, usually the functional residual

Compliance measurement Compliance is a

capacity (FRC), resulting in the specific

measure for elastic properties of the

compliance. Interestingly, volume decreases

respiratory system; it describes how much

less in relation to pressure during expiration

change in pressure (DP) is necessary for a

than inspiration. The pressure-volume

specific change in volume (DV). Its

curves for inspiration and expiration are not

reciprocal counterpart is the elastance (E),

identical, which is known as hysteresis. This

describing how much change in volume is

is possibly due to reorganisation of

necessary for a specific change in pressure.

surfactant molecules during expiration with

C [L?kPa^-1 or cmH₂O] 5 DV/DP 5 1/E

complex folding processes, the creation of

several surfactant layers and perhaps even

The compliance of the whole respiratory

partitioning into different surfactant sub-

system (CRS) is made up by the compliance

compartments.

of the thoracic wall (Ccw) and that of the

Influence of age on CL, CCW and CRS FRC

lung (CL). These add up like electrical

reflects the intrapulmonary volume at which

resistances connected in series, hence, by

elastic properties of both CCW and CL equal

the addition of their reciprocal units

each other. Here, tendencies towards

(individual elastance values):

expansion and collapse are in balance.

1/CRS [kPa or cmH₂O/L] 5 1/CCW + 1/CL

Generally, this is the case for a higher FRC in

ERS Handbook: Paediatric Respiratory Medicine

100

Upper

inflection point

●

Throracic wall

tendency

to expand = 0

∆V

∆P

Resting

breathing

FRC

position

●

Lower

inflection point

–20

-10

+10

+20

+30

Pressure cmH₂O

Figure 1. Inspiratory pressure-volume curves for CCW, CL and CRS. The dashed lines represent CCW

(thoracic wall) and CL (lung). The solid line represents CRS (whole respiratory system, i.e. lung and

thoracic wall). The different states of the respiratory system and resulting forces are shown on the left of

the graph (red arrows). VC: vital capacity; RV: residual volume; DP: pressure gradient, DV: volume

gradient.

older children and in adults than it is for

regard to their tendency for airway collapse

newborns or toddlers. In addition to

below the closing volume which is,

surfactant, elastic properties of the

therefore, itself age-dependent. This is also

pulmonary system also depend on lung

the reason for the higher amount of

structure, especially elastic fibres. Owing to

functional shunts early in life and the

ageing, elastic retraction forces increase

increasing incidence of shunts among older

from birth through adolescence, but then

people. In order to circumvent airway

decrease again. Thus, in both newborns and

collapse in dependent lung areas the

in older people, FRC can be below the

newborn has several mechanisms available

closing volume. Accordingly, the newborn

to dynamically upregulate FRC, leading to

and the aged lung are very similar with

either a shorter duration of expiration or to a

ERS Handbook: Paediatric Respiratory Medicine

decrease in expiratory flow (expiratory

(Pao) over airflow, which is itself measured

braking).

at airway opening (V9):

N Increasing the respiratory rate reduces

RRS [kPa?L?s^-1] 5 (PA - Pao)/V9

the time for passive expiration (tE) in

comparison to the duration of active

RRS can be subdivided into the resistance of

inspiration (tI).

the airways (RAW) and the resistance due to

friction between chest and lung tissue.

N During expiration, vocal cords are either

Resistance due to friction is only minor

actively moved towards each other

compared to RAW, which itself accounts for

(adduction) or there is a loss of laryngeal

approximately 90% of RRS.

abductor activity, thus, resistance

increases on the vocal cord level. Due to

RAW is influenced by both airway diameter

reduced expiratory flow, lung emptying is

and fluid flow behaviour of air. Depending

slowed down. While this is noiseless in

on airway generation and pathological

the healthy newborn, it may become

conditions, such as airway obstruction,

audible in the sick infant as expiratory

airways may demonstrate different shares of

grunting.

laminar and turbulent flow. The Hagen-

N During expiration, the activity of

Poiseuille equation describes laminar flow.

respiratory muscles is adapted in such a

According to this equation, airway resistance

way that passive expiration is decelerated

is proportional to airway length (l) and

or even terminated through tonic

dynamic gas viscosity (g) and inversely

muscular activity of the diaphragm. In

proportional to the fourth power of the

addition, inspiration starts earlier than in

airway radius (r) and p:

older children or adults.

R [kPa?L?s^-1] 5 8lg/r⁴p

Dynamic upregulation of FRC lasts

approximately until the end of the first year

Under the condition of turbulent flow,

of life, when elastic retraction forces of the

movement of gas molecules seems more

thoracic skeleton increase due to

random and mathematically describing this

progressing ossification, i.e. when CCW

state is more complex. In case of turbulent

slowly decreases. At the end of the second

flow, resistance increases with flow rate and

year of life CL equals CCW in resting

is proportional to gas density and viscosity

expiratory position without any necessary

but inversely related to the fifth power of the

regulatory measures. CRS changes

airway radius. Pressure differences are thus

predominantly due to increasing numbers of

much higher than with laminar flow. The

alveoli during childhood, further influenced

Reynolds number (Re) helps to predict when

by the development of upright walking.

laminar flow changes into a turbulent one.

This is again dependent on gas density (r)

Dynamic properties of the respiratory

and dynamic gas viscosity (g), as well as

system: resistance

airway length (l) but also flow (V9).

Respiratory mechanics are not only

influenced by elastic properties of the

Re 5 V9Lr/g

respiratory system but also by its dynamic

Above a critical value of Re (.1500) laminar

properties, which are by definition

flow passes on to turbulent flow. Pure

dependent on flow. These non-elastic,

laminar flow can be found for smaller Re of

viscous resistances are made up by airway

,1000, usually in small peripheral airways,

resistance to flow, non-elastic tissue

while flow in larger airways is predominantly

resistance and resistance due to inertia.

turbulent. Airway branching and bending, as

Resistance of the whole respiratory system In

well as abrupt changes in airway diameter,

analogy to Ohm’s law, the resistance of the

as in the case of airway obstruction, play a

whole respiratory system (RRS) is defined as

role. Hence, peripheral airways only account

the ratio of difference between pressure in

for ,10-20% of RRS despite their total share

alveoli (PA) and pressure at airway opening

in airway diameter, of ,95%. The biggest

ERS Handbook: Paediatric Respiratory Medicine

portion of RRS results from airway resistance

secondary to turbulent flow in larger, more

central airways.

Time constant of the whole respiratory system

Airways and lung tissue are considered

separately regarding their influence on

respiratory mechanics. This is an

oversimplification as they are both

interdependent on each other. The time

constant (t) of the respiratory system is a

parameter taking both into consideration. In

general, t describes the duration during

which an exponential process decreases to

FRC

TLC

1/e (Euler’s constant; e), i.e. ,36.8% of the

Lung volume

default value. In case of the respiratory tract,

t is defined by the product of CRS and RRS

Figure 2. Volume dependency of resistance and

and represents the time in seconds that is

conductance; pulmonary tethering. The boxes

needed for the respiratory system to expire

represent elastic fibres stabilising airway diameter

63.2% of the lung volume in air due to

in relation to lung volume (tethering). The solid

passive retraction forces. For a full

line represents resistance, and the dashed line

expiration, the respiratory system will need

represents conductance in relation to lung volume.

approximately three to five time constants.

Any decrease in RRS is associated with an

increase in CRS and vice versa.

higher (C2-C3) in newborns and infants than

Resistance is volume dependent Due to

in adults (C3-C6), favouring breathing

pulmonary tethering and resulting elastic

through the nose and making simultaneous

retraction forces that stabilise airway

breathing and drinking possible. Accordingly,

diameter, as well as concurrent bronchiolar

due to the laryngeal anatomy breathing

distension during deep inspiration, resistance

through the mouth is rather disadvantageous

is also volume dependent. In contrast, radial

early in life. This explains the significant

tension is decreased with lower lung volumes

nuisance of infants and, to the lesser extent,

(fig 2). This volume dependency is taken into

of toddlers in case of upper airway infections

account when calculating the specific

with nasal obstruction.

resistance and specific conductance (inverse

Resistance of the lower airways

of resistance) by relating both values to the

FRC. Below FRC there is a steep increase in

In contrast to their small individual

resistance. There is a hyperbolic relationship

diameter, the total share of the small

between resistance and lung volume, on one

peripheral airways is high in relation to that

hand, and a linear relationship of the

of other airways. In older children and

conductance (inverse of resistance) and lung

adults, the portion of RRS formed by small

volume, on the other hand (fig. 2).

airways is, nevertheless, 10-20%.

Consequently, measuring resistance is not

Resistance of the upper airways

very sensitive with regards to quantifying

In infants, the nasopharyngeal space can

obstruction of small airways in these

account for up to 40% of RRS, and in adults

subjects. In infants, however, small

up to 60%. The larynx is the narrowest part of

peripheral airways may account for up to

the upper airways; in infants and toddlers this

50% of RRS. Thus, as with nasal

is due to the anatomy of the cricoid, owing to

obstructions, even minor peripheral airway

growth it is the glottis in older children and in

obstructions may be associated with

adults. Before it descends during growth, the

significant impairment in this age group.

larynx is initially located further forward and

Furthermore, in dyspnoeic infants airways

ERS Handbook: Paediatric Respiratory Medicine

are more prone to collapse due to their

Hughes GM, et al.

(1978). Static

relatively high compliance during forced

pressure-volume curves for the lung of

inspiration and due to increased transmural

the frog

(Rana pipiens). J Exp Biol;

76:

pressure in the case of crying. This is the

149-165.

Lucangelo U, et al.

(2007). Lung

reason why measures of calming down

mechanics at the bedside: make it

agitated infants or even the use of sedatives

simple. Curr Opin Crit Care; 13: 64-72.

may help to reduce resistance and thus to

Mansell A, et al. (1972). Airway closure in

improve the clinical status.

children. J Appl Physiol; 33: 711-714.

West JB, ed. Pulmonary Pathophysiology.

The Essentials. Philadelphia, Lipincott

Further reading

Williams & Wilkins, 2008.

Agostoni E (1959). Volume-pressure rela-

West JB, ed. Respiratory Physiology. The

tionships of the thorax and lung in the

Essentials.

Philadelphia,

Lippincott

newborn. J Appl Physiol; 14: 909-913.

Williams & Wilkins, 2008.

ERS Handbook: Paediatric Respiratory Medicine

Reversibility, bronchial

provocation testing and

exercise testing

Kai-Ha˚ kon Carlsen

The variability in bronchial smooth muscle

tone is an important characteristic of

Key points

bronchial asthma and is probably related to

the presence of airway inflammation. As

Bronchodilator reversibility

early as 1859, Sir Henry Hyde Salter

demonstrates reversible bronchial

described ‘‘bronchial sensibility’’ in patients

obstruction and is a diagnostic

with asthma. This variability in bronchial

marker of active asthma.

smooth muscle tone may go in two

Bronchial challenge with

directions:

methacholine/histamine is a sensitive

N towards exaggerated bronchodilation

measure of asthma, but is not so

upon a bronchodilator stimulus, also

specific.

called bronchodilator reversibility; or

Indirect measures of bronchial

N towards increased bronchial constriction

responsiveness (exercise, inhaled

and obstruction after exposure to a

adenosine monophosphate,

bronchoconstrictor stimulus, often called

hypertonic saline and mannitol, and

bronchial hyperresponsiveness (BHR).

EVH) are specific, but not sensitive,

This variability in bronchial tone is assessed

measures of asthma.

both in diagnosis and in monitoring of

Indirect measures of bronchial

asthma.

responsiveness (exercise, etc.)

Reversibility: bronchodilator responsiveness

respond rapidly (over 1-3 weeks) to

inhaled steroids.

The reversibility to bronchodilator drugs is

Direct measures of bronchial

usually measured in a standardised way by

responsiveness (methacholine and

first measuring lung function, usually FEV1_,

histamine) respond slowly to inhaled

then inhaling a bronchodilator drug and

steroids (over 3 months).

then again measuring FEV1 after a suitable

time, enabling the bronchodilator drug to

Direct measures of bronchial

have an effect upon bronchial smooth

responsiveness (methacholine and

muscle. In addition, other measures of lung

histamine) are presently the

function may be used. The procedure has

most exact monitoring tool for

been standardised by a joint Task Force of

asthma and reflect airway

European Respiratory Society (ERS) and

remodelling.

American Thoracic Society (ATS), and an

Indirect measures of bronchial

increase in FEV1 of 12% or o200 mL after

responsiveness reflect airway

inhaled bronchodilator has been selected as

inflammation.

a significant increase in lung function and as

a criterion for a positive reversibility test

BHR in childhood may predict later

(Pellegrino et al., 2005). Either salbutamol

asthma.

or another bronchodilator, such as

ipratropium bromide, may be used. Inhaled

ERS Handbook: Paediatric Respiratory Medicine

salbutamol at a dose of 100 mg given four

Baseline lung function

times from a metered-dose inhaler through

15 mins after salbutamol

▲

Predicted lung function

a suitable inhalation chamber with a

mouthpiece is the recommended dose in

adults and in children/adolescents from

▲

12 years; in younger children, half the dose

should be used. Alternatively, ipratropium

bromide 160 mg (4640 mg) may be used. If

▲

preferred, inhalation may be given by

nebuliser or powder inhaler but it is

important to know the delivery of drug from

▲

the device in order to ascertain that

▲

sufficient drug has reached the patient. Lung

Volume L

function is measured 15 min after

salbutamol inhalation or 30 min after

ipratropium bromide inhalation (Pellegrino

et al., 2005). In order to assess the full

reversibility, the patient should not be under

the influence of any other bronchodilator.

The following recommendations are given

Figure 1. Lung function in a 13-year-old boy

by the ERS/ATS Task Force (Miller et al.,

showing maximal flow-volume loops before and

2005). Short-acting inhaled drugs, such as

after inhalation of nebulised salbutamol

the b₂-agonist salbutamol or the

(5 mg?mL^-1, 0.5 mL in 2 mL isotonic saline

anticholinergic agent ipratropium bromide,

nebulised by a CR 60 nebuliser). Baseline FEV1

should be withheld for o4 h; long-acting b₂-

was 2.09 L?s^-1 (66% predicted); 15 min after

agonists (salmeterol and formoterol), and

inhalation of salbutamol, it had risen to 2.46 L?s^-1

oral therapy with aminophylline and slow

(78% predicted), presenting an increase of 18%

release b₂-agonists should be withheld for

and demonstrating a positive reversibility test. The

12 h prior to the test. It is also recommended

baseline lung function test was performed without

that smoking should be avoided for o1 h

the influence of any bronchodilator.

before the procedure.

Figure 1 shows lung function from a 13-year-

persistently reduced FEV1 may possibly

old boy as maximal flow-volume curves

indicate the presence of airway remodelling

before and 15 min after inhalation of

(Goleva et al., 2007).

salbutamol.

In addition, in preschool children,

In the Childhood Asthma Management

assessment of reversibility has been made

Program (CAMP) study, the consistent

by assessment of airway resistance by use of

presence of a positive bronchodilator

the interrupter technique (Rint), setting the

response over a 4-year period in asthmatic

limit for a positive response to a decrease in

children was associated with persistently

Rint at 32% of baseline or a decrease in Z-

lower baseline FEV1 values as well as a lack

score of 1.25 (Mele et al., 2010), as well as

of use of inhaled steroids, thus

using tidal breathing parameters (time taken

demonstrating the usefulness of

to achieve peak tidal expiratory flow (tPTEF)/

bronchodilator reversibility in the

expiratory time (tE) ratio), which was found

monitoring of childhood asthma (Sharma et

to discriminate between children with

al., 2008). In severe, steroid-resistant

asthma and healthy children. An increase in

asthma, FEV1 was persistently reduced

tPTEF/tE of at least two standard deviations

together with a reduced bronchodilator

of intrasubject variation was used as a

response in spite of therapeutic trials with

criterion for a positive response to

prednisolone. The combination of a lack of

bronchodilator, and a highly significant

bronchodilator response in the presence of

correlation between reversibility and a

ERS Handbook: Paediatric Respiratory Medicine

marker of eosinophil inflammation, serum

reduction in lung function, is brought about

eosinophil cationic protein, was reported

indirectly through an effect of mediator

(Lødrup Carlsen et al., 1995). Other lung

release.

function techniques have also been used to

Methods of measuring bronchial

assess reversibility to bronchodilators in

responsiveness

preschool children, such as the forced

oscillation technique. A change of 32% (and

Originally, direct bronchial responsiveness

z-score change of -1.85) from baseline values

was measured qualitatively through a BPT by

has been suggested as a significant relative

inhaling the test substance in 10-fold

bronchodilator response for the resistance

increasing concentrations (Aas, 1970),

of the respiratory system (Rrs) at 8 Hz

whereas during the last 25 years, quantitative

(Calogero et al., 2013). None of these

assessment has been performed by

techniques require sedation of the child.

doubling the concentration/dose of the test

Classification of BHR

substance (Cockcroft et al., 1977a).

Bronchial responsiveness, which reflects the

Figure 2 shows the dose-response curve

variability in bronchial tone in asthma, may

obtained in a BPT, with a reduction in FEV1

be described as subjective, as demonstrated

caused by inhaling doubling concentrations

by the symptoms experienced by the

of methacholine and interpolation to

asthmatic child and adolescent, or objective,

determine provocative concentration

as measured by procedures in the pulmonary

causing a 20% fall in FEV1 (PC20) (Cockcroft

physiological laboratory. BHR is defined as

et al., 1977a). Later, a simplification of the

‘‘an increase in the ease and degree of airflow

test was introduced, inhaling single

limitations in response to bronchoconstrictor

doubling doses of methacholine,

stimuli in vivo’’ (Sterk, 1996).

determining the provocative dose causing a

20% fall in FEV1 (PD20) (Yan et al., 1983).

The specific bronchial responsiveness, the

bronchial responsiveness to specific inhaled

The test is performed under standardised

allergens, may be measured by the allergen

conditions (Hargreave et al., 1981; Cockcroft

bronchial provocation test (BPT) (Aas, 1970).

et al., 1977b), with specified nebulisation

rates for the tidal breathing method (PC20),

The non-specific BHR may be measured in

inhaling the test agent for 2 min, then

several ways. According to the mechanisms

measuring FEV1, and then inhaling the

of bringing about the bronchial response,

doubled concentration. The test is stopped

the methods can be classified as direct and

when FEV1 is reduced by o20% and the

indirect (Pauwels et al., 1988). Direct

bronchial responsiveness is measured by

bronchial provocation with the transmitter

110

methacholine (Hargreave et al., 1981) or the

mediator histamine (Cockcroft et al., 1977a),

100

acting directly upon the bronchial and

vascular smooth muscle. Examples of

indirect methods of measurement of the

nonspecific BHR are by measuring exercise-

induced bronchoconstriction (EIB) (Jones et

al., 1963) or the reaction brought about by

inhalation of dry cold air (Zach et al., 1987),

hyperventilation caused by dry air

Saline

0.03

0.06

0.125

0.25

(Rosenthal, 1984), or inhalation of other

substances, such as adenosine mono-

Methacholine mg·mL-1

phosphate (AMP) or the hyperosmolar

agent mannitol (Avital et al., 1995; Brannan

Figure 2. Determination of PC20 by interpolation

et al., 2005). The reaction, measured as a

on the logarithmic x-axis.

ERS Handbook: Paediatric Respiratory Medicine

PC20 or PD20 is determined by interpolating

marathon runners) are thought to

on the semilogarithmic dose-response

contribute. Endurance training has

curve (fig. 2).

specifically been demonstrated to increase

parasympathetic tone. Thus, several factors

When determining bronchial responsiveness

probably contribute in the development of

by measuring PD20, the cumulated dose

athletes’ asthma (Carlsen, 2012).

inhaled is determined. An inspiration-

triggered nebuliser is most often used as the

Exercise testing

delivery device, such as the Spira nebuliser

Most guidelines for treating childhood

(Spira Respiratory Care Centre,

asthma have control of EIB as one of their

Hämeenlinna, Finland) (Nieminen et al.,

main aims due to the appreciation of the

1988) or the Aerosol Provocation System

importance for children of being able to

(Jaeger, Würzburg, Germany), enabling

participate in physical activity and play

inhalation by controlled tidal ventilation.

together with their peers.

Alternatively, a handheld DeVilbiss

(Mannheim, Germany) nebuliser has been

Testing for EIB also represents a measure of

used (Yan et al., 1983).

bronchial responsiveness, and is an example

of an indirect test (Pauwels et al., 1988).

Recommendations for the measurements of

Different types of exercise have been

bronchial responsiveness were given by an

standardised for testing EIB: running is

ERS/ATS Task Force (Crapo et al., 2000).

more provocative in children than cycling

(Anderson et al., 1971) and a duration of 6-

Determination of PC20 or PD20 are used

8 min gives a greater decrease in post-

both for BPT with methacholine, histamine

exercise FEV1 than shorter or longer exercise

and AMP, and may be used for allergen BPT.

periods (Godfrey et al., 1975). It is common

A mannitol BPT was recently developed and

to employ a treadmill incline of 5.5% (3u)

launched commercially; it is performed by

with rapidly increasing speed until a steady

inhaling cumulative doses of mannitol

heart rate of approximately 90-95% of the

through a powder inhaler, with a 15%

calculated maximum is reached within the

reduction in FEV1 (PD15) as the cut-off

first 2 min of running and then maintained

(Brannan et al., 2005).

for 4-6 min (Crapo et al., 2000; Carlsen et

Eucapnic voluntary hyperpnoea (EVH) is

al., 2000). In children, heart rate should be

another BPT. In this test, the subject inhales

followed electronically, whereas in adults it

dry air with 4.9% carbon dioxide for 6 min at

should be followed by ECG. The running test

should preferably be performed at room

a preferred ventilation rate of 85% of their

temperature (20-22uC) and a relative

maximal voluntary ventilation (MVV), often

humidity of ,40%. Lung function is

calculated as 306FEV1, but tolerating a

measured before, immediately after, and 3,

ventilation rate down to 65% MVV

6, 10, 15 and 20 min after running. FEV1 is

(226FEV1) (Rosenthal, 1984). A reduction

the most common lung function parameter

in FEV1 o10% is taken as a positive test.

employed, with a 10% fall in FEV1 most

EVH tests have been shown to be

frequently used for diagnosis of EIB.

particularly sensitive for asthmatic athletes,

in particular endurance athletes (Rosenthal,

Sensitivity of the test can be markedly

1984; Stadelmann et al., 2011). Endurance

increased while maintaining specificity by

athletes are particularly prone to developing

adding an extra stimulus to the exercise test,

BHR. This has been suggested to be due

such as running on a treadmill with

primarily to epithelial damage caused by the

inhalation of cold (-20uC) or dry air (Carlsen

frequent high-ventilation periods during

et al., 1998).

training and competition, leading to airway

inflammation and BHR. Environmental

There are several differential diagnoses to

factors (chlorine exposure in swimmers,

exercise-induced asthma (EIA), including

cold air exposure in winter athletes, and

exercise-induced vocal cord dysfunction as

environmental pollution in cyclists and

the most frequent (Landwehr et al., 1996;

ERS Handbook: Paediatric Respiratory Medicine

Refsum et al., 1983). The exercise test may

response after allergen bronchial

help to discriminate between EIB and

provocation increased direct BHR and that

exercise-induced vocal cord dysfunction.

nonspecific BHR increased through

With EIB, the dyspnoea is expiratory and

exposure to seasonal allergens. Thus, a

occurs after exercise with a simultaneous

seasonal allergic sensitisation may

decrease in FEV1, whereas for vocal cord

contribute to a perennial asthma by

dysfunction, the dyspnoea is inspiratory,

increasing the nonspecific BHR through

usually audible and occurs during maximum

seasonal allergen exposure. Clough et al.

exercise intensity. Vocal cord dysfunction is

(1991) reported that the presence of atopy

best diagnosed by continuous laryngoscopy

had an impact both on lung function and

during exercise testing.

BHR in asthmatic 7-8-year-old children.

Safety precautions during bronchial

Respiratory virus infections, particularly

challenges and patient preparations

rhinovirus infections, are the main

environmental factor provoking acute

Bronchial challenges with

asthma during childhood (Carlsen et al.,

bronchoconstrictive agents as well as with

1984; Johnston et al., 1995). Respiratory

indirect measures, like exercise and EVH

virus infections increase bronchial

testing, require that the laboratory has the

responsiveness to histamine in healthy

necessary competence and equipment for

subjects (Empey et al., 1976), asthmatic and

treating severe bronchoconstriction,

atopic individuals (Bardin et al., 1995), and

including the preparedness for treating

animals (Nakazawa et al., 1994).

anaphylaxis. A physician should be present

during testing and equipment for

Air pollution has also been reported to

cardiopulmonary resuscitation immediately

increase BHR (Forastiere et al., 1994a),

available. Whereas progressive

including exposure to diesel exhaust

pharmacological challenge testing with

(Nordenhall et al., 2001), and living in an

interval spirometry gradually builds up a

industrially polluted area during the first

bronchoconstriction, an exercise or EVH test

2 years of life was found to be related to BHR

represents a maximal or near-to maximal

to methacholine at school age (Soyseth et

stimulus for bronchoconstriction, requiring

al., 1995). Although not a consistent finding

special awareness. Preferably, oxygen

(Gehring et al., 2010), assessment of BHR in

saturation should be monitored during

relationship to traffic air pollution has

exercise or EVH testing. FEV1 should be at

shown that children with BHR is particularly

baseline or o75% pred before exercise and

sensitive to traffic-related air pollution

EVH testing.

(Janssen et al., 2003).

The patient should be without the influence

Second-hand smoke is among the most

of bronchodilators during testing unless the

important air pollutants, and an effect upon

exercise test is performed to assess

BHR in children has been reported, although

protection by the bronchodilator. Inhaled

the results are not unequivocal. Forastiere et

corticosteroids should not be used on the

al. (1994b) reported a dose-response

day of the test (Thio et al., 2001).

relationship between the number of

cigarettes smoked by mothers and BHR in

Vigorous exercise should be avoided for 6 h

daughters of school age.

before testing, as exercise may cause a

refractory period for eliciting EIB of up to 4 h

Exercise and physical training have been

(Edmunds et al., 1978; Stearns et al., 1981).

reported to influence bronchial

responsiveness. Short-term intensive

Effect of environmental conditions on BHR

exercise increases direct bronchial

Several environmental conditions influence

responsiveness both in asthmatic and

BHR. Cockcroft and co-workers (1977, 1983)

healthy children (Carlsen et al., 1989).

documented the link with atopy and allergen

Intensive physical endurance training and

exposure by reporting that the late allergic

competition increase bronchial

ERS Handbook: Paediatric Respiratory Medicine

responsiveness in actively training young

population-based birth cohort (Riiser et al.,

skiers (Heir, 1994; Heir et al., 1995a), and a

2012a), but in the same birth cohort, BHR to

combination of respiratory virus infections

methacholine at 10 years of age in children

and heavy training induce an increase in

without asthma was a significant though

bronchial responsiveness for 4-6 weeks

modest predictor of asthma at 16 years of

(Heir et al., 1995b). In addition, adolescent

age (Riiser et al., 2012b), suggesting that

competitive swimmers have very frequent

BHR may develop before active asthma

BHR measured both by methacholine

symptoms appear.

bronchial challenge and EVH (Stadelmann

Diagnostic significance of BHR

et al., 2011). The environment is important

in this regard, as chlorine products affect the

As BHR may be found both in children with

swimming environment and cold air

and without asthma, and asthmatic children

inhalation is an important part of daily

may not demonstrate BHR, measurement of

exposure in winter athletes.

BHR cannot be a conclusive tool for the

diagnosis of asthma. In a study of 500

Thus, several environmental factors may

young university students, Cockcroft et al.

increase BHR in susceptible subjects and

(1992) reported a sensitivity of 100% for

individuals with BHR may be particularly

histamine PC20 f8 mg?mL^-1 for current

sensitive to environmental exposures.

symptomatic asthma, a specificity of 93%, a

Conversely, for asthmatic subjects, staying

negative predictive value of 100% and a

in the mountains, with low allergen exposure

positive predictive value of current

and low air pollution, improves both in

asthmatic symptoms of only 29%. While a

respiratory symptoms and bronchial

PC20 .8 mg?mL^-1 ruled out current asthma,

responsiveness as measured by

a PC20 of 1 mg?mL^-1 was almost diagnostic

methacholine provocation (Peroni et al.,

for current asthma. Studies comparing

1994). Measuring bronchial responsiveness,

direct and indirect measurements of BHR in

either by direct or indirect means, may thus

asthmatic children and children with other

assess the effect of environmental exposure

chronic lung diseases show that direct

upon respiratory health.

measurements by histamine or

Relationship of BHR to respiratory

methacholine challenge are sensitive tools

symptoms and variation with age

to identify asthmatic children, but with a

rather low specificity towards other chronic

Tiffeneau (1955) suggested that BHR was the

lung diseases. However, indirect

most important characteristic of asthma.

measurements by exercise tests or by

Later studies have shown that BHR is not

inhalation of cold, dry air have low sensitivity

obligatory for asthma and that different ways

but high specificity (Godfrey et al., 1991).

of measuring BHR may relate differently to

When combining exercise testing with

asthma severity. Hargreave et al. (1981) found

inhalation of cold, dry air, the sensitivity of

a distinct relationship with asthmatic

the test increases while maintaining a high

symptoms and severity in asthmatic

sensitivity for comparing asthma and other

subjects, whereas Salome et al. (1987), in a

chronic lung disorders (Carlsen et al., 1998).

population-based study, found that a number

A positive diagnosis by an exercise test thus

of asthmatic children did not have BHR and

favours the diagnosis of asthma.

some children with BHR were not asthmatic.

Furthermore, by use of exercise tests in

In addition, children with mild recurrent

children, information about physical skill,

wheeze were found to include children both

fitness and motor development are obtained

with and without BHR (Roizin et al., 1996).

by an experienced observer.

Hopp et al. (1985) reported that bronchial

Effect of therapy on BHR

responsiveness to methacholine varied

markedly throughout the lifespan. Bronchial

Anti-inflammatory therapy by inhaled

responsiveness to methacholine decreased

steroids improves BHR in asthma. This may

significantly from 10 to 16 years of age in a

be assessed by repeated measurements of

ERS Handbook: Paediatric Respiratory Medicine

both direct and indirect BHR. However, it

epidemiological studies as objective

has been demonstrated that inhaled

measures. Tests of BHR are valuable tools,

steroids improve direct and indirect BHR to

particularly in assessing severe asthma, but

a different degree and with different speed.

they cannot replace careful clinical

No effect on BHR was found from a single

examination and assessment of children

dose of inhaled steroid (van Essen-Zandvliet

with asthma.

et al., 1993). However, after 1 week of inhaled

steroids, protection against EIB has already

Further reading

occurred, further increasing over the next

4 weeks (Henriksen et al., 1983). This was

Aas K (1970). Bronchial provocation tests

confirmed by Waalkens et al. (1993), who

in asthma. Arch Dis Child; 45: 221-228.

showed that the effect on EIB reached a

Anderson SD, et al. (1971). Specificity of

plateau effect within 2 months. However,

exercise in exercise-induced asthma. Br

improvement of methacholine PC20 did not

Med J; 4: 814-815.

occur until after 2-3 months of treatment

Avital A, et al. (1995). Adenosine, metha-

with inhaled budesonide, but then

choline, and exercise challenges in chil-

continued throughout a 22-month study by

dren with asthma or paediatric chronic

van Essen-Zandvliet et al. (1993). Thus, the

obstructive pulmonary disease. Thorax;

direct and indirect tests of BHR may reflect

50: 511-516.

different properties of nonspecific bronchial

Bardin PG, et al.

(1995). Increased

sensitivity to the consequences of rhino-

responsiveness in asthmatic children.

viral infection in atopic subjects. Chest;

BPT measurements may thus be used to

107: 157S.

monitor treatment effects in asthma. By

Brannan JD, et al. (2005). The safety and

efficacy of inhaled dry powder mannitol

assessment of airway inflammation and

as a bronchial provocation test for airway

airway remodelling (reticular layer of the

hyperresponsiveness: a phase 3 compar-

epithelial basement membrane) in bronchial

ison study with hypertonic (4.5%) saline.

biopsies, it has been shown that

Respir Res; 6: 144.

methacholine BPT is superior to clinical

Calogero C, et al.

(2013). Respiratory

assessment and lung function

impedance and bronchodilator respon-

measurements in the follow-up of asthma

siveness in healthy children aged

patients (Sont et al., 1999). Based upon the

13 years. Pediatr Pulmonol; 48: 707-715.

rapid response to inhaled steroids and the

Carlsen KH, et al.

(1984). Respiratory

relationship of EIB with markers of airway

virus infections and aeroallergens in

inflammation, the slower response to

acute bronchial asthma. Arch Dis Child;

treatment, and the relationship of

59: 310-315.

methacholine BHR with basement

Carlsen KH, et al. The response to heavy

membrane thickness, it has been stated that

swimming exercise in children with and

EIB reflects airway inflammation, whereas

without bronchial asthma. In: Morehouse

direct bronchial responsiveness to

CA, ed. Children and Exercise XIII.

methacholine reflects airway remodelling.

Champaign, Human Kinetics Publishers,

1989; p. 351-360.

Conclusion

Carlsen KH, et al.

(1998). Cold air

inhalation and exercise-induced broncho-

Measurements of BHR are useful tools in

constriction in relationship to metacho-

assessing the severity of childhood asthma.

line bronchial responsiveness: different

However, the different methods of

patterns in asthmatic children and chil-

assessment differ to a certain extent in their

dren with other chronic lung diseases.

ability to differentiate asthma from other

Respir Med; 92: 308-315.

chronic lung diseases, and they are

Carlsen KH, et al.

(2000). Exercise-

influenced by therapy to a different degree.

induced bronchoconstriction depends

Measurements of BHR have given insight

on exercise load. Respir Med;

94:

into the pathophysiological mechanisms of

750-755.

asthma and they are frequently employed in

ERS Handbook: Paediatric Respiratory Medicine

Carlsen KH

(2012). Sports in extreme

asthma and the effect of varying the

conditions: the impact of exercise in cold

severity and duration of exercise.

temperatures on asthma and bronchial

Pediatrics; 56: 893-898.

hyper-responsiveness in athletes. Br J

Godfrey S, et al. (1991). Exercise but not

Sports Med; 46: 796-769.

metacholine differentiates asthma from

Clough JB, et al. (1991). Effect of atopy on

chronic lung disease in children. Thorax;

the natural history of symptoms, peak

46: 488-492.

expiratory flow, and bronchial responsive-

Goleva E, et al. (2007). Airway remodel-

ness in 7- and 8-year-old children with

ing and lack of bronchodilator response

cough and wheeze. Am Rev Respir Dis;

in steroid-resistant asthma. J Allergy Clin

143: 755-760.

Immunol; 120: 1065-1072.

Cockcroft DW, et al. (1977a). Bronchial

Hargreave FE, et al.

(1981). Bronchial

reactivity to inhaled histamine: a method

responsiveness to histamine or metacho-

and clinical survey. Clin Allergy; 7: 235-243.

line in asthma: measurement and clinical

Cockcroft DW, et al. (1977b). Allergen-

significance. J Allergy Clin Immunol; 68:

induced increase in non-allergic bronchial

347-355.

reactivity. Clin Allergy; 7: 503-513.

Heir T (1994). Longitudinal variations in

Cockcroft DW

(1983). Mechanism of

bronchial responsiveness in cross-coun-

perennial allergic asthma. Lancet;

try skiers and control subjects. Scand J

253-256.

Med Sci Sports; 4: 134-139.

Cockcroft DW, et al. (1992). Sensitivity

Heir T, et al. (1995a). The influence of

and specificity of histamine PC20 deter-

training intensity, airway infections and

mination in a random selection of young

evironmental conditions on seasonal

college students. J Allergy Clin Immunol;

variations in bronchial responsiveness in

89: 23-30.

cross-country skiers. Scand J Med Sci

Crapo RO, et al. (2000). Guidelines for

Sports; 5: 152-159.

methacholine and exercise challenge test-

Heir T, et al. (1995b). Respiratory tract

ing - 1999. This official statement of the

infection and bronchial responsiveness in

American Thoracic Society was adopted

elite athletes and sedentary control sub-

by the ATS Board of Directors, July 1999.

jects. Scand J Med Sci Sports; 5: 94-9.

Am J Respir Crit Care Med; 161: 309-329.

Henriksen JM, et al.

(1983). Effects of

Edmunds AT, et al. (1978). The refractory

inhaled budesonide alone and in combi-

period after exercise-induced asthma: its

nation with low-dose terbutaline in chil-

duration and relation to the severity of

dren with exercise-induced asthma. Am

exercise. Am Rev Respir Dis; 117: 247-254.

Rev Respir Dis; 128: 993-937.

Empey DW, et al. (1976). Mechanisms of

Hopp RJ, et al. (1985). The effect of age

bronchial hyperreactivity in normal sub-

on metacholine response. J Allergy Clin

jects after upper respiratory tract infec-

Immunol; 76: 609-613.

tion. Am Rev Respir Dis; 113: 131-139.

Janssen NA, et al. (2003). The relation-

Forastiere F, et al.

(1994a). Bronchial

ship between air pollution from heavy

responsiveness in children living in areas

traffic and allergic sensitization, bronchial

with different air pollution levels. Arch

hyperresponsiveness, and respiratory

Environ Health; 49: 111-118.

symptoms in Dutch schoolchildren.

Forastiere F, et al.

(1994b). Passive

Environ Health Perspect; 111: 1512-1518.

smoking as a determinant of bronchial

Johnston SL, et al.

(1995). Community

responsiveness in children. Am J Respir

study of viral infections in exacerbations

Crit Care Med; 149: 365-370.

of asthma in 9-11 year old children. BMJ;

Gehring U, et al. (2010). Traffic-related air

310: 1225-1229.

pollution and the development of asthma

Jones RS, et al.

(1963). The place of

and allergies during the first 8 years of

physical exercise and bronchodilator

life. Am J Respir Crit Care Med; 181: 596-

drugs in the assessment of the asthmatic

603.

child. Arch Dis Child; 38: 539-545.

Godfrey S, et al. (1975). The use of the

Landwehr LP, et al. (1996). Vocal cord

treadmill for assessing exercise-induced

dysfunction mimicking exercise-induced

ERS Handbook: Paediatric Respiratory Medicine

bronchospasm in adolescents. Pediatrics;

Rosenthal RR (1984). Simplified eucap-

98: 971-974.

nic voluntary hyperventilation challenge.

Lødrup Carlsen KC, et al.

(1995).

Allergy Clin Immunol;

73:

676-

Eosinophil cationic protein and tidal flow

679.

volume loops in children

0-2 years of

Salome CM, et al.

(1987). Bronchial

age. Eur Respir J; 8: 1148-1154.

responsiveness in two populations of

Mele L, et al.

(2010). Assessment and

Australian schoolchildren. I. Relation to

validation of bronchodilation using the

respiratory symptoms and diagnosed

interrupter technique in preschool chil-

asthma. Clin Allergy; 17: 271-281.

dren. Pediatr Pulmonol; 45: 633-638.

Salter HH. On Asthma: Its Pathology and

Miller MR, et al.

(2005). General con-

Treatment. 1st Edn. London, J. Churchill,

siderations for lung function testing. Eur

1860.

Respir J; 26: 153-161.

Sharma S, et al. (2008). Clinical predic-

Nakazawa H, et al. (1994). Viral respira-

tors and outcomes of consistent bronch-

tory infection causes airway hyperrespon-

odilator response in the childhood

siveness and decreases histamine N-

asthma management program. J Allergy

methyltransferase activity in guinea pigs.

Clin Immunol; 122: 921-928.

Am J Respir Crit Care Med; 149: 1180-1185.

Sont JK, et al. (1999). Clinical control and

Nieminen MM, et al.

(1988).

histopathologic outcome of asthma

Methacholine bronchial challenge using

when using airway hyperresponsiveness

a dosimeter with controlled tidal breath-

as an additional guide to long-term

ing. Thorax; 43: 896-900.

treatment. The AMPUL Study Group.

Nordenhall C, et al.

(2001). Diesel

Am J Respir Crit Care Med; 159: 1043-

exhaust enhances airway responsiveness

1051.

in asthmatic subjects. Eur Respir J;

17:

Soyseth V, et al.

(1995). Relation of

909-915.

exposure to airway irritants in infancy to

Pauwels R, et al.

(1988). Bronchial

prevalence of bronchial hyper-responsive-

hyperresponsiveness is not bronchial

ness in schoolchildren. Lancet; 345: 217-

hyperresponsiveness is not bronchial

220.

asthma. Clin Allergy; 18: 317-321.

Stadelmann K, et al. (2011). Respiratory

Pellegrino R, et al. (2005). Interpretative

symptoms and bronchial responsiveness

strategies for lung function tests. Eur

in competitive swimmers. Med Sci Sports

Respir J; 26: 948-968.

Exerc; 43: 375-381.

Peroni DG, et al. (1994). Effective allergen

Stearns DR, et al. (1981). Reanalysis of the

avoidance at high altitude reduces

refractory period in exertional asthma. J

allergen- induced bronchial hyperrespon-

Appl Physiol; 50: 503-508.

siveness. Am J Respir Crit Care Med; 149:

Sterk PJ (1996). Bronchial hyperrespon-

1442-1446.

siveness: definition and terminology.

Refsum HE, et al. Exercise-associated

Pediatr Allergy Immunol;

7: Suppl.,

ventilatory insufficiency in adolescent

7-9.

athletes. The asthmatic child in play and

Thio BJ, et al. (2001). Effects of single-

sports. London, Pitmann Books Limited,

dose fluticasone on exercise-induced

1983.

asthma in asthmatic children: a pilot

Riiser A, et al. (2012a). Bronchial hyperre-

study. Pediatr Pulmonol; 32: 115-121.

sponsiveness decreases through child-

Tiffeneau R

(1995). L’hyperexcitabilité

hood. Respir Med; 106: 215-222.

acetylcholinique du poumon; critère phy-

Riiser A, et al.

(2012b). Does bronchial

siopharmacodynamique de la maladie

hyperresponsiveness in childhood predict

asthmatique

[Acetylcholine hyperexcit-

active asthma in adolescence? Am J

ability of the lung; physicopharmacody-

Respir Crit Care Med; 186: 493-500.

namic criterion in asthma]. Presse Med;

Roizin H, et al. (1996). Atopy, bronchial

63: 227-230.

hyperresponsiveness, and peak flow

van Essen-Zandvliet EE, et al.

(1993).

variability in children with mild occa-

Minor acute effect of an inhaled corti-

sional wheezing. Thorax; 51: 272-276.

costeroid

(budesonide) on bronchial

ERS Handbook: Paediatric Respiratory Medicine

Blood gas assessment

and oximetry

Paola Papoff, Fabio Midulla and Corrado Moretti

In clinical practice, arterial blood gas (ABG)

PaCO₂ and pH are measured directly, other

analysis is needed to assess patients with

variables, such as bicarbonates (actual and

respiratory diseases and those with other

standard) and SaO₂, are calculated using

disorders influencing pulmonary gas

well-defined equations.

exchange and acid-base disturbances. ABG

analysis is also needed to establish the

A systematic approach to ABG

diagnosis of respiratory failure.

interpretation is demonstrated in table 1.

ABG analysis helps to evaluate the following:

Compensation for respiratory or metabolic

disorders

N acid-base equilibrium (pH)

N respiratory function (PaCO₂, PaO₂ and

Because the body attempts to maintain

SaO₂)

blood pH at 7.4, respiratory or metabolic

N metabolic function (bicarbonate, base

disorders normally trigger an equal

excess and anion gap).

counterbalancing effect in the other

systems. Table 2 summarises the formulas

The principles underlying traditional ABG

used for estimating the compensation level.

measurement are based on the

Under these circumstances the respiratory

electrochemical interaction between

and metabolic components are both

respiratory gases and selected metals within

abnormal, but pH is almost normal

electrodes (Clark, 1956). Whereas PaO₂,

(table 1). The body never overcompensates,

and may even fail to reach complete

Key points

compensation (Carmody et al., 2012).

Failure to reach the predicted compensation

N Acid-base disturbances can be

level should lead the clinician to suspect a

classified using a three step

mixed disorder.

systematic approach: pH, PaCO₂,

Mixed disorders

bicarbonate.

N If pH is abnormal, determine if

Mixed acid-base disorders can be simply

acidaemia or alkalaemia.

defined as a condition in which two or more

acid-base imbalances exist. Some of the

are

N If the measured pH and PaCO₂

more common mixed acid-base imbalances

both abnormal, assess the direction of

include those that have an additive effect on

change; if they change in opposite

the change in pH (respiratory acidosis and

directions the primary acid-base

metabolic acidosis, or metabolic alkalosis

abnormality is respiratory, otherwise it

and respiratory alkalosis). The other set of

is metabolic.

imbalances will have opposite effects on pH,

When an acid-base imbalance is

resulting in apparent overcompensation

diagnosed look for compensation or

(metabolic acidosis and respiratory

mixed disorders.

alkalosis, or metabolic alkalosis and

respiratory acidosis).

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Interpretation of acid-base disorders: examine the pH, determine the primary disorder and look for

compensation

Normal pH 7.35-7.45

Acidaemia: decreased pH ,7.35

Respiratory acidosis: decreased pH, increased PaCO2

Renal compensation:

Kidneys reabsorb bicarbonate

pH <, increased bicarbonate

Metabolic acidosis: decreased pH, decreased bicarbonate

Pulmonary compensation:

Hyperventilation releases CO₂

pH <, decreased PaCO₂

Alkalaemia: increased pH .7.45

Respiratory alkalosis: increased pH, increased PaCO₂

Renal compensation:

Kidneys excrete bicarbonate

pH <, decreased bicarbonate

Metabolic alkalosis: increased pH, increased bicarbonate

Pulmonary compensation:

Hypoventilation retaining CO₂

pH <, increased PaCO₂

acidaemic, if it is .7.45

the patient is

alkalaemic. Acidosis and alkalosis, the

pH is a scale for measuring acidity or

processes leading to these states, are either

alkalinity. Normally, blood is slightly alkaline

respiratory or metabolic (Carmody et al.,

(pH 7.4) with an acceptable range of 7.35-

2012). Significant deviations in pH from

7.45. If the pH is ,7.35 the patient is

normal ranges rapidly become

Table 2. Compensatory response of a metabolic or respiratory disorder

Disorder

Expected compensation

Metabolic acidosis

PaCO₂ 5 1.5 (bicarbonate) + 8¡2 (Winter’s formula)

Metabolic alkalosis

PaCO₂ 5 0.7 (bicarbonate) + 20¡1.5

Acute respiratory acidosis

Bicarbonate will increase by 1 mEq?L^-1 for each 10 mmHg rise

in PaCO2 above 40 mmHg

Chronic respiratory acidosis

Bicarbonate will increase by 3-4 mEq?L^-1 for each 10 mmHg

rise in PaCO2 above 40 mmHg

Acute respiratory alkalosis

Bicarbonate will decrease by 2 mEq?L^-1 for each 10 mmHg

decrease in PaCO2 below 40 mmHg

Chronic respiratory alkalosis

Bicarbonate will decrease by 5 mEq?L^-1 for each 10 mmHg

decrease in PaCO₂ below 40 mmHg

Reproduced from Dzierba et al. (2011), with permission from the publisher.

ERS Handbook: Paediatric Respiratory Medicine

life-threatening; Marieb et al. (2007)

acidosis. Metabolic compensation of

suggested ‘‘absolute blood pH limits for

respiratory acidosis takes time to reverse.

life’’ are 7.0-7.8, although patients may

Rapidly correcting chronic respiratory

survive if isolated samples exceed this

acidosis will, therefore, result in a self-

range. Both carbon dioxide and bicarbonate

resolving metabolic alkalosis.

affect pH. To better quantify the relationship

Measures/indices that assess adequacy of

between pH, carbon dioxide and

oxygenation

bicarbonate, Henderson (1913) developed

PaO₂: blood oxygen measurement serves as a

the following formula demonstrating that

surrogate for tissue oxygen measurement.

the ratio of bicarbonate and carbon dioxide,

Tissue oxygen is far lower than blood

not the absolute values, determines pH:

oxygen. Oxygen in the arterial blood is

pH 5 6.1 + log ([HCO_3-]/[0.03 6 PaCO₂])

present as PaO₂ (dissolved oxygen) and SaO₂

(oxygen bound to haemoglobin). As long as

‘‘Normal’’ pH can be found under normal

the PaO₂ is .60 mmHg, SaO₂ remains above

conditions, in a compensated state or in

90%. If PaO₂ is ,60 mmHg, this may lead

mixed acid-base abnormalities.

to a significant reduction in SaO₂ and

impaired oxygen delivery to tissues (fig. 1).

Respiratory disorders

Measures that assess adequacy of ventilation

PaO₂/inspiratory oxygen fraction (FiO₂): this

Air normally contains almost no carbon

ratio can be used to compare arterial

dioxide (0.04%); blood carbon dioxide is a

oxygenation in patients breathing different

normal metabolic waste product. Normal

FIO₂ values. A patient who has a normal PaO₂

PaCO₂ ranges from 35 to 45 mmHg. Blood

of ,100 mmHg while breathing room air

levels depend on clearance, which, in turn,

should have a PaO₂/FiO₂ ratio of 100/

depends on ventilation.

0.215500. The normal range for the PaO2/

FiO₂ ratio is 300-500. Values of less than

Small tidal volumes, low frequencies or

250 imply a significant problem in the lung

obstructed airways lead to reduced carbon

gas exchange mechanisms. For this

dioxide clearance and, therefore, high blood

calculation the percentage of oxygen being

carbon dioxide (respiratory acidosis). For

administered must be entered in the blood

every increase in PaCO₂ of 20 mmHg above

gas analyser.

normal the pH falls by 0.1. For every

decrease in PaCO₂ of 10 mmHg below

Alveolar-arterial oxygen tension difference

normal the pH rises by 0.1. Any change in

(PA-aO₂): is the difference between the

pH outside these ranges suggests a mixed

alveolar oxygen pressure (PAO₂) and PaO₂.

disorder. PaCO₂ may also be elevated in

PaO₂ is derived from the ABG analysis,

compensated metabolic alkalosis (table 2).

whereas PAO₂ may be calculated from the

simplified alveolar gas equation:

Hyperventilation leads to increased carbon

dioxide removal and then to a decreased

100

PaCO₂ and an elevated pH (respiratory

alkalosis). Low PaCO₂ levels can be also

found in compensated metabolic acidosis

(table 2).

Mechanisms for metabolic compensation in a

respiratory disorder When respiratory

acidosis persists beyond 6-12 h, the kidneys

generate bicarbonate by excreting

100

ammonium with chloride in the urine and, in

this process, bicarbonate is added to the

PaO

2 mmHg

plasma leading to the hypochloraemic

alkalosis typically seen in chronic respiratory

Figure 1. The oxyhaemoglobin dissociation curve.

ERS Handbook: Paediatric Respiratory Medicine

PAO₂ 5 (Patm - 47 mmHg) 6 FIO₂ - PaCO₂/0.8

5 g?dL^-1 (i.e. blood that is approximately one-

third of the extracellular fluid).

47 mmHg is the water vapour added by the

airways and 0.8 is the respiratory quotient.

Metabolic acidosis

Metabolic acidosis is defined as a serum

In normal lungs, the PA-aO₂ is

bicarbonate ,22 mEq?L^-1 and a pH ,7.35.

,12-15 mmHg in room air and ,70 mmHg

Metabolic acidosis may be caused either by

in 100% oxygen. A high PA-aO₂ gradient

adding acid or removing buffer. Help in

implies a defect in oxygen diffusion across

distinguishing these two conditions comes

the alveolar-capillary membrane or a defect

from calculating the anion gap. With the

in ventilation/perfusion ratio or right-to-left

onset of metabolic acidosis a certain

shunting. Conversely, if the PA-aO₂ gradient

amount of respiratory compensation takes

is not increased, lack of oxygenation is due

place in the form of hyperventilation

to low respiratory effort. For example, a

(table 2). When the carbon dioxide tension

healthy person who hypoventilates would

(PCO₂) is outside the expected range for a

have hypoxia, but a normal PA-aO₂ gradient

given bicarbonate concentration, a

(Carmody et al., 2012).

superimposed respiratory acid-base

PaO₂/PAO₂ ratio: this offers better accuracy

disturbance is present.

over a broader FIO₂ range than the PaO₂/FIO₂

Anion gap

ratio. It is considered a somewhat better

index of oxygenation. When the PaO₂/PAO₂

Organisms exist in a state of electro-

ratio is very low, high FIO₂ values obviously

neutrality with major and minor cations

do not translate into improved blood

balanced by similar anions (fig. 1). The

oxygenation: in such situations, a high shunt

major extracellular cation is sodium, while

fraction can be expected.

the other minor cations (potassium,

calcium, magnesium, etc.) are grouped as

Metabolic disorders

unmeasured cations. Similarly, the major

commonly measured anions are chloride

Metabolic disorders will initially cause

and bicarbonate, whereas other anions (e.g.

alterations in the serum bicarbonate

albumin, phosphates and sulfates) are

concentrations and, thus, pH. The base

grouped as unmeasured anions (Carmody et

excess/deficit is a calculation that estimates

al., 2012). In normal conditions, a small

the metabolic component in the acid-base.

unmeasured anion excess represents the

Whereas a positive base excess may indicate

anion gap (fig. 2).

metabolic alkalosis, a negative base excess

usually suggests metabolic acidosis. Blood

Anion gap 5 unmeasured anion -

with a pH 7.4 and PaCO₂ 40 mmHg at 100%

unmeasured cations 5 10-14 mEq?L^-1

oxygen saturation has a base excess of zero.

Most blood gas analysers offer the option of

or indirectly

calculating either the base excess of the

Anion gap 5 Na⁺ - (Cl^- + HCO_3-)

blood sample, also called standard base

5 10-14 mEq?L^-1

excess, or the base excess of the

extracellular fluid, also called actual base

In low albumin states, 2.5 mEq?L^-1 should be

excess. The blood base excess does not truly

added to the calculated anion gap for every

indicate the base excess of all extracellular

1 g?dL^-1 of albumin below the usual normal

fluids, as buffering capacities (i.e.

value (Oh, 2010). Metabolic acidosis with

haemoglobin concentration) differ between

a normal anion gap occurs when the

the intravascular and the extravascular

bicarbonate concentration falls and the

compartments. Therefore, to be

chloride concentration increases

representative of the whole extracellular

proportionately to maintain electrical

compartment (intravascular and

neutrality. This happens when bicarbonate is

extravascular), the blood base excess value

lost either in the gastrointestinal tract, as in

is calculated on a haemoglobin level of

diarrhoea, or in urine (renal tubular acidosis).

ERS Handbook: Paediatric Respiratory Medicine

Total cations

Total anions

Metabolic alkalosis is classically delineated

into two types: chloride responsive and

chloride unresponsive. A helpful way to

Unmeasured

differentiate between the two is to evaluate

cations

Unmeasured

urine chloride. Patients with a low urine

Anion

anions

chloride (,10 mEq?L^-1) are those who have

gap

chloride responsive alkalosis (e.g. loss of

acids from the gastrointestinal tract and

diuretics), whereas patients who have a

Sodium

Chloride

normal or high urine chloride (.10 mEq?L^-1)

have chloride unresponsive alkalosis. In

most patients with chloride unresponsive

alkalosis, urine potassium will also be

Bicarbonate

elevated (.30 mEq?L^-1), indicating

significant renal losses of potassium. The

pathophysiology of chloride unresponsive

Figure 2. Schematic representation of the

metabolic alkalosis involves potassium

concentration of plasma cations, mainly

depletion along with excessive

represented by sodium, plasma anions

mineralocorticoid activity (e.g.

(bicarbonate and chloride), and the anion gap.

hyperaldosteronism, Cushing’s disease or

Bartter’s syndrome) (Carmody et al., 2012;

Ayers et al., 2012).

An abnormally large anion gap indicates that

Specific issues

the metabolic acidosis depends on

Type of blood sample for blood gas Although

accumulation of acids not normally found in

blood gas has historically been analysed in

significant quantities in the body (e.g.

arterial blood, obtaining arterial samples

ketoacids, lactic acid and salicylic acid).

may be difficult and lead to complications.

Metabolic alkalosis

Capillary blood is routinely used in neonates

or other patients when an arterial sample is

Metabolic alkalosis is defined as a serum

not easy to collect. Capillary blood is a mix

bicarbonate .26 mEq?L^-1 and a pH .7.45.

of arteriolar, capillary and venous blood with

Compensatory hypoventilation may cause a

a small contribution of interstitial and

slight rise in PaCO₂ (table 2), but this is

intracellular fluid. Although the relative

typically minor. The development of

higher pressure on the arterial side of the

alkalosis is usually due to excessive loss of

circulation increases the proportion of

hydrogen ions either from the stomach

arterial blood in the capillary sample, only

(vomiting) or the kidney (when excess

pH and PCO₂ are acceptable because of their

aldosterone increases the activity of a

low arterio-venous gradient; on the

sodium-hydrogen exchange), which results

contrary, PO₂, which exhibits a relatively high

in regeneration of the titrated plasma

arterio-venous difference, is less likely to

bicarbonate. Important to the pathogenesis

show good agreement between capillary and

of the alkalosis is chloride and potassium

arterial blood (Sauty et al., 1996). Increasing

local blood flow by the so-called

depletion, which also leads to bicarbonate

reabsorption. This leads to further

‘‘arterialisation’’ of capillary blood

(warming) does not show significant

reabsorption of bicarbonate. Chloride and

difference of pH and blood gas compared to

potassium depletion can be induced in a

the non-warmed capillary blood. Another

number of ways by:

acceptable alternative for the initial

N corticosteroid medication,

assessment of a patient with mild

N diuretic therapy,

respiratory problems is peripheral venous

N gastric suction.

sampling (table 3). Arterial and venous pH,

ERS Handbook: Paediatric Respiratory Medicine

Table 3. Arterial and venous blood gas reference values

Arterial blood

Venous blood

Capillary blood

7.40

(7.35-7.45)

7.36

(7.31-7.41)

7.35-7.45

PaCO₂ mmHg

(35-45)

42-55

36-45

PaO₂ mmHg

(80-100)

30-50

50-80

Bicarbonate mEq?L^-1

(22-30)

24-28

22-27

Base excess mEq?L^-1

-3-3

O₂ saturation %

.90

60-85

Data from Dzierba et al. (2011).

bicarbonate and base excess yield

Each degree above or below 37uC will result

acceptable agreement in patients with

in a 5 mmHg change in PaO₂ and a

normal peripheral circulation. The mean

2 mmHg change in PaCO₂. All blood gas

arterio-venous difference in pH is ,0.035

machines have the option of analysing the

pH units, for PCO₂ is 5.7 mmHg, and for

blood at an ‘‘actual’’ temperature but this

bicarbonate is -1.41 mmol?L^-1 (Kelly, 2010).

is rarely carried out. When blood gases are

Owing to the wide variations in venous

measured at 37uC, PaO₂ and PaCO₂ increase;

PCO₂, a venous sample can be used only to

therefore, the normal range for blood

screen for arterial hypercarbia or to monitor

gases should be increased (Thoresen,

trends in PCO₂ for selected patients, but not

2008).

to establish the diagnosis of respiratory

failure.

Further reading

Pitfalls in ABG interpretation ABG samples

must be collected, handled and analysed

Ayers P, et al. (2012). Simple acid-base

tutorial. JPEN J Parenter Enteral Nutr; 36:

properly for accurate results. Every sample

18-23.

must be obtained anaerobically and be

Carmody JB, et al.

(2012). A clinical

anticoagulated. After collection, the sample

approach to paediatric acid-base disor-

should be immediately analysed or properly

ders. Postgrad Med J; 88: 143-151.

chilled and analysed within 30 min.

Clark LC (1956). Monitor and control of

Supplemental oxygen should be entered in

blood and tissue oxygen tensions. Trans

the blood gas machine to obtain

Am Soc Artif Intern Organs; 2: 41-48.

oxygenation indices. Factors influencing the

Dzierba AL, et al.

(2011). A practical

results of ABG analysis include:

approach to understanding acid-base

abnormalities in critical illness. J Pharm

N the type of syringe used for collection

Pract; 24: 17-26.

(unless the sample is analysed within

Essin DJ (1984). The application of the

15 min),

extracellular base excess to children.

N the presence of air bubbles (causing an

Biochem Med; 32: 67-78.

artificially high PaO₂ and underestimating

Hasan A, ed. Understanding Mechanical

the true PaCO₂),

Ventilation: A Practical Handbook. 2nd

N using too much heparin as an

Edn. New York, Springer, 2010.

anticoagulant (decreased PaCO₂).

Henderson LJ (1913). The regulation of

neutrality in the animal body. Science; 37:

Blood gas analysis values during systemic

389-395.

hypothermia Physical laws determine that

Kelly AM (2010). Can venous blood gas

gas solubility within a liquid decreases

analysis replace arterial in emergency

when the temperature diminishes. During

medical care. Emerg Med Australas; 22:

therapeutic hypothermia, arterial PaCO₂

493-498.

therefore decreases and pH increases.

ERS Handbook: Paediatric Respiratory Medicine

Exhaled nitric oxide,

induced sputum and

exhaled breath analysis

Johan C. de Jongste

Noninvasive tests to assess the presence

and nature of airway inflammation in

Key points

children are particularly relevant for the

diagnosis and treatment of asthma, and

At present, FeNO is the only biomarker

may also be valuable for other inflammatory

in exhaled air that has been

conditions of the airways. Other

standardised, developed and

applications include the diagnosis and

validated for clinical application.

monitoring of respiratory infections and of

Increased FeNO is suggestive of

certain nonrespiratory metabolic conditions.

eosinophilic airway inflammation and

This chapter will focus on the use of

FeNO has a role in the diagnosis and

noninvasive markers of airway inflammation

management of asthma after

in childhood asthma.

preschool age. Low FeNO is seen in

Exhaled nitric oxide fraction

suppurative airways disease,

including CF, and low nasal nitric

Exhaled nitric oxide fraction (FeNO) is the

oxide is typical for primary ciliary

best studied and validated noninvasive

dyskinesia or sinusitis.

marker of airway inflammation, and is the

Dose titration of inhaled steroids on

only inflammation marker that has widely

the basis of induced sputum

gained acceptance in routine patient care.

eosinophilia has been shown to

Nitric oxide is a free radical gas that is

reduce exacerbations in adult

produced from L-arginine, involving

asthmatics, but studies in children are

constitutively expressed nitric oxide

few and inconclusive. The

synthases (NOS). One of the isoforms of

methodology of sputum induction in

NOS, inducible NOS, also called type 2 NOS

children is demanding and unlikely to

or iNOS, is present on airway epithelial cells,

become useful in clinical routine.

where it is upregulated by proinflammatory

cytokines and then produces relatively high

A large number of other potential

amounts of nitric oxide into the airway

biomarkers in exhaled air, or in EBC,

lumen. This nitric oxide can be measured at

await further standardisation. Careful

the mouth during exhalation, and with

evaluation is needed before these can

appropriately standardised methodology the

be applied in clinical practice.

FeNO is highly reproducible. Exhaled nitric

oxide levels are measured in parts per billion

(ppb), and hence extremely sensitive

analysers are needed. FeNO analysers for

clinical purposes are commercially available,

different devices do not necessarily produce

and have evolved from bulky, expensive,

the same results, and the smaller hand-held

delicate chemoluminescence analysers into

analysers cannot be adjusted. Hence,

hand-held, user-friendly devices using a

different equipment cannot be used

more robust electrochemical cell-based

interchangeably unless formal comparisons

technology (fig. 1). Unfortunately, the

have shown equivalence.

100

ERS Handbook: Paediatric Respiratory Medicine

various, often complicated approaches, that

require an academic setting and dedication.

Such methods have not been well

standardised and are not suitable for clinical

practice.

Several factors can affect FeNO, and should

be taken into account when FeNO is

interpreted. Maximal forced breathing

manoeuvres, including spirometry, should

be avoided as these reduce FeNO for several

minutes. Inhaling nitric-oxide-free air before

the measurement is desirable as high

ambient values may increase FeNO. For this

purpose, a nitric oxide scrubber can be used

that removes ambient nitric oxide from the

inhaled airstream.

Figure 1. Measurement of FeNO in a child using a

Cigarette smoke reduces FeNO, whereas

hand-held device with an electrochemical sensor.

nitrate- or arginine-rich foods, such as

Maintaining a low, constant expiratory flow is

vegetables, may slightly increase the levels.

facilitated by optical, auditory and visual feedback

However, the impact of food is limited and

signals. The result is immediately available.

does not need to be taken into account.

Airway infections have been reported to

Methodology of FeNO The recommended

either slightly increase or reduce FeNO.

technique to assess FeNO is an on-line

measurement during a constant expiratory

Assessing FeNO at different expiratory flows

flow of 50 mL?s^-1, for at least 10 s (children

makes it possible to calculate bronchial and

with vital capacity ,3 L: 6 s), through a

alveolar components of FeNO. It is unclear

mouthpiece. Contamination with air from

how this information could be clinically

the nose should be avoided, as the nose and

useful, and such measurements are still

paranasal sinuses produce nitric oxide in

limited to research.

much higher amounts than the lower

airways. This is accomplished by exhaling

Clinical applications of FeNO in children

against a positive pressure that ensures

Normative values of FeNO in children have

closing of the soft palate, thus closing the

been published, and show an age-dependent

nose off from the lower airways.

increase during childhood (fig. 2). The

upper level of normal ranges from 15 ppb in

Ideally, the equipment provides one or more

early childhood to 25 ppb in adolescence,

biofeedback signals to help the patient to

and is slightly higher in males than in

standardise the expiration flow and

females. Higher normal levels are also seen

duration, and accepts only attempts that

in atopic individuals and in certain non-

fulfil quality criteria. The recommended

Caucasian ethnic groups. In asthma, FeNO

procedure is feasible in children from the

shows daily fluctuations and the minimal

age of 6-7 years; in younger children the

change that may be clinically relevant has

success rate falls rapidly. For preschool

been proposed as 10 ppb if FeNO is

children, a number of offline methods have

,50 ppb or 20% with higher values.

been described, which make use of

collection devices where exhaled air is

High FeNO, especially above 40-50 ppb, is

stored and analysed, with or without tidal

strongly associated with eosinophilic airway

flow control. In infants, FeNO measurements

inflammation. An abnormally low FeNO may

have been performed by collecting mixed

be seen during suppurative airway infection,

nasal-oral exhaled air samples in a nitric

e.g. in CF, and is of some diagnostic value in

oxide inert collection bag, or online using

primary ciliary dyskinesia. For the latter

ERS Handbook: Paediatric Respiratory Medicine

101

reflects eosinophilic inflammation, but not

other types of inflammation. FeNO may be

low in neutrophilic inflammation, which

occurs in a considerable proportion of

asthmatic children, and this may alternate

with eosinophilic patterns.

Inhaled corticosteroids (ICS) reduce FeNO,

an effect that occurs within a few days of

daily treatment. The diagnostic value of

FeNO is, therefore, limited in subjects who

are already on ICS treatment. The effect of

ICS on FeNO may be used to alert for

nonadherence if a child with a documented

FeNO response on ICS exhibits high FeNO

levels. Elevated FeNO is predictive of

successful treatment with ICS, and an

Age years

increase in FeNO has been shown to precede

loss of control in children who stop or taper

Figure 2. Normative values of FeNO in children.

their ICS dose while in clinical remission.

Black lines show mean and upper 95% FeNO

FeNO above 40-50 ppb is associated with an

(n5405). Orange lines show mean and upper

increased risk of exacerbation and loss of

95% FeNO excluding outliers and atopics (n5332).

control. In an individual, the predictive value

Reproduced with modification from Buchvald et

is, however, limited and the benefits of

al. (2005) with permission from the publisher.

regular FeNO assessment to prevent loss of

control remain to be shown.

purpose, nasal nitric oxide measurements

have better specificity and sensitivity.

Studies in adults with difficult-to-treat

asthma indicated that FeNO monitoring may

A large number of clinical studies, both in

be helpful to identify patients who have an

adults and in children, support the clinical

accelerated decline in lung function, and to

use of FeNO. Firm evidence of added benefit

identify subjects who might benefit from

as compared to conventional practise is

higher doses of ICS. Similar studies in

often lacking. In practice, FeNO should be

children are lacking.

considered as one of the many pieces of

information that clinicians may want to use

Several studies in children and adults have

when making a diagnosis or for treatment

tried to improve asthma management by

decisions.

titrating the dose of ICS in FeNO. Although

most of these studies report some

FeNO can be of help in the diagnosis of

significant benefit of FeNO monitoring on

atopic asthma, especially if symptoms are

secondary end-points, only a few found an

indeterminate. Most published studies on

effect on the primary end-point that differed

the diagnostic value of FeNO in asthma

between studies. These studies had

compared clear asthma cases with normal

important methodological flaws, and

patients, thus providing a strong contrast

differed in many other aspects as well, in

that is often lacking in daily practice. Hence,

particular how often and to what degree

the diagnostic value will be lower in less

FeNO could indeed influence treatment

clearly defined populations of children. In

decisions. The dosing algorithm is entirely

contrast to spirometry, which is often

responsible for this, and had to be defined

normal in children with asthma, elevated

on arbitrary grounds. Unfortunately, the

FeNO commonly persists in asymptomatic

heterogeneity of dose titration studies

episodes and, as a diagnostic test, FeNO

impairs meta-analysis and, therefore, the

performs better than FEV1 or other tests of

issue of whether tailoring the ICS treatment

airway patency. A limitation of FeNO is that it

in asthma on FeNO is beneficial is still

102

ERS Handbook: Paediatric Respiratory Medicine

unresolved, and the use of FeNO for ICS

Induced sputum may be valuable for the

dose titration can not, at present, be

diagnosis of airway infections in children

recommended for clinical routine.

who do not expectorate, and has been used

as a diagnostic, e.g. in CF and for the

An important observation was that among

diagnosis of pulmonary TB.

adult asthma patients, there are subjects in

whom FeNO and symptoms are concordant

Inhalation of hypertonic saline may cause

while in others there is discordancy, with

bronchoconstriction, especially in

high symptom scores and normal FeNO, or

asthmatics, and pre-treatment with an

vice versa. Clearly, any added benefit of FeNO

inhaled b-agonist is therefore needed. There

monitoring compared to classical symptom

is some risk of microbial contamination of

monitoring cannot be expected if there is a

laboratory personnel due to the induced

perfect concordance of FeNO and symptoms,

coughing, and appropriate protective

and none of the paediatric ICS dose titration

measures need to be taken.

studies has taken this aspect into account.

In experienced hands, sputum induction in

The potential benefit of FeNO as a

school-age children has been reported with

monitoring tool in asthma treatment still

success rates of 60-85%, occasionally even

requires more study, focussing on well-

higher, while much lower proportions have

defined subgroups and exploring the effects

been reported for younger children, in whom

of different algorithms.

voluntary expectoration is often problematic

and specimens may be only obtained by

Induced sputum

using a suction cannula. The success rate

Several studies in adults with asthma have

will depend on subject selection and on the

examined the potential of incorporating

experience and skills of the laboratory

sputum eosinophilia as a marker of airway

technician. The success of repeated

inflammation in asthma management. The

procedures is lower, and this is a significant

first proof-of-concept study in adults showed

problem if sputum is to be used for regular

benefits of a treatment strategy that was

monitoring purposes. Paediatric normal

aimed at reducing sputum eosinophilia.

values of differential cell counts in sputum

These included a substantial reduction of

have been published previously.

the number of exacerbations and hospital

admissions, with no concomitant need for

Clinical application of sputum induction in

higher doses of anti-inflammatory

children The only paediatric study to date

medication.

that incorporated sputum eosinophils in the

management of asthma showed no benefits

Methodology of sputum induction Most

in terms of improved asthma control or

children with asthma will not spontaneously

overall exacerbation rates. This study

expectorate sputum. This makes it difficult

included a highly selected population of

to use sputum for regular assessment of

children with severe problematic asthma

airway inflammation. The procedures to

from a third-line reference centre, using

induce sputum have been standardised by a

relatively high doses of ICS. Hence, the

European Respiratory Society Task Force

findings may not be applicable to other

and are suitable for use from the age of

populations of children with more common

8 years. Commonly, sputum is induced by

forms of asthma. There are no paediatric

inhaling hypertonic saline, and whole

studies on the clinical application of soluble

expectorated samples, or selected sputum

components in sputum.

plugs, are pre-treated with a mucolytic

before examination. Reported characteristics

In summary, induced sputum as a means to

include total differential cell counts and

diagnose or monitor children with

contamination with epithelial squamous

inflammatory airway disease is still a

cells in cytospin preparations, soluble

research tool and, until now, no clear benefit

components in the supernatant, and

of measuring any sputum component in

cytokines and mediators of inflammation.

children has been documented.

ERS Handbook: Paediatric Respiratory Medicine

103

The methodology is demanding and time-

Unfortunately, the methods employed in

consuming, and requires considerable

EBC research to date have the inherent

expertise, which makes the place for induced

difficulty that the air from the lower airways

sputum in paediatric clinical practice a

passes through the pharynx and mouth,

limited one.

where contamination may easily occur.

Saliva is an important potential source of

Exhaled breath analysis

contamination as it contains molecules of

interest in vastly higher quantities than EBC.

Exhaled breath condensate (EBC) has been

In addition, the equipment itself may be a

studied for many years as an attractive

source of contamination and either rigorous

vehicle for soluble components from the

cleaning of all parts of the equipment that

lower airways that can be obtained in a

come into contact with the airstream or

noninvasive way. A large number of

disposable tubing and containers are

measurements have been described in

needed to avoid contamination.

exhaled air condensate, including

inflammatory mediators and cytokines, pH,

Clinical application of EBC in children A lot of

hydrogen peroxide and other markers of

studies have reported associations of

oxidative stress, and molecules derived from

molecules in EBC and clinical disease in

microorganisms. Substances in breath

children and adults. Examples include:

condensate are generally present in trace

amounts, which are near or well below the

N pH, which tends to be lower in severe or

acute asthma but not in mild and stable

detection limits of most routine analytical

disease;

techniques, and require extremely sensitive

N hydrogen peroxide and nitric oxide

detection methods. The reproducibility of

metabolites that are elevated in asthma;

the measurements remains an issue of

N hydrogen cyanide, which is produced by

concern.

Pseudomonas and detectable in EBC of CF

A promising new approach is the study of

patients;

‘‘metabolomics’’ in EBC, which makes use

8-isoprostane, a marker of oxidative

of spectrometric techniques and detects

stress in CF and asthma;

thousands of components, separated on the

N a large number of inflammatory

basis of molecular mass and/or charge,

mediators and proinflammatory cytokines

which can be associated with a clinical trait

in relation to wheezing or asthma.

of interest in a hypothesis-free manner. An

What is lacking for most potential

excellent overview of the present state-of-

biomarkers in EBC are studies into the

the-art regarding biomarkers in EBC is

clinical methodology, especially short- and

provided in a recent European Respiratory

long-term reproducibility studies and

Monograph.

studies associating meaningful changes in

Methodology of EBC Various methods have

disease activity to changes in biomarkers. In

been recommended to collect EBC samples,

general, the overlap with findings in healthy

and equipment for EBC collection is

subjects has been considerable, and studies

commercially available. The methodology for

that did assess reproducibility have been

EBC collection was reviewed and

disappointing. No paediatric studies have

recommendations provided in an American

been published that showed clinical benefit

Thoracic Society Task Force report. The

of measuring components in EBC in

techniques vary from a simple tube system

individual patients.

to be cooled in a refrigerator before use, to

Conclusion

more sophisticated devices that use cooled

containers through which the exhalate

Noninvasive biomarkers of airway

passes and in which EBC is retained. A nose

inflammation in exhaled air are of great

clip and saliva trap are recommended, and

interest as they may provide information on

the material of tubing and condenser should

an important aspect of disease that is

be inert for substances of interest.

otherwise difficult to assess in children.

104

ERS Handbook: Paediatric Respiratory Medicine

In theory, a reliable marker of airway

Buchvald F, et al. (2005). Measurements

inflammation would allow for better

of exhaled nitric oxide in healthy subjects

diagnosis and selecting the appropriate

age 4 to 17 years. J Allergy Clin Immunol;

treatment in the lowest possible dose that

115: 1130-1136.

suppresses airway inflammation. In practice,

Carraro S, et al.

(2010). Exhaled nitric

oxide measurements. Eur Respir Monogr;

it has proven exceedingly difficult to

47: 137-154.

substantiate these expectations. Of all

Deykin A, et al.

(2002). Exhaled nitric

noninvasive biomarkers of airway

oxide as a diagnostic test for asthma.

inflammation, only FeNO has developed into

Am J Respir Crit Care Med; 165: 1597-

a useful clinical tool with many applications,

1601.

but also with limitations and pitfalls that one

Dweik RA, et al. (2011). An official ATS

should be aware of. Induced sputum

clinical practice guideline: interpretation

requires more time and effort, and has

of exhaled nitric oxide levels (FENO) for

limited feasibility and repeatability in

clinical applications. Am J Respir Crit Care

children, especially at a younger age. As

Med; 184: 602-615.

adult studies have clearly demonstrated

Fleming L, et al. (2012). Use of sputum

benefits of induced sputum-based

eosinophil counts to guide management

monitoring of asthma, it remains desirable

in children with severe asthma. Thorax;

to pursue sputum induction further for

67: 193-198.

Haldar P, et al. (2008). Cluster analysis

application in children. At present, induced

and clinical asthma phenotypes. Am J

sputum mainly seems useful for obtaining

Respir Crit Care Med; 178: 218-224.

microbiological specimens in suspected

Horvath I, et al. Exhaled Biomarkers. Eur

airway infection, but also the evidence for

Respir Monogr 2010; 49: 1-249.

added value is scanty. Assessing biomarkers

Kovesi T, et al.

(2008). Exhaled nitric

of inflammation in EBC has been an exciting

oxide and respiratory symptoms in a

and promising development for many years

community sample of school aged

now. Despite a growing number of studies,

children. Pediatr Pulmonol;

43:

1198-

development into clinical practise is

1205.

hampered by methodological difficulties

Leung TF, et al.

(2006). Clinical and

related to the extremely low concentrations

technical factors affecting pH and other

of potential markers in EBC, a low

biomarkers in exhaled breath condensate.

reproducibility and a high risk of

Pediatr Pulmonol; 41: 87-94.

Li AM, et al. (2006). Sputum induction in

contamination in the upper airway. Sensitive

children with asthma: a tertiary-center

and robust detection methods and better

experience. Pediatr Pulmonol;

41:

720-

equipment for collection, all well

725.

standardised, may sooner or later reveal the

Nicolaou NC, et al.

(2006). Exhaled

true clinical potency of EBC biomarkers.

breath condensate pH and childhood

asthma. Unselected birth cohort study.

Am J Respir Crit Care Med; 174; 254-259.

Further reading

Pérez-de-Llano LA, et al. (2010). Exhaled

Baraldi E, et al. (2002). ERS/ATS state-

nitric oxide predicts control in patients

ment: measurement of exhaled nitric

with difficult-to-treat asthma. Eur Respir J;

oxide in children, 2001. Eur Respir J; 20:

35: 1221-1227.

223-237.

Petsky HL, et al.

(2012). A systematic

Baraldi E, et al. (2006). 3-Nitrotyrosine, a

review and meta-analysis: tailoring

marker of nitrosative stress, is increased

asthma treatment on eosinophilic mar-

in breath condensate of allergic asthmatic

kers

(exhaled nitric oxide or sputum

children. Allergy; 61: 90-96.

eosinophils). Thorax; 67: 199-208.

Beck-Ripp J, et al.

(2002). Changes of

Pijnenburg MW, et al. (2005). Titrating

exhaled nitric oxide during steroid treat-

steroids on exhaled nitric oxide in chil-

ment of childhood asthma. Eur Respir J;

dren with asthma. Am J Respir Crit Care

19: 1015-1019.

Med; 172: 831-836.

ERS Handbook: Paediatric Respiratory Medicine

105

Pijnenburg MW, et al. (2005). Exhaled

Szefler SJ, et al. (2008). Management of

nitric oxide predicts asthma relapse in

asthma based on exhaled nitric oxide in

children with clinical asthma remission.

addition to guideline-based treatment for

Thorax; 60: 215-218.

inner-city adolescents and young adults:

Rosias PP, et al.

(2008). Biomarker

a randomised controlled trial. Lancet; 372:

reproducibility in exhaled breath conden-

1065-1072.

sate collected with different condensers.

Van Jagwitz M, et al.

(2011). Reduced

Eur Respir J; 31: 934-942.

breath condensate pH in asymptomatic

Shaw DE, et al.

(2007). The use of

children with prior wheezing as a risk factor

exhaled nitric oxide to guide asthma

for asthma. J Allergy Clin Imunol; 128: 50-55.

management. Am J Respir Crit Care Med;

Van Veen IH, et al. (2008). Exhaled nitric

176: 231-237.

oxide predicts lung function decline in

Sivan Y, et al. (2009). The use of exhaled

difficult-to-treat asthma. Eur Respir J; 32:

nitric oxide in the diagnosis of asthma in

344-349.

school children. J Pediatr; 155: 211-216.

Wilson NM, et al.

(2000). Induced

Smith AD, et al.

(2004). Diagnosing

sputum in children: feasibility, repeatabil-

asthma. Comparisons between exhaled

ity, and relation of findings to asthma

nitric oxide measurements and conven-

severity. Thorax; 55: 768-774.

tional tests. Am J Respir Crit Care Med;

Zacharasiewicz A, et al. (2005). Clinical

169: 473-478.

use of noninvasive measurements of

Smith AD, et al. (2005). Exhaled nitric

airway inflammation in steroid reduction

oxide. A predictor of steroid response.

in children. Am J Respir Crit Care Med; 171:

Am J Respir Crit Care Med; 172: 453-459.

1077-1082.

106

ERS Handbook: Paediatric Respiratory Medicine

Pulmonary function testing

in infants and preschool

children

Enrico Lombardi, Graham L. Hall and Claudia Calogero

Measuring lung function in infants (first

during tidal breathing (such as tidal

year of life) and preschool children (2-

breathing measurements and the multiple

5 years old) represents a major challenge in

breath washout) are more readily used

paediatric respiratory medicine. Infants

without sedation, although test success

cannot voluntarily perform the manoeuvres

rates will decrease with increasing age.

required for pulmonary function tests

While PFTs in this age group are possible

(PFTs) used in older children and adults.

and equipment is commercially available,

The majority of lung function tests in

infant PFTs are less suitable for routine

infants and young children up to 2 years of

clinical testing. A recent survey cited the

age require sedation to ensure acceptable

‘‘need for sedation’’ and the ‘‘uncertainty

and repeatable results. The most

about how data actually impacts patient

commonly used sedative is chloral hydrate

care’’ as limitations for the use of

(80-100 mg?kg^-1, maximum 1 g); however,

infant PFTs. Infant PFTs have been

this sedative is no longer available in the

standardised by the American Thoracic

USA. Infant lung function tests performed

Society (ATS) and European Respiratory

Society (ERS).

Preschool children can be more challenging

Key points

than infants as far as lung function testing is

concerned. They are too old to sedate, have

N Measuring lung function in infants

a very short attention span and the success

and preschool children is possible

of lung function testing in this age group

because of standardised techniques

depends on the capability of the operator of

that require minimal cooperation

initiating a good relationship with the child.

from the child.

Several techniques are now available that are

Sedation is usually required in infants

performed during tidal breathing, thus only

and young children up to 2 years of

requiring passive collaboration in preschool

age (generally chloral hydrate

children. International recommendations for

80-100 mg?kg^-1, maximum 1 g) for

most PFTs in preschool children have been

most PFTs, limiting the use of infant

recently published and the evidence for the

PFTs in routine clinical care.

clinical utility of the tests has been recently

reviewed.

N In preschool children, the feasibility of

the interruptor technique and

This section will describe some of the most

plethysmographic sRaw, which are

frequently used PFTs in infants and

performed during tidal breathing, is

preschool children. Other fundamental PFTs

usually .80%.

for infants and preschool children, such as

Spirometry is also feasible in

the washout techniques and the forced

preschool children when appropriate

oscillation technique, are described in great

criteria are used.

detail separately in this section of the

Handbook.

ERS Handbook: Paediatric Respiratory Medicine

107

PFTs in infants

(ISIS) demonstrated a significant adjusted

treatment effect in FEV0.5 of 38 mL

Raised volume rapid thoracic compression The

suggesting that RVRTC outcomes may be a

measurement of forced expiratory flow and

valid choice for clinical trials in early CF lung

volumes in infants is obtained using the

disease. In infants with recurrent wheeze/

raised volume rapid thoracic compression

infantile asthma, evidence of airway

(RVRTC) technique and international testing

obstruction and improvements following

guidelines that are available. The RVRTC

treatment with montelukast or inhaled

technique is demanding in terms of staffing

corticosteroids have been reported. The

and equipment resources, as well as the

RVRTC technique has been combined with

training required to ensure high-quality

inhaled challenge tests for the assessment

measurements are obtained. Briefly, the

of airway hyperresponsiveness (AHR)

technique involves applying repeated

although these are limited to highly

inflation breaths to the sedated infant, via a

experienced centres.

facemask, to a pressure of 30 cmH₂O. An

inflatable jacket is used to rapidly compress

In summary, the RVRTC technique is

the infant’s thorax and abdomen to produce

becoming more readily available and has a

the forced expiratory flow-volume curves.

role in research studies with emerging

The jacket inflation pressure is increased

evidence of its utility in clinical trials. The

progressively until there are no further

role of the technique in the clinical

increases in forced expiratory flow (FEF),

management of infants and young children

suggesting flow limitation has been

with lung disease is less clear and further

achieved. The reported RVRTC outcomes are

studies defining normal reference ranges

FVC, FEV0.5 and FEF at a defined proportion

and clinically meaningful differences are

of FVC. Technically acceptable and

required.

repeatable outcomes are influenced by

Infant plethysmography The use of body

laboratory experience. The most commonly

used reference equations may no longer be

plethysmography in infants to measure

suitable for the current generation of

functional residual capacity (FRCpleth)

operates on the same principles as

commercially available equipment and it is

plethysmography in older children and

not clear what changes in RVRTC outcomes

adults. The primary difference is that the

constitute a clinically meaningful difference,

infant or young child is sedated, lying supine

primarily due to the difficulties associated

and breathing through a facemask that is

with repeated sedation and changes with

sealed over the nose and mouth using

lung growth over time. These place further

limitations on the use of RVRTC for the

silicon putty. Infant plethysmography

management of lung disease in individual

measurement guidelines have been

patients.

published. The success in obtaining FRCpleth

is generally high and is influenced by

The RVRTC technique has been applied in a

sedation success and experience of the

range of patient populations including CF,

personnel. Reference data in healthy infants

recurrent wheezing, infants born preterm

are available; however, the validity of these

and in infants with chest wall and

data in using currently available equipment

parenchymal lung disorders. The majority of

has been questioned. There are very few

studies reported in the literature are in

data on the repeatability of FRCpleth over

infants with CF and infants with recurrent

time and a clinically meaningful change in

wheeze. In infants and young children with

response to treatments (such as

CF diagnosed following newborn screening,

bronchodilators) or deterioration in clinical

FEV0.5 is normal or near normal in the first

status is not known. Considered together

months of life, declines over the first 12-

these limit the ability of infant

24 months of life and is reduced in infants

plethysmography to be used in a meaningful

with pulmonary infection. The recent Infant

way in individual infants with chronic lung

Study of Inhaled Saline in Cystic Fibrosis

diseases.

108

ERS Handbook: Paediatric Respiratory Medicine

The use of infant plethysmography in infants

as 21%) has been found in children

with CF, bronchopulmonary dysplasia (BPD)

aged f4 years and in those with

and recurrent wheeze has been recently

neurodevelopmental disabilities (such as

reviewed. Considering that equipment has

children with BPD).

been commercially available for a number of

Standardisation of spirometry for adults and

years there are relatively few published

children aged o6 years requires that

studies with sample sizes that allow for

subjects inhale up to TLC and forcefully

meaningful conclusions to be drawn. In

exhale for at least 3 s (for children ,10 years

general, studies in infants with CF have

of age) or at least 6 s (for children

demonstrated an elevated FRCpleth and,

.10 years of age) until residual volume (RV)

recently, this has been reported to be

is reached, so that FEV1 and FVC can be

associated with pulmonary infections. In

accurately measured. The manoeuvre

contrast to FEV0.5, there was no change in

should also have a good start, meaning an

FRCpleth in the ISIS trial. The few studies in

extrapolated volume ,5% of FVC or

infants with recurrent wheeze suggest the

,0.150 L. This manoeuvre needs to be

presence of air trapping, probably secondary

repeated until at least three manoeuvres are

to airway obstruction, which improves

obtained with the two largest values of FVC

following bronchodilation. In infants born

and FEV1 within 0.150 L of each other.

preterm (with or without BPD) the majority

of studies have reported reduced FRC

Several studies have shown that preschool

obtained with gas dilution techniques

children have difficulty in meeting such

related to the decreased alveolar complexity

acceptability criteria for spirometry.

occurring as a result of altered lung

Preschool children are physiologically

development. FRC using infant

different from older children and adults: they

plethysmography is reported to be elevated

have smaller lung volumes and larger

in infants with BPD and may suggest the

airways with respect to lung volume when

presence of trapped gas.

compared with older children. Therefore,

spirometric manoeuvres in preschool

In summary, the limited information on

children are completed more quickly than in

healthy reference ranges for both the infant

older children, sometimes even in ,1 s. As a

RVRTC and plethysmography techniques,

result, FEV1 is not always measurable and

and a limited understanding on a clinically

indices such as FEV0.75 or FEV0.5 are more

meaningful change have impacted on the

reasonable in this age group. It has been

ability of these lung function tests to

shown that extrapolated volume is lower and

contribute to the clinical management of

extrapolated volume/FVC is higher in

infants with respiratory disease. The

preschool children than in older children

application of lung function testing in

and adults. For these reasons, acceptability

sedated infants and young children is likely

criteria for spirometry in preschool children

to require a combination of tests and careful

are different from those used in older

consideration of pathophysiological changes

children and adults.

and the most appropriate PFT are required.

PFTs in preschool children

Figure 1 shows a preschool child performing

spirometry. The ATS/ERS statement for lung

Preschool spirometry In individuals .5 years

function testing in preschool children has

of age, spirometry is the most commonly

provided appropriate recommendations for

used lung function technique, while it is

spirometry in this age group, which can be

thought that preschool children are not able

summarised as follows:

to perform acceptable spirometry

manoeuvres. Recent studies have

N the child should have time to familiarise

highlighted that spirometry in preschool

themselves with the equipment and

children has a good feasibility (between 47%

operator,

and 92%), especially when an incentive

N incentive software may be used, although

software is used. A lower feasibility (as low

this is not mandatory,

ERS Handbook: Paediatric Respiratory Medicine

109

N the child’s posture (seating or standing)

It requires little collaboration and can be

and the use of a nose clip should be

performed in children as young as 2 years.

reported,

The interruptor resistance (Rint) reflects the

N if the extrapolated volume is .80 mL or

resistance of the respiratory system

12.5% of FVC, the curve should be

(airways, lung tissue and chest wall) and

inspected again but not necessarily

equipment is commercially available. It is

rejected,

assumed that during a sudden flow

N in case of early termination of expiration,

interruption at the mouth:

it may be possible to record FEV0.5,

FEV0.75 and FEV1, but not FVC,

N mouth pressure will equilibrate with

alveolar pressure,

N a minimum of two acceptable

manoeuvres should ideally be obtained,

N the valve closure time will minimise leak,

where the second largest FVC and FEV

N compliance of the upper airway is

values are within 0.1 L or 10% of the

negligible.

highest value; however, poor repeatability

The interruption time is usually ,100 ms.

should not be a reason for automatic

Rint can be calculated by dividing the change

rejection of data.

in mouth pressure at the beginning of the

interruption by the flow measured

Several reference values for spirometry in

immediately before the interruption

preschool children have been reported and

(classical technique) or dividing mouth

these data are now included in the recently

pressure at the end of the interruption by

published reference values of the ERS Global

flow measured immediately after the

Lung Function Initiative. Clinical data on the

interruption (opening technique). The

usefulness of spirometry in preschool

results obtained with the two different

children have also been published.

techniques cannot be used interchangeably.

Interrupter technique The interrupter

technique is a suitable method to measure

The test procedure, technical aspects and

lung function in preschool children.

data analysis for the classical interruptor

technique have been fully described

previously. The child should be seated,

breathing quietly through a mouthpiece and

bacterial filter, wearing a nose clip and with

the cheeks supported (fig. 2). Each occlusion

Figure 1. Preschool child performing spirometry.

Figure 2. Preschool child performing Rint.

110

ERS Handbook: Paediatric Respiratory Medicine

should be triggered during expiration by a

points of inspiratory and expiratory

flow set to coincide with peak expiratory flow

pressure;

and 10 interruptions should be recorded, with

N resistance at the peak of flow (sRaw,peak);

the aim of obtaining a minimum of five

N effective specific resistance (sReff), which

acceptable manoeuvres. At the end of the test

is the least-squared regression of

the median value of all technically acceptable

pressure and flow throughout the

interruptions should be reported.

breathing cycle.

International reference equations for males

Being a product of a volume and a

and females have been recently published.

resistance, an abnormal value can indicate

Measurements of Rint have been shown to

changes in both components. It has been

have a good intra-measurement and

recently recommended that sReff should be

between-test repeatability.

calculated since it measures sRaw over the

entire breathing cycle.

The feasibility of Rint in preschool children is

.80% in most studies. The sensitivity and

Preliminary reference equations for sRaw have

specificity for different bronchodilator

been recently published; however, the authors

response (BDR) cut-off levels to

highlight that those reference values can only

discriminate between healthy and asthmatic

be used when similar measurement

conditions are applied. In a recent study

children are available.

conducted in the UK, statistically significant

In the clinical setting, Rint can be used to

differences were reported for sRaw measured

measure lung function in children with

in three different centres, suggesting that

different respiratory diseases such as

even after a methodological standardisation

wheezing, CF or BPD. BDR assessed using

reference values cannot be used inter-

Rint is probably more useful for asthma

changeably between different laboratories.

diagnosis than for excluding asthma.

The repeatability of measuring sRaw in

However, as the definitions of different

preschool children has shown intra-subject

phenotypes of preschool wheezing are

coefficients of variation of ,9-13%.

complex, recent recommendations suggest

Feasibility is also good, being ,80% in

that in the individual patient measuring lung

3-6 year olds.

function, including BDR, can help to

differentiate common wheezing disorders

In preschool children, sRaw has been shown

from other diseases.

to be able to detect airway calibre changes

after bronchodilation. Preschool children

Plethysmographic specific airway resistance In

with asthma were found to have higher sRaw

cooperating children, airway resistance

than healthy children and, in a longitudinal

(Raw) can be measured with whole body

cohort study, high sRaw at 3 years of age was

plethysmography, where the subject is asked

found to predict the persistence of recurrent

to breathe against a closed shutter to obtain

wheezing at 5 years of age. In preschool

thoracic gas volume (TGV). In preschool

children with CF, sRaw was also found to be

children the measurement of specific Raw

higher than in healthy children and was

(sRaw), only requiring minimal collaboration

shown to be more sensitive than spirometry

during tidal breathing, has been proposed.

in detecting early lung disease, although less

sRaw is defined as the product of Raw

sensitive than the lung clearance index from

multiplied by FRCpleth and its calculation

multiple-breath washout.

avoids the need to perform breathing

manoeuvres against a closed shutter.

Conclusion

Several indices for sRaw have been

The optimal lung function test to be used in

proposed, such as:

infants and preschool children depends on

the clinical or research questions that need

N total specific resistance (sRaw,tot), which

to be answered. In preschool children with

is the slope of the line between the two

wheezing the interruptor technique,

ERS Handbook: Paediatric Respiratory Medicine

111

plethysmographic sRaw and forced

Frey U, et al. (2000). Specifications for

oscillation technique appear to be the most

equipment used for infant pulmonary

suitable to provide information on the

function testing. Eur Resp J; 16: 731-740.

change in airway calibre. However,

Kirkby J, et al.

(2010). Reference equa-

techniques that are able to detect more

tions for specific airway resistance in

peripheral changes (such as the washout

children: the Asthma UK initiative. Eur

techniques and, potentially, forced

Respir J; 36: 622-629.

Lowe LA, et al. (2005). Wheeze pheno-

oscillation technique) appear more suitable

types and lung function in preschool

in studying diseases such as CF or BPD.

children. Am J Respir Crit Care Med; 171:

231-237.

In conclusion, measuring lung function in

Mele L, et al. (2010). Assessment and

infants and preschool children is possible

validation of bronchodilation using the

thanks to standardised techniques that

interrupter technique in preschool chil-

require minimal cooperation from the child.

dren. Pediatr Pulmonol; 45: 633-638.

Further studies will need to highlight the

Merkus PJ, et al. (2010). Reference ranges

role of single tests in the clinical

for interrupter resistance technique: the

management of infants and preschool

Asthma UK Initiative. Eur Respir J;

36:

children with respiratory illness.

157-163.

Miller MR, et al. (2005). Standardisation

of spirometry. Eur Respir J; 26: 319-338.

Further reading

Pillarisetti N, et al.

(2011). Infection,

ATS/ERS statement

(2005). Raised

inflammation, and lung function decline

volume forced expirations in infants:

in infants with cystic fibrosis. Am J Respir

guidelines for current practice 2005. Am

Crit Care Med; 184: 75-81.

J Respir Crit Care Med; 172: 1463-1471.

Quanjer PH, et al. (2012). Multi-ethnic

Aurora P, et al. (2005). Multiple-breath

reference values for spirometry for the 3-

washout as a marker of lung disease in

year age range: the global lung

preschool children with cystic fibrosis.

function

2012

equations. Eur Respir J;

Am J Respir Crit Care Med; 171: 249-256.

40: 1324-1343.

Beydon N, et al.

(2007). An official

Rosenfeld M, et al. (2013). An official ATS

American Thoracic Society/European

workshop report: Optimal lung function

Respiratory Society statement: pulmonary

tests for monitoring cystic fibrosis,

function testing in preschool children.

bronchopulmonary dysplasia and recur-

Am J Respir Crit Care Med; 175: 1304-1345.

rent wheezing in children less than

Bisgaard H, et al.

(2005). Plethy-

years of age. Ann Am Thorac Soc; 10: S1-

smographic measurements of specific

S11.

airway resistance in young children.

Sonnappa S, et al.

(2010). Symptom-

Chest; 128: 355-362.

pattern phenotype and pulmonary func-

Brand PL, et al.

(2008). Definition,

tion in preschool wheezers. J Allergy Clin

assessment and treatment of wheezing

Immunol; 126: 519-526.

disorders in preschool children: an

Stocks J, et al. (2001). Plethysmographic

evidence-based approach. Eur Respir J;

measurements of lung volume and airway

32: 1096-1110.

resistance. Eur Respir J; 17: 302-312.

112

ERS Handbook: Paediatric Respiratory Medicine

Single- and multiple-breath

washout techniques

Sophie Yammine and Philipp Latzin

Inert-gas washout (IGW) has been re-

Anatomical and physiological background

established in recent years as one of the

The dichotomous branching structure of the

most sensitive lung function tests for

lung, resulting in .100 m² of lung surface,

assessing small-airway function. It can be

has evolved to facilitate gas exchange. In the

performed over a single tidal breath, termed

conducting airways (generations 0-16), gas

single-breath washout (SBW), or over a

transport mainly occurs by convection, and

series of tidal breaths, termed multiple-

in the intra-acinar airways (generations 17-

breath washout (MBW). Recent

23), mainly by diffusion. In the transition

developments have led to commercially

zone at the entry to the acinus, both

available and user-friendly washout

mechanisms show a similar contribution.

equipment, mirroring the increasing interest

The definition of small airways is derived

in a transition of IGW tests from research

from post mortem adult data and includes all

into clinical routine.

airways with a luminal diameter of ,2 mm

(corresponding to generations 8-23).

Pathological processes such as mucus

Key points

impaction, hyperinflation, obstruction and

bronchiectasis affect these gas transport

IGW is based on washing in and out

mechanisms and lead to inefficient gas

inert tracer gases to assess the gas

mixing, which can be detected and

mixing efficiency of the lung.

quantified using IGW.

The most important outcome

Evolution of IGW

parameter of MBW is the LCI,

calculated as the cumulative expired

The IGW technique was introduced in the

volume needed to clear the lungs of

1950s. Most data from the last 15 years have

the tracer gas divided by the lung size

been obtained using sulfur hexafluoride as

(FRC).

the inert tracer gas. However, because of its

potent greenhouse gas effect, in many

IGW seems most sensitive in children

countries, sulfur hexafluoride is no longer

with CF for detecting early lung

available. Furthermore, bulky and expensive

disease; its role in other disease

mass spectrometers, the gold standard for

groups is currently less well examined.

sulfur hexafluoride analysis, are not suited

After early studies demonstrating the

to routine clinical use. This has led to a

feasibility and usefulness of washout

renaissance of nitrogen washout using

measurements in children,

100% oxygen, which had previously been

commercially available equipment,

abandoned, for observing alterations in

and new guidelines for

infant breathing patterns. An ultrasonic flow

standardisation will now enable the

meter nitrogen MBW setup is now

implementation of MBW in routine

commercially available. It is based on the

clinical practice.

measurement of oxygen, carbon dioxide and

molar mass with indirect calculation of the

ERS Handbook: Paediatric Respiratory Medicine

113

nitrogen concentration. Nitrogen MBW

breathing pattern. After reaching

measurement has been demonstrated to be

equilibration of the exogenous washed-in

safe and feasible at school and preschool

gas, the gas is switched off and the washout

age, whereas in infants, sulfur hexafluoride

is started. For nitrogen MBW, the test starts

is currently still standard.

directly with the washout by switching into

100% oxygen (fig. 2). The washout is

SBW technique and parameters

terminated when the end-tidal gas

concentration reaches values below 1/40 of

SBW is classically performed using a vital

its starting concentration. The current

capacity (VC) manoeuvre (fig. 1) but can also

standard requires at least two, ideally three,

be done during tidal breathing, which has

valid test runs. New guidelines for IGW

the advantage of being feasible even in

measurement extended for all age groups

children younger than 10-12 years. The SBW

have just been published.

expirogram shows the tracer gas

concentration over expired volume, where

The main outcome parameter of MBW,

phase III represents the expired gas from the

reflecting overall ventilation inhomogeneity,

alveolar zone (fig. 1). The main outcome

is the lung clearance index (LCI), calculated

parameter of SBW is the slope of phase III

as the cumulative expired volume needed to

(SIII), representing the efficiency of gas

clear the lungs of the tracer gas divided by

mixing in the small airways.

the functional residual capacity (FRC).

Based on SIII analysis of washout breaths,

MBW technique and parameters

more specific indices have been developed

MBW is better established than SBW. As a

reflecting the convection-dependent

tidal breathing test, it is easy to perform in

inhomogeneity (Scond) and diffusion-

children. It requires an adequate

convection-dependent inhomogeneity

mouthpiece/facemask seal and a regular

(Sacin). Abnormalities in these indices allow

assignment of ventilation inhomogeneity to

proximal, conducting (increase in Scond) or

Closing volume phase IV

distal, intra-acinar (Sacin) airways.

Phase III slope

Clinical application of inert gas washout

Normative data The advantage of LCI as an

outcome parameter of MBW is an intrinsic

Alveolar phase III

correction for variations in lung size, with

FRC as the denominator. This is reflected in

the consistency of LCI normative data

ranges across wide age groups. The normal

Bronchial phase II

range is surprisingly constant, with LCI

values ,8. The availability of commercial

nitrogen MBW equipment and the effort for

standardised operating procedures will

Dead space phase I

contribute to a more uniform normative

0.0

0.5

1.0

1.5

2.0

data set for LCI.

Tidal volume L

In a tidal breathing test, it is important to

appraise the range of normal variability as a

Figure 1. Classical VC nitrogen SBW in a normal

prerequisite to distinguishing pathological

subject. The four sequential phases of the

values. Within-test repeatability is well

expirogram are: phase I, representing the absolute

dead space; phase II, the bronchial phase; phase

documented for LCI, with reported

III, the alveolar phase; and phase IV, delimiting

coefficients of variation between 3% and 8%

the closing volume (in tidal-breath SBW, phase IV

in health and disease. Current guidelines

is missing). The slope of phase III is calculated by

recommend FRC/LCI variability ideally be

linear regression over phase III (%?L^-1).

,10% for the three test runs with acceptable

114

ERS Handbook: Paediatric Respiratory Medicine

100

120

140

160

Time s

Figure 2. A nitrogen MBW test in a healthy adolescent. The raw signals flow (black), oxygen (blue) and

carbon dioxide (green) are plotted against time. The nitrogen concentration (brown) is calculated

indirectly as 100-([O₂]+[CO₂]+[Ar]).

FRC variability up to 25% if technical

airways is still debated. Regarding the clinical

reasons are ruled out. Data on

utility of LCI, longitudinal tracking could be

reproducibility over longer time periods are

demonstrated throughout childhood. Most

scarce and show variability comparable to

importantly for future studies, two

the within-test repeatability. This is

randomised controlled trials studying

important to consider for reliable clinical use

mucociliary clearance regimens in subjects

of LCI as an outcome parameter and for

with mild CF lung disease have shown that

longitudinal tracking.

LCI was a sensitive study end-point and

superior to spirometry outcomes.

Clinical utility The majority of paediatric

MBW studies have focused on CF. Few

Few promising results exist in children with

paediatric studies exist in other disease

CF using both VC and tidal SBW of tracer

groups, such as asthma or

gases. Those methods still represent

bronchopulmonary dysplasia (BPD).

research tools requiring further

development.

Airway involvement without clinical

symptoms is an early component in children

In adult asthmatics, SIII analysis from MBW

with CF due to infectious and inflammatory

and SBW has shown promising results with

lung disease. Compared to HRCT, it has been

regards to predicting the response to dose

shown that MBW is sensitive to early changes

titration of inhaled corticosteroid and

in children with CF, with clear superiority over

demonstrated that different

spirometry and other lung function tests. In

bronchoprovocative agents exhibit their

all cross-sectional studies, LCI was signifi-

effects at different sites in the airways. In

cantly higher in the CF group compared

children, only a few studies exist, yielding

to healthy controls, with increasing

less clear results. Future findings will help to

differences with age. Whether this

better understand the physiological

reflects changes in small or medium-sized

processes of different phenotypes in asthma

ERS Handbook: Paediatric Respiratory Medicine

115

and might provide new insights into specific

Beydon N, et al.

(2007). An official

diagnostic and therapeutic effects.

American Thoracic Society/European

Respiratory Society statement: pulmon-

Data in infants with BPD are controversial.

ary function testing in preschool chil-

On one hand, a pattern of increased

dren. Am J Respir Crit Care Med;

175:

ventilation inhomogeneity and decreased

1304-1345.

FRC was described in a group of infants at

Crawford AB, et al. (1985). . Convection-

term using nitrogen MBW. On the other

and diffusion-dependent ventilation mal-

hand, in two larger groups of infants at later

distribution in normal subjects. J Appl

gestational age, no effect of BPD was found

Physiol; 59: 838-846.

on LCI or FRC using sulfur hexafluoride

Estenne M, et al. (2000). Detection of

MBW. Several points may explain these

obliterative bronchiolitis after lung trans-

different findings: differences in washout

plantation by indexes of ventilation dis-

equipment and gases, especially the

tribution. Am J Respir Crit Care Med; 162:

imprecision of the older nitrogen analysers;

1047-1051.

Farah CS, et al.

(2012). Ventilation

the use of sedation; and changes in the

heterogeneity predicts asthma control in

pathophysiology of BPD over time. The

adults following inhaled corticosteroid

utility of MBW in BPD thus remains unclear

dose titration. J Allergy Clin Immunol;

and needs further study as well as

130: 61-68.

longitudinal follow-up.

Gustafsson PM, et al. (2008). Multiple-

In adults, parameters of IGW (SIII of SBW

breath inert gas washout and spirometry

versus structural lung disease in cystic

and MBW) showed a high sensitivity in

fibrosis. Thorax; 63: 129-134.

detecting the early stages of bronchiolitis

Kieninger E, et al.

(2011). Long-term

obliterans syndrome, a well-known

course of lung clearance index between

complication after haematopoietic stem cell

infancy and school-age in cystic fibrosis

transplantation. Preliminary data in children

subjects. J Cyst Fibros; 10: 487-490.

confirm these findings.

Latzin P, et al.

(2009). Lung volume,

breathing pattern and ventilation inho-

Future directions and open questions

mogeneity in preterm and term infants.

The widespread application of IGW has the

PLoS ONE; 4: e4635.

potential for early detection of diseases and

Ljungberg HK, et al. (2003). Peripheral

more specific monitoring in children. MBW

airway function in childhood asthma,

is on the verge of being implemented in CF

assessed by single-breath He and SF₆

washout. Pediatr Pulmonol;

36:

339-

clinics, opening the field for investigation of

347.

the immediate and long-term benefits of its

Owens CM, et al. (2011). Lung clearance

application. One important question will be

index and HRCT are complementary

whether LCI-directed treatment can change

markers of lung abnormalities in young

disease outcome in patients with CF. SBW

children with CF. Thorax; 66: 481-488.

in children still represents a research tool

Paiva M

(1973). Gas transport in the

and needs further development regarding

human lung. J Appl Physiol; 35: 401-410.

robustness and standardisation.

Ratjen F (2012). Cystic fibrosis: the role of

the small airways. J Aerosol Med Pulm

Drug Deliv; 25: 261-264.

Further reading

Robinson PD, et al. (2013). Guidelines for

Amin R, et al. (2010). Hypertonic saline

inert gas washout measurement using

improves the LCI in paediatric patients

multiple and single breath tests. Eur

with CF with normal lung function.

Respir J; 41: 507-522.

Thorax; 65: 379-383.

Singer F, et al. Practicability of nitrogen

Aurora P, et al. (2004). Multiple breath

multiple-breath washout measurements

inert gas washout as a measure of

in a pediatric cystic fibrosis outpatient

ventilation distribution in children with

setting. Pediatr Pulmonol 2012 [In press

cystic fibrosis. Thorax; 59: 1068-1073.

DOI: 10.1002/ppul.22651].

116

ERS Handbook: Paediatric Respiratory Medicine

Forced oscillation techniques

Shannon J. Simpson and Graham L. Hall

Theoretical background

respiratory system (Rrs), and an imaginary

part, respiratory system reactance (Xrs).

The forced oscillation technique (FOT) was

first introduced by Du Bois in 1956 as a

The majority of FOT studies in humans have

method capable of informing physicians

been conducted using medium frequency

ranges (4-50 Hz), with oscillations

about the mechanical behaviour of the

superimposed over spontaneous breathing.

respiratory system. In short, time-varying

However, low frequency oscillations have

pressures (or flows) are generated from a

been applied during apnoea, particularly

loudspeaker at one or more frequencies,

during infancy, allowing the assessment of

which in the modern day environment is

airway and tissue contributions to

generally several sinusoidal wave forms

impedance via mathematical partitioning. In

(pseudorandom noise) or a rectangular

the medium frequency range, Xrs is

wave, as with the impulse oscillation system

dominated by the tissue elastic properties at

(IOS). This signal is applied at the airway

frequencies below the resonant frequency

opening and the resulting flow (or pressure)

(fres; where Xrs 5 0) and the inertial

response of the respiratory system is

properties of the gas in the airways at higher

measured in addition to the phase shift

frequencies. In younger children, Rrs also

between these signals. This pressure to flow

exhibits some frequency dependence in the

ratio is defined as the mechanical input

medium frequency range which decreases in

respiratory system impedance (Zrs). As Zrs

older children and adults. Typical

is a complex function of frequency, it is

impedance spectra across the medium

comprised of a real part, resistance of the

frequency range in young children are shown

in figure 1.

Use of the FOT in young children

Key points

The FOT is ideal for use in young children

The FOT can be used to measure

who are unable to adequately cooperate

respiratory mechanics with oscillatory

during traditional lung function tests and

signals superimposed over tidal

has been applied in children as young as

breathing in awake children as young

2 years of age with success rates .80% in

as 2 years of age.

young children. Commercially available FOT

devices are currently available and

N Alterations in respiratory mechanics

guidelines have been established for the use

have been evaluated in several

of FOT in young children.

commonly encountered paediatric

diseases including asthma, CF and

Data collection and repeatability The child

BPD; however, further work is

should be seated in the upright position with

required to cement a place for the

a neutral head position, a nose clip in place

FOT in the routine clinical

and a good seal around the mouthpiece. The

management of such diseases.

cheeks and floor of the mouth must be firmly

supported to minimise the upper airway

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ERS Handbook: Paediatric Respiratory Medicine

signal and the frequencies of reported

Healthy

outcomes can make a comparison difficult.

Asthma

In addition, much of the available reference

BPD

data has been collected in Caucasian

populations. The majority of published

reference equations use height as the only

predictor of FOT outcomes, although sex

was shown to contribute to Rrs, Xrs and the

area under the Xrs curve (integrated area of

reactance below the resonant frequency

(AX)) in a recently published large study.

Generally, Rrs is reported at frequencies of 5-

-5

10 Hz, which is believed to approximate

values of airway resistance. However,

-10

resistances at higher frequencies are also, at

least theoretically, valuable and therefore the

Frequency Hz

resistance and reactance curves should be

considered as a function of the whole

Figure 1. Impedance spectra in a healthy child and

frequency range in clinical applications of the

in young children with lung disease. The

components of respiratory system impedance,

FOT. For example, the frequency dependence

resistance (top) and reactance (bottom) are shown

(fdep) defined as the slope of the resistance-

across the medium frequency range. An average of

frequency curve or the AX, which has been

three impedance measurements were obtained

proposed as an index of respiratory system

from four boys aged 4.4 years and 105 cm tall for

elastance, may be particularly appropriate.

comparison between disease states. Differences in

Recently published normative data for these

Rrs, Xrs, AX, fres and fdep

are evident, to varying

FOT outcomes will facilitate further

extents, in commonly encountered paediatric

information on their clinical utility.

diseases when compared to a typical healthy child.

Clinical utility

shunting of input flows. Measurements

should be obtained over several breathing

Alterations in respiratory mechanics have

cycles with no leak, vocalisation, swallowing,

been evaluated in respiratory diseases

glottic closure or movement and the average

commonly encountered in the paediatric

of three to five acceptable measurements

setting using the FOT. However, it is

should be reported.

reasonable to speculate that the FOT would

be most clinically useful in paediatric

Within a testing session, the coefficient of

diseases with pathophysiology in the distal

variation for Rrs has generally been reported

lung. Although the FOT is able to detect

as ,10%, while the coefficient of

changes in airway calibre after therapeutic

repeatability (twice the standard deviation of

interventions, to date, its role in the

the difference between two measurements

management of individual patients remains

taken 15 min apart) ranges between 1.1 and

unclear. Examples of impedance

2.6 hPa?s^-1?L^-1 for Rrs and equates to a

measurements in children with commonly

relative change of 12-30% with similar

encountered respiratory diseases in the

repeatability reported over a 2-week period

paediatric clinic are given in figure 1.

and in children with CF and

Asthma and wheeze The majority of research

bronchopulmonary dysplasia (BPD). The

using the FOT has been performed in young

repeatability of Xrs is reported as absolute

children with recurrent wheeze. The ability of

values and ranges from 1.2 to 2.0 hPa?s^-1?L^-1.

the FOT to sensitively distinguish between

Reporting of outcomes and normative data

healthy and wheezy preschool children

The upper and lower limits of normal are

before or after the administration of

defined, although differences in oscillatory

bronchodilator remains unclear.

ERS Handbook: Paediatric Respiratory Medicine

119

Some studies have shown no difference in

the FOT has been used less extensively in

baseline lung function and bronchodilator

young children born preterm. Further

responsiveness between healthy and wheezy

studies to examine the changes to FOT

children, while others have shown

outcomes during development following

significant differences, even between

preterm birth would be particularly

different wheezing phenotypes. Several

beneficial.

studies have defined the response to

Other/potential clinical utility The FOT has

bronchodilators in healthy populations with

also been used to examine the temporal

relative cut-off values (derived from the 5th

changes in respiratory mechanics, although

to 95th centiles) in the range of -33- -42%

primarily as a research tool rather than in

for Rrs, 61-70% for Xrs and 81% for AX,

clinical practice. Such studies have

regardless of the salbutamol dose; although

examined temporal changes over the normal

most studies administered 200 mg of

breathing cycle as a method of detecting

salbutamol.

expiratory flow limitation, the effect of deep

The FOT has been used to assess bronchial

inspiration on respiratory mechanics and

hyperresponsiveness in young children, with

the monitoring of upper airway patency

significant increases in Rrs and decreases in

during sleep. The technique also has

Xrs reported during both direct and indirect

potential for the noninvasive assessment of

bronchial challenge tests. The FOT

respiratory mechanics in patients receiving

outcome most useful for monitoring

mechanical ventilation for acute respiratory

bronchoconstriction during bronchial

failure. While perhaps underutilised in this

provocation is yet to be defined. The

area, the FOT is able to detect and quantify

respiratory system admittance, the

upper or central airway diseases including

reciprocal of Zrs, is more sensitive to

tracheal stenosis, tracheo-oesophageal

bronchoconstriction than the commonly

fistula, laryngeal obstruction and vocal cord

used Rrs due to the elimination of the upper

dysfunction; although separation of

airway artefact. Previous studies have used

inspiratory and expiratory impedances to

various changes in Rrs to define a positive

examine the flow dependence during each

response to bronchial provocation and the

phase of the respiratory cycle would likely

most appropriate cut-off for a positive

yield most information in this group of

response is yet to be validated. The

patients.

development of shortened protocols for

Future directions

challenge tests using the FOT, such as for

adenosine 59-monophosphate, may help to

The measurement of respiratory system

overcome the shorter attention span of

impedance has the potential to provide a

young children.

great deal of information on a variety of

conditions during the early years of life;

Cystic fibrosis CF begins in the peripheral

however, further work is required if the FOT

airways and lung function tests sensitive to

is to reach its full clinical potential. In the

small airway dysfunction are likely to be best

short term it is important to explore other

at monitoring early CF lung disease. The role

FOT outcomes in addition to the

of the FOT in monitoring CF lung disease is

traditionally reported Rrs at a single

unclear with some studies reporting that the

frequency with the knowledge that the

FOT fails to adequately identify airway

pathophysiological mechanisms of many

obstruction in young children with CF. In

respiratory diseases exhibit strong

contrast, increased Rrs and decreased Xrs

peripheral lung involvement during early life.

have been reported in young children with

For example, measures of Xrs or AX may be

CF particularly in the presence of respiratory

more sensitive at monitoring the course of

symptoms.

those respiratory disorders. We must also

Bronchopulmonary dysplasia Despite the

work towards understanding which FOT

observation that Rrs, Xrs, fres and fdep are

outcomes are most relevant for particular

frequently abnormal in children with BPD,

pathologies as one outcome for all disease

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ERS Handbook: Paediatric Respiratory Medicine

approach may not be appropriate. In the

in asthmatic children and cystic fibrosis

longer term it is important to gain an

patients. Eur Respir J; 10: 891-895.

understanding of how respiratory mechanics

Nielsen KG, et al.

(2004). Serial lung

alter longitudinally during development and

function and responsiveness in cystic

what kind of deviation from this path

fibrosis during early childhood. Am J

Respir Crit Care Med; 169: 1209-1216.

requires intervention.

Oostveen E, et al. (2010). Lung function

and bronchodilator response in 4-year-old

Further reading

children with different wheezing pheno-

types. Eur Respir J; 35: 865-872.

Bates JHT, et al.

(2011). Oscillation

Oostveen E, et al.

(2003). The forced

mechanics of the respiratory system.

oscillation technique in clinical practice:

Compr Physiol; 1: 1233-1272.

methodology, recommendations and

Beydon N, et al.

(2007). An official

future developments. Eur Respir J;

22:

American Thoracic Society/European

1026-1041.

Respiratory Society statement: pulmonary

Rigau J, et al.

(2004). Oscillometric

function testing in preschool children.

assessment of airway obstruction in a

Am J Respir Crit Care Med; 175: 1304-1345.

mechanical model of vocal cord dysfunc-

Calogero C, et al.

(2013). Respiratory

tion. J Biomech; 37: 37-43.

impedance and bronchodilator respon-

Rosenfeld M, et al.

(2013). An Official

siveness in healthy children aged 2 to 13

American Thoracic Society Workshop

years. Pediatr Pulmonol; 48: 707-715.

Report: Optimal lung function tests for

Gangell CL, et al.

(2007). Respiratory

monitoring cystic fibrosis, bronchopul-

impedance in children with cystic fibrosis

monary dysplasia and recurrent wheezing

using forced oscillations in clinic. Eur

in children

,6 years of age. Ann Am

Respir J; 30: 892-897.

Thorac Soc; 10: S1-S11.

Hall GL, et al. (2009). Application of a

Simpson SJ, et al. (2012). Clinical inves-

shortened inhaled adenosine-5’-mono-

tigation of respiratory system admittance

phosphate challenge in young children

in preschool children. Pediatr Pulmonol;

using the forced oscillation technique.

47: 53-58.

Chest; 136: 184-189.

Sly PD, et al.

(1996). Measurement of

Hellinckx J, et al. (1998). No paradoxical

low-frequency respiratory impedance in

bronchodilator response with forced

infants. Am J Respir Crit Care Med; 154:

oscillation technique in children with

161-166.

cystic fibrosis. Chest; 113: 55-59.

Thamrin C, et al. (2007). Assessment of

Hoijer U, et al.

(1991). The ability of

bronchodilator responsiveness in pre-

noninvasive methods to detect and

school children using forced oscillations.

quantify laryngeal obstruction. Eur Respir

Thorax; 62: 814-819.

J; 4: 109-114.

Udomittipong K, et al.

(2008). Forced

Klug B, et al.

(1998). Specific airway

oscillations in the clinical setting in young

resistance, interrupter resistance, and

children with neonatal lung disease. Eur

respiratory impedance in healthy children

Respir J; 31: 1292-1299.

aged 2-7 years. Pediatr Pulmonol; 25: 322-

Vrijlandt EJ, et al.

(2007). Respiratory

331.

health in prematurely born preschool

Lebecque P, et al. (1997). Respiratory resi-

children with and without bronchopul-

stance by the forced oscillation technique

monary dysplasia. J Pediatr; 150: 256-261.

ERS Handbook: Paediatric Respiratory Medicine

121

Polysomnography

Sedat Oktem and Refika Ersu

Evaluation of children with suspected sleep

Key points

disorders is primarily based on a thorough

history. In appropriate cases the diagnostic

process includes performance of

N Clinicians should enquire whether the

child or adolescent snores and, if so,

polysomnography (PSG), most commonly

obtain a PSG.

for characterisation of breathing during

sleep. Because PSG is a relatively expensive

N PSG is the gold standard for the

procedure requiring significant time and

diagnosis of sleep-disordered

healthcare resources, understanding the

breathing in children.

strengths, limitations, and clinical utility of

N If PSG is not available, then clinicians

PSG is necessary to ensure optimal

may order alternative diagnostic tests,

utilisation.

such as nocturnal video recording,

Respiratory indications for PSG in children

nocturnal oximetry, daytime nap PSG

or ambulatory PSG.

Diagnosis for sleep-related breathing disorders

N Paediatric PSG should be performed

PSG is indicated when:

in a sleep laboratory equipped for

N the clinical assessment suggests a

children and staffed by qualified

diagnosis of OSAS in children;

personnel following the American

N the clinical assessment suggests a

Thoracic Society standards for testing.

diagnosis of congenital central alveolar

N Age-adjusted rules for the scoring and

hypoventilation syndrome or sleep-

interpretation of PSGs should be used

related hypoventilation due to

for children.

neuromuscular disorders or chest wall

deformities (it is indicated in selected

cases of primary sleep apnoea in infancy);

PSG is indicated following

N there is clinical evidence of a sleep-

adenotonsillectomy to assess for residual

related breathing disorder in infants who

sleep-related breathing disorder in children

have experienced an apparent life-

with pre-operative evidence for moderate-

threatening event.

to-severe OSAS, obesity, craniofacial

anomalies that obstruct the upper airway

Pre-operative PSG is indicated in children

and neurological disorders (e.g. Down

being considered for adenotonsillectomy to

syndrome, Prader-Willi syndrome and

treat OSAS.

myelomeningocele). It is also indicated

Assess response to treatment Children with

after treatment of children for OSAS with

mild OSAS pre-operatively should undergo

rapid maxillary expansion to assess for the

clinical evaluation following

level of residual disease and to determine

adenotonsillectomy to assess for residual

whether additional treatment is necessary.

symptoms. If there are residual symptoms

Children with OSAS treated with an oral

of OSAS then PSG should be performed.

appliance should have clinical follow-up

122

ERS Handbook: Paediatric Respiratory Medicine

and PSG to assess response to

Polysomnography

treatment.

PSG in children should be performed in the

PSG is indicated for positive airway pressure

proper setting. In young children, this will

titration in children with OSAS and for

mean that the study has to be attended

noninvasive positive pressure ventilation

during the whole night by a trained

titration in children with other sleep-related

technician to ensure the quality of the study.

breathing disorders.

It is equally important to note that none of

the current polysomnographic systems can

Follow-up PSG in children on chronic

generate accurate automated reports on

positive airway pressure support is indicated

paediatric polysomnographic studies. An

to determine whether pressure requirements

automated report can both underestimate

have changed as a result of the child’s

and overestimate the clinical condition. For

growth and development, if symptoms recur

this reason, paediatric polysomnographic

while on positive airway pressure, or if

studies should be reviewed manually using

additional or alternative treatment is

the raw data by trained physicians with

required.

knowledge on paediatric polysomnographic

studies. The accuracy and agreement of

Children treated with mechanical ventilation

manual scoring is dependent on the training

may benefit from periodic evaluation with

background and the experience of the

PSG to adjust ventilator settings. PSG for

physicians. In the best hands, an interscorer

the management of oxygen therapy is not

agreement of at least 70-80% is expected.

routinely required in children treated with

In general, the result from a single night’s

supplemental oxygen. Children treated with

study is sufficient for the diagnostic purpose

tracheostomy for sleep-related breathing

of children with suspected OSAS. A ‘‘first

disorders benefit from PSG as part of the

night effect’’ has been described in adults,

evaluation prior to decannulation. These

whereby sleep differs during the first night in

children should be followed clinically after

a sleep laboratory compared to subsequent

decannulation to assess for recurrence of

nights. Two studies assessing ‘‘first night

symptoms of sleep-related breathing

effect’’ in children have shown that the

disorders.

parameters are no different between the first

Respiratory diseases PSG is indicated in the

and second nights.

following respiratory disorders, but only if

Technique Standard PSG consists of

there is clinical suspicion of an

electroencephalogram, electromyogram

accompanying sleep-related breathing

(submental and tibial), electrooculogram

disorder:

(right/left), oximetry, end-tidal carbon

dioxide tension (PetCO₂), oronasal airflow

N chronic asthma,

(thermistor), nasal pressure sensor,

N CF,

respiratory inductance plethysmography,

N pulmonary hypertension,

electrocardiography and a body position

N bronchopulmonary dysplasia,

sensor. Children are also monitored and

N chest wall abnormalities, such as

recorded on an audio/videotape using an

kyphoscoliosis.

infrared video camera. Each child is

continuously observed by a technician

Clinical evaluation alone does not have

trained in paediatric PSG who also records

sufficient sensitivity or specificity to

sleep behaviour and respiratory events

establish a diagnosis of OSAS. Clinical

(table 1 and fig. 1).

parameters such as history, physical

examination, audio or visual recordings, and

Electroencephalogram The international 10-

standardised questionnaires do not

20 system of electrode placement is used to

consistently identify the presence or absence

determine surface electrode placement. The

of OSAS when compared with PSG.

American Academy of Sleep Medicine (AASM)

ERS Handbook: Paediatric Respiratory Medicine

123

EEG

● ●

EOG

●

Nasal PETCO2

Airflow

Chin EMG (2)

Microphone

●●

●

ECG

SpO2

●

Video camera to

Respiratory

record behaviour

effort

Technician′s note

Leg EMG (2)

●

Figure 1. Components of PSG in children.

Table 1. Components of PSG in children

Electroencephalogram activity: current AASM recommendations are F4-M1, C4-M1 and O2-M1

with backup (F3-M2, C3-M2 and O1-M2), and are a change from the previous recommendation of

C3 or C4 referenced to A1 or A2

Eye movements (electrooculogram) from electrodes placed near the outer canthus of each eye

Submental electromyographic activity from electrodes placed over the mentalis, submentalis

muscle and/or masseter regions

Rhythm ECG with one lead II electrode or more chest leads at the discretion of the provider

Respiratory effort by chest-wall and abdominal movement via strain gauges, piezoelectric belts,

inductive plethysmography, impedance or inductance pneumography and endo-oesophageal

pressure

(Note: the AASM does not recommend strain gauges or piezoelectric belts)

Nasal-oral airflow via a thermistor, nasal pressure transducer or pneumotachograph, or

inductance plethysmography

SpO₂ including waveform with an averaging time of f3 s

PetCO₂ or PtcCO₂

Body position via sensor and direct observation

Limb movements (right and left legs) via electromyogram

Snoring recording or vibration (frequency and/or volume)

Audio/video recording by infrared or low-light equipment

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ERS Handbook: Paediatric Respiratory Medicine

recommends F4-M1, C4-M1 and O2-M1.

Nasal-oral airflow This is best measured

Since children frequently displace leads

and/or monitored by nasal pressure

during sleep, contralateral leads are

transduction and continuous monitoring of

typically applied as well (F3-M2, C3-M2

the capnography waveform. Thermistor

and O1-M2). Children have high-amplitude

application has been the standard technique

brain waves; thus, electroencephalogram

in adult laboratories but might not be as

recordings may need a sensitivity of 10-

sensitive a measure of airflow as pressure is

15 mV?mm^-1, as compared to 5 mV?mm^-1 in

in children.

adults.

Oxygen saturation The sensor is

Electrooculogram Eye movements are

incorporated into a soft cuff that fits around

detected by placing surface electrodes near

a finger or toe or clips to an ear lobe.

the outer canthus of each eye. The

Children tend to move frequently during

electrooculogram electrodes should be

sleep, so the monitoring of the pulse

offset from horizontal, one slightly above

waveform in addition to the saturation value

and one slightly below the horizontal plane

is helpful in distinguishing motion artifact

to detect both horizontal and vertical eye

from true desaturation. This output can also

movements. As infants and young children

be used for more sophisticated analyses,

have smaller heads than adults,

such as the measurement of pulse transit

electrooculographic leads may need to be

time.

placed 0.5 cm from the outer canthi.

Carbon dioxide Measurements of carbon

Electromyogram Two surface electrodes are

dioxide have been used in two contexts

placed either on the mentalis or submentalis

during PSG:

to detect muscle activity. Again, as infants

and young children have smaller heads than

N PetCO₂ as an indicator of airflow

adults, chin electromyogram electrodes may

obstruction and, hence, apnoea;

need to be placed 1 cm apart rather than

N measurement of end-tidal or

2 cm apart.

transcutaneous carbon dioxide (PtcCO₂)

as a quantitative measure of

Rhythm electrocardiogram A simple single

hypoventilation during sleep.

lead ECG should be used to monitor cardiac

rate and rhythm to enable cardiac

Monitoring carbon dioxide has also been

arrhythmias and changes resulting from

considered of potential value in diagnosing

respiratory disturbances to be assessed.

sleep hypoventilation syndrome. In addition,

Respiratory effort Chest and abdominal wall

the measurement of carbon dioxide is useful

motion can be measured in a number of

in children with chronic lung disease or

ways. Respiratory inductance

those receiving ventilatory support. It is

plethysmography is the preferred method.

especially important to measure carbon

Other sensors that have been used include

dioxide when supplemental oxygen is

piezoelectric belts, which are provided with

initiated in the sleep laboratory, as some

many commercial PSG systems, intercostal

patients may be dependent on their hypoxic

electromyogram and oesophageal pressure

drive to breathe. Adding oxygen without

monitoring. In one nonrandomised study of

monitoring carbon dioxide may lead to

normal children, paradoxical breathing was

worsening hypoventilation, and clinical

seen much more commonly with

deterioration of the patient.

piezoelectric belts than with respiratory

PetCO₂ can be measured directly from a

inductance plethysmography.

tracheostomy or endotracheal tube, or as a

Oesophageal pressure monitoring is rarely

side-stream measure from a nasal cannula.

used as it is invasive, and the nasal pressure

PetCO₂ values maybe inaccurate in patients

flow signal is often used as a surrogate when

with obstructive lung disease with long time

the upper airway resistance syndrome is

constants, such as in patients with

suspected.

advanced CF.

ERS Handbook: Paediatric Respiratory Medicine

125

An alternative measurement option for

electromyogram from a leg muscle

evaluating hypoventilation is PtcCO₂.The

(conventionally tibialis anterior) is a useful

transcutaneous electrode warms the skin,

measure of peripheral skeletal muscle tone

thereby arteriolising the capillary blood flow.

and allows assessments of gross body

The sensor must be moved during the night

movements and arousals during sleep.

to prevent skin burns. Transcutaneous

Interpretation of the PSG in children

measurements may be preferable to end-

tidal measurements in children with

Standard duration of the study A study of the

advanced obstructive lung disease, infants

whole night is the recommended

with rapid respiratory rates, children who

investigation to assess sleep-disordered

breathe through their mouth and children

breathing. A minimum of 6 h sleep is

receiving CPAP, in whom the CPAP airflow

desirable. The timing of the studies is also

may interfere with end-tidal measurements.

important. The study timing should be set to

Although most studies comparing PetCO₂

mimic the child’s bedtime as closely as

and PtcCO₂ to arterial samples have been

possible. The sleep study should then be

performed in the intensive care unit or

conducted during the late evening and early

during anaesthesia, these studies show a

morning.

good correlation.

Sleep stage analysis It is helpful to quickly

Body position is frequently measured during

review the patient’s sleep architecture by

PSG, although the measurement of body

viewing the hypnogram. A hypnogram is a

position is less important in young children

graphical summary of the different sleep

than in adults, as OSAS is less positional.

stages achieved (fig. 2). It is important to

review the sleep architecture in terms of

Oesophageal pH is occasionally measured

what is to be expected for the patient’s age.

to determine whether gastro-oesophageal

reflux is contributing to night wakenings,

Components of sleep architecture should be

apnoea or desaturation. pH probe insertion

assessed including percentage of total sleep

is more invasive than the rest of the leads on

time (TST) spent in stage I/II, stage III, rapid

a polysomnogram and takes specialised

eye movement (REM) stage and

skill; placement must be confirmed by

wakefulness. These percentages should be

radiography. The percentage of total sleep

compared with age-appropriate normals.

time with pH ,4 and the number and

Stage I sleep occupies 4-7.7% of TST, and

length of pH drops ,4 can be quantified,

stage II occupies 36-49% of TST, with the

and reviewed for an association with

combination of stage I and II in each study

respiratory disturbances.

ranging from 41% to 53% of the TST. Slow

wave sleep occupies 14-32% of the TST,

Video and sound recording Good quality

whereas stage REM occupies 17.4-21.1% of

video recordings are an important

the TST. Timing of sleep stages can be

component of a clinical sleep study, and can

be made using infra-red or low-light cameras

and appropriate microphones. Video and

Wake

sound recordings can provide useful

REM

information on sleep behaviour, snoring,

sleep disturbance and breathing patterns.

Limb movements Gross body movements

and limb movements may be assessed from

direct observation, a video recording or from

a peripheral electromyogram recording.

These may be of use in detecting the extent

of sleep disturbance or arousal frequency,

Sleep hours

and are necessary for assessment of sleep

state in infants. Monitoring the

Figure 2. Hypnogram.

126

ERS Handbook: Paediatric Respiratory Medicine

noted by review of the hypnogram. Children

Leg movements The scoring technician will

usually have a short period of stage I/II after

score leg movements that meet criteria for

sleep onset, and then enter stage III (slow

periodic leg movement. Criteria for periodic

wave sleep). Stage III sleep will predominate

leg movements include leg movements

early in the night, with regular cycling

noted in either or both legs that are at least

between the stages I/II, stages III and REM.

one quarter of the amplitude noted during

REM sleep will usually cycle every 60-

the biocalibration lasting 0.5-5 s. Leg

120 min, with a wide range of timing

movements must be separated by at least

between REM periods. Sleep latency, the

5 s, but not .90 s, and must occur in

time after lights out until sleep is achieved,

clusters of at least four to be considered

should also be noted. Sleep latency is

periodic leg movements. These leg

generally ,25 min. It may be prolonged if

movements should not be related to other

the child has recently had a nap, and it may

events, such as respiratory events or

be shortened in certain sleep disorders.

arousals. The periodic leg movement index

is calculated by dividing the total number of

Sleep efficiency is a measurement of the

periodic leg movements by the number of

amount of the total time in bed that the

hours of sleep. A periodic leg movement

patient spends asleep, and should also be

index of o5 is considered abnormal.

noted. Sleep efficiency in children is usually

Gas exchange should be reviewed carefully

.89%.

for the entire tracing. The pulse oximetry

REM latency, the time from onset of sleep to

tracing should be reviewed for desaturation,

the first epoch of REM sleep, is also noted.

with careful attention to whether the

REM latency can be prolonged if the first

desaturation is associated with a respiratory

REM period is difficult to detect by the

event, arousal or leg movement. In general,

scoring technician. Length of time spent in

oxygen saturation should be .92% in normal

REM is short earlier in the night, with

studies. Median baseline SpO₂ at preterm,

lengthening of REM episodes as the night

term and infancy was approximately 98%,

progresses.

98% and 96% respectively.

Arousal summary Arousals are scored by

In children outside infancy a normal

the scoring technician based on the

oximetry recording should have:

appearance of the electroencephalogram

N a median SpO₂ level o 95%,

tracing. An arousal is scored when

N no more than four desaturations of o4%

there is an abrupt change in the

per hour,

electroencephalogram lasting 3 s, following

N no abnormal clusters of desaturation.

at least 10 s of continuous sleep. Arousals

can be attributed to preceding events,

Carbon dioxide tracing should be reviewed as

including respiratory events, leg

well. Baseline carbon dioxide levels before

movements, snore events or technician

sleep onset should be noted. Children may

presence in the room, or may occur without

have a pattern of obstructive hypoventilation

an obvious trigger. Arousals are reported

with OSAS, resulting in increases of carbon

using the arousal index, which is the

dioxide without significant oxygen

number of arousals divided by the hours of

desaturation. Abnormal levels of carbon

sleep. Studies of normal children have

dioxide vary, with some studies reporting

found mean arousal indices of 8.8-9.5.

.25% of TST being spent with carbon dioxide

.50 Torr as abnormal, and some reporting

Heart rate/rhythm The ECG should be

that in normal children 2.8¡11.3% of TST was

reviewed for evidence of brady or tachy

spent with carbon dioxide o50 Torr.

rhythms, as well as abnormal ECG rhythms.

Respiratory events may be associated with a

Respiratory events Respiratory scoring in

decrease in heart rate, with subsequent

children is different from that in adults.

increase in heart rate after the event has

Paediatric scoring must be used for children

resolved or in association with arousals.

f12 years of age. Small studies indicate

ERS Handbook: Paediatric Respiratory Medicine

127

Table 2. Description of respiratory events

Obstructive apnoea

Drop in thermal sensor amplitude by o90% baseline

o2 missed breaths

o90% duration meets amplitude reduction criteria

Continued or increased inspiratory effort during reduced airflow

Central apnoea

Drop in thermal sensor amplitude by o90% baseline

Either duration o20 s OR o2 missed breaths and associated with

arousal, awakening or o3% desaturation

Absent inspiratory effort

Mixed apnoea

Drop in thermal sensor amplitude by o90% baseline

o2 missed breaths

o90% duration meets amplitude reduction criteria

Absent inspiratory effort initially, then resumption of effort during

latter part of event

Hypopnoea

Drop in nasal air pressure transducer amplitude by o50%

o2 missed breaths

o90% of duration meets amplitude criteria

Associated with arousal, awakening or o3% desaturation

RERA

o2 missed breaths

Flattening of nasal air pressure transducer waveform

Increased work of breathing

Sequence leads to arousal

Drop in amplitude ,50%

Periodic breathing

.3 episodes of central apnoea lasting .3 s separated by f20 s of

normal breathing

Apnoea index

Number of obstructive and/or central apnoeic events per hour of

sleep

Obstructive apnoea index

Number of obstructive apnoeic events per hour of sleep

Hypopnoea index

Number of hypopnoeas per hour of sleep

AHI

Sum of the apnoea index and hypopnoea index

Obstructive AHI

Sum of obstructive apnoeic events and hypopnoeic events per hour

of sleep

that adolescents have breathing patterns

children. Table 3 shows normative data for

similar to those of younger children and the

the different polysomnographic variables.

use of paediatric scoring criteria would be

These are statistical norms rather than

appropriate for adolescents. Adult criteria

clinical criteria upon which to base

are used for patients aged o18 years.

treatment decisions. It is generally accepted

that OSA is mild if the obstructive AHI is

Respiratory related arousals (RERA) are not

f5 events?h^-1, and moderate if it is

scored in all laboratories. Definitions of

.5 events?h^-1 but ,10 events?h^-1, and

respiratory events are summarised in

severe if it is .10 events?h^-1. It is generally

table 2. Examples of snoring, central

accepted that if the snoring child has

apnoea, obstructive apnoea and hypopnea

moderate or severe OSA they should be

are shown in figures 3-6.

treated. Treatment indications for children

Normal values of PSG and treatment

with mild OSA are less clear. One review

indications

suggested that treatment should be

considered if the child is at increased risk of

There are very few studies assessing the

having OSA and fulfils at least one of the

polysomnographic predictors of morbidity in

following criteria.

128

ERS Handbook: Paediatric Respiratory Medicine

LEOG

REOG

C3M2

C4M1

O1M2

O2M1

F3M2

F4M1

Chin EMG

Thermist

THO

ABD

Micro

ECGI

pO2

Pleth

RLEGEMG

LLEGEMG

Body

R R R

R R

Stage

5′′

10′′

15′′

20′′

25′′

30′′

Figure

3. Snoring.

LEOG

REOG

C3M2

C4M1

O1M2

O2M1

F3M2

F4M1

Chin EMG

Thermist

THO

ABD

Micro

ECGI

SpO2

Pleth

RLEGEMG

LLEGEMG

Body

S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S

S S S S S S S S S S S S S S S S

Stage

N3N3N3 N3N3N3N3 N3N3N3 N3N3 N3

157

158

158 159

N3N3 N3N3 N3N3 N3N3 N3N3N3N3 N3N3 N3N3N3 N3 N3N3N3 N3 N3N3 N3N3 N3N3N3 N

3 N3N3N3N3N3 N3 N3N3N3N3N3N3 N3N3N3N3 N3

10′′

20′′

30′′

40′′

50′′

60′′

Figure 4. Central apnoea.

LEOG

REOG

C3M2

C4M1

O1M2

O2M1

F3M2

F4M1

Chin EMG

Thermist

THO

ABD

Micro

SpO2

Pleth

RLEGEMG

LLEGEMG

Body

S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S

657

657 658

658

10′′

20′′

30′′

40′′

50′′

60′′

Figure 5. Obstructive apnoea.

ERS Handbook: Paediatric Respiratory Medicine

129

LEOG

REOG

C3M2

C4M1

O1M2

O2M1

F3M2

F4M1

Chin EMG

Flow

Thermist

THO

ABD

Micro

SpO2

Pleth

RLEGEMG

LLEGEMG

Body

S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S

Stage

R R R R R R R R R R R

R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R

80 81

8182

10′′

20′′

30′′

40′′

50′′

60′′

Figure 6. Hypopnoea.

N AHI 1-5 events?h^-1 and systolic or

N AHI 1-5 events?h^-1 and morbidity from

diastolic blood pressure consistently

the central nervous system (excessive

.95th percentile for sex, age and height,

daytime sleepiness, hyperactivity,

or documented pulmonary hypertension.

inattention and academic difficulties).

Table 3. PSG values in normal children

Montgomery-Downs

Verhulst

Uliel

Traeger

(2006)

(2007)

(2004)

(2005)

Subjects n

542

Age range years

3-5^#

o6^"

6-16

1-15

2.5-9.4

Sleep latency min

24.1¡25.6

23¡25.3

45.6¡29.4

Sleep efficiency %

90¡7

89.3¡7.5

80.5¡8.5

90.8¡6.5

89¡ 8

Arousals events?h^-1

9.3¡4.8

6.1¡1.8

8.8¡3.8

RERA events?h^-1

0.92¡2.0

1.2¡1.0

Hypopnoea index⁺ events?h^-1

0.03¡0.07

0.10¡0.18

0.3¡0.5

Apnoea index events?h^-1

0.86¡0.75

0.5¡0.52

Obstructive apnoea index

0.03¡0.10

0.05¡0.11

0.06¡0.16

0.02¡0.1

0.1¡0.03

events?h^-1

AHI events?h^-1

0.9¡0.78

0.68¡0.75

1.98¡1.39

0.4¡0.6

Obstructive AHI events?h^-1

0.08¡0.16

0.14¡0.22

0.08¡0.17

% TST SpO₂ .95%

99.6¡0.95

SpO2 nadir %

92.7¡4.5

92.6¡3.6

91.8¡2.7

94.6¡2.2

92¡3

SpO₂ lower limit %

ODI events?h^-1

0.29¡0.35

0.47¡0.96

0.8¡0.9

PetCO₂ % TST .50 mmHg

4.0¡15.3

2.0¡7.1

0.29¡0.24

Data are presented as mean¡SD, unless otherwise stated. ODI: oxygen desaturation index.^#: n5173;

^": n5369;⁺: with desaturation (3-4%) and/or arousal.

130

ERS Handbook: Paediatric Respiratory Medicine

N AHI 1-5 events?h^-1 and inadequate

Aurora RN, et al. (2011). Practice parameters

somatic growth.

for the respiratory indications for polysom-

N AHI 1-5 events?h^-1 and nocturnal

nography in children. Sleep; 34: 379-388.

enuresis.

Iber C, et al. The AASM Manual for the

N AHI 1-5 events?h^-1 and presence of risk

Scoring of Sleep and Associated Events:

factor(s) for persistence of OSA in

Rules, Terminology and Technical

Specifications. Westchester, AASM, 2007.

adolescence.

Kaditis A, et al. (2012). Algorithm for the

N AHI 1-5 events?h^-1 and diagnosis of

diagnosis and treatment of pediatric

muscular or neuromuscular disorders

OSA: a proposal of two pediatric sleep

(e.g. Duchenne muscular dystrophy or

centers. Sleep Med; 13: 217-227.

cerebral palsy), or major craniofacial

Katz ES, et al.

(2002). Night-to-night

abnormality (e.g. midface hypoplasia or

variability of polysomnography in children

mandibular hypoplasia), or a

with suspected obstructive sleep apnea. J

combination of pathogenetic

Pediatr; 140: 589-594.

mechanisms (e.g. Down syndrome).

Katz ES, et al. (2003). Pulse transit time

N Nocturnal pulse oximetry with three or

as a measure of arousal and respiratory

more SpO₂ decreases ,90% and three or

effort in children with sleep-disordered

more clusters of desaturation events.

breathing. Pediatr Res; 53: 580-588.

Alternatively, oxygen desaturation (o3%)

Marcus CL, et al. (1992). Normal polysom-

of haemoglobin index .3.5 episodes?h^-1.

nographic values for children and adoles-

cents. Am Rev Respir Dis; 146: 1235-1239.

In conclusion, paediatric PSG is the gold

Montgomery-Downs HE, et al. (2006).

standard for evaluation of children with

Polysomnographic characteristics in nor-

chronic snoring both for diagnosing and

mal preschool and early school-aged

assessing severity of OSA. Response to

children. Pediatrics; 117: 741-753.

various treatment modalities are also

Royal College of Paediatric and Child

objectively evaluated by PSG. It is also used

Health Working Party on Sleep Physiology

and Respiratory Control Disorders in

to evaluate cardiorespiratory function in

Childhood. Standards for Services for

infants and children with alveolar

Children with Disorders of Sleep

hypoventilation, chronic lung disease or

Physiology Report. London, Royal College

neuromuscular disease when indicated.

of Paediatric and Child Health, 2009.

Paediatric PSG should be performed in a

Schechter MS, et al.

(2002). Technical

child-friendly environment and should be

report: Diagnosis and management of

evaluated according to the paediatric rules.

childhood obstructive sleep apnea syn-

drome. Pediatrics; 109: e69.

Scholle S, et al.

(2001). Arousals and

Further reading

obstructive sleep apnea syndrome in

Clinical practice guideline

(2002). diag-

children. Clin Neurophysiol; 112: 984-991.

nosis and management of childhood

Tapia IE, et al. (2008). Polysomnographic

obstructive sleep apnea syndrome 2002.

values in children undergoing puberty:

Pediatrics; 109: 704-712.

pediatric vs. adult respiratory rules in

American Academy of Sleep Medicine.

adolescents. Sleep; 31: 1737-1744.

International Classification of Sleep

Traeger N, et al.

(2005).

Poly-

Disorders. 2nd Edn. Westchester, AASM,

somnographic values in children

2-9

2005.

years old: additional data and review of

Indications for Polysomnography Task

the literature. Pediatr Pulmonol; 40: 22-30.

Force

(1997). Practice parameters for

Uliel S, et al. (2004). Normal polysomno-

the indications for polysomnography

graphic respiratory values in children and

and related procedures 1997. Sleep; 20:

adolescents. Chest; 125: 872-878.

406-422.

Verhulst SL, et al. (2007). Reference values

Standards and indications for cardiopul-

for sleep-related respiratory variables in

monary studies in children (1996). Am J

asymptomatic European children and ado-

Respir Crit Care Med 1996; 153: 866-878.

lescents. Pediatr Pulmonol; 42: 159-167.

ERS Handbook: Paediatric Respiratory Medicine

131

Flexible bronchoscopy

Jacques de Blic

Bronchoscopy has become an invaluable

tool for the diagnosis and treatment of many

Key points

lung disorders in infants and children

(Midulla et al., 2003; Schellhase, 2002;

Cleaning and disinfection of flexible

Wood, 1984). Since its introduction in the

bronchoscopes are a major concern to

mid-1970s, an increasing number of flexible

prevent cross infection and

bronchoscopies are performed each year.

contamination.

The diagnostic value of flexible

Stridor is a common indication for

bronchoscopy is now widely accepted; it can

flexible bronchoscopy in infants and

be used to visualise the lower airways

laryngomalacia is the most frequent

directly and to take samples, particularly of

observed abnormality. Direct

bronchoalveolar lavage (BAL). Its

visualisation of the airways is

indications are not limited to exploring

necessary in all children with

stridor, persistent atelectasis or recurrent

persistent stridor because lower

pneumonia in ambulatory patients; more

airway lesions are frequently

severely ill children, who are in an unstable

associated with upper airway lesions.

respiratory status, may require

bronchoscopy, sometimes under

In older children all pathological

mechanical ventilation, in neonatal or

respiratory situations, especially

paediatric intensive care units (ICUs).

persistent or recurrent clinical

symptoms and/or radiological

Equipment

abnormalities, should lead to

endoscopic airway exploration.

Bronchoscopes Two technologies are used to

transmit light and images: glass fibres and

Measures to prevent complications

charge-coupled devices (CCD).

include: detection of high-risk

children; nebulisation of b₂-agonists if

N The classic fibreoptic bronchoscope uses

there is pre-existing bronchial

fine filaments of flexible glass fibres. With

hyperresponsiveness; careful local

this technology, the larger the

anaesthesia to prevent laryngospasm;

bronchoscope, the better the image

large oxygen supplementation; use of

obtained because of the higher number of

the lowest flexible bronchoscope

fibres.

diameter; appropriate anaesthesia;

N In a bronchovideoscope, the CCD is

and training.

incorporated into the distal extremity of

Post-BAL fever may occur in up to

the instrument; it doesn’t contain an

50% of cases.

eyepiece, needs a video screen and allows

for a very high image quality.

N The hybrid bronchofibrevideoscope

combines these two technologies. A CCD

Table 1 summarises the main characteristics of

is located in the body of the instrument,

the different instruments available for children.

which improves the quality of images.

External diameter determines the presence

132

ERS Handbook: Paediatric Respiratory Medicine

(and size) or absence of a working channel.

N an operating table;

The 2.2-mm flexible bronchoscope does not

N a workstation, including a bright light

have a working channel and is limited to

source (some equipment uses a battery-

visualisation of airways in ventilated

operated system), a video system centre

neonates. The 3.4-3.6-mm flexible

(with adaptor for older broncho-

bronchoscopes have a 1.2-mm working

fibrescopes), a flat-screen LCD monitor, a

channel, which allows suction and BAL to

keyboard and recording equipment;

be performed, and is wide enough to allow

N a trolley containing room temperature

the use of instruments such as a cytology

saline, a syringe, cytology brushes and

brush or biopsy forceps (but the procedure

biopsy forceps, trap for BAL, etc.;

is more difficult and the specimen very

N monitoring equipment (ECG, pulse

small). The 4-mm and 4.9-mm flexible

oximeter and blood pressure monitor);

bronchoscopes have a 2-mm working

N an oxygen supply system;

channel, which allows excellent quality

N high-power suction sources;

biopsies and transbronchial biopsy.

N equipment and drugs for intubation and

resuscitation.

The choice of the flexible bronchoscope is

made according to the age of the patient

Cleaning, disinfection and storage After each

and the diameter of the cricoid, but also

use, flexible bronchoscopes must be cleaned

according to the procedures that are to be

and disinfected to prevent cross infection

performed. In general, the smallest

and contamination. Disinfection may be

instrument available should be used to

performed by immersion in an appropriate

minimise obstruction of the airways. It is

disinfectant (2% alkaline glutaraldehyde) or

assumed that there must be at least a 2-mm

in a washing machine. Checks for

difference between the external diameter of

microorganism colonisation should be

the flexible bronchoscope and the diameter

performed once a week with a culture of

of the narrowest point of larynx, the cricoid

saline solution used for rinsing the flexible

cartilage. In paediatric and neonatal ICUs, it

bronchoscopes. Flexible bronchoscopes

may be necessary to pass the flexible

should always be stored in a dedicated

bronchoscope through the endotracheal

storage cabinet, hanging in a straight vertical

tube, and the recommended difference in

position to prevent development of

diameter is at least 1 mm.

unwanted curves. Finally, flexible

bronchoscopes should be regularly tested for

Endoscopy room It needs to be fully

leaks before cleaning to prevent permeation

equipped with:

of any fluids into the optical system.

Table 1. Available bronchoscopes

External

Imaging

Age

Working

BAL

Biopsy

TBB Brushing

diameter mm technique

years

channel mm

2.2

Neonate

2.7-2.8

BF/HFV

0-2

1.2

Yes

(not easy)

3.4-3.6

BF/BV

2-5

1.2

Yes

(not easy)

HFV

2-5

Yes

4.9-5.1

BF/BV

2.2-2

Yes

5.9-6

BF/BV

.15

2.2-2.8

Yes

TBB: transbronchial biopsy; BF: bronchofibrescope; HFV: hybrid bronchofibrevideoscope;

BV: bronchovideoscope.

ERS Handbook: Paediatric Respiratory Medicine

133

Procedure

In children, the main indications are the

search of airway obstruction. Stridor is one

N The procedure may be performed under

of the most common indications, especially

conscious sedation or general

in neonates and infants. Inspiratory stridor

anaesthesia.

is indicative of narrowing of the larynx, while

N Endoscopy is performed either at the

biphasic, inspiratory and expiratory stridor

head or at the bedside of the child.

suggests tracheal obstruction. In older

N The flexible bronchoscope is usually

children all pathological respiratory

passed through the nose.

situations, especially persistent or recurrent

clinical symptoms and/or radiological

Once the bronchoscope is inserted into the

abnormalities, should lead to endoscopic

upper airway, the vocal cords are inspected.

airway exploration.

The instrument is advanced to the trachea

and further down into the bronchial system

Information

and each area is inspected as the

Upper airways At the upper airways level,

bronchoscope passes (fig. 1).

laryngomalacia is the most frequent

observed abnormality. Endoscopy identifies

Indications

collapse of the epiglottis and/or aryepiglottic

Airway endoscopy provides two different

folds and/or arytenoids into the glottis.

types of information, one by direct

Direct visualisation of the airways is

anatomical observation and the other

necessary in all children with persistent

through the samples taken during the

stridor; lower airway lesions are frequently

procedure (mainly BAL, brushing and

associated with upper airway lesions. The

biopsies). Indications for bronchoscopy in

examination must be carried out carefully,

children are listed in table 2.

and the airways should be monitored during

Right lung

Left lung

Apical

Posterior

Upper

Posterior

Upper

lobe

Lingula

Lateral

Middle

Apical

lobe

Medial

lower

basal

Lower

basal

Lower

lobe

Posterior

Lateral

lobe

basal

Figure 1. Segmentation of the tracheobronchial tree.

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Main indications for endoscopy in children

Airway obstruction

Suspected foreign body aspiration

Stridor (inspiratory and/or expiratory), noisy breathing

Severe recurrent/persistent wheezy bronchitis

Severe unexplained chronic cough that is unresponsive to therapy

Persistent/chronic productive cough

Recurrent bronchopneumonia

Recurrent/persistent consolidation

Localised hyperinflation

Bronchiectasis

Mediastinal adenopathies

Chronic interstitial pneumonitis

Infectious diseases

Immunocompetent children

Severe acute pneumonia, severe acute interstitial pneumonia (that does not respond to

standard broad-spectrum antibiotic therapy within 48 h)

Immunocompromised children

Acute onset of diffuse interstitial pulmonary infiltrates

Acute focal infiltrates (that do not respond to standard broad-spectrum antibiotic therapy

within 48 h)

Chronic interstitial pneumonitis

Chronic recurrent bronchopneumonia in HIV-infected children (if organisms are not found

by less invasive techniques)

In association with TBB in lung transplant recipients, as part of a routine surveillance

programme and/or for the diagnosis of suspected lung disease

Haemoptysis

TBB: transbronchial biopsy.

the various stages of sedation. Local

N Haemangioma presenting as an

anaesthesia may worsen laryngomalacia

asymmetrical subglottic mass.

(Nielson et al. 2000). Other abnormalities

N Laryngeal cysts, laryngeal papillomatosis,

include the following.

laryngeal web or laryngeal cleft.

N Vocal cord dysfunction characterised by

N Subglottic stenosis: this may be

paradoxidal adduction of the vocal cord

congenital with membranous (or

during inspiration, or both inspiration

diaphragmatic) stenosis and symmetrical

and expiration: diagnosis may be difficult

narrowing, or acquired after prolonged

even during endoscopy of the upper

endotracheal intubation and appear

airways without sedation.

irregular with granulation tissue,

ulcerations and cysts.

Lower airways At the lower airway level,

N Vocal cord paralysis (unilateral or

endoscopy provides information on airway

bilateral): this must be evaluated when

distribution, mechanical or dynamic

the child is awake or under light sedation.

obstruction, inflammation and secretions.

ERS Handbook: Paediatric Respiratory Medicine

135

Proximal airway pattern is usually stable in

shape of comma or drop, with the narrowest

humans. Most of the abnormal bronchi are

part directed to the right. Pulmonary sling

‘variant’ and supply normal lung

obstructs the distal trachea and the origin of

parenchyma. Tracheal bronchus, which is

the right main stem bronchus. Pulmonary

observed in 1% of flexible bronchoscopes, is

sling is strongly associated with congenital

the most common. In this case, the

tracheal stenosis. Congenital heart disease

bronchus originates from the right lateral

with left to right shunt and enlarged

wall of the trachea, above the carina. It may

pulmonary arteries may compress the right

supply the entire right upper lobe or only the

main stem and right middle lobe bronchus.

apical segments. Abnormal airway

Left main stem bronchus may be

distribution includes situs inversus

compressed by heart enlargement. The left

(associated with primary ciliary dyskinesia),

main stem bronchus may also be

left or right isomerism (two right or two left

compressed between right pulmonary artery

bronchial patterns, frequently associated

and descending aorta. Absent pulmonary

with congenital heart cardiopathy), and lung

valves is associated with enlarged

agenesis/aplasia. In the latter a more or less

pulmonary arteries, which compress distal

rudimentary bronchus is observed at the

trachea, both the main stem bronchi and

main carina. Finally, opening of a tracheo-

troncus intermedius. Significant anterior

oesophageal fistula can be found on the

compression by anomalous innominate

posterior tracheal wall. Fistula can be

artery associated with tracheomalacia is

confirmed by injecting methylene blue into

rare. Likewise, posterior tracheal

the fistula and detecting its presence in the

compression of an aberrant subclavian

oesophagus (the same results is obtained

artery is usually not clinically relevant.

when injecting methylene into the

oesophagus to view the trachea).

In dynamical obstruction, tracheomalacia

and bronchomalacia are defined as an

During mechanical and dynamical airway

abnormal collapse (.50%) of the trachea or

obstruction, airway patency may be affected

the main bronchi during spontaneous

by intrinsic or extrinsic lesions.

breathing, expiration or cough, due to a

localised or generalised weakness of the

Intrinsic obstructions include inhaled

airwall (Boogaard et al., 2005). They may be

foreign bodies, stenosis (may be congenital

congenital or acquired, and are mainly seen

with complete tracheal rings or acquired

in children with vascular malformation and

post-intubation), diaphragm, granuloma,

oesophageal atresia and/or tracheo-

endobronchial tumour or bronchial cast

oesophageal fistula.

(also known as plastic bronchitis).

Inflammation and secretions In children, the

Extrinsic obstructions include compression

bronchial mucosa appears thicker than in

by congenital malformation (such as

adults and the mucosa is salmon pink. The

bronchogenic cyst or duplication),

mucosa can be pale, erythemic, thinned or

adenopathies (e.g. malignancy or TB),

thickened. Endoscopy can also identify

tumour or vascular compression. The most

granulations, for example in swallowing

frequent vascular compression is vascular

disorders or sarcoidosis. Secretions should

ring (right-sided aortic arch and double

be characterised as moderate or abundant,

aortic arch) (Chapotte et al., 1998; McLaren

localised or diffuse, being renewed or not

et al., 2008). A double aortic arch causes

after aspiration, mucous, muco-purulent,

obstruction of the distal trachea and left

purulent or haemorrhagic.

main stem bronchus. A right-sided aortic

arch with an aberrant left subclavian artery

Bronchoscopy in paediatric ICUs

and enlargement of the Kommerell

diverticulum appears with an anterior and

Children in paediatric ICUs may require a

posterior compression of the right wall of

bronchoscopy for a primary airway problem

the distal trachea and the right main stem

or a secondary complication (Bar-Zohar et al.,

bronchus. The trachea is distorted in the

2004; Efrati et al., 2009; Koumbourlis, 2010,

136

ERS Handbook: Paediatric Respiratory Medicine

Manna et al. 2006). These children are

In spontaneously breathing infants, classic

unstable and/or ventilator dependent. In

flexible bronchoscopy carries the risk of

these situations, sedation should be

inducing respiratory failure, particularly in

increased appropriately, the procedure

small patients (f2500 g) or those with a

should be fast, and should be performed by

borderline respiratory status. A 2.2-mm

an experienced bronchoscopist, assisted by

flexible bronchoscope can be passed

an intensivist. Flexible bronchoscopes are

through a 2.5 mm endotracheal tube in

useful for diagnosing and assessing therapy

intubated infants, but it has no working

in very sick children. Adverse effects of

channel. A 2.8-mm flexible bronchoscope

bronchoscopy in paediatric ICUs include

can be passed through a 3.5 mm

endotracheal tube and has a working

hypoxia, hypercapnia, inadvertent positive

channel for bronchoaspiration and BAL.

end-expiratory pressure, hypotension, raised

Similar to paediatric ICUs, an experienced

intracranial pressure and prolonged

paediatric bronchoscopist must perform the

hypoxaemia following BAL (Morrow et al.,

procedure quickly in an ICU; the heart rate,

2001). Main contraindications are severe

blood pressure, oxygen saturation and

hypoxaemia, bleeding diathesis, severe

temperature should be constantly

pulmonary hypertension, cardiac failure,

monitored throughout the procedure. The

cardiac instability/hypotension and

absence of an operator channel with the

procedures that provide no additional

ultra-thin flexible bronchoscope prevents the

information. Indications for bronchoscopy

suctioning of secretions, and the

use in paediatric ICUs are listed in table 3.

administration of anaesthesia or normal

Bronchoscopy in neonatal ICUs

saline. However, careful suctioning prior to

ultra-thin flexible bronchoscopy adequately

Persistent radiological airway obstruction is

prepares the airways for the procedure.

a constant concern in the neonatal ICU and

Risks of complication are increased,

the rapid evaluation of the airways is a major

including the risks of hypothermia,

requirement for determining whether flexible

hypotension, hypoxia, apnoea, bradycardia

bronchoscopy is needed or not. Sudden

and intra-cranial haemorrhage.

unexplained deteriorations in the respiratory

status also provide reasons for endoscopic

Flexible bronchoscopy may reveal

evaluation.

endoluminal abnormalities (e.g. granuloma

and inflammatory stenosis), malformation

(tracheal bronchus), severe extrinsic

Table 3. Main indications of endoscopy in paediatric

compression, or severe tracheo and/or

and neonatal ICUs

bronchomalacia (de Blic et al., 1991;

Koumbourlis, 2010). These airway

Paediatric ICU

anomalies can exist simultaneously, and

Endobronchial toilet

their correct diagnosis is paramount to the

Assessment of lobar collapse

management of these patients, also

providing information for possible surgical

Ventilator-associated pneumonia

intervention.

Difficult intubation

Tolerance and complications

Selective intubation

Failure to extubate

Data show that flexible bronchoscopes are well

Airway stent assessment

tolerated in most cases and that the risk of

major complications remains low (de Blic

Neonatal ICU

et al., 2002). However, the potentially

Unexplained cyanotic spells

dangerous nature of these complications

Failure to wean from mechanical

necessitates careful analysis of indications

ventilation

and clinical status for each patient and proper

monitoring during the procedure. Moreover,

Persistent atelectasis/hyperinflation

the skill of the bronchoscopist and

ERS Handbook: Paediatric Respiratory Medicine

137

anaesthesiologist may also decrease the

Anaesthetic complications The most life

incidence of complications, demonstrating

threatening adverse events during flexible

the value of training. These complications can

bronchoscopy involve drug overdose,

be divided into physiological, mechanical,

inadequate monitoring or inappropriate

infectious, anaesthetic and post-BAL fever.

sedation.

Physiological complications These represent

The following will reduce the risk of

the most frequent complications and include

complications:

hypoxaemia, with or without hypercapnia,

laryngospasm and bronchospasm, as well as

N detection of high-risk children (aged

cardiac arrhythmia and bradycardia.

,2 years, with known or suspected

Respiratory depression is the most

laryngotracheal abnormalities);

concerning adverse effect of sedation. Partial

N nebulisation of b₂-agonists, if there is pre-

or total airway obstruction by the

existing bronchial hyperresponsiveness,

bronchoscope and depression of respiratory

to avoid bronchospasm;

drive due to sedation are the most frequent

N careful local anaesthesia to prevent

causes of oxygen desaturation during flexible

excessive cough and laryngospasm;

bronchoscope in children, and may worsen

N large oxygen supplementation;

pre-existing hypoxaemia. Upper airway

N using the lowest flexible bronchoscope

pathology, persistent radiographic changes,

diameter;

oxygen dependency, weight ,10 kg and age

N use of appropriate anaesthesia;

,2-3 years are significantly associated with

N training.

increased risk of adverse events. Oxygen

desaturation may also be a consequence of

Post-BAL complications Fever is observed in

laryngospasm or bronchospasm. In children

up to 52% of cases (Fonseca et al., 2007;

undergoing bronchoscopy, when the airways

Picard et al., 2000; Schellhase et al., 1999).

are compromised by both the underlying

Post-BAL fever usually begins a few hours

condition and the procedure itself, any

after the examination, with spontaneous

depressant effect of sedation is likely to be

defervescence occurring within 24 h. It has

poorly tolerated. Oxygen supplementation

been attributed to the release of biologically

may delay detection of reduced ventilation

active mediators, such as cytokines, and to

but this should be sought by close

transient bacteraemia. Factors such as

observation of the child, and capnography

young age, a positive bacterial culture and

when appropriate. If desaturation episodes

abnormal bronchoscopic findings, including

are moderate and transient (no decrease in

whether a topical anaesthetic and saline are

oxygen saturation to ,90%, episodes lasting

administered, are related to a higher risk of

,1 min) they do not affect or preclude

developing post-BAL fever. A recent study

completion of the procedure. However, if

showed that the use of intramuscular

desaturation decreases to ,90%,

dexamethasone in immunocompetent

intervention is required and, if needed, the

children prior to the procedure caused a

procedure should be terminated.

significantly greater reduction in the

incidence of fever than placebo, favouring

Mechanical complications These include

inflammatory cytokine-induced fever (Picard

epistaxis, haemoptysis (which may be

et al., 2007).

favoured if coagulopathy is present or if the

platelet count is ,20 000 cells?mm^-3),

pneumothorax and post-flexible

bronchoscope subglottic oedema.

Further reading

Infectious complications These complications

Bar-Zohar D, et al. (2004). The yield of

are rare and, by default, are related to the

flexible fiberoptic bronchoscopy in pedia-

cleaning of the bronchoscope. The spread of

tric intensive care patients. Chest;

126:

infection appears to be a very rare

1353-1359.

complication.

138

ERS Handbook: Paediatric Respiratory Medicine

Boogaard R, et al. (2005). Tracheomalacia

McLaren CA, et al.

(2008). Vascular

and bronchomalacia in children: incidence

compression of the airway in children.

and patient characteristics. Chest;

128:

Paediatr Respir Rev; 9: 85-94.

3391-3397.

Midulla F, et al.

(2003). Flexible endo-

Chapotte C, et al. (1998). Airway compres-

scopy of paediatric airways. Eur Respir J;

sion in children due to congenital heart

22: 698-708.

disease: value of flexible fiberoptic broncho-

Morrow B, et al. (2001). Risks and compli-

scopic assessment. J Cardiothorac Vasc

cations of nonbronchoscopic bronchoal-

Anesth; 12: 145-152.

veolar lavage in a pediatric intensive care

Daniel SJ

(2006). The upper airway:

unit. Pediatr Pulmonol; 32: 378-384.

congenital

malformations.

Paediatr

Nielson DW, et al.

(2000). Topical

Respir Rev; 7: Suppl. 1, S260-S263.

lidocaine exaggerates laryngomalacia dur-

de Blic J, et al. (1991). Ultrathin flexible

ing flexible bronchoscopy. Am J Respir Crit

bronchoscopy in neonatal intensive

Care Med; 161: 147-151.

care units. Arch Dis Child;

66:

1383-

Picard E, et al.

(2000). A prospective

1385.

study of fever and bacteremia after

de Blic J, et al. (2002). Complications of

flexible fiberoptic bronchoscopy in chil-

flexible bronchoscopy in children: pro-

dren. Chest; 117: 573-577.

spective study of 1,328 procedures. Eur

Picard E, et al. (2007). A single dose of

Respir J; 20: 1271-1276.

dexamethasone to prevent postbroncho-

Efrati O, et al. (2009). Flexible broncho-

scopy fever in children: a randomized

scopy and bronchoalveolar lavage in

placebo-controlled trial. Chest; 131: 201-205.

pediatric patients with lung disease.

Schellhase DE (2002). Pediatric flexible

Pediatr Crit Care Med; 10: 80-84.

airway endoscopy. Curr Opin Pediatr; 14:

Fonseca MT, et al. (2007). Incidence rate

327-333.

and factors related to post-bronchoalveo-

Schellhase DE, et al. (1999). High fever

lar lavage fever in children. Respiration;

after flexible bronchoscopy and bronch-

74: 653-658.

oalveolar lavage in noncritically ill immu-

Koumbourlis AC. Flexible fibre-optic

nocompetent children. Pediatr Pulmonol;

bronchoscopy in the intensive-care unit.

28: 139-144.

In: Paediatric bronchoscopy. Priftis KN,

Wood RE

(1984). Spelunking in the

et al., ed. Basel, Karger, 2010; pp. 54-

pediatric airways: explorations with the

63.

flexible fiberoptic bronchoscope. Pediatr

Manna SS, et al. (2006). Retrospective

Clin North Am; 31: 785-799.

evaluation of a paediatric intensivist-led

Wood RE (2008). Evaluation of the upper

flexible bronchoscopy service. Intensive

airway in children. Curr Opin Pediatr; 20:

Care Med; 32: 2026-2033.

266-271.

ERS Handbook: Paediatric Respiratory Medicine

139

Bronchoalveolar lavage

Fabio Midulla, Raffaella Nenna and Ernst Eber

Definition

Key points

Bronchoalveolar lavage (BAL) is a procedure

used to recover cellular and noncellular

N BAL is a procedure used to recover

components of the epithelial lining fluid

cellular and noncellular components

from the alveolar and bronchial airspaces.

from the alveolar and bronchial

airspaces.

Techniques

N Clinical applications involve

Bronchoscopic BAL involves the instillation

microbiological studies and/or

and immediate withdrawal of pre-warmed

evaluation of cellular components.

sterile 0.9% saline solution through the

working channel of a flexible bronchoscope,

N BAL is performed for diagnostic and

which has been wedged into a bronchus

therapeutic indications.

with a matching diameter. Generally,

paediatric bronchoscopes with external

diameters of 2.8, 3.5 or 3.7 mm and a

Two methods are used for calculating the

working channel of 1.2 mm are used in

amount of sterile saline for lavage and the

children ,6 years of age, whereas

number of aliquots required to obtain

instruments with external diameters of 4.6-

samples that are representative of the

4.9 mm and a working channel of 2.0 mm

alveolar compartment. Some authors

are used in children .6 years of age. The

choose to use two to four aliquots of equal

preferred sites for bronchoscopic BAL are

volume (10 mL per aliquot for children

the middle lobe or the lingula because,

,6 years of age and 20 mL per aliquot

being the smallest lobes of the respective

for children .6 years of age), irrespective

lungs, they offer better fluid recovery. When

of the patient’s body weight. Others

lung disease is localised, BAL must target

suggest the use of three aliquots, each

the radiological or endoscopically identified

consisting of 1 mL?kg^-1 body weight for

involved lobe or segment. In patients with

children weighing up to 20 kg, and three

CF, samples from multiple sites should be

20-mL aliquots for heavier children.

obtained in order to avoid underestimation

While maintaining the tip of the

of the extent of infection.

bronchoscope wedged at the selected

site, gentle manual or mechanical

Alternatively, a nonbronchoscopic BAL can

suction (3.3-13.3 kPa, i.e. 25-100 mmHg)

be performed by inserting a catheter through

is applied in order to collect the lavage

an endotracheal tube. Unfortunately, this

specimen in a syringe or in a dedicated

method does not allow visualisation of the

collection trap. BAL is considered

lavage site, although turning the child’s

technically acceptable if .40% of the

head to the left predictably directs the

total saline instilled is recovered and

catheter into the right lung.

the lavage fluid (except for the first

To avoid contamination, BAL must precede

sample) contains few epithelial

any other planned bronchoscopic procedure.

cells.

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ERS Handbook: Paediatric Respiratory Medicine

Processing

cellular and noncellular components

(table 1). The mean BAL fluid total cell count

BAL specimens should be processed as

ranges from 10.3 to 59.9610⁴ cells?mL^-1,

soon as possible. To optimise cell viability,

with a range of 81.2-90% for macrophages,

BAL fluid must be kept at 4uC until analysed.

8.7-16.2% for lymphocytes, 1.2-5.5% for

The first unfiltered BAL aliquot is usually

neutrophils and 0.2-0.4% for eosinophils.

processed separately for microbiological

The BAL fluid neutrophil percentage appears

studies. Bacteria, fungi, protozoa and

to be higher in children aged ,12 months as

viruses are detected by direct light

compared to children aged 13-36 months.

microscopy after centrifugation or

Normal values of BAL fluid lymphocyte

alternatively by smears. Special stains such

subsets in children resemble those found in

as Gram, Papanicolaou, Gomori-Grocott or

healthy adults, except for the CD4/CD8 ratio,

tolouidine blue are used in air-dried

which is lower in children. Establishing

preparations. In addition, the samples that

reference values for noncellular components

are to be cultured for fungi, protozoa and

is a complex task owing to the absence of

viruses are centrifuged first, whereas those

valid BAL fluid dilution markers. Studies

for bacterial cultures are processed without

designed to investigate noncellular BAL fluid

centrifugation. The rest of the aliquots are

components have few clinical indications

filtered through sterile gauze to remove

and are more important in the research

mucus; then they are pooled and submitted

setting.

for cytological studies and analysis of BAL

solutes.

Indications

BAL fluid can be prepared in two ways by:

BAL is performed for diagnostic and

therapeutic indications. Clinical indications

N obtaining cytospin preparations of the

for BAL include nonspecific chronic

whole BAL fluid,

respiratory symptoms, nonspecific

N re-suspension of the cells pellet in a small

radiological findings and clinical signs and

amount of medium.

symptoms suggestive of chronic DPLD.

At least three to four slides should be

Clinical applications involve microbiological

prepared for each patient. The number of

studies and/or evaluation of cellular

cells per mL of the recovered BAL fluid is

components.

counted with a cytometer on whole BAL

Microbiology BAL is an important tool in the

specimens stained with trypan blue or with a

diagnosis of lung infection in both

cytoscan. Slides can be stained with May-

immunocompromised and

Grünwald, Giemsa or Diff-Quick stains for

immunocompetent patients, including

differential cell counts and the evaluation of

children with chronic pneumonia, CF and

cellular morphological features. In particular

suspected TB. BAL is diagnostic when

situations, slides can also be prepared with

pathogens not usually found in the lung are

specific stains, e.g. oil red O stain to detect

recovered, such as Pneumocystis jirovecii,

lipid-laden macrophages, iron stain to

Toxoplasma gondii, Legionella pneumophila,

identify iron-positive macrophages in

Histoplasma capsulatum, Mycobacterium

patients with alveolar haemorrhage, and

tuberculosis, Mycoplasma pneumoniae and

periodic acid-Schiff (PAS) to identify

respiratory viruses. Other infectious

glycogen. Immunocytochemical staining of

diseases, in which isolation of the infectious

lymphocyte surface markers is used to

agent from BAL fluid is not diagnostic, but

differentiate lymphocyte subsets in specific

may contribute to their diagnosis and

clinical situations, such as chronic diffuse

management, include infections with herpes

parenchymal lung disease (DPLD).

simplex virus, cytomegalovirus, Aspergillus,

The parameters measured include the

Candida albicans, Cryptococcus and atypical

percentage of the instilled normal saline that

mycobacteria. The presence of .10⁴ colony-

is recovered (as compared to the amount of

forming units per mL BAL fluid will identify

saline instilled), as well as various BAL fluid

patients with bacterial pneumonia with

ERS Handbook: Paediatric Respiratory Medicine

141

Table 1. Total and differential cell counts in BAL fluid from control children

Clement

Ratjen

Riedler

Midulla

Tessier

(1987)

(1994)

(1995)

(1996)

Alveolar macrophages

Mean¡SD

89.7¡5.2

81.2¡12.7

86¡7.8

89.9¡5.5

Median

92.5

Range

82-99

34.6-94

84-94^#

71-98

77-98

Lymphocytes

Mean¡SD

8.7¡4.6

16.2¡12.4

8.7¡5.8

8.9¡5.6

Median

12.5

7.5

Range

1-17

2-61

4.7-12.8^#

2-22

Neutrophils

Mean¡SD

1.3¡0.9

1.9¡2.9

5.5¡4.8

1.2¡1.2

Median

0.9

1.7

3.5

Range

0-3

0-17

0.6-3.5^#

0-17

0-3

Eosinophils

Mean¡SD

0.4¡0.6

0.2¡0.3

Median

0.2

Range

0-3.6

0-0.3^#

0-1

NR: not reported.^#: first interquartile to third interquartile.

reasonable accuracy. Hence, the physician

Findings from BAL may help in providing a

must consider this cut-off together with the

specific diagnosis in children with alveolar

underlying disease and the overall clinical

proteinosis, pulmonary haemorrhage,

picture. Furthermore, in children who

pulmonary Langerhans cell histiocytosis,

present with chronic wet cough, a positive

chronic lipoid pneumonia and pulmonary

culture with .10⁴ colony-forming units per

alveolar microlithiasis.

mL is indicative of a protracted bacterial

Because BAL fluid recovered from infants

bronchitis.

with alveolar proteinosis contains PAS-

Cellular components The evaluation of BAL

positive, diastase-resistant, basophilic and

fluid cellular components may have

mucin-negative amorphous material it

important clinical indications in children

typically appears milky. Electron microscopy

with chronic DPLD, a group of disorders

of the BAL fluid sediment discloses

that are characterised by alveolitis, tissue

abundant extracellular, multilamellar bodies

remodelling, fibrosis or a combination

and tubular myelin structures consistent

thereof. In these patients BAL may be a

with abnormal surfactant forms. Differential

useful tool for characterising the alveolitis

cell counts predominantly show

and for monitoring the patient during

lymphocytes with alveolar macrophages,

treatment, follow-up and in reaching or

which, on electron microscopy, have an

confirming a specific diagnosis (table 2).

enlarged foamy cytoplasm containing

Three different forms of alveolitis can be

numerous extracellular, concentrically

identified (fig. 1):

lamellar surfactant bodies (lamellar bodies).

N lymphocytic,

When the BAL fluid appears bloody or orange

N neutrophilic,

pink in children with anaemia and infiltrates

N eosinophilic.

on chest radiographs the suspected

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Forms of alveolitis in children with respiratory disorders

Lymphocytic alveolitis

Neutrophilic alveolitis

Eosinophilic alveolitis

Prevalence of CD4 cells

IPF

Eosinophilic pneumonia

Diffuse parenchymal lung

Sarcoidosis

BOOP

diseases

Crohn’s disease

Wheezy bronchitis

Asthma

Prevalence of CD8 cells

Exogenous allergic alveolitis

(hypersensitivity pneumonitis)

Histiocytosis X

Diffuse parenchymal lung

diseases associated with

collagen diseases

BOOP

BOOP: bronchiolitis obliterans organising pneumonia; IPF: idiopathic pulmonary fibrosis.

diagnosis is alveolar haemorrhage. The BAL

fluid characteristically becomes progressively

bloodier with each sequential sample.

Specific haemosiderin staining detects

haemosiderin in alveolar macrophages

(fig. 2). When haemosiderin-laden alveolar

macrophage percentages exceed 20%, the

diagnosis of diffuse alveolar haemorrhage is

usually confirmed. The diagnosis can

sometimes be delayed because

haemosiderin-laden macrophages may take

.48 h to appear after bleeding.

Figure 1. BAL fluid cytology features in eosinophilic

In patients with pulmonary Langerhans cell

alveolitis (May-Grünwald Giemsa stain, 6100

histiocytosis, Langerhans cells can be

magnification).

identified in BAL fluid through

immunostaining for S-100, CD1a and

langerin. The threshold of 5% CD1a-positive

cells in BAL fluid used for diagnosing

pulmonary Langerhans cell histiocytosis has

excellent specificity, but low sensitivity.

BAL has also been used to document the

diagnosis of pulmonary alveolar micro-

lithiasis by demonstrating microliths in the

BAL fluid, which stain pink with PAS stain.

Well-formed microliths stain black with von

Kossa stain because they have a high

calcium content.

Figure 2. Haemosiderin-laden alveolar

A cytological examination showing vacuo-

macrophages in the BAL fluid of a patient with

lated alveolar macrophages indicates chronic

alveolar haemorrhage (Prussian blue stain, 6100

lipoid pneumonia (fig. 3). The diagnosis

magnification).

ERS Handbook: Paediatric Respiratory Medicine

143

can be confirmed by specific staining with oil

Therapeutic BAL BAL has a major role in the

red O. Lipid-laden macrophages can be

therapy of certain lung diseases, in the form

quantified with the lipid-laden macrophages

of total lung lavage (alveolar proteinosis) or

index assigning to each lipid-laden

mucus plug removal (persistent atelectasis).

macrophage a score ranging from 0 to 4

In particular, children with persistent and

according to the amount of cytoplasmic lipid.

massive atelectasis, especially CF patients,

A lipid-laden macrophage index .100 has

seem to successfully undergo selective

100% sensitivity, 57% specificity, a negative

lavage with DNase or surfactant.

predictive value of 100% and a false-negative

Complications and contraindications

rate of zero.

BAL is a well-tolerated and safe procedure;

BAL remains the procedure of choice to

however, on occasion fever, cough, transient

diagnose chronic pulmonary aspiration by

wheezing and pulmonary infiltrates have been

determining the lipid-laden macrophage

observed, which usually resolve within 24 h.

index and/or by measuring gastric pepsin

concentrations. A lipid-laden macrophage

The most frequent complication, usually

index .100 is considered positive for

lasting ,24 h, is fever; the only

aspiration. With respect to other potential

treatment needed is antipyretics. In

biomarkers, tracheal pepsin has been used

immunocompromised patients antibiotic

as a marker of reflux aspiration. Pepsin

therapy must be performed for at least 48 h.

detection in the BAL fluid has been shown to

BAL may cause hypoxaemia, hypercapnia, or

have high sensitivity and specificity for

both. Severe bleeding, bronchial perforation,

reflux-related pulmonary aspiration.

mediastinal emphysema, pneumothorax

and cardiac arrest are extremely rare.

Contraindications to the procedure include

bleeding disorders, severe haemoptysis and

severe hypoxaemia that persists despite

oxygen treatment.

Further reading

Braun J, et al. (1997). Different protein

composition of BALF in normal children

and adults. Respiration; 64: 350-357.

Castellana G, et al.

(2003). Pulmonary

alveolar microlithiasis. World cases and

review of the literature. Respiration;

70:

549-555.

Clement A, et al.

(1987). A controlled

study of oxygen metabolite release by

alveolar macrophages from children with

interstitial lung disease. Am Rev Respir

Dis; 136: 1424-1428.

Corwin RW, et al. (1985). The lipid-laden

alveolar macrophage as a marker of

aspiration in parenchymal lung disease.

Am Rev Respir Dis; 132: 576-581.

Costabel U, et al. (2007). Bronchoalveolar

lavage in other interstitial lung diseases.

Figure

3. Lipoid pneumonia. a) Contrast-enhanced

Semin Respir Crit Care Med; 28: 514-524.

CT scan of the chest showing lipoid material in the

de Blic J, et al. (2000). ERS Task Force on

lungs. b) BAL fluid cytology showing vacuolated

bronchoalveolar lavage in children. Eur

alveolar macrophages (May-Grünwald Giemsa

Respir J; 15: 217-231.

stain, 6100 magnification).

144

ERS Handbook: Paediatric Respiratory Medicine

Farrell S, et al. (2006). Pepsin in bronch-

Ratjen F, et al. (1994). Differential cytol-

oalveolar lavage fluid: a specific and

ogy of bronchoalveolar lavage fluid in

sensitive method of diagnosing gastro-

normal children. Eur Resp J; 7: 1865-1870.

oesophageal reflux-related pulmonary

Ratjen F, et al. (1995). Lymphocyte subsets

aspiration. J Pediatr Surg; 41: 289-293.

in bronchoalveolar lavage fluid of children

Gutierrez JP, et al.

(2001). Interlobar

without bronchopulmonary disease. Am J

differences in bronchoalveolar lavage

Respir Crit Care Med; 152: 174-178.

fluid from children with cystic fibrosis.

Ratjen F, et al.

(1996). Adjustment of

Eur Respir J; 17: 281-286.

bronchoalveolar lavage volume to body

Krishnan U, et al.

(2002). Assay of

weight in children. Pediatr Pulmonol; 21:

tracheal pepsin as a marker of reflux

184-188.

aspiration. J Pediatr Gastroenterol Nutr; 35:

Ratjen F, et al. (1996). Immunoglobulin

303-308.

and b2-microglobulin concentrations in

Midulla F, et al. (1998). Bronchoalveolar

bronchoalveolar lavage of children and

lavage cell analysis in a child with

adults. Lung; 174: 383-391.

chronic lipid pneumonia. Eur Respir J;

Riedler J, et al.

(1995). Bronchoalveolar

11: 239-242.

lavage cellularity in healthy children. Am J

Midulla F, et al. (1995). Bronchoalveolar

Respir Crit Care Med; 152: 163-168.

lavage studies in children without par-

Ronchetti R, et al.

(1999). Bronch-

enchymal lung disease: cellular constitu-

oalveolar lavage in children with chronic

ents and protein levels. Pediatr Pulmonol;

diffuse parenchymal lung disease. Pediatr

20: 112-118.

Pulmonol; 27: 1-8.

Milman N, et al. (1998). Idiopathic pulmon-

Tessier V, et al. (1996). A controlled study

ary haemosiderosis. Epidemiology, patho-

of differential cytology and cytokine expres-

genic aspects and diagnosis. Respir Med; 92:

sion profiles by alveolar cells in pediatric

902-907.

sarcoidosis. Chest; 109: 1430-1438.

ERS Handbook: Paediatric Respiratory Medicine

145

Bronchial brushing and

bronchial and transbronchial

biopsies

Petr Pohunek and Tamara Svobodová

Flexible bronchoscopy allows detailed

Bronchial brushing

examination of the bronchial tree down to,

Bronchial brushing is a method used for

at least, the segmental and subsegmental

sampling superficial samples of bronchial

bronchi. Visual examination is the main

mucosa. Basically, two methods can be

part of the examination; it provides

used. A protected brush is a brush enclosed

information about the anatomy and

intraluminal lesions, and allows

in a plastic tube that covers the brush and

prevents unwanted contamination during

assessment of airway stability and patency.

passage of the brush through the working

Visual assessment of the bronchial mucosa

channel (fig. 1). Only after the brush is fully

gives some basic information about

passed through the channel is it pushed out

possible inflammation, swelling or atrophy.

of the cover. It is then used for sampling of

If we want to examine the processes

the desired area before being withdrawn

occurring in bronchial mucosa in more

detail, visual information alone is not

back into the covering tube. The whole

instrument is then pulled back out of the

sufficient. For detailed information about

channel, the brush is pushed out of the

the inflammatory or structural changes in

cover and sampled cellular material washed

the mucosa some additional methods are

in appropriate medium or smeared on a

needed. For sampling of bronchial mucosa

slide for further examination. The use of a

tools are available that can be passed

protected brush is limited by the size of the

through the working channel of the

working channel. The minimum channel

bronchoscope.

diameter needed for protected brushing is

2.0 mm. When using a smaller paediatric

bronchoscope (3.6 mm or 2.8 mm) we are

Key points

left with a small working channel with a

diameter of 1.2 mm. Only a thin unprotected

N Bronchial brushing is a useful

brush can be passed through this channel.

complementary method for assessing

Unprotected brushing is usually performed

cytological changes in the superficial

as a final method before the end of the

mucosal layer.

bronchoscopy. An unprotected brush is

passed through the channel and then, under

N Endobronchial biopsy allows more

visual control, the mucosal surface is

detailed evaluation of inflammation

sampled by gently scratching the surface

and structural damage of the

with the brush. The main difference to

bronchial wall. It also allows direct

protected brushing is that the unprotected

histological analysis of an

brush is then withdrawn into only the tip of

endobronchial lesion, e.g. a tumour.

the bronchoscope just to be hidden in the

TBLB samples lung parenchyma

channel. Then, with the brush left in place,

without the need for thoracoscopy or

the whole bronchoscope is withdrawn from

thoracotomy.

the patient, The brush is then pushed out of

the channel and either cut and dropped into

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ERS Handbook: Paediatric Respiratory Medicine

a vial containing the appropriate medium,

Bronchial brushing is generally safe, as it is

washed in the medium or smeared on a

limited just to the mucosal surface. Minor

slide. This method allows proper sampling

superficial self-limited bleeding can be seen.

with minimum contamination or loss of

In a deep blind sondage there is a possible

collected material during the passage of the

risk of pneumothorax and the patient should

brush through the working channel.

be properly monitored post-procedure with

this possibility in mind. Routine follow-up

Bronchial brushing is a useful method of

chest radiography is not necessary after a

sampling mucosa for cytology and has been

bronchoscopy with bronchial brushing.

successfully used both for clinical and

research purposes.

Bronchial biopsy

Main indications Usually, bronchial brushing

Bronchial (or endobronchial) biopsy is a

is performed from mucosa within the visual

method allowing sampling of a small piece

reach of the bronchoscope and sampling is

of bronchial mucosa for histological

performed from the visible lesion or from

examination.

the unselected mucosal surface in expected

Main indications Targeted biopsy is essential

general pathologies. Cytology from visible

for histological diagnosis in focal

lesions may provide a specific diagnosis;

intraluminal processes, such as tumours,

cellularity of mucosa in general conditions

mucosal nodules, granulation tissue, etc.

can be evaluated with an assessment of

Biopsy is also often indicated as a

possible mucosal dysplasia or metaplasia,

supplementary method for the evaluation of

providing contributory information about

diffuse pathological processes in the

the intensity and type of inflammation.

bronchial wall (e.g. asthma, CF, chronic

Bronchial brushing is also used for sampling

bronchitis and primary ciliary dyskinesia).

epithelial cells for an evaluation of ciliary

Bronchial biopsy only provides information

function or structure in suspected primary

about processes occurring in the superficial

ciliary dyskinesia. In selected situations,

layer of the bronchial wall; however, a

blind sampling can be performed, such as a

properly obtained biopsy usually comprises

deep sondage for cytology or culture from a

all the relevant structures involved in most

peripheral lesion. Sampling into culture

pathological processes. In a bronchial

media allows collection of material under

biopsy, bronchial epithelium, basement

visual control for targeted culture.

membrane, the subepithelial layer with

mucus glands and vessels, and, usually also,

the smooth muscle bundles are visible.

Various staining methods can be used to

increase yield of the method, including

immunohistochemistry and specific staining

for structural proteins (e.g. trichrome)

The size of bronchial biopsy depends on the

size of biopsy forceps. Larger paediatric

bronchoscopes, with a diameter of 4.9 mm,

or hybrid flexible bronchoscopes, with a

diameter of 4.0 mm, have a 2.0 mm

working channel. This allows most standard

biopsy instruments to be used. Biopsy

forceps are available in different sizes and

shapes. The most commonly used type for a

standard bronchial biopsy is an oval

fenestrated cup forceps (fig. 2). This forceps

allows appropriate embedding in bronchial

Figure 1. Protected bronchial brush.

mucosa and sampling without undesired

ERS Handbook: Paediatric Respiratory Medicine

147

damage to the sample. Various other types

are available, including alligator shape

forceps. These are usually not used for

standard biopsy as more damage to the

sample might occur. For a standard

paediatric bronchoscope with a diameter of

3.6 mm or 2.8 mm with a 1.2-mm channel

only limited types of biopsy forceps are

available (fig. 2). These are usually provided

as an oval non-fenestrated cup with or

without a rat tooth. These small instruments

are generally much less efficient in obtaining

a proper sample of bronchial mucosa and

their use, and especially handling of the tiny

samples, requires experience.

Figure 3. Position of the biopsy forceps for

Bronchial biopsies in general processes are

sampling from a secondary carina.

usually taken from some secondary or

tertiary carina. It is not recommended to

sample off the forceps branches. Depending

sample from the main carina as the mucosa

on a visual assessment of the sample size

at this level could carry some nonspecific

and quality, biopsy is repeated to guarantee

changes. Sampling from the carina is

a sufficient sample for further diagnostic

technically rather easy as there is good

evaluation.

possibility to position the forceps, close and

grab, and then withdraw the closed forceps

If the focal pathology is located in the

carrying the sample between the closed

bronchial wall and therefore sampling from

branches (fig. 3). The forceps are then

a carina would not be helpful, a different

pulled out of the channel and handed to an

technique must be used. Using the flexion of

assistant who places the sample into a vial

the tip of the bronchoscope, the forceps

containing appropriate fixation medium.

must be pressed against the wall with the

The sample can usually be liberated from

branches open parallel to the wall and the

the branches by vigorous shaking of the

pathological structure kept between the

forceps in the medium. Sometimes a small

branches. The forceps are then closed and

needle might need to be used to get the

the mucosa grabbed between the branches.

If this is not successful, the positioning

must be retried and sampling repeated.

Bronchial biopsy is generally a very safe

method. As it samples only a superficial

layer of bronchial wall, bleeding is negligible

in most cases and a risk of pneumothorax is

almost zero. It has been shown to be safe

even in children with CF whose bronchial

mucosa is generally inflamed and

hyperaemic. Even in very young children

evaluated for recurrent wheezing bronchial

biopsy has been shown to be safe and

effective. There was one case of

pneumothorax as a complication of

bronchial biopsy in a large series (de Blic et

Figure 2. Left: oval cup forceps for a thin paediatric

al., 2002). In this case, the biopsy was taken

bronchoscope (1.2-mm working channel). Right:

from an existing pathology that may have

oval fenestrated cup forceps.

caused some pre-existing lesion of the

148

ERS Handbook: Paediatric Respiratory Medicine

bronchial wall. It is recommended to take

monitoring of the whole procedure,

bronchial biopsies from one lung only to

including possible immediate

avoid theoretical risk of a bilateral

complications, such as pneumothorax

pneumothorax.

(fig. 4). Once the closed forceps are wedged

with an elastic resistance, the forceps are

Logically, any supplemental procedure

withdrawn ,10 mm, opened and pushed

prolongs the time required to perform

down with the aim to break the bronchial

bronchoscopy. Sampling of three adequate

wall and accumulate adjacent lung

biopsy samples requires ,5 min and this

parenchyma between the branches. The

should be taken into account when planning

forceps are then closed and withdrawn back

a procedure.

through the channel. A marked elastic

Transbronchial lung biopsy

resistance should be felt, which signals a

good position of the forceps and predicts an

Transbronchial lung biopsy (TBLB) is a

adequate sample. A quick release of the

special procedure that allows sampling of

resistance occurs when the sample is

pulmonary tissue via endobronchial

detached from the lung and the whole

approach.

closed forceps can then be withdrawn

Main indications A main and well-

through the channel. Three to six samples

established indication for TBLB is evaluation

from one side are usually taken to ensure

of rejection in patients with transplanted

sufficient tissue to evaluate. Sampling from

lungs. Less often, TBLB has been used for

both sides may lead to bilateral

diagnostic evaluation of diffuse

pneumothorax and severe respiratory

parenchymal lung diseases or for evaluation

compromise and should, therefore, be

of infection. Successful diagnostic TBLB has

avoided. Any bleeding from the area should

been documented mainly in homogeneous

be carefully monitored using the

pathologies, such as pulmonary sarcoidosis

bronchoscope, which should be left in place

and hypersensitive pneumonitis. The main

for ,3 min after the last sampling to ensure

advantage of TBLB is its repeatability as

that no major haemorrhage has occurred. If

there is no need for video-assisted

significant bleeding occurs the

thoracoscopy or open thoracic surgery (now

bronchoscope can be wedged into the

used much less often). It has been

relevant sub-segmental bronchus to help to

recommended to target the TBLB using

stop the bleeding.

preceding HRCT. This helps to increase yield

especially in non-homogenous pathologies.

Compared to endobronchial biopsy, TBLB

carries higher risk of complications. The

The technique of TBLB is relatively simple;

most frequent are bleeding and

however, it needs experience and practice.

TBLB is performed using standard biopsy

forceps, preferably with an oval fenestrated

cup. Use of alligator forceps is generally not

recommended as it may cause more

complications. Use of larger instruments

through the 2.0-mm channel has better

yield; however, successful TBLB can be

obtained even with thin forceps used

through a small paediatric bronchoscope.

For TBLB, the bronchoscope is positioned

into a relevant segmental or sub-segmental

bronchus. Biopsy forceps are then inserted

through the working channel and gently

pushed into the periphery beyond direct

vision. Fluoroscopy is mandatory as it helps

Figure 4. Biopsy forceps during TBLB as shown on

to position the forceps and allows

the fluoroscopy.

ERS Handbook: Paediatric Respiratory Medicine

149

pneumothorax. Overall, the frequency of any

Further reading

complications has been shown to be ,10%.

de Blic J, et al. (2002). Complications of

Conclusion

flexible bronchoscopy in children: pro-

spective study of 1,328 procedures. Eur

Sampling of bronchial mucosa and

Respir J; 20: 1271-1276.

pulmonary parenchyma is now a well-

Greene CL, et al. (2008). Role of clinically

established part of a diagnostic process in

indicated transbronchial lung biopsies in

many respiratory diseases. Cytology and,

the management of pediatric post-lung

mainly, histology significantly contribute to

transplant patients. Ann Thorac Surg; 86:

198-203.

diagnosis and therapeutic decision. Biopsy

Looi K, et al. (2011). Bronchial brushings

is generally safe but every procedure

for investigating airway inflammation and

should be properly planned in advance

remodelling. Respirology; 16: 725-737.

with possible risks kept in mind and with a

Molina-Teran A, et al. (2006). Safety of

decision as to what samples are required

endobronchial biopsy in children with

for diagnostic evaluation. As

cystic fibrosis. Pediatr Pulmonol;

41:

endobronchial biopsies contribute

1021-1024.

significantly not only to immediate

Regamey N, et al. (2009). Time required

diagnosis but also to general

to obtain endobronchial biopsies in

understanding of pathological processes,

children during fiberoptic bronchoscopy.

it is now considered ethically acceptable to

Pediatr Pulmonol; 44: 76-79.

use part of the biopsy material for

Romagnoli M, et al. (1999). Safety and

research. Of course this must be based on

cellular assessment of bronchial brushing

an appropriate protocol, informed consent

in airway diseases. Respir Med; 93: 461-

of legal representatives of the patient and

466.

approval by the Institutional Review Board.

Saglani S, et al. (2005). Airway remodel-

ing and inflammation in symptomatic

Acknowledgements

infants with reversible airflow obstruc-

tion. Am J Respir Crit Care Med; 171: 722-

This work was supported by the Ministry of

727.

Health, Czech Republic (conceptual

Visner GA, et al. (2004). Role of trans-

development of research organisation,

bronchial biopsies in pediatric lung dis-

University Hospital Motol, Prague, Czech

eases. Chest; 126: 273-280.

Republic; grant number 00064203).

150

ERS Handbook: Paediatric Respiratory Medicine

Rigid and interventional

endoscopy

Thomas Nicolai

Rigid bronchoscopy was the first method

described to visualise the lower human

Key points

airway. In 1897, Kilian removed an airway

foreign body using rigid bronchoscopy. The

N Rigid bronchoscopy is indicated for

technique was simple and has, in principle,

foreign body retrieval and pre-

remained unchanged. A rigid hollow tube is

operative diagnostic workup of

used to intubate the trachea or a bronchus.

subglottic lesions.

Ventilation can be maintained through this

N With the necessary precautions the

tube, and direct vision was used initially to

procedure is quite safe.

inspect the airway. The tube was

illuminated internally with a prism. Later

N Teaching the necessary skills to future

improvements included a rigid telescope

generations of paediatric

introduced into the hollow bronchoscope

bonchoscopists is a challenge.

tube (table 1). These telescopes are

fibreglass rods protected by a metallic

covering, with a lens at the distal and an eye

are used to intubate differently sized airways

piece at the proximal end. Light is

to achieve a reasonable seal and allow

transmitted through this instrument with a

ventilation of the patient. The rigid

coupling device from an external light

endoscope has smooth edges at the distal

source. Today, the eye piece at the proximal

end but could still potentially damage the

end can be connected to a charge-coupled

airway. Therefore, the rigid tube can only be

device camera; thus, the image can be

advanced safely if its distal edge is visible

converted to a digital signal and displayed

during its movement. If this principle is

on a video screen.

adhered to, rigid bronchoscopy is a very safe

Technical considerations

procedure.

The use of the rigid endoscope for the

If the rigid tube is advanced into the lower

trachea and bronchi is only possible if the

airways, care must be taken to smoothly

larynx can be exposed and the bronchoscopy

align the long axis of the rigid tube with the

tube can then be advanced into the airway.

airway. This is achieved by turning the head

In children with difficult airways, such as in

to the right when intubating the left

Pierre Robin sequence and other

bronchial system, and conversely on the

malformations, this may sometimes be

right side.

impossible.

The bronchoscope tubes have small lateral

As the introduction of a rigid tube into the

slits that allow the passage of air into the

airways is very irritating, full anaesthetic is

more proximal airways, even when the tip of

always necessary. Because the ventilation of

the bronchoscope has been advanced into

the patient has to be performed through the

the distal bronchi or when it may be

rigid tube, appropriate connectors are

occluded by a foreign body during an

necessary and different sizes of rigid tubes

extraction procedure. So-called

ERS Handbook: Paediatric Respiratory Medicine

151

Table 1. Rigid bronchoscopes for children

Tubes: internal diameter mm

Telescopes: outer diameter mm

3.0

1.8

3.5

2.0

4.0

2.7

4.5

3.4

5.0

4.0

5.5

6.0

These are typical examples, exact actual sizes may vary for different manufacturers; typical lengths are 28, 30

and 35 cm.

tracheoscopes are rigid tubes with the same

procedure and the possibility to introduce

diameter as the bronchoscopes but without

various instruments. In particular, if a large

lateral openings to avoid a loss of ventilation

and potentially occluding foreign body has

pressure when the tip of the tracheoscope is

to be extracted, the rigid technique allows

placed in the trachea, when, the lateral

the bronchoscopist to reposition or push

openings of a bronchoscope would still be

the foreign body if it is lost during the

proximal to the larynx.

procedure, giving more safety to a

potentially life-threatening operation. In

The rigid bronchoscope allows for the use of

addition, bleeding or secretions can be

various instruments through its lumen

controlled or suctioned. This is often

(fig. 1); these can be:

impossible when a foreign body retrieval

basket has been advanced through the thin

N forceps,

N suction catheters,

suction channel of a flexible scope. Also,

with a flexible bronchoscope, ventilation

N special magnets,

through a mask or laryngeal mask is

N biopsy needles.

necessary while the bronchoscope

Specialised bronchoscopes even allow the

obstructs part of the airway. The possible

transmission of a carbon dioxide laser

ventilation pressure is limited to 20-

through a set of mirrors and make laser

25 cmH₂O with this technique. If the

surgical procedures in the lower airways

foreign body or bodies cause increased

possible with no deeper or transmural tissue

airway resistance, sufficient ventilation

damage.

pressure may not reach the lung, leading to

dangerous hypoventilation and respiratory

Indications

instability. However, small distally

Today, most diagnostic indications are

positioned foreign bodies may be more

covered by the use of a flexible

easily extracted with a combination of both

bronchoscope. However, a few clear

methods (flexible through rigid).

indications for rigid bronchoscopy remain,

Other indications include the recanalisation

and foreign body removal is the most

of airways, e.g. in TB, the use of a carbon

frequent (fig. 2). The guidelines of the

dioxide laser for surgical interventions and,

American Thoracic Society clearly advocate

rarely, the placement of silicone stents. The

rigid bronchoscopy for foreign body removal

removal of bronchial casts in plastic

in children.

bronchitis or solidified airway secretions in

Even today the advantage of rigid

severe bacterial tracheobronchitis are also

bronchoscopy is a secure airway during the

best performed with a rigid bronchoscope.

152

ERS Handbook: Paediatric Respiratory Medicine

Figure 1. Instrument tray for rigid bronchoscopy in children, including bronchoscopy tubes, telescopes and

suction tubes.

Bronchoscopy using only a rigid telescope

table with a special device, thereby freeing

the left hand of the bronchoscopist

A variant of rigid laryngo-tracheo-

(suspension laryngoscopy) (fig. 3). During

bronchoscopy that is quite useful in children

a period of apnoea, the rigid telescope is

consists of the use of a rigid telescope alone

then advanced through the level of the

(without a rigid bronchoscopy tube) to

vocal folds into the lower airways. Great

intubate and inspect the airways.

care is taken not to touch the airway

The technique involves exposing the larynx

surface. This technique gives extremely

with a laryngoscope. If a more complicated

detailed pictures of the glottis, subglottic

examination or intervention is planned, the

region and trachea and can be used for

laryngoscope can be fixed to the operating

preoperative documentation and

instrumentation if laryngeal or subglottic

surgery is planned. It also allows for the

use of instruments, apart from the

telescope, without the limitations of space

within the rigid bronchoscopy tube.

Measurements of distances can be made

with great accuracy. This method is

particularly suited to directly inspect the

subglottic region, even in cases such as

laryngitis, without touching the airway

surface. This is useful to exclude a foreign

body in the diagnostic workup of atypical or

persistent cases of croup. The procedure

lasts only seconds and can be performed

under short anaesthetic such as for an

Figure 2. Rigid bronchoscopy for the removal of a

intubation procedure, even in a respiratory-

foreign body.

unstable patient.

ERS Handbook: Paediatric Respiratory Medicine

153

Future developments

It will be necessary to keep teaching future

generations of bronchoscopists rigid

bronchoscopy to ensure airway foreign body

extraction remains a safe procedure. This

poses a real challenge to paediatric

bronchoscopists because almost all

diagnostic bronchoscopies will be flexible,

with few indications remaining for rigid

endoscopy except foreign body removal.

Usually, ENT surgeons have the necessary

Figure 3. Rigid laryngoscopy with a telescope and

skills and a paediatric bronchoscopist who

laryngoscope blade fixed to the operating table

wants to learn this technique would be

(suspension laryngoscopy).

advised to participate in (at least adult) rigid

bronchoscopies, followed by a hands-on

This method may also be used to inspect the

simulation course in paediatric rigid

damage to the larynx in children with

bronchoscopy and supervised foreign body

intubation stenosis or glottic inflammation

extractions.

by retracting the endotracheal tube,

inspecting the subglottic region and

Further reading

immediately reintroducing the tube. This

technique allows optimal diagnosis and

Ansley JF, et al.

(1999). Rigid tracheo-

even local therapies, such as laser resection

bronchoscopy induced bacteraemia

in the paediatric population. Arch

or infiltration of laryngeal papillomas with

Otolaryngol Head Neck Surg; 125: 774-

substances like cidofovir.

776.

Contraindications and difficulties

Barbato A, et al. The bronchoscope

flexible and rigid

- in children. Treviso,

Contraindications to rigid bronchoscopy

Arcari Editore, 1995.

obviously include an airway that cannot be

Garabedian EN, et al. (1989). The carbon

intubated with a rigid bronchoscopy tube

dioxide laser in tracheobronchial diseases

without excessive force or when the use of

in children. A prospective study of

cases. Ann Otolaryngol Chir Cervicofac;

laryngoscope exposing the larynx is con-

106: 206-209.

traindicated, such as in vertebral instability.

Handler SD (1995). Direct laryngoscopy

A bleeding diathesis or severe

in children: rigid and flexible fiberoptic.

Ear Nose Throat J; 74: 100-104.

thrombocytopenia makes the use of a rigid

Helmers RA, et al. (1995). Rigid broncho-

endoscope more dangerous, without being

scopy. The forgotten art. Clin Chest Med;

an absolute contraindication. Bacteraemia

16: 393-399.

may ensue with rigid bronchoscopy and,

Holinger LD, et al., eds. Pediatric

therefore, the recommendations for

Laryngology and Bronchoesophagology.

antibiotic coverage in children with

Philadelphia, Lippincott, Williams and

congenital heart disease must be followed.

Wilkins, 1996.

Martinot A, et al. (1997). Indications for

Rigid laryngoscopy and bronchoscopy will not

flexible versus rigid bronchoscopy in

allow the diagnosis of any dynamic or

children with suspected foreign-body

functional features such as airway malacia,

aspiration. Am J Respir Crit Care Med;

vocal cord paralysis or pharyngeal instability

155: 1676-1679.

and may, therefore, be insufficient in the

Nicolai T (2001). Pediatric bronchoscopy.

diagnosis of stridor. In these cases, it may be

Pediatr Pulmonol; 31: 150-164.

combined with flexible endoscopy as indicated.

154

ERS Handbook: Paediatric Respiratory Medicine

General anaesthesia,

conscious sedation and

local anaesthesia

Jacques de Blic and Caroline Telion

The diagnostic value of bronchoscopy is

techniques are general anaesthesia for

now widely accepted to directly visualise the

babies or young children and moderate

lower airways and obtain samples,

sedation for children, teenagers or patients

particularly by performing bronchoalveolar

with ASA III-V status, according to the

lavage. Performing a safe and successful

American Society of Anesthesiology

examination and sampling of the airways

classification.

depend on the experience and skill of the

Pre-bronchoscopic procedures

operator and on the comfort of the child.

Bronchoscopy, like any invasive technique,

A detailed history and a complete physical

may induce anxiety, fear, pain and

examination should be performed. Pre-

unpleasant memory of the experience.

operative assessment of the child is

Paediatric patients should almost always be

essential, including:

sedated for bronchoscopy. The available

N general history,

N allergies and previous adverse drug

reactions,

Key points

N current medications,

N sedation/anaesthesia history with focus

Appropriate sedation is important for

on complications and airway problems,

a well-tolerated bronchoscopic

N history of upper airway problems and

procedure; available techniques

sleep-disordered breathing or snoring,

include general anaesthesia and

N major medical illnesses,

moderate sedation.

N physical abnormalities and neurological

Various protocols may be used during

problems,

flexible bronchoscopy that involve the

N recent acute illnesses (e.g. upper

administration of a single drug or

respiratory infection, fever, etc.).

drug combination (midazolam,

N written fully informed consent.

meperidine, propofol, ketamine,

Minimum fasting periods prior to the

remifentanil, etc.), or inhalation

procedure are usually 2 h for clear liquids,

agents (premixed 50% nitrous oxide

4 h for breast milk, 6 h for formula or light

and oxygen or sevoflurane).

meals and 8 h for full meals.

Rigid bronchoscopy should always be

performed under general anaesthesia.

The need for premedication is at the

discretion of the anaesthetist. In general it is

Whatever the choice of sedation and

unnecessary; however, if the child is

technique of oxygen delivery (nasal

distressed or unable to cooperate then

prongs, face mask, laryngeal mask or

premedication is advisable.

endotracheal intubation) it is

essential to maintain and preserve

Oral atropine (0.01-0.02 mg?kg^-1)

spontaneous ventilation.

minimises bradycardia induced by vasovagal

stimulation and also decreases airway

156

ERS Handbook: Paediatric Respiratory Medicine

secretions. The utility and safety of oral or

ventilation. When using inhalational agents,

intramuscular atropine premedication has

the preferred technique for administration is

yielded conflicting results

usually via a face mask with the

bronchoscope being passed through a port

Appropriate equipment in a dedicated

on the mask while the anaesthetic gas is

bronchoscopy suite including pulse

delivered. An alternative technique is the use

oximeter, blood pressure measuring device,

of a laryngeal mask.

electrocardiograhy, capnography, suction

apparatus and, if possible, a temperature

Moderate sedation

monitor is necessary.

There is no unique protocol for inducing

General anaesthesia

conscious sedation. As for general

anaesthesia, conscious sedation may be

General anaesthesia may be achieved either

achieved either by an intravenous drug (e.g.

by an intravenous drug (propofol, ketamine

midazolam or meperidine) (table 1) or a

or remifentanil) (table 1) or a volatile agent

volatile agent (inhalation of premixed 50%

(halothane or sevoflurane). They can be

nitrous oxide and oxygen). Combinations of

used alone or in combination. The presence

agents are more effective than single agents.

of a trained anaesthesiologist is necessary.

Sedation should be given in small

incremental doses until the desired effect is

Propofol is an intravenous sedative

obtained.

hypnotic agent administered in a dose of

2-5 mg?kg^-1. It has a rapid onset and a

Midazolam is a water soluble

short duration of action. The level of

benzodiazepine. It reduces anxiety and

sedation and that of respiratory

causes amnesia of the procedure.

depression are dose dependent.

Flumazemil is used as an antagonist.

The use of ketamine as an anaesthetic

Midazolam is not intended as a sole agent

agent is less common in children.

for paediatric sedation, but should be

Ketamine has been associated with

administered in association with an opioid

laryngospasm and bronchospasm. It

or nitrous oxide via a face mask.

should be used in combination with

atropine and benzodiazepine in

Meperidine is a synthetic opiate that

premedication. Ketamine can be used

produces both sedation and analgesia; it has

successfully, but requires attention to

the advantage of rapid onset of action and is

topical anaesthesia of the airway in order

easily reversible (naloxone). Mepiridine is

to reduce the risk of laryngospasm; the

preferably administered intravenously by

addition of a benzodiazepine is also

fractional doses to achieve the desired effect

recommended to prevent the emergence

with the minimum drug dose. The use of a

of hallucinations.

benzodiazepine reduces the required dosage

Remifentanil is a synthetic opioid agent

of meperidine. Known adverse effects

which is a strong analgesic. It has a short

include:

duration of action and a short half-life. Its

adverse effects include respiratory

N respiratory depression that may last

depression, hypotension, vomiting and

longer than other clinical effects,

rigid chest syndrome. It is rarely used in

N transient urticaria due to release of

anaesthesia for flexible bronchoscopy,

histamine,

but it is used in rigid endoscopy.

N transient hypotension,

N nausea,

Inhalational agents are commonly used.

N vomiting.

Sevoflurane has a rapid onset of action, its

effects quickly resolve after the

Anxiolysis and analgesia may also be

discontinuation of drug administration, it

achieved with inhalation of premixed 50%

has minimal cardiovascular and no

nitrous oxide and oxygen administered via a

bronchoconstrictive effects. It allows deep

face mask. Onset of action is 3 min and

sedation with preservation of spontaneous

duration of action is 5 min. Side-effects,

ERS Handbook: Paediatric Respiratory Medicine

157

Table 1. Main drugs used for sedation in paediatric flexible bronchoscopy

Drug

Actions

Dose

Onset of

Duration

Antagonist

action

of action

Midazolam

Anxiolysis

i.v. (bolus):

1-5 min

90 min Flumazemil

Amnesia

75-300 mg?kg^-1

0.01 mg?kg^-1

Meperidine

Analgesia

i.v. (bolus):

5 min

3-4 h

Naloxone

0.5-2 mg?kg^-1

0.01 mg?kg^-1

Ketamine

Analgesia

i.v. (intermittent bolus):

2-4 min

10-

Anaesthesia

0.25-0.5 mg?kg^-1

20 min

Amnesia

Propofol

Anaesthesia i.v. (intermittent bolus):

,1 min

30 min

0.5-1 mg?kg^-1

i.v. (continuous

infusion):

100 mg?kg^-1?min^-1

Remifentanil Anaesthesia

i.v. (intermittent bolus)

2-5 min

2-3 min

Analgesia

0.25-0.1 mg?kg^-1?min^-1

Continuous infusion

0.05 mg?kg^-1?min^-1

especially nausea, may occur when it is

Nasopharyngeal prongs are easy to pass

administered for more than 15 min.

down one nostril while the bronchoscope is

passed through the other. They allow

Local anaesthesia

inspection of most of the upper airway and

assessment of the airway dynamics.

Local anaesthesia is of particular

importance when conscious sedation is

Face masks allow the inspection of the entire

used. 2-5% lidocaine is applied on the nose

airway and the assessment of its dynamics.

and the larynx and 0.5-1% below the larynx.

This method permits application of positive

Lidocaine may be instilled directly, sprayed

end-expiratory pressure. The bronchoscope

or nebulised (1-5 mL of 2-4% lidocaine

is passed through an adaptor on the face

according to the child’s weight). The total

mask. Problems may arise if a complication

dose should not exceed 5-7 mg?kg^-1, but the

occurs as the airway is shared during the

exact amount applied is difficult to assess as

entire process between the bronchoscopist

most of the lidocaine is removed by suction,

and the anaesthesiologist (fig. 1).

spitting or swallowing. Insufficient topical

anaesthesia will result in pain, cough,

Laryngeal masks allow a larger

laryngospasm and/or bronchospasm due to

bronchoscope to be introduced, avoid

vagal stimulation. Topical lidocaine may

tracheal intubation and are well tolerated.

worsen layngomalacia.

Airway control is better achieved than with

the use of a face mask. Disadvantages are

Techniques to ensure adequate ventilation

that the upper airways and vocal cord

during flexible bronchoscopy

movement cannot be assessed (fig. 2).

Whatever the combination of drugs and the

Endotracheal intubation allows the

technique utilised to deliver oxygen, it is

bronchoscope to be re-passed easily and

essential to maintain and preserve

quickly when necessary. Disadvantages are

spontaneous ventilation. The techniques

that upper airways, vocal cord movement

available include nasopharyngeal prongs,

and airway dynamics cannot be assessed

face or laryngeal mask, and endotracheal

and that the endotracheal tube may limit the

intubation.

size of the bronchoscope.

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ERS Handbook: Paediatric Respiratory Medicine

Sedation and anaesthesia in rigid

bronchoscopy

Rigid bronchoscopy should always be

performed under deep sedation. Induction

of anaesthesia is similar to that of flexible

bronchoscopy. Inhalational anaesthesia and

oxygen delivery are maintained through a T-

piece connected to the side arm of the rigid

bronchoscope. Two modes of ventilation are

routinely used: spontaneous ventilation or

Figure 1. Face mask.

(preferably) positive pressure-controlled

ventilation. The use of jet ventilation has

Moderate sedation or general anaesthesia

also been reported. The use of a muscle

for flexible bronchoscopy

relaxant (e.g. suxamethonium 1.5 mg?kg^-1)

has been proposed for cases when

The technique of sedation used depends on:

interventional endoscopy is performed;

N respiratory status,

however, it appears to be less useful in

children than in adults.

N psychological and emotional status of the

patient,

Recovery and post-procedural care

N underlying disease,

N available drugs,

Upon completion of the procedure, the child

N availability of an anaesthetist,

must remain in the recovery area until

N procedures to be performed.

cardiovascular and respiratory stability are

assured and the child is awake and

The principal objective of moderate sedation

orientated. An intravenous line should be

is to maintain spontaneous ventilation, but

left in situ until the child is completely awake

fibroscope insertion may induce cough

and tolerating oral fluids.

reflex, laryngospasm or ventilatory

depression. For these reasons if, in the past,

Further reading

most flexible bronchoscopies were

performed under moderate sedation, most

American Academy of Paediatrics, et al.

units have currently moved to general

(2006). Guidelines for monitoring and

anaesthesia, which appears to be more

management of pediatric patients during

comfortable for both the child and the

and after sedation for diagnostic and

medical team.

therapeutic procedures: an update.

Pediatrics; 118: 2587-2602.

When sedation is used, the most frequent

American Academy of Paediatrics, et al.

agents used are sevoflurane and propofol

(2008). Guidelines for monitoring and

alone or in combination.

management of pediatric patients during

and after sedation for diagnostic and

therapeutic procedures: an update.

Paediatr Anaesth; 18: 9-10.

Amitai Y, et al. (1990). Serum lidocaine

concentrations in children during

bronchoscopy with topical anesthesia.

Chest; 98: 1370-1373.

Antonelli M, et al. (1996). Noninvasive

positive-pressure ventilation via face

mask during bronchoscopy with BAL in

high-risk hypoxemic patients. Chest; 110:

724-728.

Figure 2. Laryngeal mask.

ERS Handbook: Paediatric Respiratory Medicine

159

Berkenbosch JW, et al. (2004). Use of a

Malviya S, et al. (1997). Adverse events

remifentanil-propofol mixture for pedia-

and risk factors associated with the

tric flexible fiberoptic bronchoscopy seda-

sedation of children by nonanesthesiolo-

tion. Paediatr Anaesth; 14: 941-946.

gists. Anesth Analg; 85: 1207-1213.

de Blic J, et al. (2002). Complications of

Mason DG, et al. (1990). The laryngeal

flexible bronchoscopy in children: pro-

mask airway in children. Anaesthesia.; 45:

spective study of 1,328 procedures. Eur

760-763.

Respir J; 20: 1271-1276.

Midulla F, et al.

(2003). Flexible endo-

Erb T, et al. (1999). Fibreoptic broncho-

scopy of paediatric airways. Eur Respir J;

scopy in sedated infants facilitated by an

22: 698-708.

airway endoscopy mask. Paediatr Anaesth;

Naguib ML, et al. (2005). Use of laryngeal

9: 47-52.

mask airway in flexible bronchoscopy in

Farrell PT (2004). Rigid bronchoscopy for

infants and children. Pediatr Pulmonol; 39:

foreign body removal: anaesthesia and

56-63.

ventilation. Paediatr Anaesth; 14: 84-89.

Nielson DW, et al.

(2000). Topical

Fauroux B, et al. (2004). The efficacy of

lidocaine exaggerates laryngomalacia dur-

premixed nitrous oxide and oxygen for

ing flexible bronchoscopy. Am J Respir Crit

fiberoptic bronchoscopy in pediatric

Care Med; 161: 147-151.

patients: a randomized, double-blind,

Nussbaum E, et al.

(2001). Pediatric

controlled study. Chest; 125: 315-321.

fiberoptic bronchoscopy with a laryngeal

Hasan RA, et al. (2009). Sedation with

mask airway. Chest; 120: 614-616.

propofol for flexible bronchoscopy in

Shaw CA, et al. (2000). Comparison of

children. Pediatr Pulmonol; 44: 373-378.

the incidence of complications at induc-

Jaggar SI, et al. (2002). Sedation, anaes-

tion and emergence in infants receiving

thesia and monitoring for bronchoscopy.

oral atropine vs no premedication. Br J

Paediatr Respir Rev; 3: 321-327.

Anaesth; 84: 174-178.

Larsen R, et al. (2009). Safety of propofol

Slonim AD, et al. (1999). Amnestic agents

sedation for pediatric outpatient proce-

in pediatric bronchoscopy. Chest;

116:

dures. Clin Pediatr (Phila); 48: 819-823.

1802-1808.

160

ERS Handbook: Paediatric Respiratory Medicine

Conventional radiography

Meinrad Beer

The role of chest radiography includes:

preterm babies and polytrauma children)

demands a well-equipped radiological unit

N primary diagnosis,

and well-trained personal.

N monitoring of patients’ progress, and

N assessment for interventional

Chest radiography

procedures.

Technique For newborns and infants, the

Thorough consideration of radiation

anterior-posterior (AP) view in supine and,

protection based on optimised equipment

later, the upright/sitting position is the

includes the protection of relatives and

accepted standard for conventional chest

medical staff. Fluoroscopy allows the

radiography, as the time-point for deep

generation of functional information and

inspiration is better detectable. For

should be available as an advanced

newborns, specially designed holder

diagnostic modality in special

systems are available, which allow the

circumstances. Typical indications for chest

optimal positioning of the field of view

radiography and fluoroscopy for different

(properly centred) and radiation protection.

age groups are listed in table 1. Digital

Moreover, movements of the children are

imaging has revolutionised chest

minimised. The AP projection is also used in

radiography in the last decade. The

critically ill children at the paediatric

increasing number of severely ill children

intensive care unit (PICU) for bedside

(stem cell transplantation, very low weight

imaging. However, the technical capabilities

of the bedside X-ray machines are limited,

leading to decreased spatial resolution of

Key points

images. Moreover, as in adults, heart size is

increased and pleural effusions are more

Chest radiography is the backbone of

difficult to quantify.

the radiological diagnosis of chest

diseases. The use of fluoroscopy is

The posterior-anterior (PA) projection is

restricted to special clinical

the accepted standard for conventional

indications.

chest radiography in older children.

Historically, this was the position that

N The advent of digital imaging and

allowed the most exact judgement of the

pulsed fluoroscopy significantly

size of the heart. Moreover, the radiation

improved the imaging quality of chest

dose is about one-third higher at the site of

radiography and allowed a

entry. Most radiosensitive structures and

tremendous reduction of radiation

organs, such as eyes, thyroid glands,

dose.

thymus and mammae, are on the far side

Careful attention is necessary for

from the X-ray machine, i.e. anterior. In rare

consideration of radiation protection

conditions (exact location of basal

and necessity of imaging (role of

pneumonias, oncological follow-up and

routine follow-up examinations).

scoring of CF), the PA projection may be

combined with the lateral projection.

ERS Handbook: Paediatric Respiratory Medicine

161

Table 1. Typical indications for chest radiography and fluoroscopy for different age groups

Age years

Radiography

Fluoroscopy

0-2

IRDS

Oesophageal atresia

CLD

Lines and wires

Pneumonia

Dysplasia

2-5

Pneumonia

Foreign body aspiration

Aspiration

Lines and wires

5-10

Pneumonia

Gastric reflux

Asthma

Lines and wires

10-18

Pneumonia

Gastric reflux

Asthma

Lines and wires

IRDS: infant respiratory distress syndrome; CLD: chronic lung disease.

However, the radiation dose of these lateral

A direct readout matrix (conversion of X-ray

views is about two to three times as high as

intensity into electrical signals) is the

a standard PA view.

hallmark of digital radiography. Direct

(selenium based) are distinguished from

Table 2. Criteria for image quality and technical

indirect (scintillator/photodiode) systems.

parameters

Both systems provide high-quality images

with a resolution of ,10 pixels per

Size of focus

o0.6 to f1.3 mm

millimetre (corresponding to 5 line pairs per

Additional

1 mm aluminium + 0.1-

millimetre) and allow a significant reduction

filtering

0.2 mm copper

of radiation dose of up to 50% (depending

Anti-scatter grid

None

on the desired resolution). With the advent

Distance focus

100-120 cm (AP, children

of dual-reading systems, the spatial

detector

without the chance to

resolution is now comparable to the older

cooperate)

conventional radiographic systems. An

140-160 cm (AP, children

individual optimisation of the software for

with the possibility to

image calculation is essential. Nevertheless,

cooperate)

artefacts from extrafocal radiation may be

exaggerated by the digital systems.

Tube voltage

60-80 kV

Automatic

Should not be used in

Criteria for image quality and technical

exposure

infants; if used, then with

parameters are listed in table 2. Correct

control

both lateral detectors

adaption of tube voltage and current to age

Time of

f20 ms

and to weight is an essential prerequisite for

exposition

dose reduction as well as the age adapted

Radiation

Wrapped around,

use of filters. The distance between the child

protection

including the gonads

and tube should be not to narrow. Dose

(lead)

reference values allow an estimation of the

correctness of the radiologist’s own dose

Chest radiography in the AP/PA projection from

values. Most European national guidelines

the newborn stage up to 10 years is shown as an

recommend a range for the radiation dose of

example.

chest X-rays from 0.3 (preterm child) to

162

ERS Handbook: Paediatric Respiratory Medicine

whether chest radiography allows the

differentiation between viral and bacterial

infections. Moreover, some authors doubt the

necessity of routine chest radiography in the

assessment of ambulatory acute lower

respiratory tract infection. Figure 1 shows the

value of chest radiography in detecting

complicated pneumonia with relevant pleural

effusion in a young child. Ultrasound may be

used as follow-up modality to reduce

radiation dose.

For PICUs, the value of chest imaging is less

debated. In critically ill newborns, it is used

Figure 1. A 15-month-old girl with fever, coughing

to assess the correct position of different

and wheezing. Pneumonia on both paracardial

lines and wires, such as tracheal and gastric

sides with pleural effusion on the left side.

tubes, temperature sensors, and central

venous lines (fig. 2).

4 cGy?cm^-2 (10-year-old child). Whenever

possible, shielding (of at least the gonads)

Conventional chest imaging plays an

should be adopted with appropriate

important role in the detection of the salient

materials. In addition, radiation protection

radiographic features of CF. Different scoring

of parents and/or medical staff and/or other

systems, such as the Brasfield or Crispin-

children (e.g. in the PICU) are important.

Norman (CN) scores, have been developed to

provide objective parameters for longitudinal

Besides the exact positioning of the X-ray on

assessment of potential disease progression.

the child, deep inspiration and minimal

These scoring systems allow an objective

rotation are important quality factors. A

assessment of disease severity with low interob-

server variability. Included criteria encompass

straight run of the trachea is an indicator of

structural changes of the lung parenchyma/

a properly inspired X-ray image in newborns

tracheobronchial system itself as well as

and infants. For older children, the scapulae

secondary changes in thorax shape and

should be rotated so that they are projected

displacement of adjacent organ systems (fig. 3).

outside the lung parenchyma. The exposure

to the X-ray generator should be as short as

possible to reduce radiation exposure and

minimise potential distortion caused by

movements of the child.

Nowadays, special training programmes for

chest imaging in infants and small children

are available. Thus, even nonspecialist

medical staff can learn a high standard of

data acquisition prior to primary patient

contact. This is especially important for low

birth weight infants.

Clinical examples Most chest radiographs are

Figure 2. Newborn child at the PICU with fever.

taken for assessment of children with

Opacities are seen centrally (pneumonia on both

suspected infectious diseases of the lung,

paracardial sides). The patient is intubated (closed

focusing on exclusion/verification of

asterisk), and has a gastric tube inserted too high

pulmonary opacities and pleural effusions,

(arrow), a correctly inserted temperature sensor

sometimes also of pulmonary hyperinflation

(dotted arrow) and central venous catheter from

(obstruction). There is lively discussion of

the right jugular vein (open asterisk).

ERS Handbook: Paediatric Respiratory Medicine

163

Figure 3. A 22-year-old male patient with CF. Increased lung volumes (obstruction) with a low diaphragm,

increased retrosternal space and kyphotic thoracic spine are seen. Marked pulmonary round, linear and

confluent opacities are also evident (CN score 27).

Complications of advanced CF such as

aspergillosis, ABPA). MRI is unique in the

atelectasis, mucous impaction,

assessment of functional pulmonary

pneumothorax, pulmonary haemorrhage

parameters such as perfusion and

and cor pulmonale can be detected.

ventilation.

However, CT is superior in detection of

extent of bronchiectasis or special kinds of

Chest radiography also constitutes the first

infections (e.g. allergic bronchopulmonary

step in the radiological diagnosis of

Figure 4. A boy with suspected aspiration of a foreign body. Fluoroscopy detected regional

hypertransparency/hyperinflation in the left lower lobe, mostly due to a valve mechanism (increased

volume on the left side in end-expiratory (right) compared to end-inspiratory (left) ventilation).

164

ERS Handbook: Paediatric Respiratory Medicine

noninfectious chest diseases like tumours,

De Lange C (2011). Radiology in paedia-

trauma, malformation and foreign bodies.

tric non-traumatic thoracic emergencies.

Insights Imaging; 2: 585-598.

Fluoroscopy

European

Commission.

Radiation

Protection

No.

162.

Criteria

for

Technique The last decade also brought

Acceptability of Medical Radiological

significant technical improvements for

Equipment used in Diagnostic Radiology,

fluoroscopy. The most important was the

Nuclear Medicine and Radiotherapy.

advent of pulsed imaging. State-of-the-art

Brussels, European Commission, 2012.

fluoroscopy allows the option of different

Grum CM, et al. (1992). Chest radio-

extents of pulse rates. Thus, functional

graphic findings in cystic fibrosis. Semin

imaging affording high (e.g. motility

Respir Infect; 7: 193-209.

disorders of the oesophagus) and low

Hammer GP, et al. (2011). Childhood

temporal resolution (e.g. slow breathing) is

cancer risk from conventional radio-

possible with a reduction in radiation

graphic examinations for selected referral

exposure of up to 70% (low temporal

criteria: results from a large cohort study.

resolution and low pulse rate). However,

Am J Radiol; 197: 217-223.

functional radiography by fluoroscopy is only

European

Commission.

Radiation

rarely used for post-operative complications

Protection

No.

109.

Guidance on

or detection of fistulas.

Diagnostic Reference Levels

(DRLs) for

medical exposures. Brussels, European

Clinical example Determination of regional

Commission, 1999.

hyperinflation is one possible indication for

Langen

HJ,

al.

(2009).

chest fluoroscopy. Fluoroscopy allows the

Trainingsprogramm fur MTRA zur

storage of a series of digitally acquired

Anfertigung von Thoraxubersichtsau-

images (‘‘cine-loop’’ and extended ‘‘last

fnahmen in Inspiration bei unkooperativen

image hold’’). Retrospectively, images in

Kindern [Training program for radiologic

technologists for performing chest X-rays

maximum end-inspiratory and end-expiratory

at inspiration in uncooperative children.].

phases can be selected to judge or rule out

Rofo; 181: 237-241.

aspiration of foreign bodies (fig. 4).

Schneider K, et al.

(2001). Paediatric

fluoroscopy

- a survey of children’s

hospitals in Europe. I. Staffing, frequency

Further reading

of fluoroscopic procedures and investiga-

American College of Radiology. ACR

tion technique. Pediatr Radiol; 31: 238-246.

standard for performance of pediatric

Swingler GH, et al. (1998). Randomised

and adult bedside chest radiography

controlled trial of clinical outcome after

(portable

chest

radiography).

In:

chest radiograph in ambulatory acute

Standards. Reston, American College of

lower-respiratory infection in children.

Radiology, 2011; pp. 31-34.

Lancet; 351: 404-408.

Brenner DJ, et al.

(2001). Estimated

Trinh AM, et al. (2010). Scatter radiation

risks of radiation-induced fatal cancer

from chest radiographs: is there a risk to

from pediatric CT. Am J Radiol;

176:

infants in a typical NICU? Pediatr Radiol;

289-296.

40: 704-707.

Calder A, et al.

(2009). Imaging of

Valk JW, et al. (2001). The value of routine

parapneumonic pleural effusions and

chest radiographs in a paediatric inten-

empyema in children. Pediatr Radiol; 39:

sive care unit: a prospective study. Pediatr

527-537.

Radiol; 31: 343-347.

ERS Handbook: Paediatric Respiratory Medicine

165

Computed tomography

Harm A.W.M. Tiddens, Marcel van Straten and Pierluigi Ciet

A wide spectrum of lung function tests has

of chest CT in children. This information will

been developed to detect and monitor

be helpful both to fill in relevant information

structural lung abnormalities+ in children.

on the chest CT order form and to discuss

Over the past decade, chest computed

the selection of the best protocol for the

tomography (CT) has gained importance as

chest CT for children more efficiently with

a more sensitive modality for diagnosing

the paediatric radiologist.

and monitoring such abnormalities. The

CT technology

radiation exposure needed for a volumetric

chest CT has fallen substantially, which has

Since their introduction in 1972, CT scanners

lowered the threshold for its usage in

and reconstruction algorithms have

children. In addition, CT scanners have

improved greatly. The time needed to obtain

become much faster making it feasible to

the information for reconstructing a cross-

perform a chest examination within a single

section has been reduced to the order of

breath-hold or even in free breathing. This

one second, and the spatial resolution has

section of the Handbook focuses on key

improved substantially. Most CT scanners

issues needed for the optimal and safe use

use so-called fan beam geometry, meaning

that the X-ray tube rotates around the

patient and attenuation measurements are

Key points

obtained with an array of detectors, which

also rotates. Early scanners acquired data

N Use of chest CT in children requires

during full rotation of the X-ray tube, before

special expertise of the radiologist to

the scanner table moved to scan the next

follow the ‘‘As Low As Reasonably

longitudinal position (fig. 1a). This

Achievable’’ (ALARA) principle.

technique, called sequential scanning, was

A chest CT investigation requires a

used for nearly two decades

well-defined clinical question, detailed

patient history, and deliberation with

In the late 1980s, a new technique, called

the radiologist prior to the

spiral or volumetric CT, was introduced by

investigation to maximise diagnostic

the German physicist Willi Kalender. The

yield and minimise radiation

patient moves through the CT scanner while

exposure.

simultaneously projection data are acquired

from the continuously rotating X-ray source

N Careful instruction of the child prior to

and detector array (fig. 1b). The

the investigation is important to

performance of the spiral CT scanner was

reduce anxiety, optimise volume

further improved by the introduction of

control during the procedure and

scanners which measured multiple fans

reduce movement artefacts.

simultaneously. With multi-slice spiral CT,

N Volume control during the chest CT

multiple fan measurements are made and

should be considered whenever

an arbitrary number of slices can be

possible.

reconstructed. (In the literature, a number of

alternative terms can be found for this

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ERS Handbook: Paediatric Respiratory Medicine

by sequentially acquiring thin (0.5-1.5 mm)

slices at intervals of 0.5-2 cm (fig. 1a).

These are usually obtained in inspiration

from the apex of the lung to the diaphragm.

A disadvantage of this procedure is that

acquisition time will be longer, requiring a

longer breath-hold and thus more

cooperation by the child. Furthermore,

relevant information between the slices can

be missed. Finally, for longitudinal follow-up

it is unlikely that slices will be taken at the

same anatomical levels, making comparison

difficult. The only advantage of

noncontiguous sequential scanning is a

lower radiation exposure than volumetric

scanning, which might be considered

preeminent in specific cases. Using a

Figure 1. a) Noncontiguous sequential CT. Data

volumetric acquisition mode the complete

are acquired during full rotation of the X-ray tube,

lung is scanned (fig. 1b). An important

and then the scanner table moves to scan the next

advantage of this mode is that the scanning

longitudinal position. Typically thin (0.5-

procedure is faster. With modern scanners,

1.5 mm) slices at intervals of 0.5-2 cm are

the entire lung can be scanned in less than

acquired using this technique. b) Volumetric or

one second or only a few seconds,

Spiral CT. The patient moves through the CT

depending on the size of the child and the

scanner while simultaneously projection data are

speed of the scanner. Scanning usually

acquired from the continuously rotating X-ray

begins at the lung apices and works toward

source and detector array.

the diaphragm. In case of long breath-hold

times, movement artefacts near the level of

technique, such as multi-section, multi-

the diaphragm can be observed. When

channel, and volumetric CT). The coverage

breath-hold times are critical, it can be

in the longitudinal direction per fan

considered to scan the lung starting at the

measurement is given by the total beam

level of the diaphragm up to the apices of

collimation, i.e. the width of a single

the lung to reduce movement artefacts.

detector row times the total number of rows.

Currently available CT scanners allow

The major advantages of volumetric CT

acquisition of 256-320 fans simultaneously

include comprehensive assessment of the lung

with a beam collimation of up to 320 6

structure, allowing reconstruction into multiple

0.5 mm 5 16 cm. Thanks to multi-slice CT,

planes and of three-dimensional images. In

the time needed for a chest CT scan has

addition it enables matching and sensitive

been reduced dramatically, without

comparison of slices at identical anatomical

decreasing the spatial resolution. More

positions for longitudinal follow-up.

recently, scanners have been introduced

Resolution

with two X-ray tubes and two detector arrays

rotating simultaneously. These dual-source

The achievable spatial resolution of a scan

scanners are capable of scanning the whole

depends on the scan speed and indirectly on

chest of a child in less than one second.

the radiation dose. The scan speed is

Volumetric or sequential scan

determined by the speed of table movement

and the speed of rotation of the X-ray tube.

Multi-detector CT (MDCT) scanners allow

The speed of table movement mainly

imaging of the chest using either

depends on the ‘‘pitch value’’. The pitch is

noncontiguous sequential CT scans or by

defined as table feed per full rotation of the

continuous volumetric acquisition.

X-ray tube divided by the total width of the

Sequential CT techniques sample the lung

collimated X-ray beam. The lower pitch

ERS Handbook: Paediatric Respiratory Medicine

167

value, the more information is collected per

low-dose chest CT protocols are considered

unit length. Young children have small

to be low. Radiation exposures for a

airway diameters, hence for detailed

combined inspiratory and expiratory chest

information of the lung a low pitch is

CT protocol are in the order of 0.5-1 year of

required. When scanning is performed with

the annual background radiation in the USA.

a low pitch, thin slices can be reconstructed

For an expiratory scan, a lower radiation

without interpolation artefacts. When

dose protocol should be used than for an

scanning is done with a high pitch,

inspiratory scan. The required radiation

reconstruction artefacts will appear. Spatial

dose can be in the order of half to one third

resolution will generally also improve when

of that for the inspiratory scan. An expiratory

the rotation speed of the X-ray tube is

scan should only be requested when small

lowered, because this allows for the

airways disease and/or perfusion defects

acquisition of more detailed measurements.

are suspected.

The level of detail needed will primarily

Contrast media

depend on the clinical question. For

In order to image the vascular system of the

example, for CT angiography, high

lungs, administration of contrast is needed.

resolution is needed to allow the

Several issues complicate the

reconstruction of vessels in great detail.

administration of i.v. contrast media to

When trapped air on an expiratory scan is

neonates and children, including the use of

evaluated, a low resolution is often

small volumes of contrast medium, the use

sufficient. High-resolution images have

of small-gauge angiocatheters (for example,

more image noise. This image noise can

24-gauge), and unusual vascular access sites

affect the visibility of the structures of

(hand or foot). Ideally, angiocatheters should

interest despite the resolution improvement.

be inserted 0.5-1 hour prior to the chest CT

Therefore more detailed information can

so the child is not too upset to lie down

only be acquired at the cost of higher

quietly in the CT scanner. The dose of

exposure to ionising radiation. High-

contrast media varies between 2-4 mL?kg^-1

resolution volumetric datasets are required

body weight, with very small volumes of

for (semi-) automated image analysis of

contrast media typically administered to

lung parenchyma and airways.

neonates and infants (typically 2 mL?kg^-1

Radiation

Since contrast media are cleared through the

kidneys, a normal kidney function is required.

A disadvantage of chest CT scanning is the

In case of suboptimal renal function, the

relatively high doses of ionising radiation

dose of contrast needs to be adjusted.

needed compared to, for example,

conventional chest radiography. It is

Adverse reactions to iodinated contrast

assumed that exposure to ionising radiation

media are classed as acute or late. The

in CT increases lifetime risk of cancer. This

former occur within 1 hour of contrast

risk is higher in paediatric patients, who

medium injection and are further classified

have a higher number of active dividing cells

as mild, moderate or severe (table 1). For

than adults. Hence, radiation dose should

this reason, resuscitation equipment, a

be justified and minimised to a level ‘‘as low

paediatric resuscitation protocol and

as reasonably achievable’’ (ALARA

qualified personal should be close at hand in

principle). Since the effects of radiation are

case a severe allergic reaction occurs. Late

assumed to be cumulative, the number of

adverse reactions occur 1 hour to 1 week

CTs should be kept within acceptable limits.

after contrast medium injection and are

Care should be taken to tailor the CT

represented by a variety of late symptoms

protocol to the size of the patient and to use

(nausea, vomiting, headache,

the minimum radiation dose that will

musculoskeletal pain, fever) or by skin

produce images of diagnostic quality and

reactions, which are usually mild and self-

allow sensitive image analysis. The risks

limited. While most minor physiological

related to exposure levels of state-of-the-art

side-effects of i.v. contrast medium

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ERS Handbook: Paediatric Respiratory Medicine

on the level of inflation of the lung. When

Table 1. Classification of adverse reactions to

the lung is well inflated, lung parenchyma is

intravenously administered contrast media

positioned between the heart and sternum.

Mild

Nausea, mild

In addition the trachea has a round

vomiting

appearance and the contour of the

Urticaria

diaphragm is flattened. For an optimal

Itching

diagnostic result, volume control is

Moderate

Severe vomiting

important and should be aimed for

Marked urticaria

whenever possible. Furthermore, it is

Bronchospasm

important that movement of the subject and

Facial/laryngeal

of the lungs is minimised. However, most

oedema

young children below the age of 4 years are

Vasovagal attack

not able to perform a voluntary breath-hold

Severe

Hypotensive shock

at the correct volume level and at the correct

Respiratory

moment. There are two methods available to

arrest

scan the lungs in these young children.

Cardiac arrest

Convulsion

The first technique is the noninvasive

pressure-controlled ventilation (PCV)

technique under general anaesthesia or

administration in adults are of minimal

sedation. The PCV technique starts off by

significance, such events are often of

hyperventilating the child by giving a short

increased importance in children. For

series of augmented breaths using high

example, local warmth at the injection site

positive pressure applied via a facemask,

and nausea, generally regarded to be

laryngeal mask, or tube to recruit all lung

physiological side-effects to contrast medium

areas and to allow for a respiratory pause.

administration, may cause a child to move or

Next, for inspiratory images, the lung is

cry. Such a response to contrast medium

inflated to a positive transpulmonary

injection may result in the acquisition of a

pressure of 25 cmH₂O and the lungs are

nondiagnostic imaging study, necessitating

imaged while pressure is maintained. For

repeat imaging and additional exposure to

expiratory images, no pressure is applied,

contrast medium and radiation.

hence the lung will deflate to a volume level

near functional residual capacity. PCV

There are several difficulties in interpreting

techniques have been shown to be highly

the available literature on the incidence of

reproducible. A disadvantage, however, is

allergic-like reactions to i.v. iodinated

that atelectasis can develop within minutes

contrast media in children. Many studies fail

in children under general anaesthesia.

to discriminate between physiological side-

Atelectatic regions of the lung cannot be

effects and allergic-like reactions. In addition,

evaluated for the presence of bronchiectasis

these studies lack agreement on what

or other structural abnormalities. When

constitutes mild, moderate, or severe

high-resolution images are required, for

reactions. Finally, there is a lack of controlled

example when interstitial lung abnormalities

prospective paediatric studies on the topic.

are suspected, PCV should be selected as

Therefore, not surprisingly, the reported

the technique of choice.

incidence of paediatric allergic-like reactions

to contrast media is variable, and ranges

The second technique to acquire a CT scan

0.18-0.46%. It is generally agreed, however,

in children below the age of 4 years is to use

that the incidence of allergic-like reactions in

an ultra-fast CT scanner that can obtain

children is lower than that in adults.

motion-free images of the lung in free-

breathing children even without sedation or

Volume control

general anesthesia. A disadvantage of this

Lung volume, and configuration and

method is that there is no strict control of

orientation of airways, is highly dependent

lung volume. Spontaneous breathing will be

ERS Handbook: Paediatric Respiratory Medicine

169

in a volume range between functional

the evaluation of lung parenchyma and for

residual capacity and functional residual

the detection of bronchiectasis (fig. 2a-c).

capacity plus tidal volume. Scans acquired

during tidal breathing are less sensitive than

To diagnose bronchiectasis, the diameter

those acquired using PCV in detecting

of the airway is compared to the diameter

of the adjacent or nearby pulmonary artery.

bronchiectasis. However, the specificity of

When the bronchoarterial ratio exceeds 1.0,

bronchiectasis detection is good. For

it is considered bronchiectasis. It has been

children aged o4 years, chest CT can be

shown that the airway:artery ratio is

carried out mostly without sedation or

dependent on the inspiration level. The

anaesthesia. Breath-hold instructions during

current consensus is that the diagnosis of

the in- and expiratory CT scan are routinely

bronchiectasis can best be made on an

given by a CT technician, often resulting in

suboptimal volume levels. The inspiratory

inspiratory CT near TLC. At lower lung

volume level of these radiographer-guided

volumes, the diameter of the airway is

reduced more relative to that of the

scans results in a lung volume in the range

adjacent artery. Hence, at lower lung

of 80% of TLC. The expiratory volume level

volumes the bronchoarterial ratio can be

of such scans is in most subjects near

less than 1.0 even for a bronchiectatic

functional residual capacity, which is well

airway. In addition, at low lung volumes

above residual volume. For many years, it

the orientation of airways is different

has been recognised that spirometer-

relative to that at inspiration, and airway

controlled breathing manoeuvres during the

length is reduced as well, making

CT scan result in improved standardisation

identification of abnormal widened airways

of in- and expiratory volume levels and

cut in cross-section more difficult. Finally,

fewer movement artefacts and thus

at low lung volumes, a lower number of

improve the diagnostic yield substantially.

airways can be evaluated relative to an

In this case, the patient can be trained by a

inspiratory scan. Similarly, to measure

lung function technician 30-60 minutes

airway wall thickness a standardised

prior to the CT scan to perform the

volume level near total lung volume is

requested breathing manoeuvres in supine

needed. At lower lung volumes, the inner

position using a spirometer. The same

wall of the airway will fold into the lumen,

technician instructs the patient during the

which will appear as a thickened airway

CT scan. The spirometer operated by the

wall on a chest CT.

patient is connected to a monitor

positioned in front of the window of the CT

Expiratory scans can be important when

control room, and the lung function

perfusion defects and/or small airways

technician focuses on the patient during the

disease are suspected (fig. 2d-f). While

CT scan while the CT technician can focus

airways ,1 mm in diameter are in general

on operating the scanner. The lung function

not visible on CT scans, small airway disease

technician indicates when the CT

can be detected indirectly as lucent regions

acquisition can be started, taking into

on expiratory scans. These lucent regions

account the delay (1-4 s) between pushing

can be the result of trapped air with or

the start button of the CT scanner and start

without hypoperfusion. Trapped air areas

of the actual acquisition. The sensitivity for

can be distinct to the adjacent healthier

the detection of trapped air of spirometer-

deflated and normally perfused or

controlled expiratory scans is superior to

hyperperfused dense parenchyma. When

that of uncontrolled scans.

multiple lucent areas are present in the lung

combined with normal or hyperperfused

Inspiration and/or expiration scan

dense areas, the term mosaic attenuation

For many chest CT scan indications,

pattern is used. Areas of trapped air can be

acquisition of both inspiratory and

differentiated from hypoperfused areas by

expiratory chest CTs is relevant. An

comparing their density in inspiratory and

inspiratory CT scan near TLC is needed for

expiratory scans. Trapped air areas without

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ERS Handbook: Paediatric Respiratory Medicine

Figure 2. a-c) A spirometer-controlled inspiratory chest CT reconstructed in the axial (a), coronal (b) and

sagittal (c) planes. Note that the lung is positioned between the heart and the sternum and that the lung

is protruding between the ribs. d-f) A spirometer-controlled expiratory chest CT reconstructed in the axial

(d), coronal (e) and sagittal (f) plane. Arrows indicate lucent regions of the lung caused by hypoperfusion

and/or trapped air. The lucent areas are adjacent to normal dense regions, representing a mosaic pattern.

hypoperfusion appear lucent only on the

method can be used as an alternative

expiratory scan. Optimal expiration to a

method to bronchoscopy to diagnose

volume level near residual volume increases

tracheomalacia. Unfortunately, dynamic

the contrast between lucent regions and

information requires exposure to ionising

normal or hyperperfused healthier lung

radiation for the duration of the scan, which

regions. However, lucent regions can be

will increase the total radiation dose needed

considered as trapped air areas only when

for the study. MRI is an alternative

they follow the distribution of a secondary

technique in development to acquire

pulmonary lobule (defined as the smallest

dynamic information. Hence, further

unit of lung surrounded by fibrous septa).

research is needed to define whether cine-

When up to five secondary lobules are

multidetector CT or MRI will become a

involved, especially if positioned in the

competing technique for bronchoscopy in

dependent regions of the lung (superior

the near future.

segments of the lower lobes, anterior parts

Image processing

of middle lobe and lingula), areas of trapped

air are still considered physiological.

Generated images need to be reconstructed

However, reference studies to support this

and stored in the correct way. After a chest

are lacking.

CT has been performed, the raw data are

post-processed to generate relevant series

Dynamic versus static imaging

and specific reconstructions. The generated

Dynamic cine-multidetector CT has been

images are stored in the Picture Archiving

used to study the dynamic behaviour of

and Communication System (PACS) system.

central airways in adult patients. This

Raw data are in general automatically

ERS Handbook: Paediatric Respiratory Medicine

171

Figure 3. The effect of administration of an intravenous contrast medium. a) A slice (3 mm) in the axial plane

acquired before the administration of a contrast medium. b) The same patient scanned after the administration

of a contrast medium. Note that the contrast-enhanced image appears slightly sharper and noisier as compared

to the native image because of a small change in reconstruction kernel and windowing. c and d) The lung

reconstructed in the coronal (c) and sagittal (d) plane using a maximum intensity projection. Note that the

contrast-enhanced blood vessels contrast clearly with the surrounding lung tissue.

deleted 1-2 weeks after the scan. Hence, it

speaking, there is a tradeoff between spatial

is important that all relevant series are

resolution and noise for each kernel. A

reconstructed and stored before the raw

smooth kernel generates images with lower

data are deleted. The radiologist will

noise but with reduced spatial resolution

determine scan protocol and reconstruction

(fig. 3a). A sharp kernel generates images

series needed based upon the clinical data

with higher spatial resolution, but increases

and questions as defined on the order form.

the image noise (fig. 3b). Other important

Reconstruction protocols define

reconstruction algorithms are maximum

reconstruction planes (axial, coronal,

intensity projection (MIP) (fig. 3c-d) and

sagittal), slice thickness (for example 0.65, 1,

minimum intensity projection (MinIP)

1.25, 3, or 5 mm), windowing (parenchyma

(fig. 4). MIP consists of projecting the voxel

or mediastinum) and definition of

with the highest attenuation value on every

reconstruction kernels (soft or hard). The

view throughout the volume onto a two-

reconstruction kernel, also referred to as

dimensional image. This technique is

‘‘filter’’ or ‘‘algorithm’’ by some CT vendors,

normally used to detect lung nodules or in

is one of the most important parameters

scans with contrast to improve vessel

that affect the image quality. Generally

depiction. MinIP is a data visualisation

172

ERS Handbook: Paediatric Respiratory Medicine

method that enables detection of low-

be performed both for the inspiratory and

density structures in a given volume. The

the expiratory CT scan. Slice-by-slice

MinIP algorithm is particularly useful for

comparison enables determination of

analysing the airways, which are hypodense

whether observed structural changes on the

compared the surrounding tissue. It is often

baseline CT have progressed, are stable, or

worthwhile to discuss with the radiologist

have improved on the follow-up CT - or

the case before the scan is made, especially

whether new abnormalities have developed.

for non-routine patients. At least one series

Ideally, structural changes on chest CT, such

of thin-slice images (f1 mm) in the axial

as bronchiectasis or trapped air, should be

plane should be stored using an appropriate

quantified when possible. To date for chest

predefined reconstruction kernel. These thin

CT in CF, the method of choice has been

slices are needed to evaluate the airways and

scoring. A CT scoring system is a tool to

this series allows additional post-processing

describe the abnormalities that can be

for example reconstruction of thicker slices

observed on the slices obtained from a

in the axial, coronal or sagittal plane or for a

single CT investigation in a semi-

three-dimensional reconstruction.

quantitative way. Several scoring systems

Furthermore, thin slices are mostly required

have been developed (see de Jong et al.,

for commercially available image analysis

2004). For all these systems, the reader

platforms.

identifies various abnormalities on the CT

scans and assesses their severity. Important

Image analysis

abnormalities that are included in most of

the scoring systems are bronchiectasis,

For clinical use, it is possible to monitor

mucous plugging, airway wall thickening

progression of structural lung changes on

and parenchymal opacities. Other

chest CTs. This can best be examined by

abnormalities such as small nodules,

comparing slice by slice the follow-up to the

mosaic attenuation, sacculations and air

baseline examination in the axial or other

trapping on expiratory images are included

planes. Most PACS viewers enable coupling

only in some of the systems. An advantage

of two examinations in a single window, with

of scoring systems is that they are relatively

scrolling down through the lung from the

insensitive to the CT scanner technique and

apices to base. These comparisons should

protocol being used. Recently the CF-CT

scoring system was developed. The CF-CT

scoring training module includes clear

definitions and reference images for the

structural abnormalities that have to be

scored and provides training sets. It has

been used successfully in a number of

studies. To date there are no validated

automated image analysis systems available

to quantify bronchiectasis, trapped air or

emphysema on paediatric chest CT. It is

likely that in the near future commercially

available (semi-) automated systems will

come to market and replace visual scoring.

The use of such systems will require volume

standardisation of the chest CT protocol.

Semi-automated systems to compare

airway:vessel ratios have been used in CF

studies. In addition, programs to segment

Figure 4. A slice of the lung reconstructed in the

the lung parenchyma and the bronchial tree

coronal plane using a MinIP algorithm which

have been developed. These systems will be

enables detection of low-density structures in a

used in the near future to detect and

given volume.

quantify CF and non-CF bronchiectasis.

ERS Handbook: Paediatric Respiratory Medicine

173

Furthermore, systems have been developed

Ciet P, et al. Spirometer controlled cine-

to visualise and quantify trapped air. Ideally

magnetic resonance imaging to diagnose

such a system should be able to compute

tracheobronchomalacia in pediatric

the volume of trapped air expressed as a

patients. Eur Respir J 2013 [in press DOI:

percentage of total lung volume. Similarly

10.1183/09031936.00104512].

Cody DD (2002). AAPM/RSNA physics

for chronic obstructive pulmonary disease,

tutorial for residents: topics in CT. Image

systems have been developed to quantify the

processing in CT. Radiographics; 22: 1255-

volume of emphysema. It might be possible

1268.

and useful to modify these systems to

Contrast media in children. In: ACR Manual

quantify emphysema for diseases such as

on Contrast Media. Reston, American

bronchopulmonary dysplasia and congenital

College of Radiology, 2012; pp. 47-53.

diaphragmatic hernia.

de Gonzalez AB, et al. (2007). Radiation-

induced cancer risk from annual com-

Conclusion

puted tomography for patients with cystic

fibrosis. Am J Respir Crit Care Med; 176:

Chest CT technology has been developed to

970-973.

such a level that it has become an important

de Jong PA, et al. (2005). Changes in

tool for the diagnosis and monitoring of

airway dimensions on computed tomo-

chest diseases in children. To optimally and

graphy scans of children with cystic

safely use chest CT in children, a paediatric

fibrosis. Am J Respir Crit Care Med; 172:

radiologist should be involved in defining

218-224.

the optimal protocol based on the clinical

de Jong PA, et al. (2005). Dose reduction

question. Furthermore, the referring

for CT in children with cystic fibrosis: is it

clinician should carefully describe relevant

feasible to reduce the number of images

clinical details and the clinical questions.

per scan. Pediatr Radiol; 36: 50-53.

Standardisation of lung volume is of key

de Jong PA, et al. (2005). Estimation of

importance to optimise the diagnostic yield

cancer mortality associated with repeti-

of the chest CT. Lung function technicians

tive computed tomography scanning

can play an important role in preparing

(CT) scanning in cystic fibrosis. Am J

Respir Crit Care Med; 173: 199-203.

children for a chest CT and in coaching and

de Jong PA, et al. (2008). Estimation of

monitoring breath hold manoeuvres during

the radiation dose from CT in cystic

acquisition.

fibrosis. Chest; 133: 1289-1291.

de Jong PA, et al.

(2004). Pulmonary

Further reading

disease assessment in cystic fibrosis:

Amis ES, Jr (2011). CT radiation dose:

comparison of CT scoring systems and

trending in the right direction. Radiology;

value of bronchial and arterial dimension

261: 5-8.

measurements. Radiology; 231: 434-439.

Bankier AA, et al.

(2012). Through the

Dillman JR, et al. (2007). Incidence and

Looking Glass revisited: the need for

severity of acute allergic-like reactions to

more meaning and less drama in the

i.v. nonionic iodinated contrast material

reporting of dose and dose reduction in

in children. AJR Am J Roentgenology; 188:

CT. Radiology; 265: 4-8.

1643-16477.

Bonnel AS, et al. (2004). Quantitative air-

Goris ML, et al. (2003). An automated

trapping analysis in children with mild

approach to quantitative air trapping

cystic fibrosis lung disease. Pediatr

measurements in mild cystic fibrosis.

Pulmonol; 38: 396-405.

Chest; 123: 1655-1663.

Callahan MJ, et al.

(2009). Nonionic

Hansell DM, et al. Fleischner Society:

iodinated intravenous contrast material-

glossary of terms for thoracic imaging.

related reactions: incidence in large urban

Radiology 2008; 246: 697-722.

children’s hospital - retrospective analy-

Huda W (2007). Radiation doses. risks in

sis of data in 12,494 patients. Radiology;

chest computed tomography examina-

250: 674-681.

tions. Proc Am Thorac Soc, 4: 316-320.

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ERS Handbook: Paediatric Respiratory Medicine

Kalender WA. Computed Tomography.

McDermott S, et al.

(2009).

3rd edn. New York, Wiley, 2011.

Tracheomalacia in adults with cystic

Kirpalani H, et al. (2008). Radiation risk

fibrosis: determination of prevalence

to children from computed tomography.

and severity with dynamic cine CT.

Pediatrics; 121: 449-450.

Radiology; 252: 327-329.

Lee KS, et al.

(2007). Comparison of

Mott LS, et al. Assessment of early

dynamic expiratory CT with bronchoscopy

bronchiectasis in young children with

for diagnosing airway malacia: a pilot

cystic fibrosis is dependent on lung

evaluation. Chest; 131: 758-764.

volume. Chest

2013

[in press DOI:

Lever S, et al.

(2009). Feasibility of

10.1378/chest.12-2589].

spirometry-controlled chest CT in chil-

Mott LS, et al. (2012). Progression of early

dren. Eur Respir J; 34: Suppl. 53, A344.

structural lung disease in young children

Loeve M, et al. (2009). The spectrum of

with cystic fibrosis assessed using CT.

structural abnormalities on CT scans

Thorax; 67: 509-516.

from CF patients with severe advanced

O’Connor OJ, et al. (2010). Development

lung disease. Thorax; 64: 876-882.

of low-dose protocols for thin-section CT

Loeve M, et al. (2012). Chest computed

assessment of cystic fibrosis in pediatric

tomography scores are predictive of

patients. Radiology; 257: 820-829.

survival in CF patients awaiting lung

Robinson TE, et al. (2001). Spirometer-

transplantation. Am J Respir Crit Care

triggered

high-resolution

computed

Med; 185: 1096-1103.

tomography and pulmonary function

Long FR, et al. (2005). Comparison of

measurements during an acute exacerba-

quiet breathing and controlled ventila-

tion in patients with cystic fibrosis.

tion in the high-resolution CT assess-

J Pediatr; 138: 553-559.

ment of airway disease in infants

Robinson TE, et al. (1999). Standardized

with cystic fibrosis. Pediatr Radiol;

35:

high-resolution CT of the lung using

1075-1080.

a spirometer- triggered electron beam

Long FR, et al.

(2001). Technique and

CT scanner. AJR Am J Roentgenol; 172:

clinical applications of full-inflation and

1636-1638.

end-exhalation controlled-ventilation chest

Young C, et al. (2012). Paediatric multi-

CT in infants and young children. Pediatr

detector row chest CT: what you really need

Radiol; 31: 413-422.

to know. Insights Imaging; 3: 229-246.

ERS Handbook: Paediatric Respiratory Medicine

175

Magnetic resonance imaging

Lucia Manganaro and Silvia Bernardo

MRI of the chest is a new technique in the

the diagnosis can be obtained by other

imaging of the lung. The lack of ionising

means. CT is the gold standard in:

radiation makes MRI an attractive alternative

N the evaluation of congenital anomalies,

to CT in paediatric applications, in which

N parenchymal pathologies,

repeated or serial scanning is required.

the case of chronic airway disease for a

Paediatric lung imaging

morphological study,

N the assessment of the complications of

Diseases of the respiratory system are of

inflammatory process,

great importance in paediatrics. Imaging of

N the staging of tumoural masses.

the chest has led to improvements in the

diagnosis and treatment of numerous

MRI is a radiation-free technique and offers

medical conditions in children.

alternative solutions to routine diagnostic

challenges for the imaging of the lung. It is

The first, and most widely used, modality is

especially relevant to young patients and

represented by radiographic imaging. It is

pregnant patients, as well as subjects who

fast and inexpensive and provides a good

need to undergo multiple investigations.

overview of anatomy and pathology.

However, in the approach of lung diseases,

the feasibility of MRI investigation is limited

For most paediatric pulmonary pathologies

by several technical problems. Despite this,

a plain film is the first, and only, step in the

in recent years many efforts have been made

absence of complications and when the

and there have been significant advances.

clinical course is regular. The best case is to

avoid additional imaging, especially CT, if

MRI techniques For many years MRI

imaging was considered useful in the

evaluation of mediastinal abnormalities and

Key points

not the lung parenchyma. However, the lack

of radiation exposure makes MRI of the lung

particularly attractive for paediatric

N MRI techniques allow for fast and

radiology.

reliable assessment of pulmonary

diseases in children.

The subordinate role of MRI in the

N Thoracic MRI is a radiation-free

evaluation of lung is caused by different

method and can be performed

technical problems, especially:

frequently without contrast media

N artefacts related to cardiac and breathing

application.

motion,

N The diagnostic value of MRI is shown

N the low signal-to-noise ratio because of

in patients with infectious diseases,

low proton density of the lung,

immunodeficiency, anatomic

N the susceptibility of artefacts because of

abnormalities, acquired chronic

air-soft tissue transition,

diseases and pulmonary tumours.

N the low-spatial resolution in comparison

to CT.

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ERS Handbook: Paediatric Respiratory Medicine

In addition, it is important to remember the

Contrast media use (gadolinium chelates)

heterogeneity of the paediatric population

allows for:

and that the time of acquisition of an MRI

examination is longer than for CT.

N better characterisation and extension of

disease,

More so than in radiography or CT, the

N evaluation of the process activity,

image quality in MRI depends on patient

N studies of cardiovascular and perfusion

compliance. It can be expected that some

performance.

sequences may produce unsatisfactory

results in very young patients. A drawback of

As work in progress, MRI can assess various

MRI is that, in general, it requires a longer

aspects of pulmonary function, including

scan time than CT, something that is not

lung perfusion, blood flow, respiratory

much of an issue with older children but

mechanics and, using an inhaled contrast

may preclude its use in non-sedated younger

agent, pulmonary ventilation. Thus, MRI is

children. Lung MRI is generally performed

emerging as a versatile modality for

with a high-field magnet system using ultra-

morphological and functional imaging of the

short acquisition. Different types of

lung.

sequences can be used.

MRI perfusion imaging can be performed

The spoiled gradient echo (three-dimensional

using two different techniques: contrast-

gradient-echo) sequence has multiple

enhanced MRI perfusion and noncontrast-

applications in lung MRI. For anatomical

enhanced MRI perfusion. In patients with

imaging, it can be used for two- or three-

pulmonary embolism MRI perfusion

dimensional acquisitions with or without fat

provides additional information about

suppression pre- and post-contrast

perfusion defects. Perfusion scintigraphy

administration.

has been replaced by ultrafast CT (multiple-

detector or volume CT with special child

The balanced steady-state free precession

programmes) in the imaging of pulmonary

(bSSFP) sequence has many applications, in

embolism in children. Using CT as the gold

particular in cardiac MRI, but it can also be

standard, MRI perfusion shows a

applied to anatomical lung imaging.

comparable high sensitivity and specificity

for the detection of perfusion defects. In

The single-shot fast spin echo (SSFSE)

patients affected by pneumonia, MRI

sequence is advantageous for lung imaging

perfusion contributes important information

for fast acquisition.

for the differential diagnosis of pulmonary

Diffusion-weighted imaging (DWI) provides

embolism.

qualitative and quantitative assessment of

MRI ventilation Because of the low proton

water diffusivity within tissues. In the

density and high susceptibility of lung

thoracic field, DWI is more challenging due

tissue, conventional proton MRI is not

to respiratory and cardiac motion.

suitable for visualising lung ventilation, and

Nevertheless, DWI can be used to evaluate

alternative contrast mechanisms have to be

pre-treatment cellularity and treatment

used. Oxygen-enhanced MRI has been

responses of focal thoracic lesions.

investigated for lung ventilation imaging

Control of respiratory phase Respiratory

and has a unique feature in which perfusion

motion of the diaphragm and chest wall can

and diffusion also contribute to the oxygen

be reduced by respiratory triggering using a

enhanced MRI signals. An inhaled contrast

pressure-sensing belt. Recently, respiratory

agent, either oxygen or a hyperpolarised

gating using a navigator echo has been

noble gas (hyperpolarised helium-3 is a

widely used for the same purpose. Other

gaseous MRI contrast agent that, when

motion-reducing methods, such as

inhaled, provides a very high MRI signal

saturation bands, signal averaging and

from the airspaces), is required for MRI lung

motion-insensitive pulse sequences, may be

ventilation imaging. In clinical studies, MRI

used in children.

is able to differentiate between diseases with

ERS Handbook: Paediatric Respiratory Medicine

177

Figure 3. A CT scan, performed after a chest radiograph, in a 10-year-old girl with a history of progressive

difficulty in breathing and chest pain. a) A dishomogeneous space-occupying lesion in the mediastinum

(arrow) associated with pleural effusion (short arrow) from the upper mediastinal area, in front of the

aorta and pulmonary artery, is visible. b, c) MRI confirmed the mediastinal mass causing a compressive

effect on pulmonary vessels and parenchyma with almost total collapse of the left lung (arrow) and pleural

effusion (short arrow). The signal intensity demonstrated the presence of water intensity cystic spaces with

fat-fluid levels (specific for teratoma).

and without ventilation/perfusion mismatch

ratio (the difference in signal intensity between

(V9/Q9) and has shown high sensibility in

the area of interest and the background) and

comparison to gold standard references such

difficulties in performing the examination.

as scintigraphy. However, its clinical

Further clinical studies in children are

application is limited by a low signal-to-noise

necessary to prove its great potential.

Figure 4. An 11-year-old girl with a history of fever and cough. Acute phase dorsal consolidations on the left

are well represented as hyperintense focus in a) diffusion weighted imaging sequence b600 (arrow) and b)

turbo spin echo (arrow). After 3 weeks of therapy the focus appears less hyperintense in c) diffusion

weighted imaging sequence b600 (arrow) and d) turbo spin echo (arrow) showing a response to therapy

(image courtesy of G. Morana, Department of Radiology, Ca Foncello Hospital, Treviso, Italy; personal

communication).

ERS Handbook: Paediatric Respiratory Medicine

179

Figure 5. A fetus at 23 months +4 days of gestation. a-e) Hyperinflation of the left lung (arrows)

associated with trans mediastinal hernia (arrowheads) and right medistinal shift (#). Many centimetric

lesions are present in the pulmonary parenchyma (black arrows). f) These lesions are hyperintense in T2-

and hypointense in T1-weighted fat saturation images, indicating cystic lesions suggestive of a Type II

CPAM (Stocker classification).

Paediatric lung MRI: indications and

empyema or lung abscess. In these cases

features

MRI allows the complications and the

extension of pleural empyema to be

Major clinical indications for MRI arise from

evaluated; it can also be repeated to

three major fields:

evaluate the development and to monitor

the response to treatment (fig. 4).

N lung infections, CF, asthma and

pulmonary hypertension (fig. 1),

Some authors emphasise the role of MRI in

N regular imaging in patients in whom

the characterisation of pulmonary infiltrates,

radiation exposure should be avoided

especially in patients suffering from

(fig. 2),

neutropenic fever, although cost-efficiency

N mediastinal masses (fig. 3).

has not been proven for this indication.

Lung infections The diagnostic value of MRI

CF is the most common indication for MRI.

is shown in patients with infectious diseases.

By using common proton-MRI sequences it

MRI detects pulmonary infiltrates, hilar

is possible to visualise the structural

changes and pleural or pericardial effusions

changes of CF lung disease such as:

as well as, or better than, chest radiography.

N bronchial wall thickening,

The predominant MRI findings are alveolar

N mucus plugging,

or interstitial parenchymal changes, pleural

N bronchiectasis,

thickening and fluid and lymph node

N air-fluid levels,

enlargement. It is very important to

highlight the role of MRI in complicated

N consolidation,

pneumonia when there is the suspicion of

N segmental/lobar destruction.

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ERS Handbook: Paediatric Respiratory Medicine

In patients with CF, bronchial wall

MRI plays a key role in the accurate

thickening of the small airways enhances

diagnosis of congenital chest masses,

their detectability by MRI so that small

allowing for accurate prediction of outcome,

airways with thick walls can be visualised in

parental counselling, planning of pregnancy

the lung periphery. Mucus plugging is also

and newborn management.

well visualised by MRI due to the high T2-

Congenital bronchopulmonary

weighted signal of its fluid content and is

malformations (BPMs) represent a wide

associated, in most cases, with

spectrum of lung anomalies, including

bronchiectasis. The MRI appearance of

congenital pulmonary airways malformation

bronchiectasis is dependent on bronchial

(CPAM) (fig. 5), bronchopulmonary

level, bronchial diameter, wall thickness,

sequestration (BPS) and congenital lobar

wall signal and the signal within the

overinflation.

bronchial lumen.

The normal fetal lungs demonstrate

Another sign is consolidation, which is

increasing relative signal intensity on fluid-

mainly caused by alveolar filling with

sensitive sequences as the pregnancy

inflammatory fluid. The visualisation of

progresses, secondary to the accumulation

consolidation in MRI is based on the high

of fluid within the developing lungs.

T2-weighted signal from the inflammatory

fluid. A developmental role of MRI in the

A BPM can present with different features

patients affected by CF maybe related to

and can appear as solid, cystic or mixed

follow-up after transplantation because it is

lesions. Masses may appear as iso-signal or

radiation free.

lower signal compared to normal lung tissue

in the third trimester of pregnancy. A high-

Neoplasm Although not used routinely, MRI

signal solid mass on MRI is not diagnostic

may be sensitive in the detection of

for a specific type of BPM. The identification

pulmonary metastases. The sensitivity will

of a macroscopic cyst or systemic arterial

depend on lesion size; the sensitivity in

blood supply to the mass improves

smaller nodules (,5 mm) remains to be

specificity. MRI provides alternative or

established. Much work is needed to

additional diagnoses compared with

establish the role of MRI and its relationship

ultrasound in 38-50% of fetuses.

with CT.

In conclusion, although spatial resolution is

Other important indications are anatomic

lower than CT, MRI has the advantage of

abnormalities such as pulmonary

being able to:

sequestration, acquired chronic diseases,

pulmonary arteriovenous malformations

N evaluate different aspects of tissue,

(PAVMs), vascular malformations and fetal

N improve the characterisation of a

malformations.

pathological process,

combine the morphological and

Fetal lung MRI

functional findings in one study.

Prenatal diagnosis of congenital lung

The absence of ionising radiation is the

anomalies has increased in recent years as

strength of MRI. For all these reasons, MRI

imaging methods have benefitted from

in paediatrics is a major acquisition.

technical improvements. Fetal MRI offers

several technical advantages over

Further reading

ultrasound, including:

Bauman G, et al. (2009). Non-contrast-

N a larger field of view,

enhanced perfusion and ventilation

N fewer limitations due to maternal

assessment of the human lung by means

habitus,

of Fourier decomposition in proton MRI.

N the ability to visualise fetal anatomy

Magn Reson Med; 62: 656-664.

regardless of fetal presentation.

ERS Handbook: Paediatric Respiratory Medicine

181

Goo HW (2013). Advanced functional

Levine D, et al.

(2003). Fetal thoracic

thoracic imaging in children: from basic

abnormalities: MR imaging. Radiology;

concepts to clinical applications. Pediatr

228: 379-388.

Radiol; 43: 262-268.

Puderbach M, et al. (2008). Can lung MR

Henzler T, et al. (2010). Diffusion and

replace lung CT? Pediatr Radiol; 38: Suppl.

perfusion MRI of the lung and mediasti-

3, S439-S451.

num. Eur J Radiol; 76: 329-336.

Puderbach M, et al. (2007). Proton MRI

Hubbard AM, et al. (1999). Congenital

appearance of cystic fibrosis: comparison

chest lesions: diagnosis and characteriza-

to CT. Eur Radiol; 17: 716-724.

tion with prenatal MR imaging. Radiology;

Rupprecht T, et al. (2002). Steady-state

212: 43-48.

free precession projection MRI as a

Kauczor H, et al.

(2009). Imaging of

potential alternative to the conventional

pulmonary pathologies: focus on mag-

chest X-ray in pediatric patients with

netic resonance imaging. Proc Am Thorac

suspected pneumonia. Eur Radiol;

12:

Soc; 6: 458-463.

2752-2756.

Levin DL, et al.

(2001). Evaluation of

Wagner M, et al. (2001). A fast magnetic

regional pulmonary perfusion using ultra-

resonance imaging technique for children

fast magnetic resonance imaging. Magn

with mediastinal lymphoma: work in

Reson Med; 46: 166-171.

progress. Med Pediatr Oncol; 37: 532-536.

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ERS Handbook: Paediatric Respiratory Medicine

Ultrasonography

Carolina Casini, Vincenzo Basile, Mariano Manzionna and Roberto Copetti

Newborns, infants and children present a

Technique and ultrasound anatomy

similar clinical picture on lung ultrasound

The examination is performed with the child

examination as adults. A high-resolution

in a supine position. The probe is placed

linear probe (7.5-12 MHz) is used for lung

perpendicular, oblique and parallel to the

examination through longitudinal and

ribs in the anterior, lateral and posterior

transverse sections of the anterior, lateral

(lower and upper) thorax. Posterior areas

and posterior wall of the chest.

may be better viewed in lateral recumbence.

Precocious exposure of infants and

The position with an erect trunk is practically

children to radiation may lead to a higher

never necessary.

risk of developing malignancies later in

The normal lung of the newborn does not

life due to both the latency of the effect of

differ substantially from that of adults. The

radiation exposure on the cells and the

pleural line is easily visualised beneath the

fact that growing children are inherently

ribs and it is easy to highlight the sliding

more radiosensitive, because they have a

movement of the pleural layers (sliding sign)

larger proportion of dividing cells.

(Lichtenstein et al., 1995).

Ultrasound avoids the use of ionising

radiation.

The presence of horizontal reverberation

artefacts of the pleural line (A lines) that are

The interest of the neonatal and paediatric

repeated at constant intervals below the

community in lung ultrasound is growing

pleural line is normal (fig. 1) (Lichtenstein et

very slowly. However, the use of ultrasound

al., 1995).

in respiratory diseases of the newborn and

the child needs to be encouraged not just as

At birth, is possible to observed vertical

a valid diagnostic alternative but as a

artefacts (B lines) pathognomonic of

necessary ethical choice (Cattarossi et al.,

interstitial syndrome in adults

2011).

(Lichtenstein et al., 1995, 1997; Reissig

et al., 2003; Soldati et al., 2009), even in

newborns who are absolutely healthy

Key points

(Copetti et al., 2007) (fig. 2). The fetal lung

is very rich in fluids and, therefore, B lines

A high-resolution linear probe is

also can be seen in healthy term newborns

employed for lung ultrasound

born either vaginally or by caesarean

examination in children and infants.

section, but more frequently in the latter.

This is due, in large part, to the greater

N Lung ultrasound avoids the use of

quantity of liquid contained in the lung to

ionising radiation.

prevent squeezing of the rib cage during

Lung ultrasound demonstrates very

passage through the birth canal. It can be

good accuracy in several respiratory

more often seen on the right side without a

diseases.

typical localisation and disappears

completely within 24-36 h.

ERS Handbook: Paediatric Respiratory Medicine

183

Pleural line

Rib

A lines

Acoustic shadowing

Figure 1. Normal lung. a) Longitudinal scan showing the ribs and their acoustic shadowing, the pleural line

and A lines. b) Transverse scan showing the pleural line and A lines.

Transient tachypnoea of the newborn

in both lungs, though not always

symmetrically. The boundary between the

Transient tachypnoea of the newborn (TTN)

inferior pulmonary fields, where the artefacts

is a common cause of neonatal respiratory

are coalescent, and the superior fields is so

distress, which has a similar frequency all

sharp that the lung picture is specific. It is

over the world. TTN has low morbidity but it

important to note that the pleural line is

can be severe and should be differentiated

normal in the areas of white lung. This

from other pulmonary or cardiac diseases

ultrasound finding was named ‘‘double lung

(such as pneumothorax, pneumonia, sepsis,

point’’ because it looks like two different

respiratory distress syndrome (RDS) and

contiguous lungs in the same patient (fig. 3).

congenital heart disease).

Respiratory distress syndrome

All infants with TTN show, on the first

ultrasound examination, bilateral coalescent

RDS, also known as hyaline membrane

B lines on the lung base (echographic

disease, is due, at least in part, to

‘‘white lung’’) and a normal or near-normal

appearance of the lung in the superior fields

(Copetti et al., 2007). This finding is evident

Pleural line

“Double lung point”

Normal lung

“White lung”

B lines

Figure 3. Longitudinal scan showing a clear sharp

Figure 2. Transverse scan in a healthy newborn at

difference between the upper and lower lung fields

birth. There is evidence of numerous B lines.

(double lung point).

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ERS Handbook: Paediatric Respiratory Medicine

Coalescent

B lines

Figure 4. a) Superior and b) inferior field of the lung in a newborn with RDS. In both areas, there is

evidence of coalescent B lines (white lung). The pleural line is poorly defined and coarse.

insufficiency of pulmonary surfactant and is

defined and coarse. Multiple subpleural

mainly confined to preterm infants. All

hypoechoic areas, which are generally small,

infants show B lines, which are coalescent,

are observed mainly in the posterior and

diffuse and symmetrically distributed in

lateral scans, indicating lung consolidations.

both lungs. This pattern is echographic

Larger consolidations with a tissular pattern

white lung. The pleural line is always

and with evidence of air or fluid

extensively thickened, irregular, poorly

bronchograms may be observed more

Coalescent B lines

“White lung”

“Spared area”

Subpleural

consolidations

Muitiple B lines

Figure 5. a) Evidence of a ‘‘spared area’’ in infant affected by BPD. b) Area of ‘‘white lung’’ in BPD.

c) Area of interstitial syndrome in BPD. d) Subpleural consolidations in BPD.

ERS Handbook: Paediatric Respiratory Medicine

185

Lung consolidation

Air bronchograms

Lung hepatisation

Air bronchograms

Figure 6. Liver-like appearance of the lung and

Figure 8. Typical ultrasound appearance of

parallel course of air bronchograms in pulmonary

pneumonia in children.

atelectasis.

frequently in the posterior fields. These

Bronchopulmonary dysplasia

findings are immediately present at birth

before clinical deterioration (Copetti et al.,

Bronchopulmonary dysplasia (BPD) is a

2008a). Scans of the anterior thoracic wall

form of chronic lung disease that develops

are sufficient for the diagnosis. The three

in preterm neonates treated with oxygen and

most important signs for ultrasound

positive pressure ventilation. The diagnosis

diagnosis are:

is made on the basis of oxygen requirement

at 36 weeks gestation.

N bilateral coalescent B lines involving all of

the lung (white lung);

In infants with BPD, there is evidence of

multiple B lines that have a

N absence of ‘‘spared areas’’ (areas of lung

with a normal appearance); and

nonhomogeneous distribution and diffuse

N pleural line abnormalities (fig. 4).

changes in the pleural line, which is

thickened with multiple small subpleural

consolidations. Generally, there is evidence

of spared areas and interstitial syndrome,

and pleural line changes correlate to

Small subpleural

disease severity (fig. 5) (Copetti et al.,

consolidation

2008a).

Pleural effusion

Liver

Coalescent B lines

Normal lung

Lung consolidation

Air bronchograms

Figure 7. Typical picture of bronchiolitis with

evidence of a small subpleural consolidations and

an area of coalescent B lines near an area of

normal lung.

Figure 9. Lobar pneumonia in a child.

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ERS Handbook: Paediatric Respiratory Medicine

Bronchiolitis

Small pleural effusion

Bronchiolitis is an acute, infectious,

inflammatory disease of the upper and lower

respiratory tract that may result in

obstruction of the small airways. Diagnosis

is made based on age and seasonal

Lung consolidation

occurrence, tachypnoea, and the presence of

profuse coryza and fine rales, wheezes or

Spleen

both upon auscultation of the lungs.

In our experience, the ultrasound findings

are peculiar and this is important because in

Air bronchograms

some patients with more severe symptoms,

chest radiography may be avoided. In

patients with bronchiolitis, we have

Figure 10. Left basal pneumonia in a child.

consistently observed bilateral involvement

of the lungs. Typically, areas of normal lung

Pulmonary atelectasis

adjacent to areas with subpleural

consolidations (1-3 cm) are observed, due

Pulmonary atelectasis is frequent in

to small atelectasis. These consolidations

ventilated newborns. Often, chest

are surrounded by B lines that can also

radiographic diagnosis is difficult due to the

appear coalescent (fig. 7). Larger

underlying respiratory disease. The dynamic

consolidations are less frequent and

ultrasound signs are very useful for diagnosis

generally observed in more severe disease.

and may be monitored at the bedside.

Small pleural effusions can also be seen.

The ultrasound appearance of atelectasis is

Recently, Caiulo et al. (2011) confirmed our

characterised by a liver-like appearance of

observations and demonstrated that

the lung with ‘‘lung pulse’’ (Lichtenstein et

ultrasound can avoid the need for chest

al., 2003), absence of lung sliding and a

radiography.

parallel course of air bronchograms, as

described in adult patients (fig. 6). The

Finally, unpublished observations made by

evidence of dynamic air bronchograms rules

V. Basile and P. Comes (San Giacomo

out obstructive atelectasis (Lichtenstein et

General Hospital, Monopoli, Italy) showed

al., 2009). This is very important because,

that early, pulmonary paravertebral areas are

often, lung consolidation may be caused by

affected by the appearance of B lines and

alveolar collapse (i.e. pulmonary

small subpleural consolidations. These

haemorrhage and RDS) and, in ventilated

findings often anticipate the involvement of

newborns, by hypoventilation due to low

anterior areas.

ventilatory pressure.

Pneumonia

Pneumothorax

Children and infants with pneumonia may

Pneumothorax is frequent in newborns.

present with a number of clinical symptoms

Chest radiography has the same diagnostic

and signs such as fever, cough and

limitation as in adults. Transillumination is

tachypnoea. A minority of children present

the bedside procedure used by

with fever of unknown origin and may have

neonatologists. Ultrasound signs are the

no respiratory symptoms or signs. Chest

same as described in adults:

radiography is still considered to be the first

imaging step for diagnosing pneumonia in

N absence of lung sliding;

children.

N absence of B lines; and

N presence of ‘‘lung point’’ without massive

In children, pneumonia appears as a

pneumothorax (Lichtenstein et al., 1995).

hypoechogenic area with poorly defined

ERS Handbook: Paediatric Respiratory Medicine

187

borders and compact underlying B lines.

Copetti R, et al. (2007). The ‘‘double lung

Vertical artefacts are often seen in varying

point’’: an ultrasound sign dagnostic of

numbers, in areas adjacent to the

transient tachypnea of the newborn.

consolidation. The pleural line is less

Neonatology; 91: 203-209.

echogenic in the area affected by lung

Copetti R, et al. (2008a). Lung ultrasound

in respiratory distress syndrome: a useful

consolidation. Lung sliding is reduced or

tool for early diagnosis. Neonatology; 94:

absent. In the case of large consolidations,

52-59.

branching echogenic structures

Copetti R, et al.

(2008b). Ultrasound

representing air bronchograms, are seen in

diagnosis of pneumonia in children.

the infected area. Dynamic air

Radiol Med; 113: 190-198.

bronchograms can be observed. This

Lichtenstein DA, et al. (1995). A bedside

finding rules out atelectasis. Multiple

ultrasound sign ruling out pneumothorax

lenticular echoes, representing air trapping

in the critically ill. Lung sliding. Chest;

in the smaller airways, are also frequently

108: 1345-1348.

present. Fluid bronchograms, described in

Lichtenstein D, et al. (1997). The comet-

post-obstructive pneumonia, are identified

tail artefact. An ultrasound sign of

as anechoic tubular structures with

alveolar-interstitial syndrome. Am J

Respir Crit Care Med; 156: 1640-1646.

hyperechoic walls, without a colour-Doppler

Lichtenstein DA, et al. (2003). The ‘‘lung

signal. Pleural effusion is easily detected

pulse’’: an early ultrasound sign of

and appears as an anechoic area in the

complete atelectasis. Intensive Care Med;

pleural space (fig. 8-10) (Copetti et al.,

29: 2187-2192.

2008b).

Lichtenstein D, et al. (2009). The dynamic

air bronchogram. A lung ultrasound sign

In paediatric patients, as in adults, lung

of alveolar consolidation ruling out atelec-

ultrasound demonstrates a diagnostic

tasis. Chest; 135: 1421-1425.

accuracy higher, or at least not inferior to,

Reissig A, et al.

(2003). Transthoracic

chest radiography (Volpicelli et al., 2012).

sonography of diffuse parenchymal lung

disease: the role of comet tail artefacts. J

Ultrasound Med; 22: 173-180.

Further reading

Soldati G, et al.

(2009). Sonographic

Caiulo VA, et al. (2011). Lung ultrasound

interstitial syndrome. The sound of lung

in bronchiolitis: comparison with chest X-

water. J Ultrasound Med; 28: 163-174.

ray. Eur J Pediatr; 170: 1427-1433.

Volpicelli G, et al.

(2012). International

Cattarossi L, et al.

(2011). Radiation

evidence-based recommendations for

exposure early in life can be reduced by

point-of-care lung ultrasound. Intensive

lung ultrasound. Chest; 139: 730-731.

Care Med; 38: 577-591.

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ERS Handbook: Paediatric Respiratory Medicine

Isotope imaging methods

Georg Berding

Background

can be studied using aerosols of larger

particles (.2 mm), or alveolar capillary

Radiotracer methods allow physiological

membrane integrity which can be measured

processes in the lungs to be visualised and

with water-soluble radiotracers. A more

the regional pathologic changes due to

recent approach focuses on the detection of

disease, resulting into functional

florid inflammation or vital malignant tissue

impairment, to be detected. Most

in the lungs/thorax using fluorodeoxyglucose

frequently, ventilation and perfusion of the

(18F-FDG) and positron emission

lungs are investigated. Inhaled nuclides of

tomography (PET).

inert gases that emit gamma rays or

aerosols of fine particles (,1 mm)

Indications

containing Technetium-99m (^99mTc) are

In children, ventilation/perfusion (V9/Q9)

used to display the ventilated volume of the

scintigraphy is used to characterise primary/

lungs. When injected intravenously,^99mTc-

congenital abnormalities of the lungs and

labelled albumin aggregates are retained in

pulmonary vessels, as well as the heart and

the capillary bed of the lungs and thereby

large vessels (fig. 1). Generally, V9/Q9

visualise arterial perfusion of the

scintigraphy can be used to quantify lung

parenchyma (via vasa publica). Other

function pre- and post-intervention. In

processes are less frequently investigated,

particular, essential information can be

e.g. mucociliary clearance function, which

provided by perfusion scintigraphy before

and after:

Key points

N pulmonary arterioplasty,

N intravascular stent placement,

N The use of radiopharmaceuticals

N coil occlusion of unwanted vascular

enables information on ventilated

communications,

volume and regional perfusion of the

N surgical creation of a shunt.

lungs to be obtained.

N V9/Q9 scintigraphy enables accurate

Notable per cent fractions of V9 and Q9in the

diagnosis of congenital abnormalities

left and right lung can be determined. In the

of the lungs, vessels and heart, as well

case of right-to-left shunts, these can be

as in patients with bronchiectasis or

measured semi-quantitatively based on

CF.

kidney and brain uptake during the lung

perfusion scan. These measurements can be

N V9/Q9 scintigraphy is easy to perform,

valuable in the assessment and treatment of

typically without sedation, and causes

patients with cyanosis, e.g. due to the

only low-radiation exposure.

tetralogy of Fallot or arteriovenous

A more recent method, ¹⁸F-FDG PET/

malformations. Assessment of suspected

CT, contributes to the diagnosis of

pulmonary embolism in children is, in

malignancies and inflammation.

contrast to adults, a rare indication. Damage

to lung tissue due to infection can be

ERS Handbook: Paediatric Respiratory Medicine

189

100

Figure 1. V9/Q9 scintigraphy in a 6-year-old boy with decreased physical capacity and recurring pneumonia

of the right lung. Planar^99mTc-Technegas scintigraphy showed hypoplasia of the right lung (30% versus

70%; upper row). A subsequent^99mTc-MAA scan revealed a complete lack of perfusion (from vasa

publica) in the right lung (lower row). In angiographic CT the pulmonary veins could not be detected.

Angiography showed an outflow of the contrast medium from the right to the left pulmonary artery. V9/Q9

scintigraphy helped to identify noninvasively congenital abnormality of the pulmonary vessels.

assessed. Regional lung function (V9/Q9)

in the literature so far suggests that¹⁸F-

can be evaluated in children with

FDG-PET can be useful for the detection of

bronchiectasis as well as CF. Beyond which

active infective foci in children with chronic

delayed mucociliary clearance can been seen

granulomatous disease and monitoring of

in both diseases; however, this is still an

disease activity in children with CF.

experimental indication. Effects of foreign

Patient preparation

body aspiration (e.g. air trapping) can be

demonstrated using V9/Q9 scanning. In

There is no specific preparation that is

paediatric oncology with respect to thoracic

necessary for children before V9/Q9scanning.

masses,¹⁸F-FDG-PET is used specifically in

However, mucus secretions should be

children with lymphoma for staging,

removed with mucolytics and chest

treatment response assessment and

physiotherapy to facilitate ventilation

planning of radiation therapy. In

scanning. Patients must avoid moving

inflammatory diseases, evidence provided

during acquisition. In children who are old

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ERS Handbook: Paediatric Respiratory Medicine

enough this might be achieved by careful

perfusion imaging would add 1.56 mSv.

explanation of the procedure together with

Together both scans would cause

the parents. Neonates and infants are

2.03 mSv, which is below the natural

conveniently studied when they have fallen

annual radiation exposure in Germany.

asleep after feeding. Medicinal sedation

Imaging equipment/acquisition

should be the exception. If unavoidable, at

o7 months of age the benzodiazepine

Lung scintigraphy is normally acquired with

midazolam can be given intravenously at a

a dual-head large-field gamma camera from

dose of 0.1 mg?kg^-1. Nevertheless this has to

standard projection angles (anterior,

be agreed upon with the referring physician

oblique, lateral, etc.). The use of single-

and the risk of hypoventilation has to be

photon emission computed tomography

taken into account.

(SPECT) offers the advantage of avoiding

super-imposition and thereby creating the

Radiopharmaceuticals

possibility of finer (sub-segmental)

Nowadays, ventilation studies are most

assessment. However, SPECT requires more

frequently performed using^99mTc-

patient co-operation or anaesthesia.

Technegas. This is a pseudo-gas produced

Furthermore, SPECT/CT allows correlation

using a dedicated generator containing a

of functional and morphological findings,

graphite crucible filled with^99mTc

which can provide unique diagnostic

pertechnetate in a chamber, which is

information, but specifically in children the

heated to a high temperature. Thereby an

additional radiation exposure has to be

ultrafine aerosol of solid graphite particles

balanced against it. Regarding paediatric

with a 5-30 nm diameter is produced

oncology,¹⁸F-FDG-PET/CT can be performed

which, when inhaled, shows a static

using specific CT-parameters for children to

alveolar deposition. Due to the much

reduce radiation exposure (ultralow-dose

simpler logistics, Technegas has largely

CT) or, in the case when a diagnostic CT

replaced the use of inert gases such as

investigation is required, this can be

xenon-133 (¹³³Xe) or krypton-81m.

performed in one session with PET obviating

Nevertheless,¹³³Xe allows sequential data

the inconvenience of two single

acquisitions and thereby identification of

examinations.

air trapping as a hallmark of regional

obstructive airway disease. However,¹³³Xe

Further reading

application to the lungs requires a bag-box

spirometer system, which is rarely

Bajc M, et al. (2010). Methodology for

available. With respect to producing

ventilation/perfusion SPECT. Semin Nucl

aerosols of larger particles for mucociliary

Med; 40: 415-425.

clearance a nebuliser is required. For

Charron M (2006). Application of PET/

perfusion studies^99mTc-MAA

CT in children. Paediatr Respir Rev;

(macroaggregated albumin) is injected

Suppl. 1, S41-S43.

intravenously. It embolises a small

Ciofetta G, et al. (2007). Guidelines for

lung scintigraphy in children. Eur J Nucl

proportion of (pre)capillary vessels in the

Med Mol Imaging; 34: 1518-1526.

lung. Since the number of these vessels is

Gelfand MJ, et al. Nuclear studies of the

lower in children compared to adults the

heart and great vessels. In: Miller JH, et

number of injected particles has to be

al., eds. Pediatric Nuclear Imaging. 1st

decreased. The radiation exposure induced

Edn. Philadelphia, Saunders,

1994;

by lung scintigraphy is generally relatively

pp. 83-101.

low. For example, in a 5-year-old child

Krasnow AZ, et al. Diagnostic applica-

weighing 20 kg, adapted application of

tions of radioaerosols in nuclear medi-

,10 MBq^99mTc-Technegas for ventilation

cine. In: Freeman LM, ed. Nuclear

scintigraphy would result in an effective

Medicine Annual. New York Raven

dose of 0.47 mSv. In addition, the

Press, 1993; 123-194.

application of 46 MBq^99mTc-MAA for

ERS Handbook: Paediatric Respiratory Medicine

191

Interventional radiology

Efthymia Alexopoulou, Argyro Mazioti and Dimitrios Filippiadis

The improvement of anaesthesiology

interventional radiology in the treatment of

techniques, imaging guidance and

paediatric patients.

instrumentation has contributed to the

Proper and adequate training of an

evolution of several image-guided,

interventional radiologist in paediatric

minimally invasive, percutaneous diagnostic

and therapeutic techniques, thus

patients along with strict local sterility

dramatically changing the role of

measures are prerequisites. Prophylactic

antibiotics are recommended in some of the

techniques, but are not needed in most of

the chest interventions. Although local

Key points

anaesthesia would be fine for the majority of

the procedures, deep sedation or general

anaesthesia is required in order to ensure

Proper and adequate training of the

maximum cooperation and a safe

operator along with extensive local

sterility measures and

environment for technique performance.

anaesthesiology control are

Occasionally, in older children or young

prerequisites for safe and effectively

adults, local anaesthesia might be sufficient

performed interventional radiology.

in certain techniques; however, this is not

recommended.

In cases where determining a lesion’s

nature will alter a patient’s

Parents, and older children, should be

management and benefits outweigh

informed about the invasive procedure, as

risks, a percutaneous biopsy is

well as the benefits and potential risks of

indicated; core biopsy is preferred

the technique. Written consent from

over fine-needle aspiration.

parents is required before beginning any

procedure. Pre-procedural planning

Image-guided percutaneous drainage

is a safe and efficacious technique for

includes evaluation of the patient’s medical

the treatment of pleural effusions,

record (including laboratory and imaging

abscesses and empyemas; in the case

studies), control of renal function (in

of complex effusion, abscess or

relation to intravascularly administered

empyema drainage can be combined

contrast), cardiac function and coagulation

to fibrinolytic therapy.

profile. Separate anaesthesiology evaluation

should be performed as well. Post-

Tumour localisation or

procedural follow-up includes patient

thermoablation can be performed in

monitoring, control for any delayed

selected cases of paediatric patients.

complications and evaluation of the overall

Transcatheter embolisation seems to

clinical condition of the patient. As the

be a first-line therapy for the treatment

patient is admitted for medical therapy,

of pulmonary AVM or major

most of these interventional radiology

haemoptysis in patients with CF.

techniques are not performed on an

outpatient basis.

ERS Handbook: Paediatric Respiratory Medicine

193

Image-guided percutaneous biopsy

Tumour localisation

Percutaneous biopsy in paediatric patients

The technique of localisation can be used in

is most commonly performed for diagnosis

cases of a small lung nodule under the

of a focal lesion rather than for evaluation of

pleural surface, which will not be felt during

diffuse parenchymal disease. Especially in

thoracoscopic surgery. Localisation can be

the immunosuppressed paediatric

performed by means of image-guided

population, lung biopsy can be performed in

percutaneous introduction of a hooked wire

cases where invasive pulmonary

or needle and intralesional injection of

aspergillosis cannot be diagnosed with

methylene blue dye.

imaging studies alone. Core biopsy is

Tumour ablation

preferred over fine-needle aspiration.

Absolute indication for biopsy is the case

Image-guided percutaneous thermoablation

where the management of a child will be

in the lung is most commonly performed in

altered according to the lesion’s nature and

secondary lesions that do not respond to

characterisation. Furthermore, benefits

radiotherapy (metastatic lesions from

should outweigh the risks.

osteosarcoma, Ewing’s sarcoma and

Contraindications of image-guided

hepatoblastoma). In most of the described

percutaneous biopsy in the chest include

series in the literature, radiofrequency

non-correctable coagulopathy, lack of safe

ablation seems to be the most popular, as

trajectory and other comorbidities which

opposed to the other ablative techniques.

might, for example, prohibit safe

Concerning paediatric ablation, all sessions

anaesthesia. Alternatives to percutaneous

are performed under general aesthesia and

biopsy include bronchoalveolar lavage or

for the first 24 h a patient-controlled

transbronchial biopsy.

analgesia is administered. Ablation

protocols in the lung are shorter when

Percutaneous biopsy is performed under

compared to procedures in the liver due to a

local sterility measures and anaesthesiology

lower vasculature. Complications include

control (generally intubation is required in

pneumothorax, haemorrhage and air

order to control breathing). Whenever a

embolism.

lesion is in contact with the pleural surface,

Image-guided percutaneous drainage

ultrasound can serve as a guiding modality

of choice; advantages for this include the

Occasionally, childhood pneumonias are

lack of ionising radiation, low cost and wide

complicated by pleural effusions, abscesses

availability. In cases where a lesion is

and empyemas which require drainage.

surrounded by lung parenchyma, CT is the

Image-guided drainage of such collections is

guiding modality of choice. The shortest

governed by high success (74-99%) with a

trajectory that avoids fissures and blood

suggested threshold of 95%, and low

vessels is chosen (fig. 1). Biopsy can be

complication rates (1-10%) with a

performed with direct or coaxial technique.

suggested threshold of 2-20%. Diagnosis of

Once the needle is at the lesion’s periphery

such collections is performed with chest

the biopsy system (semi-automatic or

radiographs, ultrasound or CT.

automatic depending upon operator’s

choice) is fired, thus obtaining the sample

Indications for drainage include fluid

within the trocar.

sampling, the presence of large or complex

collection (with pus or septae), and any

Success rates of image-guided percutaneous

collection (of fluid or pus) with symptoms

biopsy in children are ,85%, whilst

warranting drainage. Whenever culture and

complications include pneumothorax (10-

laboratory testing is required a sample is

15%, usually not clinically significant) and

obtained by needle aspiration. Sedation or

mild haemoptysis. Erect chest radiography

general aesthesia is a prerequisite.

is performed 2 h post-biopsy for evaluation

Ultrasound is preferred as a guiding

of delayed pneumothorax (figs 1-3).

modality due to the lack of ionising

194

ERS Handbook: Paediatric Respiratory Medicine

Figure 1. A 7-year-old girl with Louis-Barr syndrome, fever and cough. a) Initial chest radiograph and b)

subsequent CT scan revealed left lower lobe consolidation (black arrow, a). Consolidation was not resolved

after persistent appropriate treatment (antibiotics) and bronchoalveolar lavage was negative for common

bacteria, mycobacteria and fungi. An additional PCR test was negative for Cryptococcus aspergillus,

Candida and Pneumocystis carinii, whereas cytology was negative for malignancy. c) The child was

referred to our department for lung biopsy, which was performed under ultrasound guidance. The white

arrow indicates the needle inside the lesion. Histology proved lymphoproliferative syndrome. #: the spleen.

radiation, low cost and wide availability.

Under extended local sterility measures, a

tube (6-14 F in diameter) is introduced,

usually at the level of the midaxillary line

using a direct or seldinger technique, and

then connected to a water seal. Output

monitoring and catheter flushing (3-10 mL

of sterile 0.9% saline solution every 8-12 h)

are performed in order to keep the tube

patent. It must always be remembered that

the catheter should be placed at the superior

rib margin in the pleural space in order to

avoid intercostal vessels located at the lower

margin of the rib.

The technique for draining abscess or

empyema is similar; however, the need for

CT guidance is higher in these indications.

In any case, passage of the tube through

lung parenchyma or fissures must be

avoided (fig. 2).

In case of complex effusions, drainage of

Figure 2. a) A 5-year-old boy with necrotic

pneumonia and complicated right pleural effusion. A

abscesses and empyemas can be combined

10F pigtail catheter was placed under CT guidance

to fibrinolytic therapy with tissue

for drainage and adjuvant fibrinolytic therapy. A 10-

plasminogen activator (usual dose is

mm multiplanar reconstruction CT image in the

0.1 mg?kg^-1, maximum 3 mg injected).

axial plane displays the position of the catheter. b) A

Injection is performed through the tube which

10-year-old boy with necrotic pneumonia and right

then remains closed for 1 h and then suction

pleural effusion. An 8F pigtail catheter was placed

is resumed. Fibrinolytic therapy is performed

under ultrasound guidance for drainage. The arrow

with three doses injected every 12 h.

indicates the catheter inside the effusion.

ERS Handbook: Paediatric Respiratory Medicine

195

Post embo

Figure 3. A teenager with CF and massive haemoptysis. a) Angiography after selective right bronchial

artery catheterisation shows hyperaemia with dilated and tortuous vessels at the right upper lobe. b)

Superselective catheterisation with a microcatheter was performed and subsequent embolisation with

polyvinyl alcohol particles followed. c) Final post-embolisation (post embo) angiography revealed complete

vessel obstruction.

Drainage complications include septic

The majority of pulmonary AVMs are simple,

shock, bacteraemia, bleeding,

multiple and located on lower lobes of the

superinfection, bowel or pleural

lungs. Complications of transcatheter

transgression, bronchopleural fistula and

embolisation include pleurisy, transient

complications associated with sedation or

angina, severe perioral pain or leg pain,

general anaesthesia.

brachial plexus injury or deployment

complications.

Transcatheter embolisation

Due to the decreased incidence of TB and

Transcatheter embolisation is mainly

bronchiectasis, CF has become the major

indicated for treatment of pulmonary

cause of haemoptysis in childhood. Minor

arteriovenous malformations (AVM) or in

bleeding in the form of blood streaking is

cases of major haemoptysis. Embolic

more common whilst major haemoptysis

materials include coils, particles, gel foam

occurs in ,1% of children with CF. The term

and detachable balloons, as well as others

major haemoptysis implies the presence of

depending upon pathological substrate,

acute bleeding (.240 mL?day^-1) or recurrent

vessel size/location and material availability.

bleeding of small volumes (.100 mL?day^-1

Scarce data are found in the literature

over several days or weeks).

concerning pulmonary AVM in children and

Pathophysiology of haemoptysis in CF

no data are found for the same pathological

includes erosion of enlarged thin-walled

entity in infants. There is a clear association

tortuous neovasculature of the

between pulmonary AVM and hereditary

bronchovascular net, which are located in

haemorrhagic telangiectasia. Transcatheter

bronchiectatic areas secondary to chronic

embolotherapy seems to be an attractive

infection. Cases of minor bleeding are

alternative for these patients. Since this

usually self-limited. However, cases of major

technique is governed by a 15% reperfusion

haemoptysis can be self-limited or require

rate of the AVM it should be reserved for

treatment, either conservative (bed rest,

symptomatic children. However, pulmonary

intravenous antibiotics, blood transfusion,

AVMs are often embolised when they are

vitamin K administration, temporarily

o3 mm due to the risk of paradoxical

postpone positive pressure chest physio-

embolisation and stroke. Symptoms include

therapy) or transcatheter embolisation

exercise intolerance, cyanosis or clubbing,

of bronchial arteries (fig. 3). It is noteworthy

neurological or haemorrhagic complications

that both therapeutic arms are governed

(which mainly occur in cyanotic patients).

by similar success and recurrence rates.

196

ERS Handbook: Paediatric Respiratory Medicine

Complications of transcatheter bronchial

lesions in children. Pediatr Radiol;

36:

artery embolisation include post-embolic

491-497.

syndrome (fever, thoracic pain and potential

Hoffer FA (2003). Biopsy, needle localiza-

dysphagia), iatrogenic ischaemic necrosis of

tion, and radiofrequency ablation for

other organs and, very rare but severe, cases

pediatric patients. Tech Vasc Interv

Radiol; 6: 192-196.

of spinal cord ischaemia.

Hogan MJ, et al. (2012). Quality improve-

ment guidelines for pediatric abscess and

Further reading

fluid drainage. Pediatr Radiol; 42: 1527-

1535.

American Association of Pediatrics

McConnell P, et al.

(2002). Methylene

(1992). Guidelines for monitoring and

blue-stained autologous blood for needle

management of pediatric patients during

localization and thoracoscopic resection

and after sedation for diagnostic and

of deep pulmonary nodules in children.

therapeutic procedures. Pediatrics;

89:

J Pediatr Surg; 7: 1729-1731.

1110-1115.

Nanthakumar K, et al. (2001). Contrast

Barben JU, et al. (2003). Major haemop-

echocardiography for detection of pul-

tysis in children with cystic fibrosis: a 20-

monary arteriovenous malformations.

year retrospective study. J Cyst Fibros; 2:

Am Heart J; 141: 243-246.

105-111.

Roebuck DJ, et al. (2011). Interventions in

Cahill AM, et al.

(2004). CT-guided

the chest in children. Tech Vasc Interv

percutaneous lung biopsy in children.

Radiol; 14: 8-15.

J Vasc Interv Radiol; 15: 955-960.

Schidlow DV, et al. (1993). Cystic fibrosis

Faughnan ME, et al. (2004). Pulmonary

foundation consensus conference report

arteriovenous malformations in children:

on pulmonary complications of cystic

outcomes of transcatheter embolother-

fibrosis. Pediatr Pulmonol; 15: 187-198.

apy. J Pediatr; 145: 826-831.

Spies JB, et al. (1988). Antibiotic prophy-

Feola GP, et al. (2003). Management of

laxis in vascular and interventional radi-

complicated parapneumonic effusions in

ology: a rational approach. Radiology; 166:

children. Tech Vasc Interv Radiol; 6: 197-

381-387.

204.

Wood RE (1992). Hemoptysis in cystic

Fontalvo LF, et al. (2006). Percutaneous US-

fibrosis. Pediatr Pulmonol;

3: Suppl.

guided biopsies of peripheral pulmonary

82-84.

ERS Handbook: Paediatric Respiratory Medicine

197

Aerosol therapy

Hettie M. Janssens

Aerosol therapy has gained importance in

croup (Rittichier, 2004), and atelectasis

the treatment of paediatric respiratory

(Hendriks et al., 2005). Aerosol therapy is

disorders over the last few decades. It is now

considerably more complex than oral

the mainstay of asthma management in

therapy, as drugs must be delivered to an

children (GINA, 2012) and is increasingly

organ that has mechanisms to exclude

important for the treatment of other

foreign material.

respiratory disorders, such as CF

As a rule of thumb, one needs to consider

(Heijerman et al., 2009) and broncho-

the ‘‘five Ds’’ for prescribing optimal aerosol

pulmonary dysplasia (Tin et al., 2008).

therapy:

Other indications are impaired mucociliary

clearance such as in primary ciliary

N disease,

dyskinesia (PCD), neuromuscular diseases,

N drug,

tracheobronchomalacia and non-CF

N deposition,

bronchiectasis (Boogaard et al., 2007),

N device,

N disability of the patient.

Key points

One needs to be informed about the

pathophysiology and the severity of the lung

To match the correct aerosol delivery

disease, the pharmacological aspects of the

device to a patient, a clinician should

various drugs, and how the disease, drug,

be informed about the disease, drug,

device and patients characteristics will

deposition and device characteristics,

influence the deposition of the aerosol into

and the ability or disability of the

the lungs. This information and the

patient to perform an inhalation

technical qualities of the aerosol delivery

manoeuvre.

devices are needed to be able to match the

A pMDI/VHC with an attached

device to the patient. Last but not least, the

facemask is the first choice in asthma

abilities and disabilities of the child and

maintenance treatment in young

parents should be known in order to use the

children.

device correctly. Available inhaled drugs

include steroids, bronchodilators,

DPIs are convenient for older children,

mucolytics, inhaled antibiotics,

who can perform a fast, deep

prostaglandins, antiproteases, analgesia,

inhalation.

anticarcinoid therapy, proteins and

New (smart) nebulisers are promising

surfactant. Many more inhaled therapies are

but monitoring of safety and efficacy

in development. For the treatment and

is important.

choice of drugs of the different diseases,

please see the sections relating to those

Correct inhalation technique and

diseases elsewhere in this Handbook.

adherence are mandatory for

successful aerosol therapy.

This section will discuss some basic

principles of aerosol technology and the

198

ERS Handbook: Paediatric Respiratory Medicine

different delivery devices with information

Smaller particles have a higher probability of

on choosing the right device. For detailed

being deposited in the smaller airways and

background information on all available

alveoli, or being exhaled. It is important to

aerosol delivery devices, please refer to the

realize that this 1-5 mm range is mostly

recently published European Respiratory

derived from studies with healthy adult

Society (ERS)/International Society of

subjects. In the case of severe airway

Aerosols in Medicine (ISAM) Task Force

obstruction, like in CF, the deposition

consensus statement on inhaled therapies

pattern is inhomogeneous and will move

(Laube et al., 2011).

from the periphery of the lung to more

central airways. Little is known about

Basic aerosol technology

particle size deposition relation for young

An aerosol is best described as a cloud of

children. However, it is likely that the

fine particles that are small enough to

respirable fraction is in the smaller particle

remain suspended in the air for a

range. It has been shown in models and

considerable length of time. The probability

deposition studies that smaller particles

of inhaled particles being deposited in the

more effectively bypass the upper airways

respiratory tract and their distribution

and reach the periphery of the lungs, even in

pattern depends on: the particle

young children or in CF patients with airflow

characteristics, such as size, density and

obstruction (Schuepp et al., 2005; Janssens

shape; the anatomy of the respiratory tract;

et al., 2003; Laube BL et al., 1998; Roller et

and the breathing pattern. Particles are

al., 2007).

deposited by three mechanisms:

Most aerosol delivery devices used for the

treatment of children are suboptimal, as

N impaction,

they were primarily designed for adults and,

N sedimentation,

therefore, do not take into account the

N diffusion.

special characteristics needed for children.

Large particles and/or particles with high

Aerosol delivery devices: match the device

velocity tend to be deposited by impaction

to the patient

in the upper and central airways at airway

bifurcations. Smaller particles have a higher

The current methods to deliver therapeutic

probability of reaching the peripheral

aerosols can be classified in four categories:

airways where they are deposited by

sedimentation under the influence of

N nebulisers;

gravitational forces. The smallest particles

N pressurised metered-dose inhalers

can make it all the way to the alveoli. The

(pMDIs), which can be used with a press-

most important deposition mechanism of

and-breathe technique, as a breath-

these particles is by diffusion through

actuated device, or in combination with a

Brownian movements of the molecules.

spacer or valved holding chamber (VHC);

N dry-powder inhalers (DPIs);

The size distribution of aerosol particles is

N soft-mist inhalers.

usually described as the mass median

aerodynamic diameter (MMAD), which

The choice of device for children depends on

refers to the droplet diameter above and

the availability of the specific drug and the

below which 50% of the mass of the drug is

ability of the child to perform an inhalation

contained. The geometric standard

manoeuvre (fig. 1). In addition, not all

deviation (GSD) is a measure of the

devices are available in worldwide (Laube et

distribution in size of the aerosol particles.

al., 2011). Firstly, it should be known for

Aerosol particles between 1 and 5 mm are

which device the intended drug is available.

thought to have a high probability of being

Secondly, one needs to determine whether

deposited in bronchi and, therefore, are

the patient can perform an inhalation

often referred to as respirable particles.

manoeuvre and whether they can achieve an

Large particles have a higher probability of

inspiratory flow of around 30-60 L?min^-1

being deposited in the upper airways.

reproducibly. The latter is necessary for

ERS Handbook: Paediatric Respiratory Medicine

199

performing the right technique to use a DPI.

Nebulisers convert a liquid medication into a

Most DPIs give the best particle size and

mist for inhalation and can deliver a wide

dose with a flow of 60 L?min^-1. Particle size

range of drug formulations. The traditional

increases and dose decreases with lower

view of nebulisers is that they are expensive

inspiratory flows (Ross et al., 1996). Young

and bulky as well as inconvenient to handle

children and dyspnoeic patients are often

and maintain. Therefore, they are relegated

not able to achieve an inspiratory flow of

to third place in the market. However,

60 L?min^-1 (Amirav et al., 2005). For a

perhaps as a direct consequence of a lack of

breath-actuated pMDI, an inspiratory flow of

pharmaceutical vested interest, nebulisers

30 L?min^-1 is required. For children under the

remain poorly researched and understood

age of 7-8 years, it is generally

by many clinicians.

recommended to use a pMDI in

The use of nebulisers should be restricted to

combination with a VHC and to use an

delivering drugs that are only available as

additional face mask if the child cannot

liquids or that cannot be delivered by a

breath consciously through the mouth

pMDI with a VHC or autohaler, or DPI.

(usually below 3-4 years). In addition, it is

Examples of such drugs are recombinant

not recommended to use the pMDI directly

human deoxyribonuclease (rhDNase),

in the mouth for children of all ages because

tobramycin inhalation solution (TSI),

the press-and-breath technique requires

colomycin and hypertonic saline. Drugs

careful hand-mouth coordination, which is

such as rhDNase or TSI are registered for

often not correctly performed. This leads to

delivery by well-defined nebulizer-

inefficient deposition with high oro-

compressor combinations.

pharyngeal and low lung deposition. For

young children, a pMDI/VHC with a face

A child should be switched from a mask to a

mask is now the mainstay of asthma home

mouthpiece as soon as they are old enough

treatment. Nebulisers are used when a child

to inhale through the mouth voluntarily, as it

refuses to use a VHC, the medication is not

will increase the efficiency of aerosol delivery

available in other forms, large doses need to

(Chua et al., 1994). An optimal seal between

be given or aerosol inhalation needs to be

the face and mask is important to maxi-

combined with oxygen suppletion.

mise the efficiency of aerosol delivery

Drug available in pMDI or DPI

Drug available in fluid only

Inhalation through

mouth possible?

mouth not possible

(>4 years)

(<4 years)

Nebuliser

(+ mask,

Sufficient

Insufficient

<4 years)

inspiratory flow^#

>7-8 years

<7-8 years

pMDI spacer

+ mask

Breath-actuated

pMDI spacer

(nebuliser + mask)

pMDI

(nebuliser)

DPI

(nebuliser)

Figure 1. How to choose the right aerosol delivery device for a child.^#: sufficient inspiratory flow depends

on the intended inhaler; it is usually .30 L?min^-1 but for some inhalers (DPIs) is o60 L?min^-1.

200

ERS Handbook: Paediatric Respiratory Medicine

(Everard et al., 1992). Bronchodilators and

advantages of using a nebuliser over using a

inhaled steroids can be delivered faster, more

pMDI/VHC or DPI are that oxygen can be

efficiently and more safely by pMDI/VHC,

given during inhalation and that high doses

breath-actuated pMDI or DPI. Even in acute

can be administered over a prolonged time.

asthma attacks, delivery of bronchodilators

Furthermore, only tidal breathing is required

by pMDI/VHC is equally as effective as

so nebulisers can be used in patients

nebulisers (Cates et al., 2006). If a child is

of all ages and disease severities. The

very distressed during administration of

disadvantaged are numerous. For the home

aerosols by pMDI/VHC, a nebuliser can be a

setting, the equipment is expensive,

more acceptable alternative.

cumbersome and noisy, and needs a power

supply. The administration time can be as

There are different types of nebulisers, which

long as 20-30 min several times a day. This

differ in the way the aerosol is generated.

is not beneficial for patient compliance.

The differences in the delivered aerosol

Furthermore, it requires regular cleaning,

between currently available nebuliser

with a high risk of contamination if the

systems are significant. There are the jet,

cleaning instructions are not followed

ultrasonic and vibrating-mesh nebulisers,

correctly (Vassal et al., 2000). Jet nebulisers

with or without smart nebuliser technology.

use an electric compressor or compressed

Advancement in nebuliser and inhalation

gas source (oxygen or air) to create the

technology has developed modern smart

aerosol. There are numerous technical

nebulisers that are more effective than other

factors that can affect aerosol output and

devices. Nebulised drug delivery is possibly

particle size distribution of a jet nebuliser.

the most confused area of clinical practice,

These may result in highly variable doses

largely as a result of there being little or no

and poor reproducibility of particle size.

regulatory control. In the European

These technical factors include the fill

guidelines for nebulisers (Boe et al., 2001), it

volume, the operational flow, the viscosity,

is recommended that an inhaled drug is

concentration and temperature of the

registered for use with a specified nebuliser.

solution or suspension, the nebuliser

So, a pharmaceutical company should have

design, and breathing pattern (O’Callaghan,

tested the drug with a certain nebuliser in

1997). It is important that the correct

order to have recommendations for its use

operational flow or compressor is used

and guarantees for efficacy when used

while nebulising. This is mentioned in the

properly. This is, however, still not obligatory

user’s instructions. Usually, a flow of 6-

when a new nebuliser is introduced to the

8L?min^-1 is the optimal operational flow. A

market. Using an alternative system can

lower flow leads to larger particles and

have an unpredictable effect both in terms of

prolonged nebulisation time. The fill volume

efficacy and toxicity, especially for potentially

determines the concentration, particle size

toxic drugs like inhaled antibiotics. If there is

and nebulised dose. For each nebuliser and

a good reason to choose another device

drug, there is a recommended fill volume. If

than the recommended, the efficacy and

a smaller volume is used, there might be

toxicity should be closely monitored. New

less drug delivered, largely because there is

nebuliser technology offers greater

a residual volume of 1-1.5 mL that remains

convenience and portability and a significant

in the nebuliser. There are different types of

increase in aerosol delivery. On one hand,

jet nebulisers. The most widely used

this new, more efficient technology offers

unvented nebulisers, with continuous

obvious benefit to patients. On the other

output of aerosol, are inefficient, as there is

hand, adoption of this new and improved

loss of aerosol during exhalation or when a

nebuliser technology without due

patient is not breathing through the

consideration of the consequences of

nebuliser. More efficient systems have been

increased dosing presents potential risk.

developed, such as open-vent and breath-

enhanced nebulisers with in- and exhalation

The jet nebulisers are the oldest, and most

valves. The latest technology uses breath-

well-known and widely used nebulisers. The

actuated systems, which only deliver during

ERS Handbook: Paediatric Respiratory Medicine

201

inspiration, either by using a mechanism that

controlled (slow and deep) and aerosol is

opens when an inspiratory flow threshold is

delivered only during the first 50% of

reached, or electronically by following the

inspiration: the deeper the inhalation, the

patient’s breathing pattern and giving a

shorter the nebulising time (Nikander et al.,

precise dose during inhalation (Laube et al.,

2010). Almost no drug is lost during

2011; Geller, 2008). The use of breath-

exhalation. Smart nebulisers can achieve a

actuated systems results in improved lung

lung deposition of 60-80% (Bakker et al.,

deposition, dose reproducibility and reduced

2011), compared with 5-15% with the

loss by exhalation. Breath-actuated devices

traditional jet nebulisers (Laube et al., 2011).

are suitable for children from 4 years of age.

Furthermore, more peripheral lung

deposition can be achieved, which may

Ultrasonic nebulisers use a piezoelectric

result in improvement in peripheral airway

crystal to convert fluid into a fine mist. The

obstruction, as in CF (Bakker et al., 2011).

output of ultrasonic nebulisers is faster than

Another advantage is that adherence is

that of jet nebulisers, which is useful for

logged electronically and the data can be

administration of large volumes. However,

downloaded afterwards (Dhand, 2010). This

ultrasonic nebulisers are not suitable for

can be a useful tool to get insight into the

nebulising suspensions, such as steroids,

adherence to aerosol therapy and discuss

and viscous fluids, such as antibiotics.

this with the patient, in order to improve the

Furthermore, the fluid may become too

efficacy of the treatment.

warm in the ultrasonic nebuliser because

the crystal produces heat by vibrating in high

Although they have many advantages,

speed. This may inactivate certain drugs,

vibrating mesh and smart nebulisers have

like rhDNase. Ultrasonic nebulisers are not

still not been extensively tested in children

widely used because they are expensive and

and there is little clinical information

produce relatively large particles compared

available. Lung deposition is improved but

with jet nebulisers (Laube et al., 2011).

dose recommendations are lacking or based

on in vitro or adult data. There might be

The recently introduced mesh nebulisers use

indications that, especially in young children,

either a vibrating or fixed membrane with a

higher lung deposition of aerosols can lead to

piezoelectric element with microscopic holes

toxic side-effects (Guy et al., 2010). Therefore,

to generate an aerosol. Vibrating-mesh

clinicians should be cautious when using

devices have a number of advantages over

these new devices, especially in children.

other nebuliser systems. They are very

There are many good arguments to use one

efficient and quiet, and are generally portable,

of the new-generation nebulisers but efficacy

as they operate as effectively when using

and toxicity should be carefully monitored,

batteries as mains electricity. Lung

especially when using potentially toxic drugs,

deposition is substantially increased, varying

such as inhaled antibiotics.

between 30% and 80%, depending on the

device. However, they also are significantly

pMDI, pMDI/VHC and breath-actuated

more expensive than other types of

pMDI Almost all drugs available for aerosol

nebulisers, and require a significant amount

therapy of asthma are available in pMDIs. In

of maintenance and cleaning after each use

a pMDI, the drug is present in a solution or

to prevent build-up of deposit and blockage

suspension with propellants and surfactants.

of the apertures (especially when

In the case of a suspension, the pMDI should

suspensions are aerosolised), and to prevent

be shaken before use to mix the drug with the

colonisation by pathogens (Geller, 2008;

propellant. When the pMDI is fired, an

Rottier et al., 2009). They are most widely

accurately metered dose is released at a high

used for the treatment of patients with CF.

velocity. The mass of drug and its aerosol

characteristics are largely independent of the

There are breath-enhanced mesh nebulisers

inspiratory effort made by the patient.

and those with dosimetric aerosol delivery,

the so-called smart nebulisers. In smart

Inhalation from a pMDI should be precisely

nebulisers, the breathing pattern is

timed with a press-and-breath manoeuvre.

202

ERS Handbook: Paediatric Respiratory Medicine

Most patients are not able to coordinate

(Pierart et al., 1999; Wildhaber et al., 2000).

actuation of the pMDI with the breathing

Anti-static VHCs have been developed to

manoeuvre, causing high oropharyngeal and

overcome this problem (Laube et al., 2011). In

low lung deposition. This coordination

a model study, it was shown that when

problem can be resolved by using a breath-

electrostatic charge is minimised, the

actuated pMDI (Newman et al., 1991) or a

deposition in the ‘‘lung’’ is dependent on the

pMDI/VHC. Breath-actuated pMDIs

pMDI, and relatively independent of the VHC,

automatically release the drug when a patient

used (Janssens et al., 2004). The differences

is inhaling. A patient should be able to

in aerosol deposition of the different pMDIs

perform a maximal exhalation followed with a

were explained by the particle size of the

slow inhalation with a breath hold. Lung

aerosol cloud. In general, it was shown that

deposition is improved using a breath-

the smaller the particles, the higher the dose

actuated pMDI but oropharyngeal deposition

delivered to the lungs, and the lower the

is still high. VHCs are used to facilitate

oropharyngeal deposition. In particular, a

inhalation from a pMDI with normal tidal

hydrofluoroalkane (HFA)-beclomethasone

breathing and decrease the oropharyngeal

pMDI with a high proportion of extra-fine

deposition. The use of a VHC is

particles (MMAD 1.1 mm) resulted in a

recommended for all patients in principle,

considerably higher lung dose (Janssens et al.,

especially using inhaled corticosteroids, but

2003). These in vitro data were confirmed by

particularly for those who have difficulties

an in vivo lung deposition study with the same

with the press-and-breath technique with the

breath-actuated pMDI in children aged

pMDI, such as children. For children with

o5 years (Devadason et al., 2003). The higher

asthma below the age of 7 years, the pMDI/

lung deposition translates to a reduction by

VHC is the system of first choice. A VHC with

half of the effective dose in inhaled steroids if

a mouthpiece should be used whenever

extra-fine particles are used (GINA, 2012;

possible. In children below the age of 3-

Busse et al., 1999) but randomised controlled

4 years, a face mask should be added to the

trials failed to show a superior clinical effect

VHC. In children younger than 2 years, it can

(Boluyt et al., 2012). Even when an anti-static

be very difficult to obtain a proper seal

VHC and a pMDI with small particles is used,

between the face and mask (Amirav et al.,

cooperation remains the most important

1999; Janssens et al., 2000). Even a small leak

determinant for the efficiency of dose delivery

of 0.2 cm will dramatically reduce the output

(Janssens et al., 2000). Furthermore, if there

of the pMDI/VHC-mask combination

is a suboptimal face-mask seal, the increase

(Esposito-Festen et al., 2004). Each VHC

in dose obtained by minimising the

comes with its own face mask. There are

electrostatic charge of a VHC by detergent

substantial differences in the efficiency of

coating is almost completely lost (Smaldone

achieving a good face-mask seal with the

et al., 2005). Parents of young children should

different designs (Amirav et al., 2001;

be carefully instructed about the importance

Esposito-Festen et al., 2005). After the face

of an optimal mask seal, good administration

mask is positioned on the face, one puff of the

technique and good cooperation during the

pMDI needs to be fired into the VHC. As soon

administration procedure.

as the aerosol cloud is released from the

pMDI, aerosol particles start to sediment

DPI Most anti-asthma drugs are available

onto the VHC wall as a result of gravitational

as DPIs. DPIs are small, portable, handheld

forces. This effect is stronger when a plastic

devices. There are numerous different

VHC is used, due to electrostatic charge.

devices available, each with its own

Therefore, any delay between the moment the

directions for use. Older children and adults

dose is fired and the moment of effective

prefer DPIs because they are ‘‘easy’’ to use

inhalation will reduce the inhaled dose

in daily life, which may help adherence. In a

substantially (Wildhaber et al., 1996).

DPI, the drug is present in single or multiple

However when a plastic VHC is coated with

dosing chamber. DPIs are formulated with

detergent, electrostatic charge is minimised

their drug particles either attached to a carrier

and lung deposition will increase substantially

or as agglomerates in the form of pellets.

ERS Handbook: Paediatric Respiratory Medicine

203

To facilitate deposition in the lungs, drug

diameter. For this DPI, a slow, deep

particles are de-agglomerated during

inhalation manoeuvre is needed. The

inhalation. Airflow through a DPI combines

colistimethate is a micronised dry powder in

with its internal resistance to create turbulent

a low-resistance inhaler. For this DPI, a fast,

energy inside the DPI. This internal energy is

deep inhalation is required.

required to de-agglomerate the particles and

In recent years, many different types of DPI

aerosolise the dose. The turbulent energy

have been introduced. They differ in the

created during inhalation is the product of

inhalator resistance and particle size. The

the patient’s inspiratory flow multiplied by

newest technology uses feedback mech-

the DPIs resistance (Laube et al., 2011). Thus,

anisms and dose counters to check

for a set energy, a DPI with a high resistance

compliance and stimulate good inhalation.

will require a lower inspiratory flow than a

The clinician needs to be informed on which

DPI with a lower resistance. The mass of drug

drugs are available in the different devices.

and the MMAD and GSD of the released

In addition, most of the new DPIs are not

aerosol cloud depends on the inspiratory flow

well studied in children.

of the patient. When there is insufficient

inspiratory flow through the DPI

Soft-mist inhalers Currently, there is only

(,60 L?min^-1 for most DPIs), the mass of

one commercially available soft-mist

drug that is released is reduced and the

inhaler. This inhaler is available for the

MMAD is increased. Sufficiently high and

delivery of fenoterol 50 mg/ipratropium

reproducible inspiratory flows through a DPI

bromide, and tiotropium bromide. The

can be obtained in asthmatic children aged

soft-mist inhaler atomises the drug

o7 years (Amirav et al., 2005). Clearly, such

solution using mechanical energy imparted

devices can only be used when a patient is

by a spring. When the spring is released,

able to generate sufficient flow for optimal

the solution is forced through an extremely

drug dispersion. Careful inhalation

fine nozzle system. This produces a fine

instructions are important for correct use and

mist that is slow moving, giving the patient

effective aerosol delivery of DPIs. Mistakes in

time to inhale after a press-and breath,

dose preparation, no maximal exhalation

leading to lower deposition in the mouth

before inhalation, insufficient inspiratory

and throat, and relatively high lung

effort and storage in a humid environment

deposition (,39%) (Laube et al., 2011).

can lead to decreased lung deposition or

Soft mist-inhalers have not been tested in

even none at all (Laube et al., 2011). The

children.

recommended inhalation manoeuvre for a

Inhalation instructions and adherence

DPI is to inhale as quickly and deeply as

possible for optimal de-agglomeration of the

For optimal effect of aerosol therapy, correct

particles. Consequently, this causes high

use of the aerosol delivery device is crucial.

impaction of particles in the oropharynx,

Any mistake during the inhalation procedure

which may increase local side-effects. The

can influence the delivered dose sub-

high inspiratory flow also causes the aerosol

stantially. It is known that inhalation

to be deposited mainly in the larger airways

instruction needs to be repeated several

rather than the periphery. This may vary

times before the inhalation is performed

between different DPIs depending on particle

correctly (Kamps et al., 2000). For detailed

size and internal resistance.

inhalation instructions for each device,

please see the ERS/ISAM Task Force

Recently, DPIs were introduced for inhaled

consensus statement on inhalation therapy

tobramycin (Konstan et al., 2011) and

(Laube et al., 2011).

colistimethate (Schuster et al., 2012).

Tobramycin inhalation powder uses a new

If the correct device is chosen for the patient

spray drying technique (Geller et al., 2011).

and inhalation instructions have been given,

This results in hollow porous particles that

the patient still needs to use the device daily

behave like small particles because a lower

at home. It is known that adherence to

density decreases the aerodynamic

inhalation therapy is generally low, which

204

ERS Handbook: Paediatric Respiratory Medicine

can lead to more severe disease and hos-

Bakker EM, et al.

(2011). Improved

pital admissions (Murphy et al., 2012). In a

treatment response to dornase alfa in

good partnership with patients, parents and

cystic fibrosis patients using controlled

the doctor, the treatment needs to be

inhalation. Eur Respir J; 38: 1328-1335.

discussed and explained.

Boe J, et al. (2001). European Respiratory

Society Guidelines on the use of nebuli-

Conclusion

zers. Eur Respir J; 18: 228-242.

Boluyt N, et al.

(2012). Assessment of

There are many different types of aerosol

controversial pediatric asthma manage-

delivery devices. In the last few years, many

ment options using GRADE. Pediatrics;

new devices have been introduced. Aerosol

130: e658-e668.

delivery devices can be divided in four

Boogaard R, et al.

(2007). Pharma-

groups: nebulisers (jet, ultrasonic, mesh

cotherapy of impaired mucociliary clear-

and smart); pMDIs (combined with a VHC

ance in non-CF pediatric lung disease. A

or breath actuated); DPIs; and soft-mist

review of the literature. Pediatr Pulmonol;

inhalers. The prescribing physician needs

42: 989-1001.

detailed knowledge about:

Busse WW, et al.

(1999). Efficacy

response of inhaled beclomethasone

N aerosol and deposition characteristics of

dipropionate in asthma is proportional

the various aerosol delivery systems;

to dose and is improved by formulation

N availability of drugs in the different

with a new propellant. J Allergy Clin

Immunol; 104: 1215-1222.

devices;

Cates CJ, et al. (2006). Holding chambers

N advantages and disadvantages of the

(spacers) versus nebulisers for b-agonist

devices;

treatment of acute asthma. Cochrane

N the pathophysiology of the lung disease;

Database Syst Rev; 2: CD000052.

N the skills of the patient in various age

Chua HL, et al. (1994). The influence of

groups.

age on aerosol deposition in children with

cystic fibrosis. Eur Respir J; 7: 2185-2191.

Only when this knowledge is available can

Devadason SG, et al. (2003). Distribution

the appropriate delivery device for the

of^99mTc-labelled Qvar delivered using an

patient be selected. In addition, optimal

Autohaler^TM device in children. Eur Respir J;

aerosol therapy is only possible with

21: 1007-1011.

repeated inhalation instructions and well-

Dhand R (2010). Intelligent nebulizers in

informed patients and parents, which will

the age of the Internet: the I-neb Adaptive

encourage adherence.

Aerosol Delivery (AAD) system. J Aerosol

Med Pulm Drug Deliv; 23: Suppl 1, iii-v.

Esposito-Festen JE, et al. (2004). Effect of a

Further reading

facemask leak on aerosol delivery from a

Amirav I, et al.

(1999). Delivery of

pMDI-spacer system. J Aerosol Med; 17: 1-6.

Esposito-Festen J, et al. (2005). Aerosol

aerosols to children with MDI and hold-

ing chambers (MHC) is critically depen-

delivery to young children by pMDI-

dent on the facemask seal. Am J Respir

spacer: is facemask design important?

Crit Care Med; 159: A142.

Pediatr Allergy Immunol; 16: 348-353.

Amirav I, et al. (2001). Aerosol therapy

Everard ML, et al. (1992). Drug delivery

with valved holding chambers in young

from holding chambers with attached

children: importance of the facemask

facemask. Arch Dis Child; 67: 580-585.

seal. Pediatrics; 108: 389-394.

Geller DE, et al. (2011). Development of an

Amirav I, et al. (2005). Measurement of

inhaled dry-powder formulation of tobra-

peak inspiratory flow with in-check dial

mycin using PulmoSphere technology. J

device to simulate low-resistance (Diskus)

Aerosol Med Pulm Drug Deliv; 24: 175-182.

and high-resistance (Turbohaler) dry pow-

Geller DE (2008). The science of aerosol

der inhalers in children with asthma.

delivery in cystic fibrosis. Pediatr

Pediatr Pulmonol; 39: 447-451.

Pulmonol; 49: Suppl. 9, S5-S17.

ERS Handbook: Paediatric Respiratory Medicine

205

Global Initiative for Asthma. Global strat-

the I-neb Adaptive Aerosol Delivery

egy for asthma management and preven-

(AAD) system affects lung deposition of

tion 2012. www.ginasthma.org

^99mTc-DTPA. J Aerosol Med Pulm Drug

Guy EL, et al. (2010). Serum tobramycin

Deliv; 23: Suppl. 1, S37-S43.

levels following delivery of tobramycin

O’Callaghan C (1997). Delivery systems:

(Tobi) via eFlow advanced nebuliser in

the science. Pediatr Pulm; 15: 51-54.

children with cystic fibrosis. J Cyst Fibros;

Pierart F, et al. (1999). Washing plastic

9: 292-295.

spacers in household detergent reduces

Heijerman H, et al.

(2009). Inhaled

electrostatic charge and greatly improves

medication and inhalation devices for

delivery. Eur Respir J; 13: 673-678.

lung disease in patients with cystic

Rittichier KK

(2004). The role of corti-

fibrosis: a European consensus. J Cyst

costeroids in the treatment of croup.

Fibros; 8: 295-315.

Treat Respir Med; 3: 139-145.

Hendriks T, et al.

(2005). DNase and

Roller CM, et al. (2007). Spacer inhalation

atelectasis in non-cystic fibrosis pediatric

technique and deposition of extrafine

patients. Crit Care; 9: R351-R356.

aerosol in asthmatic children. Eur Respir

Janssens HM, et al.

(2000). Aerosol

J; 29: 299-306.

delivery from spacers in wheezy infants:

Ross DL, et al. (1996). Effect of inhalation

a daily life study. Eur Respir J; 16: 850-856.

flow rate on the dosing characteristics of

Janssens HM, et al.

(2003). Extra-fine

dry powder inhaler (DPI) and metered

particles improve lung delivery of inhaled

dose inhaler (MDI) products. J Aerosol

steroids in infants: a study in an upper

Med; 9: 215-226.

airway model. Chest; 123: 2083-2088.

Rottier BL, et al. (2009). Changes in perfor-

Janssens HM, et al. (2004). Determining

mance of the Pari eFlow rapid and Pari LC

factors of aerosol deposition for four pMDI-

Plus during 6 months use by CF patients.

spacer combinations in an infant upper

J Aerosol Med Pulm Drug Deliv; 22: 263-269.

airway model. J Aerosol Med; 17: 51-61.

Schuepp KG, et al.

(2005). In vitro

Kamps AW, et al. (2000). Poor inhalation

determination of the optimal particle size

technique, even after inhalation instruc-

for nebulized aerosol delivery to infants.

tions, in children with asthma. Pediatr

J Aerosol Med; 18: 225-235.

Pulmonol; 29: 39-42.

Schuster A, et al. (2013). Safety, efficacy

Konstan MW, et al. (2011). Safety, efficacy

and convenience of colistimethate sodium

and convenience of tobramycin inhala-

dry powder for inhalation

(Colobreathe

tion powder in cystic fibrosis patients:

DPI) in patients with cystic fibrosis: a

The EAGER trial. J Cyst Fibros; 10: 54-61.

randomised study. Thorax; 68: 344-350.

Laube BL, et al. (1998). The efficacy of

slow versus faster inhalation of cromolyn

Smaldone GC, et al. (2005). Variation in

sodium in protecting against allergen

pediatric aerosol delivery: importance of

challenge in patients with asthma.

facemask. J Aerosol Med; 18: 354-363.

J Allerg Clin Immunol; 101: 475-483.

Tin W, et al. (2008). Adjunctive therapies in

Laube BL, et al.

(2011). What the

chronic lung disease: examining the evi-

pulmonary specialist should know about

dence. Semin Fetal Neonatal Med; 13: 44-52.

the new inhalation therapies. Eur Respir J;

Vassal S, et al.

(2000). Microbiologic

37: 1308-1331.

contamination study of nebulizers after

Murphy AC, et al. (2012). The relationship

aerosol therapy in patients with cystic

between clinical outcomes and medica-

fibrosis. Am J Infect Control; 28: 347-351.

tion adherence in difficult-to-control

Wildhaber JH, et al.

(1996). Effect of

asthma. Thorax; 67: 751-753.

electrostatic charge, flow, delay and multi-

Newman SP, et al. (1991). Improvement

ple actuations on the in vitro delivery of

of drug delivery with a breath actuated

salbutamol from different small volume

pressurised aerosol for patients with

spacers for infants. Thorax; 51: 985-988.

poor inhaler technique. Thorax; 46: 712-

Wildhaber JH, et al. (2000). High-percen-

716.

tage lung delivery in children from

Nikander K, et al.

(2010). Mode of

detergent-treated

spacers.

Pediatr

breathing-tidal or slow and deep-through

Pulmonol; 29: 389-393.

206

ERS Handbook: Paediatric Respiratory Medicine

Epidemiology

Steve Turner

The child’s respiratory system is constantly

associated with CF (refer to relevant

exposed to infective agents and acute lower

sections in the Handbook). Infectivity,

respiratory tract infections are normal in

diagnosis, investigation, management and

children. The global burden of acute

pharmacology are covered elsewhere.

respiratory infections in children is huge and

Acute infections

the World Health Organization (WHO)

estimates that approximately one-third of all

Bronchiolitis

deaths in children are due to acute

Definition. Bronchiolitis is a clinical

respiratory infections. In contrast, chronic

diagnosis based on history and examination,

respiratory infection (arbitrarily defined here

which has been defined by a Delphi

as symptoms lasting for more than 4 weeks)

consensus in the UK as ‘‘a seasonal viral

is never normal and is usually associated

illness characterised by fever, nasal

with bacterial infection. Bacteria causing

discharge and dry, wheezy cough. On

chronic infection are usually part of the

examination there are fine inspiratory

normal upper airway flora and what is not

crackles and/or high pitched expiratory

well understood is what transforms them

wheeze’’.

from commensal to pathogenic. This

Infective agents. Approximately 75% of cases

section will describe the epidemiology and

are associated with respiratory syncytial

microbiology of acute and chronic lung

virus (RSV) infection and the remainder are

infection. For the purpose of this section,

associated with other viruses, including

croup, epiglottitis and tracheitis are

parainfluenza virus type 3, human

considered airway infections and are not

metapneumovirus and adenovirus. Infection

covered, and neither are TB nor infections

with more than one virus is increasingly

recognised with the advent of more sensitive

PCR testing.

Key points

Incidence. Approximately 20% of all infants

develop bronchiolitis and 3% of all infants in

N Acute lung infections have a very high

Europe are admitted to hospital with

incidence in children.

bronchiolitis. The median age of admitted

Chronic lung infections (i.e. lasting

infants is 2-3 months, the age range is not

more than 4 weeks) are also common

normally distributed and very young infants

in children.

are much more commonly admitted than

older infants. Figure 1 demonstrates the

N Sex, age, geography and vaccinations

seasonality of RSV infections. In many

are important determinants of lung

European countries there is evidence of

infection incidence.

alternating years of higher and lower

The incidence of many infections

incidence. An RSV vaccine is not widely

changes over time and this reflects

available at present but may be introduced

changes in pathogen and/or host.

in the near future, and this is likely to change

the epidemiology of bronchiolitis.

ERS Handbook: Paediatric Respiratory Medicine

207

800

<1 year

1-4 years

5-14 years

600

15-44 years

45-64 years

65+ years

400

200

Time week

Figure 1. Laboratory reports of respiratory syncytial virus by week of specimen and age in 2009-2010.

Reproduced from Salisbury et al. (2013) with permission from the publisher.

Risk factors. Young age, male sex, exposure

bronchiolitis suggest that RSV does not

to tobacco smoke and reduced lung function

cause asthma.

prior to onset of symptoms are associated

Pneumonia

with increased risk for bronchiolitis. More

Definition. There are a number of definitions

serious features of bronchiolitis are

of pneumonia but no single gold standard

associated with prematurity (with or without

definition. Pneumonia is a clinical diagnosis

bronchopulmonary dysplasia),

which is defined by the WHO as the

haemodynamically significant heart disease

presence of cough, fever and tachypnoea.

and infection with RSV (compared with

Community-acquired pneumonia (CAP) is

other viruses).

defined as ‘‘the presence of signs and

symptoms of pneumonia in a previously

Prognosis. Approximately 20% of infants

healthy child due to an infection which has

with bronchiolitis have respiratory

been acquired outside hospital’’. Crackles

symptoms for more than 1 month during

may be heard with a stethoscope in up to

convalescence. An association with

two-thirds of cases. A chest radiograph is

increased risk for later asthma symptoms

not required for the diagnosis of

has been described but this relationship is

uncomplicated pneumonia. Among infants,

not straightforward. The association is seen

there is some overlap between bronchiolitis

more clearly in those who were hospitalised

and pneumonia in clinical presentation. A

for bronchiolitis rather than cared for in the

broader term ‘‘acute lower respiratory tract

community. The association usually

infection’’ includes pneumonia and for the

becomes weaker as the children become

purpose of this chapter is considered

older. One explanation for these

synonymous.

observations is that a common airway

abnormality or genetic predisposition may

There are a number of classifications of

lead an individual to develop bronchiolitis

pneumonia. Different infective agents may

in infancy and asthma in later childhood.

be associated with different classifications

Observations that infants with RSV

so there is clinical merit in distinguishing

bronchiolitis are less likely to develop

between categories. Typical CAP is by far the

asthma compared to those with non-RSV

most common presentation.

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Infective agents commonly associated with acute and chronic respiratory infection in children

Bronchiolitis Pneumonia Empyema Chronic bronchitis

Respiratory viruses

Respiratory syncytial virus

++++

Parainfluenza

Influenza

Human metapneumovirus

Bacteria

Streptococcus pneumoniae

+++

Haemophilus influenzae

Streptococcus pyogenes

Moraxella catarrhalis

Mycoplasma pneumoniae

Staphylococcus aureus

+++: very common pathogen; ++: moderately common pathogen; +: not an uncommon pathogen; -: not

thought to be a pathogen.

N Typical/atypical. Atypical pneumonia is

85% of cases. Pneumonia can be caused by

characterised by respiratory distress and

a number of bacteria and viruses (table 1)

hypoxia, sometimes associated with

and approximately one-third of hospitalised

headache, vomiting or diarrhoea, with

children have both viral and bacterial

essentially normal findings on

infections identified. Viral identification is

auscultation but marked diffuse chest

more common in younger children and is

radiograph changes.

present in 80% of infants and 60% of 1-

N CAP/hospital-acquired/tracheostomy- or

2 year-olds. Wheezing and conjunctivitis are

ventilator-associated pneumonia. CAP is

more commonly associated with viral

defined as the signs and symptoms of

pneumonia compared to bacterial

pneumonia in a previously healthy child.

pneumonia. Typical pneumonias are usually

Hospital-acquired pneumonia infection is

caused by Streptococcus pneumoniae,

defined (in adults) as pneumonia that is

Haemophilus influenzae and Moraxella

acquired after at least 48 h of admission

catarrhalis, whilst the most common agents

to hospital and is not incubating at the

causing atypical pneumonia in children are

time of admission. Tracheostomy or

Mycoplasma pneumoniae and respiratory

ventilator-associated pneumonia are self-

viruses. Chlamydophila pneumoniae may also

descriptive.

cause atypical pneumonia but Legionella

N Radiological. Chest radiographs (if taken)

pneumophila is rarely seen in immune-

show patchy pneumonic changes in

competent children. Children with influenza

approximately 60% of cases, lobar

infection are at increased risk for

consolidation in approximately 20% and

Staphylococcus aureus co-infection including

perihilar changes in a further 20%.

pneumonia. Hospital-acquired and

tracheostomy-/ventilator-associated

Infective agents. The challenge in obtaining a

pneumonias are often associated with

sample of lower airway secretions in a small

methicillin resistant S. aureus and

and often unwell child means that until

Pseudomonas species.

recently an infective agent was not identified

in most cases of pneumonia. Recent

Incidence. Age and geography are major

introduction of PCR testing now means that

determinants of the annual incidence of

infective agents can be identified in up to

pneumonia in children. In Western

ERS Handbook: Paediatric Respiratory Medicine

209

countries, the annual incidence ranges from

Empyema thoracis

approximately 600 cases per 100 000 in the

Definition. Empyema is thought to

neonatal period to 10 cases per 100 000 in

complicate 1% of childhood bacterial

10-14 year-olds. In contrast, the WHO cites

pneumonias and can be defined as a

a median annual incidence for developing

parapneumonic effusion, i.e. a collection of

countries of 0.28 episodes per child-year

fluid within the pleural cavity. There is a

(fig. 2). Widespread introduction of

continuum of parapneumonic effusion from

pneumococcal vaccination reduced the

a reactive (exudative) effusion to purulent

incidence of pneumonia by approximately

effusion (empyema) to organised effusion

one-third.

(rind). Diagnosis requires imaging with

ultrasound plus pleural aspirate. Clinically,

Risk factors. Pneumonia is a seasonal

the child will present with a prolonged

disease with peak presentations occurring at

pneumonic illness where the fever fails to

the same time as bronchiolitis, i.e.

settle and pleuritic pain develops. There is

December and January in the Northern

often an acquired scoliosis towards the

hemisphere. Boys are at increased risk for

affected side. Bilateral empyema is very

pneumonia compared to girls. Abnormal

uncommon. Rarely, an empyema may be

lung function in early infancy and exposure

associated with no preceding febrile illness

to tobacco smoke are associated with higher

risk of later radiologically confirmed

and a lack of elevated inflammatory markers

pneumonia. The risk for pneumonia is

and this should raise suspicion of

reduced in cases who consult with their

underlying malignancy. In these cases a CT

primary care physician early in the illness

scan with contrast of the chest and

and in those who have the pneumococcal

mediastinum should be taken and reviewed

vaccine.

before considering drainage and/or

anaesthetics.

Prognosis. Complete resolution is the usual

outcome for childhood pneumonia although

Infective agents. The same infective agents

a small proportion (,1%) of children

associated with bacterial pneumonia are

develop bronchiectasis.

implicated in empyema causation (table 1).

Episodes per child-year

≤0.10

0.11-0.20

0.21-0.30

0.31-0.40

0.41-0.50

Figure 2. Incidence of childhood clinical pneumonia at the country level. Reproduced from the World

Health Organization (2008) with permission from the publisher.

210

ERS Handbook: Paediatric Respiratory Medicine

Bacteria are identified in pleural fluid and/or

Boys account for 70% of cases. Prior

blood culture in approximately five times as

treatment with antibiotics and

many cases when PCR is used compared to

pneumococcal vaccination are associated

standard bacterial culture, but even with

with a reduced risk for empyema.

PCR no infective agent is identified in at

Prognosis. Empyema is a serious and

least 25% of cases. Where bacteria are

potentially life-threatening infection but

identified, S. pneumoniae is present in 50-

most children survive the initial illness and

70% of cases and a recent study from

their long-term prognosis is usually

Australia reported that 97% of S.

excellent. Chest radiograph changes may

pneumoniae were non-vaccine related

persist for at least 12 months and there is a

serotypes; this demonstrates the efficacy of

risk of bronchiectasis.

pneumococcal vaccination but also the

ability for ‘‘new’’ serotypes to fill the void left

Chronic infections

by vaccination.

Chronic bronchitis

Incidence. This is currently approximately

Definition. This condition is not described in

three cases per 100 000. Figure 3

many text books and is not universally

demonstrates how incidence increased in

accepted as a diagnosis at present, but can

Scotland, UK, during the early 2000s.

be defined as a productive (i.e. wet) cough

which lasts for more than 3 weeks or

Risk factors. The mean age of children

1 month in an otherwise well child. An

presenting with empyema is 4-5 years

alternative term is protracted bacterial

which is unexpected given the higher burden

bronchitis, which includes an additional

of pneumonia among infants compared to

caveat that the symptoms should respond to

older children; a lower threshold for

a 10-14 day course of treatment with

treatment with antibiotics in younger

antibiotics. Chronic bronchitis is often

children may partly explain this apparent

associated with coarse, loud ‘‘rattly’’

inconsistency. There is evidence that the

respiratory sounds that can be wrongly

prevalence in 1-4 year-olds is increasing.

interpreted as wheeze and the child is

wrongly diagnosed with asthma. The

reluctance in parts of the clinical community

for accepting chronic bronchitis as an entity

◆

is the potential for misdiagnosis in serious

conditions, such as foreign body aspiration,

CF, immune deficiency and pertussis. It is

possible that bacterial bronchitis and non-

CF bronchiectasis are at opposite ends of

◆

the same disease spectrum.

◆

Infective agents. Bacteria are identified in

approximately 70% of cases where

◆

◆ ◆

prolonged productive cough is reported and

◆

bronchoscopy is performed; H. influenzae is

◆

◆◆◆◆

◆

present in 30-40% of cases, S. pneumoniae

◆

◆ ◆

◆

in 20-25% and M. catarrhalis in 15-10%.

◆ ◆

◆

Respiratory viruses are likely to be important

in some cases but their role is not currently

1980

1985

1990

1995

2000

2005

understood.

Year

Incidence. Different definitions of chronic

Figure 3. Empyema admissions per million per

bronchitis (or cough) have been used in

year in Scottish children between January 1981

epidemiological studies making the

and December 2005. Reproduced from Roxburgh

incidence difficult to estimate. The incidence

(2008) with permission from the publisher.

of chronic bronchitis is highest in children

ERS Handbook: Paediatric Respiratory Medicine

211

aged 1-2 years. As many as 20% of

Infective agent. Bordetella pertussis usually

preschool children may have a cough which

causes pertussis but B. parapertussis and

lasts for more than 1 month.

RSV can cause a pertussis-like illness.

Risk factors. Assuming that other alternative

Incidence. There are approximately 200

diagnoses for chronic cough are excluded,

million cases of pertussis each year and

the main risk factor is young age. There is no

there are peaks (epidemics) every 4 years.

evidence of an immune deficiency but

As in all respiratory infections, incidence is

absence of evidence is not the same as

age-dependent; a survey of cases across

evidence of absence.

Europe reported an overall incidence of 10

cases per 100 000 children but this was 100

Prognosis. This is uncertain but is probably

cases per 100 000 among infants and one

very good for most cases. There is a

case per 100 000 among older teenagers.

possibility that recurrent infection leads to

progressive airway damage (a vicious cycle

Risk factors. The major risk factor for

hypothesis) and, in some cases, to

pertussis is not being vaccinated (i.e. very

bronchiectasis.

young infants and older children who have

not been vaccinated). Prior vaccination does

Pertussis

not protect all individuals against pertussis

Definition. Pertussis (or whooping cough) is

but is associated with less severe symptoms

characterised by paroxysms of coughing

if these develop.

which can last for up to 4 months. There are

three stages to the infection:

Prognosis. Pertussis remains a serious

condition on a world-wide scale and is

N the initial catarrhal phase lasts for 1 week

associated with 200 000 deaths,

and is characterised by runny nose and

predominantly in infants. Once paroxysms

nonspecific cough;

fully resolve most children have made a

N the subsequent paroxysmal phase lasts

complete recovery although some may

for 1 month and is characterised by

develop bronchiectasis.

paroxysmal cough and often also an

inspiratory whoop and vomit at the end of

Conclusion

paroxysms;

Acute lung infections are extremely common

N the convalescent phase lasts for up to

in children and chronic infections are also

3 months and is characterised by

common. The epidemiology of acute and

paroxysms of shorter and less frequent

chronic infections is a dynamic field where

duration.

incidence changes over time due to variation

in both pathogen and host.

The catarrhal and early paroxysmal phases

are when the individual is highly infectious.

Inspiratory whoop and post-tussive

Further reading

vomiting are not necessarily specific for

pertussis. In one community study of

Celentano LP, et al. (2005). Resurgence of

children aged less than 3 years, these

pertussis in Europe. Pediatr Infect Dis J;

24: 761-765.

symptoms were present in 50% and 70%,

Chang AB, et al.

(2008). Chronic wet

respectively, of cases of pertussis and 25%

cough: protracted bronchitis, chronic

and 40%, respectively, of cases with

suppurative lung disease and bronchiec-

chronic cough but not pertussis. In older

tasis. Pediatr Pulmonol; 43: 519-531.

children with pertussis who had been

Crocker JC, et al.

(2012). Paediatric

vaccinated, less than 15% of cases had

pneumonia or empyema and prior anti-

whoop or vomiting and generally, those

biotic use in primary care: a case-control

children who have been vaccinated

study. J Antimicrob Chemother;

67:

and have pertussis have a less severe

478-487.

illness.

212

ERS Handbook: Paediatric Respiratory Medicine

Harnden A, et al.

(2006). Whooping

Rudan I, et al. Epidemiology and etiology

cough in school age children with persis-

of childhood pneumonia. Bulletin of the

tent cough: prospective cohort study in

World Health Organisation. Vol

86,

primary care. Br Med J; 333: 174-177.

Number 5. 2008. www.who.int/bulletin/

Harris M, et al. (2011). British Thoracic

volumes/86/5/07-048769/en/index.html

Society. Guidelines for the management

27a. Respiratory syncytial virus. In:

of community acquired pneumonia in

Salisbury D. et al., eds. Immunisation

children: update 2011. Thorax; 66: Suppl.

against infectious disease. London,

2, ii1-ii23.

Department of Health, 2013.

Kuehni CE, et al.

(2009). Causal links

Scottish

Intercollegiate

Guidelines

between RSV infection and asthma: no

Network. Guideline 91. Bronchiolitis in

clear answers to an old question. Am J

children: a national clinical guideline.

Respir Crit Care Med; 179: 1079-1080.

2006. www.sign.ac.uk/pdf/sign91.pdf.

McIntosh K (2002). Community-acquired

Strachan RE, et al. (2011). Bacterial causes

pneumonia in children. N Engl J Med;

of empyema in children, Australia, 2007-

346: 429-437.

2009. Emerg Infect Dis; 17: 1839-1845.

Roxburgh CS, et al.

(2008). Trends in

Yaari E, et al. (1999). Clinical manifesta-

pneumonia and empyema in Scottish

tions of Bordetella pertussis infection in

children in the past 25 years. Arch Dis

immunized children and young adults.

Child; 93: 316-318.

Chest; 115: 1254-1258.

ERS Handbook: Paediatric Respiratory Medicine

213

Microbiology testing and

interpretation

Elpis Hatziagorou, Emmanuel Roilides and John Tsanakas

Respiratory tract infections constitute a

the severity of lower respiratory tract

major health problem, with significant cost

symptoms are more pronounced in

and mortality worldwide. These infections

patients with asthma.

are mainly caused by viruses, bacteria,

Respiratory syncytial virus (RSV) follows a

mycobacteria and fungi.

well-characterised epidemiologic pattern,

with annual outbreaks occurring between

Viral infections

October and May in temperature

climates. At least half of the infant

The majority of childhood lower respiratory

population becomes infected during their

illnesses are caused by viral agents.

first RSV epidemic and almost all children

Technological developments in molecular

have been infected by 2 years of age.

biology show that known respiratory viruses

Three type of influenza virus have been

are more prevalent than previously thought

identified; they are designated A, B and C.

across the childhood age range.

Parainfluenza virus (PIV)1 and PIV2 are

generally associated with

N Rhinoviruses or ‘‘common cold’’ viruses

laryngotracheobronchitis (croup), URT

are the most prevalent, usually causing

illness and pharyngitis, whereas PIV3 is a

mild disease. Although the severity of

major cause of infant bronchiolitis and is

upper respiratory tract symptoms after

associated with the development of

rhinoviral infection does not differ

pneumonia in susceptible subjects.

between patients with asthma and

Adenoviruses may cause pneumonia,

normal subjects, both the duration and

bronchiolitis or conjunctivitis.

Human coronaviruses may cause milder

lower respiratory tract symptoms than

Key points

other viruses.

Human metapneumovirus (MPV) causes

N Rapid antigen detection and

symptoms ranging from URT disease to

molecular tests are the methods of

severe bronchiolitis and pneumonia.

choice for the identification of viral

MPV is an important cause of RSV-like

infections.

illness.

N Blood culture is positive in ,10% of

Human bocavirus accounts for 1-3% of

paediatric patients with bacterial

lower respiratory tract infection (LRTI) in

LRTIs.

infants.

Viruses may be copathogens and this

N IGRAs are the method of choice

creates difficulties in the case of positive

for discrimination between

results. More recent studies using nucleic

M. tuberculosis, M. bovis and

acid technologies have identified multiple

nontuberculous mycobacteria.

viruses in up to 27% of hospitalised

BAL GM is a reliable test for the

children with LRTI. The presence of more

diagnosis of invasive aspergillosis.

than one virus may result in more severe

or prolonged infection.

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ERS Handbook: Paediatric Respiratory Medicine

It is difficult to determine the optimal

children. Identification can be with either

method for virus detection. Although cell

culture or a rapid antigen detection test,

culture remains the gold standard, it is time-

after a throat swab. Retropharyngeal,

consuming and thus it has been replaced by

parapharyngeal and peritonsillar abscesses

antigen-detecting methods and molecular

have similar microbiology; most are

techniques. Their commercial availability,

polymicrobial infections. In acute otitis

ease of performance and rapidity have made

media, there is acute inflammation with 5%

antigen-based methods increasingly

viral, 75% bacterial and, 20% mixed bacterial

popular. They can be performed within

and viral aetiology. The most common

15 min to a few hours. Antigens of the

organism is Streptococcus pneumoniae. The

common respiratory viruses can be detected

most common causes of sinusitis are S.

by direct immunofluorescence or by

pneumoniae, Haemophilus influenzae and

commercially available enzyme

Moraxella catarrhalis. These organisms,

immunoassays. The sensitivities of these

along with Staphylococcus aureus and S.

tests vary from 50% to 90%. Serological

pyogenes, account for .90% of sinusitis in

methods attempt to detect viruses in the

children. Since the introduction of vaccines

host by assessing the presence of specific

that protect against H. influenzae type b

antibodies in blood, sputum and urine

infection, epiglottitis has become a rare

samples. Identification of the pathogen

disease. Other causative organisms include

responsible for a recent infection may be

nontypable H. influenzae, Haemophilus

achieved through detection of specific IgM

parainfluenzae, S. aureus and S. pneumoniae.

in serum 1 week after symptoms begin, or a

S. aureus is the most common bacterium

four-fold or greater increase in IgG.

causing tracheitis. A significant proportion

However, PCR has been widely used during

of infections are polymicrobial.

the last decade and its clinical use is steadily

Fresh pus, fluid or tissue from the sinuses

increasing. PCR methods allow specific

(obtained by washing, aspiration, biopsy,

amplification of defined DNA sequences to

scraping or debridement), and pharyngeal

a level at which they can subsequently be

swabs from the tonsils and/or the posterior

detected and these tests can be applied to

pharynx are the main upper respiratory tract

any virus for which part of the genome

biological specimens.

sequence is known. Recent developments of

this method include semiquantitation of

Microscopy following Gram staining is

results with the use of specialised

useful for the examination of paranasal

equipment and primers specific for

sinus smears (which are normally sterile),

additional viral and bacterial species,

pharyngeal smears or material from

allowing for the detection of as many as 19

the oral cavity for the detection of

different microorganisms in a clinical

polymorphonuclear neutrophils (PMNs) and

sample. PCR may give quantitative, as well

some microbes (e.g. corynebacteria

as semiquantitative, results. In clinical

(diphtheroids)), and nasopharyngeal smears

practice, we may use any of these tests,

for Bordetella pertussis. Following the

according to their feasibility in the particular

isolation of the pathogen, serologic typing

laboratory.

and antibiotic susceptibility testing are

Bacterial infections

usually performed.

Lower respiratory tract infections are the third

Specimens for bacteriological culture should

most important cause of mortality globally

be collected as soon as possible after the

and are responsible for .4 million deaths

onset of disease and before the initiation of

annually. The aetiology of pneumonia varies

antimicrobial therapy.

based on patient age, vaccination status,

Upper respiratory tract infections Pharyngitis

immunological status and the clinical

includes tonsillitis, tonsillopharyngitis and

setting in which the causative agent was

nasopharyngitis. Streptococcus pyogenes

acquired. Determining the aetiology of

causes 15-30% of acute pharyngitis in

pneumonia is difficult and the choice of

ERS Handbook: Paediatric Respiratory Medicine

215

antimicrobial therapy is often empirical. In

initial antibiotic treatment,

the neonate, the most common causes of

immunocompromised cases or CF.

bacterial pneumonia are group B b-

Recovery of ,10⁴ bacteria per millilitre of

haemolytic streptococci (GBS) and Gram-

BAL is most likely to represent

negative enteric bacilli, such as Escherichia

contamination, while .10⁵ bacteria per

coli and Klebsiella pneumoniae. S.

millilitre is indicative of active infection.

pneumoniae is the most common bacterial

aetiology of community-acquired

Antigen detection in blood and urine has a

pneumonia in all age groups, including

limited role in the diagnosis of bacterial

children. H. influenzae type b was an

pneumonia. The reported sensitivity for the

important cause in the pre-vaccination era

detection of group A streptococci is 60-95%

but is now rare. S. aureus pneumonia is also

but can be as low as 31%. Urine detection of

infrequent but may progress rapidly. In

the polysaccharide antigen C, which is

hospital-acquired pneumonia, Gram-

present in all pneumococcal serotypes, is

negative organisms, such as K. pneumoniae,

performed with the use of an

Pseudomonas and Serratia, and Gram-

immunochromatographic method (Binax,

positive organisms, such as S. aureus, occur

Portland, ME, USA) and has high sensitivity

most frequently.

among children with documented invasive

pneumococcal infection. However, the

N There are .100 pathogens that may

capability of this method to discriminate

infect the lower respiratory tract and

between true pneumococcal disease and

produce secondary bacteraemia.

rhinopharyngeal carriage is questionable

However, blood cultures are positive in

and is not recommended in the recent

only ,10% of paediatric respiratory tract

guidelines for diagnosis of community-

infections.

acquired pneumonia.

N Urine specimens may be used for the

detection of antigens from S. pneumoniae

Serological methods are also used for the

and Legionella.

diagnosis of pathogens responsible for

N Candidate lower respiratory tract

atypical pneumonias but are rarely used in

specimens for processing include

clinical practice for the diagnosis of bacterial

sputum (noninvasive), bronchoalveolar

pneumonia. A four-fold rise in titre or a titre

lavage (BAL) (invasive) and pleural fluid

greater than 1:32 in convalescent serum is

(via thoracentesis) (invasive).

diagnostic (sensitivity 80-95% and 60%,

respectively). ELISA for IgM detection may

Macroscopic and microscopic examination

diagnose infection using only one sample if

of a lower respiratory tract specimen (i.e.

this is collected after the 10th day of illness.

sputum or BAL fluid) gives valuable

information. The appearance, colour,

Nucleic acid persists in specimens after the

consistency (e.g. purulent, mucoid, serous

initiation of treatment, and may be detected

or bloody), quantity, odour and presence of

in smaller and noninvasive specimens. PCR

visible formations in lower respiratory tract

using blood or pleural fluid specimens is

specimens should all be considered. Direct

mainly applied for the detection of S.

examination of the specimen with Gram

pneumoniae and H. influenzae, with the

staining along with compatible

sensitivity and specificity of the method

symptomatology is sensitive in only 10% of

depending on the specimen. Detection of

cases but has a specificity of 70-80%. As it

bacterial antigens in pleural fluid is

is an easy, cheap and fast method that

potentially useful in the diagnosis of

provides information within 1 h, microscopy

empyema.

allows proper diagnosis and treatment of

A variety of nonspecific laboratory

LRTI.

evaluations have been used to support the

Culture for the identification of the

diagnosis of bacterial pneumonia; these

responsible organism and susceptibility

include an increased serum concentration of

testing are useful in the case of resistance to

C-reactive protein, an increased erythrocyte

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ERS Handbook: Paediatric Respiratory Medicine

sedimentation rate and an increased blood

later). In general, the TST should be

leukocyte count with a predominance of

interpreted in the same way for patients who

polymorphonuclear leukocytes. However, all

have or have not received a BCG

these techniques suffer from poor sensitivity

vaccination; however, this will lead to some

and positive predictive values.

children with false-positive TST results being

treated.

The diagnosis of empyema is strongly

supported by the presence of thick pus with

IFN-c release assays The identification of

bacteria demonstrable by Gram staining, a

genes in the M. tuberculosis genome that are

pH ,7.3 or a glucose concentration

absent from those of the Mycobacterium

,60 mg?dL^-1. The average white blood count

bovis BCG vaccine and most nontuberculous

in empyema fluid is 19 000 cells per cubic

mycobacteria has supported the

millimetre. These findings may be variably

development of more specific and sensitive

present and must be interpreted in their

tests for detection of M. tuberculosis. IGRAs

clinical context.

are designed to measure the host immune

response to M. tuberculosis rather than the

Mycobacterial infections

presence of the organism itself. In persons

with M. tuberculosis infection, sensitised

TB is the most prevalent chronic infection in

memory/effector T-cells produce IFN-c in

the world, with two-thirds of the global

response to M. tuberculosis antigens, which

population infected. Most infection is

is the biological basis for IGRAs. Available

asymptomatic (latent TB infection (LTBI)).

data suggest that the TST and IGRAs have

In adults and older children, reactivation of

similar accuracy for the detection of M.

LTBI causes active pulmonary TB disease in

tuberculosis infection or the diagnosis of

,10% of individuals. A variety of specimens

active TB in children. Use of M. tuberculosis-

can be collected, including sputum,

specific antigens leads to greater specificity

induced sputum, gastric aspirate, BAL,

(.90%), which decreases the probability of

transbronchial biopsy, urine, blood,

false-positive responses, particularly in

cerebrospinal fluid, tissue and other body

young, BCG-vaccinated children. Although

fluids. Gastric aspirates are frequently

the direct cost of IGRAs is greater than that

obtained, as children cannot easily produce

of the TST, IGRAs may be cost effective in

sputum. Mycobacterium tuberculosis may be

cases where there is difficulty in interpreting

recovered from gastric aspirates in almost

a TST or where the clinical index of

40% of children with radiographic evidence

suspicion is high but the TST is negative.

of significant pulmonary TB. The culture

yields are as high as 70% in infants with TB.

Tests for the detection of M. tuberculosis

infection, such as IGRAs and the TST, are

Tuberculin skin test The tuberculin skin test

most helpful as adjunctive tests to confirm

(TST) remains the most widely employed

disease in a patient with a high probability of

test for the diagnosis of TB and LTBI in

active disease. The likelihood that a positive

children. The sensitivity and specificity of

TST represents true infection (positive

the TST are significantly affected by a

predictive value) increases as the prevalence

number of factors. The tuberculin reaction

of infection with M. tuberculosis increases in

should be read 48-72 h following injection.

that population. The same is true for IGRAs.

A number of factors have been associated

Interpretation of the TST reaction is based

with false-positive tuberculin reactions and

on risk of infection.

decreased TST specificity. The TST has the

lowest sensitivity in younger children. There

Staining and microscopic examination of

is no reliable method of distinguishing

sputum or BAL fluid Acid-fast staining using

bacille Calmette-Guérin (BCG)-induced TST

the Ziehl-Neelsen technique and

cross-reactivity from TST reactivity

microscopic examination are the easiest,

secondary to mycobacterial infection;

quickest and least expensive diagnostic

interferon (IFN)-c release assays (IGRAs)

procedures. There must be 5000-10 000

have the ability to make this distinction (see

bacilli present per millilitre of specimen to

ERS Handbook: Paediatric Respiratory Medicine

217

allow detection of the bacteria in stained

N a positive TST or IGRA result; and

smears, resulting in low sensitivity rates in

N a history of contact with an infectious TB

children.

case within the past year.

Culture for mycobacteria, identification and

Fungal infections

susceptibility testing Culture is the most

important laboratory test for the diagnosis

Filamentous fungi of the genus Aspergillus

and management of TB. Mycobacterial

may cause transient asymptomatic

culture from gastric aspirates has provided a

colonisation, pulmonary hypersensitivity

more useful method of diagnosis in children

reactions, saprophytic colonisation of

with suspected pulmonary TB. The role of

pathological airway structures, and life-

bronchoscopy in evaluating children with

threatening tissue invasive infections

pulmonary TB is controversial. Cultures

predominantly of the lung with or without

from BAL fluid in children with suspected

dissemination in patients with congenital or

pulmonary TB has a low yield and does

acquired deficiencies in host defences. Most

not significantly aid bacteriological

cases of human disease are caused by

confirmation. In three studies evaluating the

Aspergillus fumigatus, followed by Aspergillus

role of bronchoscopy, only 13-62% of

flavus and, less commonly, Aspergillus

cultures in children with pulmonary TB were

nidulans, Aspergillus niger and Aspergillus

positive. Bronchoscopy can be useful to

terreus. Hypersensitivity reactions caused by

define anatomy, bronchial obstruction or

Aspergillus spp. mainly include allergic

clarify the diagnosis but it cannot be

bronchopulmonary aspergillosis (ABPA).

recommended solely to collect culture

Bronchopulmonary colonisation occurs in

specimens in children. In high-risk groups,

patients with asthma, bronchiectasis, CF

such as those patients with

and primary ciliary dyskinesia syndrome.

immunodeficiency, where a positive

Invasive pulmonary aspergillosis is the

diagnosis is needed and TSTs are often

most frequent entity. In severely

falsely negative, bronchoscopy can be

immunocompromised patients, a variety of

useful.

fungi can cause invasive sinopulmonary

disease, including the zygomycetes,

Detection of mycobacterial nucleic acid Direct

Fusarium spp. and Pseudallescheria boydii.

detection of the DNA of M. tuberculosis in

clinical samples has been performed using

Routine methods for rapid specific

nucleic acid amplification, most often by

identification of Aspergillus spp. are generally

PCR. When compared with the clinical

not available. The current diagnostic

diagnosis of pulmonary TB in children, the

markers for invasive aspergillosis include

sensitivity of PCR for sputum or gastric

conventional and more recent methods

aspirates has varied from 25% to 83% and

under evaluation. Recently, more rapid and

the specificity from 80% to 100%. A

sensitive methods have been developed, for

negative PCR never eliminates TB as a

example, the detection of antigenic markers,

diagnostic possibility, nor does a positive

such as galactomannan and b-1,3-D-glucan,

result completely confirm it. The major use

and the detection of molecular markers of

for PCR in children may be when the

Aspergillus DNA by PCR.

diagnosis of TB is not readily established on

Staining and microscopic examination of

clinical and epidemiological grounds, and

sputum or BAL fluid, and culture for fungi and

perhaps for children with HIV infection for

identification Conventional methods of

whom a greater variety of causes of

diagnosis include direct microscopy and

pulmonary disease must be considered.

histology, and culture of respiratory and

The gold standard for diagnosis of

various fluids and tissues. While microscopy

childhood tuberculosis is a triad of:

and culture obtained from the clinically

affected site remain the gold standard,

N abnormal chest radiograph and/or clinical

technical problems in obtaining an

findings consistent with TB;

appropriate specimen, the time of culture

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ERS Handbook: Paediatric Respiratory Medicine

and negative results all limit an efficient and

consecutive positive samples were 0.75

rapid diagnosis; similarly, the diagnostic

(95% CI 0.54-0.88) and 0.87 (95% CI 0.78-

yield of histology is unsatisfactory, with an

0.93), respectively. A similar meta-analysis

approximate sensitivity of 50%. Histological

evaluating PCR with BAL fluid revealed a

diagnosis requires invasive methods that are

sensitivity of 0.91 (95% CI 0.79-0.96) and

often difficult in children and are nonspecific

specificity of 0.92 (95% CI 0.87-0.96). For

for speciation. Although Aspergillus can

paediatric patients, data concerning DNA

colonise the respiratory tract, its isolation

detection of Aspergillus spp. with different

from sputum of BAL fluid in an

PCR techniques are lacking.

immunocompromised patient with

The galactomannan test can be used in

pneumonia is highly suggestive of invasive

children with caution. Molecular markers

disease.

such as PCR present the same problems and

Given this background, detection of fungal

difficulties as in adults. While progress has

cell wall antigens and DNA in blood and

been achieved in terms of galactomannan

other tissues may enhance the diagnosis of

and certain recommendations have been

invasive aspergillosis.

made, further research is needed for the

validation of newer diagnostic procedures in

Galactomannan assay in serum and BAL fluid

paediatric patients.

A serologic assay to detect galactomannan,

a molecule found in the Aspergillus cell wall,

Further reading

is commercially available for diagnosing

invasive disease but most data refer to

Balfour-Lynn IM, et al. (2005). BTS guide-

adults. The galactomannan assay also has

lines for the management of pleural

high diagnostic utility for analysis of BAL

infection in children. Thorax; 60: Suppl.

fluid of paediatric patients with suspected

1, i1-i21.

pulmonary aspergillosis. The presence of

Bradley JS, et al. (2011). Executive sum-

galactomannan in BAL fluid (BAL GM) is an

mary: the management of community-

alternative serological diagnostic marker,

acquired pneumonia in infants and chil-

especially for invasive pulmonary

dren older than 3 months of age: clinical

aspergillosis, which constitutes the most

practice guidelines by the Pediatric

common presentation of invasive

Infectious Diseases Society and the

Infectious Diseases Society of America.

aspergillosis. False-positive tests occur

Clin Infect Dis; 53: 617-630.

more commonly in children than adults and

Chi XS, et al.

(2007). Semiquantitative

a negative test does not exclude the

one-step RT-PCR for simultaneous identi-

diagnosis. The reported sensitivity of BAL

fication of human influenza and respira-

GM is in general higher than that in serum

tory syncytial viruses. J Virol Methods; 139:

due to the increased fungal burden in the

90-92.

bronchi of patients with pulmonary invasive

de Mol M, et al. (2012). Diagnosis of

aspergillosis. However, the role of BAL GM

invasive pulmonary aspergillosis in chil-

in paediatric invasive aspergillosis has not

dren with bronchoalveolar lavage galac-

been extensively evaluated. A recent

tomannan. Pediatr Pulmonol

[In press

retrospective study conducted by Desai et al.

DOI: 10.1002/ppul.22670].

(2009) suggests that BAL GM is a valuable

Desai R, et al.

(2009). The role of

adjunctive diagnostic tool.

bronchoalveolar lavage galactomannan

in the diagnosis of pediatric invasive

Detection of fungal nucleic acid PCR

aspergillosis. Pediatr Infect Dis; 28: 283-

represents one of the most investigated

286.

rapid diagnostic methods with clinical utility

Deuffic-Burban S, et al.

(2010). Cost-

for invasive aspergillosis. A recent meta-

effectiveness of QuantiFERON-TB test

analysis of the use of PCR with blood, serum

vs. tuberculin skin test in the diagnosis

or plasma samples for the detection of

of latent tuberculosis infection. Int J

invasive aspergillosis reported that the

Tuberc Lung Dis; 14: 471-481.

sensitivity and specificity for two

ERS Handbook: Paediatric Respiratory Medicine

219

Doan Q, et al. (2012). Rapid viral diagnosis

Harris M, et al. (2011). British Thoracic

for acute febrile respiratory illness in

Society guidelines for the management of

children in the emergency department.

community acquired pneumonia in chil-

Cochrane Database Syst Rev; 5: CD006452.

dren: update 2011. Thorax; 66: Suppl. 2,

Esposito S, et al. (2004). Evaluation of

ii1-ii23.

rapid assay for detection of Streptococcus

Henrickson KJ, et al.

(2007). Diagnostic

pneumoniae urinary antigen among

assays for respiratory syncytial virus disease.

infants and young children with possible

Pediatr Infect Dis J 26: Suppl., S36-S40.

invasive pneumococcal disease. Pediatr

Lehrnbecher T, et al. (2011). Invasive fungal

Infect Dis J; 23: 365-367.

infections in the pediatric population.

Getahun H, et al.

(2012). Prevention,

Expert Rev Anti Infect Ther; 9: 275-278.

diagnosis, and treatment of tuberculosis

Newton SM, et al.

(2008). Paediatric

in children and mothers: evidence for

tuberculosis. Lancet Infect Dis; 8: 498-510.

action for maternal, neonatal, and child

Roilides E, et al.

(2012). Application of

health services. J Infect Dis; 205: Suppl. 2,

diagnostic markers to invasive aspergillo-

S216-S227.

sis in children. Ann NY Acad Sci; 1272: 1-8.

220

ERS Handbook: Paediatric Respiratory Medicine

Immunisation against

respiratory pathogens

Horst von Bernuth and Philippe Stock

Acute lower respiratory tract infection (ALRI)

Key points

is still the leading cause of global child

mortality. ALRI caused by Streptococcus

pneumoniae, a Gram-positive bacterium, and

The natural course of RSV infection

respiratory syncytial virus (RSV), an

can be modified by passive

enveloped single-stranded RNA

immunisation with neutralising

paramyxovirus, and their prevention by

antibodies by monthly intramuscular

vaccination will be addressed here.

administrations of Palivizumab, a

humanised monoclonal IgG1 antibody

RSV infection

directed against the F-protein of RSV.

Epidemiology and risk factors RSV infects

There is broad agreement that

99% of all children by the age of 2 years,

prematurely born children with

with an estimate of 66 000-199 000 deaths

chronic lung disease in infancy and

being associated with RSV worldwide, 99%

children with haemodynamically

of these occurring in developing countries.

relevant heart disease during the first

Generally accepted independent risk factors

2 years of life may benefit from

for severe RSV infection requiring

passive immunisation against RSV.

hospitalisation are 1) prematurity and 2) age

Serious (in particular invasive)

,6 months at the start of RSV season

pneumococcal diseases can be

(ranging from October to March or

avoided by active immunisation with

November to April). Other risk factors are:

either polysaccharide-protein

male sex, haemodynamically significant

conjugate vaccines during the first 2

congenital heart defects, chronic lung

years of life or with 23-valent

disease (CLD) of prematurity (formerly

pneumococcal polysaccharide vaccine

called bronchopulmonary dysplasia), Down

after the first 2 years of life.

syndrome, presence of elder siblings/

Active immunisation against

residential crowding and exposure to

S. pneumoniae serotypes is highly

environmental tobacco smoke. Additional

recommended.

risk factors for RSV infection are

malformations, neuromuscular disease, liver

disease, chromosomal abnormalities,

congenital immunodeficiencies and inborn

required, or live attenuated vaccines even

errors of metabolism. For a comprehensive

led to vaccine-primed disease enhancement,

review of risk factors predisposing to RSV

which is unacceptable for children at risk.

infection, see Sommer et al. (2011).

However, the natural course of RSV infection

Immunisation The development of RSV

can be modified by passive immunisation

vaccines to actively immunise the host has

with neutralising antibodies by monthly

not yet led to satisfying results. In summary,

intramuscular administrations of Palivizu-

either the immune responses were weak or

mab, a humanised monoclonal IgG₁ antibody

short lasting, repetitive immunisation was

directed against the F-protein of RSV.

ERS Handbook: Paediatric Respiratory Medicine

221

Palivizumab was originally approved for the

Palivizumab is recommended only for

prophylactic treatment of infants born

infants younger than 12 months with severe

prematurely (before 35 weeks of gestation)

CLD or with haemodynamically significant

and for the prophylactic treatment of children

heart disease and additional risk factors. In

up to 2 years of age treated for CLD of

contrast, the Austrian guidelines

prematurity ,6 months before the

recommend the use of Palivizumab for all

anticipated RSV season. This

children 1) born prematurely below the age

recommendation was based on a double-

of 24 months with CLD, 2) born prematurely

blind, placebo-controlled, multicentre,

at ,28 weeks plus 6 days of gestation below

multinational trial mainly conducted in

the age of 12 months, 3) born prematurely at

northern America in which 10% of children

29-32 weeks plus 6 days of gestation and

with RSV infection born before the 35 weeks

with certain risk factors, 4) born prematurely

of gestation were hospitalised. Approval was

at 33-35 weeks plus 6 days of gestation

later extended to children ,2 years of age

below the age of 3 months at the beginning

with pulmonary hypertension, relevant left-

of the RSV season and with certain other risk

right or right-left shunting, and pulmonary

factors, 5) with haemodynamically

venous congestion.

significant heart disease below the age of

24 months, 6) with diseases of the

Given the high costs of passive

respiratory tract below 24 months (e.g. CF),

immunisation with Palivizumab, and the

7) with ‘‘floppy infant syndrome’’ below the

fact that Palivizumab never proved to lower

age of 24 months, 8) with inborn or acquired

RSV-associated mortality but only protects a

immunodeficiencies below the age of

subpopulation of patients from

24 months. Given the lack of evidence for

rehospitalisation, passive immunisation

the effectiveness of passive immunisation

against RSV remains a highly debated public

against RSV for many conditions, recent

health issue, as the costs of passive

recommendations of the American Academy

vaccination of large populations should be

of Pediatrics (AAP) seek an optimal balance

lower than the costs of rehospitalisation of

of benefit and cost for this intervention. In

patients with RSV infection. The number of

general, three major groups of infants that

patients needed to treat (NNT) to avoid

may benefit from Palivizumab are

rehospitalisation depends on the baseline

addressed. In infants and children younger

rehospitalisation rate without RSV

than 24 months with CLD who receive

prophylaxis, a number that depends strongly

medical therapy and infants born before

on the proportion of children developing

32 weeks of gestation, a maximum of five

CLD. If the basal proportion of prematurely

doses of Palivizumab (15 mg?kg^-1?month^-1

born children with CLD is lower, the

during the RSV season) is recommended for

rehospitalisation rate due to RSV is lower

infants within these two groups. A third

than published by the Impact trial in 1999

major group is defined as infants born at 32

(mainly the USA and Canada) and the NNT

to ,35 weeks of gestation. The usefulness of

will be higher than originally proposed in

Palivizumab in this group strongly depends

1999 for a cohort comprising almost 50%

on the presence of additional risk factors. If

prematurely born children with CLD.

two of these risk factors are present, a

Notably, national guidelines for prophylaxis

maximum of three doses of Palivizumab

with Palivizumab differ substantially. This

should be administered. For details, see the

can be exemplified by comparing the Swiss

AAP recommendations.

and Austrian recommendations. Although it

is rather unlikely that the Swiss and Austrian

In summary, almost 15 years after approval

populations differ significantly in 1) ethnic or

of passive immunisation against RSV,

genetic background, 2) risk factors for

recommendations are still mainly based on

severe RSV infections, or 3) rehospitalisation

a single multinational, randomised, placebo-

rates due to RSV infection, the Swiss

controlled trial for prematurely born children

recommendations are more restrictive than

and on a single multinational, randomised,

the Austrian guidelines. In Switzerland,

placebo-controlled trial for children with

222

ERS Handbook: Paediatric Respiratory Medicine

congenital heart disease. According to

individual disease and infections of others.

medical as well as economic criteria, there is

As pneumococcal resistance to

broad agreement that prematurely born

antimicrobial agents is a growing problem in

children with CLD in infancy and children

all age groups, active vaccination is the

with haemodynamically relevant heart

most promising strategy to prevent

disease during the first 2 years of life may

pneumococcal diseases worldwide.

benefit from passive immunisation against

Immunisation Current vaccines use bacterial

RSV. Still, many guidelines recommend the

capsular polysaccharides. These induce

use of Palivizumab for children born

serotype-specific antibodies that activate

,28 weeks of gestation regardless of

and fix complement, and promote bacterial

additional risk factors - an approach that is

opsonisation and phagocytosis. The 23-

at least debated, if not highly controversial.

valent pneumococcal polysaccharide

Conclusion Given the aforementioned

vaccine (PPV23) is based on purified

unresolved public health issue on who will

polysaccharide and was introduced in 1983.

best benefit from passive ‘‘vaccination’’

The heptavalent polysaccharide-protein

against RSV, we consider the

conjugate vaccine (PCV7) is based on seven

recommendations of the AAP as an

capsular polysaccharides covalently

acceptable compromise.

conjugated to a protein carrier and was

introduced in 2000. Recently, two further

Pneumococcal pneumonia

PCVs were introduced, PCV10 and PCV13.

Epidemiology and risk factors S. pneumoniae

PPV23 elicits antibody responses in 60-80%

leads to substantial morbidity and mortality

of children older than 2 years after a single

in children with an estimated 10 million

intramuscular injection. PPV23 is not

deaths per year worldwide, particularly in

sufficiently immunogenic in children

developing countries. The most common

form of the disease is bacteraemic

,2 years of age: it does not prevent mucosal

pneumococcal pneumonia, which shows

colonisation and does not elicit

peaks of incidence below 2 years of age and

immunological memory. The clinical

above 65 years of age. In developed

effectiveness of PPV23 in children between 6

countries, S. pneumoniae in adults is a

and 24 months of age for the prevention of

common cause of community-acquired

pneumococcal diseases is limited. PCVs, in

pneumonia, while in children in developed

contrast, are sufficiently immunogenic in

countries, S. pneumoniae is a leading cause

children ,2 years of age after three or four

of invasive bacterial diseases (IPDs)

intramuscular injections. PCVs elicit

(notably meningitis and sepsis). The annual

immunological memory and prevent

overall European incidence of IPD in

nasopharyngeal colonisation, thus

children aged ,2 years is estimated to be 44

promoting herd immunity. This has

cases per 100 000 population. Children with

probably led to an even more substantial

an increased risk of pneumococcal diseases

decrease in pneumococcal diseases in the

are those born prematurely, and those with

elderly than in the vaccinees. Since the

sickle cell disease, cochlear implants and

introduction of PCVs in 2000, vaccine

cerebrospinal fistulae, HIV infection,

efficacy has been shown to be 77-97% for

secondary loss of the spleen, or primary

the avoidance of IPD and 19-37% for the

immunodeficiencies due to either a defect in

avoidance of pneumococcal pneumonia.

opsonisation, phagocytosis of opsonised

PCVs also proved beneficial in HIV-infected

bacteria or in Toll-like receptor signalling.

children for both the prevention of IPD and

There are 40 serogroups and 91 serotypes of

pneumococcal pneumonia. Active

S. pneumoniae, and 20 of these account for

vaccination against S. pneumoniae is

.70% of IPD occurring in all age groups.

beneficial not only from the individual,

The only natural reservoir of S. pneumoniae

medical point of view but also from the

is the human nasopharynx, and colonisation

socioeconomic point of view. The saved

of the nasopharynx is a prerequisite for both

costs by reduced morbidity and mortality

ERS Handbook: Paediatric Respiratory Medicine

223

outweigh the costs of vaccination,

American Academy of Pediatrics

regardless of the epidemiological

Committee on Infectious Diseases, et al.

background and the price of the vaccine. The

(2003). Revised indications for the use of

socioeconomic benefit will most likely be

palivizumab and respiratory syncytial

even higher if PCV13 is directly introduced,

virus immune globulin intravenous for

the prevention of respiratory syncytial

whereas the benefit may be less obvious if

virus infections. Pediatrics;

112:

1442-

PCV13 replaces PCV7. The obvious current

1446.

success of PCV7 has been shadowed by

Black S, et al. (2000). Efficacy, safety and

concerns about serotype replacement.

immunogenicity of heptavalent pneumo-

Recent studies confirmed that serotypes not

coccal conjugate vaccine in children.

contained in PCV7 not only repopulate the

Northern California Kaiser Permanente

niche in the human nasopharynx but may

Vaccine Study Center Group. Pediatr

also cause pneumococcal diseases (e.g.

Infect Dis J; 19: 187-195.

serotype 19A). The challenge of serotype

Bliss SJ, et al. (2008). The evidence for

replacement has partly been met by the

using conjugate vaccines to protect HIV-

introduction of PCV10 and PCV13 vaccines

infected children against pneumococcal

comprising more serotypes. However, the

disease. Lancet Infect Dis; 8: 67-80.

approach to overcoming serotype

Bloemers BL, et al. (2007). Down syn-

replacement by introducing more and more

drome: a novel risk factor for respiratory

serotypes in one vaccine is limited

syncytial virus bronchiolitis - a prospec-

tive birth-cohort study. Pediatrics;

120:

technically. Thus, it may become necessary

e1076-e1081.

to change the strategy by vaccinating

Blount RE Jr, et al. (1956). Recovery of

against stable cell surface virulence

cytopathogenic agent from chimpanzees

protein(s), such as pneumolysin and

with coryza. Proc Soc Exp Biol Med; 92:

pneumococcal surface protein A, which are

544-549.

shared by many pneumococcal serotypes.

Carbonell-Estrany X, et

al.

(2001).

Hospitalization rates for respiratory syn-

Conclusion We strongly recommend active

cytial virus infection in premature infants

immunisation against S. pneumoniae

born during two consecutive seasons.

serotypes with PCVs during the first 2 years

Pediatr Infect Dis J; 20: 874-879.

of life as active immunisation will avoid a

Chang J

(2011). Current progress on

significant number of serious pneumococcal

development of respiratory syncytial virus

diseases.

vaccine. BMB Rep; 44: 232-237.

Choi YH, et al.

(2012). Mathematical

modelling long-term effects of replacing

Further reading

Prevnar7

with Prevnar13

on invasive

Aebi C, et al.

(2004). Konsensus

pneumococcal diseases in England and

Statement

zur

Praevention

von

Wales. PLoS One; 7: e39927.

Respiratory

Syncitial

Virus

(RSV)-

Collins PL, et al.

(2011). Progress in

Infektionen mit dem humanisierten

understanding and controlling respiratory

monoklonalen Antikoerper Palivizumab

syncytial virus: still crazy after all these

(Synagis) [Consensus statement on the

years. Virus Res; 162: 80-99.

prevention of respiratory syncytial virus

Colosia AD, et al.

(2012). Residential

(RSV) infection with the humanised

crowding and severe respiratory syncytial

monoclonal

antibody

palivizumab

virus disease among infants and young

(Synagis)]. Paediatrica; 15: 12-16.

children: a systematic literature review.

American Academy of Pediatrics

BMC Infect Dis; 12: 95.

Committee on Infectious Diseases, et al.

(1998). Prevention of respiratory syncytial

(2009). Modified recommendations for

virus infections: indications for the use of

use of palivizumab for prevention of

palivizumab and update on the use of

respiratory syncytial virus infections.

RSV-IGIV. Pediatrics; 102: 1211-1216.

Pediatrics; 124: 1694-1704.

224

ERS Handbook: Paediatric Respiratory Medicine

DiFranza JR, et al.

(2012). Systematic

Liu L, et al. (2012). Global, regional, and

literature review assessing tobacco

national causes of child mortality: an

smoke exposure as a risk factor for

updated systematic analysis for 2010 with

serious respiratory syncytial virus disease

time trends since

2000. Lancet;

379:

among infants and young children. BMC

2151-2161.

Pediatr; 12: 81.

McIntyre PB, et al.

(2012). Effect of

Doering G, et al. (2006). L The risk of

vaccines on bacterial meningitis world-

respiratory syncytial virus-related hospita-

wide. Lancet; 380: 1703-1711.

lizations in preterm infants of 29 to 35

Mehr S, et al.

(2012). Streptococcus

weeks’ gestational age. Pediatr Infect Dis J;

pneumoniae - a review of carriage, infec-

25: 1188-1190.

tion, serotype replacement and vaccina-

Feltes TF, et al.

(2003). Palivizumab

tion. Paediatr Respir Rev; 13: 258-264.

prophylaxis reduces hospitalization due

Muhammad RD, et al.

(2012).

to respiratory syncytial virus in young

Epidemiology of invasive pneumococcal

children with hemodynamically signifi-

disease among high-risk adults since the

cant congenital heart disease. J Pediatr;

introduction of pneumococcal conjugate

143: 532-540.

vaccine for children. Clin Infect Dis; 56:

Frist B, et al. (2009). Time for renewed

e59-e67.

global action against childhood pneumo-

Nair H, et al. (2010). Global burden of

nia. Lancet; 374: 1485-1486.

acute lower respiratory infections due to

Gray DM, et al.

(2010). Community-

respiratory syncytial virus in young chil-

acquired pneumonia in HIV-infected chil-

dren: a systematic review and meta-

dren: a global perspective. Curr Op Pulm

analysis. Lancet; 375: 1545-1555.

Med; 16: 208-216.

O’Brien KL, et al.

(2009). Burden of

Grijalva CG, et al.

(2007). Decline in

disease caused by Streptococcus pneumo-

pneumonia admissions after routine

niae in children younger than

5 years:

childhood immunisation with pneumo-

global estimates. Lancet; 374: 893-902.

coccal conjugate vaccine in the USA: a

O’Brien KL, et al.

(2003). Efficacy and

time-series analysis. Lancet;

369: 1179-

safety of seven-valent conjugate pneumo-

1186.

coccal vaccine in American Indian chil-

Groothuis JR, et al.

(1988). Respiratory

dren: group randomised trial. Lancet; 362:

syncytial virus infection in children with

355-361.

bronchopulmonary dysplasia. Pediatrics;

Oesterreichische Gesellschaft fuer Kinder

82: 199-203.

und Jugendheilkunde

(OeGKJ) (2008).

Hall CB, et al.

(2009). The burden of

Konensuspapier zur Prophylaxe der RSV-

respiratory syncytial virus infection in

Infektion mit Palivizumab und Post-RSV-

young children. N Engl J Med; 360: 588-

Stemwegserkrankungen

[Consensus

598.

paper on prophylaxis of RSV infection

Initiative for Vaccine Research. Acute

with palivizumab and post-RSV respira-

Respiratory Infections. www.who.int/vac-

tory disease]. Monatsschr Kinderheilkd;

cine_research/diseases/ari/en/index3.html

156: 381-383.

Date last accessed: June 7, 2013. Date last

Oosterhuis-Kafeja F, et al.

(2007).

updated: September 2009.

Immunogenicity, efficacy, safety and

Kristensen K, et al.

(2012). Chronic

effectiveness of pneumococcal conjugate

diseases, chromosomal abnormalities,

vaccines (1998-2006). Vaccine; 25: 2194-

and congenital malformations as risk

2212.

factors for respiratory syncytial virus

Picard C, et al. (2012). Clinical features

hospitalization:

a population-based

and outcome of patients with IRAK-4 and

cohort study. Clin Infect Dis; 54: 810-817.

MyD88 deficiency. Medicine; 89: 403-425.

Kristensen K, et al. (2009). Risk factors

Picard C, et al. (2003). Primary immuno-

for respiratory syncytial virus hospitalisa-

deficiencies associated with pneumococ-

tion in children with heart disease. Arch

cal disease. Curr Op Allergy Clin Immunol;

Dis Child; 94: 785-789.

3: 451-459.

ERS Handbook: Paediatric Respiratory Medicine

225

Schutze GE, et al.

(2002). Invasive

syncytial virus monoclonal antibody,

pneumococcal infections in children with

reduces hospitalization from respiratory

asplenia. Pediatr Infect Dis J; 21: 278-282.

syncytial virus infection in high-risk

Scott P, et al. (2011). Comparing pneu-

infants. Pediatrics; 102: 531-537.

mococcal conjugate vaccine schedules

van Hoek AJ, et al.

(2012). The cost-

based on

and

primary doses:

effectiveness of a 13-valent pneumococcal

systematic

review

and meta-analysis.

conjugate vaccination for infants in

Vaccine; 29: 9711-9721.

England. Vaccine; 30: 7205-7213.

Simon A, et al.

(2007). Respiratory

Wang EE, et al.

(1995). Pediatric

syncytial virus infection in 406 hospita-

Investigators Collaborative Network on

lized premature infants: results from a

Infections in Canada (PICNIC) prospec-

prospective German multicentre data-

tive study of risk factors and outcomes in

base. Eur J Pediatr; 166: 1273-1283.

patients hospitalized with respiratory

Sinha A, et al. (2007). Cost-effectiveness

syncytial viral lower respiratory tract

of pneumococcal conjugate vaccination

infection. J Pediatr; 126: 212-219.

in the prevention of child mortality: an

Watson DA, et al. (1993). A brief history of

international economic analysis. Lancet;

the pneumococcus in biomedical

369: 389-396.

research: a panoply of scientific discov-

Sommer C, et al. (2011). Risk factors for

ery. Clin Infect Dis; 17: 913-924.

severe respiratory syncytial virus lower

Wilkesmann A, et al. (2007). Hospitalized

respiratory tract infection. Open Microbiol

children with respiratory syncytial virus

J; 5: 144-154.

infection and neuromuscular impairment

Song JH, et al. (2012). The relationship

face an increased risk of a complicated

between pneumococcal serotypes and

course. Pediatr Infect Dis J; 26: 485-491.

antibiotic resistance. Vaccine; 30: 2728-

Williams TN, et al. (2009). Bacteraemia

2737.

in Kenyan children with sickle-cell anae-

The IMpact-RSV Study Group

(1998).

mia: a retrospective cohort and case-

Palivizumab, a humanized respiratory

control study. Lancet; 374: 1364-1370.

226

ERS Handbook: Paediatric Respiratory Medicine

Upper respiratory tract

infections

Rossa Brugha, Chinedu Nwokoro and Jonathan Grigg

The upper respiratory tract (URT) lies cranial

due to respiratory infections. URTIs make up

to the thoracic inlet and comprises the nose

95% of these infections. Preschool children

(in continuity with the sinuses and the

have six to eight URTIs per year. The vast

lacrimal sac) and nasopharynx, the mouth

majority of URTIs are self-limiting viral

and oropharynx (in continuity with the

infections. Human rhinovirus is the most

middle ear via the Eustachian tube), and the

common causative organism (,40% of

larynx and laryngopharynx. The respiratory

infections), and respiratory syncytial virus,

role of the URT is three-fold.

influenza, parainfluenza and adenovirus are

among the numerous (,200) viruses

N To warm inspired air before it reaches the

associated with infections throughout the

lungs.

URT (table 1).

N To trap and remove inhaled particles that

may irritate the respiratory epithelium

This chapter will outline clinical features and

(dust, smoke or organic matter such as

the management of common URTIs,

pollen).

alongside important rarer infections, rare

N To perform innate and adaptive immune

complications of common infections, and

responses against inhaled pathogens.

important differential diagnoses.

The URT is also responsible for phonation

Common cold or ‘‘viral rhinitis’’

and for preparing food and fluids for

digestion. URT infections (URTIs) are the

Common colds are self-limiting viral

most common human malady (Johnston,

illnesses involving the nasal mucosa, and

2005). For example, in the UK, one quarter

are experienced annually by the majority of

of the population visit their doctor every year

individuals.

Clinical features Inflammation of the nasal

epithelium (rhinitis) leads to a mucous or

Key points

muco-purulent discharge (coryza). There

may be associated sneezing, cough and/or

N The majority of upper respiratory tract

fever. A ‘‘cold’’ is a diagnosis of exclusion: if

infections are viral in aetiology and

there are symptoms associated with

self limiting.

adjacent structures (such as sore throat or

Consider epiglottitis or bacterial

mid-facial sinus pain) then the diagnosis will

tracheitis in a child with stridor who

be ascribed to inflammation at that site

looks unwell.

(tonsillitis/pharyngitis or rhinosinusitis) as a

matter of convention.

N Decisions regarding antibiotics for

otitis media and tonsillitis are difficult

Management Treatment is support

and involve pros and cons for the

(antipyretics) and reassurance, once

patients and for society; these should

relevant negatives have been excluded. A

be openly discussed when making

meta-analysis of the use of antibiotics for

treatment choices.

the treatment of common colds has been

published by Arroll et al. (2005). It shows no

ERS Handbook: Paediatric Respiratory Medicine

227

most episodes are self-limiting and will

Table 1. Common viruses in upper respiratory tract

resolve. Antibiotics should, therefore, be

infections

reserved for those children at risk of

Rhinovirus

complications. In young adults intranasal

Respiratory syncytial virus

corticosteroids may be of use as an adjunct

Influenza virus A and B

to antibiotic therapy (Fokkens et al., 2012).

Foul-smelling or bloody discharge should

Metapneumovirus

prompt consideration of a foreign body high

Parainfluenza virus

in the nasal cavity.

Adenovirus

Chronic rhinosinusitis is less common in

Coronavirus

children and management may require input

from an Ear, Nose and Throat surgeon, as

there may be an indication for

benefit in comparison with placebo and an

adenoidectomy. A chronic sinus infection

increase in adverse events when antibiotics

should lead the treating physician to

were prescribed in children and adults for

consider an underlying diagnosis; gastro-

acute purulent rhinitis (relative risk 1.46,

oesophageal reflux, asthma,

95% CI 1.10-1.94).

immunodeficiency, cystic fibrosis and

Rhinosinusitis

primary ciliary dyskinesia are all associated

with chronic rhinosinusitis in children. The

‘‘Rhinosinusitis’’ is the term encompassing

presence of significant central nervous

infection and inflammation of the sinuses as

system symptoms should prompt

the process involves the nasal passages

consideration of a subdural empyema.

both for route of infection and drainage.

One in every 10 colds in children will go on

Acute otitis media

to cause sinus inflammation. The infections

are initially viral in aetiology, but the

Acute otitis media (AOM) is extremely

anatomy of the drainage means that bacteria

common in childhood, with a peak

may cause secondary infections in the

incidence between 6 and 15 months of age.

sinuses. Acute rhinosinusitis should be

Viral infections are commonest, although

considered when URTI symptoms have

secondary bacterial infection may coexist or

exceeded 7-10 days, and is defined as

subsequently occur.

lasting up to 30 days by the Cochrane group.

Clinical features Younger children will

Clinical features These are similar to the

display nonspecific features of illness; fever,

common cold (coryza, cough and fever),

vomiting, minor irritability and poor feeding

and in younger children (where the sinuses

are all common, and young children with

are still developing and the child may not

these symptoms should always have their

communicate symptoms) sinusitis may be

ears examined. Older children may complain

missed. The frontal sinuses can be

of dizziness and pain in the ear or pain when

demonstrated on plain radiographs in 20-

eating. Examination of the ear should

30% of children by 6 years of age. Older

demonstrate an inflamed erythematous

children and young adults may experience

bulging tympanic membrane. The tympanic

facial ‘‘congestion’’ or ‘‘heaviness’’

membrane may rupture and there may be

alongside focal pains. The sinuses may be

pus in the ear canal on examination. Lymph

tender if gently percussed.

nodes draining the area may be inflamed.

Management In acute rhinosinusitis in

Treatment should be to:

children there is no evidence for the use of

nasal decongestants or saline irrigation.

N give adequate analgesia and antipyretics,

There is modest evidence for treatment with

N ensure parents administer sufficient

antibiotics (amoxicillin/clavulanic acid or an

doses of paracetamol and a nonsteroidal

appropriate substitute if allergic), although

anti-inflammatory.

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ERS Handbook: Paediatric Respiratory Medicine

Acute otitis media is usually a self-limiting

Chronic suppurative otitis media

viral infection. Bacterial infection may rarely

Chronic suppurative otitis media is present

be followed by spread to the mastoid air

when otitis media with effusion is

cells with associated risk of intracranial

associated with tympanic perforation and

infection and/or venous thrombosis. This

persistent (usually bacterial) discharge

risk has to be balanced against adverse

occurs. In children this may be a sign of

consequences of antibiotic use both for the

underlying disease, such as

individual and the wider population. Other

immunodeficiency or primary ciliary

complications include middle ear effusions

dyskinesia.

and hearing impairment.

Pharyngitis and tonsillitis

A meta-analysis by Glasziou et al. (2004) of

10 trials using antibiotic versus placebo in

Inflammation of the pharynx is

AOM in children (using pain as an

predominantly viral in aetiology and may

outcome measure) demonstrated no

coexist as a common pathology in many

benefit at 24 hours, but some benefit at 2

URTIs (such as a cold and a sore throat).

and 7 days: however most children’s

Posterior pharyngeal wall inflammation is

symptoms (78%) are improved at this

readily observed on depression of the

point. There was one case of mastoiditis in

tongue. Treatment is supportive with

almost 3000 trial subjects (in a child

analgesia (oral syrups and topical local

treated with penicillin). The number

anaesthetic sprays) and antipyretics.

needed to treat to prevent one child

Acute tonsillitis Waldeyer’s ring of lymphoid

experiencing ear pain was 16. The number

tissue includes the tonsils, adenoids and

needed to harm due to antibiotic side-

lymphoid aggregates in the pharynx, at the

effects (vomiting, diarrhoea or rash) was

base of the tongue and in the pharyngeal

24. The authors conclude that antibiotics

walls. Tonsillitis is inflammation of the

should be given to children with AOM who

palatine tonsils, and is most common in

are ,2 years old, and children with

children between the ages of 3 to 9 years,

bilateral AOM or with AOM plus otorrhoea.

after which age tonsillar regression occurs.

Ventilation tubes (grommets) can be

Tonsillitis may occur secondary to both viral

inserted into the tympanic membrane and

and bacterial infections. The common

one study from the early 1980s has

bacterial pathogens include group A

demonstrated that they decrease the rate of

Streptococcus, Staphylococcus aureus and

subsequent episodes of AOM.

Streptococcus pneumoniae.

Otitis media with effusion

Clinical features: Younger children may have

nonspecific features of fever, poor feeding,

Otitis media with effusion or ‘‘glue ear’’

coryza, irritability and they may have a rash

occurs when there is serous fluid in the

(either a viral exanthema, or a rash secondary

middle ear without symptoms of acute

to Streptococcal infection in scarlet fever).

infection. It occurs in association with

There may also be vomiting and diarrhoea.

Eustachian tube dysfunction, which may in

Older children and young adults may have

turn be secondary to AOM. Over time this

similar symptoms plus localising throat pain,

fluid can become tenacious. One in three

especially on eating or drinking. Local lymph

affected children has culture positive

nodes may be enlarged.

effusions. Otitis media with effusion can

lead to impaired hearing (conductive

Complications of tonsillitis include the

deafness) and antibiotics have been trialled

following.

to aid its resolution. A meta-analysis of 23

studies did not demonstrate any substantial

N A peritonsillar abscess: a unilateral

improvement in hearing or need for

purulent collection in the peritonsillar

grommets following antibiotic

fossa. Presents with pyrexia, ipsilateral

administration (van Zon et al., 2012).

otalgia (ear pain), odynophagia (pain on

ERS Handbook: Paediatric Respiratory Medicine

229

swallowing) and often trismus (pain on

for 5-7 days and exposes a child to the risk

opening the jaw). Examination shows a

of anaesthetic and surgical complications

deviated uvula and swelling of the soft

(infection and haemorrhage) despite

palate.

uncertainty over the likelihood of recurrence

N A retropharyngeal abscess should be

without surgery. A meta-analysis of

considered in children who present with

tonsillectomy or adenotonsillectomy for

fever, stiff neck, dysphagia and other

recurrent or chronic tonsillitis in childhood

symptoms related to inflammation or

found that severely affected children benefit

obstruction of the upper aerodigestive

from fewer episodes of sore throat in the

tract.

first year following surgery (3.3 episodes

N Rheumatic fever and glomerulonephritis

versus 1.8 episodes plus one surgery-

were previously associated with

associated episode) (Burton et al., 2009). In

streptococcal tonsillitis but are now rare

less severely affected children the review

outside the developing world.

concluded that ‘‘surgery will mean having an

average of two rather than three

Treatment: Acute management options

unpredictable episodes of any type of sore

include analgesia, antipyretics and in some

throat. The cost of this reduction is one

cases antibiotics. As with AOM conflict

inevitable and predictable episode of

exists between the risks of antibiotic

postoperative pain’’. Children and families

resistance and side-effects on the one hand,

should be invited to consider the relative

and acute and subacute post-infectious

risks and benefits of intervention in

complications and morbidity on the other.

comparison to a ‘‘wait and see’’ approach

Clinical scores have been developed for

when considering surgery for recurrent sore

assessing the probability of Streptococcal

throats.

infections. Of these, the Centor score is

most widely used, although it was not

Diphtheria Diphtheria is a bacterial

developed in a paediatric setting. The

pharyngitis caused by Cornyebacterium

McIsaac score (table 2) adjusts the Centor

diphtheriae. Mortality varies between 5% and

score for patient age.

10%. Affected children will have a fever and

sore throat; additionally there may be neck

b-lactam antibiotics are first-line drugs

swelling and a characteristic posterior

against bacteria that commonly cause

pharyngeal grey, adherent pseudomembrane

tonsillitis. Amoxicillin may cause rashes in

that may progress to airway obstruction in

children who have sore throats due to

which case urgent expert paediatric airway

Epstein-Barr virus (infectious

management is required. Diphtheria is

mononucleosis and glandular fever).

prevented by mass immunisation;

Tonsillectomy Tonsillectomy prevents

suggestive symptoms in an area of low

recurrent tonsillitis, but does not prevent

immunisation should prompt consideration

recurrent sore throats as only the tonsillar or

of diphtheria in the differential diagnosis.

adeno-tonsillar lymphoid aggregates are

Russia, North Africa, the Middle East and

removed. Tonsillectomy causes a sore throat

East Asia all experienced diphtheria

Table 2. Centor score and McIsaac adjustment for assessing the likelihood of streptococcal infection in tonsillitis/

pharyngitis

Centor score (1 point for each)

Guidance

Fever

Score 0-1: do not prescribe antibiotics

Absence of cough

Score 2: treat if the rapid antigen test is positive

Tonsillar exudates

Score 3: treat if the test is positive or treat empirically

Anterior cervical lymphadenopathy

Score 4: treat empirically

Aged ,15 years (McIsaac adjustment)

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ERS Handbook: Paediatric Respiratory Medicine

outbreaks in the 1990s. Treatment is

Whooping cough (pertussis), caused by

isolation, airway management, antitoxin and

Bordetella pertussis, occurs in all countries

systemic penicillins or erythromycin.

and increased nine-fold in incidence in the

USA between 1980 and 2010. The increase is

Laryngeal infections

thought to be multifactorial; but improved

diagnosis (using PCR techniques) and a

Infection of the larynx causes characteristic

change to acellular vaccines (DTaP) are

changes in cough and phonation.

implicated (Cherry, 2012). Infants aged

Croup (laryngotracheobronchitis) is a viral

,2 months are most at risk from severe

infection of the larynx and adjacent

infection as there is little transplacental

structures; the common causative

transfer of immunity. Recent anti-pertussis

organisms are rhinovirus, respiratory

strategies include maternal vaccination with

syncytial virus and parainfluenza 1 and 2.

DTaP during pregnancy.

Clinical features: The illness often begins with

Clinical features: Children present with a

rhinitis as the upper airway is infected first.

coryzal, feverish illness which mimics a self-

Distal progression irritates the larynx,

limiting URTI. At this stage the coryzal

resulting in a cough. With subsequent vocal

infant is highly infectious to non-immune

cord oedema the cough becomes harsh or

close contacts. The classic, paroxysmal

‘‘barking’’ and inspiratory stridor will

cough follows this stage and lasts for weeks

develop. Airway obstruction is progressive

or months; in China, whooping cough is

with limitation of airflow until the condition

known as ‘‘the hundred-day cough’’. The

begins to resolve or anti-inflammatory

cough has a characteristic rise in pitch and

measures are instigated. The onset of

may or may not be followed by a ‘‘whoop’’ or

stridor usually occurs over 6-12 hours.

episodes of vomiting in younger infants.

Sudden onset of stridor should prompt

There may also be episodes of cyanosis,

consideration of an inhaled foreign body or

apnoea or bradycardia in infants. The cough

anaphylaxis.

may occasionally result in petechiae,

subconjunctival haemorrhages, rib fractures

Treatment: Management should be aimed at

and pneumothoraces.

maximising airflow through the larynx. Risk

factors for significant hypoxia include

Treatment: Accurate diagnosis with

diffusion limitation (e.g. chronic lung

pernasal swab or PCR of nasopharyngeal

disease of prematurity) or pre-existing

aspirate is key; although cultures take up to

airway compromise (e.g. subglottal

1 week and decline in sensitivity the longer

stenosis). It is imperative to keep the child

the illness continues. Children requiring

as relaxed as possible as anxiety (e.g. from

hospitalisation should be isolated and

unwelcome or unwarranted interventions)

subject to barrier nursing. A macrolide

may worsen airflow. Steroids reduce vocal

antibiotic (conventionally 14 days of

erythromycin) is first-line treatment,

cord oedema, facilitating respiration. They

although shorter courses of newer

can be nebulised or delivered orally. More

macrolides may be considered (these may

severely affected children may gain

improve adherence). Supportive treatment

temporary benefit from nebulised

including mechanical ventilation may

epinephrine, with doses repeated as

be required.

necessary due to the short half-life.

Supplemental oxygen (which can be

Epiglottitis

administered by a parent with the child on

their lap) may be required and analgesia

Haemophilus influenzae type b (Hib) causes

should be offered to all children. Decreasing

epiglottitis, a severe swelling of the

the viscosity of inhaled gases results in

epiglottis that leads to airway obstruction.

improved large airway flow, and in severe

Since the introduction of the conjugate Hib

cases a helium-oxygen mixture may be

vaccine, the incidence of epiglottitis has

helpful.

fallen considerably.

ERS Handbook: Paediatric Respiratory Medicine

231

Clinical features Features of infectious

Diagnosis is usually made at bronchoscopy

airway obstruction (fever, cough, stridor and

where the differential includes severe croup

recessions) occur rapidly (onset over hours)

or epiglottitis.

in a toxic-appearing child, without a clear

Treatment The majority of children require

viral prodrome. The child sits upright with

admission to intensive care, intubation and

the head held forwards to extend the neck

systemic antibiotic therapy. Aspiration of

and hold the larynx open. As airflow

exudates and breakdown of membranes may

obstruction progresses, breathing becomes

be performed at bronchoscopy.

quieter and the child may become cyanosed

with decreasing consciousness.

Further reading

Treatment Suspected epiglottitis is an

airway emergency and children should be

Arroll B, et al. (2005). Antibiotics for the

managed in co-operation with anaesthetic

common cold and acute purulent rhinitis.

and otolaryngology teams. Examination of

Cochrane Database Syst Rev; 3: CD000247.

the throat may precipitate acute obstruction

Burton MJ, et al. (2009). Tonsillectomy or

(via distress causing laryngospasm) and

adeno-tonsillectomy versus non-surgical

should be avoided until measures are in

treatment for chronic/recurrent acute

place to secure a definitive airway at the

tonsillitis. Cochrane Database Syst Rev; 1:

point an intervention is required. The

CD001802.

epiglottis typically appears swollen and

Cherry JD (2012). Epidemic pertussis in

2012

- the resurgence of a vaccine-

‘‘cherry-red’’ in appearance. There may be

preventable disease. N Engl J Med; 367:

systemic features of sepsis and treatment

785-787.

includes fluid resuscitation and a third or

Fokkens WJ, et al.

(2012). European

fourth generation cephalosporin.

Position Paper on Rhinosinusitis and

Intravenous access should only be obtained

Nasal Polyps

2012. A summary for

once the airway is secure.

otorhinolaryngologists. Rhinology;

50:

Bacterial tracheitis

Suppl. 23, 1-298.

Glasziou PP, et al. (2004). Antibiotics for

As a result of the Hib vaccine and

acute otitis media in children. Cochrane

widespread use of steroids for croup,

Database Syst Rev; 1: CD000219.

bacterial tracheitis is now the most

Hopkins A, et al.

(2006). Changing

common, although still rare, URTI cause of

epidemiology of life-threatening upper

respiratory failure in children (Hopkins et al.,

airway infections: the reemergence of

2006). Bacterial infection of the trachea with

bacterial tracheitis. Pediatrics; 118: 1418-

S. aureus, S. pneumoniae and Streptococcus

1421.

pyogenes can result in erythema, oedema

Johnston SL (2005). Impact of viruses on

airway diseases. Eur Respir Rev; 14: 57-61.

and purulent exudates in the trachea. There

van Zon A, et al. (2012). Antibiotics for

may be pseudomembrane formation. Viral

otitis media with effusion in children.

tracheal infection may co-exist.

Cochrane Database Syst Rev;

Clinical features Children present with fever,

CD009163.

cough, hoarseness, stridor and recessions.

232

ERS Handbook: Paediatric Respiratory Medicine

Community-acquired

pneumonia

Mark L. Everard, Vanessa Craven and Patricia Fenton

Pneumonia and lower respiratory tract

inflammation primarily in the terminal and

infections

respiratory bronchioles with exudate

spreading to surrounding peri-

Pneumonia is defined as an inflammatory

bronchoalveolae often resulting in a number

disorder of the lung characterised by

of discreet foci. A wide range of organisms

consolidation due to presence of exudate in

including viruses, bacteria, ‘‘atypical

the alveolar spaces. There is, inevitably,

organisms’’ and fungi are capable of

associated inflammation in the surrounding

creating a pneumonic illness.

interstitial tissues. In classic lobar

pneumonia, watery exudates and pus filling

The limited response repertoire of the lungs

the alveoli flow directly into adjacent zones,

ensures that many of the clinical features of

which extend to create a confluent and

pneumonia, such as fever, cough,

confined area of infection generally within

respiratory distress and tachypnoea, are also

the affected lobe; spread of infection

features of other clinical entities, such as

predominantly occurs via the lumen of the

acute bronchiolitis, ‘‘wheezy bronchitis’’ and

airways (fig. 1). Invasive disease inevitably

indeed viral exacerbations of asthma.

involves organisms penetrating into the

Diagnosis remains largely clinical with most

interstitial tissues and, more importantly,

community-acquired pneumonia (CAP)

adjacent capillaries leading to bacteraemia.

guidelines recommending that chest

Bronchopneumonia is characterised by

radiographs are only undertaken in those

with a more severe or atypical clinical

course. This inevitably leads to over

Key points

diagnosis of pneumonia and this reality is

reflected in the use of the significantly less

N Around 2 million children ,5 years of

specific term ‘‘lower respiratory tract

age die from pneumonia each year.

infection’’ (LRTI) in certain guidelines,

which includes pneumonia and other clinical

While Streptococcus pneumoniae is the

entities.

‘‘classic’’ organism it probably

accounts for less than half of the

Importance of CAP

cases of pneumonia.

CAP usually refers to a pneumonia

Many guidelines do not recommend

developing in a generally well individual who

the use of chest radiographs to make

has acquired the organism outside of a

a diagnosis on pragmatic grounds but

healthcare setting.

this is associated with over and under

Worldwide, CAP remains the biggest killer of

diagnosis.

children and, thus, is a major health issue. It

Most children can be treated with oral

has been estimated that approximately 2

antibiotics unless they have severe

million deaths per year in children ,5 years

and/or atypical disease or cannot

of age are attributable to pneumonia, a fifth

tolerate oral therapy.

of all deaths in this age group. This is likely

to be an underestimate as most deaths

ERS Handbook: Paediatric Respiratory Medicine

233

significantly over estimate the true incidence

of pneumonia the catch all approach is

based on the high levels of mortality seen in

those with community-acquired bacterial

pneumonia if not treated with antibiotics.

Worldwide, under treatment is a much

greater problem than over use of antibiotics

for significant LRTIs.

Aetiology of CAP

Studies aimed at determining the causative

organisms in children with CAP have been

hampered by difficulties in obtaining

samples from the site of infection in the

distal lung as:

N young children rarely expectorate

Figure 1. Lobar pneumonia.

sputum,

positive blood cultures resulting from

invasive disease occur in a minority of

probably occur without interaction with

bacterial infections,

healthcare professionals. Epidemiological

N rapid antigen tests can be misleading due

studies would indicate that the prevalence

to false-positive results,

of CAP is significantly higher in developing

N sampling of the upper airways for viruses

countries, which would account, in part,

and bacteria may not be directly relevant

for the higher mortality in these countries.

to the organisms replicating in the

However, the true incidence of pneumonia

alveoli.

is difficult to define without confirmation

of the diagnosis being confirmed by chest

It is believed that most episodes of

radiography with many LRTIs being

pneumonia commence with colonisation of

labelled as ‘‘pneumonia’’ on clinical

the mucosa of the nasopharynx with

grounds. Studies assessing the accuracy of

subsequent spread to the lower respiratory

a clinical diagnosis of pneumonias when

tract. Less commonly, a persistent bacterial

compared with chest radiographs

bronchitis may precede an acute

have confirmed that there is significant

exacerbation with associated pneumonic

over diagnosis, as well as under

changes.

diagnosis.

A wide range of organisms including

UK and Scandinavian studies would suggest

bacteria, viruses and so-called atypical

that incidence of chest radiograph-

organisms cause CAP. Mixed viral and

confirmed pneumonia is in the region of 15

bacterial infections are very common.

cases per 10 000 children with high

Streptococcus pneumoniae is the most

incidence in those aged 0-2 years (42 out of

commonly identified bacteria and is

10 000) and 0-5 years (33 out of 10 000).

frequently considered to be responsible for

Higher incidences in excess of 100 per

the classic pneumonic illness. However,

10 000 have been suggested in European

studies have indicated that it accounts for

studies that did not include chest

less than half of all cases of paediatric CAP

radiographs and/or did not exclude infants

and indeed may account for as little as 5% of

with acute bronchiolitis. Much higher levels

cases, although this will be influenced by

are reported in the developing world,

definitions of disease and techniques

particularly sub-Saharan Africa and south-

available for diagnosis. The advent of

east Asia with estimates suggesting that

conjugated vaccines has reduced the

75% of the 150 million cases a year occur in

incidence of pneumonia although the

just 15 countries. While figures may

magnitude of the impact varies depending

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Bacteria and CAP

Organism

Predisposing factors

Suggested first-line

Comments

treatment

Streptococcus

Previously well

Amoxicillin (oral)

13-valent vaccine in use in

pneumoniae

Benzylpenicillin if i.v.

empyema?

therapy is required

Add clindamycin to

treatment

Streptococcus

Chicken pox

Benzylpenicillin and

Invasive group A

pyogenes

clindamycin

Streptococcus is notifiable to

the CCDC in the UK

Contact tracing indicated

Mycoplasma

Outbreaks every

Clarithromycin

Often mild

pneumoniae

5-7 years

Organism has no cell wall so

cannot be treated with

penicillin

Staphylococcus

Influenza A,

Linezolid, clindamycin

Health Protection Agency

aureus

PVL toxin

and rifampicin

guidelines in UK

Contact tracing indicated

Haemophilus

Immune defect if

Co-amoxiclav or

Rare

influenzae

HiB isolated from

cefotaxime/ceftriaxone

vaccinated individual

PVL: panton valentine leukocidin; HiB: Haemophilus influenzae type B; CCDC: consultant in communicable

disease control.

of the definition of pneumonia used. Using a

pneumoccocal disease or an atypical

broad definition based on clinical criteria a

organism rather than a virus, it should be

study in the Gambia found that ‘‘clinical’’

remembered that severe pneumococcal

pneumonia was reduced by 7%, increasing

disease and invasive disease, in particular, is

to 37% in patients with radiologically proven

most common in infants and pre-school

lobar pneumonia. Again this emphasises

children.

that clinically suspected pneumonia

Other bacteria that cause pneumonia

overestimates the true incidence of

include:

pneumonia and the fact that pneumococci

are responsible for a minority of all

N Haemophilus influenzae type B (HiB) and

pneumonias although it remains the target

nontypable species, although HiB is now

organism for empirical antimicrobial

very rare in developed countries and

treatment in the hospitalised child with

when it occurs in a vaccinated child it is

pneumonia. S. pneumoniae is the

an indication to look for an immune

commonest bacteria found in analysis of

defect;

parapneumonic effusion/empyema,

N group A streptococci, commonly

although any organism, including viruses,

associated with a history of recent

may be associated with a parapneumonic

chickenpox infection;

effusion. Associated invasive disease, such

N Staphylococcus aureus, especially during

as bacteraemia and meningitis, contributes

influenza A epidemics or if the strain

to the poor outcome in untreated children.

produces panton valentine leukocidin

The current conjugated vaccines have

toxin.

targeted the serotypes most likely to cause

invasive disease. While it is often remarked

In addition to these bacteria atypical

that most pneumonias in infants are viral

organisms such as Mycoplasma pneumoniae

and that an older child is more likely to have

and Chlamydia pneumoniae may account for

ERS Handbook: Paediatric Respiratory Medicine

235

20% of cases. Again they are classically

development of the pneumonia or to the

considered to be causes of pneumonia in

severity of the episode.

school-age children but are both capable of

Diagnosis The World Health Organization’s

causing a severe pneumonia in younger

(WHO) recommendations are aimed at

children (table 1).

resource-poor countries and are based on

A wide range of respiratory viruses can

simple clinical criteria. They suggest that

cause pneumonia, particularly in infants

pneumonia should be suspected in children

and, to a lesser extent, pre-school children.

with a cough and/or difficulty breathing with

As with any clinical syndrome from rhinitis

age-adjusted tachypnoea:

through to bronchitis and bronchiolitis to

.50 breaths?min^-1 for infants aged 2-

pneumonia, any of the respiratory viruses

11 months of age,

may be responsible. In general they cause

.40 breaths?min^-1 for preschool children

less severe illnesses than bacteria but

aged 1-5 years,

remain an important cause of severe disease

.20 breaths?min^-1 for children aged

and indeed death. Viral LRTIs tend to affect

.5 years.

the airways more diffusely than bacterial

pneumonias and it is not uncommon for

One study found that this approach had the

infants with clinical acute bronchiolitis

highest sensitivity (74%) and specificity

characterised by widespread crackles to

(67%) for radiographically defined

have evidence of collapse and/or

pneumonia. Associated factors are used to

consolidation on a chest radiograph.

determine severity with recession, grunting

Moreover, with increasingly sensitive

and nasal flaring being indicative of severe

diagnostic techniques it is clear that many

pneumonia while cyanosis, persistent

cases of bacterial pneumonia are preceded

vomiting, severe respiratory distress and

or accompanied by infection by one or more

confusion suggest a very severe illness. This

of these viruses.

pragmatic approach serves the needs of

healthcare systems faced with a huge

In general, studies have found that the more

burden of disease and associated morbidity

severe illnesses are associated with bacterial

where clear, unambiguous direction in

infection but this is not necessarily the case

relationship to management is required in

and this is already changing with the

order to optimise outcomes. This approach

widespread introduction of vaccines to S.

has been incorporated into the WHO

pneumoniae and HiB. However, it should be

integrated management of childhood illness

remembered that the mortality of patients

programme which has been proven to have

with viral LRTIs, such as acute bronchiolitis

had a significant impact on childhood

due to respiratory syncytial virus and other

mortality. It is widely recognised that the

viruses in the absence of good supportive

features above are not specific, with

care and oxygen therapy, in particular, is very

tachypnoea and fever being associated with

significant.

many other conditions.

While it is widely stated that most

Interestingly, a very similar approach is

pneumonias in very young children are viral

observed in several developed countries as

this is also the peak age for severe bacterial

highlighted by the British Thoracic Society

infections and death due to organisms such

(BTS) guidelines which again advocate a

as pneumococcus. Mixed viral and bacterial

clinical approach to diagnosis. The

infections are very common.

guidelines do not have clear

Clinical assessment and diagnosis

recommendations regarding making a

definitive diagnosis but state that ‘‘bacterial

When assessing a child who may have

pneumonia should be considered in children

pneumonia it is important to make a

when there is persistent or repetitive fever

diagnosis, assess the severity and consider

.38.5uC together with chest recession and a

comorbidities which may contribute to the

raised respiratory rate’’. They make no

236

ERS Handbook: Paediatric Respiratory Medicine

recommendation regarding the use of chest

pneumonias may cause abdominal pain and

radiographs other than to state that they

should be considered in the differential of

should not be a considered to be a routine

the acute abdomen even in the absence of

investigation in children thought to have

coughing. Organisms such as S.

CAP. Once again this is likely to be

pneumoniae and HiB may cause serious

associated with misdiagnosis; both false

invasive disease such as septicaemia and

positive and false negative. It is known that

meningitis with or without an obvious

chest radiograph changes lag behind the

pulmonary focus.

clinical picture and an early chest radiograph

Comorbidities While CAP is generally

may miss a developing pneumonia. In

considered to be those pneumonias that

contrast, other guidelines recommend the

develop in the community in previously well

use of chest radiographs to make a

children, it is important to obtain a full

definitive diagnosis and to assist with

history in order to try and determine whether

‘‘antibiotic stewardship’’. Clinical judgement

there may be predisposing factors. These

was shown to be associated with both over

would include possible chronic aspiration

and under diagnosis in a recent Dutch study

associated with neuromuscular or other

comparing general practitioner assessment

conditions and protracted bacterial

with chest radiographs.

bronchitis, both of which may be

accompanied by a chronic cough, as well as

Cough is not a key feature and it is known

a more acute episode such inhalation of a

that for classic bacterial lobar pneumonia

foreign body, influenza and recent

cough may be infrequent until lysis occurs

chickenpox.

as there are few, if any, cough receptors in

the distal lung. Of other symptoms that

Severity Features reflecting the severity of

might be present the most predictive is

the pneumonic illness have been outlined by

wheeze which has a very strong negative

the WHO as noted previously. These provide

predictive value. Conversely, the absence of

a guide to a step-wise approach to

wheeze in a known asthmatic with

treatment, escalating from oral antibiotics to

respiratory distress and fever may indicate

intravenous antibiotics in severe disease. In

bacterial pneumonia which generally does

Europe, determination of apparent severity

not cause an exacerbation of the asthma.

influences both the decision to admit to

Other auscultatory findings are considered

hospital and the route of administration of

to be unreliable but if localised crackles are

therapy. The BTS guidelines suggest that

present they increase the likelihood of a

any of the following would indicate that

lobar consolidation and dullness to

admission to hospital is indicated:

percussion is a good predictor of an

associated effusion/empyema. Widespread

N children with an oxygen saturation of

crackles in an infant are consistent with a

f92% in air,

diagnosis of bronchiolitis rather than

N apnoea or grunting,

pneumonia. While tachypnoea is perhaps

N significant difficulty in breathing,

the most important symptom this is less

N poor feeding or dehydration,

specific and sensitive than noted above

N concerns regarding appropriate

during the first few days of the pneumonia.

supervision.

It is likely that many children with

Pulse oximetry is an important parameter

pneumonia are treated inadvertently in

influencing the use of oxygen therapy and,

primary care with antibiotics prescribed for

indeed, antibiotic therapy.

conditions such as tonsillitis or ear

infections.

Investigations

Extrapulmonary symptoms are not

Chest radiographs Current guidelines have

uncommon. These may be nonspecific

concluded that for most cases of pneumonia

symptoms such as diarrhoea and vomiting,

a presumptive diagnosis can be made on

headaches and myalgia. Of note is that

the basis of clinical criteria outlined above

ERS Handbook: Paediatric Respiratory Medicine

237

and that treatment can be initiated

Samples can be obtained from the

empirically. A definitive diagnosis would

nasopharynx and oropharynx and may reflect

require a chest radiograph with changes

the cause of infection in the distal airways,

consistent with consolidation, although it

but inevitably there are false positives and

should be remembered that the chest

false negatives. This is particularly true for

radiograph changes may lag behind the

bacteria that are frequently present as

clinical picture, both during the evolution of

transient ‘‘commensals’’ in the upper

infection and the resolution. WHO and

respiratory tract of infants and young

North American and European guidelines

children and, hence, bacterial culture of the

do not recommend the use of chest

upper airways is not recommended. Viral

radiographs in the majority of cases for a

PCR may be helpful but a positive result

number of reasons. These include the

does not exclude a bacterial pathogen and it

apparent inability to distinguish bacterial

is increasingly recognised that more than

and viral infections on the basis of the chest

one organism may be involved. Paired

radiograph appearances and studies which

serology is useful in epidemiological studies

suggest that while in those with a clinical

but contributes little to the clinical care and

diagnosis obtaining a chest radiograph only

outcomes. The value of rapid antigen tests

leads to a change in management in a

for pneumococcus is compromised by

minority of case, this does not influence

relatively low sensitivity and specificity

outcomes in the vast majority of cases.

especially in young children when false

Furthermore, interobserver agreement

positives are common. A negative test in

regarding interpretation of chest radiograph

older children may be valuable.

changes is poor, even with clear guidance.

For all these reasons it is widely

There is certainly a consensus that they are

recommended that no investigations are

not required in the vast majority of

required in those ambulatory patients with

ambulatory patients treated in the

suspected pneumonia treated in the

community. The BTS guidelines suggest

community. In those admitted to hospital,

that a chest radiograph could be considered

blood cultures, viral PCR on nasopharyngeal

in those with fever .39uC, children aged

aspirates or nasal swabs and paired serology

,5 years, and in those not responding

for atypical organisms may all be of value.

rapidly and in whom complications, such as

Where pleural fluid is obtained culture PCR

an effusion, may have developed.

for pneumococcus and other organisms and

Microbiology Making a positive

pneumococcal antigen detection should be

identification of the causative organism(s) is

undertaken.

clearly desirable as therapy could then be

Other investigations Evidence would suggest

tailored more accurately. However,

that acute-phase reactants are not helpful in

obtaining microbiological samples from the

distinguishing viral infection from bacterial

site of infections (the distal airways) is

infection and, hence, are not indicated in the

challenging, and invasive investigations

management of uncomplicated pneumonia.

such as bronchoscopy or lung aspirates are

Clinical experience, however, would suggest

rarely indicated. Sputum cultures may be

that they can contribute to the management

helpful if present but most young children

of children who do not follow the expected

do not expectorate sputum. Blood cultures

clinical course.

are positive in a minority of patients, in part,

because many clinical pneumonias are not

Treatment

due to bacteria and, in part, because

bacteraemia is often not present or

Treatment involves both supportive and

intermittently present. The likelihood of

therapeutic components. There is no

conventional microbiological approaches

question that children with hypoxia should be

identifying bacteria in such samples is

treated with supplemental oxygen although

significantly reduced in the presence of prior

there is some debate as to whether a

antibiotic use.

saturation of 90% or 92% is the appropriate

238

ERS Handbook: Paediatric Respiratory Medicine

cut-off and altitude may need to be taken into

intubation an anti-psuedomonal agent (such

account. Studies in Zambia and other

as piperacillin/tazobactam) is a good

countries have indicated the importance of

empiric choice.

oxygen therapy in reducing mortality. General

Prevention

supportive care including fluids, possibly

restricted to 80% of maintenance, is

Vaccines against HiB and S. pneumoniae

indicated in those who are vomiting or

have had a significant impact in these

unable to tolerate oral fluids. In the most

specific diseases. While the HiB vaccine has

severe cases intensive care may be required.

largely eliminated this organism from the

list of likely pathogens, the limited cover of

Specific treatment in the form of antibiotics

conjugate pneumococcal vaccines means

should be given to all of those with a clinical

that the organism continues to cause

diagnosis of pneumonia since there is no

pneumonia. Current vaccines cover up to 13

reliable means of distinguishing viral and

of the more than 80 serotypes and, hence,

bacterial infections. It is clear that this

disease resulting from infection with other

approach will result in many children with

serotypes continues; this may, in part, be

viral LRTIs being treated with antibiotics but

due to serotype replacement. The impact of

the risk of mortality and adverse outcomes

the conjugate vaccines on the incidence of

in untreated bacterial pneumonia is such

pneumonia depends upon the rigor of

that this is indicated. There is clear evidence

diagnosis ranging from a ,15% reduction in

that the oral route is appropriate for the vast

those meeting the WHO definition of

majority of children with pneumonia.

probable pneumonia to a .35% reduction in

Intravenous therapy should generally be

confirmed lobar pneumonia. One benefit of

reserved for those with a severe illness or

the widespread introduction of the

those not tolerating oral administration.

conjugate vaccines is that they are effective

Amoxicillin is generally the antibiotic of

against both antibiotic-susceptible and -

choice as it is effective against the majority of

resistant strains while the ‘‘herd effect’’ has

bacterial pathogens. In older children where

led to an impact on the incidence in the

an atypical infection is suspected or there is

elderly as well as the very young.

poor response to therapy, a macrolide maybe

In the developing world, factors such as

used or added. Current recommendations

improved nutrition are associated with

are that co-amoxiclav is appropriate for

reduced morbidity and mortality.

influenza A-associated bacterial pneumonia.

The optimal duration of treatment is

Complications

unknown, with most courses consisting of 5-

The most common complication with CAP is

7 days of antibiotics. For streptococcal

development of pleural effusions and

pneumonia in the presence of lysis and fever,

empyemas (fig. 2). Small uncomplicated

shorter courses may be appropriate but

effusions do not need draining. Ultrasound

evidence is lacking. Benzyl penicillin is

is a valuable modality in determining the

generally appropriate for intravenous therapy

size and distribution of the collection and its

although co-amoxiclav or a second- or third-

consistency. Current evidence suggests that

generation cephalosporin may be used in

in those developing an empyema, drainage

severe disease.

with a small calibre catheter and intrapleural

Antibiotic resistance patterns vary from

fibrinolytics is as effective as other

country to country and within countries.

approaches (fig. 3), although mini

Hence the choice of antibiotics should be

thoracotomy and video-assisted thoracic

based on local guidelines developed as part

surgery (VATS) have their advocates. All of

of a multi-disciplinary approach involving

these approaches appear to shorten the

microbiologists, those specialising in

duration of hospitalisation by a similar

infectious diseases, pharmacists and

amount as compared with drainage and

paediatricians. In children with

antibiotics alone. Some 10-15% of

neurodisability or a history of recent

empyemas resolve relatively quickly with

ERS Handbook: Paediatric Respiratory Medicine

239

Figure 3. Empyema with a chest drain with

Figure 2. Ultrasound showing empyema with

urokinase.

septations secondary to pneumonia.

tachypnoea is associated with improved

clinical outcomes, particularly in the

antibiotic therapy alone and hence drainage

developing world, but inevitably results in

on the basis of chest radiograph appearance

large numbers of patients receiving

alone is inappropriate. Whichever approach

antibiotics for non-bacterial infections. While

is used, outcomes are generally good. Up to

the majority of pneumonias in infants and

15% of patients treated with drainage and

young children are viral this is also the peak

fibrinolytic therapy might subsequently

age for serious life-threatening bacterial

require further intervention, such as VATS or

infections. Most pneumonias can be treated

decortication, although fever alone is not an

effectively with appropriate oral antibiotics,

indication of failed therapy.

with intravenous antibiotics being reserved

Pneumatoceles are most commonly seen in

for those with severe infections or who are

those with S. aureus infection but may

not tolerating oral therapy. Supportive care

develop in pneumonia due to almost any of

remains a vital aspect of care for those with

the common bacteria (fig 4). The vast

severe infection.

majority regress spontaneously and surgical

management is rarely required. Lung

abscesses developing in the course of

necrotising pneumonia are often associated

with an empyema and are most commonly

treated with a prolonged course of

intravenous antibiotics, although

radiological placement of a drain has been

suggested as a way of more rapid resolution.

Surgical resection should be avoided.

Broncho-pleural fistulae may also develop in

necrotising pneumonia. They are usually

peripheral and usually resolve with

continuous chest drainage.

Conclusion

CAP remains a major healthcare issue

despite the development of vaccines directed

against two of the major bacterial pathogens.

Figure 4. Pneumatocele developing during

A clinical diagnosis based on fever and

pneumonia.

240

ERS Handbook: Paediatric Respiratory Medicine

Further reading

seven-valent pneumococcal conjugate

vaccination in England and Wales: an

Bradley JS, et al. (2011). The management

observational cohort study. Lancet Infect

of community-acquired pneumonia in

Dis; 11: 760-768.

infants and children older than 3 months

Nair H, et al. (2010). Global burden of

of age: clinical practice guidelines by the

acute lower respiratory infections due to

Pediatric Infectious Diseases Society and

respiratory syncytial virus in young chil-

the Infectious Diseases Society of

dren: a systematic review and meta-

America. Clin Infect Dis; 53: e25-e76.

analysis. Lancet; 375: 1545-1555.

Cherian T, et al.

(2005). Standardized

Palafox M, et al. (2000). Diagnostic value

interpretation of paediatric chest radio-

of tachypnoea in pneumonia defined

graphs for the diagnosis of pneumonia in

radiologically. Arch Dis Child; 82: 41-45.

epidemiological studies. Bull World

Ranganathan SC, et al.

(2009).

Health Organ; 83: 353-359.

Pneumonia and other respiratory infec-

Cutts FT, et al. (2005). Efficacy of nine-

tions. Pediatr Clin North Am; 56: 135-156.

valent pneumococcal conjugate vaccine

Sawicki GS, et al.

(2008). Necrotising

against pneumonia and invasive pneu-

pneumonia is an increasingly detected

mococcal disease in The Gambia: rando-

complication of pneumonia in children.

mised, double-blind, placebo-controlled

Eur Respir J; 31: 1285-1291.

trial. Lancet; 365: 1139-1146.

Scott JA, et al. (2012). The definition of

Hardie WD, et al. (1998). Complicated

pneumonia, the assessment of severity,

parapneumonic effusions in children

and clinical standardization in the

caused by penicillin-nonsusceptible

Pneumonia Etiology Research for Child

Streptococcus pneumoniae. Pediatrics; 101:

Health study. Clin Infect Dis; 54: Suppl. 2,

388-392.

S109-S116.

Harris M, et al. (2011). British Thoracic

Society for Healthcare Epidemiology of

Society guidelines for the management of

America, et al. (2012). Policy statement

community acquired pneumonia in chil-

on antimicrobial stewardship by the

dren: update 2011. Thorax; 66: Suppl. 2,

ii1-ii23.

Society for Healthcare Epidemiology of

America (SHEA), the Infectious Diseases

Islam S, et al. (2012). The diagnosis and

management of empyema in children: a

Society of America

(IDSA), and the

Pediatric Infectious

Diseases Society

comprehensive review from the APSA

Outcomes

and

Clinical

Trials

(PIDS). Infect Control Hosp Epidemiol; 33:

Committee. J Pediatr Surg; 47: 2101-2110.

322-327.

Jadavji T, et al. (1997). A practical guide

UNICEF/WHO. Pneumonia the forgotten

for the diagnosis and treatment of

killer

of children. United Nations

pediatric pneumonia. CMAJ; 156: S703-

Children’s Fund/World Health Organiza-

S711.

tion.

2006. www.unicef.org/publications/

Karppa H, et al. (2013). Pneumococcemia

files/Pneumonia_The_Forgotten_Killer_of_

in children - a retrospective study before

Children.pdf.

universal pneumococcal vaccinations.

Vugt SF, et al. Diagnosing pneumonia in

Acta Paediatr; 102: 514-519.

patients with acute cough: clinical judg-

Korppi M (2012a). Diagnosis and treat-

ment compared to chest radiography. Eur

ment of community-acquired pneumonia

Respir J

2013

(In press DOI:

10.1183/

in children. Acta Paediatr; 101: 702-704.

09031936.00111012).

Korppi M (2012b). Does solely clinical

Wardlaw T, et al. (2006). Pneumonia: the

diagnostics lead to over diagnoses and

leading killer of children. Lancet;

368:

overtreatments? Pneumonia in children.

1048-1050.

Pediatr Infect Dis J; 31: 885.

World Health Organization. Handbook

Miller E, et al.

(2011). Herd immunity

IMCI. Integrated management of child-

and serotype replacement 4 years after

hood illness. Geneva, WHO, 2000.

ERS Handbook: Paediatric Respiratory Medicine

241

Hospital-acquired pneumonia

Vanessa Craven, Patricia Fenton and Mark L. Everard

Hospital-acquired infections, also known as

(Foglia et al., 2007). In the 2011 English Net

nosocomial infections, are infections that

Point Study, HAP in neonates and children

are not present and that lack evidence of

was the second most common cause of

incubation at the time of admission to

nosocomial infection after clinical sepsis,

hospital. Pneumonia and other lower

accounting for 15.9% of cases and occurring

respiratory tract infections (LRTIs) account

most commonly in those aged ,2 years old.

for a large proportion of these potentially

HAP poses greatest risk to those

serious complications of hospitalisation.

undergoing mechanical ventilation in which

Such infections can be transmitted to the

case it is termed ventilator-associated

patient from another source or may be due

pneumonia (VAP). VAP is generally defined

to an organism already carried by the

as development of a pneumonia .48 h after

patient. Interventions, such as endotrachel

intubation. Many publications have

intubation or use of broad-spectrum

addressed the issue of VAP although it

antibiotics, may compromise host defences

should be remembered that most HAPs

increasing the patient’s predisposition to

occur outside the intensive care unit (ICU).

infection. Hospital-acquired pneumonia

Attempting to define HAP and VAP has been

(HAP) is generally defined as one that

challenging for those designing

presents with signs and symptoms that

epidemiological and intervention studies.

occur after, and not originating before, 48

Variations in definition probably contribute

to differing reports of incidence, with a

recent UK paediatric ICU (PICU) review of

Key points

ventilated patients reporting an incidence of

5.6%, accounting for 9.2 per 1000 ventilator

N Hospital-acquired LRTIs are

days (Hunter, 2012), while US data indicates

associated with significant mortality,

rates of 2.9 to 8.1 per 1000 ventilator days

morbidity and prolonged

(Bingham et al., 2009). Differing rates are

hospitalisation.

likely to reflect variation in the case mix of

different units.

N Risk factors include intensive care,

immunosuppression and admission

HAP in neonatal ICUs (NICU) poses an even

of infants to paediatric wards

greater challenge as it is difficult to

containing patients with LRTIs.

distinguish between hospital-acquired and

vertically transmitted infections. This

N Organisms may be part of the

uncertainty is compounded by usual NICU

patient’s normal flora or maybe

practices being early intervention in

transmitted from another patient or

suspected sepsis, often prior to chest

healthcare provider.

radiograph changes, a feature usually

Following recommended infection,

integral to the definition of VAP, in addition

control policies significantly reduces

to endotracheal secretions that can often

rates of nosocomial infection.

yield positive growth in which colonisers and

pathogens are difficult to distinguish.

242

ERS Handbook: Paediatric Respiratory Medicine

Hospital-acquired LRTIs are also relatively

However, of all the adverse factors in this

common amongst infants admitted to

setting, it appears that intubation poses the

hospital in whom viral LRTIs acquired in

greatest risk to the establishment of HAP. By

hospital contribute to increased mortality,

providing a continuous foreign object

morbidity and duration of stay. Other at risk

extending through the upper airway into the

groups include patients with

trachea, the endotracheal tube permits

immunodeficiencies such as those

organisms from the upper airway to reach

undergoing chemotherapy, patients with

the trachea more easily. Current evidence

neuromuscular disease and post-surgical

suggests that oral tubes have a lower rate of

patients.

infective complication than nasal tubes.

Endotracheal tubes also impair mucocillary

There is an extensive literature

transport while trauma from the

demonstrating the effectiveness of careful

endotracheal tube and suctioning may also

preventative strategies in greatly reducing

impair host defences. Tracheostomies have

the rates of nosocomial infection in both the

an even greater effect (Bigham et al., 2009)

ICU and paediatric wards.

and in this population, nosocomial infection

Risk factors

rates are greater still. Neuromuscular

blockade in all groups has a negative impact

HAP can be thought of as endogenous, in

on rates of pneumonia.

which auto-infection occurs when one’s own

microbes breach the usual protective

In addition to the use of endotracheal tubes,

barriers and become pathogenic, or

intensive care patients frequently have a

exogenous in which external factors lead to

nasogastric tube which is likely to facilitate

the acquiring of new pathogens that proceed

reflux and lead to aspiration of gastric

to cause infection. Certain factors in the

contents into an artificially patent airway.

host lead to this becoming more or less

The risk of infection appears to be increased

likely to occur and it is these risk factors that

by the use of drugs, such as H₂ receptor

form the basis for interventions to limit

antagonists, that are used to prevent gastric

nosocomial pneumonias.

stress ulceration as they increase gastric pH

which contributes to an increase in bacterial

Paediatric intensive care Mechanical

growth which may, in turn, contribute

ventilation poses the biggest risk in this

directly to the establishment of pneumonia

setting as it is generally used in those with

in the presence of aspiration (Kollef et al.,

the greatest illness severity and is an

2013). The risk-benefit of adding a H₂

invasive intervention that circumvents the

receptor to agents such as sucralfate

normal upper and lower pulmonary

continues to be debated.

antimicrobial defences. In this group,

nosocomial pneumonia is usually

Neonatal intensive care In addition to the

synonymous with VAP and this has been

risks addressed in the PICU setting, in NICU

linked to a prolongation of mechanical

the population has its own unique factors

ventilation, as well as an increase in

that predispose to nosocomial pneumonia.

mortality and morbidity (Bigham et al.,

Low birth weight, poor nutrition, a greater

2009).

permeability of skin and mucous

membranes, and hypogammaglobulinaemia

Patients can become colonised with new

due to a restriction in the time available for

organisms during hospitalisation, in

the placental translocation of maternal IgG

particular those who are severely unwell and

all contribute to a greater risk of infection. In

thus require PICU admission. These newly

the NICU, as in the PICU, the effect of hand

colonising organisms tend to differ between

hygiene, local equipment practices and ward

institutions and the rate of their

design also all impact on infection rates.

establishment increases with acidosis,

intubation, hypotension, broad-spectrum

Post-surgical patients The post-operative

antibiotic use and those at risk of clinical or

period, with the risk of ventilation and the

sub-clinical aspiration (Elward et al., 2003).

impact of pain or sedation predispose to

ERS Handbook: Paediatric Respiratory Medicine

243

nosocomial pneumonia, in particular

influenza and parainfluenza viruses, with

thoracic and abdominal surgery in which

RSV, by virtue of its high infectivity, being

coughing may be painful and adequate

most common. Other implicated viruses

mucous clearance difficult.

include cytomegalovirus (CMV), Epstein-

Barr virus (EBV) and adenovirus, although

Chronic disease Immunodeficiency (primary

they occur less often and tend to be of most

and secondary), CF, cardiac disease, low

importance in the immunocompromised

birth weight and malnutrition all contribute

(Hall).

to increasing rates of nosocomial

pneumonia. In addition, those with gastro-

Bacteria Gram-negative organisms

oesophageal reflux, swallowing difficulties,

including Pseudomonas aeruginosa, Klebsiella

trachea-oesophageal fistulae and

sp., Enterobacter sp. and nontypable

neurological disorders are at risk of

Haemophilus influenzae are the most

aspiration and subsequent nosocomial

common Gram-negative isolates.

pneumonia (Zar et al., 2002).

Streptococcus pneumoniae and Staphylococcus

aureus are the most common Gram-positive

Hospital factors Nosocomial infection rates

isolates (Bradley, 2010).

vary among institutions and the impact of

staffing, ward design, local hygiene practices

Antimicrobial resistance poses a great

among staff and the management of

problem in exogenous bacterial HAP and

equipment have been shown to have a

will differ between institutions according to

significant effect on infection rates,

local resistance patterns. Although one of

including pneumonias. The impact of

the rarer causes, methicillin-resistant S.

acquiring an organism, such as the

aureus (MRSA) infections do cause a

respiratory syncytial virus (RSV), in hospital

therapeutic challenge, and third-generation

is frequently overlooked in discussions

cephalosporin resistance and extended

about HAP, but studies have reported that

spectrum b-lactamase producing organisms

ICU patients who acquire the virus after

can cause significant morbidity and

admission may have a mortality rate

mortality.

approaching 25%, while acquisition during

an admission to the paediatric ward for an

Fungi The immunocompromised are at

unrelated problem is associated with

highest risk of fungal lung infections,

substantial increases in the duration of stay

particularly if exposed to broad-spectrum

and readmission rates, as well as significant

antibiotics for suspected bacterial sepsis.

morbidity.

Building work is quoted as a risk factor for

the acquisition of Aspergillus species whilst

Antibiotic usage Sensitivity results vary

endogenous Candida and Aspergillus are a

markedly between different healthcare

particular risk to neutropenic patients. It is

establishments and even within the same

due to this risk that in those with

hospital on different wards. Empiric

neutropenic sepsis, anti-fungal agents tend

guidelines are usually available but results

to be used early in those not responding to

should always be kept under review.

first-line antibacterial agents. High-efficiency

Antimicrobial stewardship guidelines should

particulate air-filtered positive pressure air

be followed by all prescribers.

supply to single rooms is recommended for

Aetiology

children in the period immediately after

bone marrow transplant.

Viruses Viruses are responsible for the

majority of nosocomial pneumonias, being

Pneumocystis jirovecii This organism,

highly contagious and having the ability to

classified as a protozoan, is an

infect relatively well children in addition to

opportunistic organism with a high mortality

those who are deemed high risk. The

that should increase the suspicion of an

epidemiology of these nosocomial

underlying immunodeficiency. This, as well

pneumonias reflect epidemic patterns and

as infections with CMV, EBV and adenovirus

are, in the most part, attributable to RSV,

in this vulnerable population, tend to reflect

244

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Antimicrobial treatment for HAP in children^#

Clinical setting

Likely organisms

Appropriate ‘‘first

Comments

guess’’ treatment

Post-operative,

Streptococcus

Co-amoxiclav^" OR

If genuine penicillin

previously healthy

pneumoniae

cefuroxime

allergy discuss oral

Haemophilus

switch with

influenzae

microbiologist

Moraxella catarrhalis

Maximise physiotherapy

Post-viral, e.g.

Streptococcus

Co-amoxiclav^" OR

If genuine penicillin

deterioration in

pneumoniae

cefuroxime

allergy discuss oral

bronchiolitis

Haemophilus

switch with

influenzae

microbiologist

Moraxella catarrhalis

Staphylococcus aureus

Ventilator-acquired

Pseudomonas

Piperacillin/

Usually requires full i.v.

pneumonia

aeruginosa

tazobactam^" OR

course

Staphylococcus aureus

ceftazidime plus

teicoplanin

Neutropenic/post-

Wide variety of

Follow local

Discuss with

transplant/immune

potential organisms;

protocols

microbiology, infectious

deficient

bacterial, fungal and

Consider anti-fungal

diseases, radiology and

viral

and anti-viral

oncology

Consider possibility of

treatment in addition

May need invasive

Mycobacterium

to antibacterial

diagnostic tests

tuberculosis

Be guided by local protocols and sensitivity patterns.

^#: consider i.v. to oral switch as soon as clinically

appropriate;^": these agents are penicillins and should be avoided in cases of genuine penicillin allergy.

endogenous rather than exogenous

ICU and in paediatric wards. Attention to

acquisition and can be life-threatening.

detail is the key to implementing well-known

infection control measures, including

Mycobacterium Mycobacterium tuberculosis

rigorous hand hygiene, the use of disposable

should not be overlooked in the search for

aprons and gloves, and isolating infectious

aetiology in HAP. Although all children are

patients. Ensuring that healthcare workers

highly susceptible to M. tuberculosis, the

are immunised against influenza and

immunosuppressed child is at increased

ensuring those with respiratory viral

risk of nosocomial infection with possible

illnesses do not look after at-risk patients are

spread from undiagnosed adults posing a

also important aspects of preventing

threat in the ward setting.

nosocomial infection. Care bundles,

including the previously mentioned

Prevention

precautions, together with

Prevention of hospital-acquired infection,

recommendations such as nursing

including HAP, should be at the forefront of

ventilated patients with their head elevated

the clinician’s approach to the care of

where possible, minimising changes in

patients. There is a substantial body of

ventilator circuits unless contaminated;

evidence that HAP is associated with

using oral rather than nasal tubes, and

increased morbidity, mortality and

avoiding re-intubation where possible, in

healthcare utilisation and a similar body of

addition to ongoing education of staff

evidence that the implementation of

have been shown to have a significant

programmes designed to prevent such

impact in lowering rates of VAP (Brierley

infections can be very effective both in the

et al., 2012).

ERS Handbook: Paediatric Respiratory Medicine

245

Not only does attention to detail

approach involving microbiologists

significantly improve clinical outcomes for

specialising in infectious diseases,

the patient, but it also reduces healthcare

pharmacists, intensivists and paediatricians.

costs and leads to much lower use of broad-

A suggested approach is outlined in table 1.

spectrum antibiotics.

Diagnosis and surveillance

Further reading

As noted above, the diagnosis of HAP and

American Thoracic Society, et al. (2005).

indeed VAP can be problematic. Common to

Guidelines for the management of adults

all definitions is deterioration in respiratory

with hospital-acquired, ventilator-asso-

status more than 2 days after admission or

ciated, and healthcare-associated pneu-

intubation that does not appear to be

monia. Am J Respir Crit Care Med; 171:

388-416.

attributable to infection apparent at the point of

Apperley J, et al., eds. EBMT-ESH

admission/intubation. New chest radiograph

Handbook on Haemopoietic Stem Cell

changes associated with fever and leukocytosis

Transplantation. Barcelona, EBMT, 2012.

or leukopenia, together with clinical features

Bigham MT, et al.

(2009). Ventilator-

such as increased cough or airway secretions

associated pneumonia in the pediatric

on suctioning, strongly support the diagnosis

intensive care unit: characterizing the

though it is clear from post mortem and other

problem and implementing a sustainable

studies that over and under diagnosis occurs,

solution. J Pediatr; 154: 582-587.

as is the case with community-acquired

Bradley JS (2010). Considerations unique

pneumonia. Hospital-acquired LRTIs, due to

to pediatrics for clinical trial design in

viruses such as rhinovirus or respiratory

hospital-acquired

pneumonia

and

syncytial virus, are often not classified as HAP

ventilator-associated pneumonia.

Clin

as they develop after discharge and if the

Infect Dis; 51: Suppl. 1, S136-S143.

patient is re-admitted are frequently assumed

Brierley J, et al. (2012). Reducing VAP by

to be community acquired.

instituting a care bundle using improve-

ment methodology in a UK paediatric

Diagnostic approaches include sampling the

intensive care unit. Eur J Pediatr; 171: 323-

lower airways in those being ventilated with

330.

simple endotracheal aspirates, blind

Elward AM (2003). Pediatric ventilator-

protected brushings, and blind and

associated pneumonia. Pediatr Infect Dis

bronchoscopic lavage. Identifying the bacteria

J; 22: 445-446.

responsible requires more focused antibiotic

FayonMJ, et al. (1997). Nosocomial pneu-

prescribing and reduces the use of broad-

monia and tracheitis in a pediatric

spectrum antibiotics. None of the sampling

intensive care unit: a prospective study.

techniques are ideal, in terms of sensitivity

Am J Respir Crit Care Med; 155: 162-169.

and specificity, with the sensitivity increasing

Foglia EE, et al. (2007). Effect of nosoco-

with combinations of techniques. For non-

mial infections due to antibiotic-resistant

ventilated patients, obtaining samples from

organisms on length of stay and mortality

the lower airway is rarely undertaken other

in the pediatric intensive care unit. Infect

than in immunosuppressed patients,

Control Hosp Epidemiol; 28: 299-306.

Gauvin F, et al. (2003). Ventilator-asso-

although upper airways sampling for

ciated pneumonia in intubated children:

respiratory viruses can be very valuable.

comparison of different diagnostic meth-

Treatment

ods. Pediatr Crit Care Med; 4: 437-443.

Healthcare Infection Control Practices

Ideally treatment should be tailored to the

Advisory Committee, et al.

(2004).

specific organism. As noted previously this is

Guidelines for preventing health-care-

not possible for many patients with HAP and

associated pneumonia, 2003 recommen-

empirical treatment is frequently used based

dations of the CDC and the Healthcare

on likely organisms. The choice of antibiotics

Infection Control Practices Advisory

should be based on local guidelines

Committee. Respir Care; 49: 926-939.

developed as part of a multi-disciplinary

246

ERS Handbook: Paediatric Respiratory Medicine

Health Protection Agency. English

Niederman MS, et al. (2011). Treatment

National Point Prevalence Survey on

of hospital-acquired pneumonia. Lancet

Healthcare-associated Infections and

Infect Dis; 11: 728.

Antimicrobial Use, 2011. Preliminary data.

Rello J (2013). Antibiotic stewardship in

London, Health Protection Agency, 201.

hospital-acquired pneumonia. Chest; 143:

Hunter JD (2012). Ventilator associated

1195-1196.

pneumonia. BMJ; 344: e3325.

Rutledge-Taylor K, et al. (2012). A point

Jansson M, et al.

(2013). Critical care

prevalence survey of health care-asso-

nurses’ knowledge of, adherence to and

ciated infections in Canadian pediatric

barriers towards evidence-based guide-

inpatients. Am J Infect Control; 40: 491-

lines for the prevention of ventilator-

496.

associated pneumonia - a survery study.

Srinivasan R, et al. (2009). A prospec-

Intensive Crit Care Nurs; 29: 216-227.

tive study of ventilator-associated pneu-

Kollef MH

(2013). Ventilator-associated

monia in children. Pediatrics; 123: 1108-

complications, including infection-related

1115.

complications: the way forward. Crit Care

Thorburn K, et al. (2012). Mortality and

Clin; 29: 33-50.

morbidity of nosocomial respiratory syn-

Langley JM, et al.

(2005). Defining

cytial virus (RSV) infection in ventilated

pneumonia in critically ill infants and

children - a ten year perspective. Minerva

children. Pediatr Crit Care Med; 6: Suppl.

Anestesiol; 78: 782.

3, S9-S13.

Venkatachalam V, et al.

(2011). The

Masterton RG, et al. (2008). Guidelines for

diagnostic dilemma of ventilator-asso-

the management of hospital-acquired

ciated pneumonia in critically ill children.

pneumonia in the UK: report of the work-

Pediatr Crit Care Med; 12: 286-296.

ing party on hospital-acquired pneumonia

Zar HJ, et al. (2002). Nosocomial pneu-

of the British Society for Antimicrobial

monia in pediatric patients: practical

Chemotherapy. J Antimicrob Chemother;

problems and rational solutions.

62: 5-34.

Paediatr Drugs; 4: 73-83.

ERS Handbook: Paediatric Respiratory Medicine

247

Lung involvement in

immunodeficiency disorders

Rifat Chaudry and Paul Aurora

Overview of clinical approach

N Open-lung biopsy may be useful and

should be considered if other causes of

N Immunocompromise may be suspected

lung damage (e.g. interstitial lung disease

in children experiencing recurrent

or toxic damage) are high on the

infections.

differential diagnosis.

N Differential diagnosis of lung disease is

N Additional advice from infectious

dependent on the underlying primary

diseases, microbiology and immunology

diagnosis. For example, in children who

specialists can be helpful.

are immunosuppressed due to

chemotherapy for malignancy, the

Immune defences in the lungs and points

possibility of toxic lung damage from

of compromise

chemotherapeutic agents must also be

Natural barriers and immunological

considered.

defences exist in order to protect our lungs

N An appreciation of the types of organisms

from infection. Primarily, these are:

immunodeficient children are susceptible

to and their presenting features is

N hair within the nasal passages;

necessary.

N lymphatic tissue within the pharynx

N Detailed history taking and examination

(adenoids and tonsils);

remain crucial in providing diagnostic

N mucociliary clearance of lower airway

clues.

secretions; and

N Radiology and bronchoscopy are

N an effective cough with swallow.

extremely useful in diagnosis.

If these mechanical barriers are breached,

then the risk of recurrent respiratory

Key points

infection increases. Specific deficiencies in

cellular defence pathways increase

N Immunocompromise/

susceptibility to particular organisms.

immunodeficiency can be broadly

Although when screening for infection, a

divided into congenital (primary

broad investigative approach should be

immunodeficiency) or acquired

used in order not to miss causal agents, an

(through immunosuppression or

understanding of the different components

infection such as HIV).

of the immune response can help to focus a

Preventative measures such as

diagnosis (table 1).

antibiotic prophylaxis along with swift

diagnosis and treatment can

Features, diagnosis and treatment of

effectively reduce lung morbidity.

opportunistic infections

N Long-term sequelae vary from mild

The most important pathogens causing

restrictive or obstructive defects to

disease in immunocompromised children

end-stage respiratory failure.

are listed here. It should be noted that this

list is certainly not exhaustive.

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Components of the immune response

Component

Mechanism of

Examples

Increased susceptibility to

compromise

Neutrophils

Reduced

CGD

Bacteria

numbers or

Children with leukaemia

Staphylococcus aureus

function

Children after cytotoxic therapy

Pseudomonas aeruginosa

Pancytopenia, either primary or

Klebsiella

in response to infection (e.g.

Escherichia coli

parvovirus infection in children

Haemophilus influenzae

with sickle cell disease)

Nocardia

More rare genetic conditions

Fungi

Candida

Aspergillus

Mucormycosis

Complement

Reduced

Mannose-binding lectin

Bacteria

production or

deficiency

Streptococcus

dysfunction

Early classical pathway (C2, C4,

pneumoniae

C1qrs) deficiency

Neisseria meningitidis

Alternate pathway deficiency

Late lytic deficiency

B-lymphocytes

Reduced

Common variable

Bacteria

production or

immunodeficiency

Streptococcus

dysfunction

X-linked agammaglobulinaemia

pneumoniae

IgG subclass deficiency

Haemophilus influenzae

SCID

Acute lymphoblastic leukaemia,

chronic lymphoblastic

leukaemia, and lymphomas

pre- and post-treatment

T-lymphocytes

Reduced

SCID

Bacteria

production or

After chemotherapy for

Listeria

dysfunction

malignancy or organ

Mycobacterium

transplantation

including M. tuberculosis

Lymphoma

Nocardia

Secondary to use of chronic

Legionella

high-dose corticosteroids

Viruses

HIV/AIDS

VZV

CMV

HSV

Fungi

Candida

Aspergillus

Cryptosporidium

Pneumocystis jiroveci

Parasites

Toxoplasma gondii

VZV: varicella zoster virus; HSV: herpes simplex virus.

Aspergillus and Candida are highly

These organisms rarely cause disease in

prevalent in our normal environment, in soil

healthy individuals, but can do in the

and as part of the skin flora, respectively.

immunocompromised.

ERS Handbook: Paediatric Respiratory Medicine

249

Diagnosis is made as follows.

Cytomegalovirus (CMV) can be transmitted

vertically from mother to fetus but also

History and examination findings: high-

through infected blood products or organs

risk patients include those with primary

post-transplantation. In children with

or secondary neutropenia, chronic

normal immune function, CMV infection is

granulomatous disease (CGD) or hyper-

often asymptomatic. In the

IgE syndrome, and those receiving high-

immunocompromised host, there is a wide

dose broad-spectrum antibiotics. Chronic

range of nonspecific presenting symptoms

or high-dose corticosteroid use also

including fever, malaise, arthralgia, pyrexia

increases risk. Pleuritic chest pain is

and macular rash. Patients post-

characteristic of invasive disease in

transplantation are at particular risk.

conjunction with cough, dyspnoea,

CMV pneumonitis presents with insidious

hypoxaemia and haemoptysis.

increase in dyspnoea, nonproductive cough

Chest radiography may reveal new

and evolving oxygen requirement. Fulminant

infiltrates or round focal opacity;

respiratory failure requiring ventilator

however, CT is extremely useful for

support due to CMV alone is rare; and, more

diagnosis as there are several

commonly, results from dual pathology or

characteristic features, including

multiple pulmonary infectious agents for

cavitations, air crescents and halo signs,

example secondary bacterial pneumonia

all suggestive of fungal parenchymal

with or without septicaemia.

erosion.

Contamination of the upper airway with

Diagnosis is made by:

fungus is common in children with

mucositis so sputum samples may give

N history and examination findings, and

false-positive results; therefore,

exclusion of other infections;

bronchoscopy with bronchoalveolar

N typical chest radiography changes of

lavage (BAL) is helpful in confirming the

bilateral diffuse infiltrates;

diagnosis. It should be noted that yield

N CT showing patchy bilateral consolidation

can be poor and false-negative results are

and nodular shadowing;

common.

N detection of CMV antigen in peripheral

Examine other organ systems for signs of

blood mononuclear cells;

infection. Oncomycosis is particularly

N possibly, the presence of giant cells in

common in immunodeficient individuals.

BAL;

Open-lung biopsy may be the only means

N PCR from blood, urine and or BAL

of diagnosis, but be cautious as, in CGD

specimens; and

in particular, the fungal load in the lung

N transbronchial or open-lung biopsy

may be very low.

specimens can be stained and cultured

for CMV.

Several antifungal agents are available but

In children with established CMV

those with broadest cover, greatest tissue

pneumonitis, intravenous ganciclovir is the

penetrance and lowest toxicity are liposomal

treatment of choice. If ganciclovir resistance

amphotericin (Ambisome; Gilead, Foster

is suspected or if there is no clinical

City, CA, USA) and caspofungin. Azoles, for

response, then foscarnet or cidofovir can be

example voriconazole, are commonly used

used as alternatives.

for prophylaxis; however, they are less

effective for treatment of Candida infection.

Neutrophil suppression by treatment drugs

Duration of treatment is titrated to response

increases susceptibility to fungal infections;

and must be discussed with specialist

therefore, fungal prophylaxis should be

teams. Treatment is often commenced

considered. Children receiving stem cell or

empirically, as confirmation of the diagnosis

solid-organ transplantation who are at high

may be difficult without biopsy. If such a

risk of CMV infection (e.g. a CMV-negative

decision is taken, then a full treatment

child receiving a CMV-positive graft) may

course should still be completed.

benefit from ganciclovir prophylaxis.

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ERS Handbook: Paediatric Respiratory Medicine

Protocols vary between centres, and by

Tuberculosis All children in high-risk groups

clinical situation.

are susceptible to pulmonary TB infection

and subsequent disease. Risk factors

Pneumocystis jiroveci , formerly known as

include: close domiciliary contacts with

Pneumocystis carinii, was originally

others who have open disease; travel to or

misclassified as a fungus but is now known

from areas of high TB incidence; children

to be a protozoan; although the

,2 years with relatively naïve immune

nomenclature has changed, the term

memory; and those infants of HIV-infected

‘‘P. carinii pneumonia’’ (PCP) is still used. It

mothers or those with some congenital

is highly prevalent in the environment and

immunodeficiencies (particularly SCID,

infection is caused by inhalation of airborne

CGD and defects of innate immunity).

cysts. In immunocompromised children,

Patients with these primary

manifestations of infection can be slow and

immunodeficiencies and infants with

subtle with increasing signs and symptoms

confirmed HIV should not be vaccinated

over several weeks. Patients with T-cell

with bacille Calmette-Guérin (BCG).

deficiency are particularly at risk (e.g. post-

transplantation, severe combined

Diagnosis is made as follows.

immunodeficiency (SCID) and HIV

infection).

History and examination findings:

suspected contact with index case, weight

Diagnosis is made as follows.

loss, chronic cough, lethargy, pyrexia,

night sweats and peripheral

N History and examination findings are

lymphadenopathy. History of BCG

intermittent fever, dry cough and

vaccination and scar should be noted.

dyspnoea with weight loss. Hypoxia is a

Gastric aspirates, and Mantoux and

classic feature of P. jiroveci pneumonitis

QuantiFERON (Qiagen, Hilden,

along with tachypnoea. Poor adherence

Germany) tests can all be used to focus

to or prescription failure of prophylactic

the diagnosis. Use local age-appropriate

co-trimoxazole should always raise PCP

guidelines.

as a differential diagnosis.

Bronchoscopy with BAL permits staining

N Chest radiography findings include

and culture for alcohol- and acid-fast

increased bilateral interstitial and alveolar

bacilli.

markings. HRCT may only add a picture

Complications include: endobronchial

of ground-glass opacification and

lesions causing airway obstruction,

therefore is not always necessary, given

pleural effusion, miliary disease with

the increased radiation exposure.

haematogenous spread, spinal lesions

N Bronchoscopy with BAL if often

and meningitis.

diagnostic: cytology reveals characteristic

Typical chest radiography changes are

foamy macrophages and casts with low

hilar lymphadenopathy, calcification of

neutrophilia suggestive of minimal

lymph nodes, consolidation, atelectasis,

inflammation. Lung biopsy is rarely

effusions and miliary shadows. All of the

required unless there is treatment failure.

changes noted on chest radiography,

including cavitations in reactivation or

High-dose intravenous co-trimoxazole is

more advanced disease in adolescents,

recommended and the treatment course will

can be seen by HRCT.

depend on clinical response. Pentamidine is

an alternative should co-trimoxazole fail.

Diagnostic and treatment guidelines will

Concomitant use of pulsed high-dose

differ geographically depending on strains

corticosteroids can expedite recovery as

and population mix. Four oral drugs are

seen in adults with HIV; however, they can

conventionally used for uncomplicated TB

cause deterioration if there is co-infection

treatment: rifampicin, isoniazid,

with CMV. Milder disease may respond to

pyrazinamide and ethambutol. Adherence

treatment with combined oral antimicrobials

can be problematic as treatment courses

such as clindamycin with primaquine.

generally last for 6 months (all four drugs for

ERS Handbook: Paediatric Respiratory Medicine

251

the first 2 months followed by rifampicin and

are malnourished or have been on long-term

isoniazid for the remaining 4 months).

corticosteroids should also be considered.

Support from specialist nursing teams in the

Examples of long-term sequelae are:

community with regular outpatient follow-up

is vital to ensure correct and complete

N scoliosis, thoracic growth arrest and

eradication. A diagnosis of multidrug

crush fractures of the vertebrae;

resistance to rifampicin and isoniazid

N restrictive lung function defects;

(multidrug-resistant TB) requires specialist

N obliterative bronchiolitis;

advice on treatment. Ethambutol can rarely

N pulmonary fibrosis and traction

cause reversible ocular toxicity; therefore,

bronchiectasis;

ophthalmology screening and titration of

N pulmonary hypertension;

drug doses is recommended.

N pulmonary veno-occlusive disease; and

N pulmonary infarcts after recurrent acute

Differential diagnosis

chest syndrome in sickle cell disease.

This will depend upon primary diagnosis,

Conclusion

but the following must be considered.

Paediatric pulmonologists should have a

N Infiltration by disease process, as in

good understanding of the systemic and

lymphoma and leukaemia

pulmonary manifestations of both infectious

N Radiation pneumonitis

and noninfectious disease processes in the

N Drug-induced inflammation and fibrosis

immunocompromised child. Consultation

N Adult respiratory distress syndrome

with specialist colleagues in related

N Lymphoid interstitial pneumonitis in HIV

disciplines will permit a holistic and effective

infection

approach to each individual patient’s needs.

N Pulmonary embolism

N Alveolar haemorrhage

Further reading

N Graft-versus-host disease

N Post-transplant lymphoproliferative

Bellanti JA. Immunology IV: Clinical

disease

Applications in Health and Disease.

N Alveolar proteinosis

Bethesda, I Care Press, 2011.

N Acute chest syndrome in sickle cell

Chapman S, et al. Pulmonary disease in

disease

the immunocompromised (non-HIV). In:

Oxford Handbook of Respiratory

Long-term sequelae and follow-up

Medicine.

2nd Edn. Oxford, Oxford

University Press, 2009; pp. 67-77.

Immunocompromised children are

Chernick V, et al., eds. Kendig’s Disorders

susceptible to chronic, progressive damage of

of the Respiratory Tract in Children. 7th

the lung parenchyma and airways from both

Edn. Philadelphia, Saunders, 2006.

infectious and noninfectious factors.

Hull J, et al. The immunocompromised

Physiological monitoring (i.e. spirometry),

child. In: Oxford Specialist Handbook of

bronchodilator reversibility, transfer factor

Paediatric Respiratory Medicine. Oxford,

measurement and polysomnography can

Oxford University Press, 2007; pp. 55-58.

provide objective information about the

Hull J, et al. Primary immuno-deficiency.

clinical course and guide supportive

In: Oxford Specialist Handbook of

management. Echocardiography to assess

Paediatric Respiratory Medicine. Oxford,

pulmonary hypertension and dual-energy

Oxford University Press,

2007; pp.

X-ray absorptiometry (DEXA) scans for

425-444.

measurement of bone density in children who

252

ERS Handbook: Paediatric Respiratory Medicine

Non-CF bronchiectasis

Elif Dagli

In 1819, Laennec first described the finding

nutrition, vaccination and use of early

of ectatic bronchi in pathological specimens.

antibiotics. However, the ability to recognise

Since then, bronchiectasis has been a

bronchiectasis improved with novel imaging

morphological term used to describe

techniques has renewed the interest in this

dilatation of the airways, supported by

clinical condition globally.

radiological and clinical evidence. Dilated

Pathophysiology

airways are often manifested with a

thickened wall, bacterial colonisation and

Bronchiectasis is categorised into three

destruction of the surrounding tissue due to

main phenotypes according to the shape of

excessive inflammation.

the dilatation:

Epidemiology

N tubular,

N varicose,

Non-CF bronchiectasis (NCFB) is still an

N cystic.

important cause of chronic suppurative lung

disease in low-income countries and among

This classification describes the progression

disadvantaged populations of high-income

of the disease without providing information

countries. A decline in prevalence has been

about aetiology. The aetiology of NCFB is

noted since the 1950s in high-income

variable, but the common

countries with improved sanitation,

pathophysiological mechanism contains

infection, inflammation and tissue damage.

The airway excessive inflammatory response

Key points

triggered by bacterial burden may result in

an increased production of proinflammatory

N The diagnosis of non-CF

cytokines and uncontrolled activation of

bronchiectasis may be delayed as

effector cells.

chronic wet cough can be

misdiagnosed as other respiratory

Aetiology

diseases.

An underlying cause for bronchiectasis

N HRCT scanning is necessary as chest

cannot be determined in all patients.

radiography is not sensitive for

Improvements in diagnostic techniques, and

detecting early disease.

facilities for more subtle immunological

N Prognosis has been related to the

abnormalities and primary ciliary dyskinesia

extent of disease and the type of

have decreased the proportion of idiopathic

bronchiectasis.

patients. Nevertheless, the prevalence of

idiopathic cases in different series ranges

N Treatment is based on optimising

from 17% to 40% depending on the

airway clearance techniques and

facilities.

intermittent courses of antibiotics

for pulmonary exacerbations.

The period between the first symptom and

diagnosis is usually too long to prove

ERS Handbook: Paediatric Respiratory Medicine

253

causality in most clinical series. Among the

Symptoms

identified aetiologies, severe childhood

Cough is the primary presenting symptom

infections (measles, pertussis, adenovirus

followed by sputum production, dyspnoea

and TB), primary ciliary dyskenesia, a₁-anti-

and wheeze. The most common reason for

trypsin (AAT) deficiency, atypical CF,

referral was reported as recurrent chest

immune deficiencies and congenital

infection. Recurrent otitis media, failure to

anomalies have been recognised. Missed

thrive, gastro-oesophageal reflux, rhinitis

opportunities such as undertreated asthma

from neonatal period, exercise intolerance

and undiagnosed foreign body aspirations

and haemoptysis were among other reasons

may commonly be reported. Aspiration and

for admission to a special care centre.

gastro-oesophageal reflux, collagen vascular

disorders and other conditions, such as

The distribution of bronchiectasis within the

sarcoidosis, Young syndrome, Mounier-

lung fields was not found to be correlated

Kuhn syndrome, Ehler-Danlos syndrome,

with the underlying aetiology. However, in

Marfan syndrome and yellow nail syndrome,

most series localisation was in the middle

are less frequently reported aetiologies.

and lower lobes.

In affluent countries, primary

Microbiology

immunodeficiency remains the most

common cause accounting for 20-39% of

Sputum culture is standard in evaluating

paediatric bronchiectasis (table 1), whereas

airway colonisation and infection in NCFB. If

in non-affluent countries bronchiectasis as a

sputum cannot be produced spontaneously,

result of past infection is much more

sputum induction could be used as an

common.

alternative. The most common bacterial

isolates are non-typeable Haemophilus

Missed diagnosis CF may be an underlying

influenzae, Pseudomonas aeruginosa,

cause. 20% of patients with NCFB had

Streptococcus pneumoniae, Staphylococcus

diagnosis of CF after a comprehensive

aureus and Moraxella catarrhalis.

analysis in a clinical series. All patients with

Colonisation with P. aeruginosa is associated

apparent NCFB should have comprehensive

with more severe bronchiectasis and a

analysis to detect cystic fibrosis

worse prognosis as demonstrated by

transmenbrane conductance regulator

physiological and radiographical studies.

(CFTR) mutations.

Diagnosis

The possibility of bronchiectasis must be

Table 1. Immunodeficiencies usually identified in

considered under the following clinical

patients with bronchiectasis

conditions:

Agammaglobulinaemia

N chronic moist or productive cough,

Common variable immunodeficiency

lasting longer than 8 weeks,

IgA deficiency

N asthma unresponsive to treatment,

Selective antibody deficiency

N incomplete resolution of pneumonia after

Severe combined immunodeficiency

treatment or recurrent pneumonia,

N persistent and unexplained lung crackles,

TAP deficiency

N respiratory symptoms in children with

Ataxia telangiectasia

structural or functional disorders of the

Hyper-IgE syndrome

oesophagus and upper respiratory tract,

N haemoptysis.

Cartilage-hair hypoplasia

Chronic granulomatous disease

Imaging

TAP: transporter associated with antigen

As chest radiograph findings and HRCT

presentation.

scans of the chest show poor agreement,

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ERS Handbook: Paediatric Respiratory Medicine

a normal chest radiograph cannot exclude

progression; however, it is not sensitive at

bronchiectasis in a symptomatic child.

detecting early bronchiectatic structural lung

damage.

Before the development of HRCT scans,

diagnosis was made by bronchograms using

A study that investigated clinical,

contrast material to map the airways. When

radiological and laboratory features of

CT appeared as a diagnostic tool it replaced

children with NCFB reported a significant

bronchography as the ‘‘gold standard’’ for

correlation between HRCT severity scores

the diagnosis of bronchiectasis. At present,

and symptoms, FEV1, sputum interleukin

chest HRCT is the gold standard for

(IL)-8 and tumour necrosis factor-a levels

diagnosis with a sensitivity of 97%. Most

proving ongoing inflammation.

paediatric studies report bronchiectasis as a

multilobar disease.

The pulmonary function of children with

NCFB declines significantly over time,

The Bhalla scoring system is generally used

despite treatment. Aetiology has a

for evaluation of the severity of

significant impact on severity which may

bronchiectasis by CT. Bronchiectasis is

indicate an opportunity to target screening

present when the internal luminal diameter

and treatments.

is slightly greater than the adjacent blood

Treatment

vessel. Peribronchial thickening is present

when the wall thickness is equal to or larger

There is no evidence-based consensus on

than the diameter of the adjacent vessel.

the treatment of NCFB. Management

recommendations are mostly based on

Evaluating the extent of mucus plugging,

evidence extrapolated from trials in CF in

bronchiectasis, the presence of abscesses or

high-income countries.

sacculation, the generation of bronchial

divisions, the presence of emphysema,

There are some general therapeutic

collapse, and/or consolidation can be made

recommendations for NCFB patients as

during further assessment.

follows.

MRI is a new method used in the diagnosis of

N Chest physiotherapy and exercise are

NCFB. Chest MRI was found to be equivalent

essential for airway clearance.

to HRCT in determining the extent of lung

N Annual influenza and 5-yearly

disease in children with non-CF lung disease.

pneumococcal vaccinations should be

The findings support the use of chest MRI as

given.

an alternative to HRCT in diagnostic pathways

N The use of inhaled steroids remains

for paediatric chronic lung disorders.

controversial, however, cessation of

A sweat test must be performed in all

inhaled steroids with bronchial

patients with bronchiectasis and repeated in

hyperreactivity was reported to increase

the case of doubt. Immune function test,

bronchial hyperresponsiveness and

such as serum Ig, IgG subclasses, specific

decrease in neutrophil apoptosis.

antibody levels to vaccinations, T- and B-cell

N Prompt and effective antibiotic use is

lymphocyte subsets, a Mantoux test and

essential in acute infectious

HIV detection, tests for primary ciliary

exacerbations, increase in wheeze,

dyskinesia in the form of nasal brushing to

breathlessness and sputum purulence.

examine cilial motility under light

Antibiotic therapy should be prescribed

microscopy and ultrastructure under

based on bacterial cultures and

electron microscopy, tests for aspiration

sensitivity.

contrast study of swallowing, and

There is no evidence for the use of

oesophageal pH studies may be performed

carbocysteine, mannitol, leukotriene

to investigate underlying aetiology.

receptor antagonists, anti-inflammatory

Spirometry does not provide diagnostic

drugs and methylxanthines. However, some

information but may serve as a marker of

beneficial effects on lung function were

ERS Handbook: Paediatric Respiratory Medicine

255

reported of long-term, oral, low-dose

Prognosis

azithromycin use. Azithromycin also

Long-term consequences of childhood

reduced bronchoalveolar lavage neutrophilia

bronchiectasis have been recently

and interleukin-8 mRNA.

documented. Many reports, regardless of

Children with NCFB will require inpatient

analysis strategy, have shown that children

treatment for the following:

with bronchiectasis have significant airway

obstruction which deteriorates over time. In

N increased respiratory rate and increased

one study, FEV1 was reported to have

work of breathing,

declined by a mean of 1.6% predicted per

N circulatory or respiratory failure,

year.

N fever (a body temperature .38uC),

Patients with NCFB may have complications

N no oral intake,

of the disease which may contribute

N infection not controlled with oral

negatively to the prognosis.

antibiotics.

NCFB patients have been found to have

Surgery

disturbed sleep associated with severity of

disease. Night-time symptoms and

Surgery is indicated in patients with mild

hypoxaemia during sleep may affect sleep

bronchiectasis confined to resectable limits

quality in children with bronchiectasis. Poor

who are unresponsive to medical treatment,

sleep quality may impair growth, learning

or in patients with severe tissue damage

and emotional development of children.

causing threat to the intact part of the lung.

Patients with bronchiectasis who snored had

Surgery has been performed in fewer cases

poorer sleep quality and patients with

as the diagnosis is made earlier and the

wheezing had a significantly higher rate of

medical treatment improves.

snoring.

There are few data about long-term results

Other long-term outcomes of childhood

of medical and surgical treatment.

bronchiectasis include impaired left

Nevertheless, correctly chosen cases may

ventricular diastolic functions and

benefit from surgery. A study on 19 cases of

osteopenia. Osteopenia is reported to be

bilateral surgical resection, six cases of

more common in children with NCFB

complete pneumonectomy, 165 cases of

compared to controls and the risk of

complete resection and 11 cases of

osteoporosis and osteopenia increases with

incomplete resection, with mean age of

age.

12.3 years, reported a perfect outcome in

73.3% of patients.

Further reading

Lung transplantation

Al Subie H, et al.

(2012). Non-cystic

N Lung transplantation might only be an

fibrosis bronchiectasis. J Paediatr Child

option in patients with advanced lung

Health; 48: 382-388.

disease and declining lung function.

Barker AF, et al. (1988). Bronchiectasis:

update of an orphan disease. Am Rev

N Comorbidities of advanced

Respir Dis; 137: 969-978.

bronchiectasis should be detected and

Bhalla M, et al.

(1991). Cystic fibrosis:

treated before referral for transplantation,

scoring system with thin-section CT.

as the underlying disease may cause

Radiology; 179: 783-788.

morbidity after surgery.

Dagli E

(2000). Non cystic fibrosis

N Patients with CF and NCFB generally

bronchiectasis. Paediatr Respir Rev;

have a good outcome following lung

64-70.

transplantation.

Eastham KM, et al. (2004). The need to

N Management of infection is a key

redefine non-cystic fibrosis bronchiecta-

issue both pre- and post-lung

sis in childhood. Thorax; 59: 324-327.

transplantation.

256

ERS Handbook: Paediatric Respiratory Medicine

Goeminne P, et al.

(2010). Non-cystic

Karadag B, et al.

(2005). Non-cystic-

fibrosis bronchiectasis: diagnosis and

fibrosis bronchiectasis in children: a

management in

21st century. Postgrad

persisting problem in developing coun-

Med J; 86: 493-201.

tries.. Respiration; 72: 233-238.

Hilla AT, et al.

(2011). Primary care

Li AM, et al. (2005). Non-CF bronchiectasis:

summary of the British Thoracic Society

does knowing the aetiology lead to changes

Guideline on the management of non-

in management? Eur Respir J; 26: 8-14.

cystic fibrosis bronchiectasis. Prim Care

Montella S

(2012). Magnetic resonance

Respir J; 20: 135-140.

imaging is an accurate and reliable method

Kapur N, et al. (2011). Differences and

to evaluate non-cystic fibrosis paediatric

similarities

non-cystic fibrosis

lung disease. Respirology; 17: 87-91.

bronchiectasis between developing and

Sirmali M, et al. (2007). Surgical manage-

affluent countries. Paediatr Respir Rev;

ment of bronchiectasis in childhood. Eur J

12: 91-96.

Cardiothorac Surg; 31: 758.

ERS Handbook: Paediatric Respiratory Medicine

257

Pleural infection, necrotising

pneumonia and lung abscess

Fernando M. de Benedictis, Chiara Azzari and Filippo Bernardi

Pleural infection, necrotising pneumonia

continuum, but classically it has been

and lung abscess are serious conditions in

divided into three stages according to the

children and deserve a systematic,

evolution of the inflammatory process:

multidisciplinary approach.

exudative (simple parapneumonic effusion),

fibropurulent (complicated parapneumonic

Pleural infection

effusion) and, eventually, overt pus in the

pleural space (empyema). A simple

In children, the presence of pleural fluid

parapneumonic effusion (PPE) is present in

collection is usually the consequence of

up to 40% of community-acquired

underlying pneumonia. Pleural infection is a

pneumonia (CAP) and more than half of

cases may complicate further. In our setting,

Key points

the term of empyema is used generically to

describe an advanced stage of PPE.

The incidence of pleural empyema is

Evidence suggests that the incidence of

increasing in many countries.

pleural empyema has increased in many

The most common pathogens

countries over the past few years. The

associated with empyema, necrotising

reasons for this dramatic increase are not

pneumonia and lung abscess are

known, but possibilities include changing

S. pneumoniae and S. aureus.

bacterial resistance and virulence,

introduction of the pneumococcal

Chest CT is unnecessary for most

vaccination, adjustments to primary care

cases of complicated pneumonia and

antibiotic prescribing practices and referral

should be considered in selected

patterns.

cases.

Diagnosis

Therapeutic choices should be

Clinical features of empyema can closely

evaluated individually and shared in a

resemble those of an uncomplicated

multidisciplinary team.

pneumonia, but the possibility of a pleural

Antibiotics remain the mainstay of

complication should be considered

treatment.

especially in children who remain pyrexial or

unwell 48 h after starting antibiotic therapy.

Chest drain with fibrinolysis is the

Judicious use of appropriate investigations

preferred primary therapy in

can clarify what is often a difficult clinical

empyema; VATS should be reserved

diagnosis.

for use in patients refractory to

medical treatment.

Imaging studies may help to confirm the

clinical suspicion and to better follow the

The long-term outcome for children

evolution of the infectious process.

with complicated pneumonia and no

predisposing conditions is usually

Chest radiographs are usually the first

good.

investigation to confirm the presence of

PPE. Early signs include blunting of the

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ERS Handbook: Paediatric Respiratory Medicine

costophrenic angle and a rim of fluid

ascending the lateral chest wall (meniscus

sign) (fig. 1). Large effusions may appear as

complete ‘‘white out’’ of the lung field,

making it impossible to differentiate

between pleural fluid and consolidated lung.

Lateral chest radiographs are not necessary

in most cases.

Chest ultrasound scans are critical in the

diagnosis of PPE, especially as they do not

involve radiation and sedation is not

necessary. Although it cannot reliably

establish the stage of pleural infection, it can

Figure 2. Empyema: consistent amount of infected

differentiate pleural fluid from consolidated

fluid in the right pleural space and a totally

lung in children with complete white out of

collapsed right lung.

the lung field, estimate the size of the

effusion, reveal fibrinous septations and

before surgical intervention in order to

assess loculation of fluid. It can also be used

delineate the anatomy further.

to guide chest drain insertion and assess

treatment response.

Laboratory

Blood Acute reactants such as white cell

Chest CT scans do not appear able to reliably

count, C-reactive protein, erythrocyte

distinguish the stage of pleural collection

sedimentation rate and procalcitonin are

and predict the outcome of empyema. While

unhelpful in distinguishing bacterial from

unnecessary for most cases of paediatric

viral pneumonia. However, an initial

empyema, CT scans should be considered

evaluation of acute reactants should be

when there is concern that infection is not

obtained to provide supportive evidence for

the underlying cause (i.e. blood-stained

an infective aetiology of PPE. Serial

pleural fluid or tumours) or when clinical

measurements can be helpful in monitoring

improvement is not obtained with

the progress.

appropriate treatment (fig. 2). Many

surgeons will require that a CT be performed

Blood cultures should be obtained despite

the low isolation rate in PPE (10-22%), as

they may be positive when pleural fluid

culture proves sterile.

Real-time PCR analysis of blood and

respiratory specimens has become more

widely available over the past years, enabling

rapid identification of potential pathogens.

This molecular technique appears to add

diagnostic value and should always be

considered for specific pathogens, if

available, especially when cultures are

negative.

Sputum Any available sputum should be

sent for culture, as microbiology isolation is

likely to represent the infecting organism

from the lower airways. However, the low

Figure 1. Pleural effusion: blunting of the right

quality of specimens often obtained from

costophrenic angle and a rim of fluid ascending

children, and the inability to distinguish

the lateral chest wall.

colonisation from infection of the respiratory

ERS Handbook: Paediatric Respiratory Medicine

259

tract limit the usefulness of this analysis, the

Indeed, most small PPE will respond to

results of which should always be

antibiotics without the need for further

interpreted with caution.

intervention. Decisions on empirical

antibiotic therapy should be based on

Pleural fluid Although frequently sterile due

pneumonia treatment guidelines and take

to prior administration of antibiotics, any

into consideration whether the infection was

pleural fluid that is available should undergo

community or hospital acquired, local

biochemical, cytological and microbiological

antibiotic resistance patterns, and whether

analysis including Gram stain, acid-fast

the child has any underlying medical

bacilli stain, culture and antibiotic sensitivity

problems (i.e. CF or immunodeficiency). The

testing. Molecular analysis by PCR of pleural

choice of antibiotics should be modified

fluid more than doubled the detection of

accordingly once the causative pathogens

pathogens causing empyema.

and sensitivities are known. If culture results

are negative, the adjustment may depend on

Other analysis In children, the

the response of clinical and radiography

immunochromatographic membrane test

parameters.

(Binax Now) for rapid detection of

pneumococcal C polysaccharide antigens in

Given evidence from epidemiological

urine showed false-positive results which

studies, it is imperative that initial

make this test unhelpful for diagnostic

antibiotics provide good Streptococcus

purposes. Mantoux testing and

pneumoniae cover pending culture results. If

microbiology for Mycobacterium tuberculosis

there is radiological evidence of

should be performed if there is a

pneumatocoeles, adequate staphylococcal

predominance of lymphocytes in the pleural

cover is required. Anaerobic cover should be

fluid or risk factors for TB are present.

added if the child is at risk of aspiration. A

Management

second- or third-generation cephalosporin

Despite the fact that empyema has been

(cefuroxime, cefotaxime or ceftriaxone), or

recognised for over 2000 years, its

amoxicillin-clavulanate are often used

management in childhood remains

empirically intravenously. In areas where

controversial, mainly because of the paucity

there is a high prevalence of methicillin-

of evidence-based studies at this age. This

resistant S. aureus, clindamycin or a

has led to treatment being determined by

glycopeptide can be used as additional first-

personal experience and local availability of

line agent. In children with known allergy to

different therapeutic options.

penicillin, clindamycin should be considered

as the first-line antibiotic treatment.

The goals of treatment are sterilisation of

the pleural cavity and drainage of excessive

Intravenous antibiotic therapy is usually

pleural fluid, in order to allow re-expansion

continued until there is definite evidence of

of the lung and restoration of normal pleural

clinical improvement and resolving fever, or

fluid circulation. Since management is

at least until the chest drain is removed.

harder in those with an advanced organised

While there is no evidence to guide the

empyema, prompt recognition and

duration of treatment, oral antibiotics, such

treatment remains important. Preferably,

as amoxicillin-clavulanate or a second-

children with PPE should be transferred to a

generation cephalosporin, are generally

tertiary paediatric respiratory unit,

continued for 2-3 weeks following

particularly if the effusion is large or the

discharge.

child is unwell. The therapeutic choices

Routine diagnostic thoracentesis is not

should be evaluated individually and shared

recommended in children, unless there is a

in a multidisciplinary team.

suspicion of a noninfectious aetiology.

Treatment

Unlike adults, biochemical analyses of

Antibiotics There is undoubtedly a role for

pleural fluid (pH, glucose levels, proteins or

antibiotic treatment alone in children with

lactate dehydrogenase) has not been shown

mild PPE and no respiratory compromise.

to be of any value in the practical

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ERS Handbook: Paediatric Respiratory Medicine

management of children with pleural

Surgery The role of surgery in the

effusions. In addition, obtaining a sample of

management of childhood empyema is

pleural fluid is technically challenging in

controversial. While surgery was previously

children, requires sedation and results in a

reserved for cases of failed medical therapy,

significantly higher re-intervention rate when

the advent of less invasive techniques has

compared to insertion of a pigtail catheter

led to an increasing interest in surgery’s

as a primary procedure.

potential role in primary treatment.

Chest drain alone Following the introduction

Video-assisted thoracoscopic surgery (VATS)

of appropriate antibiotics, the decision to

achieves debridement of fibrinous material,

proceed to drainage should take into

breakdown of loculations and drainage of

consideration a number of factors including

pus from the pleural cavity under direct

clinical and laboratory response to antibiotic

vision. The more controversial area is the

therapy at 48-72 h and evidence of

role of VATS versus chest drainage with

enlarging effusion on repeated ultrasound.

intrapleural fibrinolysis in the primary

management of empyema. In a systematic

Development of respiratory compromise is

review of 67 studies published over a period

an indication for drainage. While chest drain

of .20 years, primary operative therapy was

insertion alone can be effective in children

associated with a lower LOS, time of

with empyema, the length of stay (LOS) in

drainage, time of antibiotic therapy, re-

hospital is prolonged (20 versus 10.7 days)

intervention rate and mortality rate

and there is a higher failure rate (23.6%

compared with nonoperative treatment.

versus 9.4%) compared to chest drain with

However, the majority of these studies did

intrapleural fibrinolytics.

not include treatment with fibrinolytics in

addition to chest drainage.

Chest drain plus intrapleural fibrinolytic agent

The aim of instilling a fibrinolytic agent in

Two prospective randomised trials have

the pleural cavity is to break down fibrin

compared primary VATS to chest drain with

strands in order to improve drainage and re-

intrapleural fibrinolysis, either urokinase or

establish pleural circulation. Numerous case

tissue plasminogen activator, in children.

series and a few randomised controlled

No difference between treatment groups

trials on the use of intrapleural fibrinolytic

was found in the main outcomes, but VATS

therapy in childhood empyema have been

cost significantly more. Current evidence

published to date. They have used different

suggests that chest drain with fibrinolysis is

agents, dosage schedules and treatment

the preferred primary therapy in empyema,

protocols, and there was a great diversity in

and that VATS should be reserved for failure

the stage at which treatment was started.

of medical management. In clinical practice,

Not surprisingly, outcomes varied greatly.

the choice of one of these options is often

conditioned by local experience and

Urokinase is actually the preferred fibrinolytic

tradition.

agent for the treatment of empyema. The

most widely used dosage regimen is 40 000

Open thoracotomy enables removal of the

units of urokinase in 40 mL of normal saline,

thickened pleural rind and irrigation of the

or 10 000 units in 10 mL of normal saline for

pleural cavity. Potential drawbacks include a

children ,1 year of age, which is

large scar and the risk of wound infection,

administered twice daily for 3 days. After

persistent air leaks and bleeding. Mini-

instillation, the chest drain is clamped for 4 h

thoracotomy involves a similar procedure

and the child is encouraged to mobilise. The

through a small incision.

drain is then left on a suction pressure of -

20 cmH₂O until the next dose. There is some

A number of retrospective studies have

evidence to suggest a potential advantage for

compared VATS to open thoracotomy for

smaller catheters in reducing the time of

rescue treatment demonstrating less post-

drainage, time until the patient became

operative pain, a better cosmetic result and,

afebrile, and LOS.

in some cases, a shorter LOS.

ERS Handbook: Paediatric Respiratory Medicine

261

Open thoracotomy procedures should,

occurs as a result of inflammatory response

therefore, only be reserved for late

due to toxins produced by the invasive

presenting empyema with significant pleural

pathogen or the associated vasculitis with

fibrous rind.

thrombotic occlusion of alveolar capillaries.

The process may rapidly progress to tissue

Prognosis The prognosis in children with

destruction and intraparenchymal bullae,

empyema is usually very good. Unlike

even in the presence of proper antibiotic

adults, empyema in childhood is associated

therapy. At such stage, the process may

with a low mortality (,0.5%) with the

further extend to the pleural space and

majority of children eventually making a

create a bronchopleural fistula, especially

complete recovery. Follow-up studies have

when the necrotic segment is adjacent to the

shown that chest radiography returns to

pleural surface. When multiple necrotic foci

normal in almost all patients by 6 months

are involved, they may coalesce and a large

and that lung function returns to normal or

cavity can result.

shows only minor abnormalities long-term.

Clinical features Children with necrotising

Pneumatoceles are generally complications

pneumonia usually present with symptoms

of a staphylococcal pneumonic process and

of severe pneumonia, such as high fever,

may be associated with empyema. They are

cough, and tachypnoea, lasting for several

more common in infants and young

days. Necrotising pneumonia should be

children. They usually regress spontaneously

suspected when a patient with pneumonia

with the improvement of the pneumonic

develops progressive respiratory distress,

process, but sometimes they require

haemoptysis or septic shock despite

surgical intervention when they become taut

appropriate antibiotic treatment. Pleural

or infected, or when they break in the pleural

effusion is often detectable at physical

cavity, thus inducing pneumothorax or

examination.

pyopneumothorax.

Imaging The diagnosis of necrotising

Necrotising pneumonia

pneumonia can be detected by chest

Necrotising pneumonia is a severe

radiography, but the presence of pleural

complication of CAP and is characterised by

effusion may obscure the underlying lung

liquefaction and cavitation of lung tissue. In

process. Chest radiography underestimates

the last few years, increasing cases of

the degree of parenchymal destruction,

necrotising pneumonia in previously healthy

therefore contrast-enhanced CT may be

children have been reported with special

needed for a more definitive diagnosis when

emphasis on laboratory, pathology,

necrotising pneumonia is suspected.

radiology and clinical aspects. This

Radiographic criteria for necrotising

increased incidence is probably due to a

pneumonia include the loss of the normal

combination of improved recognition of

lung architecture and the presence of areas

necrotising pneumonia as a specific entity

of decreased parenchymal enhancement,

and heightened detection resulting from the

representing liquefaction, that are

use of CT scans in the evaluation of children

progressively replaced by multiple small air

with complicated pneumonia. However, the

or fluid filled cavities. Transition from

observed increase of necrotising pneumonia

liquefaction to cavitation may progress

parallels that of complicated PPE observed

rapidly within 48 h. Although CT offers the

in several nations over the past years. The

advantage of being able to identify

necrotic process can occur at any lobe of the

parenchymal complications over chest

lung, but involvement of lower lobes is more

radiography (fig. 3), clinical management is

frequent. The affected extent may be patchy,

not changed in the majority of cases and

segmental, lobar or even an entire lung.

routine use of CT is therefore not justified.

The pathogenetic mechanisms of

Abnormal laboratory findings of increased

necrotising pneumonia are not clear, but it

acute reactants, low haemoglobin level and

is commonly believed that tissue necrosis

hypoalbuminaemia are observed in many

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ERS Handbook: Paediatric Respiratory Medicine

do not warrant specific intervention

strategies beyond a prolonged course of

antibiotics.

Antibiotics Unlike adults, exclusive treatment

with high-dose antibiotics is frequently

successful in children, with unexpected

parenchymal conservation and lung re-

expansion over time, even in cases of severe

pulmonary involvement. As for empyema,

the choice of initial antibiotics should be

directed at broad coverage of commonly

implicated pathogens and modified

Figure 3. Necrotising pneumonia: multiple

accordingly once the causative agent and

cavitary lesions and air bronchogram in the

sensitivities are known. Penicillins or

consolidated right upper lobe.

cephalosporins may be administered

initially, while clyndamycin or metronidazole

patients. The pleural fluid characteristics

can be added to cover possibly involved S.

associated with necrotising pneumonia

aureus or anaerobes.

reflect those usually found in PPE.

A chest drain may be mandatory in cases of

Microbiology Like empyema, S. pneumoniae

concomitant pleural effusion. Intrapleural

is the more frequent aetiological agent of

fybrinolysis may potentially result in a risk in

necrotising pneumonia. Mycoplasma

necrotising pneumonia, since the

pneumoniae and S. aureus strains, often

breakdown of the fibrinous seal in the pleura

methicillin-resistant, producing cytotoxin

may favour the lack of air from necrotic

Panton-Valentine leukocidin have been also

peripheral areas of the lung.

involved in the genesis of necrotising

pneumonia. Other bacteria less frequently

Surgery VATS has been used successfully in

reported include S. pyogenes, S. viridans,

children with necrotising pneumonia. It

Pseudomonas aeruginosa and anaerobes.

should be reserved for patients with

Almost 50% of the cases of necrotising

associated empyema or to resolve

pneumonia have no identified aetiological

bronchopleural fistulae that do not close

cause with common microbiological

with conservative treatment. Surgical

resection of the lung should be reserved to

methods. However, new methods, such as

particularly severe cases, bearing in mind

PCR analysis, could potentially increase the

potential complications of surgical

diagnostic yield in necrotising pneumonia.

intervention and the possible long-term

Treatment There is not a general agreement

impairment of pulmonary function.

on the best therapeutic strategy for

necrotising pneumonia, mainly because the

Prognosis Long-term outcome for children

frequent coexistence of empyema prevents

with necrotising pneumonia is usually good.

uncoupling of the two conditions and the

Follow-up chest radiography and, in a few

cases, CT scan have shown almost complete

separate evaluation of their respective

normalisation of pulmonary parenchyma

contribution to overall morbidity. Studies

within months of hospitalisation. This pattern

comparing the effect of different

of improvement suggests that the lung

interventions (i.e. conservative versus

damage caused by necrotising pneumonia in

surgical) on the evolution of necrotising

children is transient and that no or minimal

pneumonia are unfortunately lacking, and

functional sequelae are expected.

there is an urgent need for these to be

addressed. However, it should be borne in

Lung abscess

mind that, in children, parenchymal

complications of pneumonia do not carry a

A lung abscess is a thick walled cavity

particularly adverse prognosis and usually

containing purulent material resulting from

ERS Handbook: Paediatric Respiratory Medicine

263

suppuration and necrosis of the lung

parenchyma. It is an uncommon paediatric

condition, with a paucity of quality data in

the literature.

Lung abscesses may be single or multiple

and are classically divided into primary and

secondary according with their appearance

in previously well children or in those with

predisposing comorbidities, such as

significant neurocognitive disability,

immunodeficiency, CF or congenital lung

malformation (i.e. pulmonary

sequestration). Lung abscesses may develop

in any area of the lung, but are more

frequent in the lower lobes.

A lung abscess may arise from the

aspiration of infected fluid, aspiration of

noninfected fluid which triggers a chemical

reaction (i.e. gastric content), a primary

bacterial infection of the lung,

Figure 4. Lung abscess: well-circumscribed shadow

haematogenous spread of bacteria or spread

containing an air-fluid level in the left upper lobe.

of infection from a contiguous organ. The

time course for progression from initial

involvement to abscess formation is usually

improved microbiological diagnostic

slow.

techniques, such as PCR, have increased the

yield of pathogens identified from abscess

Clinical features Children may present for

fluid samples. S. aureus, group B

several days with a low grade cough and

Streptococci, Escherichia coli and Klebsiella

mild fever. Less commonly, chest pain,

pneumoniae are the more common

dyspnoea, sputum production and

pathogens in primary abscesses and in

haemoptysis may be seen suddenly. The

young children. In older children, the

clinical history is important in revealing

likelihood of aspiration increases, and oral

predisposing conditions, such as recurrent

anaerobic bacteria (Peptostreptococcus,

pulmonary aspiration of airway secretions,

Fusobacterium spp., etc.) or mixed flora may

neurocognitive disability, immunodeficiency

be found. More rarely, fungi such as Candida

and proximal airway structural

albicans or Aspergillus spp. can cause lung

abnormalities. Physical examination may

abscess in children.

reveal normal chest auscultation or signs of

consolidation.

Treatment

Antibiotics Treatment with a course of

Imaging Typically, the diagnosis of lung

systemic antibiotics will usually successfully

abscess is based on the chest radiograph,

treat a lung abscess. The choice and

which will reveal a well circumscribed

duration of antibiotic therapy will be guided

shadow containing an air-fluid level (fig. 4).

by local experience, the type of abscess

Less frequently, multiple abscesses may be

(primary or secondary), and the ability to

present. Distinction between parenchymal

isolate pathogenic organisms. At baseline

abnormalities and pleural collections is

therapy, antibiotics will cover S. aureus,

normally possible by ultrasound, but CT may

streptococcal species and Gram-negative

be reserved for the occasional cases where

bacilli that are usually found in the upper

there is unresolved doubt.

respiratory tract. Treatment may include

Microbiology More invasive procedures,

cephalosporins, vancomycin, clindamycin,

aspiration and drainage, together with

aminoglycosides, quinolones and

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ERS Handbook: Paediatric Respiratory Medicine

carbapenems. In patients where anaerobic

Calder A, et al. (2009). Imaging of para-

infection is suspected, metronidazole

pneumonic pleural effusions and empyema

should be considered. Generally, a 2-3 week

in children. Pediatr Radiol; 39: 527-537.

course of intravenous antibiotics is

de Benedictis FM, et al.

(2009).

sufficient to induce clinical and radiological

Aspiration lung disease. Pediatr Clin

improvement of the lesion. Once the child

North Am; 56: 173-190.

has improved, the intravenous route may be

Grijalva CG, et al.

(2010). Increasing

replaced by oral antibiotics to complete a 4-

incidence of empyema complicating

week treatment course.

childhood community-acquired pneumo-

nia in the United States. Clin Infect Dis;

Interventional procedures and surgery Many

50: 805-813.

centres will use ultrasound or a CT scan for

Hoffer FA, et al.

(1999). Lung abscess

interventional, image-guided aspiration and

versus necrotizing pneumonia: implica-

drainage of the abscess cavity with a

tions for interventional therapy. Pediatr

percutaneously placed pigtail catheter for

Radiol; 29: 87-91.

both diagnostic and therapeutic purposes.

Hsieh Y-C, et al.

(2006). Necrotizing

pneumococcal pneumonia in children:

Thoracoscopic drainage of lung abscesses

the role of pulmonary gangrene. Pediatr

may be obtained concurrently with

Pulmonol; 41: 623-629.

treatment of empyema. In children, the role

Islam S, et al. (2012). The diagnosis and

of surgical therapy for lung abscess should

management of empyema in children: a

be limited to a minority of patients who are

comprehensive review from the APSA

refractory to medical treatment or who

Outcomes

and

Clinical

Trials

develop complications such as

Committee. J Pediatr Surg; 47: 2101-2110.

bronchopleural fistula.

Nagasawea KK, et al.

(2010).

Thoracoscopic treatment of pediatric lung

Prognosis Complications of a lung abscess

abscesses. J Pediatr Surg; 45: 574-578.

may include pneumothorax, bronchopleural

Resti M, et al.

(2010). Community-

fistula, lung compression and mediastinal

acquired bacteremic pneumococcal pneu-

shift with progressive respiratory

monia in children: diagnosis and serotyp-

compromise. The existence of underlying

ing by real-time polymerase chain

conditions will influence the prognosis. The

reaction using blood samples. Clin Infect

long-term outcome of lung abscesses in

Dis; 51: 1042-1049.

immunocompetent children is favourable.

Sawicki GS, et al.

(2008). Necrotising

Mortality rate is estimated about 5%,

pneumonia is an increasingly detected

predominantly in children with predisposing

complication of pneumonia in children.

conditions.

Eur Respir J; 31: 1285-1291.

Sonnappa S, et al. (2006). Comparison of

urokinase and video-assisted thoraco-

Further reading

scopic surgery for treatment of childhood

Alsubi H, et al. (2009). Lung abscesses in

empyema. Am J Respir Crit Care Med; 174:

children. J Pediatr Inf Dis; 4: 27-35.

221-227.

Avansino JR, et al.

(2005). Primary

St Peter SD, et al. (2009). Thoracoscopic

operative versus nonoperative therapy for

decortication vs tube thoracostomy with

pediatric empyema: a meta-analysis.

fibrinolysis for empyema in children: a

Pediatrics; 115: 1652-1659.

prospective, randomized trial. J Pediatr

Balfour-Lynn IM, et al. (2005). BTS guide-

Surg; 44: 106-111.

lines for the management of pleural

Walker W, et al. (2011). Update on the

infection in children. Thorax; 60: 1-21.

causes, investigation and management of

Blaschke AJ, et al.

(2011). Molecular

empyema in childhood. Arch Dis Child;

analysis improves pathogen identification

96: 482-488.

and epidemiologic study of pediatric

Yen CC, et al.

(2004). Pediatric lung

parapneumonic empyema. Pediatr Infect

abscess: a retrospective review of 23 cases.

Dis; 30: 289-294.

J Microbiol Immunol Infect; 37: 45-49.

ERS Handbook: Paediatric Respiratory Medicine

265

Bacterial bronchitis with

chronic wet cough

Petr Pohunek and Tamara Svobodová

Protracted bacterial bronchitis (PBB) is a

clinical condition characterised by isolated

Key points

wet cough lasting for .4 weeks with

absence of pointers suggestive of an

N Bacterial bronchitis should be

alternative specific cause of cough, which

suspected in a child with protracted

resolves fully following appropriate

wet cough.

prolonged antibiotic treatment. It should be

N Detailed differential diagnostic

differentiated from bronchiectasis and

protocol aims to exclude other

chronic suppurative lung disease (CSLD),

underlying causative factors.

which presents with excessively prolonged

moist cough with persistent purulent

N Treatment should target the most

secretions.

frequent pathogens.

Epidemiology

N Protracted bacterial bronchitis can be

a precursor of chronic suppurative

The general epidemiology of PBB is not

lung disease and bronchiectasis, if left

known. In a study of 108 children with

untreated.

chronic wet cough PBB was the final

N If detected early and adequately

diagnosis in 39.8% of patients. In a recent

treated, prognosis of protracted

study analysing 197 children with protracted

bacterial bronchitis is good.

wet coughing, bacterial cultures were

positive in 91 (46%) children. More than half

of the study patients (55%) were aged 0-

3 years, 36% were aged 3-7 years and only

presence of serotypes not included in the

9% were .7 years of age.

vaccine. Infection by Pseudomonas

aeruginosa or other more difficult pathogens

Aetiology

does not occur in PBB. When these

Among the positive bacterial cultures the

pathogens are found in a child with chronic

leading pathogen is usually nontypable

cough, the search for underlying aetiology

Haemophilus influenzae (,50%), followed by

should be actively undertaken (e.g. CF,

Streptococcus pneumoniae and Moraxella

primary ciliary dyskinesia and

catarrhalis (,20% each). Staphylococcus

immunodeficiency).

aureus is less common with a frequency of

Risk factors

,12%. Combinations of more than one

pathogen at the same time have been

The main risk factors for developing PBB are

described. A recent study that compared

as follows.

serotypes of S. pneumoniae in children with

bacterial bronchitis from the UK with those

Impaired mucociliary clearance after viral

from Greece found an important impact of

respiratory infections Lack of convalescence

vaccination. In children vaccinated with a

after viral bronchitis may lead to impaired

pneumococcal vaccine they found a trend to

airway clearance (secondary disorders of

serotype replacement with more frequent

ciliary epithelium and persistent

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ERS Handbook: Paediatric Respiratory Medicine

inflammation of airway mucosa) and

mucosal barrier. With some risk factors this

facilitation of bacterial infection.

may start gradually and be based on

continuous damage of the mucosa (e.g.

Airway malacia Tracheomalacia/

recurrent aspiration, environmental triggers

bronchomalacia has been detected in

or gastro-oesophageal reflux) with no

children with PBB more frequently than in

apparent initial acute event. Additionally,

the general population. In one study

high presence of neutrophils with their

evaluating children with PBB aged

enzymatic activity enhances the process. In

,60 months the authors found

various studies the fraction of neutrophils in

laryngomalacia or tracheomalacia in 74%.

differential count from bronchoalveolar

Another study found tracheomalacia in 30%

lavage fluid (BALF) was as high as 90%.

of young children with PBB. How far the

Uncontrolled bacterial infection, mucus

malacia is a causative factor or to what

retention and high proteolytic activity of the

extent instability of the airways may be

neutrophils can lead to CSLD, damage to

secondary to prolonged infection and

the bronchial wall and gradual development

protracted coughing remains to be

of bronchiectasis. If diagnosed early, this

speculated.

can be interrupted by appropriate treatment

Immunodeficiency Disorders of humoral

and even the development of mild

immunity can be associated with insufficient

bronchiectasis can be reversed. Changes in

protection and may facilitate bacterial

the properties of some of the pathogens also

growth in the airways.

contribute to chronicity. Microbes can

regulate their gene expression based on the

Environmental burden An important

environment and signalling within the

environmental risk for the development of

bacterial population and develop protective

PBB is environmental tobacco smoke (ETS).

mechanisms that suppress host defence

In many countries the frequency of smoking

mechanisms. Biofilm formation by some

in families with children is as high as 40-

pathogens (e.g. nontypable H. influenzae and

50%. Local heating by burning wood or coal

P. aeruginosa) is well documented. Bacteria

has been described as a significant risk

can also cleave Ig and, thus, suppress

factor for the paediatric airways.

specific immune response.

Industrial pollution Industrial pollution has

Symptoms

been found to be a risk factor for respiratory

infections in children. The most important

The leading symptom of bacterial bronchitis

part of industrial emissions is particulate

is wet cough with or without sputum

matter (PM). The concentration of PM may

production. Generally, the wet sound of the

increase under local adverse climatic

coughing suggests an intrabronchial content

conditions. For respiratory health, particles

of secretions of various quality and

with a 50% cut-off aerodynamic diameter of

consistency. The ability to produce sputum

10 mm (PM10) or smaller play a major role

is age and training dependent. Infants and

as these particles are respirable and can

very young children are generally not able to

easily reach the lower airways. A correlation

spit out sputum; however, this can be

of PM exposure with increased respiratory

successfully trained by a physiotherapist as

symptoms has been repeatedly

early as in the third year of life. Coughing is

documented.

usually present both during the day and the

night, which is often more pronounced in

Pathogenesis

the mornings as secretions tend to

PBB usually develops as a result of an insult

accumulate during the night. Physical

that suppresses the local mechanism of the

exercise can also exacerbate coughing.

airway defence. There may be initial acute

Wheezing is not a typical symptom. In

viral bronchitis followed by inappropriate

bacterial bronchitis the patient may wheeze

regrowth of damaged cilia, healing of airway

on occasion based on obstruction by

mucosa, and re-establishment of a proper

mucus; this is usually only transient and

ERS Handbook: Paediatric Respiratory Medicine

267

variable and changes after coughing.

The most reliable method of

Recurrent wheeze may signal bronchial

microbiological sampling with high yield is

hyperresponsiveness and should raise

bronchoscopy. It is not indicated in

suspicion of asthma.

children with a single episode of PBB. Even

in children with recurrent PBB it is usually

Fever is generally absent in PBB. The

not necessary if they expectorate

infection is mostly limited to the bronchial

sufficiently. Bronchoscopy may be

tree and does not trigger general systemic

considered in cases with inadequate

inflammatory response. Fever and elevation

expectoration or in those with other

of acute phase proteins may signal an acute

suspected underlying pathology. Flexible

exacerbation or more severe affection of

bronchoscopy is best performed with

lung parenchyma.

preserved spontaneous breathing. It allows

visual assessment of airways anatomy,

Diagnosis

excluding aspirated foreign body. It also

The main task in early detection of PBB lies

helps to assess the level of mucosal

with a general practitioner (GP). Children

inflammation, observe stability of the

with protracted wet cough should be noticed

airways during breathing and coughing and

early in the general practice. An important

find possible tracheomalacia/

initial task for the GP is to map and properly

bronchomalacia. Removing mucus plugs,

providing appropriate bronchial toilette

characterise the symptoms. Basic

and direct sampling of mucus specimens

differential blood count, C-reactive protein

are essential. In addition, a standardised

and erythrocyte sedimentation rate belong

bronchoalveolar lavage should be

to standard first-line investigations. GPs

performed and a specimen of BALF sent for

should also trace possible environmental

microbiology, differential cytology and

risk, such as smoking, local heating or other

staining for lipid-laden macrophages.

local risk in the household.

Anaerobic and mycotic cultures should also

Detailed investigation is needed, mainly in

be considered.

children with repeated episodes of PBB. In

Additional examinations must include

further investigation algorithm, a plain chest

detailed ENT assessment to exclude focal

radiograph is mandatory. A sweat test

infection in the upper airways area

excludes CF and assessment of clinical risks

(adenoids and sinuses).

for primary ciliary dyskinesia helps to

exclude this condition. Pulmonary function

Immunological testing should mainly

testing using basic forced expiration test,

include testing of humoral immunity,

with recordings of flow-volume loop, is then

including concentration of vaccination-

performed. Forced expiration testing can

specific antibodies and total serum IgE.

even be performed with children as young as

Allergic sensitisation should be tested in

3 years of age if properly trained.

context with symptoms and history either by

Reversibility testing should be performed

skin prick tests or specific IgE antibodies.

using an inhaled rapid acting b₂-agonist.

When there is suspicion of a development of

Microbiological testing of sputum is a

bronchiectasis, the diagnostic method of

crucial step. If the child is able to properly

choice is HRCT. Current protocols are fast

expectorate, the sputum should be sent for

and use low-dose techniques. Therefore,

cultures and microscopic evaluation. This

they are considered safe and can even be

should be done before any antibiotics are

used in young children.

administered. If the child is already treated,

the antibiotics should be stopped for at least

Testing of older school children and

48 h. In a child not able to expectorate, deep

adolescents for active smoking using

suctioning from the pyriforms in the

cotinine in urine or carbon monoxide in

morning or after physiotherapy or the cough

exhaled breath can reveal another

swab may help.

contributing factor.

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ERS Handbook: Paediatric Respiratory Medicine

Management and prognosis

of severe sequelae, such as chronic

suppurative lung disease or bronchiectasis.

Uncomplicated PBB is easily treated;

however, untreated persistent bacterial

Acknowledgements

infection and accompanying inflammation is

This work was supported by the Ministry of

associated with development of chronic

Health, Czech Republic (conceptual

suppurative lung disease and

development of research organisation,

bronchiectasis. In most cases the treatment

University Hospital Motol, Prague, Czech

is based on expected or confirmed microbial

Republic; grant number 00064203).

aetiology and broad-spectrum antibiotics

targeted against Haemophillus spp.,

Pneumococcus spp. or Moraxella spp. are

used. As Haemophillus spp. and M.

Further reading

catarrhalis usually produce penicilinase, this

should be respected in the selection of

Bialy L, et al. (2006). The Cochrane Library

antibiotics. Generally, there is an agreement

and chronic cough in children: an

that uncomplicated PBB should resolve after

umbrella review. Evid-Based Child Health;

a 2-week course of an appropriate antibiotic.

1: 736-742.

This was also shown in a randomised

Chang AB, et al.

(2008). Chronic wet

cough: protracted bronchitis, chronic

controlled trial analysing a 2-week course of

suppurative lung disease and bronchiec-

amoxycilline-clavulanate against placebo.

tasis. Pediatr Pulmonol; 43: 519-531.

Children in the active arm showed a

Chang AB, et al. (2011). Diagnosing and

significantly higher resolution rate (48%)

preventing chronic suppurative lung dis-

than children in the placebo arm.

ease (CSLD) and bronchiectasis. Paediatr

Respir Rev; 12: 97-103.

The benefit of antibiotics has also been

Hoek G, et al. (2012). PM10, and chil-

shown in a systematic review that found the

dren’s respiratory symptoms and lung

use of inhaled corticosteroids to be justified

function in the PATY study. Eur Respir J;

in limited situations. There are no consistent

40: 538-547.

data available on the effect of physiotherapy

Kompare M, et al.

(2012). Protracted

in PBB. It is certainly reasonable to employ

bacterial bronchitis in young children:

at least some basic techniques of airway

association with airway malacia. J Pediatr;

clearance, especially in young children.

160: 88-92.

Marchant JM, et al. (2006). Evaluation

Even though the effect of antibiotic

and outcome of young children with

treatment is usually very good, a rather high

chronic cough. Chest; 129: 1132-1141.

frequency of relapse (up to 70%) has been

Marchant J, et al.

(2012). Randomised

described, with good effect when the

controlled trial of amoxycillin clavulanate

antibiotic course is repeated. In a child with

in children with chronic wet cough.

high frequency of recurrence, a prolonged

Thorax; 67: 689-693.

course of antibiotics may be considered. If

Priftis KN, et al.

(2013). Bacterial bron-

an underlying condition is found, it is critical

chitis caused by Streptococcus pneumo-

to treat this pathology together with the

niae and nontypable Haemophilus

treatment of infection.

influenzae in children: the impact of

vaccination. Chest; 143: 152-157.

Conclusion

Qian Z, et al.

(2007). Respiratory

responses to diverse indoor combustion

PBB with chronic wet cough is a diagnosis

air pollution sources. Indoor Air; 17: 135-

that requires attention and should be

142.

suspected in children with protracted

Zgherea D, et al. (2012). Bronchoscopic

coughing. Appropriate diagnosis and early

findings in children with chronic wet

institution of proper management should

cough. Pediatrics; 129: e364-e369.

lead to complete resolution and prevention

ERS Handbook: Paediatric Respiratory Medicine

269

Pulmonary TB, latent TB, and

in vivo and in vitro tests

Zorica Zivković and James Paton

Burden of disease in children

concentration of organisms in children,

,30% of paediatric cases will have

TB in children has been called a ‘‘hidden

bacteriological confirmation of TB;

epidemic’’. Poor ascertainment and

N lack of awareness of multidrug-resistant

reporting of cases in children have hindered

(MDR)-TB in adults and, more especially,

accurate estimates of the global burden of

in children.

TB in children, but in 2011 the World Health

Organization (WHO) estimated there were

In Europe, overall TB rates in children have

490 000 cases of TB in children aged

been declining, and were 4.2 per 100 000 in

,15 years with 64 000 deaths. Children are

2009 although there is wide variation in

also susceptible to the dual epidemics of

rates both within and between countries.

TB/HIV with HIV-infected children at 20

Natural history in children

times greater risk of TB disease than HIV-

uninfected children.

The natural history and presentation of

Mycobacterium tuberculosis infection in

The reasons for underestimating TB in

children is different from adults, being

children include:

strongly influenced by age and immune

status. Children aged ,4 years have a

N children with TB are generally not

greater risk of developing clinical and

infectious: at ,10 years of age children

radiographic complications shortly after

develop pauci-bacillary types of TB and

infection, but will rarely present with

are usually not infectious compared to

reactivation of disease in adulthood.

adults with caseating pulmonary TB;

Teenagers develop forms of the disease

N difficulties in confirming a case of

more typical of adults.

childhood TB: because of the inability to

produce sputum and the low

M. tuberculosis infects almost all children via

inhalation by the respiratory tract, usually

from an infectious adult in their close

Key points

environment. A number of factors influence

the likelihood of infection including:

N TB remains a major, but often

unrecognised, cause of disease and

N intensity and duration of exposure to the

death in children.

infectious case,

N ability of the infectious case to cough and

Children with TB are generally not

generate an infectious aerosol,

infectious.

N virulence of the organism,

N TB in children generally reflects active

N age,

disease in the adult population.

N innate and acquired immune defences of

the child exposed.

N Treating TB in children is not

straightforward.

In the pulmonary alveoli, M. tuberculosis

organisms are ingested by alveolar

270

ERS Handbook: Paediatric Respiratory Medicine

macrophages and may be killed without

Enlarged mediastinal lymph nodes do not

causing further problems (fig. 1).

usually cause problems but they can

compress the airways producing ventilation

The organisms that survive initiate a

disturbances and, occasionally, complete

localised granulomatous inflammatory

bronchial obstruction and distal atelectatic

process in the mid to upper zones of the

changes in the affected segment. If

lung, the Gohn focus. In most cases, the

caseating lymph nodes liquefy, there may be

centre of this focus undergoes caseous

local extension and distant haematogenous

necrosis. M. tuberculosis bacilli, either free or

spread of M. tuberculosis organisms. If the

within phagocytes, drain to the main

lymph nodes are sub-carinal, infection can

regional, mediastinal lymph nodes (hilar,

spread to adjacent structures such as the

para-tracheal and sub-carinal), which also

heart, causing pericarditis, or the

often caseate. Enlarged regional lymph

oesophagus resulting in a tracheo-

nodes along with the Gohn focus and the

oesophageal fistula. Haematogenous

local tuberculous lymphangitis constitute

spread seeds M. tuberculosis in others

the primary complex. The enlarged regional

tissues and organs. Disseminated TB

lymph nodes can be seen in 50-70% of

appears when multiple foci develop in the

children on good quality plain radiographs.

lungs or other organs.

From the regional lymph nodes, bacilli can

The natural history of primary TB in children

enter the systemic circulation. Occult

follows a typical time-course. In the vast

haematogenous spread can occur before the

majority, disease occurs within 2 years of

immune response contains the disease. The

primary exposure infection with the very

disseminated bacilli can then survive in

young (0-4 year) and the

target organs for long periods of time.

immunocompromised being most at risk.

Massive lympho-haematogenous

The immune response, marked by the

dissemination leading to miliary or other

development of a positive tuberculin skin

disseminated disease is uncommon and

test (TST), develops about 3-8 weeks after

occurs in 0.5-2% of cases usually between 3

primary infection and it usually stops the

and 39 months after lymph node

multiplication of M. tuberculosis. The end of

involvement. Bone and joint TB develop

the asymptomatic incubation period and the

later, usually a few years after infection.

development of an immune response may

be marked by immune hypersensitivity

Only a small proportion of children with TB

reactions. These include nonspecific, self-

develop post-primary TB, either due to

limiting viral-like symptoms such as fever,

reactivation or re-infection. Adult-type

or, more rarely, florid reactions such as

disease can follow recent primary infection

erythema nodosum. In most cases the child

in children aged .10 years, particularly girls

will have no symptoms.

around the age of menarche.

In the majority of children, the primary

Age and risk of progression The risk of TB

complex heals completely and the organisms

after infection in children varies with age

are contained by the cell-mediated immune

(table 1). In children aged ,2 years, the risk

response within the tissues. In up to 50% of

is as high as 50% with most disease

children, the regional lymph nodes calcify

occurring within 6 months of infection. With

within 12-24 months indicating the disease

the onset of puberty, the risk rises again and

is quiescent. But M. tuberculosis can persist in

there is a switch in disease phenotype to

calcified lymph nodes and dormant orga-

adult-type cavitary disease.

nisms may reactivate to cause TB later in life.

Sites of disease Pulmonary TB Most children

Sometimes, following primary infection, a

with TB have pulmonary TB (fig. 2).

parenchymal lesion continues to enlarge

and spread resulting in focal pneumonitis

More than half of children with TB will have

and pleural involvement (primary

chest radiographic changes with no

progressive TB).

symptoms or clinical signs of disease and

272

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Age-specific risk of progress after primary infection in immunocompetent children

Age years

Risk of disease progression following exposure

No disease: 50%

Pulmonary disease (Ghon focus, lymph node or bronchial): 30-40%

Tuberculous meningitis or miliary disease: 10-20%

1-2

No disease: 70-80%

Pulmonary disease (Ghon focus, lymph node or bronchial): 10-20%

Tuberculous meningitis or miliary disease: 2-5%

2-5

No disease: 95%

Pulmonary disease (lymph node or bronchial): 5%

Tuberculous meningitis or miliary disease: 0.5%

5-10

No disease: 98%

Pulmonary disease (lymph node, bronchial effusion or adult type): 2%

Tuberculous meningitis or miliary disease: ,0.5%

.10

No disease: 80-90%

Pulmonary disease: 10-20%

Tuberculous meningitis or miliary disease: 0.5%

Reproduced from Marais et al. (2004) with permission from the publisher.

are identified only through contact tracing.

Extra-pulmonary TB in children develops by

Infants have more intensive symptoms of

dissemination of M. tuberculosis through

TB, while school age children may have

lymphatic and haematogenous spread with

disease that is not clinically apparent.

the development of foci in various organs.

Adolescents develop adult-type TB and can

present with parenchymal destruction and

Miliary TB characteristically occurs in

cavity formation. Such children will be

immunocompromised and malnourished

sputum-smear positive and are able to

children with infants being the most

transmit infection. Pleural effusions are rare

vulnerable. Typical miliary changes on chest

in children aged ,5 years and are most

radiographs take 1-3 weeks to develop. The

common in adolescent boys.

illness can progress rapidly and the

prognosis is poor. TB meningitis is the most

200

serious complication in childhood with a

risk of significant long-term neurological

150

seqeulae and death if diagnosis is delayed or

treatment inadequate. Bone and joint TB is

100

mainly mono-articular involving the spine,

hip or knee.

Congenital TB: M. tuberculosis infection may

be acquired before birth during intrauterine

life, perinatally or post-natally. In a pregnant

female with active TB, M. tuberculosis can be

transmitted transplacentally from the blood

stream of the mother to fetal blood. Once in

Site of infection

the fetal circulation, the organisms spread

by the umbilical veins to tissues and organs,

Figure 2. The different sites of infection in children

mainly to the liver and spleen. Symptoms

with TB in the UK from 1988-1998. Orange bars

(failure to thrive, jaundice and

signify pulmonary disease. CNS: central nervous

hepatosplenomegaly) develop within a

system. Information from Balasegaram et al. (2003).

couple of weeks after birth.

ERS Handbook: Paediatric Respiratory Medicine

273

A newborn infant may also acquire M.

onset were highly sensitive and specific

tuberculosis infection during delivery or soon

markers of TB. A persistent non-remitting

after through the close contact with an

cough in childhood was almost exclusively

infectious case, e.g. breast feeding mother.

associated with TB (table 2). As a result, in

In this situation, nonspecific respiratory

this setting clinical follow-up was a useful

symptoms develop after 3-4 weeks. Chest

diagnostic tool because a non-remitting

radiography is not diagnostic and a TST may

cough persisting beyond 2-4 weeks was

be negative.

uncommon other than with TB, and no child

whose symptoms spontaneously resolved

Diagnosing TB

was diagnosed with TB in the following

History and examination Children are usually

6 months.

evaluated for TB either after presenting with

There are no specific identifying physical

symptoms or signs suggestive of TB

signs that unequivocally establish that a

(passive case finding) or, most commonly,

child has TB. Some signs are highly

as a result of contact investigation or routine

suggestive of extrapulmonary TB (e.g.

new entrant immigrant screening (active

gibbus of recent onset and painless cervical

case finding). The clinical presentation is

adenopathy with fistula) while other signs

different between these two groups with

require investigation to exclude

children detected through active case

extrapulmonary TB (e.g. pleural effusion,

finding often having either TB infection or

phlyctenular conjunctivitis and erythema

TB disease in a very early phase.

nodosum).

History of contact Since children generally

Tests of adaptive immunity

acquire TB following exposure to a sputum-

positive case of pulmonary TB, a key piece of

For more than 100 years, the TST was the

diagnostic information is a history of close

only test available to detect infection with M.

contact with an infectious source case. The

tuberculosis. The test involves the

WHO defines close contact as living in the

intradermal injection of purified protein

same household as or being in frequent

derivatives derived from M. tuberculosis.

contact with sputum smear-positive

There are a number of TSTs available but the

pulmonary TB cases. Cases of smear-

WHO recommends using the Mantoux test.

negative TB that are sputum culture positive

Interpretation of the TST test depends on

are also infectious but to a much lesser

the clinical situation. In children identified

degree.

by active case finding, or in those where TB

is suspected clinically, induration of .5 mm

The infection risk from close household

in children who have not had a Bacillus

contact is greatest for infants and young

Calmette-Guérin (BCG) vaccination or are

children ,5 years of age (table 1). Apart

at high risk, or induration of .10 mm

from age, other important risk factors for TB

(according to WHO or .15 mm in other

include HIV infection and severe

countries) in all other children (whether they

malnutrition.

have had a BCG vaccination or not) should

Symptoms and signs In children identified

be considered to indicate infection.

through active case finding who have

radiographic changes of TB, more than half

Unfortunately, the TST has problems with

will have no symptoms or signs of disease.

both false-positive and false-negative

results. This has led to the development of

For children with symptoms, well-defined

peripheral blood T-cell-based interferon

symptoms of recent onset that are

(IFN)-c assays. Two are commercially

persistent and non-remitting are typical of

available:

TB. The frequency of the five most relevant

symptoms from a community study in South

N whole blood IFN-c release assay (IGRA)

Africa is shown in table 2. Both persistent

(QuantiFERON Gold; Cellestis Ltd,

cough and/or persistent fatigue of recent

Victoria, Australia);

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Persisting non-remitting symptoms in children aged ,13 years in Cape Town, South Africa, presenting to the

local community clinic with a cough .2 weeks duration

Symptom

No TB^#

TB^"

Odds ratio

Cough

(1.6)

(93.8)

2010.0

Chest pain

(0)

(25)

Weight loss

(2.6)

(37.5)

25.0

Fatigue

(0.8)

(81.3)

580.7

Fever

(0)

(25)

Data are presented as n (%), unless otherwise stated. NA: not available.^#: n5135;^": n516. Reproduced from

the International Union Against Tuberculosis and Lung Disease; Copyright The Union (Marais et al., 2005)

with permission.

N an enzyme linked immunospot assay (T-

typically hilar and mediastinal

SPOT.TB; Oxford Immunotec, Oxford,

lymphadenopathy (figs 3 and 4).

UK).

Extraluminal compression of the enlarged

lymph nodes may cause partial luminal

IGRAs measure IFN-c production ex vivo by

obstruction of the airway leading to

circulating T-lymphocytes when incubated in

radiographic signs of hyperinflation and

the presence of highly specific M.

‘‘air-trapping’’. Caseous lymph node may

tuberculosis antigens (early secreted

ulcerate into the airway closing the lumen

antigenic target (ESTA)-6 and culture filtrate

completely and causing distal atelectasis.

protein (CFP)-10). IGRAs are more specific

Persistent pulmonary opacification,

than the TST and can distinguish a positive

especially if there is no improvement with

TST due to BCG vaccination or to

antibiotics, along with prominent hilar or

environmental atypical mycobacterial

subcarinal adenopathy is highly suggestive

(NTM) infection from a positive TST test

of TB.

due to infection with M. tuberculosis.

However, despite their greater specificity,

A chest CT may be very useful in

IGRAs cannot differentiate between active

demonstrating early cavitation and

and latent TB, and a negative IGRA test does

bronchiectasis. However, while HRCT offers

not exclude TB.

excellent visualisation of mediastinal lymph

nodes, treatment algorithms for latent TB

Neither the TST nor the IGRA test can

and pulmonary TB in children have been

differentiate latent infection from active

disease and neither test should be used for

the diagnosis of active TB. The place of

IGRA tests in children, particularly young

children aged ,5 years, is still being

evaluated. The TST and IGRA tests may be

complementary, improving the sensitivity

and specificity of the assessment in specific

clinical circumstances. At present, the WHO

recommends that for children in low- and

middle-income countries IGRA tests should

not be used in place of the TST for the

diagnosis of latent TB infection (LTBI).

Radiography and other imaging techniques

The majority of children with pulmonary TB

Figure 3. Right mediastinal lymphadenopathy in a

will have chest radiography changes,

child with TB.

ERS Handbook: Paediatric Respiratory Medicine

275

Figure 6. Chest radiograph from a 15-year-old boy

Figure 4. Right upper lobe atelectasis and hilar

with TB with right lower lobe atelectasis and

adenopathy in a child with TB.

pleural effusion.

diagnosis of TB more difficult than in adults.

based on plain radiographs. Accordingly,

Microbiological confirmation is commonly

chest CT is usually reserved for more

not achieved, and in many cases is not even

complex cases.

attempted. The European Centre for Disease

Bronchoscopy may be useful in children with

Prevention and Control estimated between

areas of atelectasis where compression by

2000 and 2009 that less than one in six

lymph nodes or caseating material

children had their diagnosis confirmed by

ulcerating through an airway can be

TB culture. Nevertheless, a positive culture

visualised (fig. 5).

for M. tuberculosis remains the gold standard

for the diagnosis of TB. Microbiological

Ultrasound can identify and guide drainage

confirmation is increasingly important

of pleural, pericardial or abdominal

because of the increase in drug-resistant TB.

effusions (fig. 6) and can help in guiding

The WHO recommends that bacteriological

fine-needle aspiration of lymph nodes.

confirmation should be sought wherever

possible. Appropriate samples from

Microbiological confirmation

suspected sites of involvement should be

Children generally have pauci-bacillary

obtained for microscopy and culture and, if

disease, which makes microbiological

appropriate, histopathology. However,

culture can take weeks and is consequently

unavailable to inform clinical decisions at

the start of treatment.

Collecting samples Sputum samples from

spontaneous coughing may be obtainable in

older children (.10 years). In younger

children, particularly those ,5 years,

sputum is more difficult to obtain. Smaller

amounts of sputum are produced and are

swallowed rather than expectorated.

Consequently, most children are sputum-

smear negative even when optimised

techniques are used. Bacteriological

samples can be collected by three early

Figure 5. Extramural compression demonstrated

morning gastric washings via nasogastric

on bronchoscopy with broadening of main carinal

tube, following an overnight fast. More

bifurcation due to subcarinal lymphadenopathy.

recently, sputum induction following

276

ERS Handbook: Paediatric Respiratory Medicine

nebulisation with hypertonic saline (3-5%)

sputum and was not affected by whether a

has been shown to be safe and effective in

child had HIV or not.

children of all ages with bacterial yields as

HIV testing In high prevalence areas where

good, or better than, for gastric aspirate.

TB and HIV are likely to coexist, or in low

One induced sputum specimen provides a

prevalence areas where risk factors are

similar microbiological yield to three gastric

identified for HIV, HIV counselling and

lavage specimens in children admitted to

testing is indicated.

hospital with pulmonary TB. However, the

technique requires training and equipment

Making the diagnosis: putting it altogether In

and staff need to follow effective infection

children, because microbiological

control procedures appropriate for

confirmation is commonly not available, the

infectious aerosol exposure. At least two

diagnosis of TB is often based on a careful

samples should be collected.

assessment of the available evidence and a

TB lymphadenitis is a common form of

high index of suspicion. TB can mimic many

extrapulmonary TB. Fine-needle aspiration

common childhood diseases. However, a

of accessible enlarged lymph glands has

combination of clinical, radiological and

been shown to be useful with a high

laboratory findings along with a history of

bacteriological yield. Aspiration of

TB exposure and immunological evidence of

cerebrospinal fluid, pleural or other fluids

M. tuberculosis allows an accurate diagnosis

may also provide material for microscopy

in most cases.

and culture in appropriate situations.

Treatment of TB

Molecular testing Molecular testing

Management of active TB Because large

techniques are being developed for TB. One

studies in children are generally lacking, the

system, the Xpert MTB/RIF (Cepheid,

principles of drug treatment and

Sunnyvale, CA, USA) has been endorsed by

recommended drug regimens are the same

the WHO as an initial diagnostic test in

as for adults. TB should never be treated

people suspected of having drug-resistant or

with a single drug; a single drug should

HIV-associated TB. This system combines

never be added to a failing regime because

integrated sample processing and a nucleic

acid amplification test for the detection of

of the risk of developing drug resistance.

M. tuberculosis and rifampicin resistance.

Although every effort should be made to

The test can detect resistance to rifampicin

attain a microbiological diagnosis, the

with a high degree of sensitivity and

threshold for starting treatment therapy

specificity. Results are available much more

empirically is lower for children, especially

quickly than culture results, often within

for young children where potentially life-

1 day of testing.

threatening conditions such as TB

In one large South African study in children,

meningitis or miliary TB can develop quickly.

when two induced sputum samples were

Fortunately, drug-related adverse events are

used, the MTB/RIF tests were shown to

rare in young children treated with first-line

detect three-quarters of culture confirmed

drugs and they are at low risk for acquiring

cases of pulmonary TB with a very high

or transmitting drug-resistant disease.

specificity. The test had a lower sensitivity in

smear negative cases with two tests

The goals of treatment are to cure the

detecting ,60% of cases. Thus a negative

individual and prevent late complications, as

MTB/RIF test cannot rule out TB and has to

well as to decrease transmission to others and

be interpreted in the context of other clinical

prevent the development of drug resistance.

and radiological findings. MTB/RIF testing

Successful TB treatment requires more than

was more sensitive than smear microscopy

just anti-TB chemotherapy medicines.

detecting twice as many cases. It worked

Medications need be provided within an

well with gastric lavage aspirate samples

appropriate clinical and social framework if an

with an accuracy similar to testing induced

effective cure is to be achieved.

ERS Handbook: Paediatric Respiratory Medicine

277

Combination anti-tuberculous regimens

Recommended treatment regimens are listed

Combination regimens are used to treat

in table 3.

active disease. The aim is to eliminate both

Recommended drug doses The WHO has

actively replicating and dormant or near-

recently recommended revising the doses of

dormant mycobacteria by using a

the main first-line anti-TB drugs for HIV-

combination of drugs with different anti-

uninfected children (table 4). At present,

mycobacterial actions while minimising

HIV-infected children should receive the

toxicity and preventing the emergence of

same dosages of anti-TB therapy as HIV-

drug-resistant organisms.

uninfected children.

Bactericidal drugs are used to kill actively

Treatment should be given daily. Thrice

metabolising and replicating organisms.

weekly regimens should only be considered

They bring about a rapid reduction in

during the continuation phase for children

microbial load leading to clinical

known to be HIV uninfected living in

improvement, preventing disease

settings with well-established directly

progression and stopping transmission.

observed therapy (DOT) programmes.

Isoniazid (H) and rifampicin (R) are the

most important first-line drugs with

Adherence Ensuring adherence to the long

isonizaid having the most important

courses of treatment used for treating TB is

bactericidal activity.

a major problem. Poor adherence is an

important factor in the emergence of

Sterilising drugs aim to eradicate organisms

resistance to TB therapy and in treatment

that are less metabolically active in order to

failure. The WHO recommends that all

prevent relapse. Rifampicin (R) and

children should receive TB drugs free of

pyrazinamide (Z) are important first-line

charge irrespective of whether the child is

sterilising agents. Protection against the

smear positive at diagnosis or not. Fixed-

emergence of drug-resistant organism is

dose combinations of drugs should be used

achieved through the combination of

whenever possible. These simplify

effective bactericidal activity with effective

adherence and minimise the risk of

sterilising activity and is strengthened by the

developing drug resistance. However, this is

addition of ethambutol (E).

often not possible in children because of a

Treatment regimens The drugs and

lack of suitable drug combinations. In

treatment regimens for TB in children are

addition, there is a lack of drug formulations

the same as those used in adults.

suitable for children, e.g. liquids.

Recommended regimens are based on

Children, parents and families should be

national programmes recommended for a

educated about TB and the importance of

particular country (if one exists), or by the

completing treatment. Providing anti-TB

WHO.

medications directly to the patient and

In Europe, the most frequent scenario is that

watching them take them is termed DOT

the M. tuberculosis is sensitive to all first-line

and is recommended for all patients

agents. Consequently, for new cases of

diagnosed with TB. As a minimum, all

pulmonary TB in children (smear positive or

children and families should be assessed for

negative), the current WHO recommenda-

the risk that adherence is likely to be poor

tions for Europe are treatment with the four

and DOT should be used for those at high

first-line drugs (HRZE) for 2 months as an

risk of non-adherence. A healthcare worker

initial bactericidal regimen. After 2 months,

or a trained community worker can

treatment is continued with a prolonged

administer DOT. In some settings, children

sterilising regime of H and R for a further

with severe disease, such as TB meningitis,

4 months. In some less developed countries,

or with severe side-effects may need

the initial 2 months of treatment is given in

prolonged hospitalisation during the first

hospital to ensure administration. In children,

2 months of treatment to ensure that

TB relapse or reactivation occurs rarely.

treatment is successfully delivered.

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ERS Handbook: Paediatric Respiratory Medicine

Table 3. Treatment regimens for children with TB as recommended by the World Health Organization (WHO)

TB cases and diagnostic criteria

Anti-TB drug regimen

Intensive phase

Continuation phase

New smear-positive pulmonary TB

2 months HRZE

4 months HR

Smear-negative pulmonary TB

2 months HRZE

4 months HR

with extensive parenchymal

involvement

Extrapulmonary TB-peripheral

2 months HRZE

4 months HR

adenitis

Tuberculous meningitis

2 months HRZE

10 months HR

TB osteoarthritis

2 months HRZE

10 months HR

MDR-TB

Individualised regimens

H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol.

Side-effects Hepatotoxicity is the major

childhood. Screening for visual related side-

drug-related adverse event, with case

effects is not required.

reports of hepatic failure even when

Other drugs Corticosteroids may be used for

recommended doses of anti-tuberculous

the management of some specific cardio-

therapies are used. However, extensive

respiratory complications of TB, e.g. airway

experience has demonstrated that the first-

obstruction and atelectasis secondary to TB

line drugs used in treating TB are well

mediastinal lymph gland enlargement, or

tolerated in children with a low risk of side-

pericardial TB. Corticosteroids have been

effects. Indeed, the drugs are better

used in advanced pulmonary disease with

tolerated in children than adults perhaps

clinical and radiological benefits. They are

because of the lower peak serum levels

recommended for all children with TB

achieved in children when using the same

meningitis. Prednisolone (1-2 mg?kg^-1 daily

dose per kg as adults.

for 3-4 weeks and then tapered) has been

Hepatotoxicity may be detected more

the most commonly used drug. Rifampicin

frequently in children who are malnourished,

induces hepatic enzymes that catabolise

immunocompromised, e.g. with HIV

corticosteroids and reduce effective

infection, or who present with extensive and

bioavailability by ,50%.

serious TB disease. If signs of hepato-

Corticosteroids are also used in the

toxicity develop (vomiting, jaundice, liver

management of the immune reconstitution

tenderness and hepatomegaly) all drugs

syndrome (also known as paradoxical

should be stopped and levels of hepatic

reaction). In this, a temporary deterioration

enzymes monitored. Reintroduction of anti-

occurs after the start of anti-tuberculous

TB therapy should not be tried until liver

treatment due to restitution of the capacity

function is normal and should then proceed

to mount an inflammatory immune

on a step-wise basis with one drug

response. It may cause fever, increased

reintroduced at a time.

lymph node size and tuberculomas. It can

Ethambutol is now recommended for use in

occur after the start of anti-TB treatment,

children of all ages including those aged

e.g. commonly as the enlargement of the

,5 years. At the recommended doses and

mediastinal lymph node on chest

durations, a review of the evidence

radiographs, after improved nutrition or

suggested that ethambutol is safe with a

following the initiation of antiretroviral

negligible risk of toxicity throughout

therapy in children with HIV infection.

ERS Handbook: Paediatric Respiratory Medicine

279

Table 4. Recommended doses for first-line anti-TB drugs for the treatment of TB in children aged .3 months

Drug

Daily dose (range) mg?kg^-1

Isoniazid

(10-15), maximum 300 mg daily

Rifampicin

(10-20), maximum 600 mg daily

Pyrazinamide

(30-40)

Ethambutol

(15-25)

Management of drug-resistant TB in

Children with TB who are co-infected with

children

HIV

Rates of resistant TB are increasing. Drug

Children with TB should be screened for

resistance originates in adults with TB who

HIV. Similarly, children newly diagnosed for

have a high bacillary load and who receive

HIV should be screened for TB by history

inadequate anti-tuberculous therapy or are

and chest radiograph. Drug interactions

poorly compliant. Acquisition of resistance

between HIV antiretroviral therapy and the

is rare in the pauci-bacillary disease that

similar side-effect profiles of the drugs

occurs in children.

involved in treating the two diseases make

managing the two treatments challenging.

Resistance to isoniazid and/or rifampicin is

Rifampicin, in particular, reduces the

most important because these two drugs are

concentrations of many HIV drugs. For

the mainstay of current first line treatment.

children with significant

In MDR-TB, the organism is resistant to

immunosuppression, treatment for HIV

both rifampicin and isoniazid with or

should be delayed for 2-8 weeks once anti-

without resistance to other anti-TB drugs.

tuberculous treatment is started. For those

Infection is usually the result of

with mild or no immunosuppression,

transmission of a strain of MDR-TB from an

treatment for HIV may be deferred until

adult index case.

treatment of TB is completed.

Treatment is often complex and specialist

Guidelines recommend that TB in HIV-

advice should be sought. There is

infected children should be treated with a 6-

uncertainty about activity and safety of the

month regimen as for uninfected children.

available second line drugs. Suitable

The WHO recommends that rifampicin

formulations for children are often not

should be used for the entire duration of

available. If an isolate from the child is not

treatment. In children, intermittent

available, the best guide to treatment is the

regimens (twice or thrice weekly) should not

susceptibility pattern of the adult source

be used in areas with high HIV prevalence

case. In general, at least four drugs certain

for the treatment of pulmonary TB or TB

to be effective (and to which the child is

lymphadenitis.

naïve), including an injectable and a

fluorquinolone, are given on a daily basis

Immune recovery in children with HIV after

using DOT for an extended initial period of

initiation of antiretroviral therapy, nutritional

6 months followed by at least three of the

rehabilitation or sometimes just beginning

most active and best tolerated drugs for a

anti-TB therapy may unmask subclinical

further period of 12-18 months.

disease or induce a paradoxical temporary

deterioration despite adequate therapy for

Current recommendations are to avoid

TB, the so-called immune response

using primary chemoprophylaxis or

inflammatory syndrome (IRIS). This can

treatment for latent TB in cases of close

simulate worsening TB disease with fever

contact with a case of MDR-TB if the child is

and increased size of lymph nodes or

clinically well, and to observe for 2 years.

tuberculomas. Treatment for TB should not

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ERS Handbook: Paediatric Respiratory Medicine

be interrupted. A course of steroids may be

For the last 20 years, WHO guidelines have

required for severe IRIS.

recommended that all children aged

,5 years (irrespective of BCG status) in

In adults with HIV-infection in endemic areas,

close contact with an infectious (usually

the use of secondary isoniazid preventive

smear positive) case of TB receive 6-

therapy after completion of TB therapy

9 months isoniazid therapy. However,

significantly reduces the risk of recurrent TB.

screening is frequently not provided in

The WHO has therefore recommended 6-

endemic areas. Treatment with isoniazid for

36 months isoniazid therapy in all patients

9 months has been established to reduce

with HIV infection including children living in

the risk in exposed children by .90% if

high-prevalence areas of TB.

adherence is good. A shorter 3-month

course of rifampicin and isoniazid has been

The WHO has recently published updated

shown to be equally effective and may

policy guidelines for the collaborative

improve treatment compliance. Before

management of TB and HIV.

treating latent TB it is important to exclude

TB control and prevention

active TB by a chest radiograph and/or

symptom review.

Preventive chemotherapy TB preventive

therapy is important in two broad categories

Unfortunately, the implementation of

of children:

preventive strategies has been poor because

parents are often reluctant to provide

children who have been recently

preventive treatment to a well child and

exposed to M. tuberculosis, e.g. following

because of the long duration of treatment

close contact with an infected case;

required.

children at increased risk of progression

Treatment for TB exposed children with HIV

of M. tuberculosis infection to TB

In HIV-infected children the value of post-TB

because of age or other clinical

exposure prophylaxis and the need for

conditions, such as HIV.

careful ongoing screening is clear. Isoniazid

preventive therapy is indicated following

Controlled trials have focused on preventing

every documented exposure to TB,

progression from latent infection to active

particularly for the young and the

disease by providing a limited course of

immunosuppressed. The value of pre-

treatment (either in duration or number of

exposure routine chemoprophylaxis in

drugs) to sterilise existing subclinical

children with HIV remains uncertain.

lesions and prevent future progression to TB

disease (treatment of LTBI). Genuine

BCG vaccination is a live attenuated vaccine

primary prevention (primary

derived from Mycobacterium bovis prepared

chemoprophylaxis) is used to prevent

as a freeze-dried powder for suspension

primary infections from becoming

prior to injection. It was first used in

established during/after a period of contact

humans in 1921 and is one of the most

with an infectious case. Preventing

widely used of all vaccines.

recurrence of TB may be targeted by

‘‘secondary chemoprophylaxis’’ provided

The BCG vaccination is given intradermally

after successful completion of therapy.

normally into the lateral aspect of the left

upper arm at the level of the insertion of the

Treatment of children recently infected

deltoid muscle (the left arm is

Treating recently infected children and

recommended by the WHO).

preventing progression to active TB

(treatment of LTBI) eliminates reservoirs of

Vaccination soon after birth is

M. tuberculosis and prevents later

recommended in high-prevalence countries.

reactivation disease. Such treatment is

Low-prevalence countries use risk-based

particularly important in young children

strategies targeting neonatal BCG

because of the higher risks of disease

vaccination to protect those children most

progression.

at risk from exposure to TB. Targeted

ERS Handbook: Paediatric Respiratory Medicine

281

approaches require careful ongoing audit to

New developments Intensive research is

ensure that high proportions of those at-risk

underway to develop more effective TB

continue to be vaccinated.

vaccines and has followed two basic

approaches. The first aims at replacing BCG

Effectiveness in preventing progression to

by either improved recombinant (r)BCG or

disease Studies of the effectiveness of BCG in

by genetically attenuated M. tuberculosis. The

protecting against TB have given widely

second approach focuses on subunit

varying results, ranging from no protection

vaccines, which may be used as booster

in some studies in India to 70-80%

vaccines on top of BCG-, recombinant BCG-

protection in UK school children. The

or attenuated M. tuberculosis-priming

reasons for the variation in efficacy in

vaccines. Around 12 candidate vaccines are

different regions of the world are not well

currently in clinical testing.

understood.

Importance of well-functioning TB control

BCG vaccination has been shown

programmes

consistently to be 70-80% effective in

preventing against TB meningitis and

Children are generally infected with TB by

miliary TB, the more severe forms of

close contact with an infectious adult,

disseminated disease that occur in young

therefore, early diagnosis and treatment of

children. Recent studies combining IGRA

adult infectious cases is the best way to stop

and TST have suggested that BCG may also

children from becoming infected. A well-

protect against TB infection reducing the

functioning TB control system, which

risk of primary TB infection and the

ensures the early diagnosis and treatment of

development of latent TB infection by up to

infectious adults with TB, has a key role in

50%. However, BCG offers no consistent

preventing TB in children.

protection against adult-type TB with the

most limited protection in geographical

Within hospitals and clinics, the risk of

areas such as India where TB is most

infection to healthcare workers from

prevalent.

paediatric patients with primary TB

appears to be minimal, and most children

Levels of protection from the BCG fall with

with TB do not need isolation. However, it

time with the best estimates of suggesting

is important to remember that

protection for around 10 years. BCG is not

symptomatic parents or caregivers may

protective if given to those already infected

have TB and pose an infection risk.

and revaccination does not seem to offer

Infection control efforts should, therefore,

substantial re-protection.

be focused on accompanying adults and

adult visitors.

Side-effects BCG is the one of the most

widely administered vaccines worldwide and

only a small number of children (1-2%)

Further reading

develop an adverse effect. The most

Balasegaram S, et al. (2003). A decade of

common complications are local abscesses,

change: tuberculosis in England and

secondary bacterial infections and

Wales 1988-98. Arch Dis Child; 88: 772-

suppurative adenitis or keloid formation.

777.

Serious adverse effects are rare.

Ena J, et al. (2005). Short-course therapy

with rifampin plus isoniazid, compared

However, individuals with genetic defects in

with standard therapy with isoniazid, for

key immune genes or, more commonly,

latent tuberculosis infection: a meta-

infants with clinically active HIV infection

analysis. Clin Infect Dis; 40: 670-676.

are highly susceptible to developing

Manabe YC, et al.

(2000). Latent

disseminated BCG disease. As a live vaccine

Mycobacterium tuberculosis - persistence,

BCG should not be used in children with

patience, and winning by waiting. Nat

HIV/AIDS or in children with congenital

Med; 6: 1327-1329.

immune deficiencies.

282

ERS Handbook: Paediatric Respiratory Medicine

Mandalakas AM, et al. (2011). Interferon-

Stop TB Partnership Childhood TB

gamma release assays and childhood tuber-

Subgroup World Health Organization

culosis: systematic review and meta-analy-

(2006b). Guidance for national tubercu-

sis. Int J Tuberc Lung Dis; 15: 1018-1032.

losis programmes on the management of

Marais BJ, et al.

(2004). The natural

tuberculosis in children. Chapter 2: anti-

history of childhood intra-thoracic tuber-

tuberculosis treatment in children. Int J

culosis: a critical review of literature from

Tuberc Lung Dis; 10: 1205-1211.

the pre-chemotherapy era. Int J Tuberc

World Health Organization. Rapid advice:

Lung Dis; 8: 392-402.

treatment of tuberculosis in children.

Marais BJ, et al.

(2005). Well defined

Geneva, WHO, 2010.

symptoms are of value in the diagnosis of

World Health Organization. Use of tuber-

childhood pulmonary tuberculosis. Arch

culosis interferon-gamma release assays

Dis Child; 90: 1162-1165.

(IGRAs) in low- and middle-income

Nicol MP, et al. (2011). Accuracy of the

countries. Policy Statement. Geneva,

Xpert MTB/RIF test for the diagnosis of

WHO, 2011.

pulmonary tuberculosis in children

World Health Organization. Global tuber-

admitted to hospital in Cape Town,

culosis report. Geneva, WHO, 2012a.

South Africa: a descriptive study. Lancet

World Health Organization. Policy on

Infect Dis; 11: 819-824.

collaborative TB/HIV activities; guidelines

Stop TB Partnership Childhood TB

for national programmes and other sta-

Subgroup World Health Organization

keholders. Geneva, WHO, 2012b.

(2006a). Guidance for National Tuber-

Wright CA, et al.

(2009). Fine-needle

culosis Programmes on the management

aspiration biopsy: a first-line diagnostic

of tuberculosis in children. Chapter

procedure in paediatric tuberculosis

introduction and diagnosis of tuberculosis

suspects with peripheral lymphadeno-

in children. Int J Tuberc Lung Dis; 10: 1091-

pathy? Int J Tuberc Lung Dis; 13: 1373-

1097.

1379.

ERS Handbook: Paediatric Respiratory Medicine

283

Extrapulmonary TB and TB in

the immunocompromised

host

Toyin Togun, Uzor Egere and Beate Kampmann

Globally, an estimated 11% of the nearly 10

The risk of disease progression and

million new cases of active TB diagnosed

extrapulmonary dissemination is highest in

annually occur in the paediatric population,

the first 2 years of life, with risk of disease

but the true burden of TB in children

progression estimated at 40-50% in the

remains underestimated.

absence of Bacille Calmette-Guérin (BCG)

vaccination or prophylactic therapy. The

Extrapulmonary TB is common in children

majority of disease occurs within 2-

and refers to the isolated occurrence of

12 months of initial infection with

active TB at body sites other than the lung.

pulmonary TB accounting for 60-80% of all

The exact mechanisms that determine the

cases.

clinical outcomes following infection in

Extrapulmonary TB usually originates from

children are not completely understood, but

lymphohaematogenous spread of TB bacilli

include:

from a primary pulmonary focus,

contiguous spread from infected lymph

N age,

nodes or direct inoculation of bacilli.

N nutritional status,

Generally, superficial lymphadenopathy is

N underlying immunity,

the most common form followed by central

N vaccination status,

nervous system (CNS) disease, pleural,

N genetic susceptibility,

miliary/disseminated and skeletal TB. Less

N microbial virulence.

common forms include abdominal,

pericardial, renal and cutaneous TB.

Key points

The role of age-related immune responses

in clinical manifestations of TB in children

N Young children are more likely to

It is well established that less mature or

develop extrapulmonary

impaired immune responses contribute to

manifestations of TB, associated with

the disseminated forms of TB seen in

age-related impairment of cellular

children and immunocompromised hosts.

immune responses.

A number of studies have reported an age-

N Extrapulmonary TB can have very

related functional impairment of both innate

severe consequences and thorough

and adaptive immune responses in children.

investigations and prolonged therapy

The current paradigm in TB immunology is

are required.

the crucial importance of Mycobacterium

Conditions of immunosuppression, in

tuberculosis-specific CD4⁺ T-cells and the key

particular HIV, are more likely to lead

cytokines such as interferon gamma (IFN)-c

to extrapulmonary severe

produced in the protection against M.

manifestations. This is proportionate

tuberculosis. However, M. tuberculosis-

to the level of suppression of T-cell

specific IFN-c responses alone are not an

function.

absolute correlate of protection against the

development of TB.

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Following inhalation of M. tuberculosis in

increase the risk of TB disease progression

infected aerosols into the terminal alveoli, it

in children.

is immediately engulfed by resident

Genetic susceptibility to TB

phagocytes including the alveolar

macrophages and dendritic cells. Activated

Mendelian susceptibility to mycobacterial

macrophages infected with M. tuberculosis

diseases (MSMD) Additional evidence of the

induce the synthesis and secretion of

importance of cell-mediated immune

chemokines and cytokines which recruit

response and Th-1 IFN-c response in the

other inflammatory cells to the site of

protection against M. tuberculosis infection

infection. The dendritic cells, which are the

has come from genetic studies reporting an

major antigen presenting cells in the lung,

increased risk of progressive disease in

migrate to regional lymph nodes where they

specific genetic defects affecting the IL-12/

present processed M. tuberculosis antigens

IFN-c pathway.

to naïve CD4⁺ T-cells via major

MSMD is a familial inherited disorder

histocompatibility complex (MHC)-class II

associated particularly with an increased

molecules. The antigen presentation by

susceptibility to severe disseminated

dendritic cells with the aid of co-stimulatory

mycobacterial diseases that often manifest

molecules such as CD80 and synthesis of

in childhood. Affected children have a

polarising cytokine such as interleukin (IL)-

diminished ability to induce activation and

12 promotes the priming, proliferation and

upregulation of the killing mechanism of M.

differentiation of naïve CD4⁺ T-cells into M.

tuberculosis-infected macrophages because

tuberculosis-specific CD4 T-cells with T-

of a number of specific mutations in the

helper (Th)-type 1 effector function, which

genes encoding major components of the

produces classical Th-1 cytokines including

IL-12/IL-23 IFN-c axis of the Th-1 cytokine

IFN-c, tumour necrosis factor (TNF)-a and

pathway. A number of mutations have been

IL-2. IFN-c produced by the M. tuberculosis-

identified in the autosomal genes including

specific CD4⁺ T-cells is critical for the

IFNGR1 (encoding IFN-gR1), IFNGR2

optimal activation of infected macrophages

(encoding IFN-gR2), STAT-1 (encoding

to become microbicidal, promoting killing of

signal transducer and activator of

the phagocytosed bacilli and thus protection

transcription-1), IL12P40 (encoding IL-12p40

against TB.

subunit), IL12RB1 (encoding IL-12Rbeta1

chain), TYK2 (encoding tyrosine kinase 2)

Specifically, it has been reported that the

and NEMO (encoding nuclear factor-kB-

alveolar macrophages in children show

essential modulator).

diminished phagocytosis, cellular

recruitment and microbial killing when

Acquired susceptibility to TB

compared with adults, which could promote

HIV infection The most compelling evidence

delayed initiation of antigen-specific T-cell

for the crucial role of CD4⁺ T-cells in

responses and disease progression. Further

protection against human mycobacterial

studies are needed to define the role and

infection is the increased risk of infection,

importance of CD8 T-cells in immune

reactivation and progression to TB disease

responses to TB in children.

in individuals with HIV co-infection. A

These immunological differences described

number of studies have reported a higher

above could largely be a reflection of

risk of TB and poorer survival among HIV-

immaturity of the immune response and

infected children when compared with HIV-

explain the high rate of progressive TB seen

negative children with TB, while the reported

in young children.

risk of disseminated BCG disease (called

BCG-osis) in HIV-infected children has

Apart from the intrinsic deficiencies in cell-

prompted the World Health Organization

mediated immune responses in children,

(WHO) to recommend avoiding BCG

there are other primary and acquired causes

vaccination in newborns with known HIV-

of immune suppression which could further

positive status.

ERS Handbook: Paediatric Respiratory Medicine

285

Although the attributable effect of the HIV

transplant recipients due to compounded

epidemic on the burden of TB in children is

immunosuppression. Therefore, efficient

less well defined than in adults, the HIV

pre-transplant risk assessment and

epidemic has resulted in a shift of TB

screening of both the transplant recipient

disease burden to younger adults resulting

and the donor/donor organ is an important

in an increased exposure of both HIV-

part of the management of recipients which

infected and -uninfected children at a very

will allow for preventive intervention in the

young age. While HIV is known to be a

pre- and/or post-transplant period.

strong risk factor for TB, this risk is further

Helminth infestation, nutritional deficiencies

increased in HIV-infected children by

and vitamin D Several studies have

younger age and underlying immune status

suggested that helminth infection could

as defined by the CD4 count and viral

downmodulate the protective immune

loads. The incidence of TB has been

response against M. tuberculosis thereby

reported to be four times higher in children

facilitating progression to active TB disease.

with a CD4 count ,15% and 30 times

Heavy helminth infection in humans has

higher in children with viral load .5 log₁₀

been shown to be associated with a

copies per mL when compared with

generalised state of immune

other children.

hyporesponsiveness, probably facilitated

The diagnostic difficulties in childhood TB

through immunoregulatory pathways

are further compounded in HIV/TB co-

involved in mycobacterial control.

infection, as the clinical presentations in

The association between malnutrition and

both diseases are similar and radiological

risk of TB is largely derived from

features are nonspecific. The tuberculin

observational studies in humans,

skin test (TST), which is the most widely

experimental studies in animal models and

used immunological test supporting the

in vitro studies. However, it is still unclear

diagnosis of TB, is frequently false

whether malnutrition facilitates TB or TB

negative because of HIV-associated

leads to malnutrition. Similarly the effect of

‘‘anergy’’ in delayed-type hypersensitivity

different forms and degrees of malnutrition

to purified protein derivatives. Thus,

and the population attributable risk due to

diagnosis of TB in children, especially in

malnutrition in communities where both TB

resource-limited settings, relies on

and malnutrition are endemic remain to be

practical algorithms, which lack standard

defined.

symptoms definitions and adequate

validations, with HIV co-infection

Vitamin D deficiency is associated with TB

aggravating these shortcomings.

among children and immigrants in low-

Transplant-related immune suppression

endemic settings, as well as in people in

Impairment of immune control of M.

TB-endemic settings regardless of HIV

tuberculosis can also result from the

status. A seasonal variation in the notified

immunosuppression, either due to disease

cases of TB related to exposure to UV light

and/or treatment in solid organ transplant

and vitamin D deficiency has also been

and/or haematopoietic stem cell transplant

reported from several populations. Vitamin

(HSCT). Lung transplantation has the

D, through its active metabolite 1-alpha-25-

highest risk of such donor-derived

dihydroxy-vitamin-D, contributes to the

transmission and of post-transplant TB. As

host immune protection against TB

such, the incidence of TB and its associated

through ‘‘non-classical’’ mechanisms

mortality is higher in transplant recipients

including upregulation and activation of

than in the general population and the

antimicrobial peptides such as

incidence is directly proportional to

cathelicidins, promoting IFN-c induced

endemicity of M. tuberculosis infection in the

activation of M. tuberculosis-infected

general population. These risks are further

macrophages as well as the maturation and

heightened or amplified in paediatric

activation of dendritic cells.

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Clinical manifestations of extra-

bacteria into the subarachnoid space causes

pulmonary TB

meningitis. In some individuals, Rich foci

enlarge to form tuberculomas.

Lymph node TB Superficial tuberculous

lymphadenitis involves mainly cervical

Clinical features TBM can manifest in

lymph nodes and is the most common form

progressive phases. The first stage (stage 1)

of extrapulmonary TB in children from TB-

presents with nonspecific symptoms such

endemic areas. Environmental factors and

as headache, nausea and fever, and vague

other mycobacteria can also cause cervical

CNS symptoms, such as behaviour changes,

lymphadenitis depending on their

irritability, drowsiness and vomiting. Stage 2

prevalence in a given setting.

is marked by signs of meningeal irritation

and cranial nerve palsies involving mainly

Clinical features Lymphadenitis presents 6-

nerves III, VI and VII. Stage 3 is

12 months after initial TB infection as non-

characterised by raised intracranial pressure

tender, non-erythematous solid masses 2-

and altered sensorium. Some stage 3

4 cm in size. They may become matted

patients present in a coma. Seizures may

together and develop a chronic discharging

occur at any stage. Late presentation is

sinus. Constitutional symptoms such as

common in developing countries;

fever, fatigue and failure to thrive are

tuberculomas are more common in the

observed in .50% of the children. Anterior

older child, present with focal seizures or

cervical lymph nodes are more commonly

with symptoms and signs of raised

involved; posterior cervical, supraclavicular

intracranial pressure and may coexist with

and submandibular nodes are less involved.

meningitis in up to 10% of cases (fig. 1).

Infants are rarely affected.

Diagnosis Lumbar puncture is mandatory.

Diagnosis Fine-needle aspiration for acid-fast

The cerebrospinal fluid (CSF) shows a clear

bacilli, cytology and culture are usually

hyper-concentrated fluid with high protein

adequate for accurate diagnosis. Lymph

(.0.4 g?L^-1), low glucose (,60 mg?dL^-1)

node biopsy confirms diagnosis and

and a high white cell count of 100-

excludes other causes of lymphadenopathy

1000 cells?mL^-1 of which at least 80% are

such as malignancy. Histology shows the

lymphocytes. Acid-fast bacilli staining and

typical features of necrosis and epitheloid

culture of CSF rarely yield mycobacteria.

granulomata.

Partially treated bacterial meningitis, and

viral and fungal meningitis (especially

CNS TB constitutes around 13% of all cases

of extrapulmonary TB in children and

complicates the clinical course of TB in 0.5-

2% of cases. Tuberculous meningitis (TBM)

is the most common form (,95% of cases);

tuberculomas and abscesses are less

common. The spinal cord is rarely involved.

CNS TB develops 3-6 months after primary

infection, usually in children ,2 years of

age. TBM is a devastating illness. It may

develop acutely or more commonly evolve

slower than other forms of bacterial

meningitis. Serious neurological sequelae

develop in almost 50% of cases and overall

mortality is ,13%. TBM is very rare in low-

TB prevalence countries. Seeding of TB

bacilli in the CNS leads to formation of

small subpial and subependymal foci in the

brain and spinal cord referred to as Rich

Figure 1. A transverse section of the brain showing

foci. Rupture of Rich foci and release of

dilated ventricles in a child who died of TBM.

ERS Handbook: Paediatric Respiratory Medicine

287

cryptococcal meningitis in HIV-positive

children) should be ruled out.

Complications include hydrocephalus,

seizures and cranial nerve palsies. Learning

difficulties, deafness, blindness and

hemiplegia may persist in the long term.

Imaging in CNS TB MRI with gadolinium

enhancement is the most sensitive test for

detecting the extent of leptomeningeal

disease and is superior to CT scanning in

detecting parenchymal abnormalities

such as tuberculomas, abscesses and

infarctions.

A CT scan with contrast enhancement can

show meningeal enhancement,

hydrocephalus and focal infarcts from

Figure 2. Miliary TB. Chest radiograph of a 2-year-

vasculitis. Tuberculomas appear as hyper

old boy showing bilateral distribution of miliary

dense, rim-enhancing lesions 1-5 cm in

nodules.

dimension. Neurocysticercosis has a similar

appearance and needs to be differentiated

from tuberculomas, especially in developing

countries.

acid-fast bacilli and culture should be

performed; culture might be positive in up

Miliary TB Classic miliary TB refers to

to 50% of cases.

millet-like (1-5 mm) seeding of TB bacilli in

the lung as evidenced by radiography. Very

Chest CT has a higher sensitivity and

young and/or immunocompromised

specificity compared to radiography in

children, such as HIV infected or severely

displaying the nodules. It is useful in

malnourished children, are usually affected

resolving suggestive but inconclusive chest

and miliary TB tends to develop soon

radiography findings. Ultrasonography may

after primary infection from an adult

reveal diffuse liver disease, splenomegaly

source case.

and para-aortic lymph nodes. A head CT

scan or MRI scan may show involvement of

Clinical features Progressive symptoms

the CNS. Echocardiography helps to exclude

similar to other forms of pulmonary TB

pericardial involvements.

develop over days or weeks and the

diagnosis is then apparent on the

Pleural TB Pleural TB occurs in 2-38% of

cases of pleural TB in children and may be a

pathognomonic chest radiograph (fig. 2).

manifestation of primary or reactivation

Diagnosis Chest radiographs show the

disease. Primary pleural TB results from a

typical, bilaterally distributed, miliary

hypersensitivity reaction to bacilli in the

nodules in the majority of cases.

pleural space. The effusion usually develops

Lymphocytic interstitial pneumonitis (LIP)

6-12 weeks after infection.

and opportunistic infections such as

Pneumocystis jirovecii may present with a

Clinical features Pleural TB is more common in

similar picture in HIV-infected children.

adolescents. It presents with chest pain,

cough, shortness of breath, weight loss,

The TST may be negative in miliary TB as

fatigue and anorexia. Examination reveals

disseminated disease may cause TST

wasting, pyrexia, respiratory distress, dullness

anergy. This should never rule out TB.

to percussion and reduced breath sounds,

Fundoscopy may identify retinal tubercles.

mimicking pneumonia. Effusion is usually

Gastric washings or induced sputum for

unilateral and more common on the right.

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Diagnosis Radiological examination reveals

30-60 Units?L^-1 indicate disease and aid

effusion, mediastinal shift, parenchymal

therapeutic decisions. Acid-fast bacilli in

consolidation, bulging lung fissures and

pericardial fluid or pericardial tissue

hilar or mediastinal adenopathies. Pleural

histology establish the definitive diagnosis.

aspiration and analysis shows straw

Myocardial TB is very rare and remains

coloured fluid, an exudative lymphocytic

mainly a post mortem diagnosis. It presents

effusion with 1000-6000 white blood cells

with arrhythmias, conduction blocks,

per mL, protein .4 g?dL^-1 and glucose level

valvular insufficiency and CHF.

,70 g?dL^-1. Elevated pleural fluid ADA levels

Skeletal TB is seen in 1-2% of all childhood

(.40-60 Units?L^-1) can support the

TB cases. TB bacilli get deposited at the

diagnosis. Sputum acid-fast bacilli and

bone site forming a caseating focus, which

culture should be performed on sputum,

then causes bone trabecular destruction.

pleural fluid and pleural biopsy specimen;

50% of children have concurrent active

however, pleural fluid is rarely acid-fast

pulmonary TB at the time of diagnosis. Most

bacilli positive. Culture may be positive in

affected children are in their second decade

40-60% of cases. Histopathological

of life except for TB dactylitis, which is

examination of pleural tissue demonstrates

common among children ,5 years of age.

granulomata with or without caseous

Symptoms often begin 1-3 years after

necrosis.

primary TB infection and diagnosis is often

Pericardial TB TB can involve the

delayed because of lack of exposure history,

pericardium in ,1-2 % of cases and causes

nonspecific symptoms and lack of systemic

,70% of all cases of large pericardial

illness. The most common manifestations

effusions. Most cases of constrictive

are spondylitis (TB of the spine), arthritis

pericarditis in developing countries and

and osteomyelitis.

,4% of cases in industrialised countries are

Spinal TB constitutes ,50% of skeletal TB

due to TB.

cases and mostly involves the

Clinical features Common presenting

thoracolumbar spine (Pott’s disease). The

symptoms include shortness of breath,

infection spreads to involve the adjacent

cough, fever and weight loss. Chest pain is

tissues initially and intervertebral disc later

less common. Hepatomegaly and jugular

on in the process. Contiguous spread to the

venous distension are common. Cardiac

paraspinal muscles results in abscesses.

tamponade has been noted in up to 90% of

Swelling, pain and tenderness at the site are

cases. Pulsus paradoxus and pericardial

the most common presenting symptoms.

rubs are occasionally demonstrated.

Gibbus (swelling and angulation along the

spine) may be observed on clinical

Diagnosis Chest radiograph shows

examination. Features of paraparesis or

cardiomegaly in .90% of cases and may

quadriparesis due to spinal cord

also demonstrate features of active TB. ECG

compression may be observed.

shows nonspecific ST and T-wave

abnormalities. Echocardiography shows

Diagnosis MRI is the imaging modality of

non-TB specific features; effusion with

choice and determines the extent of soft

fibrinous strands on the visceral

tissue involvement and the level of cord

pericardium. CT scans show pericardial

compression. Radiography of the spine later

effusion and thickening. Typical changes in

in the disease progression shows loss of

mediastinal lymph nodes are seen in almost

height of vertebral bodies, bony erosions,

100% of cases.

periosteal reaction, sequestra and vertebral

collapse. Chest radiograph may

Pericardiocentesis is both diagnostic and

demonstrate active pulmonary disease in

therapeutic and shows blood-stained

50% of cases. CT scans demonstrate bony

exudative fluid with high protein and high

sclerosis and destruction. Histopathological

leukocyte count, with lymphocyte and

examination of bone biopsy specimen

monocyte predominance. ADA levels of

showing granulomatous lesions confirms

ERS Handbook: Paediatric Respiratory Medicine

289

Table 1. Extrapulmonary TB treatment regimen

Manifestation

Drug regimen

Dosage

Duration of

treatment

Intensive phase

All forms of extrapulmonary TB

HRZE

H 10 mg?kg^-1?day^-1

2 months

R 15 mg?kg^-1?day^-1

Z 35 mg?kg^-1?day^-1

E 20 mg?kg^-1?day^-1

Continuation phase^#

Pleural, pericardial,

H 10 mg?kg^-1?day^-1

6 months

abdominal and renal

R 15 mg?kg^-1?day^-1

CNS TB

HR as above

10 months

Skeletal TB

HR as above

10 months

H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol.^#: a thrice weekly regimen is used in the

continuation phase but this is not recommended in high HIV prevalence settings, except where the child is

HIV negative and DOTS (directly observed treatment, short-course) is well established.

the diagnosis. Acid-fast bacilli stains of bone

ribs with forearm bones and clavicles often

specimen are often negative but culture may

involved. Short bones of the hands and feet

be positive in up to 75% of cases.

may be affected in younger children (TB

dactylitis). Systemic symptoms may be

TB arthritis is usually a monoarticular

observed.

disease affecting the large weight-bearing

joints; the hips or knees are involved in

Diagnosis Radiography shows soft tissue

,30% of cases.

swelling, osteoporosis, cystic bone changes

and sequestrum. An infiltrative pattern

Clinical features resemble those of spinal TB.

resembling Ewing’s sarcoma, fungal

The diagnosis is established through

infection and chronic pyogenic osteomyelitis

radiography of the affected joint and reveals

may sometimes be seen. Cyst-like cavities

joint effusion, periarticular osteopenia,

with expansion of the diaphysis, the so-

irregularity of the bone cortex, lytic lesions

called ‘‘Spina ventosa’’, may be seen. BCG

and periosteal new bone formation.

osteomyelitis presents similarly and can

Decreased joint space and widening of the

occur a few months to 5 years post-BCG

intercondylar notch in the knee are observed

vaccination. Culture of the BCG strain

in advanced disease. Marked joint

establishes this differential diagnosis.

destruction and fibrous or bony ankylosis

are seen in end-stage disease. An ultrasound

Abdominal TB is generally less common in

scan demonstrates joint effusion and aids

children. It may complicate untreated

the aspiration for acid-fast bacilli and

pulmonary TB in ,6-38% of cases.

culture. MRI demonstrates marrow changes,

Abdominal TB due to M. bovis can result

joint effusions and cartilage and bone

when unpasteurised milk is ingested, but

erosions. Joint fluid aspiration or synovial

this is now rare.

biopsy is necessary for confirmation of

diagnosis.

Clinical features Abdominal TB is more

common in older children and adolescents,

Tuberculous osteomyelitis is a very rare form

and usually presents as enteritis or

of skeletal TB in children. Lesions are either

peritonitis. Patients suffer with chronic

solitary or multifocal.

abdominal symptoms over several months:

Clinical features are local pain, swelling and

vague abdominal pain, abdominal mass,

tenderness of the skull vault, hands, feet and

anorexia and vomiting in association with

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ERS Handbook: Paediatric Respiratory Medicine

weight loss. Physical examination shows a

therapy, requires ongoing support for

distended abdomen that feels ‘‘doughy’’ on

parents and children and regular clinical

palpation. Abdominal TB could present

reviews to assess response to treatment,

acutely with intestinal obstruction,

adherence and possible side-effects/

perforation and peritonitis as a complication

interference of medication. Drug dosage

of adhesions.

should be adjusted according to the

patients’ weight. Children with proven or

Diagnosis CT scans show bowel wall

suspected multidrug-resistant (MDR)-TB

thickness, ascites and the abdominal viscera

should be treated by experts and within the

and detect para-aortic and mesenteric

context of a well-functioning MDR-TB

lymphadenopathy and calcifications, which

control programme. Hospitalisation is

are often also visible on ultrasound. Chest

mandatory during the initial phase for

radiography may reveal abnormality in 50-

disseminated forms of TB.

70% of patients. Evaluation of ascitic fluid

shows lymphocytic exudates; acid-fast bacilli

and culture are positive in up to one-third of

Further reading

patients.

Allen JE, et al.

(2011). Diversity and

Other forms of disseminated TB include

dialogue in immunity to helminths. Nat

renal TB and cutaneous TB. Both are

Rev Immunol; 11: 375-388.

extremely rare in children.

Bumbacea D, et al. (2012). The risk of

tuberculosis in transplant candidates and

Treatment of extrapulmonary TB

recipients: a TBNET consensus state-

ment. Eur Respir J; 40: 990-1013.

The treatment of EPTB follows the same

Cottle LE (2011). Mendelian susceptibility

basic principles as for pulmonary TB.

to mycobacterial disease. Clin Genet; 79:

Treatment is divided into intensive and

17-22.

continuation phases. The intensive phase

Geldmacher C, et al. (2012). Interaction

rapidly eliminates the majority of TB bacilli

between HIV and Mycobacterium tubercu-

and prevents the emergence of drug

losis: HIV-1-induced CD4 T-cell depletion

resistance. The continuation phase

and the development of active tubercu-

eradicates dormant organisms. The

losis. Curr Opin HIV AIDS; 7: 268-275.

recommended drug regimen is shown in

Hewison M

(2012). Vitamin D and

table 1.

immune function: an overview. Proc

Nutr Soc; 71: 50-61.

Corticosteroids

Jones C, et al. (2011). Immunology and

pathogenesis of childhood TB. Paediatr

Corticosteroids are indicated in children

Respir Rev; 12: 3-8.

with TB meningitis, TB pericarditis and

Marais B, et al. (2006). The spectrum of

possibly also in severely ill children with

disease in children treated for tuberculo-

disseminated TB (miliary). The

sis in a highly endemic area. Int J Tuberc

recommended treatment is prednisone 1-

Lung Dis; 10: 732.

2 mg?kg^-1 daily orally for 4-6 weeks in

Marais BJ, et al. (2011). TB and HIV in

addition to TB drugs. The dose can be

children

- advances in prevention and

tapered to stop over 2-4 weeks, depending

management. Paediatr Respir Rev; 12: 39-

on resolution of symptoms.

45.

Mwachaka PM, et al.

(2011). Spinal

General considerations

tuberculosis among human immunodefi-

Any child presenting with disseminated

ciency virus-negative patients in a Kenyan

forms of TB should be screened for HIV or

tertiary hospital: a 5-year synopsis. Spine

other forms of immunodeficiencies, if

J; 11: 265-269.

Newton SM, et al.

(2008). Paediatric

known to be HIV negative.

tuberculosis. Lancet Infect Dis;

498-

Prolonged treatment with several drugs,

510.

possibly also including anti-retroviral

ERS Handbook: Paediatric Respiratory Medicine

291

Epidemiology and phenotypes

of bronchial asthma and

wheezing disorders

Franca Rusconi, Ben D. Spycher and Claudia E. Kuehni

Studies of the epidemiology of asthma have

diagnosis, which cannot be made by a single

flourished in the last 30 years, reflecting the

measurement or test. Physicians diagnose

fact that the disease is common in

asthma on the basis of medical history,

developed and developing countries, the

physical examination and assessment of

aetiology still largely unknown, and costs are

reversibility of airway obstruction. In

high. This section explains how asthma is

epidemiological studies, the most common

assessed in epidemiological surveys,

approach uses questionnaires to ascertain

describes time trends and prevalence

whether subjects have had symptoms of

differences by age and sex, explains the

asthma or have ever received a diagnosis of

concept of asthma phenotypes, and

asthma from a physician.

summarises the current knowledge on

The prevalence of asthma diagnosis and

natural history and long-term outcome.

symptoms is dependent on the awareness of

Assessment of asthma in epidemiologic

the disease in the populations studied and

studies and time trends

on diagnostic labels. The same child might

be diagnosed with ‘‘asthma’’ by one doctor

Paediatric asthma guidelines emphasise

and with ‘‘wheezy bronchitis’’ by another.

that asthma remains a complex clinical

Thus, the preferred approach to assessing

asthma prevalence in epidemiological

studies is based on symptoms, particularly

Key points

current wheeze (wheeze during the past

12 months).

N Asthma and wheezing disorders are

The International Study of Asthma and

heterogeneous conditions in terms of

Allergies in Childhood (ISAAC) is a major

risk factors, age of onset, clinical

initiative involving nearly 2 million

phenotype, severity, response to

schoolchildren aged 6-7 and 13-14 years

treatment and long-term course.

from .100 countries. It was designed to

Despite a large body of research, the

compare prevalence of asthma, rhinitis and

factors explaining time trends and

eczema between countries (phase I, 1994-

international disparities in asthma

1995) and their trends over time (phase III,

prevalence remain largely unknown.

5-10 years later) using standardised

questionnaires (Asher et al., 2006). Key

N Both severity of asthma and lung

findings included the high prevalence of

function show a track from early

asthma symptoms and asthma diagnosis in

childhood to adulthood.

English-speaking countries and Latin

It is important to study phenotype and

America (.20% in most centres),

clinical course of wheezing illness

intermediate prevalence in Western Europe,

early in life when it might still be

and low prevalence (,5%) in Eastern

possible to modify the natural history

Europe, with a clear northwest-southeast

of the disease.

gradient. The lowest prevalence is found in

Africa and Asia with the exception of affluent

ERS Handbook: Paediatric Respiratory Medicine

293

countries such as Singapore and Japan. In

Prevalence by age and sex

most high-prevalence regions, particularly

Only a few cohort and cross-sectional

English-speaking countries, prevalence of

studies have described changes in asthma

current wheeze changed little between

symptoms from infancy to adulthood.

phase I and III, and even declined in some

Existing studies suggest that the prevalence

cases, while most countries with low and

of current wheeze is highest in infants and

intermediate prevalence reported increases.

toddlers, then decreases slightly to remain

Other recent reports of time trends in

relatively stable throughout the school years.

Western countries, outside of ISAAC, also

However, the relevance of different trigger

suggest that prevalence of wheeze might

factors changes strongly with age: while

have reached a peak (Patel et al., 2008).

virally induced wheeze decreases, wheezing

Virtually all countries reported increases in

episodes triggered by pollen or exercise

the lifetime prevalence of an asthma

become more common with age.

diagnosis, irrespective of the prevalence of

wheeze. This might indicate better

Sex differences in asthma also change with

recognition and diagnosis of the disease,

age. In many (but not all) surveys, young

and more frequent use of the diagnostic

boys are reported to have more wheeze and

label, which is considered less stigmatising

asthma than girls. In adolescence, the

today than it has been in previous years.

pattern changes and new-onset wheeze

becomes more frequent in females.

Wide variations of asthma prevalence were

Explanations for this include age-related

found within genetically similar groups;

differences in the growth of the airways and

therefore, environmental and cultural factors

lung parenchyma, sex-specific differences in

are likely to play a role in explaining regional

environmental exposures and exercise,

and temporal variations. However, the

hormonal changes occurring during puberty,

asthma risk factors studied (e.g. infant

changes in symptom reporting, and sex-

feeding, diet, maternal smoking,

related underdiagnosis and under-treatment

immunisations, allergens and air pollution)

in female adolescents (Almqvist et al.,

explain only a small part of the regional

2008).

variability and time trends (Asher et al.,

2010).

Asthma phenotypes

Wheezing disorders might comprise several

Studies in migrants also point to the

distinct phenotypes, possibly representing

importance of socio-cultural and

different disease entities (Silverman et al.,

environmental factors. These studies

1997). If this is true, early distinction of

generally found a steep increase in

phenotypes would allow more focused

prevalence among groups migrating from

research into aetiology and pathophysiology,

low- to high-prevalence areas, particularly

prescription of treatments and preventive

among those who were born in the host

measures targeted to the phenotypes, and

country or migrated during the first years of

improvement in the prediction of long-term

life. Unfortunately, numerous changes occur

outcome. Classical approaches for

simultaneously in migrants, so it is difficult

distinguishing asthma phenotypes have

to disentangle the role of environmental

relied on trigger factors or time course. A

factors (e.g. climate and allergens),

distinction by the main triggers led to the

behaviours (diet and smoking) and social

definitions of:

factors that might affect their interaction

with the healthcare system; for example, the

N episodic viral wheeze (wheeze occurring

likelihood of being diagnosed and treated

episodically only during viral infections);

(Kuehni 2011). Asthma risk factors are

N multiple-trigger wheeze (wheeze also

described in detail in the Genetic and

occurring in response to other factors

environmental factors in bronchial asthma

such as crying, laughter, exercise or

and wheezing disorders section in this

allergens, and often associated with

Handbook.

atopy).

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ERS Handbook: Paediatric Respiratory Medicine

While the prevalence of the former

defined by these methods have confirmed

decreases during the first years of life, the

some of the previously suggested patterns

latter becomes relatively more frequent, is

such as transient viral wheeze and

more persistent and more likely to be

persistent atopic wheeze. Currently,

diagnosed as ‘‘asthma’’ (Brand et al., 2008).

phenotype research is thriving, and it is

However, these phenotypes, based on

important to keep in mind that phenotype

triggers of wheeze only, show limited

definitions only have value if they improve

stability through early childhood, suggesting

patient care or lead to a better

that triggers of wheeze alone are not

understanding of disease processes.

sufficient to distinguish underlying disease

Natural history and long-term prognosis

processes or that the disease processes

change in some children throughout this

Childhood asthma is characterised by a

period (Spycher et al., 2012).

highly variable time course differing by age

of onset, duration of symptomatic periods,

An alternative approach distinguishes

and remissions and relapses. This

children based purely on the time course of

complicates the study of the natural history

wheezing episodes during childhood. A

of asthma. Nevertheless, long-term

common distinction is between:

prospective studies have revealed important

N early transient wheeze (wheezing only

aspects of the disease.

during the first 2-3 years of life);

In one of the oldest cohort studies, the

N persistent wheeze (wheezing beginning

Melbourne Asthma Study (Australia), a

in early life and persisting up to school

population-based sample of 7-year-old

age);

children with a history of wheeze and an

N late-onset wheeze (beginning to wheeze

asymptomatic control group were followed

after the age of 3 years) (Martinez et al.,

over several decades (Phelan et al., 2002).

1995).

The study found consistent associations

Novel statistical approaches in large cohorts

between severity of symptoms in childhood,

have distinguished more temporal patterns

defined by frequency of wheeze, and

(Henderson et al., 2008). Classifications by

persistence of asthma up to the age of

time course, however, have the

42 years: children with frequent episodes in

disadvantage that they can only be applied

childhood had more severe asthma and a

retrospectively, once a child has reached a

lower FEV1/FVC throughout adolescence and

certain age. Therefore, they cannot be used

adulthood. Eczema, hay fever or allergic

to decide how to treat a preschool child or

sensitisation in childhood also tended to

inform parents about the likely prognosis.

result in more severe asthma later in life.

Recently, multidimensional approaches

In the Dunedin birth cohort (New Zealand)

have been used whereby phenotypes are

(Sears et al., 2003), children with persistent

defined based on a wider range of

wheeze throughout follow-up were more

concurrently assessed features using

likely to be sensitised to common allergens

statistical methods such as latent class

and had lower FEV1/FVC ratios at 26 years of

analysis (Spycher et al., 2010). These

age than nonwheezers. In both the

analyses can include different asthma-

Melbourne and Dunedin studies, the lung

related symptoms and measurements such

function deficit was already established by

as lung function, bronchial responsiveness,

school age, suggesting an early loss of lung

atopy or exhaled nitric oxide simultaneously,

function in some asthmatic children and

and identify groups that are relatively

that lung function tracks over time into

homogeneous with respect to these

adulthood. These and other studies show

features. Such phenotypes are closer to the

that a considerable proportion (20-30%) of

clinical situation, where a number of patient

children with asthma at school age continue

characteristics are evaluated by the

to have symptoms as adults, although some

physician simultaneously. The phenotypes

experience long asymptomatic periods.

ERS Handbook: Paediatric Respiratory Medicine

295

A limitation of these older cohort studies is

Further reading

that respiratory symptoms and lung function

Almqvist C, et al.

(2008). Impact of

were first assessed at school age. Thus,

gender on asthma in childhood and

information on the first years of life was

adolescence: a GA2LEN review. Allergy;

lacking. More recent cohort studies that

63: 47-57.

have followed children prospectively from

Asher MI, et al. (2006). Worldwide time

fetal life or birth and have assessed lung

trends in the prevalence of symptoms of

function in infancy, before the onset of

asthma, allergic rhinoconjunctivitis, and

disease, can shed more light on this critical

eczema in childhood: ISAAC Phases One

period (www.birthcohorts.net). Importantly,

and Three repeat multicountry cross-

it was suggested that lung function deficits

sectional surveys. Lancet; 368: 733-743.

might be congenital in some children, while

Asher MI, et al. (2010). Which population

in others they are probably a consequence of

level environmental factors are associated

severe asthma. These hypotheses must be

with asthma, rhinoconjunctivitis and

tested using repeated measurements of

eczema? Review of the ecological analyses

lung function from birth to late childhood.

of ISAAC Phase One. Respir Res; 11: 8.

Brand PLP, et al. (2008). Definition, assess-

Long-term follow-up of these cohorts will

ment and treatment of wheezing disorders

clarify which children with persistent asthma

in preschool children: an evidence-based

are at risk of developing irreversible airway

approach. Eur Respir J; 32: 1096-1110.

obstruction, the clinical hallmark of COPD

Henderson J, et al. (2008). Associations

(Martinez, 2009).

of wheezing phenotypes in the first

6 years of life with atopy, lung function

Several approaches have been taken to

and airway responsiveness in mid-child-

predict the long-term prognosis of young

hood. Thorax; 63: 974-980.

children with wheezing illness based on risk

ISAAC. The International Study of Asthma

factors such as symptom severity, markers

and Allergies in Childhood. http://isaac.

of atopy, parental history of asthma and

auckland.ac.nz/

environmental exposures (Savenije et al.,

Kuehni CE (2011). Do migrant studies

2012). However, the ability of currently

help to identify causes of asthma? Clin

available prediction scores to identify

Exp Allergy; 41: 1054-1058.

children who go on to have asthma in later

Leonardi NA, et al. (2011). Validation of

childhood has been disappointing. The most

the Asthma Predictive Index and compar-

important commonly assessed predictor of

ison with simpler clinical prediction rules.

future asthma is severity of current

J Allergy Clin Immunol; 127: 1466-1472.

symptoms (frequency and severity of

Martinez F (2009). The origins of asthma

and chronic obstructive pulmonary dis-

wheezing episodes) (Leonardi et al., 2011).

ease in early life. Proc Am Thorac Soc; 6:

The additional prognostic value of

272-277.

investigations such as blood eosinophils or

Martinez FD, et al. (1995). Asthma and

exhaled nitric oxide remains to be shown. In

wheezing in the first six years of life. The

addition, currently proposed prediction

Group Health Medical Associates. N Engl

models have been developed for specific age

J Med; 332: 133-138.

groups, and might not be generalisable to

Patel SP, et al. (2008). Systematic review

older or younger children.

of worldwide variations of the prevalence

of wheezing symptoms in children.

In summary, the concept of an early window

Environmental Health; 7: 57.

of susceptibility, beginning in fetal life, and

Phelan PD, et al. (2002). The Melbourne

the tracking of certain characteristics of

Asthma Study: 1964-1999. J Allergy Clin

asthma from childhood to adulthood,

Immunol; 109: 189-194.

including severity and impairment of lung

Savenije OE, et al. (2012). Predicting who

function, stress the importance of

will have asthma at school age among

characterising the clinical course of the

preschool children. J Allergy Clin Immunol;

disease early in life, when, in principle, it is

130: 325-331.

still possible to modify natural history.

296

ERS Handbook: Paediatric Respiratory Medicine

Genetic and environmental

factors in bronchial asthma

and wheezing disorders

Oliver Fuchs and Erika von Mutius

Asthma is a disease with a strong genetic

pathways or aetiologies of asthma-related

background. Asthma heritability, i.e. the

traits and intermediate phenotypes such as

variance caused by genetic factors, has been

allergic rhinitis, atopic eczema, IgE levels or

estimated to be between 35% and 95%.

lung function parameters, e.g. bronchial

Asthma heritability can be explained by

hyperresponsiveness (BHR). So far, there is

genetic or by epigenetic effects.

evidence for both common and distinct

Understanding the genetic disease

aetiological pathways. For the latter, loci

background is important, as it offers the

identified to be associated with lung

opportunity of new therapies or even

function were not related to asthma,

preventive measures. Moreover, it helps to

implying that causal pathways are distinct. It

understand the overlap between pathogenic

is still unclear whether these reflect diverse

pathways or whether some phenotypes

share a number of them, at least partly.

Key points

Historically, different methods have been

used to assess genetic associations with

For childhood asthma and wheezing

asthma-related traits. Table 1 displays all

disorders both genes and the

existing approaches, their concepts as well

environment play a role, which is why

as their individual benefits and downsides

they are complex diseases.

relating to study design, sample size

Genetic studies have identified

requirements and need for replication. The

numerous risk loci for childhood

first studies were genome-wide family-

asthma, in particular the GSDMB-

based linkage studies and subsequent

ORMDL3 locus on 17q21, which has

positional cloning. Generating hypotheses

replicated numerous times and has

to be tested in subsequent analyses, they

the strongest effect on childhood-

led to the discovery of various genetic loci

onset asthma found to date.

and genes related to asthma, e.g. ADAM33

(potential role in airway remodelling),

Epidemiological observations have

SPINK5 (role in integrity of airway

identified both protective

epithelium), or STAT3 (IgE level). Based

environments and risk factors

on the hypothesis that they were

associated with childhood asthma

asthma-related due to biological,

and wheezing disorders. The most

pathophysiological or functional relevance,

robust and consistent finding relating

the majority of genetic variants associated

to risk is ETS exposure, particularly

with asthma, however, were discovered by

maternal smoking during pregnancy.

candidate-gene approaches. Within these

Gene-environment interactions, for

studies, numerous genetic variants, such as

example ETS, and the association of

CD14 (involved in innate immunity), TGFB1,

the 17q21 locus could be established

ADRB2, NOS1-3 (roles in lung function,

in relation to childhood asthma.

lung growth and development, allergic

airway inflammation) have been identified.

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ERS Handbook: Paediatric Respiratory Medicine

Emerging high-throughput techniques

childhood-onset asthma could be explained

helped to detect asthma-related genetic loci

by the seven identified genetic loci. Figure 1

in large populations. Genome-wide

displays the genetic loci discovered in

association studies (GWAS) included

asthma GWAS until the end of 2012.

several hundred thousand single-nucleotide

polymorphisms (SNPs) across the whole

What is the best approach to identify genetic

human genome. Due to decreasing costs,

variants conferring risk for development of

their number is steadily increasing. Until the

childhood wheeze and asthma? As all

end of 2012, 1489 GWAS, 22 thereof on

methods have their advantages and

asthma, were listed on www.genome.gov/

disadvantages, they may play a role

gwastudies. The first asthma GWAS

altogether and consequently, there will be

described the GSDMB-ORMDL3 locus on

trade-offs for their benefits and downsides.

chromosome 17q21. This locus was

Moreover, careful disease phenotyping is

replicated in independent populations and

necessary as childhood asthma is not one

disease entity but many. If one is interested

has the strongest effect on childhood-onset

in discovery and analysis of genes conferring

asthma. Being involved in intracellular Ca2+

only modest effect sizes, GWAS and

flux and possibly contributing to airway

candidate gene approach would be

remodelling, there is also a plausible

favourable. If one is interested in rare

mechanism related to ORMDL3. The

variants, sequencing might be the best

GABRIEL Consortium performed the largest

approach, perhaps even family-based

GWAS for childhood asthma to date. Seven

linkage studies (table 1).

loci, IL18R1, HLA-DQ, IL33, SMAD33, IL2RB,

GSDMA, and GSDMB-ORMDL3, were

The epigenome

identified. More recently, it has become

possible to apply extensive sequencing of

In addition, alterations in gene expression

whole genomes for the discovery of

by activation and deactivation of genes

mutations associated with childhood

without any changes in the underlying DNA

wheeze and asthma. As whole-genome

sequence may influence the risk of

sequencing is still overly expensive, whole-

childhood asthma and wheezing disorders.

exome sequencing, i.e. analysing enriched

This is called the epigenetic effect. It can be

coding sequences (exons) of the human

mediated by methylation of cytosine to

genome, may be a way to go until whole-

5-methylcytosine and vice versa mostly at

genome sequencing, including other but

sites with a cytosine in linear sequence with

putatively nonetheless important non-

a guanine base on the same DNA strand,

coding sequences such as introns, will

leading to gene silencing. Epigenetic effects

become affordable in large studies.

can also be mediated by non-coding RNA

species (such as miRNAs) and through

Unfortunately, the genetic basis of asthma is

alterations of chromatin by histone

as yet unknown. Instead of discovering

modification (methylation, acetylation,

‘‘the’’ asthma gene or a few genes with

ubiquitinylation, phosphorylation and

strong effect sizes, analyses to date

sumoylation).

discovered several loci each with small

effects. With relatively low positive

The possible role of epigenetics in asthma is

predictive values even for highly associated

highlighted by several findings. So far, pure

risk alleles, the utility of genetic data in

genetics explain only limited heritability.

personalised medicine for diagnostic or

Moreover, affected mothers transmit

even predictive testing of asthma in the

asthma more often to their offspring than

individual is still science fiction.

affected fathers, i.e. there is a clear parent-of-

Nevertheless, current evidence has

origin effect for asthma, possibly due to

promoted the field on a population level. An

maternofetal immune-interactions or to

example for this is the population under

imprinting. However, epigenetic studies in

study in the GABRIEL Consortium

asthma are complex and their possible use

mentioned above. Here, at least 38% of

is still unclear. First of all, unlike genetic

ERS Handbook: Paediatric Respiratory Medicine

299

Table 1. Methods to assess genetic associations with asthma-related traits

Best for

Approach

Concept

Comparisons

Advantages

Disadvantages

Study of

Currently

Hypothesis driven

Frequency of alleles

Cheap

Limited as it relies

common

done:

Includes genes a priori

in gene of interest of

Results can be

on existing evidence

variants

candidate-

thought to be asthma-

individuals with

rapidly interpreted

Does not lead to

gene

related due to

asthma versus healthy

Straight-forward

discovery of genes

approach

biological,

controls

because hypothesis

or SNPs

pathophysiological or

Risk of asthma can be

driven

functional relevance or

computed depending

known to be

on study design (case

associated with

control: OR;

asthma

prospective: RR).

SNP analysis within

genes or regions of

interest, targeted SNP

analysis possible,

tagging of non-

represented SNPs by

analysis of SNPs in LD

Currently

Hypothesis free, can

SNPs of whole

Is becoming

Limited to common

done: GWAS

be hypothesis

genomes of

cheaper, several

SNPs (usual MAFs

generating

individuals with

platforms available

are 1-5%) and to

SNP analysis covering

asthma versus healthy

May lead to

SNPs represented

the whole genome,

controls

discovery of genes

on platform or that

tagging of non-

Risk of asthma can be

or SNPs

can be tagged

represented SNPs by

computed depending

High resolution due

(needs LD)

analysis of SNPs in LD

on study design (case

to proceeding SNP

Large sample sizes

control: OR;

discovery

and replication in at

prospective: RR)

Imputation of

least one

additional SNPs in

independent

LD to covered

population are

variants possible

needed

Study of rare

Currently

Can be both

Gene of interest or

May reveal rare

Expensive

variants

done:

hypothesis free

exomes as well as

variants (MAFs

Can be difficult to

sequencing,

(exome or whole

whole genomes of

below thresholds of

interpret,

either genes,

genome) or

individuals with

GWASs)

computational and

exomes or

hypothesis driven

asthma versus healthy

Enables fine-

bioinformatic

whole

(gene), may generate

controls

mapping of ROIs

analysis is

genomes,

new hypotheses

Risk of asthma can be

demanding

so-called

Enables analysis of

computed depending

Large sample sizes

‘‘next-

DNA sequence and

on study design

and replication in at

generation

thus of all sequence

(case-control: OR;

least one

sequencing’’

variation

prospective: RR)

independent

population are

needed

Historically

Hypothesis free, can

Studied in families

May lead to

Relatively expensive

and currently

be hypothesis

(usually with two

discovery of new

Laborious and time

done:

generating

affected siblings and

ROI or gene,

intensive

linkage study

Gene identified by

unaffected parents)

perhaps SNP of

Needs families

followed by

genome-wide linkage

Risk of asthma

interest

Needs several steps

positional

study

computed as log of

May also lead to

for discovery of gene

cloning

Genomes screened

odds in favor of

discovery of rare

of interest

study

with genetic markers

linkage (LOD score)

variants

Limited resolution

evenly dispersed over

Identification of

Requires relatively

whole genome

genes or SNPs by

few markers

Linkage: marker is

fine-mapping

inherited together with

(positional cloning)

disease more often

is possible

than expected by

Further analyses are

chance

needed to define

gene function

LD: linkage dysequilibrium; OR: odds ratio; RR: relative risk; MAF: minor allele frequency; ROI: region of interest.

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ERS Handbook: Paediatric Respiratory Medicine

36.3

36.2

36.1

34.2

ATPAF1*

IL5RA*

15.3

15.1

NOTCH4*

PBX2*

11.2

C6orf10*

HLA-DQA1*

GNAI3*

11.2

IL1RL1*,***

HLA-DQB1*

IL33*,***

IL18R1*

HLA-DPB1*

11.2

HLA-DRA*

14.1

DPP10*

PDE4D*

HLA-DOA*

ACO1*

IL6R*

14.3

BTNL2*

FLG*****

11.

AGER-PPT2****

11.2

CRCT1*

13.

FAM13A***

PYHIN1*

GSTCD****

11.2

FCER1A**

13.

INTS12****

GATA2***

TSLP*

WDR36***

21.2

TLE4-

DENND1B*

CHCHD9*

CRB1*

32.1

HHIP****

SLC22A5*

RAD50*,**

21.3

32.3

LOC729675*

IL13*,IL5***

MYB***

PTCH1****

CHI3L1*

SPATS2L*,****

2526.

GAB1*

HTR4****

IKZF2***

C5orf56*

GPR126****

TNS1****

26.

NDFIP1*

3233

PID1****

2728

3334

TNIP1*

SLC30A8

ADRA1B*

C1orf100*

ADAM19****

GAPDHP72-T*

24.3

1514

LOC338591*

1312

11.2

1211.2

11.2

PRKG1*

11.2

IKZF4

CDK2*

DCLK1*

HS3ST3A1-

LRRC32*

STAT6**

11.2

CDRT15P1*

C11orf30*****

11.2

KIAA1271*

PCDH20*

SCG3*

PERLD1*

PRNP*

RORA*

GSDMA*

11.2

2223

SMAD3*

GSDMB*

THSD4****

ORMDL3*

11.2

C11orf71*

SH2B3***

24.1

1213.1

KIRPEL3-

24.2

IL2RB*

ETS1*

24.3

13.3

CRTAM*

Figure 1. Genetic loci discovered in GWASs until the end of 2012 on asthma (*) and related traits: IgE

levels (**), eosinophil count (***), lung function (****) and atopic dermatitis (*****). Locus positions

are shown down to chromosome, region and bands. Arrows represent partly sub-bands. Short arms of

chromosomes (p) face upwards and long arms (q) face downwards. Data courtesy of D. Vercelli (Arizona

Respiratory Center, Tucson, AZ, USA; personal communication). Image courtesy of M. Rocchi (University

of Bari, Bari, Italy; personal communication).

variants, epigenetic modifications may be in

and of FOXP3 for regulatory T-cells (Treg)).

a constant state of flux. It is difficult to

Thus, epigenetic modification may possibly

decide when to measure and what cell types

impact asthma with Th2-skewing, as it is

or tissue to analyse. Likewise, their relative

known that such immune responses

contribution to gene expression and

contribute to asthma development. Here,

especially their heritability across

human studies have demonstrated the

generations is unknown.

impact of air pollution as an environmental

factor on FOXP3 methylation and Treg cell

There is evidence from both animal and

function in asthmatic children. Furthermore,

human studies for epigenetic regulation in

epigenetic effects on more intermediate

asthma and wheezing disorders. Mouse

outcomes such as atopy and allergic airway

studies demonstrated an influence of

inflammation, lung function and on

maternal methyl-donor rich diet on BHR,

childhood wheeze subtypes are also

airway inflammation and serum IgE levels in

supported by data derived from human

offspring. Also exposure to environmental

studies. Due to ethical constraints, human

microbes can act by epigenetic regulation as

studies have examined epigenetic effects in

shown by a study in mice where prenatal

cells outside the lung, mostly peripheral

administration of the farm-related bacterial

blood cells, but also in possibly more

species Acinetobacter lwoffii F87A prevented

relevant buccal and nasal cells or in cells

an asthmatic phenotype in the offspring. In

from sputum. Such easily obtained material

immunology, epigenetic mechanisms are

might be useful for markers of childhood

known to be involved in T-cell differentiation

asthma as demonstrated by the fact that

(e.g. by modification of the IFNG promoter

hypo-methylation in Alox12 even in

for T-helper (Th)-1 cells, as well as for Th2,

peripheral blood cells was associated with

ERS Handbook: Paediatric Respiratory Medicine

301

persistent wheeze. For exhaled nitric oxide

compounds (VOCs) and PM), VOCs and

as a marker of allergic airway inflammation

formaldehyde from new furniture, for

data are conflicting.

example, have been related to childhood

asthma. Moisture damage, as well as

The environment

mouldy spots indoors, has been shown to

increase the risk of childhood asthma and

There is evidence that the environment plays

wheezing disorders.

a significant role as populations with very

similar genetic backgrounds show different

Importantly, viral infections in early life have

rates of childhood asthma and wheezing

been related not only to asthma

disorders. Epidemiological observations

exacerbations but also to the development

have identified protective environments and

of childhood wheeze and asthma, especially

risk factors associated with the development

if they occur against a background of early

of childhood asthma and wheezing

atopic sensitisation. In turn, the role of

disorders. The most robust and consistent

allergen exposure has been highly debated.

finding conferring risk is environmental

There is evidence that indoor allergen

tobacco smoke (ETS) exposure, particularly

exposure is a determinant for the

maternal smoking during pregnancy. In

development of allergic sensitisation

numerous studies, these exposures have

towards this particular allergen. In contrast,

been shown to be associated with an

allergen exposure has not convincingly been

increased risk of wheezing and childhood

associated with the development of

asthma. Passive smoke exposure through

childhood asthma and wheezing disorders.

other family members also increases the risk

Avoidance of house dust mite exposure has

of wheeze and childhood asthma in many

not achieved a reduction in asthma risk.

studies. Interestingly, the ban on tobacco

However, carers of children who are already

smoking in public places established in

sensitised and allergic to indoor allergens

Scotland in 2001 significantly decreased the

such as house dust mite, cat or dog dander

rates of hospitalisation for asthma by ,15%.

should clear indoor environments of these

Moreover, active smoking in children and

allergens as they may trigger symptoms.

adolescents has been related to increased

Lifestyle factors have also been shown to

risk for new-onset or progression of asthma

play a role. These include maternal diet

in this age group.

during pregnancy as well as diet in early and

With respect to outdoor air pollution,

later childhood, in particular breastfeeding,

studies relating to the density of car traffic,

a Mediterranean diet and vitamin intake.

in particular truck traffic on roads in close

BMI and obesity have been debated for a

proximity to the child’s residence, have been

number of years. These might be related to a

most conclusive. Here, particles with

changed inflammatory state, especially due

aerodynamic diameters between 2.5 mm

to central obesity, increased insulin

(PM2.5, able to enter the alveoli) and 10 mm

resistance and further metabolic alterations,

(PM10, too large to enter the alveoli), ozone

which may lead to asthma. Furthermore,

and nitrogen dioxide were demonstrated to

there is evidence that, particularly in

affect lung growth and to be associated with

adolescent females, an increase in body

reduced lung function and airway

weight, which may be related to early

inflammation in children, even prenatally.

menarche, is a determinant for new onset of

This underlines the importance of adverse

asthma in these subjects. The role of

effects during the most vulnerable phases of

physical activity remains unclear. Reduced

lung development early in life and it is not

physical activity may be a consequence of

limited to outdoor air pollution. Indoor

asthma and wheeze rather than a causal

parameters in addition to ETS may play a

factor for the new onset of disease.

role. Besides pollutants resulting from

indoor heaters and fireplaces (carbon

In the context of protective environments,

monoxide, nitrogen dioxide, polycyclic

studies have consistently shown that

aromatic hydrocarbons, volatile organic

growing up on a traditional farm reduces the

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ERS Handbook: Paediatric Respiratory Medicine

risk for asthma and hay fever. These studies

clear need for similar stringent quality

have consistently been reproduced in many

control and replication and the same

countries worldwide. The important

necessities in study design and careful

exposures relate to contact with farm

phenotyping as discussed previously.

animals, their fodder and unprocessed

There are examples for gene-environment

cow’s milk which have been identified in a

interactions in the field of asthma and

number of studies. The protective farm

wheezing disorders on different levels of

effect on asthma is, at least in part,

analytical approach. The first level is that of

attributable to environmental bacteria and

fungi, which are highly prevalent in these

a known candidate gene and a well-defined

environments. Experimental studies using

environmental exposure with suspected

microbes cultured from farming

gene-environment interactions, such as in

environments confirm the preventive effect

the interaction of endotoxin (a component

of exposure for the development of allergic

of the cell wall of Gram-negative bacteria)

with the gene for its receptor CD14 for the

asthma in mice.

risk of asthma and/or atopy. Another

The role of gene-environment interaction

example is ETS exposure and the 17q21

locus. Here it has been shown that the

Given the high prevalence of asthma, it is of

increased risk for childhood-onset asthma is

major public health relevance to elucidate

further increased by ETS exposure in early

the effects of genes and the environment in

life, itself known to confer a risk for early-

the study of pathological pathways in

onset disease. The first GEWIS for asthma

asthma. By fixing one parameter in the

assessed gene-environment interactions in

equation, it is possible to disentangle their

the field of the protective farm effect on

individual impacts. As highlighted above,

asthma in children. Neither significant

one may identify genetic factors by studying

interaction of farm-related exposures with

populations sharing similar environments;

common SNPs nor with previously

by studying populations sharing the same

published genetic markers of asthma was

genetic background but living under

found.

different environmental conditions, one can

identify relevant environmental impacts.

Thus, in the field of asthma and wheezing

However, asthma and wheezing disorders

disorders, few gene-environment

probably result from a joint effect of genes

interaction mechanisms have been

and the environment and their interaction,

established although epidemiological

i.e. the dependence of effects by one factor

studies have demonstrated numerous

on the presence or absence of another

environmental exposures associated with

factor. Technological progress has advanced

asthma and studies to date on the genetic

the field of gene-environment interactions

background have identified a number of

in asthma, as the analysis of gene-

asthma-associated loci. Future research will

environment interactions on a genome-wide

have to take into account windows of

level, i.e. gene-environment-wide interaction

opportunity for exposures under study as

studies (GEWIS) have been introduced

well as better characterised wheezing

recently. This poses a challenge to even

phenotypes.

highly advanced computational systems. In

addition to what has been mentioned for the

Further reading

study of genetic and epigenetic effects, there

is probably even more complexity in gene-

Eder W, et al.

(2006). The asthma

environment interactions analysis.

epidemic. N Engl J Med; 355: 2226-2235.

Moreover, the time-point when exposures

Gauderman WJ, et al. (2007). Effect of

have the biggest effect on the outcome

exposure to traffic on lung development

under study has to be taken into account

from 10 to 18 years of age: a cohort study.

(window of opportunity). Thus, for gene-

Lancet; 369: 571-577.

environment interaction studies there is a

ERS Handbook: Paediatric Respiratory Medicine

303

Henderson AJ, et al. (2012). Fetal origins

century perspective. Immunol Rev; 242:

of asthma. Semin Fetal Neonatal Med; 17:

10-30.

82-91.

Papoutsakis C, et al. (2013). Childhood

Kauffmann F, et al. (2012). Gene-environ-

overweight/obesity and asthma: is there a

ment interactions in asthma and allergic

link? A systematic review of recent

diseases: challenges and perspectives. J

epidemiologic evidence. J Acad Nutr

Allergy Clin Immunol; 130: 1229-1240.

Diet; 113: 77-105.

Latzin P, et al.

(2009). Air pollution

Sleiman PM, et al.

(2010). Recent

during pregnancy and lung function in

advances in the genetics and genomics

newborns: a birth cohort study. Eur Respir

of asthma and related traits. Curr Opin

J; 33: 594-603.

Pediatr; 22: 307-312.

Moffatt MF, et al. (2010). A large-scale,

von Mutius E, et al. (2010). Farm living:

consortium based genomewide associa-

effects on childhood asthma and allergy.

tion study of asthma. N Engl J Med; 363:

Nat Rev Immunol; 10: 86-88.

1211-1221.

Yang IV, et al. (2012). Epigenetic mechan-

Ober C, et al.

(2011). The genetics of

isms and the development of asthma. J

asthma and allergic disease: a

21st

Allergy Clin Immunol; 130: 1243-1255.

304

ERS Handbook: Paediatric Respiratory Medicine

Acute viral bronchiolitis

Fabio Midulla, Ambra Nicolai and Corrado Moretti

Definition

North American definition, in particular,

might engender an overlap between

Bronchiolitis is an acute viral respiratory

bronchiolitis and early wheezy bronchitis.

infection involving the terminal and

respiratory bronchioli in infants, resulting in

Epidemiology

small airways obstruction. Bronchiolitis is a

Bronchiolitis is the most frequent infectious

clinical diagnosis but, despite its high

disease in children ,1 year of age (90% of

frequency, its definition is still controversial.

patients are 1-9 months of age), and is the

The American Academy of Pediatrics

leading cause of hospitalisation in this

subcommittee defines bronchiolitis as a

group of infants. Bronchiolitis is epidemic

disorder in infants ,24 months of age that

between November and April. Annually, 11

is most commonly caused by a viral lower

out of every 100 infants have bronchiolitis

respiratory tract infection characterised by

and 11-13% of patients require

wheezing. In contrast, European guidelines

hospitalisation. Each year 150 million new

define bronchiolitis as a seasonal viral

cases of bronchiolitis are reported

illness in infants ,12 months of age

worldwide. Only 1-3% of infants require

characterised by nasal discharge, cough,

admission to intensive care, particularly

tachypnoea, retractions and bilateral

those in whom risk factors are present.

crackles. These definitions reflect differences

in how the disease is interpreted and the

Aetiology/risk factors

Bronchiolitis is caused by viruses. The most

Key points

common viruses responsible are respiratory

syncytial virus (RSV), human bocavirus,

rhinovirus, human metapneumovirus,

N Bronchiolitis is the first episode of

influenza A and B, and parainfluenza viruses

acute viral infection of terminal and

1-3.

respiratory bronchioli in infants

,1 year of age.

Risk factors for severe bronchiolitis are age

N Symptoms of bronchiolitis are

,3 months, male sex, low socioeconomic

moderate-to-severe respiratory

conditions, maternal smoking and RSV

distress with rales at auscultation.

infection. Other risk factors for severe

bronchopulmonary are prematurity with

Supportive therapies aim to keep the

bronchopulmonary dysplasia and coexisting

upper airways clear, and the infant

co-morbidities, such as cardiovascular

oxygenated and hydrated.

diseases, immunodeficiency and chronic

N A bronchodilator mixed with 3%

respiratory diseases. The only protective

hypertonic saline might be tried and

factor is maternal breastfeeding.

this combination should be continued

Pathophysiology

only if it achieves a documentable

clinical benefit.

Viral respiratory infection results in

respiratory epithelium necrosis, loss of

ERS Handbook: Paediatric Respiratory Medicine

305

epithelial cilia, collection of desquamated

blood tests are required only if suggested by

airway epithelial cells, lymphocyte and

clinical indications; blood gas analysis is

neutrophil infiltration within terminal and

recommended only in more severe cases.

respiratory bronchioli, and oedema around

Rapid virus detection could reduce

the airway. Cellular debris, inflammatory

antibiotic use.

cells and fibrin cause airway obstruction.

Symptoms

Mucus plugs can partially or totally occlude

the bronchioli. When the bronchioli are

The natural history of bronchiolitis is of a

completely occluded, atelectasis develops; if

self-limited disease that usually lasts for 3-

bronchioli are only partially occluded, diffuse

7 days with an average duration of

air trapping occurs (fig. 1).

hospitalisation of 3.9 days. A small minority

The increase in airway resistance and

of infants, especially those with associated

decrease in dynamic lung compliance

comorbidities, may require intensive care

increase the work of breathing. Atelectasis

and mechanical ventilation.

and air trapping result in hypoxaemia and

The initial symptoms of bronchiolitis are

increased carbon dioxide due to an altered

rhinorrhoea and cough, sometimes

ventilation/perfusion ratio. Tachypnoea,

accompanied by a low-grade fever. The first

increased work of breathing and reduced

clinical symptom could also be episodes of

feeding can cause dehydration with

apnoea, especially in preterm infants, but

metabolic acidosis.

most infants with bronchiolitis manifest

Diagnosis

tachypnoea, retractions, nasal flaring, rales

at auscultation and hypoxaemia. Other

Bronchiolitis is commonly diagnosed on

symptoms might include dehydration with

clinical grounds alone without help from

metabolic acidosis. SIADH (syndrome of

diagnostic tests. The criteria for the

inappropriate secretion of antidiuretic

diagnosis of bronchiolitis include exposure

hormone) is common in infants with severe

to other children or adults with respiratory

respiratory distress and can cause

viral infection, age ,12 months, preceding

hyponatraemia and accidental fluid

upper respiratory illness and signs of acute

overload. Bronchiolitis is a ‘‘dynamic

lower respiratory illness (respiratory

disease’’ and its clinical characteristics can

distress, low oxygen saturation, rales and,

quickly change.

rarely, wheezing). Chest radiographs and

Admission criteria include respiratory

distress, apnoea, tachypnoea, oxygen

requirement, poor feeding, dehydration,

continuous clinical assessment of airway

clearance requirement, underlying chronic

disease, and inappropriate social and family

conditions.

The major discharge criteria are oxygen

saturation that stably remains .90-94% in

room air in the absence of respiratory

distress, and adequate daily oral intake

(.75% of usual intake) at a level to prevent

dehydration followed by adequate parental

care and family education about the

potential duration of acute symptoms.

Figure 1. Chest radiograph of an infant with severe

Indications for intensive care unit

acute bronchiolitis showing diffuse air trapping

consultation and admission include failure

and peribronchial thickening.

to maintain SpO₂ .92% with oxygen

306

ERS Handbook: Paediatric Respiratory Medicine

therapy, deteriorating respiratory status with

in preventing mechanical ventilation could

exhaustion, and recurrent apnoea.

not be evaluated.

Supportive therapy

Pharmacological therapy

General management includes therapies

Current clinical evidence shows that

intended to reduce the work of breathing

bronchodilators produce small short-term

(keep upper airways clear by using

improvements in clinical scores. A trial with

vasoconstrictors and nasal suction), and to

salbutamol is justified in infants with severe

restore clinical stability (oxygenation and

respiratory distress. Inhaled salbutamol

hydration). Heart rate, respiratory rate and

should be continued only if clinical

SpO₂ should be monitored for at least the first

examination documents a significant clinical

24 h. A small minority of patients with severe

response (e.g. decreased respiratory rate or

bronchiolitis need airway support either via

an improvement in SpO₂).

CPAP or mechanical ventilation (fig. 2).

Nebulised racemic adrenalin provides better

In infants with mild bronchiolitis, breast

short-term improvement in the clinical score

feeding should be supported and small

than placebo, particularly in the first 24 h.

volume and frequent feeding should be

Clinical trials have shown adrenaline to be

encouraged. Nasogastric feeding should be

superior to placebo and salbutamol. Inhaled

considered in infants with severe

adrenalin should be continued only if clinical

bronchiolitis and intravenous hydration

examination documents a significant clinical

should be given only if nasogastric feeding

response.

is not possible or in infants with severe

dehydration. Intravenous fluid should be

A recent Cochrane Review of seven trials

administered carefully to avoid fluid

showed that nebulised 3% hypertonic saline

overload (SIADH).

alone or together with a bronchodilator

effectively reduces the length of

According to the American Academy of

hospitalisation among infants with

Pediatrics oxygen should be administered

nonsevere acute viral bronchiolitis, and

only when saturation at room air is ,90% in

improves clinical severity scores in

the absence of respiratory distress, while the

outpatient and inpatient populations.

Scottish Intercollegiate Guideline Network

Hypertonic saline, through osmosis, causes

guidelines recommend the use of oxygen

water to move from the interstitium into the

until oxygen saturation remains permanently

airway thereby decreasing interstitial

.95%. Oxygen is usually administered via

oedema and mucosal viscosity.

nasal cannula or a head box. Recent

evidence shows that oxygen can be given

Current evidence provides no support for a

efficaciously with heated humidified high-

clinically beneficial effect of systemic or

flow nasal cannula; its presumed role is

inhaled glucocorticoids.

reduction of the work of breathing,

prevention of dynamic airways collapse and

No evidence justifies using antibiotics in

improvement of gas exchange.

bronchiolitis because it is a viral disease and

affected infants rarely undergo bacterial

Indications for CPAP include severe

superinfection. Antibiotic treatment should

respiratory distress, a need for an inspiratory

be recommended only in infants with severe

oxygen fraction (FIO₂) .0.5 or the presence

bronchiolitis requiring intubation, a group in

of apnoea. It is hypothesised that the

whom bacterial superinfection is more

addition of heliox to CPAP, transforming

common.

turbulent gas flow into laminar gas flow,

could improve the washout of carbon

Nebulised DNase and montelukast are not

dioxide as well as oxygenation in the newly

indicated in the treatment of bronchiolitis.

recruited airways with a consequent

In infants with a history of prematurity with

decrease of the work of breathing.

episodes of apnoea, caffeine appears to be a

Unfortunately, the potential benefit of CPAP

rational choice of treatment.

ERS Handbook: Paediatric Respiratory Medicine

307

History, physical and risk-

factor assessment

YES

Toxic or in severe

Admission to PICU

respiratory distress?

Nasal suction

Assess respiratory status

Start oxygen if SpO₂ consistently ≤90-94%

Manage without

Single administration trial with 3%

Improvement of

medications

hypertonic saline + adrenaline or

clinical status?

salbutamol (consider

YES

bronchodilators if family history of

allergy, asthma or atopy)

Consider repeat

inhalation

Admit

treatment(s)

Respiratory care

Nasal suction prior to

feeding as needed

Period of observation

Monitor

Heart rate,respiratory

rate and SpO

2 during

the first 24 h

Stable and/or

Meets admit

Frequent clinical

improving?

criteria?

assessment of

YES

respiratory status

YES

Spot checks for SpO

If on oxygen, consider

YES

weaning when SpO

Meets discharge

Discharge with parent education

consistently higher than

PCP follow-up

criteria?

90-95%

YES

Meets discharge

criteria?

Continue observation

Figure 2. An algorithm for the management of bronchiolitis in the emergency department. PICU:

paediatric intensive care unit; PCP: primary care physician.

308

ERS Handbook: Paediatric Respiratory Medicine

Prevention and prophylaxis

Chowdhury MM, et al.

(2013). Heliox

terapy in bronchiolitis: phase III multi-

Preventative measures include adequate

center double-blind randomized con-

healthcare professional education about

trolled trial. Pediatrics; 131: 66-669.

epidemiology and control of viral infection,

Donlan M, et al. (2011). Use of contin-

such as washing the hands before and after

uous positive airway pressure (CPAP) in

caring for patients with viral respiratory

acute viral bronchiolitis: a systematic

symptoms and single rooms for infected

review. Pediatr Pulmunol; 46: 736-746.

patients. Equally important, adequate local

Fernandes RM, et al.

(2010).

policies should restrict hospital visiting by

Glucocorticoids for acute viral bronchio-

those with symptoms of respiratory infections.

litis in infants and young children.

Cochrane Database Syst Rev;

10:

Palivizumab is a humanised monoclonal RSV

CD004878.

antibody licensed for preventing the

Gadomski AM, et al.

(2010).

development of severe diseases arising from

Bronchodilators

for

bronchiolitis.

an RSV infection. Palivizumab prevents

Cochrane Database Syst Rev;

12:

hospital admission for RSV infections, but

CD001266.

does not decrease length of stay or oxygen

Hartling L, et al. (2011). Epinephrine for

requirements for those who are hospitalised.

bronchiolitis. Cochrane Database Syst Rev;

Palivizumab is a useful therapeutic option in

6: CD003123.

infants ,12 months who have severe

Kennedy N, et al. (2005). Is nasogastric

comorbidity (extreme prematurity, congenital

fluid therapy a safe alternative to the

or acquired lung diseases, congenital heart

intravenous route in infants with bronch-

disease and immune deficiency).

iolitis? Arch Dis Child; 90: 320-321.

Martinòn-Torres F (2012). Non invasive

Prognosis and follow-up

ventilation with helium-oxygen in chil-

dren. J Crit Care; 27: e1-e9.

Mild respiratory symptoms may last for

McKiernan

al.

(2010).

,3 weeks after bronchiolitis. About 50% of

High flow nasal cannulae therapy in

children with bronchiolitis may have

infants with bronchiolitis. J Pediatr; 156:

episodes of wheezing in later years. The

634-638.

most important risk factors for recurrent

Midulla F, et al.

(2010). Respiratory

and persistent wheezing after bronchiolitis

syncytial virus, human bocavirus and

are rhinovirus infection and a positive family

rhinovirus bronchiolitis in infants. Arch

history for atopy.

Dis Child; 95: 35-41.

Plint AC, et al. (2009). Epinephrine and

dexamethasone in children with bronch-

Further reading

iolitis. N Engl J Med; 360: 2079-2089.

Andabaka T, et al.

(2013). Monoclonal

Scottish

Intercollegiate

Guideline

antibody for reducing the risk of respira-

Network

(SIGN). Bronchiolitis in chil-

tory syncytial virus infection in children.

dren. A national clinical guideline.

Cochrane Database Syst Rev; 4: CD006602.

Guideline no. 91. Edinburgh, SIGN, 2006.

Blom DJ, et al. (2007). Inhaled corticoster-

Spurling GK, et al. (2011). Antibiotics for

oids during acute bronchiolitis in the

bronchiolitis in children. Cochrane

prevention of post-bronchiolitis wheezing.

Database Syst Rev; 6: CD005189.

Cochrane Database Syst Rev; 1: CD004881.

American Academy of Pediatrics

Bronchiolitis Guideline Team, Cincinnati

Subcommittee on Diagnosis and

Children’s Hospital Medical Center.

Management of Bronchiolitis.

(2006).

Evidence-based care guidelines for manage-

Diagnosis and management of bronchio-

ment of bronchiolitis in infants 1 year of age

litis. Pediatrics; 118: 1774-1793.

or less with a first time episode. Bronchiolitis

Zhang L, et al. (2008). Nebulized hyper-

Pediatric Evidence-Based Care Guidelines,

tonic saline solution for acute bronchio-

Cincinnati Children’s Hospital Medical

litis in infants. Cochrane Database Syst

Center. Guideline 1, 2010, pages 1-16.

Rev; 4: CD006458.

ERS Handbook: Paediatric Respiratory Medicine

309

Preschool wheezing

Paul L.P. Brand, Annemie M. Boehmer, Anja A.P.H. Vaessen-Verberne

Wheezing and dyspnoea in preschool

have at least one episode of wheeze before

children are among the most common

their third birthday. There is much clinical

presenting symptoms in paediatric practice.

heterogeneity in phenotypes of children with

Approximately one in three children will

preschool wheeze, which appears to be

similar between populations. Due to this

heterogeneity, and despite its common

occurrence, relatively little evidence is

Key points

available on the pathophysiology and

treatment of wheezing in preschool children.

Despite the favourable natural history

Therefore, considerable controversy exists in

in the majority of children with

the literature about the classification and the

wheeze during preschool years,

treatment of preschool wheezing disorders.

symptoms in this age range can be

To end this controversy, the underlying

severe or frequent, justifying

pathophysiology and aetiology of preschool

maintenance treatment.

wheezing disorders need to be properly

Limited information is available on

understood.

the pathophysiology of recurrent

Epidemiology

wheeze in preschool children, which is

likely to be complex and

Much of the knowledge on recurrent wheeze

multifactorial. As a result, one-

and dyspnoea in preschool children comes

dimensional classification systems

from a series of well-designed, large-scale

(e.g. episodic viral versus multiple-

birth cohort studies. The most well-known of

trigger wheeze) are of limited value in

these was conducted in Tucson, AZ, USA.

diagnosis and management.

The main results of this landmark study, the

Tucson Children’s Respiratory Study, are as

ICS are recommended as first choice

follows:

maintenance therapy in children with

frequent or severe symptoms

826 infants were followed from birth;

irrespective of phenotype.

N during the first 3 years of life 30% of

Montelukast is an alternative

children had had at least one episode of

maintenance treatment option,

wheeze and half of these children had

although it is less effective than ICS.

wheezed more than once;

If symptoms persist despite

60% of wheezy preschool children ceased

maintenance treatment ongoing

to wheeze before the age of 6 years

exposure to relevant inhalant

(transient wheeze associated with

allergens and tobacco smoke, poor

maternal smoking and with wheeze

adherence or inhalation technique,

occurring only during viral colds);

alternative diagnoses and relevant

40% continued to wheeze after their sixth

comorbidity should be excluded

birthday (persistent wheeze associated

before stepping up therapy.

with eczema, maternal asthma and

elevated cord blood IgE).

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ERS Handbook: Paediatric Respiratory Medicine

In contrast with asthma in school-aged

episodes, with numerous triggering factors

children, which is more likely to persist

including viral colds, mist, exercise, etc.

throughout childhood, many wheezy

(table 1). Based on the evidence available at

preschool children outgrow their symptoms

that time, this distinction was considered to

by school age. This prompted efforts to

be both clinically plausible (most experts in

identify factors that could predict

the ERS Task Force felt they could

persistence of preschool wheeze into school

distinguish these phenotypes reliably based

age, and to classify preschool wheezing

on the patient’s history) and meaningful,

disorders into different phenotypes with

because the few published studies appeared

different treatment response or outcome.

to support the view that inhaled

corticosteroids (ICS) were the treatment of

Predicting the outcome of preschool

choice for MTW, and that EVW might

wheeze

respond more favourably to maintenance

treatment with montelukast. The ERS Task

Despite differences between studies, atopy

Force acknowledged that these

during early childhood has consistently been

recommendations were likely to change with

identified as the most important risk factor

new evidence becoming available.

for wheeze persisting beyond the sixth

birthday, in a dose-effect relationship: the

Limitations of the EVW-MTW phenotype

more allergens the child is sensitised to, and

distinction

the stronger the degree of sensitisation, the

greater the likelihood the child’s wheeze is

Although the ERS Task Force classification

going to be persistent. Although asthma risk

system has been widely adopted, it has been

indices constructed of different risk factors

criticised as being too simple to capture the

are significantly associated with persistent

multidimensional nature of preschool

wheeze in groups of children in birth cohort

wheezing, and it has been suggested that

studies, they have not been validated

EVW and MTW do not represent different

prospectively, and the predictive value of

phenotypes, but rather different degrees of

these indices is too poor to allow

severity of the same disease. In addition, the

meaningful prediction of outcome of

classification system is hampered by the fact

preschool wheeze in individual cases.

that viral colds are the main cause of

exacerbations, both in EVW and in MTW.

Classification of preschool wheeze

Evidence from a range of recent studies

The finding in the Tucson study that wheeze

suggests that the ERS classification system

occurring only during viral colds was

should be reconsidered.

associated with transient wheeze suggested

First, prospective studies have shown that

that exclusive viral-induced wheeze in early

these phenotypes are not stable over time;

childhood might be an innocuous disease,

when repeatedly taking a history from

which is likely to disappear when children get

parents about their preschool child’s wheeze

older. However, this hypothesis is not

symptoms, the symptom pattern changes

supported by follow-up studies, which showed

over time from EVW to MTW and vice versa.

that the majority of children with episodic viral

Secondly, the distinction between EVW and

wheeze (EVW) seen in secondary care

MTW does not take the severity and

continue to wheeze beyond the age of 6 years.

frequency of episodes of wheeze into

In 2008, a European Respiratory Society

account, while in clinical practice these

(ERS) Task Force report proposed to

factors are more important in determining

distinguish two wheezing phenotypes in

the initiation and choice of maintenance

preschool children. 1) EVW: wheezing in

therapy than the temporal pattern of

discrete episodes associated with viral

symptoms. Thirdly, although statistically

upper respiratory tract infections (URTIs)

significant differences in physiology and

and no symptoms between episodes; and 2)

pathology between the two phenotypes have

multiple-trigger wheeze (MTW): wheeze

been demonstrated, the two phenotypes

both in discrete episodes and between

also show considerable clinical overlap.

ERS Handbook: Paediatric Respiratory Medicine

311

Table 1. Different classification systems for preschool wheeze

Atopic versus non-atopic wheeze

Atopic wheeze (or allergic asthma): three or more episodes of wheeze and dyspnoea AND

demonstrated sensitisation to inhalant or food allergens

Non-atopic (or viral) wheeze: three or more episodes of wheeze and dyspnoea, only occurring

during URTIs, AND no evidence of allergic sensitisation to inhalant or food allergens

EVW versus MTW

EVW: wheezing during discrete time-periods, often in association with clinical evidence of a

viral cold, with absence of wheeze between episodes

MTW: wheezing that shows discrete episodes, but also symptoms between episodes

Mild and infrequent wheeze versus severe or frequent wheeze

Mild and infrequent wheeze: wheeze with little impact on daily life of affected children, and

with a low frequency of episodes (less than one episode per month)

Severe or frequent wheeze: wheeze with considerable impact on daily life of affected children

(requiring hospital admission or emergency room visit), or with a high frequency of episodes

(two or more per month)

Data from Brand et al. (2008), Pedersen et al. (2011), and Schultz et al. (2011).

With respect to inhaled steroid treatment, a

conditions. The initial diagnostic approach

systematic review showed that ICS are

to a preschool child with wheeze is aimed at

effective in reducing preschool wheeze,

excluding serious underlying conditions,

irrespective of the reported symptom pattern

which usually present in the form of

(EVW or MTW). A recent large trial in the USA

‘‘atypical wheeze’’ (table 2). A detailed

showed that daily nebulised low-dose

history and thorough physical examination

budesonide was no more effective in reducing

when the child is symptomatic are usually

the number and severity of wheezing

sufficient to exclude atypical wheeze. If

episodes in preschool children than

history and physical examination suggest

intermittent use only during symptomatic

the possibility of atypical wheeze, specific

episodes. While episodic nebulised

further diagnostic testing is indicated.

budesonide was no more effective than

episodic use of montelukast in preschool

The majority of preschool children

children with viral-induced wheeze, daily use

presenting with troublesome wheeze and

of nebulised budesonide was more effective

dyspnoea will have ‘‘typical wheeze’’, after

than daily montelukast in children aged 2-

exclusion of the unlikely causes listed in

8 years with mild persistent wheezing.

table 1. Because parents differ from

physicians in their understanding of the

Different ways to classify preschool wheeze

term ‘‘wheeze’’, confirmation of the

presence of wheeze by a physician is

Based on the available evidence, several

recommended before initiating therapy. In

classification systems of preschool wheeze

children with confirmed typical wheeze, the

have been proposed (table 1). None of these

systems is universally accepted, which is not

only potentially useful diagnostic test is a

surprising given the limited evidence on

test of allergic sensitisation (either skin-

which they are based. There is no consensus

prick test or measurement of specific IgE to

on the preferred terminology.

a panel of allergens in blood) for

classification purposes (table 1).

Diagnostic approach to preschool children

with recurrent wheeze and dyspnoea

Treatment of acute episodes

Wheeze is a nonspecific symptom, which

The initial treatment of choice in episodes of

may be caused by a range of clinical

acute wheeze is an inhaled bronchodilator

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Atypical wheeze: warning signs and possible underlying conditions

Warning sign

Possible underlying causes

Persistent symptoms from birth

Tracheobronchomalacia and PCD

Productive wet cough as a main symptom

PCD, CF, immune deficiency and TB

Never completely symptom free

Tracheobronchomalacia, vascular ring, foreign

body aspiration and neonatal chronic lung

disease

Failure to thrive

CF and immune deficiency

Recurrent pneumonia

CF and immune deficiency

PCD: primary ciliary dyskinesia.

such as salbutamol, preferably by metered-

their child. If sensitisation to aeroallergens

dose inhaler-spacer combination because

has been demonstrated, reducing the

this is more effective than treatment

exposure to these allergens is likely to be

delivered by a nebuliser. Oral corticosteroids

effective, although evidence in this area is

are less effective in preschool children with

lacking.

an episode of acute wheeze than in older

Because wheezing in preschool children

children with asthma, and are only

largely occurs in discrete episodes with

recommended in children who require

sometimes relatively long symptom-free

hospitalisation and supplemental oxygen for

intervals, parents should understand that

a severe exacerbation, or those with atopic

the effect of maintenance therapy can only

wheeze. Pre-emptive high-dose ICS for viral

be judged after the child had one or more

induced wheeze, at the start of a viral upper

subsequent URTIs. This may require

airway infection and continued until this is

prolonged continuation of medication,

resolved, although effective, is not

which parents will be more likely to provide

recommended because of its effect on

when they trust, and can collaborate

growth.

constructively with, their child’s physician.

Maintenance treatment

The choice of whether or not to initiate

Principles of maintenance treatment are

maintenance therapy in preschool children

outlined in table 3, and these are in line with

with wheeze depends primarily on the

asthma guidelines in older children and

severity and frequency of episodes. After a

adolescents. Based on the realisation that

systematic review of all available studies

parental cooperation is necessary to ensure

using the GRADE (Grading of

optimal effects of therapy, the first, and

Recommendations Assessment,

perhaps most important, step of

Development and Evaluation) methodology,

maintenance therapy is to achieve and

the Dutch Paediatric Respiratory Society, in

maintain a therapeutic alliance with patients

collaboration with the Dutch Cochrane

and parents. Tailored self-management

Centre, recommended ICS as maintenance

education is needed to ensure that parents

treatment in preschool children with

understand how and why treatment works. A

troublesome wheeze, irrespective of

recommendation to reduce exposure to

wheezing phenotype. Although inhaled

tobacco smoke can only be achieved if this

steroids do not alter the long-term outcome

is discussed with parents in a constructive

or persistence of wheeze, they are effective

and non-judgmental fashion. Tailored self-

in controlling symptoms, which is why their

management education is most effective

use in preschool children with troublesome

when it is delivered repeatedly, addresses

wheezing symptoms is justified. There is no

parental concerns and cognitions, and

preference for any specific inhaled steroid

incorporates parents’ treatment goals for

preparation. The assumed superiority of

ERS Handbook: Paediatric Respiratory Medicine

313

Table 3. Principles of maintenance treatment of preschool children with recurrent wheeze

Therapeutic alliance with parents and patient

Non-pharmacological therapy

Self-management education

Maximal reduction of passive smoke exposure

When sensitised to aeroallergens reduce aeroallergen exposure

Repeated scheduled follow-up

Pharmacological therapy

Inhaled salbutamol on demand

Train and maintain correct inhalation technique

If repeated troublesome symptoms and parents motivated for maintenance therapy then start

low-dose ICS or montelukast

If low-dose ICS do not control symptoms

Check inhalation technique and adherence to treatment

Exclude relevant comorbidity or alternative diagnosis

Add additional controller (inhaled steroid, montelukast or long-acting b-agonist)

inhaled steroid preparations with ultrafine

be controlled effectively by inhaled steroids

particles is theoretical, with no evidence

or montelukast alone, or by a combination

from randomised trials to support their use.

of controller medications.

Although data on side-effects of long-term

use are lacking, inhaled steroids in this age

Because of preschool wheezing’s favourable

group appear to be safe.

natural history, maintenance treatment

should be tapered off when the child is

Montelukast is a reasonable alternative as a

completely symptom free for 3-6 months,

controller therapy, although it is less

or for 12 months in children who have had a

effective than ICS in children with recurrent

serious exacerbation requiring long-term

wheeze.

hospitalisation or admission to intensive

care.

If symptoms fail to improve sufficiently

during inhaled steroid or montelukast

Conclusion

maintenance treatment, physicians should

Recurrent wheeze in preschool children is

exclude reasons for failure of such therapy

common. Due to the limited amount of

before starting additional medication.

Treatment failure can often be explained by

evidence on its complex and multifactorial

insufficient adherence to medication, poor

pathophysiology, different classification

inhalation technique, an alternative

systems with associated treatment

diagnosis such as bronchomalacia, or

recommendations have been proposed,

relevant comorbidity such as allergic

none of which can be recommended for

rhinitis. If these are properly addressed and

universal use at present. After excluding

treated, and symptoms remain problematic,

cases with atypical features, most patients

addition of other controllers (montelukast,

with severe recurrent wheeze in this age

ICS or long-acting b-agonists) can be

range can be managed effectively by ICS or

considered. There is no evidence from

montelukast, either alone or in a

randomised trials to prefer any add-on

combination regimen. Mild intermittent

treatment schedule over another. Most

wheeze can be treated with an inhaled

cases of troublesome preschool wheeze can

bronchodilator only.

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ERS Handbook: Paediatric Respiratory Medicine

Further reading

Panickar J, et al. (2009). Oral predniso-

lone for preschool children with acute

Bacharier LB, et al. (2008). Episodic use

virus-induced wheezing. N Engl J Med;

of an inhaled corticosteroid or leukotriene

360: 329-338.

receptor antagonist in preschool children

Pedersen SE, et al. (2011). Global strategy

with moderate-to-severe intermittent

for the diagnosis and management of

wheezing. J Allergy Clin Immunol;

122:

asthma in children 5 years and younger.

1127-1135.

Pediatr Pulmonol; 46: 1-17.

Boluyt N, et al.

(2012). Assessment of

Savenije OE, et al. (2011). Comparison of

controversial pediatric asthma manage-

childhood wheezing phenotypes in 2 birth

ment options using GRADE. Pediatrics;

cohorts: ALSPAC and PIAMA. J Allergy

130: e658-e668.

Clin Immunol; 127: 1505-1512.

Brand PL, et al.

(2008). Definition,

Savenije OE, et al. (2012). Predicting who

assessment and treatment of wheezing

will have asthma at school age among

disorders in preschool children: an

preschool children. J Allergy Clin Immunol;

evidence-based approach. Eur Respir J;

130: 325-331.

32: 1096-1110.

Schultz A, et al.

(2010). The transient

Castro-Rodriguez JA, et al.

(2009).

value of classifying preschool wheeze into

Efficacy of inhaled corticosteroids in

episodic viral wheeze and multiple trigger

infants and preschoolers with recurrent

wheeze. Acta Paediatr; 99: 56-60.

wheezing and asthma: a systematic

Schultz A, et al.

(2011). Episodic viral

review with meta-analysis. Pediatrics; 123:

wheeze and multiple trigger wheeze in

e519-e525.

preschool children: a useful distinction

Dean AJ, et al.

(2010). A systematic

for clinicians? Paediatr Respir Rev;

12:

review of interventions to enhance med-

160-164.

ication adherence in children and adoles-

Simpson A, et al. (2010). Beyond atopy:

cents with chronic illness. Arch Dis Child;

multiple patterns of sensitization in

95: 717-723.

relation to asthma in a birth cohort study.

Ducharme FM, et al. (2009). Preemptive

Am J Respir Crit Care Med; 181: 1200-

use of high-dose fluticasone for virus-

1206.

induced wheezing in young children. N

Sonnappa S, et al.

(2010). Symptom-

Engl J Med; 360: 339-353.

pattern phenotype and pulmonary func-

Fouzas S, et al. (2013). Predicting persis-

tion in preschool wheezers. J Allergy Clin

tence of asthma in preschool wheezers:

Immunol; 126: 519-526.

crystal balls or muddy waters? Paediatr

Sonnappa S, et al. (2011). Relationship

Respir Rev; 14: 48-52.

between past airway pathology and cur-

Kappelle L, et al. (2012). Severe episodic

rent lung function in preschool wheezers.

viral wheeze in preschool children: high

Eur Respir J; 38: 1431-1436.

risk of asthma at age 5-10 years. Eur J

Szefler SJ, et al.

(2007). Comparative

Pediatr; 171: 947-954.

study of budesonide inhalation suspen-

Kotaniemi-Syrjanen A, et al.

(2011).

sion and montelukast in young children

Symptom-based classification of wheeze:

with mild persistent asthma. J Allergy Clin

how does it work in infants? J Allergy Clin

Immunol; 120: 1043-1050.

Immunol; 128: 1111-1112.

Zeiger RS, et al.

(2011). Daily or inter-

Martinez FD, et al. (1995). Asthma and

mittent budesonide in preschool children

wheezing in the first six years of life. N

with recurrent wheezing. N Engl J Med;

Engl J Med; 332: 133-138.

365: 1990-2001.

ERS Handbook: Paediatric Respiratory Medicine

315

Bronchial asthma

Mariëlle Pijnenburg and Karin C. Lødrup Carlsen

Asthma is the leading chronic disease in

Key points

children in the Western world, affecting 5-

20% of school-age children in Europe.

Asthma prevalence has increased during the

There is no universally accepted

last two decades, although this trend seems

definition of asthma, although

to being levelling off, at least in high-income

reversible airway obstruction, airway

countries. Childhood asthma is a serious

hyperresponsiveness and chronic

public health problem for several reasons.

inflammation are key features.

First, asthma causes considerable morbidity

There is accumulating evidence that

and healthcare utilisation. High frequencies

the interaction between respiratory

of sleep disturbances due to asthma (up to

viral infections and atopy is important

34%), absence from school (23-51%) and

in the cause and pathogenesis of

limitation of activities (47%) have been

atopic asthma.

reported in several studies. Asthma is the

Airway remodelling is a common

third-ranking course of hospitalisation in

feature in adult severe asthma but this

children and the major cause of school

is less clear in childhood, particularly

absenteeism due to chronic disease among

as to when it starts and what elicits

children in the USA (www.afaa.org). In

the process.

Europe, unscheduled emergency visits to

healthcare accounted for 47% of total asthma

The ultimate goal of asthma

costs in infants and 45% in children; 7% of all

treatment is to achieve and maintain

children reported at least one hospitalisation.

clinical control with a minimum of

Secondly, as asthma is associated with

side-effects and to reduce future risks

reduced growth of lung function and lung

to the patient.

function at a young age is a determinant of

There is no uniform definition of

lung function in adult life, optimal treatment

severe childhood asthma and several

is of major concern for long-term prognosis.

criteria are used such as the need for

or use of high-dose corticosteroids,

The main characteristics of asthma are

severe and/or frequent exacerbations,

reversible airway obstruction and airway

chronic asthma symptoms, or

hyperresponsiveness; chronic inflammation

reduced lung function.

of the airways plays a central role in the

pathogenesis of asthma and anti-

Severe childhood asthma should be

inflammatory treatment with inhaled

referred to and managed in

corticosteroids (ICS) is the treatment of

specialised paediatric units.

choice. A stepwise approach to asthma

management has been suggested by all

international guidelines, and the ultimate

The underlying mechanisms of asthma are

goal of asthma treatment is to achieve and

poorly understood. However, there is

maintain clinical control with the least

accumulating evidence that the interaction

possible unwanted effects.

between respiratory viral infections,

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ERS Handbook: Paediatric Respiratory Medicine

against a background of atopy, is

The main features, therefore, for diagnosing

important in the cause and pathogenesis

asthma are:

of atopic asthma.

N history taking,

Diagnosis

N objective documentation of reversible

bronchial obstruction,

Diagnosing asthma may be challenging,

particularly in infants and pre-school

N allergy and bronchial

children, and no universally accepted

hyperresponsiveness (BHR) testing,

definition of asthma exists that embraces

N assessing airway inflammation whenever

children from infancy to post-puberty.

possible.

Difficulty in studying asthma arises from the

The medical history should focus on

fact that asthma is not a single disease but a

symptoms of bronchial obstruction or

compilation of diseases presenting as a

syndrome or a collection of symptoms.

cough, triggers of these symptoms, and

Particularly in childhood, reversible

should include all items in figure 1, with

bronchial obstruction may be a final

attention to the age-specific questions.

common feature of a number of different

Furthermore, triggers of symptoms are

diseases with distinct aetiologies, and

distinct from inciters of asthma

different environmental and genetic

development, mechanisms of the latter

associations. However, most cases of

being less clear. Common triggers of

asthma start in childhood and early-life

symptoms are viral infections, exercise,

asthma, particularly in boys, is a significant

allergen exposure and irritants such as

risk factor for later COPD, and the severity

tobacco smoke.

and number of obstructive episodes in early

childhood appear to be reasonable

Pathophysiology

predictors for later on-going childhood

Asthma is a chronic inflammatory airway

asthma.

disease characterised by reversible airway

Several phenotypes of asthma have been

obstruction and BHR. However, there is no

described and are being identified,

current consensus on the underlying

commonly based upon the time of

pathophysiology of asthma throughout

presentation of ‘‘wheeze’’ within the first

childhood. This said, the underlying chronic

part of childhood. However, phenotypes

inflammation is often characterised by

based on the presence or absence of allergic

eosinophilic activity and allergic

sensitisation, eosinophilic or

inflammation, but nonallergic asthma is not

noneosinophilic inflammation, or response

uncommon in childhood.

to treatment are also recognised. The

asthma-like clinical presentations often

Bronchial obstruction is a result of bronchial

referred to as ‘‘wheezy’’ disorders in children

muscle constriction, acting particularly

are common prior to signs or

through the b-receptors, as well as mucosal

documentation of allergic markers, although

oedema and increased airway secretions

nonallergic childhood asthma is common in

resulting from airway inflammation. All

many areas.

contribute to reduced airway flow, which is

reflected in reduced lung function and

With this background, various definitions are

classical symptoms such as wheezing,

used, and common to them all are reversible

dyspnoea and coughing. Reversibility of the

airway obstruction and chronic airway

bronchial obstruction may occur

inflammation. Thus, a descriptive and

spontaneously or with bronchodilators

pragmatic approach is necessary in the clinic,

(particularly b₂-agonists), whereas anti-

as the diagnosis will elicit targeted treatment.

inflammatory medications, such as

Classical symptoms of asthma are wheeze,

corticosteroids, are necessary to reduce the

cough (particularly at night or during

underlying pathophysiological causes of

exertion), dyspnoea and chest tightness.

bronchoconstriction (see later).

ERS Handbook: Paediatric Respiratory Medicine

317

In all children, ask about:

• Wheezing, cough

• Specific triggers, e.g. passive smoker, pets, humidity, mould and dampness, respiratory

infections, cold air exposure, exercise/activity, cough after laughing/crying

• Altered sleep patterns: awakening, night cough, sleep apnoea

• Exacerbations in the past year

• Nasal symptoms: running, itching, sneezing, blocking

Additionally

In infants (<2 years)

In children (>2 years)

• Noisy breathing, vomiting associated

• Shortness of breath (day or night)

with cough

• Fatigue (decrease in playing compared to peer

• Retractions (sucking in of the chest)

group, increased irritability)

• Difficulty with feeding (grunting

• Complaints about "not feeling well"

sounds, poor sucking)

• Poor school performance or school absence

• Changes in respiratory rate

• Reduced frequency or intensity of physical

activity, e.g. in sports, PE classes

• Avoidance of other activities, e.g. sleepovers,

visits to friends with pets

• Specific triggers: sports, classes, exercise/activity

Figure 1. Specific symptoms that should be asked in assessing asthma diagnosis. PE: physical education.

Informaton from Bacharier et al. (2008).

Airway inflammation The underlying airway

cells (APCs) that facilitate presentation to

inflammation in asthma is generally

the T-cells. IgE is synthesised in the

considered to be eosinophilic. However, the

presence of interleukins (ILs) (e.g. IL-4 and

strength of the association between atopic

IL-13) and other cytokines. The allergic

sensitisation and asthma varies, and most

inflammation is characterised by a T-helper

sensitised subjects do not have asthma.

cell (Th) type 2 cascade involving Th2

Allergen exposure may, in some, lead to a

cytokines and other immune mediators. It is

break in natural tolerance, triggering allergic

currently believed that directing naïve T-cells

inflammation, and an allergen-specific

to Th1 versus Th2 immunity involves

immune response involving T- and B-

regulatory T-cells (Tregs), a process which is

lymphocytes. The innate immune system is,

important in tolerance development and

in effect, the barrier between the organism

suppression of allergic inflammation.

and external environment, being the

important first line of defence against

In addition, dendritic cells in the airway

infections and intruders. The adaptive

epithelium facilitate uptake of allergens

immune system, however, classically

bound to FceRI. Such mechanisms are

involves (T-)cellular responses to antigens

probably propagated through defects in

(or allergens), typically with production of

barrier function that have recently been

specific IgE antibodies from B-cells, and

shown in the airway epithelium of asthmatic

adapts to environmental challenges.

subjects.

The allergic response is initiated when an

Viral infections are important triggers of

allergen binds to the high-affinity receptor

symptoms and exacerbations of asthma in

for IgE (FceRI) on the antigen-presenting

childhood, whereas many children with

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ERS Handbook: Paediatric Respiratory Medicine

‘‘viral wheeze’’ may later not have asthma.

entirely clear. There is no doubt that asthma

Recent studies suggest that respiratory

is associated with reduced lung function as

viruses, possibly (subtypes of) human

well as a more rapid decline in lung function

rhinovirus in particular, may play a role in

compared to healthy individuals. In a few

triggering the immune system. The

birth cohorts, reduced lung function has

mechanisms are currently not known,

been found to precede asthma in some, but

although several hypotheses exist, including

not all children with asthma.

an immune circle in asthma development in

Airway remodelling, being a common

which repeated airborne irritant stimuli

(such as allergens or viruses) evoke cycles of

feature in adult asthma, is less clear in

inflammation, giving intermittent

childhood, particularly as to when it starts

inflammation resulting in episodic

and what elicits the process. Nevertheless,

symptoms at first. However, with repeated

lung function reductions in older children

insults, the inflammatory resolution

are likely to reflect structural changes in the

becomes less complete, leading to tissue

airways such as subepithelial reticular

basement layer thickening, epithelial cell

repair and regeneration that may set off

disruption, imbalance of proteases and

prolonged periods of pathological changes.

antiproteases, and neoangiogenesis

These periods may progress to deterioration

(remodelling).

in respiratory function and, perhaps, to

remodelling.

Management

A potential causal association between

Several guidelines address asthma

allergic sensitisation and viral infection is

treatment in adults and children.

currently the focus of research, and is has

been suggested that allergic sensitisation

This section discusses management of

precedes rhinovirus-induced wheezing.

asthma in children aged o5 years. For

Another aspect of the damaged epithelium

children under the age of 5 years, please see

in asthma is the reduced ability to handle

the section on Pre-school wheezing in this

viruses in an optimal way. It appears that

Handbook. Details on aerosols, delivery of

reduced ability of airway epithelial cells to

drugs to the lung, inhaler devices and

produce interferon-c may lead to cytotoxic

instructions on optimal inhaler technique

cell death and subsequent dissemination of

can be found in the Aerosol therapy section

viruses, rather than apoptosis, possibly

in this Handbook.

explaining the prolonged symptomatic viral

Nonpharmacological management Most

infection observed in asthmatics.

nonpharmacological interventions in

BHR is a common, but not obligate, feature

asthma have limited effect and often lack

of childhood asthma. It typically presents as

sufficient evidence, except for avoidance of

a general liability to develop symptoms by

active or passive smoking. Exposure to

exposure to various physiological or

environmental tobacco smoke (ETS) is

environmental stimuli, exercise being a

associated with decreased lung function

classical childhood asthma symptom

from birth, increases the risk of asthma

trigger. The underlying mechanisms for BHR

development, increases the frequency and

development are not clear but may involve

severity of asthma symptoms, decreases

barrier dysfunction as well as possibly neural

asthma related quality of life and is

parasympathetic mechanisms involving heat

associated with persistent asthma in adults.

and fluid exchange over the epithelium. BHR

Smoking cessation by parents/caregivers or

is a modest, but significant, risk factor for

children themselves should be vigorously

later asthma and tends to decrease through

encouraged and supported.

childhood.

In obese patients, weight reduction may

The role of lung function reductions in the

increase general health and improve asthma

development of asthma in contrast to lung

control, although this has not been proven

function decline with chronic asthma is not

for children. It has been suggested that

ERS Handbook: Paediatric Respiratory Medicine

319

rapid weight gain during early life is

treatment, there is an absolute need to

associated with increased risk of developing

check adherence to treatment, inhaler

asthma.

technique and ongoing exposure to

triggers (table 2). In a patient unresponsive

Single measures are unlikely to reduce

to treatment, one should confirm that the

exposure to house dust mite (HDM)

symptoms are due to asthma and consider

allergens and have not been effective in

comorbidity like untreated allergic rhinitis,

reducing asthma symptoms. An integrated

obesity or gastro-oesophageal reflux

approach aimed at reduction of HDM

disease. Step down should be considered

allergens may have some clinical benefit in

if patients are well controlled for

selected children but has not been

3-6 months, and the lowest step and dose

recommended for all HDM-allergic

of treatment that maintains control should

asthmatic children.

be sought.

In general, in pet-allergic children, removal

At each step, short-acting b₂-agonists

of these animals from the home is advised

(SABA) should be provided for quick relief of

to gain adequate asthma control, although

symptoms (step 1).

this has been questioned.

If children have symptoms and/or need

There are no dietary interventions that have

rescue SABA more than twice a week, wake

been proven beneficial in asthma, although

up at least one night a week or have had any

regular intake of fruits and vegetables have

asthma exacerbation during the last year,

been associated with reduced risk of

maintenance treatment with ICS should be

developing asthma.

started (step 2). ICS at a low-moderate dose

Aim of asthma treatment The ultimate goal

are the recommended controller treatment

of asthma treatment is to achieve and

for patients of all ages in step 2. The starting

maintain clinical control and to reduce

dose of ICS may depend on severity of disease

future risks to the patient. The level of

and will usually be 200-400 mg?day^-1 for chlo-

clinical control is defined as the extent to

rofluorocarbon (CFC)-containing beclome-

which asthma manifestations, like daytime

thasone dipropionate (BDP) and budesonide

symptoms, night waking, the use of reliever

preparations, and 200-250 mg?day^-1

medication and the ability to carry out daily

for fluticasone, mometasone and ultra-fine

activities including exercise, have been

CFC-free beclomethasone preparations. The

reduced by treatment. The future risk to the

advised starting dose of ciclesonide in

patient includes loss of control,

children 12 years and older is 160 mg?day^-1.

exacerbations, accelerated decline in lung

One should be aware that although ICS are

function and side-effects of treatment.

highly effective in reducing asthma symptoms,

Ideally, treating patients with asthma should

improving lung function and reducing airway

take into account both aspects. The Global

hyperresponsiveness, these effects do not

Initiative for Asthma (GINA) guidelines

persist when discontinuing treatment.

suggest discerning three asthma control

levels (controlled, partly controlled and

Alternative controller medications are

uncontrolled), which guide step-up or step-

leukotriene modifiers, which may be

down asthma treatment (table 1). Although

appropriate for patients who are unable or

this is a working schema and has not been

unwilling to inhale ICS.

validated, it enables physicians to assess

If children are uncontrolled at low-moderate

asthma control systematically and adjust

doses of ICS, there are three treatment

treatment accordingly.

options: add inhaled long-acting b₂-agonists

A stepwise treatment approach for asthma

(LABA), increase the dose of ICS or add a

has been proposed by all international

leukotriene receptor antagonist (LTRA).

guidelines (fig. 2). In patients with

Presently, there is no evidence for

uncontrolled asthma, step-up treatment

superiority of one of the strategies over the

should be considered. Before stepping up

other. While the interindividual response

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Levels of asthma control

Assessment of current clinical control (preferably over 4 weeks)

Characteristic

Controlled (all of the

Partly controlled (any

Uncontrolled

following)

measure present in any

week)

Daytime symptoms

None (twice or less

More than twice per

Three or more

per week)

week

features of partly

controlled asthma

Limitation of activities

None

Any

present in any week+,1

Nocturnal symptoms/

None

Any

awakening

Need for reliever/

None (twice or less More than twice per

rescue treatment

per week)

week

Lung function (PEF or

Normal

,80% predicted or

FEV1)#,"

personal best (if

known)

Assessment of future risk (risk of exacerbations, instability, rapid decline in lung function, side-

effects)

Features that are associated with increased risk of adverse effects in the future include: poor

clinical control, frequent exacerbations in the past year⁺, admission to critical care for asthma,

low FEV1, exposure to cigarette smoke, high-dose medications

^#: not reliable for children aged f5 years;^": without administration of a bronchodilator;⁺: any exacerbation should

prompt a review of maintenance treatment to ensure it is adequate;¹: by definition, an exacerbation in any week

makes that an uncontrolled week. Reproduced and modified from GINA (2012) with permission from the publisher.

may vary significantly, no predictors of

children, the convenience of their use,

response to one of the three options has

individual patient preferences and costs may

been identified, highlighting the need to

guide treatment choices in individual

regularly monitor and appropriately adjust

patients.

each child’s asthma therapy.

Although healthcare varies between and

The British Thoracic Society (BTS) and

within countries, it should be emphasised

GINA guidelines favour the addition of

that children who are not controlled on

inhaled LABA in step 3 treatment. LABA

step 3 treatments should be referred to a

should always be an add-on treatment to ICS

paediatrician specialised in asthma care.

therapy and should never be used as single

Assessment of a possible wrong diagnosis,

agents. If effective, LABA should be

lack of treatment adherence or persistent

continued, and if ineffective, LABA should

exposure to untoward environmental factors

be stopped and the dose of ICS should be

should be considered. In step 4, ICS dose

increased. If this treatment is (partly)

should be optimised to 800 mg?day^-1 BPD or

ineffective, LTRA could be added. It is

equivalent together with LABA and/or LTRA.

important to note that individual variations

Low-dose, sustained-release theophylline

in the susceptibility to side-effects of

may provide some benefit in addition to

steroids may render some children, even

medium-high dose ICS and LABA, although

those on low doses, at risk of adrenal axis

generally the clinical effects have been small.

suppression.

Step 5 treatment should be confined to

National guidelines may differ from the BTS

paediatric specialists in asthma

and GINA guidelines and should be

management. Regular systemic

consulted on a local level. In addition,

corticosteroids might be considered in step

considerations of the safety of LABA in

5, although side-effects severely limit their

ERS Handbook: Paediatric Respiratory Medicine

321

Patients should start treatment at the step most appropriate to the

initial severity of their asthma. Check concordance and reconsider

diagnosis if response to treatment is unexpectedly poor

Use daily steroid

Increase inhaled

tablet in lowest dose

1. Add inhaled LABA

steroid up to

proviving adequate

2. Assess control of

800 µg·day^-1#

control

Add inhaled steroid

asthma:

200-400 µg·day^-1#

• good response to

Maintain high dose

Inhaled SABA

(other preventer drug

LABA - contiue LABA

inhaled steroid at

as required

if inhaled steroid

• benefit from LABA

800 µg·day^-1#

cannot be used)

but control still

200 µg is an

inadequate - continue

appropriate starting

LABA and increase

Refer to respiratory

dose for many

inhaled steroid dose

paediatritican

patients

to 400 µg·day^-1# (if

not already on this

Start at dose of

dose)

inhaled steroid

• no response to LABA

appropriate to

- stop LABA and

severity of disease

increase inhaled

steroid to 400

µg·day^-1# if control

still inadequate,

institute trial of other

Step 5

therapies, leukotriene

receptor antagonist

Continuous or frequent

Step 4

or SR theophylline

use of oral steroids

Persistent poor

Step 2

control

Initial add-on

Step 2

therapy

Regular preventer

Step 1

therapy

Mild intermittent

asthma

versus

Symptoms

Treatment

Figure 2. Stepwise management of asthma treatment in children aged 5-12 years.

^#: BDP or equivalent.

Reproduced and modified from BTS et al. (2012) with permission from the publisher.

use. Monoclonal antibody therapy is an

Other options that might be considered in

option in children from the age of 6 years

step 5 are intramuscular triamcinolone and

with elevated total IgE between 76-

experimental therapies like macrolide

3000 IU?mL^-1. Omalizumab reduces asthma

antibiotics, cyclosporine, methotrexate and

exacerbations and ICS dose, and improves

subcutaneous terbutaline, and other, rare

asthma-related quality of life; however, its

treatment options.

long-term safety and efficacy are not clear.

Treatment of asthma exacerbations For

treatment of asthma exacerbations,

consultation of (inter)national guidelines is

Table 2. Factors to be assessed in poorly controlled

asthma, before step-up treatment

highly recommended as local policies may

differ between countries and settings, and

Adherence to treatment

guidelines are not uniform on all points.

Inhaler technique

Most mild-moderate exacerbations might

be treated in a community setting, whereas

Exposure to triggers (tobacco smoke,

allergens)

moderate-severe exacerbations should be

treated in acute care settings.

Allergic rhinitis

Is it asthma?

The severity of the asthma exacerbation is

assessed by a brief history and physical

Comorbidity

examination. Important signs and

322

ERS Handbook: Paediatric Respiratory Medicine

symptoms are the ability to talk in

Severe or life-threatening exacerbations

sentences, pulse rate, respiratory rate,

should be treated with nebulised salbutamol

breath sounds, use of accessory muscles,

5 mg or terbutaline 10 mg at intervals of 10-

retractions, oxygen saturation, degree of

20 min. Some countries use subcutaneous

agitation, conscious level and (if possible)

injections of adrenaline.

peak expiratory flow (PEF) or FEV1 (table 3).

Systemic steroids should be given in all but

With moderate or severe exacerbations,

the mildest exacerbations. After starting

treatment should be initiated immediately.

inhalation therapy, oral prednisolone is

equally effective as parenteral prednisolone;

Children with an asthma exacerbation who do

however, in children with altered

not respond adequately to b₂-agonists and/or

consciousness or who vomit, intravenous

are in need of supplemental oxygen and/or

corticosteroids are preferred. In children, the

have severe asthma should be admitted to

advised dose is 1-2 mg?kg^-1 prednisolone for

hospital. A follow-up visit within a short time

3-5 days up to a maximum of 40-60 mg.

after discharge by a general practitioner or

asthma specialist should be arranged.

Intravenous magnesium sulphate in a dose

of 40 mg?kg^-1 (maximum 2 g) administered

There is no absolute limit at which oxygen

over 15 min may be considered in children

therapy should be instituted. However,

unresponsive to 1 h of adequate treatment.

oxygen via a facemask or nasal cannulae

should be administered if oxygen saturation

If the response to intensive nebulised

is ,94%, although the BTS guidelines

treatment and prednisolone is poor,

accept a lower limit of 92%.

children should be referred to a paediatric

intensive care unit (PICU). Intravenous

In children with mild-moderate

salbutamol or terbutaline may be considered

exacerbations, b₂-agonists delivered via a

even before transport to the PICU under

pressurised metered-dose inhaler (pMDI)-

close monitoring of heart rate, arterial blood

spacer combination are usually sufficiently

gases and serum potassium. The starting

effective. Two to four puffs of b₂-agonists

dose is 0.1 mg?kg^-1?min^-1 continuously.

should be administered one at a time and

inhaled via tidal breathing, and repeated at

Monitoring

10-20-min intervals for the first hour as

needed. However, nebulised b₂-agonists

Asthma is a chronic disorder with a variable

should be considered in moderate-severe

course, which makes regular follow-up of

exacerbations if there is insufficient effect

asthmatic children necessary. Traditionally,

from pMDI-spacer administration. Addition

subjective parameters like symptoms, and

of an inhaled anticholinergic, like

more objective measures such as

ipratropium bromide 0.5 mg, may be

spirometry, PEF and BHR, are used to

beneficial.

assess asthma control and disease activity.

Table 3. Assessment of severity of asthma exacerbation in children aged .5 years

Moderate exacerbation

Severe exacerbation

Life threatening exacerbation

Able to talk

Too breathless to talk

Agitation

SpO2 o92%

SpO2 ,92%

drowsiness, confusion

Heart rate f120 beats?min^-1

Heart rate .120 beats?min^-1

risk factors for near fatal

Respiratory rate

asthma

f30 breaths?min^-1

.30 breaths?min^-1

Silent chest

PEF o50% best or predicted PEF ,50% best or predicted

PEF ,30%

Use of accessory muscles

PCO₂ .45 mmHg

Chest retractions

PO2 ,60 mmHg

PCO2: carbon dioxide tension; PO2: oxygen tension.

ERS Handbook: Paediatric Respiratory Medicine

323

In daily practice, parents, children and their

assessing lung function and bronchodilator

physicians usually estimate asthma control

response at least yearly.

and make therapeutic decisions on

Contrary to adults, in children, adjusting the

subjective symptom assessments. Validated

dose of ICS to symptoms and BHR did not

questionnaires may be of help in the

result in more symptom-free days compared

standardised assessment of asthma control

to titrating treatment to symptoms only.

in the clinic and for research purposes.

However, in a subgroup of children with few

There are several questionnaires available,

symptoms but hyperreactive airways,

such as the Asthma Control Questionnaire

monitoring BHR resulted in improved lung

(ACQ), the Asthma Control Test (ACT) and

function.

the Childhood Asthma Control Test (C-ACT),

the Asthma Therapy Assessment

Recently, much attention has been paid to

Questionnaire (ATAQ) and the three-item

markers of inflammation, like the exhaled

Royal College of Physicians (RCP3)

nitric oxide fraction (FeNO) and eosinophils

questionnaire. The C-ACT has been

in induced sputum, as objective tests to

developed for detecting uncontrolled

monitor asthmatic patients. However,

asthma in children aged 4-11 years; the ACT

titrating ICS based on FeNO levels or on

and ACQ have been validated for children

sputum eosinophils has not been shown to

aged o12 years. The seven-item version of

be effective in improving asthma outcomes

the ACQ has five questions on symptoms

in children. Whether FeNO may be of help in

and additionally includes FEV1 and use of

diagnosis, phenotype-specific treatment,

rescue b₂-agonists. Standardised

decisions on starting and stopping ICS, or

questionnaires seem attractive in measuring

monitoring adherence remains to be shown.

asthma control as they are cheap, easy to

At every visit, use of rescue b₂-agonists,

use and interpret, and give a quick

exacerbations, asthma symptoms and

impression on asthma control. They provide

limitations in physical activity, oral

a reproducible, objective measure that may

corticosteroid use, school absenteeism,

be repeated over time and may improve

inhaler technique, and adherence to

communication between the patient/parent

treatment should be checked.

and physician. However, no data are

available on the potential of such

Before stepping up treatment, one should

questionnaires to improve asthma outcome

consider low adherence, poor inhaler

in children.

technique, adequate avoidance of risk

factors, allergic rhinitis, (passive) smoking,

The GINA guidelines suggest the use of

other aggravating factors and comorbidities.

symptoms and lung function to assess

asthma control, and make a difference

Self-management Although self-

between controlled, partly controlled and

management education including written

poorly controlled asthma (table 1).

action plans clearly leads to improved

Subsequently, the level of asthma control

outcomes in asthmatic adults, this has not

guides medication adjustments.

been shown for children. To date, there is a

lack of studies comparing the effect of

In patients older than 5-6 years, spirometry

providing a written action plan versus no

or PEF should be measured during clinic

written action plan in children and

visits to assess asthma control and detect

adolescents. However, symptom-based

possible decline in lung function. FEV1 is

action plans seem superior to peak flow-

preferred over PEF, as PEF may be

based action plans for preventing acute care

completely normal while severe airway

visits in children. There is some evidence

obstruction is present. The presence and

that combined interventions aimed at self-

degree of airway obstruction has short- and

management (e.g. information, self-

long-term prognostic value for asthmatic

monitoring and action plan, or educational

children, and is an independent predictor of

and environmental measures) may reduce

future risk. Guidelines recommend

asthma exacerbations in children who

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ERS Handbook: Paediatric Respiratory Medicine

Table 4. Particular features that contribute to severity of asthma by age group

Infancy

Underlying pathophysiology and clinical characteristics poorly understood

Viruses are the most common precipitating factors

Many conditions to be considered in the differential diagnosis

Difficulty in objective documentation of bronchial obstruction

Many with problems in the first year of life remit long term in the second year

Preschool age

Viruses are the most common precipitating factors

Compliance with management largely depending upon carers

Some difficulty in objective documentation of bronchial obstruction or airway

inflammation

School age

Allergy is frequent

Symptoms often precipitated by exercise

Compliance with management still depending upon carers

Evaluation of lung function easy

Indirect evaluation of airway inflammation relatively easy

Adolescence

Clinical expression is variable

Tendency to deny symptoms

Risk-taking behaviour common

Low compliance

Psychological problems

Treatment may be difficult

Reproduced and modified from Hedlin et al. (2010).

visited the emergency room for asthma. The

and irritants that worsen the disease,

optimum setting and content for such

nonadherence to therapy, psychosocial

educational interventions and relative

issues, or true severe asthma that is

effectiveness of the various components are

resistant to therapy.

largely unknown.

Each age group has particular features that

In general, a written personal action plan is

contribute to the severity of asthma, as

recommended for all children with asthma

outlined in table 4.

and, in particular, for children with poorly

In contrast to adults, children with severe

controlled asthma. Furthermore, parental

asthma may not yet have developed

education in asthma is recommended to

remodelling, although increases in smooth

improve assessment of the child’s disease

muscle and evidence of reticular membrane

as well as adherence to treatment.

layer are frequently found. Furthermore, the

Problematic, difficult or severe asthma

inflammation in childhood severe asthma

may appear to be eosinophilic without the

Severe asthma is relatively rare, occurring in

classical Th2 inflammation, in contrast to

approximately 4-5% of children with asthma

the more commonly neutrophilic

and 0.5% of the general child population.

inflammation in adults.

However, there is no uniform or generally

accepted definition of severe childhood

Managing children with severe asthma

asthma, and several criteria are used, such

requires a systematic approach to assess

as the need for or use of high-dose

diagnosis, airway inflammation and

corticosteroids, severe and/or frequent

therapeutic responses to corticosteroids.

exacerbations, chronic asthma symptoms,

This should enable further differentiation of

or reduced lung function. Thus, severe or

those children who have a true severe,

difficult asthma may be related to wrong

therapy-resistant asthma, from those with

diagnosis, exposure to environmental

the wrong diagnosis, those with asthma with

factors such as allergens, tobacco smoking

significant comorbidities that need to be

ERS Handbook: Paediatric Respiratory Medicine

325

addressed, and those with asthma that is

Ducharme FM, et al. (2011). Addition to

not responding to treatment because of

inhaled corticosteroids of long-acting b₂-

factors other than medication response.

agonists versus anti-leukotrienes for

Only in those with severe therapy-resistant

chronic asthma. Cochrane Database Syst

asthma may expensive and potentially

Rev; 5: CD003137.

Dweik RA, et al. (2011). An official ATS

hazardous cytokine-specific therapies be

clinical practice guideline: interpretation

appropriate.

of exhaled nitric oxide levels (FENO) for

clinical applications. Am J Respir Crit Care

Treating severe asthma is challenging and

Med; 184: 602-615.

includes medication that is not well

Fuhlbrigge AL, et al. (2006). The influ-

documented in this age group, and should

ence of variation in type and pattern

thus be referred to specialised centres with

of symptoms on assessment in pedia-

particular expertise in diagnosis and

tric

asthma. Pediatrics;

118:

619-

treatment of severe childhood asthma.

625.

Global Initiative for Asthma

(2012).

Further reading

Global Strategy for Asthma Management

and Prevention. www.ginasthma.org

Bacharier LB, et al. (2008). Diagnosis and

Haland G, et al.

(2006). Reduced lung

treatment of asthma in childhood: a

function at birth and the risk of asthma at

PRACTALL consensus report. Allergy; 63:

10 years of age. N Engl J Med; 355: 1682-

5-34.

1689.

Baena-Cagnani C, et al. (2007). Airway

Hedlin G, et al.

(2010). Problematic

remodelling in children: when does it

severe asthma in children, not one

start? Curr Opin Allergy Clin Immunol; 7:

problem but many: a GA²LEN initiative.

196-200.

Eur Respir J; 36: 196-201.

Bhogal S, et al. (2006). Written action

Holgate ST (2012). Innate and adaptive

plans for asthma in children. Cochrane

immune responses in asthma. Nat Med;

Database Syst Rev; 3: CD005306.

18: 673-683.

Bossley CJ, et al. (2012). Pediatric severe

Holt PG, et al. (2012). Viral infections and

asthma is characterized by eosinophilia

atopy in asthma pathogenesis: new ratio-

and remodeling without T_H2

cyto-

nales for asthma prevention and treat-

kines. J Allergy Clin Immunol;

129:

ment. Nat Med; 18: 726-735.

974-982.

Lødrup Carlsen KC, et al.

(2011).

Boyd M, et al. (2009). Interventions for

Assessment of problematic

severe

educating children who are at risk of

asthma in children. Eur Respir J;

37:

asthma-related emergency department

432-440.

attendance. Cochrane Database Syst Rev;

National Asthma Elimination and

2: CD001290.

Prevention Panel

(2007). Expert Panel

BTS/SIGN British Guideline on the

Report

(EPR-3): guidelines for the

Management of Asthma. 2008. www.sign.

diagnosis and management of asthma -

ac.uk/guidelines/fulltext/101/index.html

summary report

2007. J Allergy Clin

Burke H, et al. (2012). Prenatal and passive

Immunol; 120: S94-S138.

smoke exposure and incidence of asthma

Papadopoulos NG, et al.

(2012).

and wheeze: systematic review and meta-

International consensus on

(ICON)

analysis. Pediatrics; 129: 735-744.

pediatric asthma. Allergy; 67: 976-997.

Castro-Rodriguez JA (2011). The Asthma

Petsky HL, et al.

(2012). A systematic

Predictive Index: early diagnosis of

review and meta-analysis: tailoring

asthma. Curr Opin Allergy Clin Immunol;

asthma treatment on eosinophilic mar-

11: 157-161.

kers

(exhaled nitric oxide or sputum

Custovic A, et al. (1994). Exercise testing

eosinophils). Thorax; 67: 199-208.

revisited. The response to exercise in

Saglani S, et al.

(2007). The early-life

normal and atopic children. Chest; 105:

origins of asthma. Curr Opin Allergy Clin

1127-1132.

Immunol; 7: 83-90.

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ERS Handbook: Paediatric Respiratory Medicine

Emerging therapeutic

strategies

Giorgio Piacentini and Laura Tenero

Asthma is the most common chronic

patients presents ongoing chronic

childhood disease and the major cause of

symptoms or severe exacerbations despite

hospitalisation for children. It is a chronic

high-dose medication may benefit from new

disease with repeated attacks of airways

treatment strategies.

obstruction and intermittent symptoms of

Pharmacotherapy

responsiveness to triggering factors, such as

allergens, smoke, exercise or viral infection.

Guidelines on paediatric management of

asthma aim for control of symptoms,

In the majority of asthmatic patients,

reduction of exacerbations, hospitalisation

symptoms can be controlled with a stepwise

and emergency department visits, and

approach according to guidelines

improvement of quality of life.

(Papadopoulos et al., 2012; Global Initiative

for Asthma, 2011) with inhaled steroids,

Currently, after an initial classification of

long-acting b₂-agonists (LABAs) and and

severity into the categories of mild,

leukotriene receptor antagonists.

moderate and severe at the time of

However, the prevalence of severe and

diagnosis, most guidelines propose that the

therapy-resistant asthma in a general

level of treatment be considered on the

paediatric population is 0.5% (4.5% of

basis of the evaluation of symptoms

children with asthma). This group of

according to their presentation as

intermittent or persistent, controlled or

uncontrolled. Therapy is based on an

Key points

increasing or decreasing stepwise approach

according to the level of disease control.

N New treatments based on

Inhalation therapy, which facilitates

interventions in the

administration of drugs directly into the

immunopathogenesis of asthma are

airways, is currently the preferred route for

currently under development and

most patients. The delivery of the drug

evaluation, especially in subjects

directly to the site of disease results in a

whose symptoms are not controlled

powerful therapeutic effect and minimises

by current therapy.

the occurrence of systemic side-effects.

Omalizumab is a monoclonal human

antibody which can antagonise the

Inhaled corticosteroids (ICS) are the most

role of IgE in the pathogenesis of

effective controller medications currently

allergic asthma.

available. Their regular use reduces the

severity of symptoms, decreases

N IL-5 plays an important role in

exacerbations and hospital admission,

eosinophil activation and airway

improves lung function and reduces

hyperresponsiveness and is involved

hyperesponsiveness.

in the induction of Th2 responses in

the asthmatic airway.

Critical issues regarding asthma treatment

in children are the necessity of delivering

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ERS Handbook: Paediatric Respiratory Medicine

drugs at the site of the inflamed distal

control, reduce exacerbations during

airway, the potential side-effects of long-

corticosteroid therapy and allow a reduction

term treatment with ICS and the difficulty of

of ICS dose. In 2009, the licence for the use

controlling symptoms. The ongoing need to

of omaluzimab was extended to include

solve these issues warrants research into

children aged 6-12 years as an add-on

new therapeutic strategies.

treatment for poorly controlled asthma in

patients with severe persistent allergic

New strategies for asthma treatment

disease.

Various new treatments based on

Though the treatment needs to be

interventions in the immunopathogenesis of

administered in a controlled clinical setting

the disease are currently under development

with a period of observation after injection,

and evaluation to improve asthma control.

this therapy has become increasingly

T-helper type 2 (Th2) inflammation,

popular in the past few years. It can be

mediated by interleukin (IL)-4, IL-5, IL-9 and

considered as an option in children with IgE-

IL-13, plays a central role in the pathway of

mediated sensitisation to one or more

allergic asthma. Two different phenotypes of

allergen, with chronic symptoms, recurrent

asthma patients based on high or low Th2-

severe asthma exacerbations and resistance

cytokine gene expression have been

to high doses of ICS and LABAs.

identified. ‘‘Th2 high’’ asthma patients

Omaluzimab has been shown to be safe and

present with elevated IL-5 and IL-13

beneficial in children through 1-year trial, but

expression in bronchial biopsies, serum IgE

long-term safety and efficacy have not yet

and blood and airway eosinophilia. These

been demonstrated.

patients are those for whom the best

response to ICS is expected, whereas

Children and adolescents with severe

subjects with ‘‘Th2 low’’ asthma phenotype

persistent asthma with positive skin prick

represent a subgroup with clinical

test for allergen and with reduction of FEV1

manifestations that are poorly controlled by

(,80% predicted) who are treated with ICS

current therapies since the disease is mostly

have been shown to benefit from improved

related to nonallergic, steroid-unresponsive,

quality of live with when treated with

mechanisms.

omalizumab.

A number of alternative potential therapies

Analysis of a subgroup of subjects from a

have been proposed to prevent T-cell

study evaluating the effect of omalizumab as

activation, to modulate Th1/Th2

add-on treatment in inadequately controlled

differentiation, to inhibit Th2-related

severe asthmatics suggests that patients

cytokines and to inhibit downstream

with IgE levels below 76 IU?mL^-1 are less

mediators. In paediatric patients the

likely to benefit.

inhibition of downstream mediators using

anti-IgE has been shown to be an interesting

Although free IgE is extensively and rapidly

emerging approach of practical application.

suppressed after commencing treatment

with omalizumab, it may take up to

Omalizumab Omalizumab is a monoclonal

3 months before clinical symptoms

human antibody that can antagonize the

equilibrate at a new level.

role of IgE in the pathogenesis of allergic

asthma. A number of studies, mainly in

Although omalizumab brings clinical

adults, have demonstrated that omalizumab

benefits, treatment costs are high, and while

can reduce serum levels of free IgE,

some authors have concluded that

expression of IgE receptors on basophils

omalizumab produces sufficient

and antigen stimulated histamine release.

improvement in clinical outcomes in

Studies performed with this new therapeutic

difficult-to-treat, persistent allergic asthma

strategy show that the treatment can reduce

to justify the cost, other studies have

both early and late response as well as

suggested that the clinical benefits may not

bronchial reactivity, improve asthma

offset the high cost of treatment. The UK

ERS Handbook: Paediatric Respiratory Medicine

329

National Institute for Health and Clinical

IgE levels, eosinophil counts and lower

Excellence has recommended that

mean FEV1, the strength of this evidence

omalizumab should not be routinely used

needs to be further investigated. Clinical

for the treatment of severe persistent

trials with vitamin D supplementation in

allergic asthma in children aged 6-11 years.

children with asthma are warranted.

TNFa blockers Some studies in adults have

Macrolides Macrolides are commonly used

suggested that tumour necrosis factor

as antimicrobial agents but they have been

(TNF)a may be a marker of severity in

also demonstrated to have

asthma and a target for biological therapy.

immunomodulatory and anti-inflammatory

TNFa is a cytokine produced by different cell

properties in the airway. Clinical trials have

types which plays a role in the innate

shown benefits of macrolides in the

immune response. It has been suggested

treatment of a spectrum of chronic

that TNFa can contribute to the

inflammatory respiratory diseases.

inflammatory response in asthmatic airways.

The mechanism of action remains partially

Studies evaluating the efficacy of the use of

unexplained but it may be possibly due to

anti-TNFa therapy in asthma refractory to

their antibacterial and/or anti-inflammatory

ICS have been published, and a significant

actions, which include reductions in IL-8

improvement in methacholine airway

production and neutrophil migration and/or

hyperresponsiveness, as well as

function.

improvements in FEV1 and in quality of life

Clarithromycin and azithromycin have been

in patients with severe asthma treated with

shown to exert an effect in reducing airway

etanercept (a TNFa receptor IgG Fc fusion

inflammation, with decreased airway

protein) have been reported. However, these

oedema and TNFa, IL-1, and IL-10

studies have been carried out in adult

concentrations. Furthermore, azithromycin

patients; no evidence in children is currently

has been demonstrated to reduce IL-5

available. Therefore, further investigations

production in children with atopic asthma,

are needed in order to evaluate the benefits

and to have a beneficial effect on the

and the risks of this treatment in the

pathogenesis of asthma.

paediatric population.

Nevertheless, positive effects of macrolides

Vitamin D Recent research has shown that

have not yet been fully demonstrated in

vitamin D has an important role in the

clinical trials in asthma and recent studies

modulation of the immune system

have presented conflicting conclusions on

response, especially through the inhibition

the use of macrolides in routine clinical

of Th1 response and T-cell proliferation.

practice in patients with uncontrolled

An epidemiological study suggested that

asthma. Further studies investigating the

low concentration of vitamin D in children

effects of macrolides in asthma

with asthma is associated with more severe

management are, therefore, required.

symptoms, frequent exacerbations,

Theophylline Theophylline may act through

reduction in lung function and an increase

different molecular mechanisms to inhibit

in medication use. Vitamin D has been

phosphodiesterase and adenosine receptor

postulated to play an important role in the

antagonism at therapeutic concentrations.

modulation of inflammatory response and

Some studies show that low doses of oral

maintenance of airway homeostasis as well

theophylline increase histone deacetylase-2

as to have a role in the improvement of the

(HDAC2) expression in alveolar

anti-inflammatory action of glucocorticoids

macrophages in patients with COPD and it

in patients with refractory asthma.

also downregulates inflammatory gene

Though some observational studies show

expression via effects on histone acetylases

lower plasma levels of vitamin D in

(HATs) and histone deacetylases (HDACs).

asthmatic patients as well as inverse

In asthma, HAT levels are increased while

associations between vitamin D and total

HDACs are reduced; this is inverted by

330

ERS Handbook: Paediatric Respiratory Medicine

glucocorticoids as well as by theophylline,

These studies, performed in adult patients,

with a reduction in IL-8, TNF-a and

demonstrate the utility of anti-IL5 but the

granulocyte-macrophage colony-stimulating

general applicability of the studies is still

factor (GM-CSF) in response to

under debate because of the the strict

lipopolysaccharide. Moreover, theophylline

selection criteria used and the low numbers

may prevent downregulation of the b-

of participating patients. However, these

receptors by b₂-agonists.

studies explore a very attractive rationale for

the modulation of eosinophils activity in

Through these mechanisms, theophylline

asthma and demonstrate that anti-IL-5

has been demonstrated to re-establish

antibodies represent a promising avenue for

steroid responsiveness, thus representing a

asthma therapy.

potential new approach in steroid-resistant

patients.

At present, no study on IL-5 in children has

been published.

Anti-IL antibodies Eosinophils are major

actors in airway inflammation and

Conclusion

remodelling mechanisms in asthma. They

Different guidelines and consensus

release a wide range of mediators which can

documents are currently available for

promote airway inflammation, induce

asthma treatment. They all agree regarding

epithelial damage and cause airway

the main objective of the treatment

hyperresponsiveness.

intervention, which is to achieve and

maintain control of the disease, including

The complex networks of cytokines and cells

reduction of exacerbations, need for

involved in the pathology of asthma provide

scope for intervention with monoclonal

emergency visits and hospitalisation.

antibodies that block cytokine- or

The stepwise therapeutic model, with step-

chemokine-receptor interactions, to deplete

up of treatment in case of poor control is

cells expressing a specific receptor or to

not always adequate to achieve control of

block cell-cell interactions.

symptoms and exacerbations in patients

with severe asthma.

Though, at present, anti-IgE is the only

monoclonal antibody approved for asthma

New strategies to improve asthma control

treatment in children, other antibodies have

have been proposed in recent years and are

been clinically tested in asthma, including

currently under development and

anti-IL-5, anti-IL-4, anti-IL-13, anti-TNFa,

evaluation.

anti-CCR3, anti-CCR4 and anti-OX40L.

New drugs are involved in the modulation of

In particular, IL-5 plays an important role in

Th1/Th2 differentiation, inhibition of Th2-

eosinophil activation and airway

related cytokines and inhibition of the

hyperresponsiveness and it is involved in the

downstream mediators.

induction of Th2 responses in the asthmatic

airway. IL-5 also plays a role in the migration

While omalizumab is currently approved for

of eosinophils from the bone marrow to the

the treatment of severe persistent allergic

blood circulation and subsequently to the

asthma unresponsive to traditional theapy

sites of inflammation and it is also active in

in children aged 6-11 years, other drugs are

promoting the survival of eosinophils at the

under evaluation to improve the control of

the disease in clinical practice.

site of airway inflammation by preventing

apoptosis.

Further reading

The compelling evidence linking IL-5 to

asthma pathology led to the development of

Bacharier LB, et al. (2008). Diagnosis and

therapies targeting IL-5 and a few studies

treatment of asthma in childhood: a

have been performed in patients with severe

PRACTALL consensus report. Allergy; 63:

asthma and sputum eosinophilia and

5-34.

hypereosinophilic syndromes.

ERS Handbook: Paediatric Respiratory Medicine

331

Barnes PJ

(2006). Theophylline for

European Medicines Agency. Summary of

COPD. Thorax; 61: 742-743.

the European public assessment report

Barnes PJ

(2012). Severe asthma:

(EPAR) for Xolair. 2009. www.ema.europa.

advances in current management and

eu/ema/index.jsp?curl5pages/medicines/

future therapy. J Allergy Clin Immunol;

human/medicines/000606/human_med_

129: 48-59.

001162.jsp&mid5WC0b01ac058001d124

Brehm JM, et al. (2010). Serum vitamin D

&jsenabled5true.

levels and severe asthma exacerbations in

Fonseca-Aten M, et al. (2006). Effect of

the Childhood Asthma Management

clarithromycin on cytokines and chemo-

Program study. J Allergy Clin Immunol;

kines in children with an acute exacerba-

126: 52-58.

tion of recurrent wheezing: a double-blind,

Brightling C, et al.

(2008). Targeting

randomized, placebo-controlled trial. Ann

TNFa: a novel therapeutic approach for

Allergy Asthma Immunol; 97: 457-463.

asthma. J Allergy Clin Immunol;

121:

Freishtat RJ, et al.

(2010). High preva-

5-10.

lence of vitamin D deficiency among

Brusselle GG, et al. (2013). Azithromycin

inner-city African American youth with

for prevention of exacerbations in severe

asthma in Washington, DC. J Pediatr; 156:

asthma (AZISAST): a multicentre rando-

948-952.

mised double-blind placebo-controlled

Gjurow D, et al. (2009). Tumor necrosis

trial. Thorax; 68: 322-329.

factor inhibitors in pediatric asthma.

Burch J, et al. (2012). Omalizumab for the

Recent Pat Inflamm Allergy Drug Discov;

treatment of severe persistent allergic

3: 143-148.

asthma in children aged

6-11

years: a

Global Initiative for Asthma

(GINA).

NICE single technology appraisal.

Global Strategy for Asthma Management

Pharmacoeconomics; 30: 991-1004.

and Prevention 2011. www.ginasthma.org.

Bush A, et al.

(2011). Pharmacological

Good JT Jr, et al. (2012). Macrolides in the

treatment of severe, therapy-resistant

treatment of asthma. Curr Opin Pulm

asthma in children: what can we learn

Med; 18: 76-84.

from where? Eur Respir J; 38: 947-958.

Gupta A, et al. (2012). Vitamin D and

Cameron EJ, et al.

(2012). Long-term

asthma in children. Paediatr Respir Rev;

macrolide treatment of chronic inflam-

13: 236-243.

matory airway diseases: risks, benefits

Hedlin G, et al.

(2010). Problematic

and future developments. Clin Exp Allergy;

severe asthma in children, not one

42: 1302-1312.

problem but many: a GA²LEN initiative.

Carr TF, et al. (2012). Asthma: principles

Eur Respir J; 36: 196-201.

and treatment. Allergy and Asthma Proc;

Howarth PH, et al. (2005). Tumour necro-

33: S39-S43.

sis factor (TNFa) as a novel therapeutic

Catley MC, et al.

(2011). Monoclonal

target in symptomatic corticosteroid

antibodies for the treatment of asthma.

dependent asthma. Thorax; 60: 1012-1018.

Pharmacol Ther; 132: 333-351.

Humbert M, et al. (2005). Benefits of

Chang TW (2000). The pharmacological

omalizumab as add-on therapy in patients

basis of anti-IgE therapy. Nat Biotechnol;

with severe persistent asthma who are

18: 157-162.

inadequately controlled despite best avail-

Corren J

(2011). Anti-interleukin-5

anti-

able therapy (GINA 2002 step 4 treat-

body therapy in asthma and allergies. Curr

ment): INNOVATE. Allergy; 60: 309-316.

Opin Allergy Clin Immunol; 11: 565-570.

Lanier B, et al. (2009). Omalizumab for

Cosio BG, et al.

(2004). Theophylline.

the treatment of exacerbations in children

restores histone deacetylase activity

with inadequately controlled allergic (IgE-

and steroid responses in COPD macro-

mediated) asthma. J Allergy Clin Immunol;

phages. J Exp Med; 200: 689-695.

124: 1210-1216.

Dal Negro RW, et al. (2011). Cost-utility of

Lin SJ, et al. (2011). Azithromycin inhibits

addon omalizumab in difficult-to-treat

IL-5 production of T helper type 2 cells

allergic asthma in Italy. Eur Ann Allergy

from asthmatic children. Int Arch Allergy

Clin Immunol; 43: 45-53.

Immunol; 156: 179-186.

332

ERS Handbook: Paediatric Respiratory Medicine

Lowe J, et al.

(2009). Relationship

Shi HZ, et al. (1998). Effect of inhaled

between omalizumab pharmacokinetics,

interleukin-5 on airway hyperreactivity and

IgE pharmacodynamics and symptoms in

eosinophilia in asthmatics. Am J Respir

patients with severe persistent allergic

Crit Care Med; 157: 204-209.

(IgE-mediated) asthma. Br J Clin

Silvestri M, et al.

(2006). High serum

Pharmacol; 68: 61-76.

levels of tumour necrosis factor-alpha

Marwick JA, et al. (2008). Oxidative stress

and interleukin-8 in severe asthma: mar-

modulates theophylline effects on steroid

kers of systemic inflammation? Clin Exp

responsiveness. Biochem Biophys Res

Allergy; 36: 1373-1381.

Commun; 377: 797-802.

Soler M, et al.

(2001). The anti-IgE

Massanari M, et al. (2009). Efficacy of

antibody omalizumab reduces exacerba-

omalizumab in cat-allergic patients with

tions and steroid requirement in allergic

moderate-to-severe persistent asthma.

asthmatics. Eur Respir J; 18: 254-261.

Allergy Asthma Proc; 30: 534-539.

Staple LE, et al. (2011). Evidence for the

Milgrom H, et al. (2001). Treatment of

role of inadequate vitamin D in asthma

childhood asthma with antiimmunoglo-

severity among children. J Investig Med;

bulin

E antibody

(omalizumab).

59: 1086-1088.

Pediatrics; 108: e36.

Wenzel SE, et al. (2009). A randomized,

Papadopoulos NG, et al.

(2012).

double-blind, placebo-controlled study of

International Consensus on

(ICON)

tumor necrosis factor-alpha blockade in

pediatric asthma. Allergy; 67: 976-997.

severe persistent asthma. Am J Respir Crit

Searing DA, et al.

(2010). Decreased

Care Med; 179: 549-558.

serum vitamin D levels in children with

Woodruff PG, et al. (2009). T-helper type

asthma are associated with increased

2-driven inflammation defines major sub-

corticosteroid use. J Allergy Clin Immunol;

phenotypes of asthma. Am J Respir Crit

125: 995-1000.

Care Med; 180: 388-395.

ERS Handbook: Paediatric Respiratory Medicine

333

Differential diagnosis

of bronchial asthma

Giorgio Piacentini and Laura Tenero

Epidemiology

of objective lung function measurements and

biomarkers. Differential diagnosis may also

Although asthma is considered the most

be challenging in older children, due to

common condition presenting with

conditions which may mimic asthma, such as

wheezing, not all children who wheeze are

dysfunctional breathing.

affected by asthma. Wheezing can be an

isolated symptom or it may be accompanied

Childhood asthma and wheezing are not

by cough, chest tightness, shortness of

synonymous, these terms characterise a

breath and dyspnoea in different clinical

number of conditions that may have different

conditions. Recurrent wheezing is common

outcomes. Some children present with

in young children and population studies

transient wheezing and have a reduction in

have shown that one third of children have

pulmonary function at birth but do not go on

had at least one episode of wheezing before

to develop asthma, whereas other children

the age of 3 years and 50% of children have

have persistent wheezing and have an

had at least one episode by the age of

increased risk of developing asthma.

6 years. Recurrent wheezing is, therefore, a

Definition of wheezing

common condition in paediatric practice and

the differential diagnosis represents a

Wheezing is noisy breathing that can be

challenging clinical procedure for

classically defined as a musical, high-

paediatricians. The main issue is to correctly

pitched, airway-derived noise detectable

distinguish between the different phenotypes

during exhalation. Wheeze results from

of wheezing in pre-schoolers, for whom the

narrowing of the intrathoracic airways,

diagnosis is further complicated by the lack

which produces expiratory flow turbulence.

Therefore, a number of different conditions,

including airways narrowing, airways

Key points

abnormalities, cystic fibrosis and

bronchomalacia, may cause a child to

Although asthma is considered the

wheeze. Although this definition is well

most common condition presenting

known to medical personnel, parents and

with wheezing, not all the children

patients, it is often improperly used to

who wheeze are affected by asthma.

describe respiratory symptoms that are not

Recurrent wheezing is a common

really wheezes. It is important to clearly

condition in paediatric practice and

define the features of the sound in order to

the differential diagnosis represents a

confirm or reject wheezing as the

challenge for paediatricians.

appropriate descriptor of the symptom

under consideration. Stridor, which is an

N The diagnosis of asthma is more

inspiratory noise associated with

difficult in preschoolers.

extrathoracic or upper airway obstruction, is

The symptoms of asthma can be

often confused with wheezing; however, its

associated with other diseases.

presence prompts consideration of an

alternative differential diagnosis.

334

ERS Handbook: Paediatric Respiratory Medicine

Clinical conditions presenting with

to adequate inhaled corticosteroid

wheezing

treatment, viral and bacterial infections are

frequent. The main pathogens involved are

Alternative conditions must be taken into

Mycoplasma pneumoniae, Chlamydia

account before a diagnosis of asthma is

pneumoniae, Moraxella catarrhalis and

defined permanently. Alternative causes of

Streptococcus pneumoniae. The chronic

recurrent episodes of wheezing, especially in

inflammatory response to infection may be

early childhood, are shown in table 1. The

related to persistent wheezing despite

main differential diagnoses are respiratory

therapy. Antimicrobial therapy should be

infections, congenital and structural

considered in these patients. Chronic cough

problems, foreign bodies, and gastro-

is also a frequent symptom in young

oesophageal reflux. In children with severe,

children that could be confused with

recurrent wheezing that is nonresponsive to

asthma. In sinusitis, purulent rhinorrhea,

inhaled corticosteroids, leukotriene receptor

sneezing and post-nasal drip are related to

antagonists and/or bronchodilators, other

chronic cough, but sinusitis is often

diagnoses should be considered.

misdiagnosed especially if it persists for

longer than 4 weeks. Chronic sinusitis

Major causes of wheezing to consider

requires a long course of antibiotics (10-

during diagnosis

15 days). Other respiratory infections

Respiratory infections In children with

causing wheezing and cough in children that

persistent wheezing that does not respond

could be confused with asthma are

Table 1. Differential diagnosis in bronchial asthma

Symptoms and history

Medical findings

Respiratory infections

Fever

Wheezing

Cough with respiratory distress

Rales

Relatives with the same symptoms

Rhonchi

GORD

Frequent regurgitation

Failure to thrive

Post-prandial vomiting

Loss of weight

Crying in supine position

Nocturnal symptoms

Foreign body aspiration

‘‘Cough/suffocation’’ with sudden

Bronchial breathing

onset

Sudden cough

Vocal cord dysfunction (VCD)

Shortness of breath, wheezing,

Inspiratory flow-volume

stridor, or cough

loop

Laryngomalacia

Inspiratory stridor present from

The volume loop is

birth

characterised by a

‘‘tooth’’ deflection in the

inspiratory phase

Cardiovascular causes of airway

Recurrent respiratory difficulty,

Wheezing

compression

dyspnoea, dysphagia, wheezing

and stridor

Present from birth

Genetic disease

Recurrent dyspnoea

Wheezing and dyspnoea

Recurrent infections

Congenital malformations

Respiratory symptoms at birth, but

Malformations on

can remain asymptomatic for long

radiological

periods

investigation

ERS Handbook: Paediatric Respiratory Medicine

335

pertussis, bronchiolitis and epiglottitis.

or cough, which may be interpreted as

Cough and upper respiratory symptoms

uncontrolled or worsening asthma, leading

could also be related to tuberculosis, which

to unnecessary therapy or step up in

may manifest without the typical symptoms

medication. The diagnosis could be

(night sweats, haemoptysis, weight loss and

suspected when there is a truncation of the

fatigue). In this case it is necessary to

inspiratory flow-volume loop. Direct

perform chest radiography, which may show

visualisation during an attack permits

upper lobar infiltrates, cavitary infiltrates or

definitive diagnosis. In these children the

adenopathy.

exhaled nitric oxide fraction (FeNO) is

expected to be normal.

Gastro-oesophageal reflux disease (GORD)

Infant wheezing that is unresponsive to

Cardiovascular causes of airway compression

bronchodilator therapy may be related to

Compression of the airways is a relatively

GORD or silent aspiration. GORD has been

common complication of congenital

shown to be associated with chronic upper

vascular malformation in children. The main

airway respiratory symptoms, including

symptoms are recurrent respiratory

reactive airways disease, recurrent stridor,

difficulty, dyspnoea, dysphagia, wheezing

chronic cough and recurrent pneumonia in

and stridor without other causes. The

infants who do not respond to common

differential diagnosis may start from

anti-asthma medications (Bhatia et al.

spirometric evaluation, but confirmation

2009).The gold standard for investigation of

requires chest radiography, eventually with

this problem is 24-h pH monitoring.

barium contrast, echocardiography, MRI, CT

and bronchoscopy.

Foreign body aspiration In children with

sudden cough and wheezing, the risk of

Genetic diseases Genetic conditions such as

inhalation of a foreign body should be

primary ciliary dyskinesia and CF may be

considered. In this case, it is important to

relevant in the differential diagnosis in

analyse the history and look for temporal

children presenting with recurrent dyspnoea.

relationships with onset of symptoms.

Congenital abnormalities Congenital

Though chest radiography could be helpful if

the foreign body is radiopaque or if indirect

malformations of the lower airways are rare

signs, such as peribronchial inflammation of

anomalies and include a wide spectrum of

mediastinal dislocation, develop, the

conditions with a broadly varying clinical

diagnostic and therapeutic gold standard is

presentation. Individuals with congenital

bronchoscopy.

lung malformations can present with

respiratory symptoms at birth or can remain

Airway abnormalities Laryngomalacia is the

asymptomatic for long periods. Usually, the

most common congenital abnormality and

diagnosis requires an imaging evaluation.

cause of stridor in children. The

Depending on the pathophysiological

manifestations can vary from mild noisy

mechanisms and structures involved, lung

breathing with feeding to life-threatening

malformations can be divided into several

airway obstruction to failure to thrive.

categories: bronchopulmonary anomalies;

Stridor is inspiratory for the collapse of

combined lung and vascular abnormalities;

supraglottic airway structures. The volume

and vascular anomalies.

loop is characterised by a ‘‘tooth’’ deflection

in the inspiratory phase. Vocal cord

Pulmonary sequestration is characterised by

dysfunction is a disorder characterised by an

normal, nonfunctioning lung tissue that has

upper episodic and involuntary airway

no connection with the bronchial tree and

obstruction caused by adduction of the

receives its blood supply from the systemic

vocal cords, primarily on inspiration,

circulation. Pulmonary sequestrations can

inducing paroxysms of the glottis. This

be classified as extralobar or intralobar

disease is often confused with refractory

depending on their location in relation to the

asthma as symptoms are intermittent

adjacent normal lung and on their visceral

shortness of breath, wheezing, stridor,

pleural covering.

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ERS Handbook: Paediatric Respiratory Medicine

Congenital cystic adenomatoid malformations

Further reading

are hamartomatous lesions, with focal

Amimoto Y (2012). Lung sound analysis

dysplasia and anomalous development, and

in a patient with vocal cord dysfunction

are characterised by a cystic mass of lung

bronchial asthma. J Asthma; 49: 227-229.

tissue with proliferation of bronchial

Andrade CF, et al. (2011). Congenital lung

structures and lung tissue showing aberrant,

malformations. J Bras Pneumol; 37: 259-

differentiated architecture, with various

271.

degrees of cyst formation. The most

Bhatia J, et al.

(2009). GERD or not

common symptoms are recurrent infections,

GERD: the fussy infant. J Perinatol; 29:

and there have been reports of malignant

Suppl. 2, S7-S11.

transformation.

Bisgaard H, et al. (2007). Prevalence of

asthma-like symptoms in young children.

Congenital lobar emphysema, also known as

Pediatr Pulmonol; 42: 723-728.

infantile lobar hyperinflation, is a rare lung

Brand P, et al. (2008). Definition, assess-

malformation. Entrapment of air in the

ment and treatment of wheezing disor-

ders in preschool children: an evidence-

affected lobe during the expiratory phase

based approach. Eur Respir J; 32: 1096-

results in progressive distension and a

1110.

consequent effect on lung structures and

Brown SC, et al.

(2012). Treatment

adjacent mediastinal mass. All this leads to

strategies for pulmonary sequestration

breathing problems due to alteration of

in childhood: resection, embolization,

normal gaseous exchange.

observation? Acta Cardiol; 67: 629-634.

Epelman M, et al. (2010). Current ima-

Various terms have been used to designate

ging of prenatally diagnosed congenital

arteriovenous malformations, including

lung lesions. Semin Ultrasound CT MR; 31:

arteriovenous fistula, pulmonary

141-157.

arteriovenous aneurysm, pulmonary

Guilbert TW, et al. Approach to infants

haemangioma, pulmonary cavernous

and children with asthma. In: Adkinson

angioma, and pulmonary telangiectasia.

NF Jr, et al., eds. Middleton’s Allergy:

Principles and Practice.

7th Edn.

Another differential diagnosis that should be

Philadelphia, Mosby, 2008; pp. 1319-133.

considered is bronchopulmonary dysplasia

Herzog R, et al. (2011). Pediatric asthma:

(BPD). It is an important cause of morbidity

natural history, assessment, and treat-

and mortality in preterm infants. Its

ment. Mt Sinai J Med.; 78: 645-660.

incidence in infants with birth weight

Hsu CC, et al. (2012). Embolisation for

pulmonary arteriovenous malformation.

,1500 g ranges 23-26%. BPD is defined as

Cochrane Database Syst Rev; 8: CD008017.

the presence of oxygen dependence to

Jobe AH, et al. (2001). Bronchopulmonary

36 weeks of post-conceptional age or at

dysplasia. Am J Respir Crit Care Med; 163:

28 days of life, in combination with

1723-1729.

persistent clinical respiratory symptoms and

Juvén T, et al.

(2000). Etiology of

radiological pulmonary abnormalities. It is

community-acquired pneumonia in 254

discussed in detail elsewhere in this

hospitalized children. Pediatr Infect Dis J;

Handbook.

19: 293-298.

Kotecha S, et al. (2012). Antenatal and

Conclusion

postnatal management of congenital cys-

tic adenomatoid malformation. Paediatr

The symptoms of asthma, not always

Respir Rev; 13: 162-170.

specific, can be associated with other

Kussman BD, et al.

(2004).

diseases, and differential diagnosis should

Cardiovascular causes of airway compres-

always be considered to confirm or exclude a

sion. Paediatr Anaesth; 14: 60-74.

definitive diagnosis of asthma. Particular

Lemons JA, et al. (2001). Very low birth

attention should be considered in preschool

outcomes of the National Institute of Child

children in order to identify the specific

Health and Human Development

phenotype of wheezing.

ERS Handbook: Paediatric Respiratory Medicine

337

Neonatal Research Network, January 1995

Rosbe KW, et al.

(2003). Extraeso-

through December 1996. Pediatrics; 107: E1.

phageal reflux in pediatric patients with

Martinez FD, et al. (1995). Asthma and

upper respiratory symptoms. Arch

wheezing in the first six years of life. N

Otolaryngol Head Neck Surg;

129:

Engl J Med; 332: 133-138.

1213-1220.

Morton RL, et al. (2001). Evaluation of the

Tenenbaum T, et al.

(2012). Clinical

wheezy infant. Ann Allergy Asthma

characteristics of children with lower

Immunol.; 86: 251-256.

respiratory tract infections are dependent

Ramanuja S, et al. (2010). The approach

on the carriage of specific pathogens in

to pediatric cough. Ann Allergy Asthma

the nasopharynx. Eur J Clin Microbiol

Immunol; 105: 3-8.

Infect Dis; 31: 3173-3182.

Ramanuja S, et al. (2010). The approach

Wilson N, et al.

(2012). Sinusitis and

to pediatric cough. Ann Allergy Asthma

chronic cough in children. J Asthma

Immunol.; 105: 3-8.

Allergy.; 5: 27-32.

338

ERS Handbook: Paediatric Respiratory Medicine

Pathophysiology and

epidemiology of allergic

disorders

Karin C. Lødrup Carlsen

Allergic disorders include asthma, allergic

rhinitis, allergic rhinoconjunctivits, atopic

Key points

eczema, urticaria, food allergy and

anaphylaxis. Allergic diseases are chronic

Manifestations of allergic diseases

and often complex diseases with

may appear at any age, but most

environmental, as well as genetic,

commonly occur in childhood.

influences. With the recent ‘‘asthma and

The so-called ‘‘allergic march’’

allergy epidemic’’ in the Western world, it

portrays a succession from atopic

has been suggested that environmental

eczema, through food allergy to

factors play a more important role in disease

inhalant allergy, often accompanied

development than previously thought. In

by asthma and subsequently allergic

addition, more than 100 different genes are

rhinitis, all of which commonly occur

implicated in allergic diseases to some

by school age.

extent; however, there is no clear specific

gene, suggesting a less prominent role of

Viral infections are important triggers

genes in the current epidemic of allergic

of symptoms and exacerbations of

diseases. Whether this is related to more

asthma in childhood; however,

abundant risk factors or the loss of

allergic sensitisation appears to

potentially protective factors is not known.

precede viral infection in children with

Current research is investigating whether

viral wheeze and allergic sensitisation

environmental effects on genes causing

who develop asthma.

epigenetic changes are involved in disease

The observed increase in allergic

modification. However, neither the factor(s)

diseases is particularly worrying since

nor the timing of triggers that off-set the

it not only affects the subjects with the

immune system from normal development

diseases, but is likely to increase the

into an allergic inflammatory pathway are

burden of allergic disease in the

known.

offspring of the current younger

generation.

Pathophysiology

Manifestations of allergic diseases may

appear at any age, but most commonly

subsequent female predominance after

occur in childhood. The so-called ‘‘allergic

puberty. The causes of this change are not

march’’ portrays a succession from atopic

known, but hormonal changes with

eczema, through food allergy to inhalant

increasing allergic manifestation in females

allergy, often accompanied by asthma and

during puberty are considered a probable

subsequently allergic rhinitis, all of which

cause of the changing sex predominance.

commonly occur by school age. Puberty is

the second life-phase with major changes in

Allergic sensitisation, particularly to mites,

allergic disease, and is when the male

cockroaches, pollen and pet allergens, are

predominance of allergic diseases seen in

among the strongest risk factors for asthma.

childhood gradually changes into a

However, allergic diseases may also occur in

ERS Handbook: Paediatric Respiratory Medicine

339

individuals without detectable serum IgE or

cytokines and other immune mediators

positive skin prick tests to allergens.

leading to:

Children with atopic eczema, asthma or

asthma-like symptoms often lack detectable

N survival of the Th2 cell;

serum IgE antibodies, suggesting that there

N mast cell differentiation and maturation;

are alternative mechanisms for initiating the

N B-cell isotype switching to IgE synthesis;

underlying inflammation. This is commonly

N maturation and survival of eosinophils;

seen as differing phenotypes of allergic

N recruitment of basophils.

diseases, with allergic sensitisation being a

It is not known what triggers T-cells and how

pivotal phenotypic criterion. This view is

the naïve T-cells mature into Th2 immune-

currently challenged, as allergy is probably

active cells. However, it is believed that

not an all-or-nothing phenomenon, but

directing naïve T-cells to Th1 versus Th2

rather a continuum of immunological

immunity involves regulatory T-cells (Tregs),

mechanisms underlying allergic disease

a process that is important in tolerance

presentations. However, some common

development and suppressing allergic

underlying pathophysiological mechanisms

inflammation.

within and between allergic diseases are

probable in view of the frequent comorbidity

The innate immune system is, in effect:

of allergic diseases, typically allergic rhinitis

and asthma, or atopic eczema preceding

N the barrier between the organism and the

asthma and allergic rhinitis.

external environment;

N an important defence against infections;

In general, most individuals do not respond

N the first line of defence against intruders.

adversely to allergens. However, in some,

allergen exposure leads to a break in natural

Innate immune cells (such as mast cells),

tolerance triggering allergic inflammation

granulocytes, mononuclear phagocytes,

(fig. 1), and an allergen-specific immune

lymphocytes and epithelial cells, express

surface and internal receptors, including

response that is maintained by host T- and

Toll-like receptors and those involved in

B-cells. The allergic inflammation typically

recognising and removing microbial

involves the production of specific serum

substances.

IgE antibodies against allergens (allergic

sensitisation). Allergic inflammation

However, the adaptive immune system

involves local, as well as systemic, immune

classically involves T-cell responses to

cells and biomarkers of the innate and

antigens (or allergens), typically with

adaptive immune system (fig. 1). The

production of serum IgE-antibodies from B-

allergic response is initiated when an

cells adapting to environmental challenges.

allergen binds to the high-affinity receptor

In addition, dendritic cells (APCs in the

for IgE (FCeRI) on the antigen presenting

airway and gut epithelium) (fig. 2) are not

cell (APC). The APC will then process the

present at birth, but move from the bone

allergen into small peptides that will be

marrow to the epithelium, possibly as a

presented via the major histocompatibility

result of damage to the airway epithelium,

complex (MHC) class II molecules for

like viral infections in asthmatic subjects. In

recognition by the T-cells. The immediate

subjects with established allergic

allergic response involves isotype switching

sensitisation, the dendritic cells, which

of a B-cell into IgE synthesis, a process that

contain receptors that are able to attach to

requires the presence of several interleukins

allergens, engulf the ‘‘intruding’’ allergen,

(IL; such as, IL-4 and IL-13) and cytokines,

processing them to form peptides that can

resulting in a cascade of immunological

be presented to the T-cell receptors as

events. In contrast to normal immune host

complexes formed with the MHC. The

responses to microbial products involving T-

dendritic cell uptake of allergens is

helper type 1 (Th1) lymphocytes, the allergic

facilitated by allergens bound to FceRI

inflammatory cascade involves Th2

(fig. 1), which may be particularly abundant

340

ERS Handbook: Paediatric Respiratory Medicine

lgE-specific

FcεRl

antibody

IL-9-specific

antibody

Mast cell

Eosinophil

IL-9

lgE

IL-4-specific

IL-4

IL-4- and

antibody

IL-13

IL-13-specific

MHC

antibodies

Allergen

IL-4

class ll molecule

IL-4

TH2 cell

IL-5

TCR

IL-5-specific

Eosinophil

antibody

TH0 cell

APC

IL-12

IFN-γ

rhIL-12

TH1 cell

rhIFN-γ

Figure 1. Schematic diagram showing the interplay between local, as well as systemic, immune cells and

biomarkers of the innate and adaptive immune system in allergic inflammation. TCR: T-cell receptor;

rhIL: recombinant human IL; IFN: interferon; rhIFN: recombinant IFN. Reproduced from Holgate

(2008), with permission from the publisher.

as the cells move from the bone marrow to

cycle in asthma development suggests that

the mucosal lining.

repeated airborne irritant stimuli (such as

allergens or viruses) evoke cycles of

Such mechanisms are probably propagated

inflammation leading to intermittent

through defects in barrier function, and have

inflammation and initially resulting in

recently been demonstrated in the airway

episodic symptoms. However, with repeated

epithelium of asthmatic subjects and the

insults the inflammatory resolution becomes

skin of subjects with atopic eczema, as well

less complete leading to tissue repair and

as in other allergic diseases. A link has been

regeneration, which may trigger prolonged

reported through a common genetic variant

periods of pathological changes. These

of filaggrin.

periods may progress to deterioration in

Viral infections are important triggers of

respiratory function and perhaps to

symptoms and exacerbations of asthma in

remodelling. A commonly asked question,

childhood, whereas many children with ‘‘viral

the answer to which is not clear at present, is

wheeze’’ will not go on to develop asthma.

what is the role and potential interaction

Recent studies suggest that respiratory

between allergic sensitisation and viral

viruses, possibly (sub-types of) human

infections in eliciting disease development,

rhinovirus in particular, may play a role in

in contrast to both viruses and allergens

triggering the immune system. The

being potential triggers of disease

mechanisms are not known, but a series of

exacerbations? However, it was recently

interactions between antiviral and atopic

deduced that allergic sensitisation appears to

inflammatory pathways mediated by local

precede viral infections in children who have

activation of myeloid cell populations are

both conditions. Another aspect of the

probable in the airways, as well as in the bone

damaged epithelium in asthma is the

marrow. A recently hypothesised immune

reduced ability to handle viruses in an

ERS Handbook: Paediatric Respiratory Medicine

341

Eosinophil

Mast cell

GM-CSF

Basophil

IL-4

IL-5

IL-3

IL-9

IL-5

GM-CSF

IL-13

IL-3

IL-13

IL-4

Mucus

Mucocyte

TH2

IL-13

Mucus

IL-9

IL-33

IL-4

IL-25

NKT

Thymus

TH9

IL-9

IL-21

IL-4

IL-15

TGF-β

TH0

IL-10

TGF-β

IL-10

TGF-β

IL-6

TGF-β

IL-12

IL-18

IL-17A

TH17

iTreg

Smooth muscle

IFN-γ

IL-17A

TH1

IL-17A

IL-17F

IL-22

TNF-α

IFN-γ

Neutrophil

Figure 2. Different T-cell subtypes are involved in the pathogenesis of asthma. Cytokines and contact

signals, together with dendritic cells and the thymic epithelium, drive the inflammatory process into

various cell lines (blue circle), maintaining inflammatory responses involved in asthma and airway

hyperreactivity. GM-CSF: granulocyte-macrophage colony-stimulating factor; TNF: tumour necrosis

factor; IFN: interferon; NKT: natural killer T-cell; Th: T-helper; iTreg: inducible regulatory T-cell.

Reproduced and modified from Holgate (2012), with permission from the publisher.

optimal way. It appears that the reduced

parasympathetic mechanisms involving heat

ability of airway epithelial cells to produce

and fluid exchange over the epithelium. BHR

interferon-c may lead to cytotoxic cell death

is a modest, but significant, risk factor for

and subsequent dissemination of viruses,

later onset of asthma and tends to decrease

rather than apoptosis, possibly explaining the

throughout childhood.

prolonged symptomatic viral infection

The role of lung function reductions in the

observed in asthmatics.

development of asthma, in contrast to lung

function decline with chronic asthma, is not

Bronchial hyperresponsiveness (BHR) is a

entirely clear. There is no doubt that asthma

common, but not necessary, feature of

is associated with reduced lung function as

childhood asthma. BHR typically presents as

well as a more rapid decline in lung function

a general tendency to develop symptoms via

compared to healthy individuals. In a few

exposure to various physiological or

birth cohorts, reduced lung function has

environmental stimuli, with exercise being a

been found to precede asthma in some, but

classical childhood asthma symptom trigger.

not all, children with asthma.

The underlying mechanisms for BHR

development are not clear, but may involve

Airway remodelling is a common feature in

barrier dysfunction, as well as possibly neural

adult asthma but this is not as clear in

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ERS Handbook: Paediatric Respiratory Medicine

childhood, particularly with reference to

between perceived and documented (usually

when it starts and what elicits the process.

by food challenges) symptoms of food allergy.

Nevertheless, lung function reductions in

However, in a recent study in Australia, 13% of

older children are likely to reflect structural

1-year-old children with atopic mothers were

changes in the airways, such as subepithelial

found to have a food allergy whereas 4% of

reticular basement layer thickening,

those with a non-atopic mother had

epithelial cell disruption, imbalance of

confirmed a food allergy. However, cow’s milk

proteases and anti-proteases, as well as

allergy has been reported in up to 40% of 5-

neoangiogenesis (remodelling).

16-year-olds, but was only confirmed in 5%.

Anaphylaxis is increasing, and although there

Epidemiology

are shortcomings in definitions and

Allergic diseases in children have increased

methodology, an annual incidence rate of

over the past decades to epidemic

0.4-9% has been reported, with peanuts and

proportions. In a recent Swedish birth

tree-nuts being the most common triggers. In

cohort study from 1994, .50% of 12-year-

a recent Swedish study the population

old children had at least one allergic disease,

incidence was found to be 32 per 100 000

and 7.5 % had at least two diseases out of

person, with food involved in 92% of the

atopic eczema, asthma or allergic rhinitis.

episodes.

In the International Study of Asthma and

The observed increase in allergic diseases is

Allergy phases I-III, asthma prevalence

particularly worrying since it not only affects

varied up to 15-fold in the .50 included

the subjects with the diseases, but is likely

countries and almost 200 000 6-7-year-old

to increase the burden of allergic disease in

children and 300 000 13-14-year-old

the offspring of the current younger

children. In 2001-2003, the prevalence of

generation.

current asthma symptoms in 6-7-year-olds

ranged from 5.0% (Nigeria) to 37.6% (Costa

Further reading

Rica) with respective figures in 13-14-year-

olds ranging from of 5.1% (Georgia) to

Annamalay AA, et al. (2012). Prevalence

31.2% (Isle of Man). The corresponding

of and risk factors for human rhinovirus

figures for allergic rhinitis were 2.2% (Iran)

infection in healthy aboriginal and non-

to 24.2% (Taiwan) for 6-7-year-olds and

aboriginal Western Australian children.

4.5% (Baltic countries) to 45.1% (Paraguay)

Pediatr Infect Dis J; 31: 673-679.

Ballardini N, et al. (2012). Development

in 13-14-year-olds, and for atopic eczema

and comorbidity of eczema, asthma and

were 2.0% (Iran) to 22.3% (Sweden) and

rhinitis to age 12: data from the BAMSE

1.8% (Georgia) to 21.8% (Morocco),

birth cohort. Allergy; 67: 537-544.

respectively. Overall, since the mid-1990s,

Bousquet J, et al. (2012). Severe chronic

an increase in allergic disease prevalence

allergic (and related) diseases: a uniform

has been found more often than a decrease,

approach

- a MeDALL/GA²LEN/ARIA

most often in the younger age group and

position paper. Int Arch Allergy Immunol;

particularly for atopic eczema. In Europe,

158: 216-231.

pooled data from 11 birth cohorts (.14 000

Carlsen KH

(2012). Sports in extreme

children) demonstrated a mean prevalence

conditions: the impact of exercise in cold

of current asthma in children aged 6-

temperatures on asthma and bronchial

10 years of 8.1%; approximately half of the

hyper-responsiveness in athletes. Br J

children had concomitant allergic

Sports Med; 46: 796-799.

sensitisation, 7.7% had current allergic

Haland G, et al.

(2006). Reduced lung

rhinitis and 29.5% had allergic sensitisation,

function at birth and the risk of asthma at

demonstrating large variations between

10 years of age. N Engl J Med; 355: 1682-1689.

countries and cohorts.

Holgate, et al. (2008). Treatment strate-

gies for allergy and asthma. Nat Rev

The prevalence of food allergy is more difficult

Immunol; 8: 218-230.

to assess due to the relatively large difference

ERS Handbook: Paediatric Respiratory Medicine

343

Holgate ST (2012). Innate and adaptive

Minnicozzi M, et al.

(2011). Innate

immune responses in asthma. Nat Med;

immunity in allergic disease. Immunol

18: 673-683.

Rev; 242: 106-127.

Holt PG, et al. (2012). Viral infections and

Palmer CN, et al. (2006). Common loss-

atopy in asthma pathogenesis: new ratio-

of-function variants of the epidermal

nales for asthma prevention and treat-

barrier protein filaggrin are a major

ment. Nat Med; 18: 726-735.

predisposing factor for atopic dermatitis.

Jackson DJ, et al. (2012). Evidence for a

Nat Genet; 38: 441-446.

causal relationship between allergic sensi-

Prescott S, et al.

(2011). Food allergy:

tization and rhinovirus wheezing in early

riding the second wave of the allergy

life. Am J Respir Crit Care Med; 185: 281-285.

epidemic. Pediatr Allergy Immunol;

22:

Lodrup Carlsen KC, et al. (2012). Does pet

155-1560.

ownership in infancy lead to asthma or

Riiser A, et al.

(2012a). Does bronchial

allergy at school age? Pooled analysis of

hyperresponsiveness in childhood predict

individual participant data from

active asthma in adolescence? Am J

European birth cohorts. PLoS One;

Respir Crit Care Med.; 186: 493-500.

e43214.

von Hertzen L, et al.

(2006).

Martinez FD, et al. (1988). Diminished

Disconnection of man and the soil:

lung function as a predisposing factor for

reason for the asthma and atopy epi-

wheezing respiratory illness in infants. N

demic? J Allergy Clin Immunol; 117: 334-

Engl J Med; 319: 1112-1117.

344.

344

ERS Handbook: Paediatric Respiratory Medicine

In vivo and in vitro diagnostic

tests in allergic disorders

Gunilla Hedlin

Many children who start to wheeze during

is also a clear relationship between exposure

airway infections in early life will improve

and allergic symptoms, yet this may not

with age when infections become less

always be the case. Exposure to dander

frequent and the airways grow. There is,

present on clothes, hair or on surfaces at

however, a large group of children who start

home and school or in other public places

with viral wheeze and continue to develop

constitutes an invisible source of allergen.

persistent asthma. In many of these

Under these and other circumstances it can

children, IgE-mediated allergy will play an

be difficult to evaluate the impact of allergy

important role as a trigger of symptoms. In

on a child’s symptoms. These examples

some, allergy testing will confirm an IgE-

highlight the importance of performing a

mediated sensitisation sometimes

careful, thorough, diagnosis of allergy before

preceding the clinically relevant allergy. In

the decision is made to take action on

others, asthma symptoms at allergen

allergen avoidance and/or initiate

exposure will appear before sensitisation

immunotherapy. The allergens responsible

can be confirmed. Thus, although allergy is a

for causing asthma symptoms have to be

common cause of symptoms of asthma and

confirmed.

often of asthma exacerbations, it is not

Prevalence of allergic sensitisation

always clear what role a specific allergen

plays in the severity of the disease. This is

Allergic sensitisation can start at any age

particularly obvious when the relationship

and is a common phenomenon. In the US

between exposure and symptoms is not

National Health and Nutrition Survey 54%

clear. In pollen allergy, the relationship

of 10 500 participants had one or more

between exposure and symptoms is easy to

positive SPT to one or more of 10 allergens.

assess using pollen count reports. There is

The sensitisation rate had more than

usually no need to confirm a relationship

doubled between the tests performed during

between sensitisation, exposure and

1976-1980 and 1988-1994. Similar trends

symptoms by any other means than taking a

have been seen in European longitudinal

history and performing a skin prick test

and/or cross-sectional population-based

(SPT) and/or an analysis of allergen-specific

studies. In a Swedish study of the

IgE in serum. In animal dander allergy there

sensitisation rate in schoolchildren the

prevalence of one or more positive SPT

increased from 21-30% between 1996 and

Key points

2006.

Diagnosis of allergy

N Allergy is a common trigger of

asthma.

History The first and foremost step in the

evaluation of children with asthma is a

N Allergy can start at any age.

careful detailed history. Important questions

Allergy testing should be performed in

include family history of allergic disease,

all children with asthma.

known triggers of symptoms, frequency and

severity of symptoms, other signs of atopic

ERS Handbook: Paediatric Respiratory Medicine

345

Table 1. Advantages of allergy testing

SPT

Serum IgE

No blood sample needed

No need to withhold antihistamines

Reliable with good extracts

Reliable with validated methods

Immediate results

Always available

Visible results

Can be used when skin is impaired

disease like rhinitis without relation to colds,

has developed tolerance. A SPT can be

atopic dermatitis and adverse reactions to

performed at any age but skin reactions tend

food. In some children allergic rhinitis may

to be smaller in young children (table 2).

precede asthma and act as a predictor of an

IgE in serum can be analysed for:

increased risk of asthma. Early development

of eczema and/or food allergies can also be

N single allergens,

signs of risk of later allergic asthma in

N allergenic molecules (components) of

children.

single allergens,

Allergy sensitisation testing: practice and

N a mix of allergens (mix of rodents,

interpretation The most common mode of

moulds and dust mites),

allergy testing is in vivo testing by the SPT;

N for screening purposes by a multi-

usually the test of choice. The alternative is

allergen test, including the common SPT

in vitro testing, which is analysis of allergen-

panel of allergens (table 3).

specific IgE antibodies in serum. Both tests

The in vitro IgE measurement and the SPT

have advantages and disadvantages

result usually agree, but not always. If the

(table 1).

SPT does not agree with the history IgE in

serum should be measured before rolling

SPTs should be performed with well-

out a suspected allergy. Analysis of serum

standardised extracts. Usually a panel of

IgE can be performed at any age or any time;

aeroallergens are used. The test is applied

current pharmacotherapy does not

by drops of allergen extract on the volar side

interfere with the test result. Negative test

of the forearm. The drops are then

results in young children should be

punctured by a needle-like device (fig. 1).

interpreted with caution. Low specific-IgE

After 15-20 min any wheal and skin flare

levels (0.1-0.35 kUa?L^-1) can indicate

reactions are recorded and the longest

sensitisation. There are a number of

diameter of each wheal is measured. A

companies that provide assays for the in vitro

wheal diameter o3 mm is considered a

IgE antibody tests. Most commonly, a solid

significant skin reaction. A false-negative

phase matrix with allergen extract is used.

test result can be seen when the patient has

ongoing antihistamine therapy, ongoing

dermatitis and/or when a topical

corticosteroid has recently been applied on

the skin. A false-negative result can also be

seen at an early stage of sensitisation or if

sensitisation is weak. A false-positive SPT

can be seen if the child suffers from

dermographism or when sensitisation does

not reflect clinical allergy; in the latter case

the history is more important than the test

result, although a positive test can precede

the clinical allergy. In food allergy that

subsides, such as egg and milk allergy, the

skin sensitivity can remain after the child

Figure 1. Performance of a SPT.

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Interpreting allergy test results

Allergy can be an asthma trigger in spite of a negative allergy test

Allergic sensitisation may not have any relation to asthma symptoms

The degree of sensitisation (e.g. wheal size and antibody level) may or may not reflect disease

severity

SPT and in vitro IgE tests often agree but sometimes both tests are needed

When allergy testing and history disagree there can be a need for an allergen challenge test, if

allergy needs to be confirmed or excluded

After adding the patient’s serum an anti-IgE

whose symptoms are mainly caused by

antibody is added and the amount of bound

other factors in spite of confirmed allergen

allergen-specific IgE in the patient’s serum

sensitisations.

is analysed. The result is usually expressed

Food challenges, open or double-blind, are

in arbitrary mass units (kUa?L^-1).

sometimes warranted to confirm an allergy

Allergen challenge tests While in vitro tests or

but also to support development of

SPTs are good enough for confirming pollen

tolerance, which is common in children

and animal dander allergy, it may be

with, for instance, milk and egg allergy.

necessary to perform allergen provocation

Total IgE measurements in serum are mainly

tests in the eyes and/or the nose to confirm

needed when treatment with anti-IgE

a dust mite or mould allergy. Bronchial

(omalizumab) is considered, an injection

allergen challenge is rarely indicated. It can

therapy with monoclonal anti-IgE

be dangerous in children with asthma,

antibodies. Dosing is based on the patient’s

inducing a severe asthmatic reaction, and

age, weight and level of total IgE.

should be avoided.

Molecular diagnosis in allergy is usually

Nasal and conjunctival allergen challenges

performed by measuring IgE antibodies

can be important if there is doubt about the

towards individual allergenic components.

impact of the specific allergy on the severity

An alternative is microarray-based testing

of symptoms. This may be the case when

against multiple recombinant or purified

allergen immunotherapy is considered.

natural allergen components. This has

The rationale is to avoid treating a child

made it possible to analyse IgE antibodies

to numerous allergen components of many

common allergens simultaneously in small

Table 3. Common panels of allergens included in SPT

samples of serum (20 uL). The allergen

and/or IgE antibody screening

components can be classified by protein

Tree pollen (relevant for geographical area)

families. This detailed analysis improves

Grass pollen (relevant for geographical area)

the possibility to identify antibodies to

proteins that cross-react between different

Weed pollen (relevant for geographical area)

allergens from a sensitisation that is

Animal dander

species specific. Currently, the only

Cat

commercially available component

resolved microarray diagnostic method is

Dog

the Immuno Solid phase Allergen Chip

Horse

microarray (Phadia, Uppsala, Sweden).

Dust mite

Allergy diagnostics is an important part of

Mould

the evaluation and management of children

Alternaria

with preschool wheeze and asthma.

Together with a careful history it is one of

Cladosporium

the first steps in identifying possible triggers

ERS Handbook: Paediatric Respiratory Medicine

347

in children of all ages. Allergy becomes more

Hoest A, et al. (2003). Allergy testing in

common as a trigger in children with

children: why, who, when and how?

recurrent wheeze and is a major cause of

Allergy; 58: 559-569.

symptoms and exacerbations in children

Platts-Mills TA, et al.

(2011). Allergens

with persistent and/or seasonal asthma.

and their role in the allergic immune

response. Immunol Rev; 242: 51-68.

Sastre J

(2010). Molecular diagnosis in

Further reading

allergy. Clin Exp Allergy; 40: 1442-1460.

Sicherer SH, et al. (2012). Allergy testing

Bousquet J, et al. (2012). Practical guide

in childhood: using allergen-specific IgE

to skin prick tests in allergy to aeroaller-

tests. Pediatrics; 129: 193-197.

gens. Allergy; 67: 18-24.

Zuberbier T, et al. (2010). GA²LEN/EAACI

Cox L (2011). Overview of serological-

pocket guide for allergen-specific immu-

specific IgE antibody testing in children.

notherapy for allergic rhinitis and asthma.

Curr Allergy Asthma Rep; 11: 447-453.

Allergy; 65: 1525-1530.

348

ERS Handbook: Paediatric Respiratory Medicine

Anaphylaxis

Antonella Muraro

Anaphylaxis is a serious allergic reaction

anaphylaxis can be triggered by physical

that is rapid in onset and may result in

exercise, aeroallergens and contact with

death. The epidemiology of the disease is

latex, radiocontrast media and ethanol.

hindered by difficulties in timely

Almost all episodes are IgE-mediated

assessment of symptoms and in the lack of

reactions, although sometimes other, non

proper coding according to the

IgE-mediated, immunological mechanisms

International Classification of Disease. In

might be involved, or there may be direct

addition, anaphylaxis in infants and

mast cell activation such as in physical

children might be even more difficult to

exercise. Idiopathic anaphylaxis, i.e. when

recognise and needs a high degree of

the cause is unknown, is also relatively

suspicion. However, although no exact

common.

incidence can be established, based on

In contrast with older patients, in which

current data it is reasonable to assume that

drugs and hymenoptera venom are the main

1-2% of the population may be affected,

causes, food allergens are the most

with food and drugs being the most

common trigger of anaphylaxis in children.

common cause of anaphylaxis.

Among them, cow’s milk, egg, peanuts, tree

nuts and seafood are most frequently

Triggers

reported.

The most common causes of anaphylaxis

Clinical manifestation and diagnosis

are food allergens, medications and

hymenoptera venoms. Less frequently,

The diagnosis of anaphylaxis is primarily

based on clinical symptoms and signs, as

well as a detailed description of acute

Key points

episodes, including antecedent activities

and events occurring within the preceding

Anaphylaxis is a serious allergic

minutes to hours.

reaction that is rapid in onset and may

Typically, exposure to a triggering allergen is

result in death.

followed by rapid development of symptoms

The most common causes are food

over minutes to several hours. Investigation

allergens, medications and

is mandatory, especially if exposure to a

hymenoptera venoms.

likely allergen is reported. Sudden onset of

urticaria, swelling of the oropharynx,

N Infants are usually not able to

rhinorrea, cough, breathing difficulties,

describe symptoms; therefore,

vomiting and progressive abdominal pain,

physicians need to have a high index

pallor, irritability and sleepiness (i.e.

of suspicion in order to diagnose

hypotension) should be carefully evaluated

anaphylaxis.

in any allergic child. In infants, anaphylaxis

Adrenaline is the medication of choice

may be even more difficult to recognise

for anaphylactic episodes.

because they are usually unable to describe

the symptoms. Moreover, some signs of

ERS Handbook: Paediatric Respiratory Medicine

349

anaphylaxis, such as irritability, flushing,

Role of laboratory tests

hoarseness, drooling, regurgitation, loose

The diagnosis is hampered by the lack of

stools, colicky abdominal pain and

reliable markers of the disease. Serum

somnolence, may be difficult to interpret

tryptase, which should be obtained 15 min

since they are quite common in this age

to 3 h after onset of the symptoms, has low

group.

sensitivity and specificity and its level is

Recently, the National Institute of Allergy

typically normal in food anaphylaxis.

and Infectious Disease and the Food Allergy

Histamine blood levels obtained 15-60 min

and Anaphylaxis Network have established

after onset may also be useful. However,

three diagnostic criteria, allowing 95% of

both tests are not universally available, not

anaphylaxis events to be diagnosed

performed on an emergency basis and not

(table 1).

specific for anaphylaxis. A recent report

highlights the possible role of platelet-

In both adults and children, the time course

activating factor in the pathogenesis of more

of the reaction may be:

severe reactions.

N Uniphasic, occurring immediately after

Management

exposure and resolving with or without

The management of anaphylaxis encompasses

treatment in minutes to hours;

both the treatment of acute episodes and the

N Biphasic, recurring after the apparent

preventive strategies in the community to

resolution of initial symptoms, usually

avoid recurrences and new cases.

about 8 h after the first reaction;

N Protracted, persisting for hours or days

Basic management As with the treatment of

following the initial reaction.

any critical patient, the treatment of

Table 1. Clinical criteria for diagnosing anaphylaxis

Anaphylaxis is highly likely when any one of the following three criteria are fulfilled

Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue

or both (e.g. generalised hives, pruritus or flushing and swollen lips-tongue-uvula), and at least

one of the following:

Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced PEF and

hypoxaemia)

Reduced BP or associated symptoms of end-organ dysfunction (e.g. hypotonia (collapse),

syncope and incontinence)

Two or more of the following that occur rapidly after exposure to a likely allergen for that patient

(minutes to several hours):

Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush and swollen lips-

tongue-uvula)

Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor, reduced PEF and

hypoxaemia)

Reduced BP or associated symptoms (e.g. hypotonia (collapse), syncope and incontinence)

Persistent gastrointestinal symptoms (e.g. cramping abdominal pain and vomiting)

Reduced BP after exposure to known allergen for that patient (minutes to several hours):

Infants and children: low systolic BP^# (age specific) or .30% decrease in systolic BP

Adults: systolic BP ,90 mmHg or .30% decrease from that person’s baseline

PEF: peak expiratory flow; BP: blood pressure.^#: defined as ,70 mmHg at 1 month to 1 year of age,

,70 mmHg+[26age] at 1-10 years of age and ,90 mmHg at 11-17 years of age.

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anaphylaxis begins with a rapid assessment

and maintenance of airway, breathing and

circulation. Patients experiencing acute

anaphylaxis should be kept in a position of

comfort, which usually involves lying

recumbent or semi-recumbent. This

accomplishes two therapeutic goals:

N preservation of fluid in the circulation

(the central vascular compartment), an

important step in managing distributive

shock;

N prevention of empty vena cava/empty

ventricle syndrome, which can occur

within seconds when patients with

anaphylaxis suddenly assume or are

placed in an upright position.

Patients with this syndrome are at high risk

for sudden death and unlikely to respond to

adrenaline, regardless of route of

administration, because it does not reach

the heart and therefore cannot be circulated

throughout the body.

After removing exposure to the trigger (if

possible), if any of the three criteria of

anaphylaxis outlined in table 1 are fulfilled,

the patient should receive adrenaline

immediately.

Adrenaline is the medication of choice for

anaphylactic episodes; all other medications

should be regarded as ancillary. Prompt

injection of adrenaline has been associated

with better outcomes. A severity score can

be helpful in the diagnosis and in ensuring

the timely administration of adrenaline

(table 2).

The intramuscular route is acknowledged as

the optimal route for adrenaline

administration. Adrenaline in a

concentration of 1 mg?mL^-1 should be used

in a dose of 0.01 mg?mL^-1 body weight

(maximum single dose 0.5 mg). This

dosage can be repeated at short intervals

(every 5-10 min) until the patient’s

condition stabilises.

Although frequently administered, the role

and efficacy of antihistamines and

corticosteroids in anaphylaxis has not yet

been clarified. These medications should

not be considered as first-line treatments for

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351

Table 3. Indications for prescribing a self-injectable adrenaline device

Absolute indications

Relative indications

A previous cardiovascular or respiratory

Any reactions to small amounts of a food

reaction to a food (and to other triggers such

including airborne or contact of the food

as insect sting or latex)

allergen only via skin

Exercise-induced anaphylaxis (often also

History of previous, even mild, reactions to

related to food)

peanut or tree nuts

Idiopathic reaction

Remoteness of home from medical facilities

Child with food allergy and asthma

Food allergy reaction in a teenager

anaphylaxis as they do not act quickly. The

Prescription of self-injectable adrenaline The

efficacy of corticosteroids in reducing the

decision about whether to prescribe a self-

risk of late-phase reactions has not been

injectable adrenaline device involves

proven. High-flow oxygen should be given to

analysis of the risks of experiencing

any patient with respiratory symptoms or

anaphylaxis, the benefits of a self-injectable

evidence of shock. Volume support with

adrenaline device, the risks associated with

crystalloid solution or colloid expander is

it and its cost on health services and

mandatory in the case of hypotension.

individual families. Absolute and relative

indications about prescribing adrenaline are

Long-term management Identification of

shown in table 3.

triggers In order to identify the allergen,

patients with a history suggestive of an

Immunomodulation Venom immunotherapy

anaphylactic reaction need urgent referral to

is 95-100% and ,80% successful in wasp

an allergy clinic for a diagnostic assessment,

and bee sting allergies, respectively.

based on clinical history and in vivo and in

Desensitisation protocols have also been

vitro examinations (skin prick test,

established for some medications, such as a

intradermal test, prick-by-prick with raw

few antibiotics and nonsteroidal anti-

food, IgE for suspected allergens and

inflammatory drugs, although they are only

recombinant allergens, and oral challenges

recommended in exceptional cases.

for food or drugs).

Food-induced anaphylaxis could

Risk reduction Strategies to avoid the

theoretically be modulated by allergen

precipitants should be customised taking

desensitisation through immunotherapy,

into consideration factors such as age,

similarly to hymenoptera sting anaphylaxis.

occupation, activities, hobbies, living

However, food allergen immunotherapy

conditions and access to medical care. As

remains experimental and although several

most episodes of anaphylaxis occur in the

trials of oral tolerance induction are

community, children and their caregivers

underway, this procedure is not yet

must know how to prevent further reactions

recommended in routine clinical practice.

and how to promptly recognise and

appropriately manage any anaphylactic

reactions that occur outside the hospital.

Further reading

Allergists, emergency physicians and general

Boyle RJ, et al.

(2012).

Venom-

paediatricians/practitioners, as well as

immunotherapy for preventing allergic

teachers and caregivers, need to develop a

reactions to insect stings. Cochrane

coordinated approach, including actions for

Database Syst Rev; 10: CD008838.

primary and secondary prevention and

Castells M

(2006). Desensitization

emergency response, in order to prevent

for drug allergy. Curr Opin Allergy Clin

fatalities and improve quality of life of

Immunol; 6: 476-481.

patients and families.

352

ERS Handbook: Paediatric Respiratory Medicine

Dhami S, et al. (2013). The acute and

with suspected food allergy. Allergy; 63:

long-term management of anaphylaxis:

1521-1528.

protocol for a systematic review. Clin

Panesar SS, et al. (2013). The epidemiology

Transl Allergy; 3: 14.

of anaphylaxis in Europe: protocol for a

Dinakar C (2012). Anaphylaxis in children:

systematic review. Clin Transl Allergy; 3: 9.

current understanding and key issues in

Pumphrey RS (2003). Fatal posture in

diagnosis and treatment. Curr Allergy

anaphylactic shock. J Allergy Clin

Asthma Rep; 12: 641-649.

Immunol; 112: 451-452.

Gold MS, et al. (2000). First aid anaphy-

Sampson HA, et al.

(2006). Second

laxis management in children who were

symposium on the definition and man-

prescribed an epinephrine autoinjector

agement of anaphylaxis: summary report

device (EpiPen). J Allergy Clin Immunol;

- Second National Institute of Allergy and

106: 171-176.

Infectious Disease/Food Allergy and

Muraro A, et al. (2007). The management

Anaphylaxis

Network

symposium.

of anaphylaxis in childhood: position

J Allergy Clin Immunol; 117: 391-397.

paper of the European academy of

Simons FE (2004). First-aid treatment of

allergology and clinical immunology.

anaphylaxis to food: focus on epinephr-

Allergy; 62: 857-871.

ine. J Allergy Clin Immunol; 113: 837-844.

Muraro A, et al. (2008). New visions for

Simons FE

(2007). Anaphylaxis in

anaphylaxis: an iPAC summary and future

infants: can recognition and management

trends. Pediatr Allergy Immunol; 19: Suppl.

be improved? J Allergy Clin Immunol; 120:

19, 40-50.

537-540.

Ott H, et al. (2008). Clinical usefulness of

Simons FE (2010). Anaphylaxis. J Allergy

microarray-based IgE detection in children

Clin Immunol; 125: S161-S181.

ERS Handbook: Paediatric Respiratory Medicine

353

Allergic rhinitis

Michele Miraglia Del Giudice, Francesca Galdo and Salvatore Leonardi

The allergic pathologies are frequent and

paediatric population and is often

bothersome diseases. In the past 30 years,

associated with other allergic diseases.

epidemiological studies have shown that the

According to various epidemiological

prevalence of allergic rhinitis continues to

studies this disease affects more than 10%

increase worldwide although it is often

of children ,14 years of age and 20-30% of

underestimated, underdiagnosed and

adolescents and young adults.

undertreated. Allergic rhinitis is the most

Definition

frequent allergic, chronic disease in the

Allergic rhinitis is defined as a symptomatic

disorder of the nose characterised by:

N itching,

Key points

N nasal discharge,

Allergic rhinitis is a symptomatic

N sneezing,

disorder of the nose characterised by

N nasal airway obstruction induced by an

itching, nasal discharge, sneezing and

IgE-mediated immune reaction after

nasal airway obstruction induced by

allergen exposure.

an IgE-mediated immune reaction

It is accompanied by inflammation of the

after allergen exposure.

nasal mucosa and nasal airway

According to ARIA guidelines, allergic

hyperreactivity. Although it is not life

rhinitis is divided into intermittent or

threatening, it can have a significantly

persistent disease and the severity is

detrimental effect on a child’s quality of life,

classified as mild or moderate/severe

and it may exacerbate a number of common

depending on the severity of

comorbidities, including asthma and

symptoms and their impact on social

sinusitis.

life, school and work.

Mechanisms

The diagnosis of allergic rhinitis is

Allergic rhinitis is the result of IgE-mediated

based on the concordance between a

allergy and nasal mucosa inflammation. IgE

typical history of allergic symptoms

is produced in the lymphoid tissues and

and diagnostic tests.

locally in the nasal mucosa in response to

The therapeutic strategies of allergic

common environmental allergens. When

rhinitis are patient education,

allergens bind to mast-cell-bound IgE, mast-

pharmacotherapy and allergen-

cell degranulation occurs. Degranulation of

specific immunotherapy.

mast cells results in the release of a myriad

of biochemical mediators that regulate and/

The inflammation of the nasal

or mediate the different aspects of allergic

mucosa may affect the eye mucosa,

inflammation.

air sinuses, the ear and the lower

airways.

Among other preformed mediators,

histamine is released into the surrounding

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ERS Handbook: Paediatric Respiratory Medicine

tissues binding to H1-receptors on various

Late-phase allergic reactions and chronic

target cells and eliciting a powerful allergic

inflammatory changes involve many cell

response (fig. 1). This response is

types including T-cells, mast cells and

characterised by an increase in vascular

eosinophils. Eosinophilic inflammation also

permeability and by stimulation of local

plays an important role. A T-helper (Th)2

nerve endings and mucus-secreting cells.

response ensues with the release of

The clinical manifestations of these

interleukin (IL)-4 and IL-5. Eosinophils are

biological activities include sneezing,

increased in numbers and activated in the

rhinorrhoea, nasal and ocular itching, and

nasal mucosa of symptomatic allergic

red watery eyes. Thus, histamine is the key

patients. They release proinflammatory

player in the acute allergic response.

mediators, including granule-stored cationic

proteins, newly synthesised eicosanoids and

Other important mediator classes involved in

cytokines. The major basic protein (MBP) is

the acute-phase allergic response include

highly cationic and lacks enzymatic activity,

prostaglandins (e.g. PGD2) and leukotrienes

and toxicity is believed to be mediated by

(e.g. LTC₄). Prostaglandins, of which PGD2

enhanced membrane permeability resulting

appears to be the most important, have

from interactions of the cationic protein with

vasodilatory and bronchoconstrictive

the plasma membrane. After allergen

properties. Prostaglandin D2 produces nasal

exposure, rhinitis can persist for several

inflammation in the acute phase, but does not

weeks. In the late phase the predominant

appear to play a key role in chronic

symptom is nasal congestion. Eosinophils

inflammation. Evidence derived from topical

release mediators that can induce tissue

application of cysteinyl leukotrienes (cysLTs)

damage, and pre-treatment with topical

in the nose and from the effects of leukotriene

glucocorticoids reduces eosinophil

receptor antagonists (LTRAs) indicates that

infiltration and cytokine release.

cysLTs contribute to nasal mucous secretion,

Classification

congestion, and inflammation. CysLTs

promote allergic inflammation by enhancing

The classification of allergic rhinitis was

immune responses and the production,

previously based on the time of exposure

adhesion, migration and survival of

into seasonal or perennial. Perennial allergic

inflammatory cells such as eosinophils.

rhinitis is generally caused by indoor

Preformed &

Allergen

Cytokines

newly formed

Chemokines

IgE

mediators/cytokines

Endothelial

Allergen

Mast cell

cell activation

Dendritic cell

Leukocyte

IL-4

T-lymphocyte

infiltration and activation

IL-13

(lymphocytes, eosinophils,

B-lymphocyte

basophils)

Immediate (early)

response

Late-phase

responses

Sneezing

Nasal obstruction

Nasal

Pruritus

Rhinorrheoa

hyperresponsiveness

Rhinorrhoea

IgE

Nasal obstruction

To allergens To irritants and to

Ocular symptoms

(priming) atmospheric changes

Figure 1. The nasal allergic response. Reproduced from Van Cauwenberger et al. (2003) with permission

from the publisher.

ERS Handbook: Paediatric Respiratory Medicine

355

allergens such as dust mites, moulds and

reversible either spontaneously or with

animal danders. Seasonal allergic rhinitis is

treatment include:

most frequently related to pollens or

moulds.

N rhinorrhoea,

N nasal obstruction,

Recently, an expert panel proposed a new

N nasal itching,

classification of allergic rhinitis. In this

N sneezing.

classification allergic rhinitis was divided

into ‘‘intermittent’’ or ‘‘persistent’’ disease

Other concurring symptoms may affect the

and the severity of allergic rhinitis was

eyes such as:

classified as ‘‘mild’’ or ‘‘moderate/severe’’

depending on the severity of symptoms and

N lachrymation,

their impact on social life, school and work

N conjunctivae itching,

(fig. 2).

N swelling.

This classification was proposed in the

Ocular symptoms are common, in

Allergic Rhinitis and its Impact on Asthma

particular in patients allergic to outdoor

(ARIA) guidelines, the first ever evidence-

allergens. Allergic rhinitis due to pollen

based guidelines for allergic rhinitis.

allergy occurs in the relevant seasons and

there are large geographical differences.

Another important aspect of the ARIA

Apart from season and pollen exposure,

guidelines was to consider co-morbidities of

other factors are also important for severity

allergic rhinitis. The eye, ear and lower

of symptoms including the weather: rain

airways are involved in allergic rhinitis.

reduces the exposure and mild wind in dry

Interactions between the lower and the

weather may increase exposure, in addition

upper airways are well known; over 80% of

wind may result in exposure far away from

asthmatics suffer from rhinitis and 10-40%

the source. Perennial allergens may be

of patients with rhinitis have asthma.

house dust mites (HDMs) as well as animal

Diagnosis

danders. The major cat allergen (Fel d 1) is

transported in the air by particles ,2.5 mm

The diagnosis of allergic rhinitis is based on

and can remain airborne for long periods.

the concordance between a typical history of

Fel d 1 is also adherent and can

allergic symptoms and diagnostic tests.

contaminate an entire environment for

Typical symptoms of allergic rhinitis that are

weeks or months after cessation of allergen

Intermittent

Persistent

Symptoms

< 4 days / week

> 4 days / week

or < 4 week

or > 4 week

Mild

Moderate - severe

Sleep: normal

Sleep: disturbed

Daily activities (incl. sports): normal

Daily activities: restricted

Work and school activities: normal

Work and school activities: disturbed

Severe symptoms: no

Severe symptoms: yes

Figure 2. Allergic rhinitis classification. Reproduced from Bousquet et al. (2001).

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ERS Handbook: Paediatric Respiratory Medicine

exposure. HDMs are most often found in

extending across the junction of the lower

bedding, especially in humid environments.

and middle thirds of the bridge of the nose

Since HDM allergy often induces late

named ‘‘nasal crease’’.

reactions, these children often experience

Clinical testing

nasal congestions and may also have

symptoms during the daytime and seldom

Diagnostic tests are based on the

specifically in early morning. Allergic

demonstration of allergen-specific IgE in vivo

rhinitis due to HDM allergy also occurs

or in vitro. A skin prick test (SPT) is

most often in older children, though even

recommended as the ‘‘gold standard’’

young children may have allergic rhinitis

method for the diagnosis of IgE-mediated

and allergy to pollen as well as HDMs.

allergies in allergic rhinitis.

The main symptom of allergic rhinitis

It has advantages of relative high sensitivity

caused by perennial allergens is nasal

and specificity, rapid results, low cost and

congestion whereas conjunctival swelling,

good tolerability. However, the quality of the

itching and watery discharge can occur. The

allergens is very important and only

congestion is a consequence of the

standardised extracts should be used.

inflammation that involves all the upper

Moreover, the skin of very young children

airways. Nasal congestion can result in

may not be as reactive as older children and

chronic mouth breathing, associated with

adults.

the development of a high-arched palate,

upper lip and overbite. As a matter of fact,

In children, the number of allergens to be

children often suffer from a sore throat

tested is limited. The most important

caused by oral respiration. Other symptoms

allergens in early childhood are HDM and

may include: coughing caused by post-nasal

animal dander but in older children pollens

drip, cephalalgy caused by oedema of the

and moulds must be investigated.

nasal mucosa, and hearing impairment

caused by tympanic dysfunction. Sudden

The measurement of allergen-specific IgE in

night awakening and apnoea can affect

serum is available using either radio- or

sleep. Therefore, this alteration of sleep

enzyme-labelled anti-IgE. This test has a

phase can affect the child in their everyday

diagnostic value similar to SPTs but it is

life and activities.

more expensive than the latter. For this

reason the measurement of allergen-specific

In children suffering from allergic rhinitis

IgE in serum is recommended if history of

social problems can occur with

allergic symptoms and SPTs disagree, or in

embarrassing repeated actions, such as

children affected by dermographism or

blowing their nose, grimacing in order to

widespread skin lesions, or during treatment

relieve their nasal itching or producing

by drugs affecting the reactions to SPTs,

‘‘strange noises’’.

such as antihistamines.

Children with allergic rhinitis may have

However, the diagnosis of allergic rhinitis is

swelling and dark discolouration under the

based upon the coordination between a

eyes due to congestion of small blood

typical history of allergic symptoms and

vessels beneath the skin in this area.

diagnostic tests. No diagnosis can be based

In children with persistent allergic rhinitis,

solely on responses to SPTs in in vitro tests

the habitual manipulation of the nose due to

or nasal challenges. In some cases with a

chronic obstruction and itching is typically

very clear history, e.g. with clear seasonal

accomplished by pushing the tip of their

symptoms or mild symptoms and the child

nose with the palm of their hand in an

being well treated on symptomatic

upward motion: this action is known as the

treatment, e.g. antihistamines in normal

‘‘nasal salute’’ or the ‘‘allergic salute’’. This

doses, further diagnosis with SPTs, specific

may result in a persistent transverse

IgE or even nasal challenges may not be

hyperpigmented or hypopigmented line

necessary.

ERS Handbook: Paediatric Respiratory Medicine

357

Recently, the nasal allergen provocation test

rhinitis and asthma as well. Patients allergic

has been needed to identify local allergic

to furred pets may benefit from allergen

rhinitis. This new entity is a localised nasal

avoidance at home, but they may encounter

allergic response in the absence of systemic

allergens on public transportation, and in

atopy characterised by local production of

schools and public places. A systematic

specific IgE antibodies, a Th2 pattern of

review of dust mite allergen avoidance has

mucosal cell infiltration during natural

shown that single measures are not effective

exposure to aeroallergens, and a positive

in reducing symptoms of allergic rhinitis,

nasal allergen provocation test response

although the general consensus is that

with release of inflammatory mediators

allergen avoidance should lead to an

(tryptase and eosinophil cationic protein).

improvement of symptoms. However,

Several non-allergic conditions can mimic

improving air quality by ventilating airtight

allergic rhinitis symptoms, but because

homes to prevent a build-up of biological

management differs in each case, it is very

pollutants and volatile organic compounds

important to differentiate between allergic

(VOCs) may be useful.

rhinitis and non-allergic rhinitis.

Medications used for the treatment of

Management of a child affected by allergic

allergic rhinitis in children are

rhinitis

antihistamines (oral or topical), steroids,

The control of the nasal mucosa allergic

chromones and antileukotrienes, which are

inflammation is the goal of all the

particularly useful when the allergic rhinitis

therapeutic strategies in the management of

is associated with asthma and

allergic rhinitis. The key points of the

immunotherapy.

management of allergic rhinitis are patient

Antihistamines Oral H1-antihistamines are

education, pharmacotherapy and allergen-

effective against symptoms mediated by

specific immunotherapy (fig. 3).

histamine (rhinorrhoea, sneezing, nasal

A lot of perennial allergens have been

itching and eye symptoms) but have nearly

associated with allergic rhinitis, of which

no effect on nasal congestion. Second-

HDM and animal dander are the most

generation antihistamines are preferred and

important. Mould spores can provoke

they may have some, though usually very

Moderate-

severe

Mild

Moderate-

persistent

severe

Mild

intermittent

Intranasal steroid

Oral or local nonsedative H1-blocker

Intranasal decongestant (<10 days) or oral decongestant

Leukotriene receptor antagonists

Avoidance of allergens, irritant and pollutants

Immunotherapy

Figure 3. Management of allergic rhinitis: ARIA guidelines. Reproduced from Bousquet et al. (2001).

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ERS Handbook: Paediatric Respiratory Medicine

mild, sedative effect. The possible anti-

The newer formulations of topical

inflammatory effect of some antihistamines

corticosteroids for allergic rhinitis, such as

is very modest and probably not clinically

ciclesonide, fluticasone furoate and

relevant. Oral H1-antihistamines have been

mometasone furoate, which have less

shown to be safe and effective in children

systemic bioavailability, may be safer for

and also for long-term treatment. Nasal

long-term use. Fluticasone furoate nasal

corticosteroids and oral antihistamines also

spray is a new topical intranasal

result in an improvement of objective

corticosteroid with enhanced affinity for the

measurements of pulmonary function.

glucocorticoid receptor and low systemic

Intranasal antihistamines have been found

exposure, which has recently been approved

in some adult studies to be as effective as

in the USA for the treatment of seasonal or

oral antihistamines, with fewer adverse

perennial allergic rhinitis in adults and in

effects but there are few data in children.

children aged o2 years. In well-controlled

clinical trials, intranasal fluticasone furoate

Corticosteroids The rationale for using

110 mg once daily for 2 weeks in adults and

intranasal corticosteroids in the treatment of

adolescents with seasonal allergic rhinitis

allergic rhinitis is that high drug

reduced nasal and ocular symptoms.

concentrations can be achieved at receptor

sites in the nasal mucosa with a minimal

The treatment of rhinitis reduces asthma

risk of systemic adverse effects. Topical

severity: asthma and allergic rhinitis

corticosteroids stabilise the membranes of

commonly occur together, treatments for

mast cells and exert most of their effects via

one condition could potentially alleviate the

such membranes and partial blocking of the

coexisting condition. The use of nasal

late phase reaction. The current intranasal

corticosteroids in patients with rhinitis and

preparations are well tolerated and can be

asthma reduces not only rhinitis symptoms

used on a long-term basis without atrophy

but also asthma symptoms and airway

of the mucosa. Side-effects are generally

reactivity to methacholine challenge.

mild (crusting, dryness and minor

It should be made very clear that systemic

epistaxis).

treatment with corticosteroids for allergic

rhinitis in children is not standard

Due to their mechanism of action, efficacy

treatment, although a short course with low-

appears after 7-8 h of dosing, but maximum

dose prednisolone in some severe cases can

efficacy may require up to 2 weeks to

be necessary: patients with severe

develop. They are generally safe, and there is

symptoms who do not respond to other

little evidence to support suppression of the

drugs or those who are intolerance to

hypothalamic-pituitary-adrenal axis (HPA

intranasal drugs may need to be treated with

axis) with prolonged use. The safety of

systemic corticosteroids (e.g. prednisolone,

intranasal corticosteroids is particularly

starting dose 10-15 mg?day^-1) for a short

relevant in paediatric and adolescent

period of time.

patients because these agents are widely

used in this population. The effect of

Allergen-specific immunotherapy Allergen-

6 weeks of once-daily treatment with

specific subcutaneous immunotherapy is

beclomethasone dipropionate (BDP) nasal

not usually recommended before the age of

aerosol on HPA-axis function, as measured

5 years. In older children the clinical efficacy

by 24-hour serum cortisol concentrations, in

of allergen-specific immunotherapy is well

adolescent and adult subjects with perennial

established for both rhinitis and asthma.

allergic rhinitis has been evaluated. The

Traditionally, immunotherapy has been

results of this randomised, double-blind,

administered by the subcutaneous route but

placebo- and active-controlled study,

the sublingual route is now available.

indicated that BDP nasal aerosol was not

Subcutaneous specific immunotherapy is

associated with HPA-axis suppression in

burdened with a risk of inducing systemic

adolescent and adult subjects with perennial

side-effects. When treating rhinitis patients,

allergic rhinitis.

the risk of serious anaphylactic reactions is

ERS Handbook: Paediatric Respiratory Medicine

359

rather limited compared to treating asthma

rhinitis are more prone to middle ear otitis

patients. The sublingual route is safer.

and otitis media with effusion. A probable

mechanism is that allergic inflammation in

Allergen-specific immunotherapy is

the respiratory epithelium at the entrance to

recommended for the treatment of patients

and inside the Eustachian tube can result in

with pollen and mite allergy and it may alter

tube dysfunction due to swelling in this

the natural course of allergic diseases.

region and possibly cause a secondary

Indeed, administered to patients with

inflammation in the middle ear. In some

rhinitis, immunotherapy appears to reduce

cases there is a difficulty in the interpretation

the development of asthma (secondary

of the symptoms of nasal occlusion caused

prevention of asthma). The duration of

by allergy and often these symptoms get

immunotherapy is usually 3 years to show

confused by the physical inflammatory cause

long-term efficacy after its cessation.

(e.g. dental malocclusion combined with

adenoidal obstruction).

All these different treatments are to be

modified or combined together depending

Integrated handling of the allergic rhinitis

on the:

may require the prevention of

complications, therefore foreseeing the

N single case,

best treatment through the expertise of an

N age of the subject,

otolaryngologist, surgeon or an

N duration of the symptoms,

orthodontist. Referring a patient for

N causal allergens,

surgical treatment is the only solution in

N seriousness of the clinical symptoms.

order to correct certain anatomical

anomalies of the nasal bones, or removal of

The main goal of the therapy isn’t just

enlarged tonsils or adenoids, only in the

ending the symptoms, but preventing and

case in which, along with the allergic

treating all the possible complications that

inflammation, they aggravate nasal

may affect the structures close to the nasal

obstruction and breathing.

cavities and lower air system.

Numerous studies have demonstrated that

Comorbidities and complications

allergic rhinitis may be a risk factor for both

Allergic rhinitis cannot be considered as an

the onset and the worsening of asthma. The

isolated pathology. The inflammation that

nasal and bronchial mucosa are

affects the nasal mucosa will consequently

characterised by the same pseudo-stratified

affect the eye mucosa, air sinuses, ear and

epithelium and the ‘‘united airways

lower airways.

concept’’ suggests that the respiratory

system functions as an integrated unit.

The chronic exposure to perennial allergens,

Support for this concept can be found in

especially in domestic environments, induces

studies showing that pathophysiological

a gradual nose occlusion that will be very

processes involving the upper airways

subtle in its manifestation, therefore the

generally occur in conjunction with lower

subject will physically adapt to the

airway diseases and that diffuse

symptoms. Permanent signs found in allergic

inflammation often affects the respiratory

rhinitis subjects can be malocclusion or

mucosa at different sites simultaneously.

misalignment of teeth and jaws and

adenoidal face (long face syndrome). For

Finally, in relation to the close connection

subjects affected by allergic rhinitis the co-

between lower and upper airways, the

existence of multiple diverse conditions such

physical examination should always

as deviated septum, nasal turbinate

carefully investigate the breathing condition

dysfunction, sinusitis and adenoid

of the patient and consider lung function

hypertrophy can occur. Moreover, physical

testing. Bronchial hyperreactivity (BHR) is

examination of the allergic rhinitis subject

characteristic of bronchial asthma. Patients

should also include an otoscopic

with allergic rhinitis who do not report

examination. Children affected by allergic

symptoms of bronchial asthma on

360

ERS Handbook: Paediatric Respiratory Medicine

spirometry may show signs of BHR, which

Bousquet J, et al. (2008). Allergic Rhinitis

could indicate the presence of subclinical

and its Impact on Asthma (ARIA) 2008

inflammation of the lower respiratory

update (in collaboration with the World

airway. The presence of bronchial

Health Organization, GA(2)LEN and

hyperresponsiveness and concomitant

AllerGen). Allergy; 63: 8-160.

Bousquet J, et al. (2012). Practical guide

atopic manifestations in childhood

to skin prick tests in allergy to aeroaller-

increases the risk of developing asthma and

gens. Allergy; 67: 18-24.

should be recognised as a marker of

Ciprandi G, et al.

(2011). FEF(25-75)

prognostic significance, whereas the

might be a predictive factor for bronchial

absence of these manifestations predicts a

inflammation and bronchial hyperreactiv-

very low risk of future asthma.

ity in adolescents with allergic rhinitis. Int

Measurement of the exhaled nitric oxide

Immunopathol Pharmacol; 24: 17-20.

fraction (FeNO) may be considered a

Ciprandi G, et al. (2012a). Rhinitis and

surrogate marker for airway inflammation.

lung function in asthmatic children. Clin

Forced expiratory flow at 25-75% of FVC

Exp Allergy; 42: 481-482.

(FEF25-75%) has been previously

Ciprandi G, et al. (2012b). Recent devel-

demonstrated to be able to predict BHR and

opments in united airways disease.

bronchial reversibility.

Allergy Asthma Immunol Res; 4: 171-177.

Ciprandi G, et al.

(2012c). Impaired

Patients with allergic rhinitis due to pollen

FEF25-75

values may predict bronchial

often display adverse reactions upon the

reversibility in allergic children with rhi-

ingestion of plant-derived foods as a result

nitis or asthma. J Biol Regul Homeost

Agents; 26: Suppl. 1, S19-S25.

of IgE cross-reactive epitopes shared by

Ciprandi G, et al.

(2012d). Impaired

pollen and food allergen sources. The

FEF25-75 may predict high exhaled nitric

symptoms of such pollen-food syndromes

oxide values in children with allergic

range from local oral allergy syndrome to

rhinitis and/or asthma. J Biol Regul

severe systemic anaphylaxis. The best

Homeost Agents; 26: Suppl. 6, S27-S33.

known association is between birch pollen

de Benedicitis FM, et al.

(2001).

and a series of fruits (including apple),

Rhinitis, sinusitis and asthma: one linked

vegetables and nuts.

airway disease. Paediatr Respir Rev;

358-364.

Allergic rhinitis can often be a debilitating

Kaliner MA, et al. (2011). The efficacy of

condition which, if untreated, can result in

intranasal antihistamines in the treat-

considerable health-related and economic

ment of allergic rhinitis. Ann Allergy

consequences. For example, numerous

Asthma Immunol; 106: Suppl. 2, S6-S11.

studies have demonstrated that poorly

La Rosa M, et al. (2011). Specific immu-

controlled symptoms of allergic rhinitis

notherapy in children: the evidence. Int J

contribute to decreased health-related

Immunopathol Pharmacol; 24: 69-78.

quality of life (HRQoL), reduced sleep

Leonardi S, et al. (2012). Function of the

quality, daytime fatigue, impaired learning,

airway epithelium in asthma. J Biol Regul

Homeost Agents; 26: 41-48.

impaired cognitive functioning and

Meltzer EO, et al. (2012). Allergic rhinitis

decreased long-term productivity.

substantially impacts patient quality of

life: findings from the Nasal Allergy

Survey Assessing Limitations. J Fam

Further reading

Pract; 61: Suppl. 2, S5-S10.

Blaiss MS, et al.

(2011). Safety update

Miraglia Del Giudice M, et al. (2011a).

regarding intranasal corticosteroids for

Allergic rhinitis and quality of life in

the treatment of allergic rhinitis. Allergy

children. Int J Immunopathol Pharmacol;

Asthma Proc; 32: 413-418.

24: 25-28.

ERS Handbook: Paediatric Respiratory Medicine

361

Miraglia Del Giudice M, et al. (2011b).

Scadding GK, et al. (2008). Fluticasone

Fractional exhaled nitric oxide measure-

furoate nasal spray consistently and

ments in rhinitis and asthma in children.

significantly improves both the nasal

Int J Immunopathol Pharmacol; 24: 29-32.

and ocular symptoms of seasonal allergic

Miraglia del Giudice M, et al.

(2013).

rhinitis: a review of the clinical data.

Exhaled nitric oxide and atopy in children.

Expert

Opin

Pharmacother;

J Allergy Clin Immunol; 111: 193.

2707-2715.

Novembre E, et al. (2004). Co-seasonal

Simons FE, et al. (2004). Advances in H1-

sublingual immunotherapy reduces the

antihistamines. N Engl J Med; 351: 2203-

development of asthma in children with

2217.

allergic rhinoconjunctivitis. J Allergy Clin

Stone KD, et al. (2010). IgE, mast cells,

Immunol; 114: 851-857.

basophils, and eosinophils. J Allergy Clin

Ratner PH, et al. (2012). Once-daily treat-

Immunol; 125: Suppl. 2, S73-S80.

ment with beclomethasone dipropionate

Van Cauwenberger P, et al. (2003). Global

nasal aerosol does not affect hypothalamic-

resources in allergy

(GLORIA): allergic

pituitary-adrenal axis function. Ann Allergy

rhinitis and conjunctivitis. Clin Exp All

Asthma Immunol; 109: 336-341.

Rev; 3: 46-50.

Rondón C, et al. (2012). Local allergic

Vitaliti G, et al. (2012). Mucosal immunity

rhinitis: concept, pathophysiology, and

and sublingual immunotherapy in

management. J Allergy Clin Immunol; 129:

respiratory disorders. J Biol Regul

1460-1467.

Homeost Agents; 26: 85-93.

362

ERS Handbook: Paediatric Respiratory Medicine

Atopic dermatitis

Paolo Meglio, Elena Galli and Nunzia Maiello

Atopic dermatitis (AD) is a chronic/

responsible for the symptoms. Moreover,

relapsing, inflammatory skin disease that

complex interactions between genetic and

can affect 7.5% or more of children and

environmental factors make the clinical

about 1-3% of adults. In children, about

spectrum of AD very variable (fig. 1).

70% of cases start before age 5 years. The

Clinical manifestations, diagnosis and

disease is characterised by recurrent, acute

monitoring

flare-ups on skin that often exhibits chronic

eczematous pruritic skin lesions. Frequently,

AD can present a broad spectrum of

the platform of these manifestations is dry

dermatological manifestations and over

skin. Its impact on the quality of life of

time various diagnostic criteria have been

affected children is high.

proposed. Those of Hanifin and Rajka

(1980), are the most frequently used and

Since the early attempts to clearly and

consist of four major and 23 minor criteria

comprehensively define diagnostic criteria, it

based on consensus reached by experienced

has been evident that AD is a complex,

dermatologists. Even if such criteria are

multifactorial disease. Due to recent

those used most frequently, they are less

advances, we are now aware that an

suitable for use as a diagnostic tool by

impaired skin barrier and complex immune

nonspecialist or primary care doctors, due

dysregulation, sometimes including IgE-

to their complexity. Moreover, they lack

mediated mechanisms, are largely

clinical validation. The UK’s diagnostic

criteria (Williams et al., 1994), introduced

with the aim of perfecting Hanifin and

Key points

Rajka’s criteria, are the best validated and

indicate the six most useful criteria to use

N AD is a multifactorial disease.

when diagnosing AD for children above

The environmental factors interact

2 years of age.

with skin and allergic genetic factors

so that the clinical appearance is

AD may display three clinical aspects. In the

multifaceted and therapy is complex.

acute phase, it manifests itself with vesicular,

weeping and crusting eruptions. In the

Therapy mainstays are emollients,

subacute phase, dry, scaly, erythematous

avoidance of irritants and allergens,

papules that may converge into plaques may

topical anti-inflammatory drugs

be present. Symptoms of chronic AD are dry,

(mainly corticosteroids) and control

lichenified skin with papules and/or nodules

of infections and pruritus.

and signs of scratchmarks (excoriations).

N In a subgroup of children, early and

Pruritus is almost invariably present in all

severe manifestation of AD has been

three phases even if it varies in intensity,

associated with an increased risk of

usually worsening in the early evening and at

asthma (the so-called ‘‘atopic

night. Normally, AD involves the large joint

march’’).

flexures (elbow flexure, wrist joint, popliteal

region), forehead, face, eyelids, anterior and

ERS Handbook: Paediatric Respiratory Medicine

363

Genetic factors

Loss-of-function

Allergic shift

FLG gene

predisposition

(and other structural/

(Th2 polarisation)

functional genes)

Der P and other

Epidermal

Possible co-existing

aeroallergens

barrier functions

food allergy

sensitisation

Direct proteolytic

allergen activity

Allergic and

Therapeutic

(Der p, others)

immunological

options

inflammation

Irritant/allergen

Irritants, allergens,

avoidance

infective agent

Environmental

entry

Emollients

Atopic

factors

Dermatitis

Anti-inflammatories

Humidity,

aggressive

(TCs, TCIs, others)

substances

Control of infections

Control of pruritus

Figure 1. AD is a multifactorial disease that arises from multiple genetic and environmental interactions.

Genetic factors include complex epidermal barrier and immunological defects. Mutations of filaggrin (FLG)

and other structural genes induce damage to epithelial barrier functions. In this way, cutis may become more

permeable to irritants, allergens and infective agents. If an allergic predisposition also exists (T-helper (Th)2

polarisation), potential allergens that come into contact with the skin can provoke an allergic inflammation.

Irritants can further worsen epithelial barrier functions. Moreover, AD cutis is defective in controlling

infections, and Staphylococcus aureus, in particular, may in turn worsen AD. It is now hypothesised that if

the damaged skin of a potential allergic subject comes into contact with a food allergen this can result in food

allergy. Avoiding irritants/allergens, restoring epithelial barrier functions, fighting inflammation and

controlling infections and pruritus are the mainstays of AD therapy. Der p: Dermatophagoides

pteronyssinus allergen; TCs: topical corticosteroids; TCIs: topical calcineurin inhibitors.

lateral neck and the dorsa of the feet and

more extensive, severe forms, with

hands. This distribution can vary from patient

widespread erythrodermic rash.

to patient and can differ according to age.

The distribution of lesions and the typology

Moreover, it should be remembered that all

and severity of AD may vary according to the

these divisions are artificial and that in any

patient’s age and disease activity. During

individual case, acute relapsing of subacute

infancy, AD generally presents more acute

or chronic lesions may occur. Both the

lesions mainly affecting the face, scalp, and

extent and severity may vary. Thus, AD

extensor surfaces of the extremities.

presents a broad clinical spectrum ranging

Bacterial secondary infection

from minor and less severe forms (dry

(impetiginisation) is frequent. In older

depigmented skin, hand eczema) to major,

children and in those with persisting AD,

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ERS Handbook: Paediatric Respiratory Medicine

symmetrical lichenification and localisation

Epidermal barrier dysfunction

of rash to the flexural folds of the

Defects in the epidermal barrier due to

extremities are prominent. The sites of

genetic and/or functional alterations of

predilection are the face, neck, upper chest

structural proteins (filaggrin, loricrin,

and shoulder girdle, large joint flexures and

involucrin) and functional proteins

the back of the hands. Flattened

(proteases and their inhibitors,

inflammatory infiltrated lesions that may be

antimicrobial peptides) play a critical role in

hyperpigmented and have a tendency

the pathogenesis of AD. The most

to confluence, may be a prominent

significant genetic factor is loss-of-function

feature.

mutation found within the filaggrin (FLG)

A useful method to assess the severity of

gene encoding profilaggrin, the ,500-kDa

AD, named SCORAD (from SCORing and

precursor for the structural protein FLG. It is

AD), was developed in the 1990s (European

detected in about 22% of patients with AD

Task Force on Atopic Dermatitis, 1993) and

and is associated with early onset and

has subsequently been validated. To

persistence of the disease. FLG gene

calculate the SCORAD index, extension

mutations are also implicated in immune

dysregulation, as they are associated with

(parameter A), intensity (parameter B) and

increased allergen-specific CD41 T-helper

subjective symptoms (parameter C) must be

(Th)2 cells. Moreover, epidermal

taken into account.

homeostasis is regulated by proteases,

N Extension is graded up to 100 and it is

including kallikreins, which are important for

divided along the entire body according

skin desquamation and the activity of which

to the rule of nines. Slight differences

is tightly controlled by protease inhibitors.

exist between children under or over

Proteolytic activity from allergens (as well as

2 years of age.

possible IgE-linked activity) has been known

N Intensity is graded up to 18, with a

to play a role in the pathogenesis of AD by

severity score (0: no symptoms; 1: mild

directly affecting the structure and function

symptoms; 2: moderate symptoms, 3:

of the epidermal barrier (including the tight

severe symptoms) applied to six items

junctions), thereby facilitating further

(erythema, oedema/papules,

penetration of allergens. This can possibly

scratchmarks, oozing/crust formation,

switch the non-IgE-associated form of AD to

lichenification and dryness).

the IgE-associated form by driving dendritic

N Subjective symptoms are itchiness and

cells to enhance Th2 polarisation. Moreover,

sleeplessness. They are calculated by

in susceptible individuals, allergen-induced

means of two ‘‘visual analogue scales’’

inflammation promotes Th2 and Th17

graded from 0 to 10, with 20 being the

cytokines (interleukin (IL)-17) that in turn

maximum total score.

are able to stimulate keratinocytes to

produce other pro-inflammatory cytokines

At this point, an arithmetical formula

and to downregulate FLG expression or the

considering parameters A, B and C (A/5 + 7B/2

proper processing of profilaggrin.

+ C) is applied in order to obtain the SCORAD

index, which ranges 0-103. Conventionally,

FLG breakdown products, such as urocanic

AD is defined as mild with a SCORAD of ,25,

acid and pyrrolidone carboxylic acid, are

moderate with a SCORAD of 25-50 and

important for maintaining an acidic pH that

severe with a SCORAD of .50. A variant of

plays a critical role in regulating epidermal

this method is the Objective-SCORAD (O-

permeability, barrier homeostasis,

SCORAD), which excludes subjective

epidermal antimicrobial barrier and stratum

symptoms from the evaluation. In this case,

corneum integrity/cohesion, by regulating

the maximum score is 83 (A/5 +7B/2) and AD

the activity of various enzymes including

is defined as mild with an O-SCORAD of ,15,

serine proteases and lipid-processing

moderate with an O-SCORAD of 15-40, and

enzymes. Disorders in FLG expression and

severe with an O-SCORAD of .40.

degradation also result in decreased

ERS Handbook: Paediatric Respiratory Medicine

365

expression of the FLG-derived natural

plausible explanation for nocturnal

moisturising factor in AD skin.

exacerbations.

In the lesions in AD patients, the pH of the

Even if histamine is the best-known

skin has been reported to be significantly

pruritogen in humans, the histamine

raised. This results in a reduced expression

receptor (HR) 1 is unlikely to play a major

of proteins that inhibit colonisation by and

role in AD, as the efficacy of non-sedating

growth of Staphylococcus aureus. Indeed,

antihistamines in this disease is very

S. aureus colonisation and the resulting

limited. Indeed, recent studies showed that

production of toxins are also due to the

the HR4 plays a more important role

decreased production of anti-microbial

inducing Th2 cell increases and IL-31

peptides (defensins and cathelicidins),

production, another important itch inducer

which are downregulated by the

in AD, particularly in severe forms.

inflammatory AD micro-milieu. Decreased

Moreover, the expression of IL-31’s

serum levels of the cathelicidin LL-37 have

heterodimeric receptor (IL-31R) can be

been observed in patients with AD,

induced or upregulated in keratinocytes,

correlating to decreased vitamin D levels.

monocytes, macrophages or dendritic cells

Inflammation is further amplified by S.

by microbial factors (S. aureus superantigens

aureus toxins that aggravate the defects in

and exotoxins, Toll-like receptor (TLR)

the epidermal barrier (ceramidase) and

agonists), as well as endogenous mediators

induce IL-17 production by T-cells. Other

of inflammation (proteases, such as trypsin,

tryptase, cathepsins, kallikreins, PAF,

negative effects of S. aureus colonisation are

prostaglandins, opioid peptides), including

to upregulate the expression of the skin-

interferon (IFN)-c.

homing receptor cutaneous lymphocyte-

associated antigen on T-cells (CLA) and

Even if skin lesions in AD often result in

induced thymic stromal lymphopoietin

increased density of the peripheral nerve

(TSLP) that is able to activate dendritic cells

fibres, including substance P-positive nerve

with subsequent proliferation of naive CD4⁺

fibres, the central sensitisation of itch-

T-cells and their differentiation into Th2 cells

signalling systems seems to be a key feature

producing the inflammatory cytokines IL-4,

of chronic pruritus in AD because of

IL-5 and IL-13, and Th17/Th22 cells

sensitisation of the spinal neurons in the

producing IL-22 that is able to induce

dorsal horn, which leads to greater

epithelial proliferation, possibly causing the

sensitivity to pruritic input. Two forms of

thickened AD epidermis. Finally, S. aureus-

central sensitisation are associated with

specific IgE, generated by the immune

pruritus: allokinesis and punctate

system, can bind to FceRI receptors on

hyperkinesis. Allokinesis is observed when

dendritic cells and initiate an IgE-mediated

touch- or brush-evoked itch occurs around

reaction to this microbe.

an itching site. This is commonly seen in

children with AD, where sweating, sudden

Pruritus

changes in temperature, contact with fabrics

Pruritus (or itching) is the diagnostic

and dressing and undressing induce severe

hallmark of AD and has a significant impact

pruritus. Punctuate hyperkinesis consists of

on quality of life including agitation, anxiety,

an intense itching sensation in the area

changes in eating habits, poor self-esteem,

surrounding histamine induction. Stress

difficulty concentrating, and depression.

may also induce or aggravate itch in AD with

Pruritus generally leads to scratching, which

a neurogenic mechanism involving

further damages the skin barrier function, so

neuropeptides.

worsening inflammation (‘‘itch-scratch

Immunological dysregulation and link to

cycle’’). Patients with AD are often unaware

allergic diseases

of the extent to which they are scratching,

especially during the night when increased

Allergic diseases frequently coexist with AD.

transepidermal water loss may provide a

A significant association between early food

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ERS Handbook: Paediatric Respiratory Medicine

sensitisation and AD has been found,

of asthma, suggesting that AD can be the

especially at an early age. Food allergy,

first step in the so-called ‘‘atopic march’’.

which is generally the result of failure to

Like AD, asthma is also a complex genetic

develop tolerance, or the loss of pre-existing

and multifactorial disorder with high

tolerance, may be caused by defects in

prevalence in the paediatric population,

immune or nonimmune intestinal barriers

largely attributable to the interactions

(e.g. a defective digestive process or

between multiple genes and the environ-

abnormalities in the development of

ment. According to some longitudinal

regulatory T-cells, soluble IgA, Peyer’s

prospective studies, the relationship

plaques, and associated dendritic cells).

between AD and the subsequent onset of

Moreover, perturbation of the skin barrier

asthma is more evident if children with AD

allows allergen penetration that in turn

have a parental history of asthma, have had

triggers the activation of Langerhans cells,

a severe, early onset of AD and if atopic

facilitating the subsequent uptake of

sensitisations exist. Thus, the atopic march

antigens through the tight junction barrier of

is not a general phenomenon as it affects

the epidermis. The Langerhans cells then

only a subgroup of children with AD, in

presumably migrate to draining lymph

whom it is supposed that an FLG gene null

nodes and activate antigen-specific T-cells.

mutation allows the skin to be attacked by a

This can lead to Th2 responses and IgE

range of factors (irritants, allergens, house

production by B-cells. In humans, food

dust mites or S. aureus proteases) thereby

allergen-specific T-cells have been isolated

predisposing such children to developing

from lesional skin in patients with eczema.

asthma.

It is proposed that in some individuals,

Therapeutic options

allergic sensitisation to food may occur

through low-dose cutaneous sensitisation

Treatment of AD is aimed at suppressing

and that early consumption of food protein

inflammation, restoring the skin barrier and

induces oral tolerance. The timing and

controlling itching. Various strategies and a

balance of cutaneous and oral exposure

broad number of treatments are available

determines whether a predisposed child has

that can help achieve these goals. Optimal

allergy or tolerance. This suggestion rises

management is tailored to the patient and

from studies in which preschool children

often involves multimodal strategies. Patient

with low-dose exposure to peanut in the

education to maximise compliance is

form of arachis oil applied to inflamed skin

essential.

had an increased risk of peanut allergy at

Avoidance of irritants and allergens Irritants

age 5 years. Randomised controlled trials

that worsen eczema should be assessed

supporting this hypothesis are expected

during medical evaluations. Textiles made of

soon. The grounds for this phenomenon

silver-loaded, seaweed-based cellulosic

come from animal models where it has

fibers have been shown to significantly

been shown how sensitisation to ovalbumin

reduce S. aureus colonisation without

(measured by sIgE production) occurs

affecting the normal flora, and to decrease

through epicutaneous exposure, following

trans-epidermal water loss in patients with

the removal of the stratum corneum or if

mild-to-moderate AD. Exposure to passive

the skin barrier is genetically impaired. This

smoking, extreme temperatures and bright

was not seen in mice exposed to ovalbumin

sunlight should be avoided. Preventing

via intraperitoneal injection. This

contact with the house dust mite may be

assumption is reinforced by the fact that

useful if there is sensitisation, but also to

ovalbumin allergy has been demonstrated

prevent the proteolytic and irritative

in a murine model for loss-of-function

properties of mites. In very selected cases,

mutations in the FLG gene.

especially if a certain food has been shown

The atopic march Early manifestation of AD

to cause immediate or very severe reactions,

has been associated with an increased risk

an elimination diet may be proposed.

ERS Handbook: Paediatric Respiratory Medicine

367

Emollients Measures to restore the

There is a need to address concerns

dysfunction of the skin barrier should be

regarding so-called ‘‘steroid phobia’’, which

considered as first-line therapy, essential for

constitutes a barrier to TC use. Exaggerated

effective treatment and prevention. For

fear and inappropriate withholding of TCs by

patients with mild-to-moderate eczema,

patients, pharmacists, caregivers and the

topical therapy may be sufficient to control

general community are significant barriers

disease activity. Emollients may contain

to successful management of AD.

both occlusive substances that provide a

Topical calcineurin inhibitors Topical

lipid layer on the surface of the skin to slow

calcineurin inhibitors (TCIs) work by

water loss and increase moisture content in

inhibiting the phosphatase activity of

the skin, and humectants, which are

calcineurin, blocking the expression of

substances introduced into the stratum

cytokines. They act ‘‘downstream’’ in the

corneum to increase its moisture-retaining

glucocorticoid receptor pathway and thus

capacity. They may be applied several times

are thought to represent a more targeted

a day, especially after bathing, and their

way to contain inflammation and avoid

continued use during quiescence can reduce

possible adverse effects of topical

the tendency for eczema flares.

corticosteroids. Tacrolimus and

Topical corticosteroids Topical

pimecrolimus may be used either as a

corticosteriods (TCs), of the appropriate

monotherapy or as a combination or

potency and duration, remain the

sequential therapy. The labelled indication is

cornerstone of AD therapy for acute flare-

for application twice daily for up to 6 weeks

ups, insofar as they have anti-inflammatory,

as a second-line therapy for adults and

immunosuppressive and vasoconstrictive

children aged .2 years of age exhibiting an

properties and inhibit fibroblast activity. TCs

inadequate response or adverse effects to

are divided into seven classes based on

topical corticosteroids.

potency, where class I is the strongest, and

Treatment of skin infection Improving

class VII the weakest. Commonly used

eczema with an anti-inflammatory regimen

options include low-potency (class VI and

(TCs, TCIs) decreases staphylococcal

VII; e.g. hydrocortisone), mid-potency (class

colonisation, but patients with high

III-V; e.g. triamcinolone, mometasone,

numbers of colonising S. aureus may require

fluticasone) and high-potency (class I and II;

e.g. fluocinonide, desoximetasone,

a short-term topical treatment with topical

betamethasone dipropionate, clobetasol)

antiseptics and/or topical antibiotics. In

severe exacerbations, systemic antibiotic

TCs. For the management of flare-ups, the

therapy may be helpful. Mycosis,

use of mid-to-high potency TCs once/twice

dermatophytosis, streptococcal or viral

daily for up to 5 days/2 weeks (on the trunk

infections should be treated only if present.

and extremities) is generally recommended.

Lower-potency steroids are recommended

Ancillary therapy Oral sedating and

on the face, in young children or as a

nonsedating antihistamines have a limited

maintenance therapy. Steroid potency may

role in the treatment of AD. Leukotriene

be increased to control inflammation and

receptor antagonists have not been developed

once control is gained, TCs should be

for regular therapy of AD. Probiotics have

suspended or used intermittently. Recently

been studied extensively to define their role in

this approach has been challenged by the

the treatment and prevention of AD in

proactive treatment concept that consists of

children. Unfortunately, the results are varied

a combination of predefined, long-term, low-

and, to date, inconclusive.

dose, anti-inflammatory treatment applied

to previously affected areas, in combination

Complementary and alternative therapies

with liberal use of emollients. Twice-weekly

There is evidence of growing interest in the

application of fluticasone has been shown to

use of complimentary alternative medicine

significantly reduce the risk of relapses of

to treat AD, such as Chinese herbal

eczema in a proactive strategy.

medicine, essential fatty acids,

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ERS Handbook: Paediatric Respiratory Medicine

phytotherapy, homoeopathy, acupuncture,

Glazenburg EJ, et al. (2009). Efficacy and

bio-resonance, salt baths, and vitamins

safety of fluticasone propionate 0.005%

(especially vitamin D, if a low level/intake is

ointment in the long-term maintenance

documented) and minerals. To date, there is

treatment of children with atopic derma-

no evidence to support the use of

titis: differences between boys and girls?

complementary alternative therapies in

Pediatr Allergy Immunol; 20: 59-66.

routine treatment.

Hanifin JM, et al.

(1980). Diagnostic

features of atopic dermatitis. Acta Derm

Systemic therapies Systemic agents are

Venereol; 92s: 44-47.

generally reserved for persistent, widespread

Kanda N, et al. (2012). Decreased serum

and severe AD that is unresponsive to other

LL-37

and vitamin D3 levels in atopic

therapies. Such patients should be treated

dermatitis: relationship between IL-31 and

by experienced specialists and therapies

oncostatin M. Allergy; 67: 804-812.

include corticosteroids, cyclosporine,

Krakowski AC, et al. (2008). Management

methotrexate, azathioprine, mycophenolate

of atopic dermatitis in the pediatric

mofetil and, more recently, biological agents

population. Pediatrics; 122: 812-824.

(soluble receptors, monoclonal antibodies,

Kubo A, et al. (2012). Epidermal barrier

dysfunction and cutaneous sensitization in

intravenous immunoglobulin and cytokines

atopic diseases. J Clin Invest; 122: 440-447.

such as recombinant interferon, TNF and

McPherson T, et al. (2010). Filaggrin null

IgE/IL-5 pathway inhibitors).

mutations associate with increased fre-

quencies of allergen-specific CD41

T-

Phototherapy Ultraviolet therapy can be a

helper

cells in patients with atopic

useful treatment for recalcitrant AD.

eczema. Br J Dermatol; 163: 544-549.

Oranje AP, et al. (2007). Practical issues

on interpretation of scoring atopic der-

Further reading

matitis: the SCORAD index, objective

Barker JN, et al. (2007). Null mutations in

SCORAD and the three-item severity

the filaggrin gene (FLG) determine major

score. Br J Dermatol; 157: 645-648.

susceptibility to early-onset atopic der-

Ring J, et al.

(2012). Guidelines for

matitis that persists into adulthood. J

treatment of atopic eczema. Part I. J Eur

Invest Dermatol; 127: 564-567.

Acad Dermatol Venereol; 26: 1045-1060.

Chahine BG, et al. (2010). The role of the

Rubel D, et al. (2013). Consensus guide-

gut mucosal immunity in the develop-

lines for management of atopic dermatitis:

ment of tolerance versus development of

An Asia-Pacific perspective. J Dermatol;

allergy to food. Curr Opin Allergy Clin

40: 160-171.

Immunol; 10: 394-399.

Schneider L, et al. (2013). Atopic derma-

Denby KS, et al. (2012). Update on systemic

titis: A practice parameter update 2012.

therapies for atopic dermatitis. Curr Opin

J Allergy Clin Immunol; 131: 295-299.

Allergy Clin Immunol; 12: 421-426.

Spergel JM (2010). From atopic derma-

Dirven-Meijer PC, et al.

(2008).

titis to asthma: the atopic march. Ann

Prevalence of atopic dermatitis in chil-

Allergy Asthma Immunol; 105: 99-106.

dren younger than 4 years in a demar-

Valdman-Grinshpoun Y, et al.

(2012).

cated area in central Netherlands: the

Barrier-restoring therapies in atopic derma-

West Veluwe Study Group. Br J Dermatol;

titis: current approaches and future per-

158: 846-847.

spectives. Dermatol Res Pract; 2012: 923134.

Elias PM, et al. (2008). Basis for the barrier

Williams HC, et al.

(1994). The U.K.

abnormality in atopic dermatitis: Outside-

Working Party’s Diagnostic Criteria for

inside-outside pathogenic mechanisms. J

Atopic Dermatitis. I. Derivation of a

Allergy Clin Immunol; 121: 1337-1343.

minimum set of discriminators for

European Task Force on Atopic

atopic dermatitis. Br J Dermatol;

131:

Dermatitis

(1993). Severity scoring of

383-396.

atopic dermatitis: the SCORAD Index.

Yosipovitch G, et al. (2003). Itch. Lancet;

Dermatology; 186: 23-31.

361: 690-694.

ERS Handbook: Paediatric Respiratory Medicine

369

Food allergy

Alessandro Fiocchi, Lamia Dahdah and Luigi Terracciano

Food allergy is an ‘‘adverse health effect

foods cause the majority of allergic

arising from a specific immune response

reactions: peanuts, tree nuts, eggs, milk,

that occurs reproducibly on exposure to a

fish, crustacean shellfish, wheat and soy

given food’’ (Boyce et al., 2010). This

(Boyce et al., 2010).

definition of food allergy includes IgE-

Symptoms of food allergy (table 2) can occur

mediated and non-IgE-mediated immune

within minutes to hours of ingesting the

responses, or a combination of both, and is

trigger food and can vary in severity from

in agreement with recent international

mild to life threatening. Co-factors of

guidelines (Urisu et al., 2011; Fiocchi et al.,

severe allergic reactions include co-

2010a; Sackeyfio et al., 2011) and statements

ingestion of other foods, exercise and

(Burks et al., 2012). Table 1 shows specific

comorbid conditions. Food-induced

food-induced allergic conditions on the

anaphylaxis is the most serious, potentially

basis of pathophysiology, with particular

lethal allergic reaction. Fatalities are

emphasis on respiratory manifestations.

primarily reported from allergic reactions to

peanuts and tree nuts.

Food allergens can cause reactions when

ingested, touched or inhaled. Cross-

The natural history of food allergy resolution

reactivity can occur when a food allergen has

is variable and some patients reach

structural or sequence similarity with a

tolerance (i.e. they develop a specific

different food allergen or aeroallergen. More

nonreactivity to the food). The time courses

than 170 foods have been reported to cause

appear to be influenced by several factors.

IgE-mediated reactions but a minority of

N Age of development: food allergy that

starts in adulthood often persists.

N Type of food: allergy to milk, eggs, soy or

Key points

wheat is more likely to be outgrown than

allergy to fish, shellfish, tree nuts or

N Food allergy is on the rise especially in

peanuts.

children.

N Level of IgE: patient with high specific IgE

Its symptoms may include respiratory

level by ImmunoCAP assay (Quest

complaints.

Diagnostics, Madison, NJ, USA) are at

risk of persistence (Fiocchi et al., 2008).

N The presence of asthma is a negative

N Size of skin-prick test (SPT) wheal: but in

prognostic factor for anaphylactic

some cases, SPT responses remain

reactions.

positive long after tolerance has

Severe asthma may be associated with

developed.

food allergy.

N IgE patterns: the epitope-binding profile

of IgE might help to predict the clinical

N Currently, the treatment for food

course of food allergy (Wang et al., 2010).

allergy treatment is avoidance, but

OIT is a promising new approach.

Prevalence determined on the basis of

patient self-report is higher than that

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Food allergy conditions associated with respiratory complaints

Key features

Common triggers

IgE mediated (acute onset)

Anaphylaxis

Rapidly progressive, multiple

Peanut

organ system reaction up to

Tree nuts

cardiovascular collapse

Fish

Aggravated by co-existing

Shellfish

asthma

Milk

Egg

Food-dependent, exercise-induced

Food triggers anaphylaxis only if

Wheat

anaphylaxis

ingestion followed temporally by

Shellfish

exercise

Celery

May be confused with exercise-

Moulds

induced asthma

Combined IgE and cell mediated (delayed/

chronic onset)

Eosinophilic oesophagitis

Symptoms may include feeding

Multiple

disorders, reflux symptoms

including cough, vomiting,

dysphagia and food impaction.

Food-induced asthma

Asthma induced by food

Cow’s milk

ingestion/inhalation (e.g.

Wheat

bakers’ asthma)

Food-induced rhinitis

Rhinitis induced by food

Cow’s milk

ingestion/inhalation

Tree nuts

Peanut

Cell mediated (delayed/chronic onset)

Heiner syndrome

Pulmonary infiltrates

Cow’s milk

Failure to thrive

Iron-deficiency anaemia

determined by clinical testing and medical

Prevalence rates of admissions for food

history. In general, food allergy affects more

anaphylaxis in Australia increased by 350%

than 1-2% but ,10% of the population (Keil

between 1994 to 2005, and rates of increase

et al., 2010). It seems that prevalence is

were greater for children ,4 years of age and

rising: a large population-based study of

for peanut and tree nut anaphylaxis, with

challenge-proven food allergy in 12-month-

more modest increases noted for older age

old infants in Australia reported prevalences

groups and other allergies such as cow’s

of 3% for peanut allergy, 8.9% for egg allergy

milk or egg.

and 0.8% for sesame allergy (Osborne et al.,

2011). The prevalence of food allergy

Food allergy symptoms include:

appears to have increased in recent years.

Self-reported survey data in the USA

N food refusal in young children,

suggested there has been an 18% increase in

N skin symptoms (urticaria, angio-oedema,

food or digestive allergies from 1997 to

erythema, itching and eczema),

2007, and Chinese paediatricians reported

N gastrointestinal tract symptoms

an increased rate of challenge-confirmed

(oropharyngeal tingling and burning, oral

food allergy from 3.5% in 1999 to 7.7% in

allergy syndrome, vomiting, and

2009

(p50.017) (Chen et al., 2011).

abdominal pain),

ERS Handbook: Paediatric Respiratory Medicine

371

Table 2. Symptoms of food-induced allergic reactions

Target organ

Immediate symptoms

Delayed symptoms

Cutaneous

Erythema

Pruritus

Flushing

Urticaria

Pruritus

Morbilliform eruption

Angio-oedema

Angioedema

Eczematous rash

Ocular

Pruritus

Conjunctival erythema

Tearing

Periorbital oedema

Upper respiratory

Nasal congestion

Pruritus

Rhinorrhoea

Sneezing

Laryngeal oedema

Hoarseness

Dry staccato cough

Lower respiratory

Cough

Chest tightness

Dyspnoea

Wheezing

Intercostal retractions

Accessory muscle use

Gastrointestinal (oral)

Lip oedema

Tongue swelling

Oral pruritus

Gastrointestinal (lower)

Nausea

Reflux

Colicky abdominal pain

Abdominal pain

Vomiting

Haematochezia

Diarrhoea

Vomiting

Diarrhoea

Cardiovascular

Tachycardia

Hypotension

Dizziness

Loss of consciousness

Reproduced and modified from Boyce et al. (2010) with permission from the publisher.

N airway symptoms (persistent cough,

and non-IgE-mediated food allergy

hoarse voice, wheeze, stridor and

syndromes present with predominantly

respiratory distress), and

abdominal symptoms (vomiting, diarrhoea,

N disturbances of the circulatory system

pain and haematochezia) that develop

(pale and floppy infant or young child,

several hours after ingestion of the food.

hypotension, or collapse).

Neither medical history alone not physical

IgE-mediated symptoms develop within

examination is diagnostic of food allergy

minutes to an hour of ingesting the food. In

(Boyce et al., 2010). IgE-mediated food

contrast, non-IgE-mediated and mixed IgE-

allergies require the presence of specific IgE

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ERS Handbook: Paediatric Respiratory Medicine

to confirm a diagnosis. These can be

of immediate allergic reaction and

identified by SPT or by immunoassays of

anaphylaxis is high and cannot be calculated

serum levels of specific IgE. SPT can be

a priori. An absolute contraindication to

performed using standardised extracts or, in

challenge procedures is a recent

case of fruit and vegetables, fresh products.

anaphylactic reaction: if a patient had a

These tests identify sensitisation to foods

reaction to a known food, they should not

that may provoke IgE-mediated reactions

undergo a challenge with that food.

but neither is directly diagnostic of food

Food allergy and respiratory disease

allergy, nor is, despite many attempts, the

patch test with foods. The test results must

Children with food allergy have a four-fold

be reviewed against the clinical history

increased likelihood of having asthma and

(Boyce et al., 2010; Fiocchi et al., 2010b). For

3.6-fold increased likelihood of respiratory

non-IgE-mediated or mixed IgE-mediated

allergies compared with children without

and non-IgE-mediated food allergies, the

food allergy (Branum et al., 2009). Allergic

situation is even more complex: in these

rhinitis, in particular, has been reported in

cases, no laboratory tests can assist the

children allergic to peanuts, tree nuts or

clinician, and the diagnosis relies upon an

milk. Food is rarely a trigger for exacerbation

elimination/reintroduction challenge diet

of symptoms in asthma (,2% of patients

with the suspected food.

with asthma) but may be an important co-

factor in severe asthma (Roberts et al.,

Although serum concentrations of specific

2003). Conversely, the presence of asthma is

IgE and SPT wheal sizes generally correlate

a risk factor for fatal anaphylaxis and longer

with the likelihood of a clinical reaction, they

persistence of food allergy (Fiocchi et al.,

do not correlate with or predict the severity of

2008). It is therefore important to evaluate

allergic reaction to the food (Sampson,

the possible presence of asthma in patients

2001). The availability of recombinant

with food allergy and to keep it under

allergen-specific IgE tests against the major

adequate control. It seems that ongoing

allergens in a food (e.g. Arah2 in peanuts,

airway inflammation (increased exhaled

Bosd8 in cow’s milk and Gald2 in eggs) has

nitric oxide levels) may persist in children

paved the way for improving the diagnosis of

with food allergy even after asthma is

clinical allergy but the exact use of these tests

thought to have resolved (Kulkarni et al.,

is still to be studied (Fiocchi et al., 2011).

2012). Such persistent airway inflammation

might be important in the evolution of

The double-blind, placebo-controlled food

respiratory symptoms after food allergen

challenge (DBPCFC) is the most specific test

exposure, even in children whose previously

for identifying a true food allergy. It reliably

clinically relevant asthma has been

distinguishes sensitisation from clinical

apparently quiescent recently.

allergy. Ideally, the challenge is performed as

a double-blind procedure; however, it is

Treatment

time- and labour-intensive, and many health

systems do not reimburse it. For these

For IgE-mediated, non-IgE-mediated, and

reasons, single-blind or open-food

mixed IgE-mediated and non-IgE-mediated

challenges often replace the DBPCFC in

food allergy syndromes, the first-choice

everyday clinical practice and may be

therapy is avoiding the causal food(s)

considered diagnostic under certain

(Boyce et al., 2010). Patients should be

circumstances. They contribute to food

instructed on the interpretation of ingredient

allergy diagnosis in young children or in

labels to avoid their specific allergens.

presence of objective (rather than

However, even in children with severe food

subjective) symptoms. However performed,

allergy, avoidance of responsible foods may

a food challenge must be done in a medical

be difficult to maintain and accidental

facility with onsite medical supervision and

ingestion may occur. Therefore, patients at

appropriate resources for emergency

risk for anaphylaxis should be provided with

management of allergic reactions. The risk

an emergency action plan indicating signs

ERS Handbook: Paediatric Respiratory Medicine

373

and symptoms of mild-to-moderate and

to induce immunological tolerance,

severe reactions. These plans can guide

however, remains uncertain and the

medical personnel in treatment, including

approach is plagued with the risk of severe

how and when to administer adrenaline if an

reactions. Given the overall very low quality

autoinjector is prescribed (Simons et al.,

of the evidence and very imprecise estimates

2012).

of the effects, the true effect of OIT in

patients with food allergy is unknown.

Adrenaline is the mainstay of the treatment

Consequently, today, patients and clinicians

of anaphylaxis (i.e. acute, severe, systemic

willing to avoid possibly serious adverse

allergic reactions). Antihistamines can be

effects are likely to continue the elimination

used to manage symptoms of nonsevere

diet and re-evaluate the possibility of oral

allergic reactions (Boyce et al., 2012). As

immunotherapy when more robust and

biphasic reactions may occur in up to 20%

precise data are available. Those determined

of cases, patients who receive adrenaline for

to achieve tolerance and who are less

a food-induced anaphylactic reaction should

worried about possibly serious adverse

be immediately admitted to an emergency

effects may choose to undergo

facility for observation. Systemic

immunotherapy with foods (Broz˙ ek et al.,

corticosteroids are also often recommended

2012). Thus, OIT is not yet appropriate for

to prevent biphasic or protracted

widespread use.

anaphylactic reactions but the evidence

beyond their use is thin (Simons et al.,

Treatments using modified antigens,

2012). For most patients who have

epicutaneous administration of allergens or

experienced anaphylaxis, observation for 4-

Chinese herbal therapy could also represent

6h is in order. Patients with severe or

safe and efficient alternatives in the future.

refractory symptoms require prolonged

Additionally, treatment with anti-IgE

observation or hospital admission.

monoclonal antibodies may increase

threshold doses needed to stimulate an

Food allergy is a quality-of-life disruptor:

allergic reaction and provide enhanced

anxiety can arise from the perceived risk of

safety profiles for patients. Probiotics, widely

anaphylaxis and the burden of allergen

used for food allergy, deserve further

avoidance. The caregivers of these children

evaluation (Fiocchi et al., 2012). Recent

are also anxious, and intra- and interfamilial

reports about anaphylaxis to

relationships can be heavily influenced by the

galactooligosaccharides cast a shadow on

disease (King et al., 2009). Education related

the possibility of use of prebiotic fibres in

to managing food allergy may improve

the prevention and treatment of food allergy

patient and caregiver self-efficacy, quality of

(Chiang et al., 2013).

life, and successful allergen avoidance.

Oral immunotherapy

Further reading

Boyce JA, et al. (2010). Guidelines for the

Strict avoidance of allergens is not curative

diagnosis and management of food

and the patients remain at risk of accidental

allergy in the United States: report of

exposure. For this reason, several new

the NIAID-sponsored expert panel. J

therapeutic approaches are being tested in

Allergy Clin Immunol; 126: S1-S58.

clinical trials, but none is ready for clinical

Branum AM, et al. (2009). Food allergy

care (Nowak-We˛ grzyn et al., 2011). Systemic,

among children in the United States.

subcutaneous immunotherapy has been

Pediatrics; 124: 1549-1555.

investigated in the past but gave severe

Broz˙ ek JL, et al. (2012). Oral immunother-

adverse effects. Newer forms of therapy (e.g.

apy for IgE-mediated cow’s milk allergy: a

immunotherapy) have sought to provide

systematic review and meta-analysis. Clin

systemic treatment with reduced risk and

Exp Allergy; 42: 363-374.

side-effects. For a variety of food allergens,

Burks AW, et al. (2012). ICON: Food allergy.

oral immunotherapy (OIT) is able to reduce

J Allergy Clin Immunol; 129: 906-920.

clinical reactivity in some patients. Its ability

374

ERS Handbook: Paediatric Respiratory Medicine

Chen J, et al. (2011). The prevalence of food

Kulkarni N, et al.

(2012). Eosinophilic

allergy in infants in Chongqing, China.

airway inflammation is increased in

Pediatr Allergy Immunol; 22: 356-360.

children with asthma and food allergies.

Chiang WC, et al. (2012). Anaphylaxis to

Pediatr Allergy Immunol; 23: 28-33.

cow’s milk formula containing short-

Nowak-We˛ grzyn A, et al.

(2011). Future

chain galacto-oligosaccharide. J Allergy

therapies for food allergies. J Allergy Clin

Clin Immunol; 130: 1361-1367.

Immunol; 127: 558-557.

Fiocchi A, et al.

(2008). Incremental

Osborne NJ, et al. (2011). Prevalence of

prognostic factors associated with cow’s

challenge-proven IgE-mediated food

milk allergy outcomes in infant and child

allergy using population-based sampling

referrals: the Milan Cow’s Milk Allergy

and predetermined challenge criteria in

Cohort study. Ann Allergy Asthma

infants. J Allergy Clin Immunol;

127:

Immunol; 101: 166-173.

668-676.

Fiocchi A, et al. (2010a). Diagnosis and

Roberts G, et al. (2003). Food allergy as a

Rationale for Action Against Cow’s Milk

risk factor for life-threatening asthma in

Allergy (DRACMA): a summary report. J

childhood: a case-controlled study. J

Allergy Clin Immunol; 126: 1119-1128.

Allergy Clin Immunol; 112: 168-174.

Fiocchi A, et al. (2010b). World Allergy

Sackeyfio A, et al. (2011). Diagnosis and

Organization

(WAO) Diagnosis and

assessment of food allergy in children

Rationale for Action against Cow’s Milk

and young people: summary of NICE

Allergy

(DRACMA) guidelines. World

guidance. BMJ; 342: d747.

Allergy Organ J; 3: 57-61.

Sampson HA (2001). Utility of food-

Fiocchi A, et al. (2011). The fascinating

specific IgE concentrations in predicting

world of molecular diagnosis in the

symptomatic food allergy. J Allergy Clin

management of food allergy: nondum

Immunol; 107: 891-896.

matura est. Curr Opin Allergy Clin

Simons FE, et al. (2012). 2012 Update:

Immunol; 11: 200-203.

World Allergy Organization Guidelines for

Fiocchi A, et al. (2012). Clinical Use of

the assessment and management of

Probiotics in Pediatric Allergy (CUPPA): a

anaphylaxis. Curr Opin Allergy Clin

World Allergy Organization position

Immunol; 12: 389-399.

paper. World Allergy Organ J; 5: 148-167.

Urisu A, et al. (2011). Japanese guideline

Keil T, et al.

(2010). The multinational

for food allergy. Allergol Int; 60: 221-236.

birth cohort of EuroPrevall: background,

Wang J, et al. (2010). Correlation of IgE/

aims and methods. Allergy; 65: 482-490.

IgG₄ milk epitopes and affinity of milk-

King RM, et al. (2009). Impact of peanut

specific IgE antibodies with different

allergy on quality of life, stress and

phenotypes of clinical milk allergy. J

anxiety in the family. Allergy; 64: 461-468.

Allergy Clin Immunol; 125: 695-702.

ERS Handbook: Paediatric Respiratory Medicine

375

Allergic bronchopulmonary

aspergillosis

Andrew Bush

Unlike in adults and for reasons which are

N Ensure that atypical forms of CF have

not clear, allergic bronchopulmonary

been excluded. Even if the sweat test is

aspergillosis (ABPA) in children is virtually

unequivocally normal, genetic testing and

always seen in the context of CF. ABPA

measurement of transepithelial potential

complicating paediatric asthma has only

differences should be considered.

been the subject of isolated case reports.

N Consider alternative differential

Other, even more rarely, reported

diagnoses, such as mucus plugging and

associations in children include hyper IgE

atelectasis, gastro-oesophageal reflux

syndrome, chronic granulomatous disease,

disease, eosinophilic or other

bronchocentric granulomatosis, previous TB

noninfective pneumonias, and collagen

and treatment of sarcoidosis with infliximab.

vascular disease.

In adults, it has been described in

N Consider the possibility of the rare

association with COPD. Unsurprisingly, late

associations mentioned above.

diagnosis after a prolonged clinical course is

common in this rare setting. If ABPA is

Aspergillus fumigatus is ubiquitous in the

suspected in the context of another

environment. Two features make it

paediatric respiratory illness, three steps are

particularly prone to infect the human lower

essential.

airway.

N The spores have a mass median diameter

in the range of 2-5 mm, meaning that

they are the ideal size for impacting in the

lower airway.

Key points

N They grow at 37uC, i.e. body temperature.

N Unlike in adults where asthma with

However, an ABPA-like picture has rarely

ABPA is common, ABPA is rarely seen

been reported as being caused by other

in children other than complicating

fungi, for example other strains of

CF.

Aspergillus, and non-Aspergillus species such

In the context of CF, ABPA is difficult

as Scedosporium apiospermum. These are not

to diagnose because it mimics CF

covered further in this chapter.

lung disease.

Manifestations of A. fumigatus lung disease

are summarised in table 1. The rest of this

N The single most useful diagnostic test

is an abrupt, four-fold rise in serum

chapter discusses ABPA in the context of CF.

IgE.

Definition

The mainstay of ABPA treatment is

systemic corticosteroids, increasingly

ABPA is the clinical manifestation of a T-

pulsed methyl prednisolone rather

helper (Th)2 driven hypersensitivity

than oral prednisolone.

response within the airway to A. fumigatus

and its exoproducts.

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Manifestations of Aspergillus fumigatus lung disease

Disease

Manifestation

ABPA

Positive sputum culture which may be associated with

worse lung function and more pulmonary exacerbations

Allergen provoking wheeze

Large airway plugging

Mycetoma

Invasive aspergillosis

Asthma

Isolated positive skin test

Allergen provoking wheeze due to atopic sensitisation

Severe asthma with fungal sensitisation

Immunocompromised host

Invasive aspergillosis

(congenital or acquired)

Lung cavity (congenital thoracic

Mycetoma

malformation, TB, post pneumonic)

Interstitial lung disease

Hypersensitivity pneumonitis

Prevalence of ABPA

certainly an underestimate) reported an

increasing prevalence up to 20 years of age,

The prevalence of ABPA is difficult to

which thereafter declined. 10% of ABPA

determine due to the different diagnostic

patients had a normal FEV1 and .80% did

criteria used, and the different indices of

not report wheeze. Infection with

suspicion prevailing in the various clinics.

Pseudomonas aeruginosa was common

The latest European CF Society Registry

(,70%). The European registry study (967

report (which unfortunately does not yet

ABPA patients out of a total of 12 447 CF

contain comprehensive information across

patients in the registry) reported a peak

the whole of Europe), using the diagnostic

between 13-18 years, and ABPA was rare

criteria shown in table 2, reported

below 6 years of age. There is no convincing

prevalence that varied from 1.4% (Sweden)

sex difference in prevalence when the two

to 17.9% (Switzerland). Whether these

databases are combined. ABPA was

differences reflect different levels of

associated with a poorer general clinical

diagnostic suspicion, differences in

condition (10% lower FEV1, lower weight Z-

diagnostic testing or a genuine geographical

score, more commonly infected with P.

variation in disease prevalence is not clear.

aeruginosa, Burkholderia cepacia,

The UK CF Trust registry report (7937

Stenotrophomonas maltophilia, and,

patients) reported a total of 725 (prevalence

surprisingly, Haemophilus influenzae, but not

9.1%) cases of ABPA in 2010, of which 156

with Staphylococcus aureus infection) and

were new (incidence 2%). Although the

there was an association with pneumothorax

incidence of new cases was the same in

and massive haemoptysis, presumably

adults and children, the prevalence, perhaps

related to the underlying severe lung

surprisingly, was higher in those aged

disease. There were no associations with

.16 years (10.8% versus 7.0%).

particular genotypes or mutation classes.

There are two other older, but still useful,

Pathophysiology

registry studies from the USA and Europe.

The US study (281 (2%) ABPA patients out

A. fumigatus may provoke an intense allergic

of 14 210 total registered patients, almost

response leading to secondary airway

ERS Handbook: Paediatric Respiratory Medicine

377

Table 2. Summary of diagnostic criteria for ABPA used in the European registry

Acute or subacute clinical deterioration, no other aetiology found

Total IgE .500 IU?mL^-1

Positive skin prick test (.3 mm) or specific IgE for Aspergillus fumigatus

Either:

IgG precipitins or in vitro demonstration of IgG antibody response to Aspergillus fumigatus

New or recent imaging abnormalities (chest radiograph or CT) not clearing with standard

therapy

damage, but proteolytic and other enzymes

patients will have a positive sputum culture

may lead to non-allergic, direct pulmonary

for A. fumigatus.

toxicity. ABPA is the result of a skewed

Confirming the diagnosis of ABPA

CD4⁺, Th2 T-cell response to A. fumigatus

leading to interleukin (IL)-4 and IL-5

Making the diagnosis of ABPA in the context

production and, hence, elevation of serum

of CF may be difficult; there is no single

IgE and airway eosinophilia. A. fumigatus

diagnostic test. The classical case is easy to

may directly lead to the production of pro-

diagnose. However, many of the symptoms

inflammatory cytokines from bronchial

and signs of ABPA are common to the

epithelial cells. The importance of genetics

underlying CF. Furthermore, markers of

has been suggested by the occurrence of

sensitisation to A. fumigatus and positive

familial cases. Important factors include

sputum cultures are frequently seen in

HLA-DR and HLA-DQ (the latter protective),

otherwise uncomplicated CF; and true cases

and polymorphisms in the genes for IL-4RA,

of ABPA may be culture negative for A.

IL-10, surfactant protein A and Toll-like

fumigatus. We found that the single most

receptor 9. Recently, elevated levels of the

useful test is an abrupt, at least four-fold rise

co-stimulatory molecule OX40 ligand

in total IgE to .500 IU?mL^-1; IgE may

(OX40L) have been shown to be important

sometimes, but not always, fall with

in driving the Th2 response to A. fumigatus

treatment so serial IgE measurements

in peripheral CD4⁺ T-lymphocytes. Of

should be used with caution in monitoring

possible therapeutic interest, OX40L levels

response. A high level of IgG precipitating

fell with in vitro addition of vitamin D.

antibodies to A. fumigatus may also be

However, A. fumigatus downregulates the

suggestive (.90 mg?mL^-1; ImmunoCap;

vitamin D receptor, which may affect the

Thermo-Fisher Scientific, Uppsala, Sweden);

response to vitamin D therapy.

multiple positive precipitins are more

Presentation

suggestive of mycetoma. Major and minor

criteria for ABPA have been proposed, but

ABPA should be at least suspected in CF

atypical cases may not meet classical criteria

children with increased respiratory

yet still require treatment, which should not

symptoms, particularly if there is wheeze,

be delayed if the index of suspicion is high

chest tightness or pleuritic chest pain and

but ‘‘classical’’ criteria are not met. In

an audible pleural rub. Exceptionally, pleural

doubtful cases, many would initially give a

effusion and pneumomediastinum have

trial of intravenous antibiotics and then treat

been described in ABPA. There may be a

for ABPA if there was no response.

sharp decline in spirometry, and the chest

radiograph typically shows one or more new

The tables of major and minor criteria are

soft fluffy shadows (fig. 1), with a ‘‘gloved

useful guides to the diagnosis of ABPA, but

finger’’ appearance of mucus impaction in

are no more than guides, and atypical cases

the airways, which are very unusual in a CF

will continue to be diagnosed on an

pulmonary exacerbation. Less than half the

individual clinical basis. The United States

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ERS Handbook: Paediatric Respiratory Medicine

Figure 1. Chest radiograph from a CF patient recently diagnosed with ABPA. a) A combination of

widespread indistinct nodular opacities, ring shadows (bronchiectatic airways) in the right mid zone, and

consolidation in the left lower lobe can be seen. b) Several months later, most of the shadowing has

resolved but there is a new elliptical opacity (a plugged bronchiectatic airway) just above the left hilum.

Cystic Fibrosis Foundation (USCFF)

studies using targeted allergy testing to

Consensus Conference proposed criteria for

specific purified A. fumigatus antigens

classic ABPA, minimal diagnostic criteria

including Asp f1, f3, f4 and f6, and serum

and recommendations for screening

thymus- and activated-regulated chemokine

(table 3). These are a useful guide to the

(TARC) levels looked promising. Only TARC

clinician, and very helpful for ensuring

has been studied in a second prospective

uniformity of diagnosis in registries, but

cohort, but its measurement currently

cannot be considered definitive under all

remains in the research domain.

circumstances.

Lung function testing in ABPA

Novel, more sophisticated, testing has been

proposed. Cytoplasmic A. fumigatus

There are no changes specific to ABPA.

antigens may be elevated in ABPA. Initial

Characteristically, there is an acute

Table 3. Diagnostic criteria for ABPA in the context of CF

Classical ABPA

Acute or subacute clinical deterioration not attributable to another cause

Serum total IgE .1000 IU?mL^-1 in a patient not receiving oral corticosteroids

Positive skin prick test to Aspergillus fumigatus

Positive IgG precipitins to Aspergillus fumigatus

New or recent chest radiograph abnormalities not clearing with conventional therapy, such as

physiotherapy and antibiotics

Minimal diagnostic criteria for ABPA

Acute or subacute clinical deterioration not attributable to another cause

Serum total IgE .500 IU?mL^-1 (retest in 1-3 months if 200-500 IU?mL^-1)

Positive skin prick test to Aspergillus fumigatus

Either: positive IgG precipitins to Aspergillus fumigatus, or new or recent chest radiograph

abnormalities not clearing with conventional therapy, such as physiotherapy and antibiotics

ERS Handbook: Paediatric Respiratory Medicine

379

worsening of pre-existing airflow obstruction

would be 2 mg?kg^-1 for 2 weeks (maximum

or its de novo development. This is initially,

60 mg), then 1 mg?kg^-1 for 2 weeks, then

at least partially, reversible, but becomes

1 mg?kg^-1 on alternate days for 2 weeks,

fixed with low lung volumes if the disease

followed by a slow taper. The alternative to

progresses. Diffusing capacity may be low in

oral corticosteroids is pulsed methyl

an acute exacerbation, and remain low in

prednisolone, 500 mg?m^-2 on three

end-stage disease. Spirometry is probably

successive days every 4 weeks. It is

the most useful marker of response to

suggested that there is improved efficacy

treatment, being better than serum IgE or

and fewer side-effects. Certainly, the use of

more sophisticated biomarkers.

pulsed therapy means that adherence is not

an issue, provided the child is brought to the

Screening

hospital.

An annual measurement of total IgE is

Antifungal therapy: The Cochrane review

recommended, with further investigation if

identified only two trials of antifungal

IgE is .500 IU?mL^-1 or 200-500 IU?mL^-1

therapy in ABPA, neither suitable for

and the index of suspicion is high. The

inclusion here. Itraconazole in combination

possibility of ABPA should be considered in

with steroid treatment is used for two

all pulmonary exacerbations, in particular if

reasons. First, in ABPA complicating asthma

there are fresh chest radiographic infiltrates

there is clear evidence that this is beneficial,

or response to treatment is poor; an

and there is weak retrospective evidence of

admission measurement of total IgE is

benefit in CF. Secondly, rare cases of

routine in our CF unit.

invasive aspergillosis complicating CF have

Management

been described and at least, in theory,

itraconazole may prevent this. Oral

Prevention Playing or working in damp

absorption of itraconazole is poor, and

places such as stables where A. fumigatus

serum levels should be measured and the

spores are in high concentrations must be

dose adjusted. Furthermore, at least in

discouraged. Although there is less

adults, azole resistance in A. fumigatus is

evidence, it would seem sensible to ensure

common. Itraconazole inhibits the

there are no moulds in the house, and to

cytochrome p450 enzyme CYP3A, which can

check that that A. fumigatus (or indeed other

lead to Cushing’s syndrome and iatrogenic

organisms) are not cultured from the

adrenal suppression in patients also taking

nebuliser by maximising hygiene. Recent

inhaled budesonide or fluticasone and oral

immunological work suggests that

methyl prednisolone (but not prednisolone).

optimising vitamin D levels may be helpful.

Other anti-fungal options include nebulised

Treatment As with much of paediatric

respiratory medicine, there are no

randomised controlled trials to inform

treatment decisions, and no satisfactory

evidence base on which to recommend the

nature and duration of treatment of ABPA. If

there is any doubt about the diagnosis, then

intravenous antibiotics should be given first.

Treatment is aimed at reducing the

inflammatory and tissue-damaging

consequences of fungal infection, and also

reducing the burden of the fungal infection.

Corticosteroids: Conventionally, the mainstay

Figure 2. HRCT through the upper lobes showing

of treatment is oral prednisolone, which may

bilateral bronchiectasis; the varicose pattern of

need to be given in high dose for a

bronchiectasis in the anterior segment of the right

prolonged period of time. A typical regimen

upper lobe is typical of APBA.

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ERS Handbook: Paediatric Respiratory Medicine

Table 4. Stages of ABPA

Stage 1: Acute phase

There are acute infiltrates that clear completely with prednisolone

Stage 2: Remission

No prednisone therapy or infiltrates for 6 months

Stage 3:

Recurrent exacerbation similar to stage 1

Stage 4:

Phase of steroid dependent asthma

Stage 5:

Fibrotic disease no longer completely responds to prednisolone therapy

Although frequently described, the clinical utility of this staging is not great.

amphotericin (liposomal if the standard

Complications of treatment are generic to

preparation cannot be tolerated) with or

the medications used but for CF, loss of

without nebulised budesonide,

bone mineral density and precipitation of

voriconazole, posaconazole and intravenous

CF-related diabetes are particularly

liposomal amphotericin. The evidence for

important.

usage of these agents is minimal.

Prognosis

Other current treatment options: There are

small case series reporting the use of the

Mild cases of ABPA may resolve

anti-IgE monoclonal antibody omalizumab

spontaneously, but the majority relapse after

(xolair) in ABPA. Inhaled corticosteroids are

treatment. Accelerated decline in lung

commonly employed, but there is only the

function is reported in patients treated for

most limited evidence that they are

ABPA. ABPA has been divided into five

beneficial. There are occasional anecdotal

stages with different prognoses (table 4); it

reports of bronchoscopic airway toilet in

is arguable whether these are clinically

recalcitrant airway plugging.

useful. They are not a chronological

progression in clinical practice. Prolonged

The future: The evidence of Th2 driven

and recurrent ABPA is common, so

responses suggests that monoclonal

prognosis must be guarded.

antibody-directed signature Th2 cytokines

(IL-4, IL-5 and IL-13), which are already

researched in asthma, may also be useful in

Further reading

ABPA

CF Registry. Cystic Fibrosis Trust Annual

Complications of ABPA

Data Report

2010. www.cysticfibrosis.

org.uk/media/108230/CR_Annual_Data_

These are the complications of the disease

Report_2010_Dec_11.pdf

itself, and complications of treatment.

Elphick HE, et al.

(2012). Antifungal

therapies for allergic bronchopulmonary

Disease-specific complications are severe

aspergillosis in people with cystic fibro-

proximal bronchiectasis (fig. 2) and, in

sis. Cochrane Database Syst Rev;

some, but not all series, accelerated decline

CD002204.

in lung function. ABPA is a risk factor for

European Cystic Fibrosis. ECFS Patient

infection with atypical Mycobacteria

Registry Annual Report 2008-2009. www.

infection, although whether because of

ecfs.eu/files/webfm/webfiles/File/ecfs_

steroid therapy rather than the underlying

registry/ECFSPR_Report0809_v32012.pdf

disease is not known.

ERS Handbook: Paediatric Respiratory Medicine

381

Specific immunotherapy,

prevention measures and

alternative treatment

Susanne Halken and Gunilla Hedlin

The majority of schoolchildren with asthma

associated with chronic inflammation, in

are allergic to airborne allergens and allergy

contrast to exposure to pet allergens, which

is a common trigger of asthma symptoms.

may induce acute reactions as well.

The allergens associated with allergic airway

Subcutaneous immunotherapy (SCIT) is still

disease depend on the age, climatic,

questioned as a safe and efficacious way of

seasonal and social factors, and housing

treating allergic asthma in children. Children

conditions. In temperate and humid

with severe allergic asthma are often

regions, allergy to house dust mites shows

sensitised to multiple allergens, which

the strongest association with asthma

makes SCIT both complicated and less safe

followed by allergy to furred pets (especially

to administer. In a Cochrane review

cats). In arid climates, allergy to the fungus

published in 2010, however, it was

(Alternaria spp.) is prevalent.

concluded that SCIT has significant and

Allergic asthma is most often associated

beneficial effects on symptoms and

with indoor inhalant allergens, whereas

medication use in both children and adults

allergic rhinitis most often is associated with

with mostly mild asthma. Only a few studies

outdoor allergens such as pollen. In children

have been performed specifically on SCIT in

with allergic asthma, persistent allergen

children with moderate and severe asthma.

exposure is associated with airway

Sublingual immunotherapy (SLIT) has also

inflammation, bronchial

been shown to improve asthma symptoms

hyperresponsiveness, and an increased risk

and decrease medication use.

of persistent and severe asthma.

Anti-IgE (omalizumab) is the only

The aerodynamic characteristics of the

monoclonal antibody so far with a

allergen-carrying particles vary considerably.

documented effect in children with severe

Thus, most house dust mite and cockroach

allergic asthma. Although this drug could

allergens are carried on relatively large

turn out to be very efficacious in children with

particles, whereas most pet allergens are

milder disease, the cost of the treatment is

carried on small particles. Therefore, house

one limitation of the use of this therapy

dust mite exposure is most commonly

Allergen avoidance

Avoiding exposure to relevant allergens is a

Key points

logical way to treat allergic airway diseases,

when the offending allergen can be

Immunotherapy with seasonal and

identified and effective avoidance is feasible.

perennial airborne allergens

In the case of allergy to pollen and foods, it

has beneficial effects on allergic

is well recognised that avoidance of these

asthma.

allergens results in less or no symptoms.

The case of allergy and exposure to

N Anti IgE therapy reduces the risk of

perennial airborne allergens is more

asthma exacerbations on children

complex, as exposure is not restricted to

with severe allergic asthma.

specific situations or environments, but may

ERS Handbook: Paediatric Respiratory Medicine

383

occur throughout the community. Moreover,

Table 1. Recommendations for children with asthma

many children with allergic asthma are

and allergy to house dust mites

allergic to a number of allergens (e.g. both

Ensure sufficient ventilation

house dust mites and pets). Pet allergens

are, to a high degree, airborne and

Avoid damp housing conditions

ubiquitous. Significant concentrations are

Encase mattresses

also found in clothes and places without

Wash pillows, duvets, blankets and bed

direct contact with pets, even several years

pads every 3-4 months (.55uC)

after removal of a pet.

Wash soft toys and other mite reservoirs

A clinical effect of allergen avoidance was

first suggested by studies in which patients

were removed from their homes to low-

measures have been recommended for

allergen, mountain environments, which

house dust mite allergen avoidance, most of

resulted in improved lung function and

them focusing on the bedding environment

normalised markers of allergic inflammation

(table 1).

in children with allergic asthma. Later,

A recent update of the Cochrane meta-

several studies on different measures of

analysis concluded that current chemical

environmental control in patients’ homes

indicated a clinical effect of allergen

and physical methods aimed at reducing

avoidance. Still, much controversy exists

exposure to house dust mite allergens

over the evaluation of results from these

cannot be recommended for patients with

studies and from meta-analyses, mainly due

asthma and house dust mite allergy

to methodological problems. In order to

(table 2). However, this conclusion may

document a cause-effect relationship,

have many explanations (e.g. heterogeneity

avoidance measures should be capable both

in studies, inclusion criteria and the fact that

of reducing the allergen level sufficiently and

some of the allergen avoidance measures

of resulting in a clinical effect.

did not sufficiently reduce allergen

exposure).

Most of the previous studies on

environmental allergen avoidance measures

Well performed, controlled, randomised

have focused on a single allergen, and the

studies with adequate design and methods

measures for exposure have been

have demonstrated that some avoidance

concentrations of allergens in dust from

measures, such as mattress encasings with

mattresses, floors or furniture. This may not

mite allergen-impermeable coverings, have

represent personal exposure to

proven effective both in reducing the level of

aeroallergens. Individual differences in

house dust mite allergens and in improving

sensitivity to exposure may be important. In

disease control in children.

addition, the level of anti-inflammatory

treatment may be important for evaluation

There is no evidence that synthetic fillings of

of a possible effect of different

bedding (duvets and pillows) are more

environmental measures.

beneficial than feather fillings. Some recent

studies indicate that feather fillings result in

House dust mite allergen avoidance House

lower exposure to house dust mite allergens.

dust mites are an important and widely

distributed allergen source. House dust

mites require high humidity and a

Table 2. No documented effect of allergen avoidance

temperature of ,24uC for their life cycle and

Synthetic filling of pillows and duvets

reproduction, and the best conditions are in

Foam mattresses

temperate, humid regions. House dust

Chemical treatment of mattresses

mites are mainly in our bedding but may

also be detected in, for example, carpets and

Special vacuum cleaners

upholstered furniture, although in lower

Air filters, ionisers, etc.

concentrations. Many different single

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ERS Handbook: Paediatric Respiratory Medicine

It has also been argued that foam or water

demonstrated, and the results are

mattresses should result in lower exposure,

encouraging, but further studies are needed.

as compared with spring mattresses, but the

few available data indicate no difference

A large trial provided evidence of

except that using a washable bed pad may

improvement of asthma control by

reduce exposure from the mattress.

multifaceted intervention that was tailored to

the child’s sensitisation and exposure

Different floor coverings may have different

status. This included several measures, such

effects. Carpeted floors contain different

as education, encasing of mattresses and

particles and allergens to which small

pillows, high-filtration vacuum cleaners, and

children playing on the floor are especially

HEPA filters.

exposed. It has been assumed that hard

floors have a beneficial effect, but available

Apart from attempts to reduce the reservoirs

data suggest a complex and small effect.

of allergens, it is obvious to try to remove

the conditions for the house dust mites to

Washing of bedding and clothing at .55uC

live and reproduce by reducing humidity (to

kills house dust mites and effectively

below 45-50% relative humidity), avoiding

removes allergens. Washing at low

moisture problems and increasing the

temperatures also removes allergens.

ventilation of the home, although clinical

However, it is not known whether washing

data are limited.

has any clinical effect.

Pet allergen avoidance In the case of asthma

Vacuum cleaners remove allergens and

and allergy to pets, repeated exposure is

vacuum cleaning may result in a modest

associated with bronchial hyperreactivity

decrease of allergen reservoirs, but it also

and eosinophil inflammation, even without

causes a brief increase in personal

obvious symptoms. Cat allergens in

aeroallergen exposure while vacuum

particular are airborne, and are found at

cleaning and high-efficiency particulate

varying levels in houses and public places

arrest (HEPA) filters make only little

without cats. Removal of a pet from the

difference. Data on the quantity of a possible

home reduces the allergen level but does

reduction of personal allergen exposure and

not abolish exposure (table 3). Washing of

its clinical effect are lacking.

bedding and clothes might reduce exposure.

The effect of air filtration is still debated and

Washing of the pet has been tried in some

there is no good evidence for a possible

studies and it has been shown that it may

effect.

reduce the allergen level but only for a short

Acaricides have been included in some

time. We lack good data on the clinical

studies but there is no good evidence of

effectiveness of different measures to

clinical benefits, and concerns about human

reduce pet allergen levels and exposure.

health and environmental toxicity remain.

Pest avoidance Particularly in inner-city

Recently, a clinical effect of a novel concept

environments, cockroach allergy is a major

with nocturnal temperature controlled

cause of allergic asthma. Approaches

laminar airflow treatment has been

include pesticides and sanitation (e.g.

Table 3. Advice for children with asthma and allergy to pets

The only effective method is removal of the pet

General cleaning and vacuum cleaning is advised, although there is no good evidence for this

Even after removal of a pet, it may take many months before the reservoir of allergens is reduced

sufficiently and it may take 6-12 months before the full benefit is seen

Complete avoidance of pet allergens is impossible as the allergens are ubiquitous and can be

found in many environments outside the home including schools

ERS Handbook: Paediatric Respiratory Medicine

385

avoiding making food available to the

Immunotherapy for allergic asthma

cockroaches, control of water leaks and

Criteria for commencement of

control of entrances). After such elimination

immunotherapy Before considering

procedures, thorough cleaning is necessary

immunotherapy, the allergens triggering

for a long period to remove the pesticides

asthma symptoms must be identified and

and allergens.

the allergic sensitisation confirmed (table 4).

Likewise, mouse exposure, particularly in

While in vitro or skin tests are good enough

bedrooms, is prevalent, especially in

for confirming pollen and animal dander

inner-city dwellings, and methods for

allergy, it may be necessary to perform

effective rodent control have been

allergen provocation tests in the eyes and/or

shown to reduce exposure and

the nose to confirm other perennial allergies

improve symptoms. However, to date,

like dust mite and Alternaria allergy. More

the evidence is limited.

information on the relevant procedures can

be found in the position paper published as

Mould avoidance Many studies have shown

a Global Allergy and Asthma European

that exposure and allergy to fungi are often

Network (GA²LEN)/European Academy of

associated with severe asthma. Some

Allergy and Clinical Immunology (EAACI)

fungi (often Aspergillus) may colonise and

pocket guide on allergen-specific

even infest the lungs, thereby causing

immunotherapy for allergic rhinitis and

severe disease. Many other fungi, most

asthma.

often Alternaria but also others such as

Cladosporium or Penicillium, appear to

Immunotherapy to improve and/or prevent

play an important role in severe asthma.

deterioration of asthma The majority of

There is limited evidence about the role

immunotherapy studies in children (and

of fungal allergen avoidance in asthma.

adults) with asthma have been performed in

Moisture issues cause most instances

those with mild allergic asthma, usually

of fungal growth in the indoor

combined with rhinitis. Most of the studies

environment, and control of indoor

have been performed using single allergens,

environmental humidity and removal

the most predominant perennial allergen

of contaminated material has been

being dust mite, and the dominant seasonal

recommended. There are no convincing

allergens being birch, olive/Parietaria, grass

trials of avoidance of Alternaria,

and ragweed (mostly in the USA). The best

which is primarily an outdoor

evidence of efficacy of immunotherapy in

allergen, though it can also be

children with asthma emanates from studies

found indoors.

of children allergic to pollen and house dust

mites (table 5).

In the case of suspicion of significant

problems with fungal growth in the indoor

SCIT with cat allergen extracts has also

environment, it is often necessary to

shown beneficial effects both on allergen

investigate which fungus is present, and to

sensitivity and bronchial

involve experts and technicians with special

hyperresponsiveness, while so far, dog

expertise in this area.

allergen extracts have been less efficacious.

A recent study of treatment with Alternaria

Table 4. Indications for allergen immunotherapy

Table 5. Documented effects of immunotherapy

Allergic asthma triggered by allergen

exposure

Less severe symptoms on allergen exposure

Confirmed specific allergy

Decreased medications use during the

allergy season

Seasonal allergy to pollens

Quality of life improvements

Perennial allergy to house dust mite,

Alternaria, cat

Lasting effect after cessation of therapy

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ERS Handbook: Paediatric Respiratory Medicine

extracts in children has been shown to have

adjustments have to be made if the subject

convincing clinical effects, reducing

had side-effects like major local swelling

symptoms of asthma.

and/or any sign of systemic effects. A

standard procedure for required dose

Few studies have been carried out in

adjustments should be followed. After the

children with both seasonal and perennial

injection, the subject should stay at the

allergies. One placebo-controlled American

clinic for observation for o30 min, as most

study of multi-allergic children

SSEs occur within that time. At any sign of a

demonstrated no significant effect of SCIT

SSE - cough, sneezing, itch or signs of

on medication use and symptom control. A

anaphylaxis - adrenaline injection(s) should

few other studies have been more

be promptly given. Local side-effects can

successful; thus, the possibility remains that

usually be treated or prevented by oral

SCIT may alter the severity of asthma by

antihistamines. It is mandatory at any clinic

inducing allergen tolerance. More studies

that administers SCIT that there is

are needed; however, in the mentioned

equipment and trained staff to take

Cochrane report and two recent extensive

immediate action in case of a SSE.

reviews conclude that there is evidence for

efficacy of SCIT and SLIT in both children

The available guidelines serve an important

and adults with asthma.

role in providing standards for the

indications, use and administration of SCIT

Dosing schedules for SCIT and side-effects

and SLIT.

Different up-dosing regimens are used for

the stepping up of the dose phase of SCIT

SLIT for asthma SLIT has been shown to

treatment. There are ‘‘rush’’ up-dosing

improve asthma symptoms and medication

schedules, cluster regimens and the

use. SLIT is safe, although the efficacy

conventional ‘‘one injection per week’’

compared to SCIT has been very little

regimen. The advantages and disadvantages

studied. In one recent paediatric review, the

of immunotherapy have been discussed

efficacy of both SCIT and SLIT were

(table 6).

reported. In another recent review, SLIT

studies in both children and adults were

The risk of systemic side-effects (SSEs) has

reported. In the paediatric review, it is stated

to be considered and the highest risk has

that there is good evidence that SLIT has

been reported when a rush regimen is used.

effects on asthma in children; this is in

However, none of the schedules is without

agreement with the other reviews. However,

risk of SSEs, which is an important reminder

dose and dosing are still major issues for

that requires special attention.

SLIT. There is, for example, in different SLIT

Implementation of safety measures and

studies, a large variation of the cumulative

standardised procedures are mandatory

dose of house dust mite administered,

when the injections are administered.

ranging from 0.25 to 12 mg Der p. This is an

Precautions are important. Lung function

issue that has been discussed and has

should be checked. Injections should not be

caused some concern, in that there are still

given if the subject has ongoing allergic

few dose-response studies that have

symptoms or a current infection; asthma

confirmed the standard doses that should

symptoms have to be controlled and recent

be used for SLIT. The first dose of SLIT

allergen exposure should be checked. Dose

should be given at a clinic and followed by

>30 min observation time. The best

documented SLIT to date is for treatment of

Table 6. Problems with allergen immunotherapy

pollen and dust mite allergy.

Mostly an injection therapy

Immunotherapy combined with anti-IgE:

Long-term therapy (.3 years)

safety and efficacy in children with severe

Loss of school attendance

allergic asthma Few studies have addressed

this question in children. One of the

Risk of systemic side-effects

paediatric studies was performed in

ERS Handbook: Paediatric Respiratory Medicine

387

polysensitised children with seasonal

pharmacotherapy. Studies of SCIT for pollen,

rhinitis and included children with birch or

house dust mite and cat allergy have shown

grass allergy. Results showed that the

convincing effects on the specific allergies. A

combination of omalizumab and pollen

couple of recent reviews have confirmed the

SCIT had superior effects on symptom load

utility of SCIT and SLIT for asthma and

in both birch- and grass-allergic children.

rhinitis in children. The treatment can

Other studies performed in groups of

improve the quality of life for the allergic child

children and adults have shown similar

but the overall effect on asthma severity, as

results. Pre-treatment with omalizumab in

demonstrated by a decreased need for

patients with severe multi-allergic asthma

pharmacotherapy for asthma control, has

was the subject of another study of

been uncertain in children with multiple and

combined therapy, although omalizumab

perennial allergies.

treatment only overlapped at the start of

immunotherapy in symptomatic patients

Anti-IgE is a treatment possibility for severe

with asthma. The risk of SSEs was reduced,

allergic asthma and, so far, the documented

although severe systemic reactions still

effects on risk of exacerbation have been

occurred in the group pre-treated with

shown in children needing high-dose

omalizumab. There is a need for more

inhaled corticosteroids for symptom control.

studies of this combination before it can be

The efficacy increases in those with high

considered an additional therapy in children

exhaled nitric oxide fraction (FeNO) and

with asthma and severe allergies. At this

other signs of ongoing eosinophilic airway

stage, SCIT alone or in combination with

inflammation.

omalizumab should not be used in children

with severe and/or uncontrolled asthma.

Further reading

Conclusion

Abramson MJ, et al.

(2010). Injection

allergen immunotherapy for asthma.

A pragmatic approach in clinical practice

Cochrane Database Syst Rev; 8: CD001186.

should involve interventions tailored to the

Bush RK (2011). Does allergen avoidance

patient’s sensitisation and exposure in a

work? Immunol Allergy Clin N Am; 31:

multifaceted allergen avoidance regime, based

493-507.

on removal of the accumulating allergens. The

Busse WW, et al. (2011). Randomized trial

extent of such avoidance measures should

of omalizumab (anti-IgE) for asthma in

also be tailored to the severity of the disease,

inner-city children. N Engl J Med;

364:

and combined with education and other

1005-1015.

relevant treatment options.

Cox L, et al. (2011). Allergen immunother-

apy: a practice parameter third update. J

Environmental avoidance measures have

Allergy Clin Immunol; 127: 840.

proven effective as a specific treatment of a

Custovic A, et al.

(2012). The role of

specific allergy under the right conditions, but

inhalant allergens in allergic airways dis-

it requires defining specific sensitivity,

ease. J Investig Allergol Clin Immunol; 22:

education and an overall plan to reduce

393-401.

exposure in the child’s home, and its success

Gøtzsche PC, et al. (2008). House dust

depends on the relevance of other allergens

mite control measures for asthma.

and exposure outside home. Thus, in children

Cochrane Database Syst Rev; 2: CD001187.

with allergic asthma, measures to reduce

Halken S, et al. (2003). Effect of mattress

allergen levels significantly should be included

and pillow encasings on children with

in an individual treatment plan as well as an

asthma and house dust mite allergy. J

Allergy Clin Immunol; 111: 169-176.

appropriate pharmacological treatment and

Hedlin G, et al.

(2012). The role of

avoidance of exposure to tobacco smoke.

immunotherapy in the management of

If allergen avoidance is not possible, the

childhood asthma. Ther Adv Respir Dis; 6:

137-146.

addition of immunotherapy could be the next

step, provided it is combined with adequate

388

ERS Handbook: Paediatric Respiratory Medicine

Kennedy JL, et al.

(2012). The role of

Lin SY, et al. (2013). Sublingual immunother-

allergy in severe asthma. Clin Exp Allergy;

apy for treatment of allergic rhinoconjuncti-

42: 659-669.

vitis and asthma. JAMA; 309: 1278-1288.

Kilburn S, et al.

(2003). Pet allergen

Massanari M, et al. (2010). Effect of pretreat-

control measures for allergic asthma in

ment with omalizumab on the tolerability of

children and adults. Cochrane Database

specific immunotherapy in allergic asthma. J

Syst Rev; 1: CD002989.

Allergy Clin Immunol; 125: 383-389.

Kim JM, et al. (2013). Allergen specific

Penagos M, et al. (2008). Meta-analysis

immunotherapy for pediatric asthma and

of the efficacy of sublingual immunother-

rhinoconjuctivitis: a systematic review.

apy in the treatment of allergic asthma in

Pediatrics; 131: 1-13.

pediatrix patients,

3 to 18 years of age.

Lanier B, et al. (2009). Omalizumab for

Chest; 133: 599-609.

the treatment of exacerbations in children

Zuberbier T, et al. (2010). GA²LEN/EAACI

with inadequately controlled allergic (IgE-

pocket guide for allergen-specific immu-

mediated) asthma. J Allergy Clin Immunol;

notherapy for allergic rhinitis and asthma.

124: 1210-1216.

Allergy; 65: 1525-1530.

ERS Handbook: Paediatric Respiratory Medicine

389

Genetics, pathophysiology

and epidemiology of CF

Sabina Gallati

CF has been recognised as a distinct

of the two parental CF mutations and a 25%

inheritable clinical entity for more than

chance that the child will inherit two intact

70 years. It is the most common life-

genes. Phenotypically healthy siblings of CF

threatening autosomal-recessive disorder

patients have a 66% risk of a positive carrier

among Caucasians with an incidence of

state.

approximately one in 2500 and a carrier

The CFTR gene and protein

frequency of 4%. Heterozygotes carry one

normal and one mutant CF gene and are

The gene causing CF, identified in 1989, is

therefore healthy, but they have a 50% risk

located on chromosome 7q31.2 spanning

of passing the defective gene on to their

,200 kb of genomic DNA and containing

offspring. If two partners are carriers they

27 exons. It is transcribed into 6.13 kb

face a 25% risk of having a child with CF, a

messenger ribonucleic acids (mRNAs)

50% chance that the child will carry only one

encoding a transmembrane protein of 1480

amino acids known as the cystic fibrosis

transmembrane conductance regulator

Key points

(CFTR). The CFTR protein is a member of

the ATP-binding cassette (ABC) transporter

CF is the most common life-

superfamily whose proteins transport

threatening autosomal-recessive

various molecules across extra- and

disorder in Caucasian populations

intracellular membranes. The predicted

with an incidence of 1/2500 and a

structure of CFTR includes:

carrier frequency of 1/25.

N a symmetrical, multi-domain structure

CF is caused by mutations in the

consisting of two membrane-spanning

CFTR gene on chromosome 7.

domains (MSD1 and MSD2) with six

The CF phenotype is very

hydrophobic transmembrane helices

heterogeneous and depends on both

forming the channel through the

nature and localisation of the

membrane;

underlying CFTR mutations, as well as

N two nucleotide binding domains (NBD1

genetic background and

and NBD2) gating the channel through

environmental influences.

ATP-binding and hydrolysis;

N a central, highly charged regulatory

CFTR analysis is indicated for

domain with multiple consensus sites for

diagnostic purposes in individuals

phosphorylation by protein kinase (PK)A

with clinical suspicion of CF or CFTR-

and PKC.

related disorders, fetuses with

echogenic bowel or whose parents are

The regulatory domain is unique for CFTR as

proven CF carriers, and for carrier

it is not present in the other members of the

testing in persons with a positive

ABC superfamily. CFTR is mainly located at

family history or in partners of proven

the apical membrane of polarised epithelial

CF carriers.

tissues. Its main function is that of a cyclic

AMP-regulated chloride channel, which is

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ERS Handbook: Paediatric Respiratory Medicine

expressed in several functionally diverse

phenotypes (fig. 1). The second class of

tissues including the lung, sweat ducts,

mutations contains many missense

pancreas, gastrointestinal tract and vas

mutations as well as in-frame deletions or

deferens. Moreover, CFTR directly mediates

insertions, including the F508 deletion. The

secretion of bicarbonate across the apical

corresponding proteins fail to be properly

membrane linking ion transport and luminal

processed to a mature glycosylated form

pH with mucin secretion, mucus plugging

and will not, or only exceptionally, appear at

and retention, the hallmarks of CF

the apical membrane. Interestingly, some of

pathology. CFTR-mediated chloride

the class II mutations, e.g. F508del, if

secretion across epithelial cells is controlled

correctly processed, possess residual

by both modulating channel activity and

chloride channel activity and may lead to a

regulating the total number of CFTR

milder phenotype. For this reason,

channels in the membrane.

mutations in this group are targets of

potential therapies, aimed at correcting the

CFTR mutations

processing and delivery of a mutated CFTR

protein to the apical membrane (fig. 1).

To date, nearly 2000 mutations have been

Mutations of class III affect the regulation of

reported to the Cystic Fibrosis Genetic

CFTR function by preventing ATP binding

Analysis Consortium. The most common CF

and hydrolysis at NBF1 and NBF2 required

causing defect is the F508del mutation

for channel activation. However, the

(c.1521_1523delCTT; p.Phe508del according

missense mutation G551D within NBF1

to the current standard nomenclature), a

disrupts not only the binding site through

3 bp deletion in exon 10 (current

which ATP-dependent gating normally

nomenclature: exon 11) causing the loss of

occurs, but also allows some ATP-

the amino acid phenylalanine at position

independent chloride transport making it a

508 of the protein. There are another 23

promising candidate for therapeutic

relatively common mutations (frequency

approaches using CFTR potentiators (fig. 1).

.0.5%) worldwide and a few mutations with

The fourth class of mutations involves

an unusually high frequency in specific

amino acids located within MSD1 and MSD2

populations indicating founder effect

and results in a CFTR channel with defective

genetic drift. The remaining mutations

conductive properties. Mutations (e.g.

represent rare or even individual sequence

R117H, R334W, R347H and R347P) in this

changes that are distributed throughout the

class are typically associated with a milder

entire gene. Mutations (missense,

clinical phenotype (fig. 1). Various

nonsense, frame-shift, splice, small and

mutations are associated with reduced

large in-frame deletions, and insertions)

biosynthesis of fully active CFTR due to

contribute to the phenotype by their nature

partially aberrant splicing (3849+10kbC-.T,

and position in the gene. Therefore, they can

T5), promotor mutations or inefficient

be grouped into different classes based on

trafficking (A455E). These mutations,

their known or predicted molecular

forming class V, result in reduced amounts

mechanisms of functional consequences for

the protein.

of functional gene products and, thus, in

milder CF phenotypes (fig. 1). Class VI

Class I mutations include mainly nonsense,

includes nonsense and frame-shift

frame-shift and splice site mutations

mutations (e.g. Q1412X, 4326delTC and

resulting in premature termination signals

4279insA) causing a 70- to 100-bp

or defective splicing and, as a consequence,

truncation of the C-terminus of the CFTR

producing truncated, deleted or elongated

that leads to a marked instability of an

protein variants. Such proteins tend to be

otherwise fully processed and functional

unstable and rapidly degraded and cleared

protein, and as a consequence to a severe

from the cell. In effect, virtually no functional

CF presentation (fig. 1). Mutations in any of

CFTR reaches the apical membrane of

the classes II to V display a broad range of

epithelial cells and, therefore, class I

phenotypic effects making prediction of the

mutations are expected to cause severe

clinical course of a patient impossible

ERS Handbook: Paediatric Respiratory Medicine

391

Class IV

CI-

MSD1

MSD2

NBD1

NBD2

ATP

Class III

ATP

Class V

Nucleus

Golgi

apparatus

Gene defect

Class VI

Class I

Class II

Figure 1. Class I (A): nonsense, frame-shift and splice site mutations resulting in no functional CFTR

protein. Class II (B): mutations (e.g. F508del) that lead to abnormal processing and trafficking of proteins.

Class III (C): mutations in this group (e.g. G551D) affect the regulation of CFTR and channel gating

activity. Class IV (D): mutations (e.g. R117H, R334W, R347P and R347H) within the MSDs reducing CFTR

channel conductance. Class V (E): mutations associated with reduced biosynthesis of fully active CFTR due

to alternative splicing (e.g. T5). Class VI (F): nonsense and frame-shift mutations causing truncation of the

C-terminus of CFTR and leading to highly unstable proteins. ER: endoplasmic reticulum; RD: regulatory

domain.

simply based on mutation classification.

alterations in the synthesis or sequence of

Moreover, the potential of a mutation to

the CFTR protein may affect the number of

contribute to the phenotype depends not

channels in the plasma membrane and/or

only on its nature, localisation in the gene

channel activity and/or intracellular

and molecular mechanism, but also on its

trafficking of CFTR. Reduced or missing

interaction with the second mutated CFTR

CFTR function leads to a failure of chloride

allele, as well as on disease modifiers.

and sodium transport across epithelia. The

defective ion conductance and the

Pathophysiology of the mutated CFTR gene

associated water transport abnormalities

and protein

produce increased viscosity of secretions in

As mentioned before, pathogenic CFTR gene

a variety of exocrine epithelia, such as the

mutations can disrupt CFTR protein

respiratory tract, pancreas, gastrointestinal

function through a variety of mechanisms

tract, urogenital tract and sweat glands and

ranging from complete loss of protein

result, as a consequence, in the multi-

synthesis to normal apical membrane

organic disease of classic CF. Moreover,

expression of the protein with, however,

there is growing recognition of atypical CF

reduced chloride conductance. Furthermore,

and CFTR-related disorders including

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ERS Handbook: Paediatric Respiratory Medicine

primary male infertility, isolated idiopathic

healthcare provider such that meaningful

pancreatitis, chronic rhinosinusitis, nasal

informed consent from the patients may be

polyposis and idiopathic bronchiectasis,

obtained. Performing a molecular genetic

presenting in adolescence or adulthood and

diagnostic test is a complex process

making diagnosis and prognosis much

requiring internal quality control systems

more complex.

such as good laboratory practice procedures

or some form of accreditation. A wide range

Based on the considerable technical

of mutation testing methods are available

problems in successfully targeting the basic

and can be divided into two groups: specific

defects of CF on the one hand, and on the

mutation detection based on the well-known

major advances in the understanding of

spectrum of CF mutations in a defined

CFTR pathophysiology on the other, the

ethnic group or population (e.g. using

focus of treatment strategies has turned

commercial kits), and mutation screening

toward pharmacotherapy and the

methods (e.g. sequencing of the entire

development of agents that may increase

coding region of the CFTR gene) with a high

residual protein synthesis and/or transport

detection rate and the ability to identify

to the cell membrane and/or ion

novel mutations independent from allele

conductance. Therefore, mutation-specific

frequencies and ethnic origin (table 1).

‘‘orphan drug’’ therapies are currently the

Genotypic and phenotypic heterogeneity

most favoured strategies. However, they

represent a symptomatic treatment option

Although CF is considered a monogenic

rather than a cure and gene therapy may yet

disorder, studies of clinical phenotype in

provide the best solution.

correlation with the genotype have revealed

Genetic testing

a very complex relationship. Some

phenotypic features are closely determined

Genetic testing should be performed in the

by the genotype in an essentially monogenic

context of appropriate genetic counselling,

fashion, whereas others are strongly

and it is the laboratory technician’s

influenced by both modifying genetic factors

responsibility to explain CF testing to the

and the environment. There is a close

Table 1. CFTR analyses indications

CFTR analyses are indicated for:

Diagnostic testing in

Patients with a definite or possible clinical diagnosis of CF

Newborns with positive neonatal screening test

Infants with meconium ileus

Males with proven congenital bilateral absence of vas deferens or suffering from primary

infertility

Patients with idiopathic pancreatitis

Patients with idiopathic bronchiectasis or chronic rhinosinusitis or nasal polyposis

Carrier testing in

Individuals with positive family history

Partners of proven CF carriers

Gamete donors

Prenatal and pre-implantation diagnostic testing

If both parents are proven carriers and both mutations have been identified

In fetuses present with an echogenic bowel during the second trimester

ERS Handbook: Paediatric Respiratory Medicine

393

Table 2 Incidence and carrier frequency of CF in different countries

Country

Carrier frequency

Incidence

Europe

Finland

1/79 (1.3)

1/25 000

Turkey

,1/50 (2.0)

,1/10 000

Sweden

1/43 (2.3)

1/7300

Poland

1/39 (2.6)

1/6000

Russia

1/35 (2.9)

1/4900

Denmark

1/34 (2.9)

1/4700

Norway

1/33 (3.0)

1/4500

Netherlands

1/30 (3.3)

1/3600

Greece

1/30 (3.3)

1/3500

Spain

1/30 (3.3)

1/3500

Germany

1/29 (3.4)

1/3300

Czech Republic

1/27 (3.7)

1/2800

1/26 (3.8)

1/2600

Switzerland

1/25 (4.0)

1/2500

Italy

1/25 (4.0)

1/2500

France

1/24 (4.2)

1/2400

Scotland

1/22 (4.5)

1/2000

Republic of Ireland

1/21 (4.8)

1/1800

North America

USA

1/30 (3.3)

1/3500

Canada

1/27 (3.7)

1/3000

Latin America

Mexico

1/46 (2.2)

1/8500

Brazil

1/41 (2.4)

1/6900

Chile

1/32 (3.1)

1/4000

Cuba

1/31 (3.2)

1/3900

Middle East

United Arab Emirates

1/63 (1.6)

1/15 900

Bahrain

1/38 (2.6)

1/5800

Asia

India

1/100-1/158 (1.0-0.6)

1/40 000-100 000

Japan

1/158-1/296 (0.6-0.3)

1/100 000-350 000

South Africa

1/42 (2.4)

1/7100

Australia

1/25 (4.0)

1/2500

Data are presented as one case per 6

persons of a population 6 births.

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ERS Handbook: Paediatric Respiratory Medicine

relationship between the CFTR genotype and

homologous genotypes and well-defined

the pancreatic phenotype revealing ‘‘severe’’

phenotypes, as well as on functional

mutations (e.g. F508del, all class 1

consequences, are required to provide

mutations) to be associated with pancreatic

clinical utility.

insufficiency and ‘‘mild’’ mutations with

In complex diseases such as CF,

residual function, such as a series of

contribution of epigenetic factors such as

missense and alternative splice mutations,

DNA methylation, chromatin remodelling,

to be associated with pancreatic sufficiency.

histone modification and RNA interference

The development of meconium ileus,

might be substantial. It is well established

diabetes and liver disease is mainly confined

that polymorphisms in a poly-T tract

to patients with severe mutations without

(c.1210-12T [5_9]) and a TG repeat (c.1242-

residual function. However, because of its

35_1242-12GT [8_13]) in intron 8 (standard

complexity and patient exposure to a

nomenclature: intron 9) of the CFTR gene

multitude of endogenous and exogenous

causes alternative splicing resulting in

factors, pulmonary outcome is clinically the

variable exon 9 (standard nomenclature:

most variable, as well as the most

exon 10) skipping. Moreover, several

unpredictable, component of the CF

polymorphisms have been reported to lead

phenotype. Several studies have shown

to alterations in transcription factor binding

significant correlations between CFTR

and, therefore, to be involved in the

genotypes and pulmonary status concluding

modulation of CFTR transcription. Hence, it

that patients with class I or II mutations on

is very likely that a significant number of

both chromosomes have more rapid

polymorphisms, transcription factors and

deterioration in lung function and lower

splicing factors interact to effect the

survival rates than patients with other

complex tissue-specific regulation of the

genotypes. Moreover, F508del homozygous

CFTR gene.

patients were found to present the most

considerable variation in severity of

Epidemiology

pulmonary disease. The broad range of

disease severity, even in patients with the

CF causing mutations have existed for more

same genotype (e.g. F508del homozygotes),

than 50 000 years and many are strongly

associated with specific European

point to the understanding that a CFTR

populations. The most common CFTR

genotype constitutes only the source or

mutation, the F508 deletion, accounts for

potential for CF disease and that the overall

,60% of all CF chromosomes worldwide

genetic background, as well as

with considerably variable frequencies

environmental factors, may have a major

depending on populations and

effect on clinical phenotype.

geographical locations. There is a clear

Modifying factors

North West to South East gradient in

F508del frequency across Europe with a

A multitude of genetic loci and genes have

maximum of 100% in the isolated Faroe

been investigated as modifiers of CF

Islands of Denmark and a minimum of

expression at the pulmonary,

,20% in Turkey. Caucasians in Canada and

gastrointestinal and liver levels suggesting

North America present with an F508del

that a number of genes could interact in

frequency of 68-71%, whereas Hispanic

different ways to produce the highly

populations and African-Americans show

variegate CF phenotype. Some of the most

significantly lower frequencies (42-48%).

promising potential modifiers of CF include

The overall frequency of non-F508del

mannose-binding lectin (MBL)2, endothelial

mutations is low, except for some

receptor type A (EDNRA), transforming

population-specific mutations such as

growth factor (TGF)-b1, interleukin (IL)-8,

W1282X, which accounts for ,48% of CF

transcription factor 7-like 2 (TCF7L2) and a₁-

chromosomes in Ashkenazi Jews or

antiprotease (SERPINA1). However, further

621+1G.T accounting for 23% of French

studies on large numbers of cases with

Canadian CF chromosomes. Therefore, it is

ERS Handbook: Paediatric Respiratory Medicine

395

the presence of the F508del mutation that

gene is pathogenic or benign. Am J Hum

increases the frequency of CF in Caucasians

Genet; 74: 176-179.

compared to other races (table 2).

Kim D, et al. (2009). The role of CFTR in

bicarbonate secretion by pancreatic duct

and airway epithelia. J Med Invest;

56:

Further reading

Suppl., 336-342.

Knowles MR, et al. (2012). The influence

Bombieri

al.

(2011).

of genetics on cystic fibrosis phenotypes.

Recommendations for the classification

Cold Spring Harb Perspect Med;

of diseases as CFTR-related disorders. J

a009548.

Cyst Fibros; 10: Suppl. 2, S86-S102.

Kraemer R, et al. (2009). Long-term gas

Cystic Fibrosis Genetic Analysis Consortium.

exchange characteristics as markers of

Cystic Fibrosis Mutation Database. www.

deterioration in patients with cystic fibro-

genet.sickkids.on.ca/cftr/app

sis. Respir Res; 10: 106.

Davies JC, et al. (2010). Gene therapy for cystic

Lubamba B, et al. (2012). Cystic fibrosis:

fibrosis. Proc Am Thorac Soc; 7: 408-414.

Insight into CFTR pathophysiology and

Dequeker E, et al. (2009). Best practice

pharmacotherapy. Clin Biochem; 45: 1132-

guidelines for molecular genetic diagno-

1144.

sis of cystic fibrosis and CFTR-related

MacDonald KD, et al.

(2007). Cystic

disorders

- updated European recom-

fibrosis transmembrane regulator protein

mendations. Eur J Hum Genet; 17: 51-65.

mutations: ‘‘class’’ opportunity for novel

Eckford PDW, et al. (2012). Cystic fibrosis

drug innovation. Paediatr Drugs; 9: 1-10.

transmembrane conductance regulator

Pezzulo AA, et al. (2012). Reduced airway

(CFTR) potentiator VX-770

(ivacaftor)

surface pH impairs bacterial killing in the

opens the defective channel gate of

porcine cystic fibrosis lung. Nature; 487:

mutant CFTR in a phosphorylation-

109-113.

dependent but ATP-independent manner.

Quinton PM (2010). Role of epithelial

J Biol Chem; 287: 36639-36649.

HCO3

transport in mucin secretion:

Geborek A, et al.

(2011). Association

lessons from cystic fibrosis. Am J Physiol

between genotype and pulmonary pheno-

Cell Physiol; 299: C1222-C1233.

type in cystic fibrosis patients with severe

Riordan JR (2008). CFTR function and

mutations. J Cyst Fibros; 10: 187-192.

prospects for therapy. Annu Rev Biochem;

Groman JD, et al. (2004). Variation in a

77: 701-726.

repeat sequence determines whether a

World Health Organization. The World

common variant of the cystic fibrosis

Health Report 2004. Changing History.

transmembrane conductance regulator

Geneva, WHO, 2004.

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ERS Handbook: Paediatric Respiratory Medicine

Screening and diagnosis

of CF

Jürg Barben and Kevin Southern

Diagnosis of CF

o60 mmol?L^-1) should always be

confirmed with a second sweat test and

A diagnosis of CF is based on one or more

CFTR mutation analysis. The 40 most

typical phenotypic features (table 1): a

frequent disease-associated CFTR

history of CF in a sibling or a positive

mutations will detect .90% of affected CF

newborn screening result, and a laboratory

patients in most European populations. Up

confirmation of cystic fibrosis

to now, more than 1900 CFTR mutations

transmembrane regulator (CFTR) protein

have been identified, but only a small

dysfunction and/or identification of two CF

percentage (,10%) have been shown to

causing mutations. In most cases, the

definitely cause CF.

diagnosis of CF will be confirmed by

measurement of sweat chloride

The sweat test comprises three phases:

concentration using quantitative

pilocarpine iontophoresis, which measures

N stimulation of the sweat glands

chloride transport through the CFTR

(pilocarpine iontophoresis),

channel. A positive result (sweat chloride

N sweat collection,

N sweat analysis.

The collection of a sufficient amount of

Key points

sweat can sometimes be difficult, especially

N The gold standard confirmation

in very young children, but there have been

method for a suspected CF diagnosis

many improvements in the sweat collection

is the measurement of sweat chloride

method. Newer techniques have reduced the

using pilocarpine iontophoresis.

amount of sweat needed, including the

macroduct collection system or the

N A borderline or positive result should

nanoduct sweat analysing system (fig. 1).

always be confirmed with a second

Sweat testing should always be carried out

sweat test or by CFTR mutation

in accordance with the current guidelines

analysis.

and by a trained and experienced

N Until recently, the diagnosis has

professional. Sweat testing is vulnerable to

usually been made based on clinical

many sources of errors. Table 2 lists some

manifestations, but newborn

of the common causes of false-negative and

screening for CF has been

false-positive sweat test results.

implemented in many European

Sweat chloride concentration increases with

countries.

age in people without CF, but a sweat

Once CF diagnosis has been

chloride concentration of o60 mmol?L^-1 is

confirmed, other family members

usually diagnostic for CF (fig. 2). Values

should be offered screening for the

between 30 and 59 mmol?L^-1 are

disease using sweat testing, especially

intermediate. However, undoubted cases of

all siblings.

CF with normal sweat electrolytes have been

described. The measurement of other

ERS Handbook: Paediatric Respiratory Medicine

397

Table 1. Age-related signs and symptoms of CF

Age

Presentation

Common respiratory

Common non-respiratory

Less common

General (any)

Moist cough with

Salty-tasting skin

sputum production

Respiratory infection with

typical CF pathogen (e.g.

Staphylococcus aureus,

Pseudomonas aeruginosa,

Burkholderia cepacia)

Neonatal

Diagnosis made by newborn

Protracted jaundice

screening (elevated

Intestinal atresia

immunoreactive trypsinogen)

Intestinal atresia

Meconium ileus (10-15% of

Fat soluble vitamin deficiency

patients with CF) causing

(e.g. bleeding due to

bowel obstruction, partly with

vitamin K deficiency)

perforation and peritonitis

Abdominal cramps, fatty stool

Infancy and

Recurrent respiratory

Failure to thrive due to exocrine

Rectal prolapse

childhood

symptoms (chronic cough,

pancreas insufficiency with

Anaemia, oedema and

wheeze and pneumonia)

steatorrhoea, diarrhoea and

hypoproteinaemia

abdominal distension

Dehydration and electrolyte

disturbance (Pseudo-Bartter’s

syndrome, hypochloraemic

metabolic alkalosis)

Cholestasis

Chronic sinusitis

Adolescence

Recurrent respiratory

Azoospermia (secondary

Acute pancreatitis

and adulthood

symptoms (cough and

to congenital bilateral absence

Liver disease and portal

wheeze)

of vas deferens)

hypertension

Bronchiectasis

Pulmonary infection

Clubbing of fingers and toes

with atypical mycobacteria

Chronic pansinusitis

Haemoptysis

and nasal polyps

Allergic bronchopulmonary

aspergillosis

electrolytes (potassium and sodium) is not

Newborn screening

recommended as they are not diagnostic for

Newborn screening for CF, using

CF, but a ratio of sodium/chloride .1 can be

immunoreactive trypsinogen (IRT) in dried

supportive for CF. The measurement of

blood spots taken from infants at the third/

conductivity is approved for screening, but a

fourth day of life, has been implemented in

value o50 mmol?L^-1 should always be

many European countries (fig. 3). The first

confirmed with a sweat chloride

newborn screening programmes were

measurement.

based on IRT measurements from a heel

For patients with an unclear diagnosis, there

prick test with repeat testing for infants

are two main methods of further

with an elevated initial measurement

characterisation of the salt transport defect:

6 weeks later. With the detection of the

CFTR gene in 1989, many countries

N nasal potential difference,

introduced DNA analysis as the second

N intestinal current measurement.

tier of analysis. To date, more than 30

screening programmes have been

Both are challenging and only available in a

developed, with quite marked variation in

few centres. In certain cases, however, they

protocol design. All screening algorithms

can provide valuable further information to

rely on testing for IRT as the primary

help support or refute a diagnosis of CF.

screen for CF. Infants who have an

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ERS Handbook: Paediatric Respiratory Medicine

BorderlineBorderline

(children)

(adults)

Normal

Error

100

120

140

160

Sweat chloride concentration mmol.L^-1

Figure 2. Sweat chloride measurement.

Screen-positive infants are referred to a CF

centre for sweat testing, where the

suspected CF diagnosis will be confirmed or

rejected. The aim of a newborn screening

programme is primarily to detect as many

children with CF and pancreas insufficiency

as possible in order to start treatment as

early as possible, whilst avoiding false-

positive screening results resulting in

unnecessary recalls and sweat tests. The

advantages of early diagnosis include

nutritional benefits, early substitution of

Figure 1. a) A child with a macroduct collection

pancreatic enzymes and fat soluble

system. After pilocarpine iontophoresis to

vitamins, treatment of CF specific

stimulate sweating, the system is firmly attached

pathogens, access to specialised care, a

to the skin of the forearm. Sweat can be seen

reduction in the time of diagnostic

entering the tube system (blue rings). Chloride

uncertainty and the ability to counsel

analysis can be performed on as little as 15-30 mL of

parents for prenatal testing. However,

sweat. b) A child with a nanoduct analysing

screening programmes also have some

system. After pilocarpine iontophoresis to

negative effects. Newborn screening

stimulate sweating, the system measures sweat

identifies some healthy heterozygote

conductivity while attached to the patient.

carriers, which can cause anxiety and

Measuring conductivity can be performed on as

depression in affected families. In addition,

little as 3-5 mL of sweat

some CF-affected individuals will be missed

even in the best newborn screening

programme, depending on the chosen cut-

elevated IRT (usually .99th percentile)

off value of the initial IRT measurement

undergo further assessment either by

(false negatives in up to 8%). Another

another IRT measurement (IRT/IRT

negative impact is the unnecessary

algorithm), genetic testing for the most

medicalisation of infants with an equivocal

common CFTR mutations (IRT/DNA

diagnosis who turn out not to have CF.

algorithm) or further screening algorithms.

Within these two categories, a variety of

Once CF diagnosis has been confirmed,

modifications are used because no single

other family members may be offered

algorithm is perfect. The screening

screening. All siblings need to be screened

algorithm of each country depends on

for the disease (sweat test), which may be

programme resources, and goals including

pre-symptomatic or unrecognised.

mechanisms available for sample

Asymptomatic adult family members may

collection, regional demographics, the

wish to be screened for carrier status to

spectrum of disease phenotype that is to

allow them to make informed choices about

be detected and acceptable failure rates.

prenatal screening.

ERS Handbook: Paediatric Respiratory Medicine

399

Further reading

Farrell PM, et al. (2008). Guidelines for

diagnosis of cystic fibrosis in newborns

Balfour-Lynn IM (2008). Newborn screen-

through older adults: Cystic Fibrosis

ing for cystic fibrosis: evidence for

Foundation consensus report. J Pediatr;

benefit. Arch Dis Child; 93: 7-10.

153: S4-S14.

Castellani C, et al. (2010). European best

Green A, et al. (2007). Guidelines for the

practice guidelines for cystic fibrosis neo-

performance of the sweat test for the

natal screening. J Cyst Fibros; 8: 153-173.

diagnosis of cystic fibrosis. Ann Clin

Clinical and Laboratory Standards Institute.

Biochem; 44: 25-34.

Sweat testing: sample collection and quan-

Mayell SJ, et al.

(2009). A European

titative chloride analysis; approved guide-

consensus for the evaluation and man-

line. 3rd Edn. Wayne, CLSI , 2009.

agement of infants with an equivocal

Comeau AM, et al. (2007). Guidelines for

diagnosis following newborn screening

implementation of cystic fibrosis new-

for cystic fibrosis. J Cyst Fibros; 8: 71-78.

born screening programs: Cystic Fibrosis

Rosenstein BJ, et al.

(1998). The diag-

Foundation workshop report. Pediatrics;

nosis of cystic fibrosis: A consensus

119: e495-e518.

statement. J Pediatrics; 132: 589-595.

De Boeck K, et al. (2006). Cystic fibrosis:

Southern KW, et al. (2007). A survey of

terminology and diagnostic algorithms.

newborn screening for cystic fibrosis in

Thorax; 61: 627-635.

Europe. J Cyst Fibros; 6: 57-65.

ERS Handbook: Paediatric Respiratory Medicine

401

CF lung disease

Nicolas Regamey and Jürg Barben

Lung disease accounts for most of the

episodes of acute worsening of respiratory

morbidity and mortality in CF. CF lung

symptoms, often referred to as ‘‘pulmonary

disease begins early in life. It is

exacerbations’’. Tissue damage ultimately

characterised by impaired mucociliary

results in lung failure and death in most

clearance and mucus obstruction, as well as

people with CF.

chronic pulmonary infection and

Pathophysiology

inflammation, leading to tissue destruction.

Early CF lung disease is characterised by

The most commonly accepted

small airways obstruction and the

pathophysiological explanation for airway

development of bronchiectasis. There is a

disease in CF is the ‘‘low volume’’

progressive decline of lung function with

hypothesis. This hypothesis postulates that

cystic fibrosis transmembrane conductance

regulator (CFTR) dysfunction leads to a loss

Key points

of inhibition of airway epithelial sodium

channels which, in turn, leads to excess

CF lung disease begins early in life. It

sodium and water reabsorption. This results

is characterised by impaired

in dehydration of airway surface liquid.

mucociliary clearance and mucus

Reduced volume of the airway surface liquid

obstruction, and chronic pulmonary

causes failure of mucociliary clearance,

infection and inflammation.

which leads to mucus obstruction of the

small airways. The lungs are not able to

There is a progressive decline of lung

effectively clear inhaled bacteria, viruses,

function with episodes of acute

fungi and airborne pollutants. The thickened

worsening of respiratory symptoms,

mucus on the epithelium forms plaques

referred to as pulmonary

with hypoxic areas that can harbour bacteria

exacerbations.

and other pathogens.

Pulmonary effects of CF typically have

the largest impact on morbidity and

The lungs of children with CF appear normal

mortality, and account for over 80%

at birth but quickly become infected by

of fatalities due to the disease.

organisms that are not adequately cleared.

Infants with CF develop persistent

Current management of CF lung

endobronchial infections early in life due to

disease is predominantly

Staphylococcus aureus, nontypable

symptomatic. The cornerstones of CF

Haemophilus influenzae and Gram-negative

respiratory care are airway clearance

bacilli. By the end of the second decade of

and treatment of pulmonary

life, Pseudomonas aeruginosa is the

infections.

predominant pathogen. Chronic bacterial

Lung transplantation is the final

endobronchial infection is associated with

therapeutic option for patients with

an intense neutrophilic inflammatory

end-stage lung disease.

response that damages the airway, impairs

local host-defence mechanisms and

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ERS Handbook: Paediatric Respiratory Medicine

facilitates further infection. For a given

newborn screening. Both infection and

bacterial load, a person with CF will have up

inflammation are detected by

to 10-times more inflammation than a

bronchoalveolar lavage in CF infants as

person with a lower respiratory tract

young as a few weeks of age. CT scans in CF

infection but without the disease. This

infants show the presence of structural

vicious cycle of inflammation and infection

airway wall changes including thickened

with airway damage results in progressive

airway walls, narrowed airway lumens, air

bronchiectasis, gas trapping, impaired gas

trapping and bronchiectasis. Once present,

exchange (hypoxaemia and hypercarbia) and

bronchiectasis persists and is progressive.

ultimately leads to respiratory failure (fig. 1).

Lung function has also been shown to be

diminished in infants with CF, and lung

Airway disease in CF is present early, even in

function declines over time throughout life.

asymptomatic infants diagnosed through

Pulmonary insufficiency is responsible for at

least 80% of CF-related deaths.

CFTR dysfunction

Clinical manifestations

Pulmonary manifestations of the disease

appear throughout life with a great

Dehydrated airway surface liquid

variability from patient to patient (table 1;

Further reading

Since most patients with pulmonary

Borowitz D, et al. (2009). Cystic Fibrosis

exacerbations have P. aeruginosa in their

Foundation evidence-based guidelines for

airways, the usual in-hospital treatment is a

management of infants with cystic fibro-

combination of a b-lactam and an

sis. J Pediatr; 155: S73-S93.

aminoglycoside. In vitro antibiotic sensitivity

Boucher RC (2007). Airway surface dehy-

tests do unfortunately not predict clinical

dration in cystic fibrosis: pathogenesis

outcome in patients with chronic infection

and therapy. Annu Rev Med, 58: 157-170.

and routine testing of the susceptibility of

Cohen-Cymberknoh M, et al.

(2011).

bacteria to combinations of antibiotics

Managing cystic fibrosis. Strategies that

(synergy testing) is not recommended. In

increase life expectancy and improve

some centres, intravenous antibiotics are

quality of life. Am J Respir Crit Care Med;

given on a routine basis independent of

183: 1463-1471.

pulmonary exacerbations.

Döring G, et al. (2012). Treatment of lung

infection in patients with cystic fibrosis:

Late disease stages Low-flow oxygen therapy

current and future strategies. J Cyst Fibros;

at home, especially with sleep, is applied in

11: 461-479.

case of chronic respiratory failure. Lung

Flume PA, et al. (2009a). Cystic fibrosis

transplantation is the final therapeutic option

pulmonary guidelines: airway clearance

for patients with endstage lung disease.

therapies. Respir Care; 54: 522-537.

Transplantation has the potential to extend

Flume PA, et al. (2009b). Cystic fibrosis

and substantially improve quality of life in

pulmonary guidelines: Treatment of pul-

properly selected patients. How to select

monary exacerbations. Am J Respir Crit

patients (especially children) in an optimal

Care Med; 180: 802-808.

Flume PA, et al. (2010). Cystic fibrosis

way for this high-risk procedure, is still the

pulmonary guidelines: pulmonary com-

subject to debate (see the Prognosis,

plications:

hemoptysis and pneu-

management of end-stage lung disease and

mothorax. Am J Respir Crit Care Med;

indications for lung transplantation in CF

182: 298-306.

section in this Handbook). CF patients with

Kerem E, et al. (2005). Standards of care

chronic respiratory failure who are on a lung

for patients with cystic fibrosis: a

transplant waiting list may be candidates for

European consensus. J Cyst Fibros; 4: 7-

nocturnal non-invasive ventilatory

26.

assistance.

Mott LS, et al. (2012). Progression of early

structural lung disease in young children

Respiratory treatments represent the

with cystic fibrosis assessed using CT.

greatest challenge to patients and families;

Thorax; 67: 509-516.

proper physiotherapy and inhaling

Mogayzel PJ Jr, et al.

(2013). Cystic

hypertonic saline, antibiotics and/or

fibrosis pulmonary guidelines. Chronic

rhDNase is very time consuming and takes

medications for maintenance of lung

1-2 h per day during periods of good health

health. Am J Respir Crit Care Med; 187:

and much longer during a respiratory

680-689.

exacerbation.

ERS Handbook: Paediatric Respiratory Medicine

409

Extrapulmonary

manifestations of CF

Anne Munck, Manfred Ballmann and Anders Lindblad

Nutritional approach in patients with CF

guidelines provide an invaluable tool in daily

care management. Neonatal screening

Maintaining adequate nutritional status in

programmes enabling very early follow-up

terms of lung health and survival is a

care, prior to clinical pulmonary

cornerstone of the CF multidisciplinary

involvement, offer a unique opportunity for

approach. Consensus-based nutritional

nutritional assessment at a crucial period of

rapid growth.

Nutrition When providing nutritional intake

Key points

to achieve normal growth in children and

Nutritional status is strongly

maintain adequate weight in adults, sex, age

associated with pulmonary function

(rapid growth rate in infants and

and survival in CF.

adolescents), specific needs during

pregnancy, nutritional and pancreatic status,

Nutritional management should be

family circumstances, cultural dietary

started as soon as possible after

beliefs, and patient food preferences all

diagnosis.

must be taken into account.

Patients’ height and weight should be

Energy requirements of newly diagnosed

measured at each clinical visit and

infants with CF may range from 110% to

BMI calculated (percentile or z-score

150% of the recommended daily allowance

in children, absolute BMI in adults).

(RDA) (Borowitz et al., 2002; Sinaasappel et

EPI should be confirmed by a

al., 2002; Stallings et al., 2008; Munck,

biological test (steatorrhoea or faecal

2010). Infants with CF can be safely

elastase-1) and PERT should be

breastfed. Additional calories (carbohydrate

started as soon as possible.

content up to 10-12 g per 100 mL and fat

density 5 g per 100 mL) can be added to

Fat-soluble vitamins need to be given

expressed breast milk and/or infant formula

in association with pancreatic

can be concentrated (1.2-1.5 cal?mL^-1) if

enzymes in EPI patients.

weight gain is poor, rather than increasing

The gastrointestinal tract is a major

milk volumes, due to the enhanced risk of

source of comorbidity in CF patients.

gastro-oesophageal reflux (GOR). There is

no evidence to support the use of protein

Entities such as fibrosing

hydrolysate formulas with the exception of

colonopathy, appendiceal mucocoele

infants undergoing small bowel resection for

and DIOS are specific to CF.

meconium ileus, severe failure to thrive or

In the case of acute abdominal pain,

with co-existing cows’ milk protein

surgical conditions need to be sought;

intolerance. Solid food can gradually be

all surgical aetiologies may take on

introduced between 4 and 6 months;

the appearance of recurrent pain with

parents should seek the dietician’s advice on

mild symptoms.

the most suitable foods and pancreatic

enzyme dosage. Young children should later

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ERS Handbook: Paediatric Respiratory Medicine

eat three regular meals and two snacks of

and textures may help in preventing

high nutrient and calorie density.

lassitude. In children, behavioural

interventions have been shown to improve

Protein needs are unknown but may be

nutritional outcome.

higher than normal. Dietary fat intake is

considered adequate at 50% of total energy

Nocturnal enteral feeding through a

intake at ,6 months, and between 40% and

nasogastric tube or gastrostomy, according

50% in older patients.

to the patient’s preference, has to be

considered to provide long-term nutritional

Sodium supplementation is recommended

support in patients not gaining (children) or

for all infants, in hot climates, and in the

keeping (adults) weight. The majority of

case of fever or sport activities.

patients tolerate high-energy polymeric feed

but a semielemental feed may be beneficial

Adolescence is another crucial period, with

for some. All feeds need pancreatic enzyme

increased energy requirements related to

replacement therapy (PERT). Patients may

rapid physical growth.

need up to 70% of RDA by enteral feeding to

Maintaining optimal nutritional status in

improve their weight and are encouraged to

adulthood is a challenge, as the prevalence

continue with a high-energy diet during the

of malnutrition increases with age-related

day. It is important to monitor for glucose

CF complications. Patients’ height and

intolerance and GOR symptoms.

weight should be measured at each clinical

Pancreatic enzyme replacement therapy

visit and BMI calculated (percentile or z-

Exocrine pancreatic insufficiency (EPI)

score in children, absolute BMI in adults).

(Munck, 2010) is present in 85-90% of

Patients who develop CF-related diabetes

patients. Symptoms include: pale, oily

are encouraged to continue eating a diet rich

stools; abdominal pain; and poor weight

in energy and fat (Moran et al., 2010a). A

gain. Even if the patients show these

minimal change in the quantity of

symptoms, a biological confirmatory test is

carbohydrates is generally advised but

required to define pancreatic status. The

distribution may need to be adapted.

faecal elastase-1 test is now widely used and

a level of ,200 mg?g^-1 is diagnostic of EPI.

Pregnancy is possible in women with CF but

Once EPI is confirmed, PERT should start as

the risk of a negative impact on survival may

soon as possible. Currently available

increase with more severe disease and,

preparations are derived from porcine

therefore, it is not recommended in these

pancreas. Enteric-coated preparations

patients. Additional recommended energy

dramatically decrease enzyme degradation

requirements for pregnancy vary from 200

by stomach acidity and improve the release

to 300 kcal?day^-1 (Edenborough et al., 2008).

of enzymes in the duodenum.

Nutritional status before and during

pregnancy influences the evolution of

For some patients with poor response to

pregnancy and newborn outcome.

PERT needing high doses, H2-receptor

antagonists or proton pump inhibitors may

Careful monitoring of the growth chart at

be beneficial.

each consultation is mandatory to prevent

malnutrition. Dietary diary intake with the

Following the occurrence of fibrosing

help of a dietician and evaluation of

colonopathy in the early 1990s in young

treatment compliance are part of

children receiving very high doses of daily

multidisciplinary assessment, and are

PERT and despite the rareness of this

needed for early nutritional intervention. If

complication, the severity of the condition

the principal cause of poor nutritional status

led to consensus guidelines for PERT in

is insufficient food intake despite a high-

2002 recommending not exceeding a daily

energy diet, the use of oral nutritional

dose of 10 000 IU lipase per kilogram per

supplements may be of some use at an

day (2500-3000 IU lipase per 120 mL breast

individual level; a large variety of flavours

milk or formula, 500-2500 IU lipase per

ERS Handbook: Paediatric Respiratory Medicine

411

kilogram per meal or 500-4000 IU lipase

supplementation for all patients might be

per gram of fat) of ‘‘standard’’ or ‘‘high-

beneficial.

strength’’ enzyme preparations. Enzymes

should be given with all fat-containing foods

Low plasma 25-hydroxyvitamin D levels have

at the beginning and middle of the meal,

often been reported and suboptimal status

after adjusting for season remains common.

with the dose gradually increased.

Cholecalciferol (vitamin D₃)

Capsules can be opened for infants and

supplementation is more effective than

toddlers. In infants, micro- or mini-

ergocalciferol (vitamin D₂). Recent

microspheres can be mixed with a small

improvement in our knowledge of the

amount of breast milk, formula or fruit

different roles of fat-soluble vitamins

puree. Microspheres should not be crushed,

emphasises the need for optimal

chewed or mixed with the meal.

supplementation. Water-miscible

multivitamins formulations with satisfactory

There is insufficient evidence to establish a

bioavailability profiles have been developed.

dose-response association between PERT

Current guidelines (Sinaasappel et al., 2002;

and weight gain. Usually, adequacy of PERT

Maqbool et al., 2008) on fat-soluble vitamin

is evaluated clinically by growth, weight,

prescriptions are old and may require

stool pattern and abdominal pain. In some

updating.

cases, it may be helpful to assess the

coefficient of fat absorption (3-day stool

Gastrointestinal complications in CF

collection and diet intake).

Digestion, absorption and motility In CF, the

three main gastrointestinal functions are

Fat-soluble vitamin supplementation Patients

impaired (Borowitz et al., 2005).

with EPI should be supplemented with fat-

Maldigestion and malabsorption are

soluble vitamins (table 1) (Maqbool et al.,

secondary, and the main cause is abnormal

2008) from the time of diagnosis and serum

pancreatic function with reduced

levels measured annually. Pancreatic-

bicarbonate secretion (thus impairing

sufficient patients should have their serum

pancreatic enzyme lipase activity and

fat-soluble vitamin levels checked annually,

precipitating bile acids, inhibiting lipid

with doses adjusted accordingly.

emulsification) and a dramatic decrease in

enzyme secretion. Other luminal factors are

To ensure satisfactory oral bioavailability, all

excessive mucus production with abnormal

fat-soluble vitamin (A, E, D and K)

composition, impaired gut motility, small

formulations need to be ingested

intestine bacterial overgrowth, chronic gut

concomitantly with pancreatic enzymes

inflammation and gut lumen dehydration

during the meal. Vitamin A is stored in the

closely related to a CF transmembrane

liver. Plasma retinol measurements should

conductance regulator (CFTR) basic ion

be taken during clinical stability. b-carotene,

transport defect (i.e. decreased chloride

a pro-vitamin A antioxidant, is subject to

secretion, and enhanced sodium and water

regulation in its conversion to vitamin A,

absorption from the lumen).

potentially decreasing the risk of

hypervitaminosis A. Vitamin E represents an

Physiological and pathological abnormalities A

important, powerful antioxidant. Vitamin E

variety of abnormalities have been identified

status can be evaluated by serum level

in the gastrointestinal tract but their role in

concentration or serum concentration/lipid

clinical syndromes remains poorly

ratio. Vitamin K deficiency is common in

understood. Gut histology shows dilated

pancreatic-insufficient patients with

mucus glands with inspissated mucus and a

additional risk factors: first year of life,

normal enterocyte brush border.

frequent antibiotic use (reduced production

Ultrasonography identifies a marked

of menaquinones by the modified gut flora)

increase in small and large bowel wall

and cholestasis. Prothrombin time is

thickness (Wilschanski et al., 1999).

monitored annually. Routine

Recently, duodenal pH studies with wireless

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Fat-soluble vitamins: current daily intake

Vitamin

Age group

Intake recommendations mg

Monitoring recommendations

(IU)

0-12 months

510

(1500)

Serum retinol (deficiency

,20 mg?dL^-1)

1-3 years

1700

(5000)

(RBP zinc level)

4-8 years

1700-3400 (5000-10 000)

.8 years/adults

3400

(10 000)

0-12 months

40-50 (40-50)

Serum a-tocopherol

1-3 years

80-150 (80-150)

4-8 years

100-200 (100-200)

.8 years/adults

200-400 (200-400)

0-12 months

0.3-0.5

Serum prothrombin time

1-8 years

0.3-0.5

Adults

2.5-5 per week

0-12 months

(400)

Serum 25(OH)D in late autumn

or winter

.1 year

10-20 (400-800)

RBP: retinol binding protein; 25(OH)D: 25-hydroxyvitamin D. Reproduced and modified from Maqbool et al.

(2008).

capsules demonstrated low pH as a

presentation includes recurrent acute

consequence of decreased pancreatic

abdominal pain, vomiting, increased

bicarbonate secretion. Transit time was also

amylase and lipase levels, and pancreatic

evaluated with this technique and identified

ultrasonography or CT abnormalities.

delayed small bowel transit without a

Amylase and lipase levels may also be

compensatory increase in whole-gut transit

normal or only slightly elevated.

(Gelfond et al., 2012). Chronic gut

Management consists of pain relief, fasting,

inflammation has been identified in

intravascular hydration, use of proton pomp

duodenal biopsies and by increased

inhibitors and progressive diet

calprotectin levels in stools and pro-

reintroduction (initially lipid-free diet).

inflammatory cytokines in gut lavage (Werlin

Because pancreatitis may be a presenting

et al., 2010).

feature of CF or CFTR-related disorder

(Munck, 2004), sweat testing and CFTR

Pancreatic exocrine and extrahepatic biliary

genetic testing are recommended in

complications Pancreatitis (De Boeck et al.,

pancreatitis of unknown cause.

2005; Ooi et al., 2012) occurs in up to 20%

of pancreatic-sufficient patients carrying at

Extrahepatic biliary manifestation with

least one mild CFTR mutation (class IV or

undetectable gallbladder in CF fetuses is

V). It is more common in adolescents and

common. Later, gallstones with cholesterol

adults. Patients are at risk of recurrent acute

or calcium bilirubinate are frequent and are

or chronic pancreatitis. Progression to EPI

a consequence of chronic bile salt loss and

with acinar destruction - which may take

enhanced unconjugated bilirubin in the

years - contributes to the resolution of the

colon impairing colonic reabsorption.

pancreatitis. Possible triggering factors

Medical treatment with ursodeoxycholic acid

include alcohol, gallstones, abnormalities of

(UDCA) is ineffective. In the case of

the pancreaticobiliary junction, dehydration,

complications (pain and jaundice), which

modifier genes and specific non-CFTR

occur in 4-10% of patients, surgery is

mutations (Ooi et al., 2012). The typical

required.

ERS Handbook: Paediatric Respiratory Medicine

413

Gut manifestations GOR is very frequent in

is discussed. Meconium ileus is not

CF, even in infants (Vic et al., 1995). It has

exclusive to CF patients (although the

been postulated that GOR is a consequence

majority have CF) and thus diagnostic tests

of respiratory disease but there is no

should be performed as soon as possible to

correlation between GOR and lung disease

confirm or refute CF diagnosis. The

severity. The underlying mechanisms are not

tendency to express the meconium ileus

completely understood and appear to be

phenotype might also be related to non-

multifactorial: the majority of reflux episodes

CFTR genetic factors called modifier genes

are caused by transient lower oesophageal

(Dorfman et al., 2009). The clinical

relaxation rather than decreased lower

presentation of this distal bowel obstruction

oesophageal sphincter pressure (Pauwels et

combines distension, bilious vomiting and

al., 2012). Other factors are involved such as

failure to pass the meconium within 48 h of

thoracic distension, coughing, malnutrition,

birth. Radiography identifies abdominal

delayed gastric emptying, postural drainage

distension and dilated loops. Barium enema

head-down and certain drugs. The most

shows a microcolon with a ‘‘soap bubble’’

common symptoms are heartburn (pyrosis),

aspect in the right iliac fossa corresponding

nocturnal cough, vomiting, abdominal

to meconium pellets in the distal ileum.

epigastric pain, dysphagia and unexplained

Management of uncomplicated meconium

pulmonary deterioration, but GOR may also

ileum relies on enema with diluted

remain asymptomatic. GOR may affect both

Gastrografin, a hyperosmolar, water-soluble,

respiratory function and nutritional status. It

radio-opaque meglumine diatrizoate

is reasonable to start a trial of medical

solution containing 0.1% polysorbate 80

therapy based on clinical symptoms. An

(Tween 80) slowly infused at low pressure

upper endoscopy is indicated in case of

under fluoroscopy control to relieve

dysphagia, haematemesis or suspicion of

obstruction. Enema can be repeated and the

peptic ulceration; a 24-h ambulatory

success rate is close to 40%. In case of

oesophageal pH probe is useful when there

failure, surgery is required. Complicated

is doubt as to whether GOR is the cause of

meconium ileus (40%) with peritonitis,

symptoms, prior to starting enteral feeding

volvulus and intestinal atresia requires

and when lung transplant is considered.

immediate surgery. Depending on the

Standard management combines thickening

severity of the newborn’s clinical condition,

food in infants, raising the head of the bed

different surgical approaches can be

and acid suppression with proton pump

considered: enterostomy irrigating the distal

inhibitors. Prokinetic drugs are no longer

bowel through the stoma, resection of the

available in many countries. For patients

compromised bowel with complete proximal

who fail to respond, a surgical

and distal meconium evacuation, and either

fundoplication can be discussed and may

a primary anastomosis or a temporary

slow pulmonary decline, reduce the number

enterostomy (Carlyle et al., 2012). Post-

of exacerbations and improve weight gain

operative care and nutritional support by a

(Sheikh et al., 2012).

gastroenterology team is part of meconium

ileus management. With early detection,

Meconium ileus is the earliest CF clinical

appropriate therapy and nutritional support,

manifestation occurring in up to 20% of CF

death is now uncommon, and long-term

newborns. Diagnosis can be made through

nutritional and pulmonary outcomes are

ultrasonography in utero during the second

equivalent to those of other CF patients.

trimester revealing polyhydramnios with a

dilated, hyperechogenic fetal bowel. The

Meconium plug syndrome consists of

distal intestinal obstruction is caused by

abnormal meconium accumulation located

accumulation of abnormal viscous

in the colon that produces mild abdominal

meconium in the lumen. Careful diagnostic

distension and failure to pass meconium.

evaluation and a consultation with a genetic

Management relies on contrast enema.

counsellor are recommended, including

About 25% of patients present

CFTR gene analysis if pregnancy termination

underlying CF.

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ERS Handbook: Paediatric Respiratory Medicine

Distal intestinal obstruction syndrome

may be tried before considering resection of

(DIOS) is specific to CF and is a common

the ileocaecum. Patients presenting

complication in adolescents and adults (five

incomplete DIOS usually respond to oral

to 12 cases per 1000 patients per year)

rehydration combined with osmotic laxative

(Houwen et al., 2010; Colombo et al., 2011).

lavage containing PEG. Maintenance

It is characterised by the accumulation of

therapy with oral PEG for a few months is

viscid faecal material in the terminal ileum

recommended and, in cases of a decline in

and/or the right colon. Patients are at high

the frequency of bowel movements, this has

risk of recurrence (50%). The

been shown to decrease the risk of

physiopathology is not fully understood and

recurrence of DIOS episodes in up to 50%.

probably multifactorial, involving

Bowel preparation before surgery

gastrointestinal lumen dehydration,

(transplantation) has been suggested to

impaired motility and abnormal bile acid

prevent DIOS post-operatively.

absorption. Reported risk factors include a

severe genotype, pancreatic insufficiency

Fibrosing colonopathy was first described in

(but it does not play a central role because

the 1990s (Smyth et al., 1995) in four young

DIOS does not occur in pancreatic

children thought to have DIOS. They

insufficiency out of CF and may occur in

presented acute abdominal pain, diarrhoea

pancreatic-sufficient CF patients),

and partial to complete abdominal

dehydration, poorly controlled fat

obstruction. Investigation with contrast

malabsorption, intestinal dysmotility, history

enema showed loss of haustral folds and

of myocardial infarction and surgery. DIOS

mild to complete occlusion, mainly in the

typically has an acute onset of symptoms.

right colon. In most cases, a laparotomy had

Complete DIOS is defined as the

to be performed with a right hemicolectomy.

combination of 1) complete intestinal

Histology identified submucosal thickness

obstruction with bilious vomiting or fluid

due to fibrous connective tissue and an

levels on radiography with 2) a faecal mass

intact epithelium border. A case-control

in the right iliac fossa and 3) abdominal pain

study confirmed a strong association

and/or distension. Incomplete DIOS gathers

between fibrosing colonopathy and

the two latter symptoms. A surgical

excessive PERT supplementation

aetiology has to be ruled out (appendicitis,

(.50 000 IU lipase per kilogram per day).

intussusception, volvulus adhesions, etc.),

Thus, European and American guidelines

thus an ultrasonography or an abdominal

(Sinaasappel et al., 2002; Borowitz et al.,

CT may be needed. Treatment of DIOS relies

2002) published in 2002 agreed to

on a stepwise approach depending on the

recommend restrictions on PERT doses to

severity of the syndrome. Complete DIOS

f10 000 IU?kg^-1?day^-1; since then, cases

with moderate obstruction can be treated

have virtually disappeared.

with polyethylene glycol (PEG) lavage; in the

case of more severe presentation with

Acute appendicitis is less common in CF

bilious vomiting, hospitalisation with

patients (1.5-5% compared with 7% in

fasting, intravascular hydration and diluted

healthy peers). Surveys have shown a high

sodium meglumine diatrizoate

rate of perforation and abscesses related to

(Gastrografin) enema under direct vision

subacute presentation and delayed

until the terminal ileum is reached may

diagnosis probably as a consequence of

achieve resolution of obstruction. Close

frequent antibiotic prescriptions for

monitoring of the patient is recommended

pulmonary exacerbations (Coughlin et al.,

because Gastrografin enema may cause

1990). Appendiceal mucocoele is a mucoid

major ion and water shifts. In the case of

distension of the appendix that can remain

failure, because surgery is a high-risk

asymptomatic, or cause chronic pain or

intervention, a colonoscopy with local

mimic appendicitis. It can occur at all ages.

instillation of Gastrografin in the caecum

Clinical examination of the right iliac fossa

and ileum lavage may be an alternative. If it

identifies a small ovoid mass.

fails an attempt of washout, enterostomy

Ultrasonography focusing in the right iliac

ERS Handbook: Paediatric Respiratory Medicine

415

fossa shows a multilayer mass with an

considered in any CF patient presenting with

enlarged appendix (.6 mm) filled with

chronic diarrhoea or abdominal pain despite

echogenic material. To rule out other

adequate PERT replacement. The presence

aetiologies, CT or contrast enema may be

of anti-endomysium and anti-

indicated and may reveal the caecal defect.

transglutaminase antibodies has good

In the case of symptoms, appendectomy

sensitivity but a duodenal biopsy is required

with resection of the appendix edges and

to confirm diagnosis and start the patient on

resection of the caecal tip will avoid the risk

a lifelong, strict gluten-free diet.

of recurrence (Munck et al., 2000). At

Crohn’s disease has been reported in CF.

histology, the appendix is distended with

Symptoms are difficult to differentiate from

inspissated mucus.

symptoms in CF, including diarrhoea,

The incidence of intussusception is 1%, and

abdominal pain, weight loss and

it occurs mainly in children and adolescents.

inflammatory parameters. A colonoscopy

It is usually ileocolic, but can also be

with multiple biopsies is essential to

ileoileal; it may resolve spontaneously. It is a

confirm diagnosis.

consequence of dehydrated mucus and

There is an increased risk of digestive tract

impaired intestinal motility but a starting

cancer, mainly colon, bowel, biliary tract,

point is frequent, such as inspissated

liver and pancreas, but these remain rare

secretions, lymphoid follicles, the appendix

conditions. However, patients with CF have

or polyps (with a malignancy risk in adults).

earlier onset with a markedly increased risk

Clinical presentation combines severe

between 20 and 29 years of age (Alexander

colicky abdominal pain, vomiting, bloody

et al., 2008).

stools and a palpable mass in the right iliac

fossa. Abdominal radiography may show

CF-related liver disease

obstruction, ultrasonography may reveal the

CF-related liver disease (CFLD) accounts for

characteristic ‘‘bull’s eye’’ and abdominal CT

,2.5% of overall mortality in CF. 27-35% of

can confirm the diagnosis if there is a doubt

patients will develop some sort of liver

concerning the differential diagnosis.

involvement while about 5-10% will develop

Intussusception reduction in children is the

multilobular cirrhosis (MLC) with portal

first choice unless complicated

hypertension (PHT) (Flass et al., 2012;

(perforation). If it fails or is complicated,

Debray et al., 2011). In patients developing

immediate surgery is required (Nash et al.,

severe liver disease, liver involvement

2011).

commonly starts during the first decade of

Rectal prolapse occurs mainly at preschool

life and develops to MLC with PHT during

age and usually resolves after adjustment of

the second decade of life. Often, the PHT is

PERT, an adequate-fibre diet, stool softeners

complicated by variceal bleeding before liver

and advice concerning voiding. Rectal

failure develops. The variceal bleeding

prolapse may be also be a presenting feature

demands treatment with variceal banding/

of CF.

sclerosing and, sometimes, nonselective b-

blockers. The final option is often orthotopic

Comorbid gastrointestinal conditions Milk

liver transplantation.

protein intolerance occurs more often in CF.

Infants present nonspecific symptoms such

Pathophysiology CFTR is expressed on the

as diarrhoea, constipation, vomiting, failure

apical surface of the cholangiocytes, and the

to thrive and eczema. Abnormal biological

current belief is that missing CFTR results in

tests, including IgE levels, specific

obstruction of the small intrahepatic bile

antibodies and prick tests, are helpful for

ducts and retention of toxic substances,

indicating a semielemental diet.

leading to the most common histological

feature in CFLD, focal biliary cirrhosis. The

Coeliac disease has a prevalence of 1.2% in

reason for its focality is unknown. The focal

CF, which is higher than in the general

biliary cirrhosis slowly develops into MLC

population (Pohl et al., 2011). It should be

without any symptoms (Debray et al., 2011).

416

ERS Handbook: Paediatric Respiratory Medicine

Most commonly, only patients with two

ultrasonography may be even more sensitive

severe mutations (class I-III) and

than clinical or biochemical abnormalities.

pancreatic insufficiency develop MCL

In some situations, liver biopsy can be

(Colombo et al., 2002). No CF mutations

indicated (Debray et al., 2011).

have been related to more severe liver

Treatment The liver disease in CF develops

disease and the liver phenotype in patients

slowly, and may remain stable for years and

with the same genotype varies. Modifying

maybe decades. In many cases, liver

genes have been sought but, so far, only the

transplantation is not needed. Based on the

SERPINA1 Z-allele shows an association

hypothesis that the starting event of CFLD is

with MLC and PHT (Bartlett et al., 2009).

bile duct obstruction, UDCA, a bile acid that

Other liver involvement Neonatal

has hydrophilic and choleretic properties

hyperbilirubinaemia can be associated with

and may act as a cytoprotective agent, is

CF but normally resolves spontaneously

used for treatment of CFLD, mostly in

(Shapira et al., 1999). Liver enzymes are

Europe. Although evidence of an effect on

often raised during the first year after

the level of liver enzymes, biliary drainage,

diagnosis and not related to later severe

ultrasound changes and possibly liver

liver disease. Up to 75% have steatosis of

histology exist, there is no information

differing degrees, most probably related to

about long-term effects of halting the

nutritional deficiencies. Massive steatosis in

progression of CFLD. It has been suggested

the early years has become less common,

that patients would gain from early

probably due to improved care and

treatment when there are less severe

nutrition. Currently, steatosis in CF is

pathological changes, although there is no

considered a benign condition not related to

evidence to support this. The recom-

the development of MLC.

mended starting dose is 20 mg?kg^-1?day^-1

(Debray et al., 2011). Common

Screening for liver disease Since the

recommendations include contraindication

development of MLC with or without PHT is

of salicylic acid and nonsteroidal anti-

asymptomatic, screening for CFLD is

inflammatory drugs, vaccination against

necessary. At the annual review, liver

hepatitis A and B, and special attention to

enzymes and other biochemical markers of

nutritional status to ensure adequate caloric

liver disease, including alanine

intake (increase energy intake, and enteral

transaminase (ALT), aspartate transaminase

nasogastric feeding when awaiting a liver

(AST), serum alkaline phosphatase, c-

transplant).

glutamyl transpeptidase (GGT), albumin

and prothrombin time, and a thorough

All patients with signs of CFLD should be

physical examination must be included.

evaluated by a paediatric gastroenterologist

Regular ultrasound of the liver and the

with knowledge of liver disease in CF.

biliary tract are often performed, at least

CF-related diabetes

during childhood and adolescence, and are

suggested if the liver enzymes are raised at

CF-related diabetes (CFRD) is the most

the annual review. The presence of CFLD

frequent comorbidity in CF. Starting with a

should be suspected when the liver enzymes

prevalence of ,3% at the age of 10 years, the

(ALT, AST and GGT) are raised three times

prevalence increases and peaks at 25-30%

over a 12-month period after excluding other

at 35-40 years. CFRD mimics some aspects

causes of liver disease, and ultrasonography

of type 1 and other aspects of type 2 diabetes

shows hepatomegaly/splenomegaly,

(Moran et al., 2010a): it is an insulin-

increased/irregular echogenicity or irregular

deficient status but with some remaining

margins. Signs of PHT are leukopenia,

insulin secretion. CFRD is associated with a

thrombocytopenia and splenomegaly. It is

faster decrease in lung function, weight loss

important to emphasise that not all patients

and reduced survival compared with age-

developing CFLD display pathologically

and sex-matched nondiabetic CF patients. It

increased liver enzymes and

is difficult to diagnose CFRD at an early

ERS Handbook: Paediatric Respiratory Medicine

417

stage because typical clinical symptoms are

patients, including self-managed glucose

often absent. There is no simple laboratory

measurements, blood pressure control and

test to screen for CFRD. Glycated

3-monthly HbA1c measurements. The aim is

haemoglobin (HbA1c), as a single laboratory

HbA1c ,7% and no hyper- or hypoglycaemic

marker, will miss ,30% of all CF patients

situations. The risk of hypoglycaemia is real

with CFRD. The oral glucose tolerance test

and must be addressed with education of

(OGTT) is the ‘‘gold standard’’ for

the patient and monitoring of blood glucose

diagnosing CFRD (Moran et al., 2009a).

levels. Since ketoacidosis is untypical in

Some specialised centres use continuous

CFRD, in these rare cases, type 1 diabetes

glucose monitoring, a more sophisticated

must be excluded. In CF centres, treatment

method for early identification of CF patients

of CFRD is by a team approach including

with CFRD. Annual OGTTs starting at the

pulmonologists, diabetologists, dieticians

age of 10 years are a recommended

and psychologists.

screening procedure for CFRD. Screening for

Sinus disease in CF

CFRD is especially important for patients

who are on nocturnal feeding, pregnant,

Sinus abnormalities are prevalent in CF and

experiencing a severe acute exacerbation or

chronic rhinosinusitis has been shown in up

on systemic steroids.

to 74-100% of the patients, increasing with

age, but is not always symptomatic. The

It is well accepted to start treatment of

pathophysiology is unclear but is believed to

CFRD independent of fasting

be a combination of increased viscosity of

hyperglycaemia (Moran et al., 2009b).

mucus, decreased clearance and chronic

Clinical studies in the last 15 years have

infection (Schraven et al., 2011). Problems

shown positive clinical effects of insulin

from the upper airways should be handled in

treatment of CFRD, with an increase in lung

close cooperation with an otolaryngologist

function and nutrition, and decreasing risk

with experience of CF sinus disease.

of exacerbation. The recommendation is

initially single insulin doses with main meals

Common radiological findings are frontal

and adding long-acting insulin as soon as

sinus agenesis/hypoplasia and opacification

fasting hyperglycaemia is observed (Moran

of the maxilla ethmoid sinus. There is no or

et al., 2009a; UK Cystic Fibrosis Trust

only low correlation of CT findings with

Diabetes Working Group, 2004). In general,

symptoms. Nasal polyps are common from

nutritional advice differs significantly

childhood, increasing with age. Symptoms

between diabetes treatment in general and

of the upper airways, like nasal obstruction,

in the case of CFRD. CF patients have to

chronic or recurrent headache due to

maintain a high caloric intake not to lose

sinusitis and anosmia/hyposmia, are

weight. Management of CFRD must be

frequently found when the patient is asked

individualized (UK Cystic Fibrosis Trust

and it is important to include these

Diabetes Working Group, 2004). Oral

symptoms in the annual assessment.

antidiabetic drugs have been used in the

treatment of CFRD. Up to now, prospective

Medical management includes nasal steroids,

randomised controlled clinical studies

saline irrigation and antibiotics (adapted to

demonstrating a positive clinical effect of

local sampling). The type of bacterial

colonisation of the upper airways may differ

these drugs in the treatment of CFRD are

from the colonisation of the lower airways. Up

lacking. The use of oral antidiabetic drugs is

to 25% of cases undergo sinus surgery, where

therefore not recommended outside clinical

endoscopic sinus surgery has been more

trials. Late complications of CFRD are well

successful than polypectomy alone or

described for microvascular (retinopathy,

Caldwell Luc procedures (Haworth, 2010).

neuropathy and nephropathy) but not for

macrovascular diseases (van den Berg et al.,

CF-associated osteoporosis

2008). CF patients on insulin should

participate in CFRD education programmes

Osteoporosis is a common medical problem

and follow their treatment like other diabetic

in adults with CF. Although osteoporosis is

418

ERS Handbook: Paediatric Respiratory Medicine

seldom symptomatic in the paediatric age

Borowitz D, et al. (2005). Gastrointestinal

group, osteopenia/osteoporosis starts

outcomes and confounders in cystic

during childhood/adolescence. It is therefore

fibrosis. J Pediatr Gastroenterol Nutr; 41:

of vital importance that this problem is

273-285.

addressed during these age periods, with

Carlyle BE, et al.

(2012). A review of

special attention to the risk factors

pathophysiology and management of

mentioned below, to be able to decrease the

foetuses and neonates with meconium

prevalence of osteopenia/osteoporosis in

ileus for the pediatric surgeon. J Pediatr

adults.

Surgery; 47: 772-781.

Colombo C, et al. (2002). Liver disease in

The pathogenesis is a combination of

cystic fibrosis: a prospective study on

factors: malnutrition/malabsorption, delayed

incidence, risk factors and outcome.

puberty and hypogonadism, vitamin D and

Hepatology; 36: 1374-1382.

K deficiency, systemic inflammation due to

Colombo C, et al. (2011). Guidelines for

pulmonary infections, use of oral

the diagnosis and management of distal

glucocorticosteroids, low activity level and

intestinal obstruction syndrome in cystic

possibly a direct effect of CFTR dysfunction

fibrosis patients. J Cyst Fibros; 10: Suppl.

on bone cells (Aris et al., 2005).

2, S24-S28.

Coughlin JP, et al. (1990). The spectrum

For the recommended frequency of

of appendiceal disease in cystic fibrosis.

performing dual-energy X-ray

J Pediatr Surg; 25: 835-839.

absorptiometry (DEXA), refer to the Further

De Boeck K, et al. (2005). Pancreatitis

reading list. At all ages, the frequency of

among patients with cystic fibrosis:

DEXA should be increased if there are

correlation with pancreatic status and

significant risk factors or before prescribing

genotype. Pediatrics; 115: 463-469.

bone protective therapy.

Debray D, et al.

(2011). Best practice

guidance for the diagnosis and manage-

Preventive measures rely on normal

ment of cystic fibrosis-associated liver

nutritional status, weight-bearing exercise,

disease. J Cyst Fibros; 10: Suppl. 2, S29-

supplementation with cholecalciferol to

S36.

achieve optimal plasma 25-hydroxyvitamin D

Dorfman R, et al. (2009). Modifier gene

levels, high dietary intake of calcium and

study of meconium ileus in cystic fibrosis:

possibly supplementation with vitamin K₁

statistical considerations and gene map-

(Aris et al., 2005; Sermet-Gaudelus et al.,

ping results. Hum Genet; 126: 763-778.

Edenborough FP, et al. (2008). Guide-

2011).

lines for the management of pregnancy in

women with cystic fibrosis. J Cyst Fibros;

Further reading

7: Suppl. 1, S2-S32.

Flass T, et al. Cirrhosis and other liver

Alexander CL, et al. (2008). The risk of

disease in cystic fibrosis. J Cyst Fibros

gastrointestinal malignancies in cystic

2012; pii: S1569-1993(12)00227-5.

fibrosis: case report of a patient with a

Gelfond D, et al. Intestinal pH and

near obstructing villous adenoma found

gastrointestinal transit profiles in cystic

on colon cancer screening and Barrett’s

fibrosis patients measured by wireless

esophagus. J Cyst Fibros; 7: 1-6.

motility capsule. Dig Dis Sci 2012 [In press

Aris RM, et al.

(2005). Guide to bone

DOI: 10.1007/s10620-012-2209-1].

health and disease in cystic fibrosis. J Clin

Haworth CS (2010). Impact of cystic

Endocrinol Metab; 90: 1888-1896.

fibrosis on bone health. Curr Opin Pulm

Bartlett JR, et al. (2009). Genetic modi-

fiers of liver disease in cystic fibrosis.

Med; 16: 616-622.

JAMA; 302: 1076-1083.

Houwen RH, et al. (2010). Defining DIOS

Borowitz D, et al.

(2002). Consensus

and constipation in cystic fibrosis with a

report on nutrition for pediatric patients

multicentre study on the incidence, char-

with cystic fibrosis. J Pediatr Gastroenterol

acteristics, and treatment of DIOS.

Nutr; 35: 246-259.

J Pediatr Gastroenterol Nutr; 50: 38-42.

ERS Handbook: Paediatric Respiratory Medicine

419

Maqbool A, et al. (2008). Update on fat-

Sermet-Gaudelus I, et al.

(2011).

soluble vitamins in cystic fibrosis. Curr

European cystic fibrosis bone mineralisa-

Opin Pulm Med; 14: 574-581.

tion guidelines. J Cystic Fibros; 10: Suppl.

Moran A, et al. (2009a). Cystic fibrosis-

2, S16-S23.

related diabetes: current trends in pre-

Shapira R, et al.

(1999). Retrospective

valence, incidence, and mortality.

review of cystic fibrosis presenting as

Diabetes Care; 32: 1626-1631.

infantile liver disease. Arch Dis Child; 81:

Moran A, et al. (2009b). Insulin therapy

125-128.

to improve BMI in cystic fibrosis-related

Sheikh SI, et al.

(2012). Outcomes of

diabetes without fasting hyperglycemia:

surgical management of severe GERD in

results of the cystic fibrosis related

patients with cystic fibrosis. Pediatr

diabetes therapy trial. Diabetes Care; 32:

Pulmonol; 48: 556-562.

1783-1788.

Sinaasappel M, et al. (2002). Nutrition in

Moran A, et al.

(2010). Clinical care

patients with cystic fibrosis: a European

guidelines for cystic fibrosis-related dia-

Consensus. J Cyst Fibros; 1: 51-75.

betes. Diabetes Care; 33: 2697-2807.

Smyth RL, et al. (1995). Fibrosing colono-

Munck A (2004). Heat wave and acute

pathy in cystic fibrosis: results of a case-

pancreatitis: very unusual cystic fibrosis

control study. Lancet; 346: 1247-1251.

presentation. Pediatrics; 113: 1846.

Stallings VA, et al.

(2008). Evidence-

Munck A (2010). Nutritional considera-

based practice recommendations for

tions in patients with cystic fibrosis.

nutrition-related management of children

Expert Rev Respir Med; 4: 47-56.

and adults with cystic fibrosis and

Munck A, et al. (2000). Ultrasonography

pancreatic insufficiency: results of a

detects appendicular mucocele in cystic

systematic review. J Am Diet Assoc; 108:

fibrosis patients suffering recurrent

832-839.

abdominal pain. Pediatrics; 105: 921.

Cystic

Fibrosis

Trust

(2004).

Nash EF, et al. (2011). Intussusception in

Management of cystic fibrosis related

adults with cystic fibrosis: a case series

diabetes mellitus. Report of the UK

with review of the literature. Dig Dis Sci;

Cystic Fibrosis Trust Diabetes Working

56: 3695-3700.

Group. www.cysticfibrosis.org.uk/media/

Ooi CY, et al.

(2012). Cystic fibrosis

82028/CD_Diabetes_Mellitus_Management_

transmembrane conductance regulator

Jun_04.pdf

(CFTR) gene mutations in pancreatitis. J

van den Berg JM, et al.

(2008).

Cyst Fibros; 11: 355-362.

Microvascular complications in patients

Oomen K, et al. (2012). Sinonasal man-

with cystic fibrosis-related diabetes

ifestations in cystic fibrosis. Int J

(CFRD). J Cyst Fibros; 7: 515-519.

Otolaryng; 2012: 789572.

Vic P, et al. (1995). Frequency of gastro-

Pauwels A, et al. (2012). Mechanisms of

esophageal reflux in infants and in young

increased gastroesophageal reflux in

children with cystic fibrosis. Arch Pediatr;

patients with cystic fibrosis. Am J

2: 742-746.

Gastroenterol; 107: 1346-1353.

Werlin SL, et al.

(2010). Evidence of

Pohl JF, et al. (2011). Cystic fibrosis and

intestinal inflammation in patients with

celiac disease: both can occur together.

cystic fibrosis. J Pediatr Gastroenterol

Clin Pediatr; 50: 1153-1155.

Nutr; 51: 304-308.

Schraven SP, et al. (2011). Prevalence and

Wilschanski M, et al. (1999). Findings on

histopathology of chronic polypoid sinu-

routine abdominal ultrasonography in

sitis in pediatric patients with cystic

cystic fibrosis patients. J Pediatr

fibrosis. J Cyst Fibros; 10: 181-186.

Gastroenterol Nutr; 28: 182-118.

420

ERS Handbook: Paediatric Respiratory Medicine

Emerging treatment

strategies in CF

Melinda Solomon and Felix Ratjen

Traditionally, treatment has included airway

clearance therapies, and inhaled and

Key points

systemic antibiotics, as well as strategies to

improve nutritional status. More recent

N Despite the successes of CFTR

therapeutic interventions have focused on

modulation, treatment of infection

correcting the protein defect or the

and inflammation remain important

abnormal ion composition in the CF airway.

targets.

The hope is that this form of therapy/

N Therapeutic options in CF are

intervention could change the prognosis of

increasing rapidly.

CF patients by altering the disease

progression.

N CFTR directed pharmacotherapy is

moving into the clinic.

CFTR pharmacotherapy

Cystic fibrosis transmembrane conductance

Ivacaftor (previously VX-770) is an orally

regulator (CFTR) gene mutations result in

bioavailable CFTR potentiator with

protein dysfunction by affecting a variety of

impressive clinical efficacy and a good safety

different steps in CFTR protein production

profile. Studies have focused on CF patients

and function, including synthesis,

carrying the most common gating mutation

maturation, intracellular transport, epithelial

(G551D), but clinical trials for other

expression and gating function (fig. 1). CF

mutations in this class are currently under

drugs are currently being evaluated to

way. In patients carrying at least one allele of

improve CFTR protein expression at the cell

G551D, ivacaftor was found to improve ion

surface and/or CFTR function. CFTR

transport as illustrated by nasal potential

pharmacotherapy affects aspects of

difference measurements and to reduce

disturbed intracellular function including

sweat chloride concentrations after oral

protein trafficking, CFTR expression or

administration of the drug in CF patients.

function of CFTR at the cell membrane.

The mean sweat chloride concentrations in

Therapies currently being evaluated target

treated patients fell below 60 mmol?L^-1; the

class I to III mutations, but it is important to

diagnostic threshold for making a CF

recognise that these therapies could

diagnosis. This effect has not been observed

potentially also benefit patients with class IV

for any other treatment in CF care.

and V mutations as well.

Significant clinical effects included a more

than 10% absolute change in FEV1,

CFTR potentiators Class III mutations are

reductions in pulmonary exacerbations and

characterised by a reduced opening

improvements in symptom scores. This

probability of the CFTR channel, but the

medication was approved by the US Food

CFTR expression at the cell surface is not

and Drug Administration in 2012 for

altered. Potentiators are pharmaceuticals

patients older than 6 years of age with a

that increase the probability of the CFTR

G551D mutation and has recently received

channel opening.

approval in Canada and Europe as well.

ERS Handbook: Paediatric Respiratory Medicine

421

Defect

Normal

III

classification

Defect

No synthesis

Block in

Altered

Reduced

result

processing

regulation

conductance

synthesis

Types of

Nonsense;

Missense;

mutation

frameshift

amino acid

premature

deletion

change

stop codon

(ΔF508)

(G55ID)

(R117H)

(A445E)

(G542X)

(R347P)

alternative

spllcing

Potential

Ataluren

CFTR corrector

Ivacaftor

Ivacaftor?

therapy

(VX-809)

(Kalydeco)

Figure 1. Potential options of CFTR directed therapies. Reproduced from Welsh (2001) with permission

from the publisher.

While these gating mutations are relatively

known therapeutics. The lead compound is

rare, this has proven the concept that CFTR

currently called VX-809 and has recently

directed pharmacotherapy can have

shown some promising results in early

significant beneficial effects in patients that

phase clinical studies. In CF patients

exceed the efficacy of any other treatment

homozygous for the F508del mutation, oral

previously studied in this disease.

application of the compound VX-809 was

well tolerated and there was a dose-

CFTR correctors Class II mutations, such as

dependent effect on sweat chloride levels at

the most common mutation, F508del, result

higher doses, suggesting an effect of this

in misfolded CFTR protein which, when

drug on F508del activity. However, no

expressed at the apical membrane, has

change in lung function was observed.

some chloride conducting ability, but with a

much shorter half-life than wild-type CFTR.

It is important to appreciate that CFTR

Most of this misfolded protein will be

corrector therapy alone may not be sufficient

recognised as abnormal by the intracellular

to induce a clinically meaningful response

quality control machinery and degraded

and for this reason VX-809 is currently being

prior to leaving the endoplasmic reticulum.

studied in combination with a CFTR

Thus, a potential treatment strategy is

potentiator to enhance activity (described

rescue of CFTR (rescue from endoplasmic

below).

degradation). Compounds that result in

CFTR rescue are called ‘correctors’ referring

Combining potentiator and corrector While

to their effect on correcting the intracellular

VX-809 is designed to move CFTR to the cell

trafficking defect. A number of drugs have

surface, ivacaftor is intended to improve the

been identified to potentially improve

protein’s function once it has reached the

mutated CFTR processing using high-

cell surface. A recently completed phase II

throughput assays to screen libraries of

clinical trial studying multiple dose

422

ERS Handbook: Paediatric Respiratory Medicine

combinations of ivacaftor with VX-809

lower decline in lung function and a lower

showed improvements in lung function in

rate of pulmonary exacerbations compared

CF patients with two copies of the F508del

with the placebo group. A stronger effect

mutation at higher doses of the drug

was seen in patients not receiving inhaled

combination; VX-809 alone did not have any

antibiotics as inhaled tobramycin may

effect on lung function and no effect was

potentially interfere with the effect of this

seen in a group of patients heterozygeous

drug. Therefore, the current evidence for its

for this mutation. The effect size for this

efficacy is not convincing and it may be that

drug combination in F508del patients was

only a subgroup of patients will respond.

much smaller than the one observed for

Many patients carrying stop mutations in

ivacaftor alone in G551D patients indicating

one allele are also compound heterozygotes

that CFTR pharmacotherapy addressing

for F508del and potentially a combination of

intracellular trafficking is a much more

drug therapy directed toward a PTC could be

difficult target. This is not surprising as

combined with CFTR corrector therapy in

intracellular trafficking involves multiple

the future. Alternatively, an effective therapy

steps; each of which could be a potential

for stop mutations could be combined with

target for therapy. Other correctors are

a potentiatior such as ivacaftor thereby

currently in development and future therapy

maximising the function of any CFTR protein

may require the combination of more than

expressed at the cell surface.

one corrector plus a potentiator, such as

ivacaftor.

Gene therapy: CFTR replacement therapy The

goal of gene therapy in CF is that delivery of

Suppressors of premature stop codons

a normal CFTR gene to the lung would result

Premature termination codons (PTCs) are

in expression and restored function of CFTR

the cause of CF in only 5% of cases in

in the CF airway epithelium. There are

countries other than Israel, where class I

several challenges, including: which vector

mutations are more frequent. This potential

to use for gene delivery and the problem of

treatment strategy will be an option for only

short-term gene expression, which would

a small fraction of the CF patient population.

require repeated dosing. Viral vectors like

Aminoglycosides have been shown to

adenovirus seem more efficacious, but more

induce read through of PTCs (class I

likely to cause side-effects compared to

mutations) in CF. The first drug to have

liposomal vectors which demonstrate lower

shown this effect is gentamicin. Ataluren,

transfection efficacy. Gene therapy is

previously called PTC 124, has been

currently not close to clinical use, but a

developed as a compound sharing the

multi-dose clinical trial conducted by the UK

action on stop codons, but lacking both

Gene Therapy Consortium using a liposome

aminoglycoside antibiotic function and

vector is currently on its way.

toxicity. It is an oral medication. In vitro

studies have shown that ataluren improves

Mucus hydrators

read through of stop codons without

affecting nonsense mediated decay, which is

Inhaled hypertonic saline Dysfunction of the

an important cellular mechanism that is

CFTR protein results in an imbalance of ion

needed to protect the cell from

homeostasis and consequently dehydration

dysfunctional proteins. So far, data from

of airway secretions. This leads to disruption

phase II clinical studies in CF patients have

of ciliary function and mucociliary clearance.

been variable in terms of treatment

A treatment option addressing the depletion

of airway surface liquid in CF is the

response suggesting that it may not be

inhalation of hypertonic saline solution. A

equally effective in all CF patients within a

given class of mutations.

study in Australia showed that inhaled

hypertonic saline improves mucociliary

Recently a phase III clinical trial of ataluren

clearance in a dose-dependent fashion up to

has been completed. Study participants who

7% hypertonic saline. A double-blind parallel

received ataluren showed a trend towards a

group (7% hypertonic saline versus 0.9%

ERS Handbook: Paediatric Respiratory Medicine

423

normal saline) treatment trial showed a

Unfortunately, trials of topical

small absolute difference in lung function

administration of this short-acting sodium

between the two groups, and significantly

channel blocker in CF patients did not show

fewer pulmonary exacerbations for the group

any evidence that it improves lung function

treated with 7% hypertonic saline. Inhaled

and one study showed that it may even

hypertonic saline is now part of standard of

deteriorate lung function. Newer studies are

care in most centres. The beneficial effects

looking at novel ENaC blockers that are

are probably multi-factorial including:

more potent and less reversible than

amiloride.

N effect on mucus hydration,

N improved mucociliary clearance,

Modulators of ion channel function

N increase of airway-surface liquid height,

Chloride channels other than CFTR exist and

N cough induction.

a calcium dependent chloride channel has

Inhaled hypertonic saline is known to be

been shown to secrete chloride in epithelial

safe to use in infants with CF. However, a

cells. Therefore, increasing the activity of

recent study did not show clear effect of

alternative chloride channels in CF airways

treatment on pulmonary exacerbation in

could potentially be therapeutic. Two drugs

infants and young children and the role of

have been in clinical trials. Lancovutide,

hyertonic saline in this age group is still

previously known as Moli 1901, is a chloride

unclear.

transport activator that was studied and,

initially, showed some early promising

As hypertonic saline is an irritant for the

results. A large trial was completed in

airways, it is recommended to test

Europe, but did not show clear evidence of

tolerability in patients in the clinic before

efficacy.

initiating long-term therapy. It should be

used only after pre-treatment with a

Denufosol, a P2Y₂ agonist designed to

bronchodilator, such as salbutamol.

restore chloride transport and to increase

mucocilicary clearance, also yielded

Mannitol Mannitol was developed as a dry

promising results in early phase studies but

powder formulation as an alternative

ultimately showed nonsignificant results

treatment to hypertonic saline. It has been

compared with placebo in a large

used as a hyperosmolar agent used to

confirmatory trial. Therefore, there is

encourage the flux of water across the lung

currently no ion channel modulator that is

surface to improve mucociliary clearance.

close to clinical use.

Phase II and III trials show promising

evidence that long-term inhalation of

Modulation of airway inflammation

mannitol improves lung function in patients

The beneficial effects in anti-inflammatory

with CF and decreases the frequency of

treatments, such as systemic steroids, have

pulmonary exacerbations. The main side-

been outweighed by the risks, which are

effect is bronchoconstriction and associated

related to the side-effect profile. In addition,

cough. At the present time mannitol is only

the use of non-steroidals has also been

approved for treatment in CF in Australia

studied, but the side-effects of

and for adults in Europe, but additional

gastrointestinal bleeds and potential

studies in children are under way.

nephrotoxicity has prevented more extensive

Sodium channel blockers

use.

Decreased CFTR-related chloride secretion,

Oral N-acetylcysteine Oral N-acetylcysteine

in association with increased sodium and

has also been studied and although it is well

water absorption, results in depletion of

tolerated and does not cause significant

airway surface liquid. Theoretically,

adverse effects, the trials have not shown

amiloride improves mucociliary clearance by

significant pulmonary function test

blocking airway epithelial sodium channels

improvements or significant clinical benefit.

(ENaC) and expanding airway surface liquid.

However, in one study there was marked

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ERS Handbook: Paediatric Respiratory Medicine

post-treatment decrease in elastase activity,

in the frequency of pulmonary exacerbations

which needs to be confirmed before

and an increase in body weight.

treatment can be recommended.

It is important to assess patients for atypical

Inhaled glutathione Reduced glutathione is

mycobacterial infections by sputum culture

known to be decreased in the

prior to starting azithromycin, as this could

bronchoalveolar lavage fluid in CF patients.

be subtherapeutic/partial treatment for

Glutathione is a major antioxidant and

these organisms. In addition, there is some

mediator of cell proliferation. Inhaled

recent evidence suggesting that

glutathione has been used as a means to

azithromycin may predispose patients to

modify CF respiratory tract oxidative

mycobacterial infection.

processes. A few small studies have shown

Antibiotics

mild improvements in the pulmonary

function in CF patients but larger, longer

Chronic infection continues to be a

studies are required. At this time there is

significant challenge in CF care.

inadequate evidence to recommend inhaled

Pseudomonas aeruginosa is one of the major

glutathione as a treatment for CF patients.

pathogens in CF lung disease and has been

a major target for antibiotic therapy. The

Anti-protease therapy is currently being

reasons for failure of antibiotics to eradicate

evaluated, but the studies are still in early

mucoid P. aeruginosa are multiple and may

stages. The most convincing effect to date

include:

has been seen with drugs that target both

infection and inflammation, such as

N high bacterial loads,

azithromycin.

N bioflims,

N poor penetration of antibiotics into the

Azithromycin Azithromycin has both anti-

mucus,

infective and anti-inflammatory properties.

N antibiotic resistance.

In CF, recurrent airway infections and

chronic inflammation result in progressive

Recent anti-infective tactics have utilised

airway damage. Treatment with

currently available antibiotics in inhaled

azithromycin in subtherapeutic doses for an

forms. Inhalation of antibiotics allows higher

antibiotic effect has been shown to improve

concentrations at the location of the

lung function and decrease exacerbation

infection, while decreasing the potential

rates in CF patients who are chronically

systemic side-effects that could occur with

infected with Pseudomonas aeruginosa.

oral or parenteral treatment. Early

Furthermore, a randomised, placebo-

eradication of P. aeruginosa to delay the

controlled trial of azithromycin in CF

establishment of chronic infection is also

patients with P. aeruginosa showed a

very important and the use of tobramycin

significant reduction in both oral and

inhalation solution alone has been shown to

parenteral antibiotic use and significant

be highly effective.

weight gain in the treatment group. The

mechanism of action is still not completely

Chronic maintenance therapy for P.

clear. Azithromycin is also used to treat

aeruginosa consists of the inhalation of

bronchiolitis obliterans, a condition not

antibiotics such as tobramycin and colistin.

associated with chronic infection. This

Tobramycin can be administered as a

would support the idea that a major factor of

nebulised solution and more recently has

its effect is its anti-inflammatory properties.

been introduced as a dry powder

formulation (tobramycin inhalation

A more recent study showed no

powder), allowing shorter administration

improvement in pulmonary function in

time and greater portability. Aztreonam

children and adolescents with CF uninfected

lysinate for inhalation is currently available

with P. aeruginosa, who were treated with

and is being utilised as an alternative to

azithromycin for 24 weeks. However, the

inhaled tobramycin by either adding it

treatment group had a significant decrease

during the off months of cycled tobramycin

ERS Handbook: Paediatric Respiratory Medicine

425

or as a replacement for tobramycin

changing patients’ outcomes, it is important

inhalation.

to explore new therapies for other targets

including infection and inflammation.

Other inhaled antibiotics being developed

and studied include inhaled liposomal

Further reading

amikacin, ciprofloxacin inhaled powder,

inhaled levofloxacin and fosfomycin.

Clancy JP, et al.

(2012). Personalized

medicine in cystic fibrosis: dawning of a

Conclusion

new era. Am J Respir Crit Care Med.; 186:

Many new therapies are currently in

593-597.

Flume PA, et al. (2012). State of progress

development and will probably change our

in treating cystic fibrosis respiratory

therapeutic approach in the near future. The

disease. BMC Med; 10: 88.

goal for emerging therapies is to find

Ratjen F, et al. (2012). New therapies in

treatments that slow down the progressive

cystic fibrosis. Curr Pharm Des; 18: 614-

decline in lung function, decrease hospital

627.

admissions, and improve quality of life. The

Ramsey BW, et al.

(2011). A CFTR

success of ivacaftor, a CFTR potentiator,

potentiator in patients with cystic fibrosis

demonstrates that this approach is feasible,

and the G551D mutation. N Engl J Med;

but not yet available for many patients. As

365: 1663-1672.

we learn more about CFTR mutation-specific

Welsh, M, et al. Cystic fibrosis. In: Scriver

abnormalities we can hopefully decrease

C, et al., eds. The Molecular and

symptoms, decrease treatment burden, and

Metabolic Basis of Inherited Disease.

improve the outcome for CF patients. While

McGraw-Hill, New York, 2001; pp. 5121-

treatment strategies targeting the basic

5188.

defect have the highest likelihood of

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ERS Handbook: Paediatric Respiratory Medicine

Prognosis, management and

indications for lung

transplantation in CF

Helen Spencer and Andrew Bush

The CF patient with end-stage or rapidly

in the 2003-2004 cohort. In the paediatric

deteriorating lung disease will usually have

series all but one of the children had severe

been followed up in a specialist centre for

obstructive lung disease, and most were

many years, with intensive therapeutic

being actively managed at the time of death;

attempts to improve lung function. Part of

most deaths were in the paediatric intensive

the management should be a detailed re-

care unit (PICU). A key message from these

evaluation of all aspects of care to ensure

two studies and other data is that

that nothing has been missed.

spirometry is a poor predictor of prognosis,

although frequently used clinically as such.

The nature of the problem

The combined Royal Brompton Hospital/

Lessons from problematic severe asthma:

Great Ormond Street Hospital (both

are the basics right?

London, UK) experience of death and

More than half of all children referred to the

transplantation in CF in the decade 2000-

Royal Brompton Hospital quaternary referral

2009 was of 1022 children cared for, there

severe asthma service for consideration of

were 11 deaths (median age 14.2 years) and

‘‘beyond guidelines’’ therapy in fact do not

eight transplantations (median age

have severe asthma at all, but merely need

13 years), with a female predominance for

both. Of note, spirometry 5 years before

to get the basics right for good asthma

death was not predictive. This is in

control to be restored. No comparable study

agreement with an adult study which

has been performed in CF, but it seems

showed that median survival for patients

likely that similar issues are present in what

with an FEV1 ,30% predicted had increased

we term ‘‘challenging CF’’ (table 1). The

from 1.2 years in the 1991 cohort to 5.3 years

definition is somewhat arbitrary; it should be

noted that children may become challenging

very quickly (e.g. failure to improve after two

Key points

or more courses of intravenous antibiotics

in quick succession) or gradually, with a

Every effort should be made to

series of small, almost subclinical,

optimise standard therapy in patients

deteriorations.

with apparently end-stage CF lung

disease.

Experience from asthma has identified four

key areas often needing attention as:

Prediction of prognosis in end-stage

CF lung disease is difficult, and more

N medication adherence and

prolonged survival than previously

administration;

expected can be anticipated.

N adverse environmental circumstances,

N Timely referral for lung transplant

particularly environmental tobacco

assessment is essential to maximise

smoke;

chances of benefit.

N allergen exposure;

N psychosocial factors.

ERS Handbook: Paediatric Respiratory Medicine

427

Table 1. Definition of challenging CF

Lung function is o2 Z-scores below normal from the CF-specific charts

At least three courses of i.v. antibiotics annually (whether planned electively or unplanned)

Requirement for home oxygen or nasal mask ventilation

Nutritional failure: BMI f2 Z-scores below the mean; drop in weight or BMI centiles by 10% over

1 year

Any severe CF pulmonary complication, such as massive haemoptysis, pneumothorax, therapy-

resistant ABPA or other causes of oral severe steroid dependency

Any child whose self- or parent-reported symptoms are significantly different to those expected by

a clinician (either overestimated or underestimated)

Any child in whom there is refusal or extreme reluctance to give prescribed treatment by the

carers

Note, that these are arbitrary and not evidence based.

In the context of asthma, a nurse-led home

before deploying some of the experimental

visit is often enlightening, and perhaps this

therapies described below.

should be used more in CF. Adherence is

Is the diagnosis really CF?

notoriously difficult to judge in the clinic;

doctors obtain prescription records

This may seem an odd question, but it is

(acknowledging that collecting a

important for two reasons. First, if the

prescription does not mean that the

diagnosis is wrong it is important to

medication has been administered, but

determine whether there is a disease-

failure to collect prescriptions does

specific treatment for what is actually the

guarantee non-adherence) and the nurses

problem, for example bone marrow

assess the availability and accessibility of

transplantation for certain

medications in the home, and whether they

immunodeficiencies. Secondly, innovative

are in date. Obviously inhaler and nebuliser

therapies are increasingly being discovered

techniques are also checked. More objective

that are CF gene mutation or mutation class

data about nebuliser usage can be

specific. It would be ludicrous to try to apply

downloaded from the microchips in some

these therapies to a patient who did not

modern nebulisers. Active and passive

have CF! So, it is essential to make every

tobacco smoke exposure is checked by

effort to establish the genotype of the

measuring urinary or salivary cotinine.

patient with whole gene sequencing if this

Allergic sensitisation and allergen exposure

has not already been done, to check

is less important in CF than in really severe

eligibility for these potential treatments. The

asthma, but should at least be considered in

Clinical and Functional Translation of CFTR

the atopic CF patient. Finally, psychosocial

website (www.cftr2.org) provides current

factors are explored. Most referrals in the

knowledge of the probable disease causing

asthma context are made after discussions

status of rare mutations and should be

in the home, where families are much more

consulted in cases of doubt.

ready to discuss personal matters. It is

suggested that adaptations of this sort of

Management of end stage lung disease:

approach may be beneficial in challenging

pulmonary aspects

CF. This should include ensuring that all

standard therapies have been trialled, or

Our experience is that there are two main

discarded as having not been beneficial,

types of end-stage lung disease: the more

including nebulised antibiotics, rhDNAse,

common is characterised by severe

hypertonic saline and azithromycin, certainly

bronchiectasis, chronic infection and

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ERS Handbook: Paediatric Respiratory Medicine

copious purulent secretions. Less usually, a

these very sensitive molecular techniques is

so-called ‘‘dry and distal’’ lung disease is

unclear, and how (if at all) they should be

seen, characterised by distal airway

used to guide treatment at any stage of

obstruction and air trapping with no or

disease is unknown. In the context of end-

minimal bronchiectasis, and little or no

stage lung disease, it might be worth

sputum production. The evidence for the

considering molecular studies and intensive

existence of the dry and distal phenotype is

treatment of any dominant organism,

based on personal experience and case

particularly if frequently detected. Certainly,

reports, although we suspect most

an empirical trial of anti-anaerobic

experienced CF physicians will have seen

antibiotics should be considered, in

cases. There is little or no evidence base for

particular if there is severe bronchiectasis.

the treatment of either phenotype, but

suggested lines of management differ. The

Use of antibiotics in end-stage CF lung disease

evidence for most is so scanty that the right

Any isolated Gram-negative rods should

have extended sensitivities performed;

approach is to discuss options with the

occasionally they may be sensitive to

patient and family, and form an

unlikely oral antibiotics such as minocycline.

individualised plan on the basis of those

discussions.

While accepting that the link between in vitro

sensitivity and clinical efficacy is at best

Are resistant or unusual microorganisms

weak, there would seem to be little to be lost

present? Standard sputum culture, if

by prescribing an oral antibiotic to which the

available, will identify most of the common

organism appears to be sensitive, at least in

pathogens, but other samples should be

the laboratory.

considered. Bronchoscopy and

bronchoalveolar lavage is considered the

Most, if not all, patients with end-stage lung

gold standard, but there are regional

disease, especially those with severe

variations in culture results and not all lobes

bronchiectasis, will have been prescribed

are usually sampled. Induced sputum may

either inhaled tobramycin or colistin

have a greater yield than spontaneously

because of chronic infection with P.

expectorated. Both techniques should be

aeruginosa. Particularly in those patients with

used with caution in patients with severe

severe bronchiectasis, a trial of nebulised

airway obstruction. Infection with

aztreonam lysine should be considered, also

nontuberculous mycobacteria appears to be

rotating combinations of nebulised

becoming increasingly common and

antibiotics, such as tobramycin, with

Mycobacterium abscessus, in particular, may

alternate months of aztreonam. There is

be associated with decline in lung function.

some evidence that combined nebulised

A HRCT scan should be considered to look

tobramycin and amiloride may be effective

for suggestive features, such as the presence

against some genomovars of Burkholderia

of extensive tree-in-bud. If re-evaluation

cepacia. Combinations of nebulised

results in the detection of new

fosfomycin and tobramycin have also shown

microorganisms, then energetic attempts

efficacy against some antibiotic-resistant

should be made to eradicate them.

organisms.

Recent molecular microbiology studies have

Intravenous antibiotics should be used

shown that CF is a far more polymicrobial

liberally. Most would use planned regular

disease than was previously thought and, in

(usually 3-monthly) courses, with interval

particular, anaerobes may be as prevalent as

courses as needed. The optimal duration of

Pseudomonas aeruginosa. End-stage CF

such courses is not known, but it is likely

seems to be characterised by loss of

that longer than the conventional 10-

bacterial diversity, but it is not known

14 days will be beneficial. Anecdotally, we

whether this is as a reflection of disease

have used intravenous colistin for many

progression or as a consequence of multiple

consecutive weeks in this situation. Here, as

courses of antibiotics. The interpretation of

elsewhere, there are no randomised

ERS Handbook: Paediatric Respiratory Medicine

429

controlled trial data to guide the

However, there is increasing evidence that

paediatrician.

airway infection per se is associated with

worse lung function and an increased rate of

Antibiotic allergy is a frequent problem in

exacerbation. In the setting of end-stage

CF. A history of possible allergic reactions

lung disease, we recommend intensive anti-

should be taken and cautious challenge

fungal treatment if A. fumigatus is isolated.

testing should be performed in conjunction

Itraconazole is poorly absorbed, and in this

with an experienced allergist to determine

setting we would use prolonged courses of

which antibiotics truly cannot be used

voriconazole, posaconazole or even

without desensitisation. The transplant

intravenous liposomal amphotericin B.

centre should be contacted to discuss

Anecdotally, nebulised amphotericin

whether desensitisation to particular

(standard or liposomal) has been used, but

antibiotics would be helpful.

again the question of not over-burdening the

Optimising airway clearance A very

child with multiple treatments must be

experienced physiotherapist should assess

considered.

the patient. There are numerous aids to

Corticosteroids and other standard treatments

sputum clearance, including positive airway

We know that the inflammatory response is

pressure and external oscillation, and all

protective, and indeed in CF anti-

options should be reviewed. Anecdotally,

inflammatory therapy with a leukotriene

cough-assist devices have been beneficial in

(LT)B₄ antagonist actually led to more

some patients, despite fears that the

infective exacerbations. Conversely, we know

negative pressure phase might lead to

that at some stages of CF (those patients

airway collapse if there is significant

bronchomalacia.

chronically infected with P. aeruginosa)

prednisolone improves spirometry, albeit at

Clinically significant expiratory muscle

the cost of unacceptable side-effects.

dysfunction is rarely, if ever, seen in CF, so

Various anti-inflammatory strategies may be

cough strength should be normal. However,

tried especially in dry and distal disease. A

stress incontinence is common in both

trial of systemic corticosteroids is the first to

sexes in CF, even in children, and this may

be considered, balancing the risks of

lead to reluctance to cough forcefully.

worsening CF-related diabetes and reducing

Tactful questioning should elicit whether

bone mineral density against possible

this is a problem and, if so, referral for

benefit. Dry and distal disease is treated

treatment is mandated.

with pulsed intravenous methyl

prednisolone (500 mg?m^-2) on 3 successive

Pharmacological adjuncts to mucus

days every 4 weeks, to try to reverse the

clearance include rhDNase, hypertonic

airflow obstruction, combining this with

saline and inhaled mannitol. There is

high-dose inhaled corticosteroids. A trial of

marked and unpredictable individual

variation in response to these agents, and all

oral prednisolone is indicated in CF patients

should be trialled. Combinations should be

with severe bronchiectasis but only in those

considered, with two caveats. The first is

who are atopic and have acute

adherence; it is all too easy to overburden

bronchodilator reversibility. If neither of

the patient with excessive numbers of

these features is present, we would be

nebulised therapies, in particular. The

reluctant to risk the side-effects of prolonged

second is the theoretical possibility that

steroid therapy.

therapies may be antagonistic, as was found

Should oxygen therapy and NIV be initiated?

in one study when mannitol and rhDNAse

Whereas in hypoxaemic COPD patients

were combined.

there is clear evidence of benefit with oxygen

Anti-fungal therapies It used to be thought

supplementation in terms of survival, there

that Aspergillus fumigatus was only a

are no such data in CF. Nonetheless, most

significant problem in CF if it caused allergic

paediatricians would actively screen for

bronchopulmonary aspergillosis (ABPA).

overnight hypoxaemia with saturation

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ERS Handbook: Paediatric Respiratory Medicine

studies, and correct it if present.

determining the patient’s genotype (some of

Assessment by a skilled occupational

these nine mutations are not detected on

therapist is mandatory if daytime oxygen is

routine testing). CFTR channel opening is a

prescribed, to allow mobility to be

function of the number of apical channels,

maintained as far as possible by using

their open probability and channel

lightweight portable systems.

conductivity. VX-770 may increase channel

opening time in non-gating mutations, and

There is no general consensus as to when

there is interest in combining this agent with

and how to initiate NIV. Positive-pressure

potentiators such as VX-809 in class II

devices may be used to assist daytime

mutations such as DF508. Undoubtedly in

sputum clearance by a skilled

these days of internet-based knowledge,

physiotherapist, with due regard to the risk

families will want to discuss compassionate

of a pneumothorax. In terms of use during

ground use of some of these and other novel

sleep, polysomnography should be part of

molecular therapies, such as Ataluren

the work-up of these patients. If there is

(PTC₁₂₄). This is unexplored territory, but

clear cut evidence of nocturnal hypercapnia

one that paediatricians will need to tackle in

then we would offer NIV, having excluded

the very near future.

any upper airway obstruction (e.g. due to

nasal polyps) as a potential cause of

Management of end-stage lung disease:

hypoxaemia. If gas exchange is adequate,

extrapulmonary aspects

but work of breathing is high (usually

Optimising nutrition/other diagnoses A full

assessed clinically outside a research

dietetic review is mandatory, because most

context), then we would still consider NIV in

with end-stage lung disease will be

the hope of improving nutritional status.

However, as stated elsewhere in this

malnourished. Obviously, additional

chapter, more work is needed.

diagnoses which may contribute to

malnutrition, such as coeliac disease,

Innovative therapies are mostly used in the

should be excluded, and insulin deficiency

dry and distal form of end-stage CF lung

evaluated. Calorie intake must be

disease, and none are evidence based. There

maximised, usually via a gastrostomy, and

are anecdotal reports of success. These

overnight and daytime bolus high-energy

include monthly infusions of intravenous Ig,

feeds, if not already instituted, will be

methotrexate and cyclosporine A. In all

required. If a gastrostomy is inserted for the

cases, careful monitoring of response and

first time consideration should be given to

alertness for side-effects is mandated. In the

performing a laparoscopic or even an

case of cyclosporine, special care should be

endoscopic fundoplication at the same time

taken to monitor renal function, which may

if gastro-oesophageal reflux is present.

already be impaired by repeated courses of

intravenous aminoglycosides and CF-related

Insulin deficiency Many patients will already

diabetes.

have been diagnosed with CF-related

diabetes and will be using insulin; in these

Compassionate ground therapies Kalydeco

patients, diabetic control must be

(ivacaftor, VX-770) has burst on the scene as

optimised. For others, CF-related insulin

a paradigm-shifting molecule addressing the

deficiency should be excluded by oral

basic defect in the class III mutation G551D,

glucose tolerance testing, random blood

rather than the downstream consequences

glucose measurements and continuous

of the cystic fibrosis transmembrane

subcutaneous monitoring. There is evidence

conductance regulator (CFTR) dysfunction,

that even in those with only occasional

as is the case with the more conventional

peaks of blood glucose, insulin therapy can

therapies described above. Although only

improve nutrition and lung function.

licensed for G551D, compassionate use

could be considered if the funding obstacles

Gastro-oesophageal reflux This has been

can be overcome in the other nine known

realised to be increasingly common in end-

gating mutations, hence the importance of

stage CF lung disease, and should actively

ERS Handbook: Paediatric Respiratory Medicine

431

Table 2. Referral for lung transplant assessment

Referral for lung transplantation should be made when the patient has:

Rapidly declining FEV1 despite maximal medical therapy (particularly females)

FEV1 approaching ,30%

Frequent hospitalisations for exacerbations

Oxygen dependency

Desaturation with exercise

Requirement for NIV

Recurrent or problematic pneumothorax

Recurrent haemoptysis despite embolisation

be excluded. Bile acids can frequently be

who are becoming difficult to manage. Early

found in CF sputum and are associated with

referral before a patient becomes critically

increased inflammatory markers, suggesting

unwell facilitates a number of processes:

that we are underdiagnosing this

complication. There is no gold standard

N careful assessment by a multidisciplinary

test, but at the very least 24-h oesophageal

transplant team,

pH monitoring should be performed. An

N suggestions for further clinical

isotope milk scan is less invasive, but

optimisation,

probably a less accurate way of determining

N information gathering for the patient,

if reflux is present. The role of impedance

family and medical team and education

monitoring is not clear pre-transplant but

about the complications,

should be completed post-transplant.

N intense follow-up required after

Gastro-oesophageal reflux, including non-

transplant.

acid reflux, may be an important factor in

Timely referral allows the patient time to

the development of post-transplant

reflect on the risks and benefits of both

bronchiolitis obliterans syndrome (BOS).

transplant and the alternative of non-

Bone mineral density Severe osteopenia is a

transplant, and also allows the transplant

relative contraindication to transplantation,

physician to monitor an individual’s clinical

so DEXA scanning and appropriate

trajectory over a period of time (table 2).

treatment (calcium supplements, vitamin D

When to list for transplant? Deciding when to

and bisphosphonates) should be instituted

list a patient for transplant is one of the

early if bone mineral density is decreased.

most difficult decisions. A transplant

Lung transplant Lung transplant is an

physician’s aim is to list a patient early

accepted therapeutic option for patients

enough that they can survive the possible

with end-stage CF lung disease who are

wait for an organ but not so early that a

failing maximal medical therapy. Paediatric

transplant does not offer a survival benefit.

recipients from the International Society for

Most centres aim to list for transplant when

Heart and Lung Transplantation (ISHLT)

the predicted chance of surviving 2 years is

international registry had a 5-year survival of

,50%, although this is an increasingly

54% for the era 2002-2010.

difficult time-point to identify.

As previously noted there is no one specific

Various survival models have been

clinical or physiological measurement that

proposed for CF, all of which are imprecise

portends poor prognosis signifying referral

and not particularly useful for an individual.

for transplant assessment. Most paediatric

In practice many clinical, physiological,

centres welcome early referral of patients

functional and quality of life factors are

432

ERS Handbook: Paediatric Respiratory Medicine

taken into account when deciding when

the transplant community to transplant

to list.

patients only if there is a good chance of a

successful outcome. It is essential to ensure

A controversial paper in 2007 suggested that

that there are no major or not too many

only five paediatric CF patients had a survival

relative contraindications. Although centre-

benefit with transplant in their US cohort of

specific decisions are made in some grey

514 patients listed for transplant. One of the

clinical areas there are a number of agreed

main criticisms of this study was that the

major contraindications.

5-year waiting list survival was 57% and that

there was a significantly lower post-transplant

N Malignancy in the last 2 years (excluding

survival than in other studies of a similar

certain skin cancers).

population. The higher waiting list survival

N Untreatable dysfunction of another major

reflected the fact that USA priority listing used

organ system (although lung/another

to be based on a time accrual basis rather

organ transplant can be offered at some

than clinical urgency, suggesting patients

centres).

were listed too early. Despite its controversial

N Infectious diseases: chronic hepatitis B,

conclusions the paper raises important

chronic hepatitis C (biopsy proven),

questions about how we measure the success

human immunodeficiency virus.

of transplant, and whether survival benefit is

N Active pulmonary TB.

the only valid measure of success or whether

N Refractory non-adherence.

quality of life is just as important.

N Significant chest wall/spinal deformity.

N Burkholderia cenocepacia (previously BCC

It is important for the CF centre to have an

genomovar III) is a contraindication in all

understanding of how the local transplant

UK centres.

centre makes decisions about listing and

N Absent or unreliable social support

organ allocation. In the UK each transplant

system.

centre manages their own waiting list and

will have local knowledge of clinical urgency

The relative contraindications are:

of patients and their own average waiting list

times. Other countries have adopted a

N critical condition, e.g. mechanical

ventilation, sepsis, extracorporal

national waiting list and have used various

membrane oxygenation (ECMO) and

lung allocation scores (LAS) incorporating

shock;

factors predicting clinical urgency and

N colonisation with highly resistant

probable post-transplant outcome to try and

bacteria, nontuberculous mycobacterium

make the best use of available organs.

and fungi;

Unfortunately, lack of donor organs continues

N severe osteoporosis;

to be a major problem, leading to a waiting

N grossly abnormal BMI (high and low).

list mortality of 30-40% in the UK. Expansion

Although invasive ventilation or ECMO were

of the donor pool is likely in the coming years

previously felt to be absolute

with the increasing use of non-heart beating

contraindications to transplant because of

donors as well the more conventional heart-

poor outcomes, recently there have been a

beating donors. EVLP programmes (Ex vivo

number of reports of good short-term

Lung Perfusion; a system for reconditioning

outcomes in adults in these scenarios.

cadaveric lungs deemed untransplantable)

Transplant will only be considered in

are also likely to boost the number of donors

patients already known to the transplant

available, with possible use of upper lobes for

centre if they have no other significant organ

children when the whole lung cannot be used

dysfunction. Invasive support systems

for adult recipients because of lower lobe

should only be instigated in end-stage

consolidation.

irreversible CF lung disease if the transplant

What are the contraindications to transplant?

centre feels that the patient has a realistic

To make the best use of the limited and

chance of receiving a suitable organ quickly.

precious organ resource it is incumbent on

This caveat is likely to rule out most

ERS Handbook: Paediatric Respiratory Medicine

433

paediatric patients who have much longer

Dobson L (2002). Clinical improvement

organ wait times.

in cystic fibrosis with early insulin treat-

ment. Arch Dis Child; 87: 430-431.

Care of the patient referred and waiting for

George PM, et al.

(2011). Improved

transplant Adequate preparation, including

survival at low lung function in cystic

discussions about prognosis prior to

fibrosis: cohort study from 1990 to 2007.

assessment is crucial to give patients and

BMJ; 342: d1008.

families a realistic picture of transplant. The

Ho SA, et al. (2004). Clinical value of

transplant journey is stressful and the

obtaining sputum and cough swab sam-

patient and family will need support.

ples following inhaled hypertonic saline in

Maximal medical therapy should continue

children with cystic fibrosis. Pediatr

once listed for transplant with particular

Pulmonol; 38: 82-87.

Kotsimbos T, et al. (2012). Update on

attention to nutrition, bone health, diabetic

lung

transplantation:

programme,

control and psychological input to address

patients and prospects. Eur Respir Rev;

issues such as adherence and needle

21: 271-305.

phobia. Unfortunately, not all patients will

Liou TG, et al. (2007). Lung transplanta-

receive a transplant and involvement of

tion and survival in children with cystic

palliative care should not be delayed

fibrosis. N Engl J Med; 357: 2143-2152.

because a patient is on a transplant waiting

Olivier KN, et al. (2003). Nontuberculous

list. A parallel approach of palliation while

mycobacteria. II: nested-cohort study of

waiting for transplant is possible and

impact on cystic fibrosis lung disease.

desirable. Some patients may become too

Am J Respir Crit Care Med; 167: 835-840.

sick to transplant and some families prefer

Pauwels A, et al.

(2012). Bile acids in

to come off the list to focus on end of life

sputum and increased airway inflamma-

care. A sensitive and individualised

tion in patients with cystic fibrosis. Chest;

approach to these difficult issues is

141: 1568-1574.

Ramsey BW, et al.

(2011). A CFTR

essential.

potentiator in patients with cystic fibrosis

and the G551D mutation. N Engl J Med;

Further reading

365: 1663-1672.

Rosenthal M (2008). Annual assessment

Adler FR, et al. (2009). Lung transplanta-

spirometry, plethysmography, and gas

tion for cystic fibrosis. Proc Am Thor Soc;

transfer in cystic fibrosis: do they predict

6: 619-633.

death or transplantation.

Pediatr

Benden C, et al. (2012). The Registry of

Pulmonol; 43: 945-952.

the International Society for Heart and

Trapnell BC, et al.

(2012). Fosfomycin/

Lung Transplantation: fifteenth pediatric

tobramycin for inhalation in patients with

lung and heart-lung transplantation

cystic fibrosis with pseudomonas airway

report - 2012. J Heart Lung Transplant;

infection. Am J Respir Crit Care Med; 185:

31: 1087-1095.

171-178.

Bush A (2011). Up the cystic fibrosis

Urquhart DS, et al.

(2013). Deaths in

pulmonary creek in a barbed wire canoe.

childhood from cystic fibrosis:

10-year

Pediatr Pulmonol Suppl; 34: 118-119.

analysis from two London specialist

Collins N, et al. (2011). Survey of the use

centres. Arch Dis Child; 98: 123-127.

of non-invasive positive pressure ventila-

Yu H, et al. (2012). Ivacaftor potentiation

tion in U.K. and Australasian children

of multiple CFTR channels with gating

with cystic fibrosis. Thorax; 66: 538-539.

mutations. J Cyst Fibros; 11: 237-245.

434

ERS Handbook: Paediatric Respiratory Medicine

Airway malformations

Ernst Eber and Andreas Pfleger

This chapter cannot cover the complete

malformations discovered incidentally. Early

spectrum of congenital airway

and accurate diagnosis as well as

malformations but rather gives an overview

appropriate management is particularly

of important anomalies (table 1).

important in children with severe central

airway stenoses. Flexible airway endoscopy

Most children with airway malformations are

is the most important diagnostic procedure.

already symptomatic in the neonatal period

In many instances, essential diagnostic

or in infancy; only rarely are airway

techniques are MRI and CT, frequently

including angiography (especially

preoperatively and in children with

Key points

associated cardiovascular anomalies).

Depending on the type and severity of the

Many children with airway

malformation, conservative or surgical

malformations are already

management options may be chosen. With

symptomatic in the neonatal period

airway growth, in particular mild to

or in infancy.

moderate stenoses in the first years of life

Airway anomalies are important

frequently become less prominent. Thus,

differential diagnoses in children with

conservative symptomatic treatment and

many respiratory abnormalities.

support is often the preferred approach.

Airway abnormalities may be part of

With adequate management, in most

complex syndromes, and in many

patients the long-term prognosis is

cases are associated with other

favourable.

congenital anomalies.

Nasopharyngeal airway

Early, accurate diagnosis and

Choanal stenosis and atresia This

appropriate management is

malformation represents one of the most

particularly important in severe

common congenital upper airway anomalies

central airway stenosis.

(1 in 8000 births). Most cases are due to

With airway growth, mild-to-moderate

bony occlusion of the airway; some children

stenoses in the first years of life

show membranous obstruction. About two-

frequently become less prominent.

thirds of patients with choanal atresia have

associated congenital anomalies (e.g.

Depending on the type and extent of

the malformation, conservative or

CHARGE association). Unilateral lesions are

surgical management options have to

twice as common as bilateral ones.

be chosen on an individual basis.

Bilateral choanal atresia causes immediate

With adequate management, in most

respiratory distress at birth; unilateral

patients the long-term prognosis is

lesions are often not detected until later in

favourable.

childhood. Some children present with

feeding difficulties and persistent

ERS Handbook: Paediatric Respiratory Medicine

435

obstruction is variable. As the mandible

Table 1. Important congenital airway malformations

grows forward with age, particularly during

Nasopharyngeal airway

the first 6 months of life, airway and feeding

Choanal stenosis and atresia

problems may gradually resolve.

Pierre-Robin sequence

Craniofacial malformations

In severe cases, the anomaly can necessitate

Larynx

intubation, especially when associated

Laryngeal atresia

airway pathologies (e.g. laryngomalacia,

Laryngeal web

tracheomalacia) exist. Prone positional

Subglottic stenosis

therapy has proved to be efficient in mild

Laryngomalacia (infantile larynx)

cases. Airway obstruction may be relieved by

Laryngeal cyst

a nasopharyngeal airway. Noninvasive

Laryngeal (laryngo-tracheo-oesophageal)

respiratory support can relieve upper airway

cleft

obstruction, with CPAP ventilation in mild

Trachea and bronchial tree

and moderate cases, or with noninvasive

Tracheal agenesis and atresia

positive pressure ventilation in severe cases.

Tracheo-oesophageal fistula and

Surgical procedures include tongue-lip

oesophageal atresia

adhesion, mandibular distraction

Isolated tracheo-oesophageal fistula

osteogenesis and tracheostomy. Feeding

(H-type fistula)

difficulties can be alleviated by upright

Tracheomalacia

feeding techniques, modification of the

Tracheal stenosis

nipple for bottle feeding, temporary use of

Tracheal bronchus and other topographic

feeding tubes and the placement of a

anomalies

gastrostomy. Palatal plates such as the pre-

Bronchial atresia

Bronchomalacia

epiglottic baton plate with a velar extension

Bronchial stenosis

pull the base of the tongue forward. This can

be helpful in the relief of airway obstruction,

facilitates the swallowing mechanism during

rhinorrhoea, especially if the patent nostril is

feeds and accelerates mandibular growth.

occluded during respiratory infections.

Other craniofacial anomalies A number of

Flexible nasal endoscopy and CT can

syndromic craniofacial anomalies can affect

confirm the diagnosis and delineate the

the patency of the upper airways. These

exact site of obstruction and also whether it

dysmorphic syndromes are typically

is bony or membranous.

characterised by mandibular or maxillary

hypoplasia and include Crouzon, Treacher

A nasal airway should be established as

Collins, Apert, Pfeiffer, and Goldenhar

soon as possible. This can be achieved by a

syndromes. 36 syndromes with craniofacial

transnasal approach with a dilating

anomalies have been found to be associated

instrument and passing airway stents

with one or more of 14 laryngotracheal

through the nasal passage to ensure

malformations. Several anomalies such as a

continued patency for several weeks.

narrowed nasopharynx with associated

Alternatively, repeated choanal dilatation

adenotonsillar hypertrophy, midface

may be performed at weekly intervals. In

hypoplasia and hypertrophy of the tongue

severe cases, transpalatal surgery may be

can cause airway compromise in children

required.

with Down syndrome.

Pierre-Robin sequence This anomaly is

Larynx

characterised by micrognathia, glossoptosis,

and resultant (pharyngeal) airway

Laryngeal atresia Laryngeal atresia is a life-

obstruction. More than half of affected

threatening malformation, and in the past

infants have an associated syndrome, most

virtually all affected newborns died.

commonly Stickler syndrome or 22q11.2

Nowadays, antenatal ultrasound

deletion syndrome. The severity of airway

examinations allow diagnosis of the

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ERS Handbook: Paediatric Respiratory Medicine

so-called congenital high airway obstruction

cricoid cartilage, resulting in circumferential

syndrome (CHAOS), which may be related

stenosis of variable appearance. Myer et al.

to intrinsic causes such as atresia of the

(1994) proposed a grading system for

larynx or upper trachea or extrinsic

subglottic stenosis based on endotracheal

laryngotracheal obstruction caused by large

tube sizes (table 2).

masses (e.g. cervical teratoma).

The presentation of affected children ranges

Identification of the condition by

from severe respiratory distress at birth to

sonography and MRI helps facilitate

the development of inspiratory or biphasic

management, including the ex utero

stridor within the first months of life

intrapartum treatment (EXIT) procedure.

(recurrent or atypical croup). Signs and

Without antenatal diagnosis, newborns with

symptoms clearly depend on the grade of

isolated laryngeal atresia may only survive

the stenosis. Children with congenital

when emergency tracheostomy is performed

subglottic stenosis are at risk of developing

immediately after birth. Bag-mask

additional acquired subglottic stenosis due

ventilation may save the lives of children

to airway trauma (mostly iatrogenic such as

with incomplete laryngeal atresia. Laryngeal

prolonged endotracheal intubation or

function in survivors is usually abnormal,

tracheostomy).

and surgical reconstruction is required later

Endoscopy is the procedure of choice to

in life. The prognosis also depends on the

establish the diagnosis and to differentiate

presence of associated malformations (e.g.

subglottic stenosis from subglottic

VACTERL association) or syndromic

haemangioma. Sonography and MRI may be

anomalies (e.g. Fraser syndrome). Long-

helpful.

term follow-up data after successful EXIT

procedure are not yet available.

As congenital subglottic stenosis generally

Laryngeal web Laryngeal webs usually are

improves with airway growth, a conservative

located at the level of the glottis;

supportive approach is recommended

supraglottic and subglottic webs may also

whenever possible. Surgery should be

occur. The webs may be complete or

reserved for severe forms; treatment options

incomplete, and vary in thickness.

include cricoid split, laryngotracheoplasty,

Incomplete laryngeal webs, usually located

and long-term tracheostomy.

anteriorly with posterior openings, are

Laryngomalacia (infantile larynx)

strongly associated with the velocardiofacial

Laryngomalacia is the most common

syndrome. Complete laryngeal webs present

congenital laryngeal anomaly (50-75%) and

like a laryngeal atresia; symptoms with

the most common cause of persistent stridor

incomplete webs range from (biphasic)

in children (approximately 60%). The term

stridor and hoarseness to aphonia and

laryngomalacia suggests that laryngeal

varying degrees of respiratory distress. The

cartilage is abnormally soft. However,

diagnosis is established by endoscopy.

whether laryngomalacia is primarily an

Treatment options include (laser) excision

anatomic anomaly or is due to delayed

and dilatation. Sometimes endotracheal

neuromuscular development, is controversial.

intubation solves the problem, but re-

stenoses are relatively common. The

prognosis mainly depends on the extent of

Table 2. Grading system for subglottic stenoses

the malformation.

Grade

Degree of obstruction of lumen

Subglottic stenosis Congenital subglottic

f50%

stenosis is the second-commonest laryngeal

51-70%

malformation. The more common

III

o71% (any detectable lumen)

membranous form is characterised by

symmetrical thickening of the soft tissues in

No detectable lumen

the subglottic area. Cartilaginous subglottic

Adapted from Myer et al. (1994).

stenosis is due to a malformation of the

ERS Handbook: Paediatric Respiratory Medicine

437

Table 3. Types of laryngomalacia

Type

Characteristics

Inward collapse of aryepiglottic folds, primarily the cuneiform cartilages which are

often enlarged

Long, tubular epiglottis (pathologic exaggeration of the normal omega shape)

Anterior, medial collapse of arytenoid cartilages

Posterior inspiratory displacement of epiglottis against the posterior pharyngeal

wall or inferior collapse to the vocal cords

Short aryepiglottic folds

Adapted from Holinger et al. (1997).

According to Holinger et al. (1997), five types

The diagnosis is suspected based on history

of laryngomalacia can be distinguished (two

and physical examination, and confirmed by

or more may occur simultaneously) (table 3).

flexible airway endoscopy. Laryngoscopy

Laryngomalacia is frequently associated with

demonstrates supraglottic collapse during

other airway lesions and with gastro-

inspiration (fig.1). Topical anaesthesia can

oesophageal reflux.

potentially exaggerate the findings; thus, the

larynx should be examined before applying

The natural history is characterised by onset

topical anaesthesia.

of inspiratory stridor usually within the first

In most cases, apart from parental

4-6 weeks of life; cry and cough are normal.

reassurance and support, no specific

Stridor varies considerably with posture and

therapeutic measures are needed. In severe

airflow, is loudest with increased ventilation

cases (failure to thrive and/or obstructive

(e.g. crying, agitation, feeding) and worsens

apnoeas) surgical treatment (various forms

during respiratory tract infections. Some

of supraglottoplasty, rarely tracheostomy) is

patients will have increasing symptoms

needed. In isolated forms prognosis is

during the first few months of life; thereafter,

excellent, with associated malformations

stridor tends to resolve with time. In the very

prognosis usually depends on the latter.

rare severe cases with significant airway

obstruction, serious complications such as

Laryngeal cyst Supraglottic cysts, commonly

failure to thrive, pulmonary hypertension

located at the aryepiglottic folds or at the

and cor pulmonale may develop.

epiglottis, are usually congenital. In contrast,

Figure 1. Laryngomalacia (infantile larynx). a) Patent airway during expiration; b) prolapse of arytenoids

and aryepiglottic folds into the glottis during mid-inspiration; c) prolapse of arytenoids and aryepiglottic

folds and folding of epiglottis along its long axis (‘‘floppy epiglottis’’) at end-inspiration, resulting in

complete obstruction of the larynx. Reproduced from Eber (2010) with permission from the publisher.

438

ERS Handbook: Paediatric Respiratory Medicine

Table 4. Classification system for laryngeal clefts

Type

Characteristics

Supraglottic interarytenoid cleft extending inferiorly no further than vocal cord level

Cleft with extension below vocal cord level (cricoid cartilage partially involved)

Cleft extending through the cricoid cartilage, with or without extension into cervical

trachea

Cleft with extension into thoracic trachea (may extend as far as the carina)

Adapted from Benjamin et al. (1989).

subglottic cysts are usually acquired as a

A contrast swallow and oesophagogram

result of airway trauma (e.g. endotracheal

may be helpful, but airway endoscopy is the

intubation). The appearance of cysts varies

diagnostic gold standard (fig. 2). A cleft may

widely; while some are covered by thin

be difficult to diagnose with a flexible

mucosa and are easy to recognise, others

instrument, as manipulation of the posterior

appear as a submucosal mass. A laryngocele

commissure may be necessary to detect the

is a rare special form of a laryngeal cyst,

cleft. Rigid bronchoscopy is the ideal

which originates from the laryngeal ventricle,

technique for the documentation of

consists of an air-filled saccule and may be

pathology of the posterior glottis, subglottis,

difficult to diagnose. Infants commonly

and trachea.

present with stridor, hoarseness, weak cry or

In the absence of complicating factors,

aphonia, and sometimes feeding difficulties.

treatment is not required for many type 1

Endoscopy confirms the diagnosis. The

clefts. Treatment of gastro-oesophageal

treatment of choice is resection of the cyst.

reflux, if existing in parallel, is of importance

Laryngeal (laryngo-tracheo-oesophageal) cleft

in all patients. Early repair should be sought

A congenital posterior laryngeal cleft is a

in children with stable respiratory and

rare lesion. Laryngeal clefts may be familial,

nutritional status. Minor clefts (types 1 and

and may be associated with other anomalies

2) may be corrected endoscopically. Surgical

of the trachea or the oesophagus (e.g.

repair of type 2, 3 and 4 clefts may be

tracheo-oesophageal fistula) and with

performed through anterior and lateral

multiple congenital anomalies of other

approaches, often with cardiopulmonary

bypass or extracorporeal membrane

organ systems. Several types of clefts are

distinguished (table 4); the most common

(approximately 50%) is type 1 cleft which

should be suspected in infants with

laryngomalacia. Anterior laryngeal clefts (e.g.

bifid epiglottis) are very rare congenital

anomalies. While a bifid epiglottis often is

associated with other malformations, other

anterior clefts appear to be isolated defects.

Aspiration of saliva and food is most likely,

and causes coughing, choking, cyanosis,

respiratory distress and recurrent

pneumonia; stridor results from laryngeal

collapse. While infants with type 1 clefts may

be asymptomatic, newborns with more

Figure 2. Type 2 laryngeal cleft extending inferiorly

extensive clefts may show severe respiratory

to, but not through, the cricoid plate; nasogastric

distress. Diagnosis is often delayed in

tube in the oesophagus. Reproduced from Eber

patients with minor clefts.

(2010) with permission from the publisher.

ERS Handbook: Paediatric Respiratory Medicine

439

oxygenation (ECMO). Post-operative

The newborn is commonly tachypnoeic,

complications are not uncommon and

cyanotic, frothing, and choking despite oral

include tracheo-oesophageal fistula

suction. An attempt to pass an orogastric

formation and swallowing difficulties.

tube should be performed. A chest and

Prognosis depends on the type of the cleft,

abdomen radiograph will show the tube in

gestational age, and potentially associated

the upper pouch and may identify

anomalies. For patients with type 1-3 clefts

pulmonary anomalies, vertebral and/or rib

it is favourable.

anomalies, and the presence or absence of

gas in the stomach, indicating the presence

Trachea and bronchial tree

or absence of a tracheo-oesophageal fistula.

Tracheal agenesis and atresia Tracheal

Depending on the anatomical situation,

agenesis and atresia are rare malformations

associated anomalies and the clinical status

ranging from complete tracheal agenesis to

of the patient various surgical techniques

short-segmental atresia, commonly

are recommended. A detailed discussion of

associated with a broncho- or tracheo-

surgical aspects is beyond the scope of this

oesophageal fistula or other anomalies in

chapter.

various organ systems (e.g. VACTERL

association). Similar to laryngeal atresia,

The postoperative course may be critical due

these malformations are usually lethal.

to various complications, such as

Without antenatal diagnosis affected

oesophageal stenosis at the site of

newborns with short-segment atresia of the

anastomosis and recurrence of the tracheo-

proximal trachea may only survive when

oesophageal fistula. Gastro-oesophageal

emergency tracheostomy is performed

reflux and dysphagia are very common and

immediately after birth; in the presence of a

contribute to respiratory morbidity.

fistula or a cleft, intubation of the

Tracheomalacia may be severe, sometimes

oesophagus may allow temporary

even life-threatening (‘‘blue spells’’, ‘‘dying

ventilation. After antenatal diagnosis an

spells’’). Many children show the typical

EXIT procedure may save the life of the

brassy ‘‘tracheo-oesophageal fistula (TOF)-

affected baby. In those who survive, the

cough‘‘, which has been reported to be still

short-term prognosis mainly depends on the

present in up to 40% of adults. Recurrent

presence of associated malformations.

aspiration is frequent and causes bronchitis

Long-term follow up data after successful

and pneumonia, causing considerable

EXIT procedure are not yet available.

respiratory morbidity. A missed diagnosis of

laryngeal (laryngo-tracheo-oesophageal)

Tracheo-oesophageal fistula and oesophageal

cleft or second fistula, or a recurrent fistula

atresia A tracheo-oesophageal fistula results

should be considered in children with

from a defective separation of the

pronounced respiratory symptoms.

developing oesophagus from the developing

lung. Oesophageal atresia is quite common,

Survival largely depends on birth weight,

with an incidence of 1 in 3000 (-4000)

associated malformations, and pulmonary

births. About 30% of affected children are

complications. The mortality in children with

born prematurely, and more than 50% have

a birth weight above 2500 g and without other

associated anomalies (e.g. VACTERL

anomalies today is close to zero. In surviving

association). Various types of oesophageal

children, the long-term outcome is good.

atresia can be distinguished. The most

common type (approximately 85%) is

Isolated tracheo-oesophageal fistula (H-type

characterised by an upper blind pouch and a

fistula) This malformation is much rarer

fistula between the lower trachea and the

than a tracheo-oesophageal fistula in

lower oesophagus. Structural anomalies of

association with oesophageal atresia, and

the tracheal wall such as abnormally shaped

commonly is not associated with other

or hypoplastic tracheal cartilages or a

anomalies. Usually, the fistula is located in

widened pars membranacea (i.e.

the extrathoracic part of the trachea and has

tracheomalacia) are common.

a narrow lumen.

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Children present with recurrent coughing

innominate artery) or a mediastinal tumour.

and choking, in particular during feedings.

After surgical repair (e.g. division of a

The chest x-ray may show pulmonary

vascular ring), the tracheomalacia very often

infiltrates or atelectases and a distended

continues to cause symptoms. The

stomach or bowel. Contrast injection into

prognosis of these anomalies is determined

the oesophagus via a tube may show the

by the respiratory tract. Tracheomalacia is

fistula, but may also (repeatedly) be false-

frequently misdiagnosed as bronchial

negative. Rigid airway endoscopy is superior

asthma or other respiratory conditions.

to flexible endoscopy in establishing the

Thus, patients may be treated unnecessarily

diagnosis as the posterior tracheal wall can

with inhaled corticosteroids for long periods

be partly distended and visualised better

of time, and may be undertreated for

than with the flexible bronchoscope.

recurrent or chronic lower airway infections.

Injection of contrast or dye (e.g. methylene

blue) into a suspected fistula with

Intrathoracic tracheomalacia leads to

dynamic airway compression on expiration,

subsequent detection of the material in the

in particular during increased respiratory

oesophagus may be useful for establishing

effort (e.g. crying) and coughing, or during

the diagnosis. Airway endoscopy may also

respiratory infections. Tracheal collapse may

facilitate intraoperative identification by

result in retention of secretions from the

cannulating the fistula.

lower airways, which in turn may cause

Treatment is surgical and consists of

bronchopulmonary infections. In contrast,

ligation and division of the fistula, in most

malacia of the extrathoracic part of the

cases through a cervical approach. In

trachea may result in partial or complete

selected cases, particularly patients with

airway collapse on inspiration. Signs and

recurrent fistula, glue injection may be used

symptoms include a ‘‘barking’’ cough, tachy-

for closure of the fistula. Long-term

and dyspnoea, retractions, cyanosis,

prognosis is excellent, unless diagnosis is

localised monophonic (expiratory)

delayed until late child- or even adulthood,

wheezing, and possibly (inspiratory) stridor.

which may result in considerable respiratory

Feeding may cause ‘‘dying spells’’ (food in

morbidity due to recurrent aspiration and

the oesophagus may compress the malacic

infection.

trachea).

Tracheomalacia This anomaly is caused by

With intrathoracic tracheomalacia, a chest

congenital absence, deficiency,

X-ray typically reveals bilateral

malformation or softness of tracheal

hyperinflation; lateral inspiratory and

cartilage. Congenital tracheomalacia has to

expiratory radiographs may show marked

be distinguished from acquired forms; the

changes in airway calibre of the malacic part

latter may develop as a result of prolonged

of the trachea. The registration of (tidal and)

intubation and mechanical ventilation,

maximal flow-volume curves allows

tracheostomy or severe tracheobronchitis.

distinction between extra- and intrathoracic

Tracheomalacia can be primary or

airway obstruction and between variable

secondary, and may be localised or

(tracheomalacia) and fixed (tracheal

generalised. Primary tracheomalacia is

stenosis) obstruction. Flexible airway

found in association with oesophageal

endoscopy is the diagnostic procedure of

atresia, Down syndrome, Ehlers-Danlos

choice; it can be done with only minimal

syndrome, and with laryngomalacia or

mechanical distortion of the airway anatomy

bronchomalacia. Its incidence has been

and dynamics, while rigid instruments

reported to be at least 1 in 2100. Localised

inevitably distort the airways. It is mandatory

secondary tracheomalacia occurs as a

that evaluation of airway dynamics is

consequence of compression from a

performed during spontaneous breathing.

vascular malformation (e.g. double aortic

CT and MRI with angiography are

arch, right aortic arch variants, left

complementary techniques, in particular in

pulmonary artery sling, ‘‘anomalous’’

patients with localised tracheomalacia

ERS Handbook: Paediatric Respiratory Medicine

441

where compression by an extrinsic lesion is

left pulmonary artery sling, abnormal

suspected.

bronchial arborisation (e.g. tracheal

bronchus), or a single right or left lung. In

Generally, in patients with isolated

the past 50 years, various classifications

tracheomalacia airway function improves

have been proposed, based on the length of

with increasing age, as the airway grows and

stenosis, the severity of symptoms, and

the airway wall stiffens. Thus, most patients

recently according to bronchial involvement.

can be managed conservatively, with chest

physiotherapy and antibiotics for secondary

Congenital tracheal stenosis may be life-

infections. In particular, infants with

threatening or may only be detected

generalised tracheo- and/or bronchomalacia

incidentally. Signs and symptoms depend

and significant airway obstruction may

on the severity and the site of the stenosis,

benefit from long-term application of CPAP

and include localised monophonic

or ventilation with positive end-expiratory

(expiratory or biphasic) wheezing or

pressure (PEEP) via tracheal cannula to

(inspiratory or biphasic) stridor, tachy- and

splint the airway. In most of these patients,

dyspnoea, retractions, cyanosis, and

gradual reduction of positive airway

respiratory distress.

pressures and eventual decannulation is

Usually, CT or MRI (with three-dimensional

possible. Clinical and radiological

reconstruction) is necessary to define the

parameters as well as flexible airway

extent of the lesion, and to confirm or rule

endoscopy and pulmonary function testing

out compression by an extrinsic lesion

enable determination of the individual

(fig. 3). Unless a severe stenosis precludes a

optimal airway pressure. One advantage of

complete endoscopic examination, flexible

this approach is the avoidance of major

bronchoscopy with an ultrathin instrument

surgery; disadvantages include long-term

is helpful in defining airway anatomy

tracheostomy and technology dependency.

including bronchial arborisation, in

Surgical treatment is indicated in children

detecting possibly associated

with life-threatening tracheomalacia.

tracheomalacia, and in planning treatment.

Aortopexy is usually effective in localised

Pulmonary function testing shows evidence

tracheomalacia, but is of limited value in

of fixed airway obstruction with plateaus in

generalised forms. Stents may be effective in

both the inspiratory and expiratory limb of

patients with diffuse tracheomalacia but

the flow-volume loop.

severe complications including death have

been reported in a significant proportion of

As tracheal stenosis may improve with

children. Thus, today most authors agree

airway growth, conservative and

that stents should only be employed in

symptomatic treatment (including chest

selected patients when there are no good

alternatives. Treatment and prognosis

depend on the type and severity of the

malacia and on associated anomalies.

Tracheal stenosis Tracheal stenosis occurs

more infrequently than tracheomalacia.

Membraneous stenoses (webs) are less

common than anomalies of the tracheal

cartilages. Complete cartilaginous tracheal

rings (‘‘napkin ring cartilages’’) mainly occur

in the intrathoracic part of the trachea along

a variable length; sometimes the whole

trachea is affected. Stenoses can occur in an

hourglass- or funnel-shape (carrot-shape,

Figure 3. Severe, short segment tracheal stenosis

‘‘rat-tail’’ trachea). They are frequently

(red arrow), and parenchymal lung malformation

associated with other anomalies such as a

in the right upper lobe.

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ERS Handbook: Paediatric Respiratory Medicine

physiotherapy and antibiotics) should be

problems despite conservative measures,

recommended whenever possible. Surgical

resection of the affected segment or lobe

options for more severe stenoses include

may be necessary.

tracheostomy to bypass stenosis of the

cervical trachea, resection and primary

Topographic anomalies of the whole lung

(situs inversus; bronchial isomerism -

anastomosis for short segment stenosis,

bilateral right or bilateral left lung) are

and, among others, slide tracheoplasty

usually associated with topographic

(including repeated balloon dilation to

anomalies of the heart and/or abdominal

prevent subsequent recurrence of the

organs (e.g. Ivemark syndrome with

stenosis) for long-segment stenosis.

asplenia).

Tracheal surgery should only be exercised in

specialised referral centres. In the future,

Bronchial atresia This malformation is

tissue-engineered tracheal replacement is

frequently associated with congenital lung

expected to play an increasingly important

malformations and is seen by many authors

role. Treatment and prognosis depend on

as the underlying cause of the latter. In this

the type and severity of the stenosis and on

rare anomaly, a lobar or (sub)segmental

associated anomalies.

bronchus ends blindly, separated by a short

gap from the distally located bronchial tree

Tracheal bronchus and other topographic

supplying the lobe or (sub)segment. The

anomalies Topographic anomalies,

representing the most common

clinical picture varies widely, from the

neonate with respiratory distress to the

malformations of the tracheobronchial tree,

asymptomatic adult. CT or MRI is used to

are mostly observed on the right side. A

confirm the diagnosis. Most authors

tracheal bronchus (‘‘pig bronchus’’) may be

recommend resection of the lesion.

associated with other anomalies in the

tracheobronchial tree or in other organ

Bronchomalacia Bronchomalacia is

systems. It supplies either the apical

characterised by abnormal weakness of the

segment of the right upper lobe (in this case

airway wall. Localised forms are

a normal right upper lobe bronchus supplies

distinguished from generalised (e.g.

the other segments), an accessory segment

Williams-Campbell syndrome), and primary

within or separated from the right upper

forms from secondary ones; the latter are

lobe, or the whole right upper lobe (in this

usually caused by vascular compression.

case the normal right upper lobe bronchus

Bronchomalacia is frequently associated

is absent). The tracheal bronchus may also

with tracheomalacia, and the left main

originate from the trachea at the level of the

bronchus is predominantly affected.

carina (‘‘trifurcation’’). For a detailed

description of the so called ‘‘bridging

Signs and symptoms depend on severity

bronchus’’ in patients with a tracheal

and include cough, localised monophonic

bronchus and a left pulmonary artery sling,

wheezing and decreased breath sounds.

the reader is referred to relevant literature.

Some children only develop symptoms

during respiratory infections. Flexible

These and other lobar or segmental

bronchoscopy is the diagnostic procedure of

bronchial anomalies are often asymptomatic

choice; echocardiography, CT and MRI are

and thus only incidentally detected.

complementary techniques, in particular for

However, if structural anomalies (stenosis,

localised bronchomalacia.

malacia) are present the malformation may

result in recurrent or persistent pneumonia

Gradual improvement may be expected with

or atelectasis, and later bronchiectasis in the

age and thus airway growth. Only a minority

respective segment or lobe. Diagnosis is

of patients with significant respiratory

established by bronchoscopy and CT or MRI.

problems requires treatment apart from the

Chest physiotherapy and antibiotics are the

usual conservative measures (chest

treatment of choice in symptomatic

physiotherapy, antibiotics). Prognosis

patients. In patients with persisting

mainly depends on associated anomalies.

ERS Handbook: Paediatric Respiratory Medicine

443

Bronchial stenosis Bronchial stenosis is rare

Eber E. Congenital and acquired abnorm-

and predominantly occurs in mainstem (left

alities of the upper airways. In: Priftis KN,

. right) and lobar bronchi. Retention of

et al., eds. Paediatric Bronchoscopy. Progr

secretions may lead to bronchopulmonary

Respir Res Vol. 38. Basel, Karger, 2010;

infections and the development of

pp. 120-129.

bronchiectases. Signs and symptoms are

Holinger LD, et al., eds. Pediatric

the same as with bronchomalacia.

Laryngology and Bronchoesophagology.

Philadelphia, Lippincott-Raven, 1997.

Diagnosis is confirmed by flexible

Laberge JM, et al. Congenital malforma-

bronchoscopy, CT or MRI. As patients tend

tions of the lungs and airways. In: Taussig

to show improvement with age, conservative

LM, et al., eds. Pediatric Respiratory

management is recommended. Resection

Medicine.

2nd Edn. St Louis, Mosby,

and primary anastomosis may be necessary

2008; pp. 907-941.

for severe short segment stenosis; localised

Myer CM 3rd, et al. (1994). Proposed

bronchiectasis may necessitate resection of

grading system for subglottic stenosis

the affected segment or lobe.

based on endotracheal tube sizes. Ann

Otol Rhinol Laryngol; 103: 319-323.

Myer CM III, et al., eds. The Pediatric

Further reading

Airway. Philadelphia, Lippincott, 1995.

Benjamin B, et al.

(1989). Minor con-

Nicolai T

(2008). Airway stents in

genital laryngeal clefts: diagnosis and

children. Pediatr Pulmonol; 43: 330-344.

classification. Ann Otol Rhinol Laryngol;

Pfleger A, et al. (2013). Management of

98: 417-420.

acute severe upper airway obstruction in

Boogaard R, et al. (2005). Tracheomalacia

children. Paediatr Respir Rev; 14: 70-77.

and bronchomalacia in children: inci-

Pohunek P, et al. Congenital and acquired

dence and patient characteristics. Chest;

abnormalities of the lower airways. In:

128: 3391-3397.

Priftis KN, et al., eds. Paediatric

Dinwiddie R

(2004). Congenital upper

Bronchoscopy. Progr Respir Res Vol. 38.

airway obstruction. Paediatr Respir Rev; 5:

Basel, Karger, 2010; pp. 130-140.

17-24.

Speggiorin S, et al.

(2012). A new

Eber E (2006). Adult outcome of con-

morphologic classification of congenital

genital lower respiratory tract malforma-

tracheobronchial stenosis. Ann Thorac

tions. Swiss Med Wkly; 136: 233-240.

Surg; 93: 958-961.

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ERS Handbook: Paediatric Respiratory Medicine

Thoracic malformations

Ashok Daya Ram, Jennifer Calvert and Sailesh Kotecha

Congenital thoracic malformations (CTMs)

(table 1); however, we will only cover

are a heterogeneous group of rare

congenital cystic adenomatoid

congenital developmental anomalies and

malformations (CCAMs) and relative

disorders of the lung parenchyma and

bronchopulmonary sequestrations (BPS).

airways with an incidence of approximately

Close multidisciplinary cooperation between

3.5 per 10 000 live births. The use of routine

fetal medicine experts, neonatologists,

antenatal ultrasound scans, post-natal CT

paediatric surgeons, geneticists,

and MRI imaging, and advances in neonatal

paediatricians and/or paediatric

surgery and intensive care have widened our

pulmonologists is crucial to the overall

knowledge of the pathophysiology of CTMs

management and outcome of children with

but at the same time have also introduced

CTMs.

complexities, especially to the management

of asymptomatic lesions. Many excellent

Embryology

recent studies and textbooks of paediatric

respiratory medicine cover all CTMs in detail

The lungs develop as an out pouching from

the developing foregut at 3 weeks of

gestation. The respiratory diverticulum

Key points

begins to grow caudally and divides at

4 weeks and further subdivides in a

N The routine introduction of antenatal

dichotomous fashion. Further lung growth

ultrasound scanning has not only

occurs in tightly regulated stages of lung

increased our knowledge of CTMs but

development, namely the embryonic,

has resulted in improved antenatal

pseudoglandular, cannalicular, saccular and

counselling and management of these

alveolar phases. By the end of the sixth

conditions.

month of gestation, 17 generations of

subdivisions have formed. Lung growth and

N Antenatal ‘‘resolution’’ of CCAMs is

development continues post-natally until at

reported in up to 20% cases but in

least 2 years of age or beyond. The exact

most cases there is evidence of their

aetiology for most CTMs remains unknown

persistence on post-natal CT images.

but for CCAMs the embryological insults are

Management of asymptomatic

speculated to occur during the

CCAMs is controversial with some

pseudoglandular stages of lung

physicians opting for regular follow-up

development for Types I to III CCAMs and

and imaging to gauge progress whilst

during the late saccular phase of lung

others opt for surgical removal.

development for Type IV lesions. It is

N Long-term follow-up studies to assess

postulated that transcription and growth

the natural history, including

factors, such as homeobox protein Hox-B5

respiratory and neurodevelopmental

(HOXb5), thyroid transcription factor 1

outcomes, especially after fetal

(TTF) and platelet-derived growth factor

intervention, are required.

(PDGF-BB), may play a role in the

pathogenesis of CCAMs.

ERS Handbook: Paediatric Respiratory Medicine

445

cysts derived from the primitive foregut

Table 1. Differential diagnosis of CTMs

containing viscid, milky mucus and

Tracheobronchial malformations

occasionally communicate with the airway.

Tracheal agenesis/atresia/stenosis

They present in several ways:

Tracheal bronchus

N on antenatal ultrasound scan,

Oesophageal bronchus/lung

respiratory distress in infancy,

Tracheomalacia/bronchomalacia

N recurrent/persistent pneumonia,

Enteric duplication cyst

an incidental finding of a smooth

mediastinal mass on chest radiography.

Neuroenteric cyst

Bronchogenic cyst

Treatment is by surgical excision.

Bronchial cyst

Modalities such as antenatal MRI (fig. 1b)

Bronchiolar cyst

can accurately delineate and quantify the

Pulmonary parenchymal malformations

CTMs providing an excellent method for

morphological and volumetric evaluation of

Agenesis/aplasia/hypoplasia of the lungs

the fetal lung, but should be used as an

Congenital lobar emphysema

adjunct to routine antenatal ultrasound

CCAM

rather than as a primary investigation.

Bronchopulmonary sequestration

CCAM of the lungs

Vascular malformations

CCAM (also termed congenital pulmonary

Haemangioma

airway malformation (CPAM)) is a

Arterio-venous malformations

congenital lung anomaly in which abnormal

Scimitar syndrome (congenital venolobar

development appears to occur in part of the

syndrome)

lung, usually at the lower lobe of either lung.

Congenital pulmonary lymphangiectasia

The lesion grows fastest between 20 and

26 weeks of gestation, and then plateaus

Lymphangioma

before decrease in volume relative to foetal

Congenital chylothorax

size towards term. The abnormal lung

consists of terminal bronchiolar or acinar

structures that can act as space occupying

Antenatal diagnosis

lesions, although it is connected to the

tracheobronchial tree. The lesions usually

The routine introduction of antenatal

draw their blood supply from the pulmonary

ultrasound scanning (fig. 1a) has not only

circulation but in hybrid lesions, i.e. lesions

increased our knowledge of CTMs but has

showing elements of both CCAM and BPS,

resulted in improved antenatal counselling

they may have a systemic blood supply.

and management of these conditions.

CCAMs can vary in size and consistency,

Improved detection may have resulted in

and their continued growth can cause

increased reporting of CTMs. While

pressure effects on the remainder of the

antenatal scanning has improved detection,

lungs, oesophagus, the mediastinum or the

it has also led to some unique challenges,

great vessels. CCAMs are usually isolated

namely the management of lesions with a

but Type 2 CCAMs are often associated with

presumed diagnosis and lesions that may

other systemic abnormalities.

resolve. A pathological diagnosis would

clearly require tissue for examination, thus,

The incidence of CCAM is 0.94 per 10 000

it is important to describe the lesion in

live births. Some, but not all, studies report

detail and formulate a differential diagnoses

a slight male preponderance with no known

(table 1). Important differential diagnoses

genetic or familial association (although

include congenital diaphragmatic hernia and

these are increasingly described for specific

bronchogenic cysts, which are congenital

lesions).

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ERS Handbook: Paediatric Respiratory Medicine

Figure 1. a) Antenatal ultrasound and b) MRI scan of an extensive right sided CCAM, which was

symptomatic at birth, with respiratory distress and mediastinal shift as confirmed by c) a chest radiograph

and d) a CT scan. It was surgically removed successfully at 3 days of age.

There have been many classifications for

ciliated cuboidal or columnar epithelial

CCAMs but the two by Stocker (2002) and

cells.

Langston (2003) are most commonly used

N Type 3 are solid lesions without cystic

with significant overlap between the two.

components with an excess of acinar

The Langston classification includes lesions

structures.

other than CCAMs, including bronchial

atresia and pulmonary hyperplasia. The

Other types have subsequently been added

Stocker classification, which focuses on

to this classification including Type 0, which

CCAMs, is based on histology and the size

is best viewed as describing congenital

of the lesions as follows.

acinar dysplasia, and Type 4, which overlaps

with type 1 pleuropulmonary blastoma. Type

N Type 1 where individual cysts are .2 cm

1 is the commonest lesion forming ,50-

in diameter and are lined by

70% of all CCAMs and has the best

pseudostratified epithelium.

prognosis. Type 2 CCAMs are often

N Type 2 where individual cysts are ,2 cm

associated with other malformations, which

in diameter with the cysts resembling

should be looked for at antenatal ultrasound

dilated bronchioles; they are lined by

screening.

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447

Since Stocker’s classification is based on

sclerosing agent into any feeding vessel.

histological observation, Adzick et al. (1998)

Hedrick et al. (2005) reported an 89%

suggested a more clinical classification

overall survival in nine patients who

based on antenatal ultrasound

underwent the ex utero intrapartum

measurements of the cysts to classify

treatment (EXIT) procedure for fetal

CCAMs into two types:

hydrops, extensive mediastinal shift or

persistently elevated CVR. Ultrasound-

N macrocystic, where the cyst or cysts are

guided intrauterine thoracoamniotic

.5 mm in diameter and constitute 75%

shunting for a macrocystic CCAM with a

of all lesions;

large cyst has the best outcome with the

N microcystic, where the cyst or cysts are

lowest fetal and maternal risk. Out of 23

,5 mm in diameter and constitute 25%

such patients treated with this approach in

of the lesions.

one series, the volume reduction of the

CCAMs act as space occupying lesions with

CCAM was 70% and survival throughout the

pressure effects on the:

neonatal period was 74%. Open maternal-

fetal surgery with pulmonary resection of a

N lungs, which can lead to lung hypoplasia,

large CCAM yields a 50% probability of

N oesophagus resulting in polyhydramnios,

survival to discharge from the neonatal

N heart, vessels and mediastinum resulting

intensive care unit, but given the technical

in pleural effusions or hydrops fetalis.

complexity this should only be performed in

a centre with experience.

Antenatal ultrasound scanning can detect

these lesions as hyperechoic pulmonary

However, most studies report a small

masses (fig. 1a), as well as features of

number of patients and report success

associated complications (e.g.

although publication bias suggests that

polyhydramnios or hydrops) in .80% of the

those that resulted in failure are unlikely to

cases. Systemic abnormalities including the

reach the wider literature. Furthermore,

cardiovascular, abdominal and mediastinal

most of these interventions have not been

structures should also be investigated.

formally assessed, thus, results need to be

Antenatal ‘‘resolution’’ of CCAMs is

interpreted with caution. Longer term

reported in up to 20% cases but in most

outcomes after fetal intervention have not

cases there is evidence of their persistence

been reported in any detail but will clearly

on post-natal CT images. 5-10% of these

need careful follow-up, especially for

lesions can lead to the development of

neurodevelopmental outcomes. Clearly it is

hydrops, which is associated with markedly

important to counsel the parents with a

increased fetal demise; thus, this

multidisciplinary team offering all available

association has received great attention for

options.

antenatal fetal surgical intervention.

Currently the best available indicator of

Post-natally, most CCAMs will have been

prognosis for CCAM is the CCAM volume

identified antenatally and infants with large

ratio (CVR). This is the ratio of the lesion

lesions may need supportive therapy for

volume compared to the head

stabilisation prior to surgical intervention.

circumference. CVR values .1.6 are

Planning to deliver in appropriate centres

associated with increased risk of between

with the required expertise is a must for

15% and 75% for developing fetal hydrops,

these babies. The majority of CCAMs,

i.e. poor prognosis. Due to the increased risk

however, are asymptomatic but some may

of developing a complicated course, the CVR

present with acute (fig. 1c and d) or chronic

is often used to guide antenatal fetal

respiratory distress, recurrent pulmonary

surgical intervention but has limited

infections, bronchiectasis, lung abscesses,

sensitivity and specificity. Antenatal

haemoptysis, pneumothorax, air embolism,

interventions include steroid administration,

haemothorax, pyopneumothorax, steroid-

thoracentesis, thoracoamniotic shunt, laser

resistant asthma or high output cardiac

ablation, fetal surgery or injection of a

failure (if there is a large systemic arterial

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ERS Handbook: Paediatric Respiratory Medicine

blood supply). They may present

it is claimed that the risks of post-natal

asymptomatically on chest radiographs

infection for asymptomatic lesions are

obtained for other reasons.

exaggerated. Furthermore, these advocates

suggest that the risks of future malignancy

There is little controversy that surgical

are small, there is no evidence for lung

resection of symptomatic lesions is

physiological improvement after early

appropriate in most cases and is relatively

surgery and the post-operative risks for

straightforward with minimal morbidity and

surgery after respiratory infection in a few

mortality in experienced paediatric/neonatal

children do not justify exposing those

surgical centres.

children who may never develop symptoms

Management of asymptomatic lesions is

to unnecessary surgery.

more controversial. Possible reasons for

Whichever route is taken for management of

surgical removal of asymptomatic lesions

include prevention of chest infections, and

asymptomatic CCAMs, it is important to

other rarer complications such as:

ensure appropriate counselling of the

parents by a multidisciplinary team and for

N bleeding and pneumothorax;

full risk assessment of any surgical

N prevention of future malignancy risk;

interventions to be balanced against the

N encourage compensatory lung growth if

need for repeated CT scans and risk of loss

performed within 2 years of age;

to follow-up of patients. For an

N decrease post-operative complications.

asymptomatic child who develops infection,

the surgical risks and complications are

In most cases surgery is performed

marginally higher than those who undergo

between 2 and 12 months. With advances

elective surgery but the absolute risk for

in surgical skills, elective surgery is

development of infection in an

considered relatively safe in expert surgical

asymptomatic child has been poorly

hands with few complications involving a

reported. Newer interventions, such as

short hospital stay but may be associated

thoracoscopic surgery, are being introduced

with poorly delineated longer term

but need to be fully assessed before they

outcomes such as scoliosis. Complete

become routine, especially for

excision of the lesion is usually achieved by

asymptomatic CCAMs.

lobectomy but segmentectomy may be

used to preserve parenchyma for small

The natural history of CCAMs is not well

lesions or if there is multiple lobe

defined. It is unclear what proportion of

involvement. If elective surgery is

children with asymptomatic CCAM develop

performed during infancy, there may be

symptoms in the future. Although some

potential for compensatory lung growth but

reports of limited numbers of children

definitive evidence is lacking.

suggests symptoms in up to 10%, the

Thoracoscopic surgery may potentially

duration of follow-up is often short, thus

decrease the risks of traditional open

the true value is likely to be higher.

thoracotomy such as scoliosis, rib

Although tumours such as

crowding, injury to nerves and vessels, etc.,

pleuropulmonary blastoma,

thus may be preferable but needs further

rhabdomyosarcoma and bronchoalveolar

evaluation.

carcinoma are reported to occur with

However, there are proponents of a ‘‘wait

CCAMs, the true risk is unclear and one

and see’’ approach, favouring a conservative

report has suggested that risk may not be

approach citing many counter-arguments to

reduced after surgery. Studies reporting

surgical intervention. For asymptomatic

physiological lung function in surgical

lesions, a recent meta-analysis of 41 series

survivors of symptomatic CCAMs are also

with 1070 patients suggests that the rate of

conflicting with some reporting normal

infection among asymptomatic infants

values whilst others report deficits. There is

beyond the neonatal period is 3.2%

a clear need for further studies to evaluate

occurring at a median age of 7 months, thus

the natural history of CCAMs.

ERS Handbook: Paediatric Respiratory Medicine

449

Bronchopulmonary sequestration

planning of intervention, delivery, etc., but

also introduce newer problems particularly

BPS can be extralobar or intralobar with the

the management of asymptomatic lesions.

lesions comprising of lung tissue with its

Whilst symptomatic lesions are amenable to

own blood supply via an aberrant blood

surgical excision, the management of

vessel. They lack continuity with the rest of

asymptomatic lesions remains controversial

the respiratory tract. Intralobar BPS

and both medical and surgical management

predominantly occurs in the posterior basal

needs to be balanced against the risks for

lateral segment of the left lower lobe. It has

each approach. New interventions are being

single or multiple systemic arterial supplies

increasingly introduced but need careful

arising from the abdominal aorta in 75% of

evaluation not only in the short term but

the cases and venous drainage is usually

also for long-term outcomes. However

into the pulmonary vein. Extralobar

CTMs are dealt with, appropriate

sequestrations are completely separated

counselling of the parents with a

from the normal lung, invested by an

multidisciplinary team is essential.

individual pleura. The commonest site is the

left lower lobe but it can occur anywhere in

the lungs and even in sub-diaphragmatic

Further reading

areas. In as many as 50% of cases, there are

other associated abnormalities including

Abel RM, et al. Congenital lung diseases. In:

CCAM, congenital cardiac anomalies,

Chernick V, et al., eds. Kendig’s Disorders

pericardial defects, pectus excavatum,

of the Respiratory Tract.

7th Edn.

bronchogenic cysts and vertebral anomalies.

Philadelphia, Elsevier, 2006; pp. 280-316.

The blood supply is usually from the

Adzick NS, et al.

(1998). Fetal lung

lesions: management and outcome. Am

systemic circulation. BPS is the commonest

J Obstet Gynecol; 179: 884-889.

differential diagnosis of CCAM; they both

Bush A, et al. (2008). Cystic lung lesions

have distinct radiological, pathological and

- prenatal diagnosis and management.

clinical characteristics. The main distinct

Prenat Diagn; 28: 604-611.

characteristics are lack of communication to

Calvert JK, et al.

(2006). Outcome of

the tracheobronchial tree and the aberrant

antenatally suspected congenital cystic

blood supply from systemic circulation. In

adenomatoid malformation of the lung:

some cases, features of both CCAM and BPS

10 years’ experience 1991-2001. Arch Dis

coexist in the same lesion, often termed

Child Fetal Neonatal Ed; 91: F26-F28.

hybrid lesions.

Correia-Pinto J, et al. (2010). Congenital

lung lesions

- underlying molecular

The treatment for both intralobar and

mechanisms. Semin Pediatr Surg;

19:

extralobar BPS is surgical resection because

171-179.

of risks of haemorrhage, infection,

Crombleholme TM, et al. (2002). Cystic

arteriovenous shuntings and late

adenomatoid malformation volume ratio

malignancy but smaller lesions may be left

predicts outcome in prenatally diagnosed

alone or selectively embolised. The most

cystic adenomatoid malformation of the

essential step in surgery of these lesions is

lung. J Pediatr Surg; 37: 331-338.

identification and control of systemic blood

Hedrick HL, et al. (2005). The ex utero

vessels. Unrecognised or uncontrolled

intrapartum therapy procedure for high-

bleeding from these vessels can be

risk fetal lung lesions. J Pediatr Surg; 40:

associated with serious morbidity or even

1038-1043.

Hsieh CC, et al.

(2005). Outcome of

mortality.

congenital cystic adenomatoid malforma-

Conclusion

tion of the lung after antenatal diagnosis.

Int J Gynaecol Obstet; 89: 99-102.

Although CTMs are rare, they are important

Joshi S, et al. (2007). Lung growth and

causes of respiratory distress in newborns

development. Ear Hum Develop;

83:

and children. They are increasingly

789-794.

diagnosed antenatally which allows for

450

ERS Handbook: Paediatric Respiratory Medicine

Knox EM, et al. (2006). In utero pulmon-

Savic B, et al. Pulmonary sequestration.

ary drainage in the management of

In: Frick HP, et al., eds. Advances in

primary hydrothorax and congenital cystic

Internal Medicine and Paediatrics. New

lung lesion: a systematic review.

York, Springer-Verlag, 1979; pp. 58-92.

Ultrasound Obstet Gynecol; 28: 726-734.

Slade I, et al. (2011). DICER1 syndrome:

Kotecha S, et al. (2012). Antenatal and

clarifying the diagnosis, clinical features

postnatal management of congenital

and management implications of a pleio-

cystic

adenomatoid

malformation.

tropic tumour predisposition syndrome.

Paediatr Respir Rev; 13: 162-170.

J Med Genet; 48: 273-278.

Langston C (2003). New concepts in the

Stanton M, et al.

(2009). Systematic

pathology of congenital lung malforma-

review and meta-analysis of the postnatal

tions. Semin Paediatr Surg; 12: 17-37.

management of congenital cystic lung

Papagiannopoulos KA, et al.

(2001).

lesions. J Pediatr Surg; 44: 1027-1033.

Pleuropulmonary blastoma: is prophylac-

Stocker JT (2002). Congenital pulmonary

tic resection of congenital lung cysts

airway malformation-a new name for an

effective? Ann Thorac Surg; 72: 604-605.

expanded classification of congenital

Roggin KK, et al. (2000). The unpredict-

cystic adenomatoid malformation of the

able character of congenital cystic lung

lung. Histopathology; 41: Suppl. 2, 424-

lesions. J Pediatr Surg; 35: 801-805.

458.

Witlox RS, et al.

(2011). Neonatal out-

Wilson RD, et al.

(2004). Thoracoa-

come after prenatal interventions for

mniotic shunts: fetal treatment of pleural

congenital lung lesions. Early Hum Dev;

effusions and congenital cystic adenoma-

87: 611-618.

toid malformations. Fetal Diagn Ther; 19:

Salomon LJ, et al. (2003). Fetal thora-

413-420.

coamniotic shunting as the only treat-

Wilson RD, et al. (2006). Cystic adeno-

ment for pulmonary sequestration with

matoid malformation of the lung: review

hydrops: favorable long-term outcome

of genetics, prenatal diagnosis, and in

without postnatal surgery. Ultrasound

utero treatment. Am J Med Genet; 140:

Obstet Gynecol; 21: 299-301.

151e5.

ERS Handbook: Paediatric Respiratory Medicine

451

Vascular malformations

Oliviero Sacco, Serena Panigada, Nicoletta Solari, Elena Ribera, Chiara Gardella,

Silvia Rosina, Michele Ghezzi and Francesca Rizzo

A wide spectrum of congenital anomalies

embryonic development of the aortic arch

can occur during the formation of the aortic

and related structures is important to

arch, brachiocephalic arteries, pulmonary

understand and classify the various form of

arteries and ductus arteriosus, due to the

vascular malformation.

failure of embryonic structures to fuse and

regress regularly. Knowledge of the normal

During fetal development, six pairs of

primitive aortic arches are sequentially

formed and, as successive arches develop,

the previous arches regress. The major

Key points

persistent arches in humans are the fourth

and sixth. The fourth arches contribute to a

The incidence of vascular

portion of the left aortic arch and of the right

malformations is ,1% but the true

subclavian artery; the proximal portions of

incidence is difficult to assess if

the sixth arches become the mediastinal

less severe abnormalities are

segment of the pulmonary arteries, while

included.

their distal portions form the ductus

arteriosus (Kellemberg, 2010). Abnormal

The most severe forms of vascular

development of the aortic arch complex may

rings can be detected during the

neonatal diagnostic work-up, cause

represent an uncommon but potentially

serious symptoms in the newborn

serious cause of variable degrees of

period and require surgery within the

compression of the trachea, bronchi and/or

first year of life.

oesophagus, due to the formation of

vascular ‘‘ring’’ or ‘‘sling’’. Some of these

The less severe abnormalities are

anomalies, such as the double aortic arch

detected in later life, when

and the right arch/left ligament, are

unexplained recurrent respiratory

anatomically complete rings, while others,

symptoms or occasional mild

i.e. anatomically incomplete or partial rings,

dysphagia leads to radiographic or

are called slings, such as the pulmonary

endoscopic evaluation. Symptoms

sling.

such as dyspnoea, wheezing and

cough are often misdiagnosed as

Clinical presentation and classification

asthma, particularly if they occur in

older children.

In children with vascular abnormalities, the

The vascular malformations that most

severity of the resulting respiratory disorder

frequently cause symptoms are:

does not appear to correlate tightly with the

double aortic arch; right aortic arch

degree of anatomical obstruction of the

with a left ligament arising from the

airways. Signs and symptoms at

descending aorta; aberrant subclavian

presentation are variable, including apnoeic

artery; pulmonary sling; and aberrant

spells, recurrent apnoeas, stridor/noisy

innominate artery.

breathing, chronic or recurrent cough, a

brassy cough similar to a seal’s bark,

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ERS Handbook: Paediatric Respiratory Medicine

recurrent respiratory infections and

commonly located on the left side of the

dysphagia for solid foods.

spine. The ligamentum arteriosum is usually

located between the distal part of the left

The most severe forms of vascular rings can

arch and the left pulmonary artery, but may

be detected during the neonatal diagnostic

be present on both sides when the aortic

work-up, particularly if associated with

arches are both patent (Kellemberg, 2010).

congenital cardiac malformations; they

Children with this anomaly usually present

cause serious symptoms in the newborn

with severe respiratory symptoms and some

period and require surgery within the first

swallowing difficulty early in life. Surgical

year of life. Less severe abnormalities are

interruption of the smaller or atretic aortic

detected in later life, when unexplained

arch and of the ligament is usually required.

recurrent respiratory symptoms or

The most severe case of tight vascular ring

occasional mild dysphagia require

can interfere with normal tracheal

radiographic or endoscopic evaluation.

development; the tracheal lumen can show

Symptoms such as dyspnoea, wheezing and

segmental stenosis with complete

cough are often misdiagnosed as asthma,

cartilaginous rings (fig. 1e).

particularly if they occur in older children.

Right aortic arch, comprising 12-25% of

The true incidence is difficult to assess if we

cases of vascular rings, is usually associated

include less severe abnormalities/

with congenital cardiac malformations such

compression. Autopsy studies suggest that

as persistent truncus arteriosus, pulmonary

3% of people have a congenital

atresia with ventricular septal defect, and

malformation of the aortic arch but about

tetralogy of Fallot. In this group of

two-thirds of cases remain undiagnosed

abnormalities, the regression of the

(McLaren et al., 2009). In this section, we

embryonic structures involves the left aortic

will focus on the vascular malformations

arch, resulting in the right arch lying to the

that most frequently cause symptoms:

right side of the trachea, passing over the

right principal bronchus and generally

N double aortic arch,

continuing as the right descending aorta,

N right aortic arch with a left ligament

located to the right of the spine (fig. 2a and

arising from the descending aorta,

c). A combination of a right aortic arch and a

N aberrant subclavian artery,

persisting left descending aorta results in a

N pulmonary sling, and

circumflex right aortic arch with an

N aberrant innominate artery.

horizontal retro-oesophageal portion of the

Double aortic arch, the most common and

dorsal aortic arch, which contributes to the

serious complete type of vascular ring, is

compression of trachea and oesophagus

usually an isolated anomaly without

from behind (fig. 3). The brachiocephalic

associated cardiac malformation; it is

vessels may originate as a mirror image of a

associated with congenital cardiac

normal left aortic arch, but many variants

malformations, such as ventricular septal

are possible. The association of a right aortic

defect or tetralogy of Fallot, in 20% of cases.

arch with a left ligament that passes from

It is due to the persistence of both fourth

the left pulmonary artery to the descending

aortic arches encircling the trachea and

aorta or to the left subclavian artery,

oesophagus in a tight ring. In 75% of affected

coursing to the left of the trachea and

infants, the right-sided arch is dominant

oesophagus, describes a complete vascular

(larger and positioned higher than the left

ring around these structures. If the left

arch), in 20% the left arch is dominant and in

fourth aortic arch regresses proximal to the

5% the arches are equal in size (fig. 1a and b).

left subclavian artery, a right aortic arch with

A portion of the left aortic arch can be atretic

an aberrant left subclavian artery as the last

and persist only as a fibrous band. Each

branch results. The artery passes behind the

aortic arch passes over the ipsilateral

oesophagus and forms a complete vascular

principal bronchus and fuses behind into a

ring together with the left-sided ligamentum

common descending aorta, which is more

arteriosum (Russell et al., 2010).

ERS Handbook: Paediatric Respiratory Medicine

453

Figure 1. a) Right-sided dominant double aortic arch (arrow); MDCT axial view. b) Same patient, MDCT

three-dimensional imaging; posterior view. c-e) Endoscopic images of double aortic arch compression of

trachea, increasing severity. e) The tracheal rings are complete or circumferential.

The origin of the left subclavian artery from

arch and has an oblique course toward the

the descending aorta is frequently dilated,

other side, across the superior

forming the so-called Kommerell

mediastinum, passing behind the

diverticulum (fig. 2a and c). In patients with

oesophagus on its way to the upper

a right aortic arch, the airway compression

extremity. An aberrant right subclavian

can be due to different mechanisms:

artery as single malformation is rarely

vascular ring due to a left ligamentum

symptomatic, although in older children and

arteriosum (fig. 2b), enlargement of the

in adults, mild dysphagia may be present

Kommerell diverticulum and/or a midline/

due to compression of the oesophagus.

left descending aorta.

However, an aberrant left subclavian artery,

crossing behind the oesophagus as the last

Aberrant subclavian artery, the most common

branch of a right aortic arch, forms a

among the aortic arch anomalies, occurs in

complete vascular ring together with a left-

nearly 1% of the population and in 25% of

sided ligamentum arteriosum, as previously

Down syndrome patients. Originally

described, and commonly causes symptoms

described by Bayford in the 18th century as

due to compression of both the trachea and

‘‘dysphagia lusus naturae’’ (dysphagia ‘‘freak

oesophagus (Kellemberg, 2010).

of nature’’), this anomaly most commonly

involves the right subclavian artery or, rarely,

Pulmonary sling The embryonic origin of

the left subclavian artery when there is a

pulmonary artery sling occurs when the

right-sided aortic arch, as previously

developing left lung captures its arterial

described. The aberrant subclavian artery

supply from the right sixth arch through

originates as the last vessel of the aortic

capillaries caudal, rather than cephalad, to

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ERS Handbook: Paediatric Respiratory Medicine

Figure 2. a) Right aortic arch, Kommerel diverticulum (arrow); MDCT axial view. b) Right aortic arch, a

rare MDCT imaging of ligamentum arteriosum; axial view. c) Kommerel diverticulum and aberrant left

subclavian artery (arrow), MDCT three-dimensional imaging; posterior view.

the developing tracheobronchial tree. As

50% of pulmonary artery sling cases, most

consequence, the anomalous left pulmonary

commonly atrial septal defect, patent ductus

artery arises from an elongated right

arteriosus, ventricular septal defect and left

pulmonary artery, turns dorsally encircling

superior vena cava.

the right main bronchus, and passes to the

Aberrant innominate artery causes tracheal

left between the trachea and oesophagus

compression of various degrees. Why an

before entering the hilum of the left lung

innominate artery, which arises from the

(fig. 4a).

aortic arch to the left and crosses in front of

The airway may also be compromised by

the trachea to the right side, should

associated complete cartilage rings, the so

compress the trachea in some cases and not

called ring-sling complex present in 40-50%

others is not well understood. In innominate

of cases, where the membranous portion of

artery compression patients, the artery

the trachea is absent and the tracheal

appears to originate somewhat more

cartilages are circumferential or ‘‘O-

posteriorly and leftward on the aortic arch

shaped’’. Associated tracheobronchial

than usual. This condition is more

abnormalities may occur, including

frequently symptomatic when associated

tracheomalacia, hypoplasia and stenosis of

with tracheomalacia and/or oesophageal

long tracheal segments (fig. 4b and c) (Elliot

atresia (fig. 5). Severe compression of the

et al., 2003). Both the right main bronchus

trachea results in chronic or recurrent brassy

and the trachea are affected and

cough, stridor, tachypnoea and recurrent

compression by the sling can result in

respiratory infection (Gardella et al., 2010).

hyperinflation or atelectasis of the right

The most severe presentations in infancy

lung. Congenital heart defects are found in

include life-threatening events.

ERS Handbook: Paediatric Respiratory Medicine

455

including heart malformation and some

aortic arch anomalies. As a consequence,

the prenatal diagnosis of some aortic arch

anomalies has become more common in the

last decade due to the widespread use of

fetal sonographic studies sufficient for

delineation of the trachea, aortic arch,

brachiocephalic arteries and ductus

arteriosus (Avni et al., 2007). After birth, the

presence of respiratory distress, wheezing,

stridor, dysphagia and recurrent respiratory

infection may require consideration of a

vascular ring or sling as the underlying

cause.

The historical approach was to perform

chest radiography and barium swallow as

the first step to evaluate children with

suspected extrinsic compression of the

airways, while conventional angiography was

reserved for confirmation of the diagnosis.

These studies have now been widely

replaced by MRI and multidetector CT

(MDCT). However, the recent literature

demonstrates variability in the preferred

diagnostic strategies for these conditions.

Chest radiography In symptomatic patients,

evaluation usually begins with frontal and

lateral chest radiograph. On the frontal

projection, the laterality of the aortic arch

can be appreciated by its density and the

side of the descending aorta by the presence

or absence of the aortic stripe on the

respective side. On the lateral projection,

anterior bowing of the trachea and an

increase in the retrotracheal density may

also be appreciated. In pulmonary sling,

chest radiographic findings include

unilateral hyperinflation, tracheal narrowing

and an unusual horizontal course of the left

and right main bronchi, resulting in a ‘‘T-

Figure

Vascular ring due to right aortic arch,

shaped’’ trachea. In any case, chest

aberrant left subclavian artery and left

radiography can only arouse suspicion of the

ligamentum arteriosum. a) Endoscopic image of

presence of a major vascular malformation.

tracheal lumen compressed on the right side. b)

Same patient, persistent indentation on barium

Barium oesophagography Upper

oesophagography from behind; lateral view.

gastrointestinal study has historically been

Clinically: mild dysphagia.

reliable and remains an excellent technique

for the diagnosis of a vascular ring, as the

Diagnosis

location of the aortic arch in relation to the

oesophagus can be determined (fig. 3b).

Fetal ultrasound may detect malformation of

Bilateral persistent indentations on the

several organs during the first trimester,

oesophagus on the anteroposterior view

456

ERS Handbook: Paediatric Respiratory Medicine

Figure 4. Pulmonary sling. a) MDCT axial view: the anomalous left pulmonary artery (arrow) arises from

an elongated right pulmonary artery, turns dorsally encircling the right main bronchus, and passes to the

left between the trachea and oesophagus before entering the hilum of the left lung. b) MDCT coronal view

of the associated long-segment tracheal stenosis: two-thirds of the trachea are stenotic and show complete

cartilage rings (line). c) MDCT three-dimensional imaging of the trachea and bronchi: the origin of the

right main bronchus is stenotic due to compression by the anomalous left pulmonary artery.

suggest a double aortic arch, while posterior

noninvasive angiography have widely

indentation with an oblique course angled

replaced other diagnostic techniques, such

toward the left shoulder suggests an

as the now obsolete catheter angiography.

aberrant subclavian artery. Anterior pulsatile

The direct multiplanar imaging capability of

indentation of the oesophagus is virtually

MRI allows accurate evaluation of vascular

pathognomonic for pulmonary artery sling.

malformation and its relationships with

adjacent organs and, possibly, associated

Echocardiography and angiography

intracardiac defects in a single sitting,

Echocardiography has the advantage of a

without ionising radiation and iodinated

comprehensive assessment of intracardiac

contrast material. However, most MRI

anatomy and function. However, it is limited

studies for vascular compression are quite

by acoustic windows, a lack of depiction of

prolonged (.30 min), the need for absolute

airway/oesophageal involvement and high

immobility during image acquisition

interobserver variability. Conventional

requires general anaesthesia with controlled

angiography is invasive and is limited by

ventilation, and sedation risks are increased

high radiation dose and the need for

in children with compromised airways.

iodinated contrast material.

Contrast-enhanced MDCT overcomes this

disadvantage by allowing accurate imaging

Although the diagnosis of a vascular ring

in very short scanning times and mild

can be established or suspected with chest

sedation is sufficient in younger,

radiography and oesophagography, the

uncooperative children. The disadvantages

exact configuration of the vascular

of MDCT include ionising radiation and the

abnormality cannot be fully defined with

need for iodinated contrast material;

conventional radiology alone. The exact

however, recent adjustment of specific

anatomy of an aortic arch malformation and

techniques minimises the radiation dose. If

its relationship to adjacent structures can be

assessment of the airways is important,

accurately defined only by cross-sectional

MDCT is currently more reliable than MRI

imaging techniques, as MRI and CT

for the definition of the airway by

(Hellinger et al., 2011).

multiplanar and three-dimensional image

MRI and MDCT Contrast-enhanced helical

reconstruction (figs 1b, 2c and 4c), including

MRI or MDCT imaging allow excellent

virtual bronchoscopy, without appreciable

delineation of the aortic arch, its branches

respiratory artefacts. For both MRI and

and their spatial arrangement. The

MDCT, the major diagnostic limit is that an

multiplanar and three-dimensional imaging

obliterated vascular segment (e.g. the

capabilities of magnetic resonance and CT

ligamentum arteriosum or an atretic aortic

ERS Handbook: Paediatric Respiratory Medicine

457

Figure 5. Tracheal compression by aberrant innominate artery in two patients, a) 15 and b) 20 months of

age. a) Endoscopic image of tracheal lumen compressed on the front right side. Good vision of the tracheal

rings is achieved and tracheal compression is visible without tracheomalacia. b) Patient with repaired

oesophageal atresia and less well-delineated tracheal rings. The association of vascular compression and

tracheomalacia caused a severe clinical picture with brassy cough, stridor and life-threatening events.

arch) can be visualised only rarely (fig. 2b).

Bronchoscopy and bronchography Despite the

The final decision to image with MRI versus

accuracy of both MRI and MDCT in

MDCT should take into consideration

evaluating the nature of the vascular

availability of equipment and ease of

compression of the airways, current MRI

scheduling, as well as the patient’s ability to

and MDCT techniques do not reliably

cooperate. In practice, the increase in speed

distinguish between dynamic or static

and quality of multiplanar reconstruction

narrowing of the airways.

provided by MDCT technology means that

CT is used more and more often than MRI in

Such distinction can have important clinical

most centres.

consequences, as many children with

Figure 6. Vascular ring due to right aortic arch, aberrant left subclavian artery and left ligamentum

arteriosum; same patient as in figure 3. Intraoperative view: a) ligamentum arteriosum (arrow) resection;

b) the two ends of the ligamentum (arrows) spontaneously move .1 cm away soon after resection.

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ERS Handbook: Paediatric Respiratory Medicine

vascular malformation can have associated

there is a strong association with long-

malacia of the compressed airway.

segment congenital tracheal stenosis with

Bronchoscopy and bronchography are still

complete tracheal cartilage rings. The

the best techniques to assess the presence

surgical procedure is the re-implantation of

of tracheo- or bronchomalacia (fig. 5b).

the left pulmonary artery and, at the same

Bronchoscopy and bronchography are

time, a slide tracheoplasty to increase the

performed at the same time, injecting

tracheal calibre (Fiore et al., 2005). Surgical

isotonic, nonionic contrast down the

treatment of patients with an aberrant right

working channel of the flexible

subclavian artery is almost never necessary;

bronchoscope. Intraoperative tracheoscopy

the artery has to be re-implanted only in the

can be indicated in the aortopexy procedure,

rare patients with severe dysphagia.

to evaluate the resolution of the tracheal

collapse during the manoeuvres of

Patients with tracheal compression by an

suspension of the aortic arch (Torre et al.,

aberrant innominate artery may have

2012). Bronchoscopy can be repeated 1-

concomitant tracheomalacia rather than

2 years after the surgical procedure to follow

pure extrinsic compression and this is

up the airway malacia evolution.

particularly frequent in children with

oesophageal atresia. Symptoms tend to

Treatment and outcome

regress, at least partially, with age if

Vascular rings and slings inducing severe

tracheomalacia is not associated, and

symptoms usually require prompt surgical

tracheoscopy can be useful to assess the

correction. Prolonged severe vascular

malacia (fig. 5b). Surgical correction,

compression of the airways is more likely to

typically requiring aortopexy, is rarely

induce severe malacia of the compressed

needed and is reserved for patients with

airway and interfere with the growth of the

severe symptoms, such as apnoeic spells in

trachea or bronchi. In most children, the

newborns or recurrent barking cough in

problem is self-limiting and eventually the

older children, when the compression

cartilage regains sufficient stiffness for the

decreases the tracheal lumen significantly

symptoms to resolve. This clinical

(Gardella et al., 2010).

observation suggests that the surgical

procedure should be performed without

Further reading

delay in symptomatic patients (Turner et al.,

Avni FE, et al. (2007). Evolution of fetal

2005). Children with a double aortic arch

ultrasonography. Eur Radiol; 17: 419-431.

usually require usually surgical correction by

Elliot M, et al. (2003). The management

resection of the nondominant arch. It is

of congenital tracheal stenosis. Int J

important to assess the arch anatomy and

Pediatr Otorhinolar;

67: Suppl. 1, S183-

the dominant arch before surgery because

S192.

such assessment determines the operative

Fiore AC, et al. (2005). Surgical treatment

approach. If there is an atretic portion of an

of pulmonary artery sling and tracheal

arch, this is the obvious site for arch division.

stenosis. Ann Thorac Surg; 79: 38-46.

Gardella C, et al. (2010). Tracheal com-

A right aortic arch with a left ligamentum

pression by aberrant innominate artery:

arteriosum and/or an aberrant left

clinical presentation in infants and chil-

subclavian artery is reported even in

dren, indication for surgical correction by

asymptomatic children. Relief of symptoms

aortopexy, and short- and long-term out-

such as dysphagia can be achieved by

come. J Pediatr Surgery; 45: 564-573.

resection of the tight ligamentum

Hellinger JC, et al.

(2011). Congenital

arteriosum and/or excision of the Kommerell

thoracic vascular anomalies: evaluation

diverticulum. The intervention will be

with state-of-the-art MR imaging and

adapted to the variant of the anomaly and is

MDCT. Radiol Clin N Am; 49: 969-996.

aimed at decompressing the upper portion

Kellemberg CJ (2010). Aortic arch mal-

of the gastrointestinal tract or the lower

formations. Pediatr Radiol; 40: 876-884.

respiratory tract (fig. 6). In pulmonary sling,

ERS Handbook: Paediatric Respiratory Medicine

459

Aetiology, pathogenesis,

prevention and evidence-

based medical management

Robert I. Ross-Russell

Bronchopulmonary dysplasia (BPD) is a

The disease was first described in 1967 but

chronic lung disease that affects premature

the pathophysiology has changed

babies, usually following mechanical

significantly since that time. Earlier

ventilation. Over the past 20 years, changes

descriptions of fibroproliferation, smooth

in antenatal steroid use, surfactant therapy

muscle hyperplasia and decreased

and changes in ventilator strategy have led

alveolarisation have changed in the post-

to major improvements in the outcomes of

surfactant era. BPD (commonly referred to

very premature infants. However, at the

as ‘‘new BPD’’) shows less regional

same time, the incidence of BPD has

variability, large alveoli and characteristic

changed very little. This has meant that a

vascular changes. The features

greater number of affected infants are

differentiating old from new BPD are shown

surviving into childhood and beyond. These

in table 1.

infants have an increased need for

The National Institutes of Health (NIH)

healthcare, with frequent readmissions to

diagnostic criteria for bronchopulmonary

hospital in the first 2 years and persistent

dysplasia are shown in table 2. All infants

abnormalities of lung function into

need to have been in room oxygen for at

adolescence and adulthood.

least 4 weeks. For infants born at less than

32 weeks gestation, assessment is made at

36 weeks post-menstrual age or discharge

Key points

(whichever comes first), whereas for those

infants born after 32 weeks, assessment is

N BPD remains a significant cause of

made at 56 days of age or discharge.

long-term respiratory illness despite

Diagnostic criteria remain an important

major advances in the care of the

issue, as studies evaluating outcomes have

preterm newborns.

historically used varying definitions of BPD,

making comparison difficult. For example,

The primary pathological process is

different units may administer additional

inflammation, driven through the NF-

oxygen at varying levels of saturation.

kB pathway, and triggered by a variety

The incidence of BPD varies with gestational

of genetic and environmental factors.

age, and particularly birth weight. Infants

N Management is directed at

with a birth weight between 500 and 750 g

minimising lung insults, by limiting

have a 42% chance of developing BPD

oxygen toxicity and ventilator-induced

whereas in infants weighing between 1250

lung trauma.

and 1500 g the chance of incidence drops to

N Drugs that may influence

4%.

development of BPD include caffeine

Aetiology and pathogenesis

and vitamin A, although new anti-

inflammatory drugs are in

The primary basis of respiratory disease in

development.

the preterm infant is a lack of surfactant

leading to the development of respiratory

ERS Handbook: Paediatric Respiratory Medicine

461

Table 1. Pathological differences between BPD before (old) and after (new) the introduction of surfactant

Old BPD

New BPD

Extensive fibroproliferation

Rare proliferative changes

Airway smooth muscle hyperplasia

Mild smooth muscle involvement

Areas of atelectasis and hyperinflation

More homogeneous lung changes

Reduced alveolarisation

Simplified, large alveoli

Pulmonary artery muscularisation

Abnormal pulmonary vascularisation

distress syndrome (RDS). Surfactant

human leukocyte antigen (HLA)-A2 may

production only starts at around 24 weeks

predispose to the condition.

gestation and, coupled with the

Inflammation There is no doubt that

underdevelopment of alveoli, gas exchange

inflammation is a major influence on the

in the extremely low birth weight infant is

development of BPD. In particular, the role

significantly compromised. This leads to a

of nuclear factor (NF)-kB has been

need for positive-pressure ventilation and

increasingly recognised as a major

increased oxygen administration, both of

determinant of inflammation mediated

which cause lung injury. These and other

injury. NF-kB normally exists in cells bound

factors (see later) influence the development

within the inhibitor of NF-kB (IkB) complex,

of the pulmonary vasculature and alveoli,

but can be released from this by a variety of

both of which are interdependent. Factors

different mechanisms, including hyperoxia,

that impair vascular growth, such as post-

trauma and infection. When released, NF-kB

natal infection, will also have a detrimental

forms several subunits that may each allow

effect on lung development. Endothelial

transcription of different pro-inflammatory

growth factors such as vascular endothelial

mediators. Hyperoxia (through oxidative

growth factor (VEGF)-A are critical factors

stress) is known to increase expression of

for both vascular branching and lung

NF-kB and has been shown to cause injury

development. Factors affecting expression

to the newborn mouse lung. It also affects

of VEGF-A will affect lung development.

expression of VEGF-A which directly affects

Similarly conditions such as pulmonary

both vascular and alveolar development.

hypertension are known to worsen the

Trauma will also increase NF-kB expression.

outcome in BPD.

Volutrauma has been shown to increase the

However, the development of BPD in such

incidence of BPD in sheep through NF-kB-

patients is quite variable and may require

mediated mechanisms.

several "hits" or insults. Genetic,

Infection Infection has long been associated

inflammatory, infective and traumatic

with the development of BPD. It has a direct

factors may all influence development of

effect on the expression of NF-kB, but can

lung injury. Other factors, such as nutrition

also stimulate inflammatory cytokines

or fluid overload, may also influence the

directly. Ureaplasma infection has long been

degree of injury seen.

thought to increase the risk of BPD, along

Genetics There is only limited

with other genital mycobacteria. Isolation of

understanding of the genetic factors

Ureaplasma from the trachea of infants has

influencing the development of BPD. It is

been shown to be associated with increased

well recognised that both sex and ethnicity

BPD but, more recently, Ureaplasma

can influence the incidence of BPD, and twin

infection in preterm lambs has not been

studies have also shown familial

shown to affect the incidence of BPD.

associations. Abnormalities in surfactant

Similarly to chorioamnionitis, early reports

protein formation can lead to a greater risk

of an association with BPD have been

of BPD, and there is a suggestion that

followed by less clear data, and there is

462

ERS Handbook: Paediatric Respiratory Medicine

Table 2. NIH criteria for the diagnosis of BPD based on gestation

,32 weeks gestation

.32 weeks gestation

Mild

In room air at 36 weeks post-menstrual age In room air by 56 days post-natal age

Moderate Needing ,30% oxygen at 36 weeks post-

Needing ,30% oxygen at 56 days post-

menstrual age

natal age

Severe

Needing .30% oxygen with or without IPPV

Needing .30% oxygen with or without

or CPAP at 36 weeks post-menstrual age IPPV or CPAP at 56 days post-natal age

IPPV: intermittent positive-pressure ventilation. Modified from Jobe et al. (2011).

some suggestion that the combination of

Again, however, there is little evidence that

antenatal steroids and chorioamnionitis

this approach will have a significant impact

may even be protective for BPD.

on the incidence of BPD.

Other factors The role of nutrition in the

Post-natally, there are several strategies

pathogenesis of BPD remains unclear. Poor

that can help to minimise risk. In the

nutrition is associated with an increased

resuscitation room there has been

incidence of BPD but equally there is no

considerable interest in minimising lung

evidence that improving nutrition in these

trauma and hyperoxia. Recent studies have

infants will reduce the risk of subsequent

suggested that normal oxygen saturations

BPD. Tight control of fluid balance in high-

in the neonate may well be lower than

risk infants may be beneficial. It is known

previously thought and that initial

that infants with a patent ductus arteriosus

resuscitation with air, adding in oxygen only

(PDA) have a greater risk of developing

when needed, may reduce morbidity. A

subsequent BPD. At the same time,

large study (SUPPORT) of 1300 babies

aggressive treatment of a PDA with fluid

evaluating CPAP against surfactant, and

restriction, indomethacin or surgery has

also high and low oxygen saturation,

been shown to reduce BPD, although the

showed no difference in outcomes

effect may be relatively minor.

(including death, BPD and

Prevention and management

neurodevelopment); however, BOOST II

(designed to specifically consider

The ideal approach to the care of preterm

oxygenation targets) was terminated early

infants would be to prevent BPD occurring.

due to an increase in mortality in the lower

This either requires a reduction in premature

oxygenated group. The use of noninvasive

delivery, or a method to prevent or attenuate

ventilation (CPAP or noninvasive positive-

BPD in those babies who are born early.

pressure ventilation (NIPPV)) has been

However this is difficult in the context of a

shown to be safe in neonates and studies

disease that is so multifactorial.

suggest that this, used in conjunction with

Prenatally, females who go into premature

early surfactant and extubation, is as safe as

labour are routinely treated with oral

conventional ventilation. However, this

steroids. It has been shown that this will

approach does not result in any significant

increase lung maturity and surfactant

reduction in BPD. Ventilation strategies

production and reduce the likelihood of

have centred on low-volume ventilation

RDS. Disappointingly, this approach

with permissive hypercapnia to minimise

appears to have little impact on the

traumatic injury to the lung, and a recent

prevalence of BPD. Similarly, an aggressive

Cochrane review has shown reduced deaths

approach to both antenatal and post-natal

and chronic lung disease in patients treated

infection would appear to be worthwhile in

with volume-targeted ventilation. The use of

view of concerns about their effect on

high-frequency oscillation has not shown

inflammation and the development of BPD.

any significant impact on BPD.

ERS Handbook: Paediatric Respiratory Medicine

463

As suggested earlier, the use of fluid

dexamethasone, hydrocortisone or inhaled

restriction may affect the development of

steroids, may have significant adverse

BPD although the evidence is somewhat

effects and their routine use, especially in

ambiguous. Good nutrition is also

the long-term, cannot be recommended.

important as avoidance of BPD is dependent

on lung growth. Infants in the lowest

The other medication that has been shown

to have a beneficial effect on the

quartile of growth develop more BPD and

development of BPD has been caffeine. This

high calorie intake is needed for those

came as a coincidental finding in a study on

infants who are fluid restricted.

apnoea of prematurity, when it was found

In terms of drug therapy, a number of

that there was a significant reduction in BPD

options have been tried. Given the central

at 36 weeks gestation. The study also

role of inflammation there has been

suggested that caffeine may provide some

disappointingly poor evidence of a

neuroprotection as well.

protective role from anti-inflammatory

treatment. Trials with azithromycin are

Conclusion

ongoing and there may be a small effect.

Similarly, vitamin A appeared to reduce the

The complex nature of BPD makes it

incidence of BPD in extremely low birth

unlikely that any single approach will

weight infants, but the drug needs to be

address all the problems. However, an

administered by intramuscular injection

understanding of the basic inflammatory

three times a week and long-term follow-up

drivers that cause lung injury will help

studies for up to 2 years following

deliver strategies that minimise iatrogenic

treatment show no benefits in respiratory

injury and help protect against the long-

or neurological outcome. Consequently its

term respiratory morbidity that is

use is not widespread. Nitric oxide has a

increasingly seen in ex-preterms.

measurable effect on oxidative stress and

alveolar development in prematurely born

animal models but the evidence in children

Further reading

remains controversial. Results from

studies to date have been ambiguous and

Bland RD (2005). Neonatal chronic lung

the 2011 NIH consensus statement

disease in the post-surfactant era. Biol

concludes that current evidence does not

Neonate; 88: 181-191.

support the use of nitric oxide in the

Carlo WA, et al. (2010). Target ranges of

neonatal period.

oxygen saturation in extremely preterm

infants. N Engl J Med; 362: 1959-1969.

The use of post-natal corticosteroids is also

Cole FS, et al.

(2011). NIH Consensus

controversial. It has been known for some

Development

Conference statement:

time that dexamethasone can facilitate

inhaled nitric-oxide therapy for premature

extubation and may reduce BPD, but there

infants. Pediatrics; 127: 363-369.

Doyle LW, et al. (2010). Dexamethasone

have been increasing concerns about

treatment after the first week of life for

adverse effects on development. It is likely

bronchopulmonary dysplasia in preterm

that such adverse effects are more common

infants: a systematic review. Neonatology;

in infants treated in the first week of life,

98: 289-296.

where the risk/benefit ratio is high whereas

Finer NN, et al. (2010). Early CPAP versus

the use of steroids for older children who are

surfactant in extremely preterm infants. N

proving difficult to wean from ventilation

Engl J Med; 362: 1970-1979.

may be of more value. There is renewed

Hayes D Jr, et al.

(2011). Pulmonary

interest in the use of low-dose steroids

function outcomes in bronchopulmonary

(dexamethasone 0.05 mg?kg^-1?day^-1) in this

dysplasia through childhood and into

group and early work suggests that this may

adulthood: implications for primary care.

be an option. Current advice, however, must

Prim Care Respir J; 20: 128-133.

remain that post-natal steroids, whether

464

ERS Handbook: Paediatric Respiratory Medicine

Jobe AH, et al. (2011). Bronchopulmonary

The BOOST II United Kingdom, Australia,

dysplasia. Am J Respir Crit Care Med; 163:

and New Zealand Collaborative Groups.

1723-1729.

Oxygen Saturation and Outcomes in

Kugelman A, et al. (2011). A comprehen-

Preterm Infants. N Engl J Med 2013 [In

sive approach to the prevention of

press DOI: 10.1056/NEJMoa1302298].

bronchopulmonary dysplasia. Pediatr

Wheeler K, et al. (2010). Volume-targeted

Pulmonol; 46: 1153-1165.

versus pressure-limited ventilation in the

Stevens TP, et al. (2007). Early surfactant

neonate. Cochrane Database Syst Rev; 11:

administration with brief ventilation vs.

CD003666.

selective surfactant and continued mechan-

Wright CJ, et al. (2011). Targeting inflam-

ical ventilation for preterm infants with or

mation to prevent bronchopulmonary

at risk for respiratory distress syndrome.

dysplasia: can new insights be translated

Cochrane Database Syst Rev; 4: CD003063.

into therapies? Pediatrics; 128: 111-126.

ERS Handbook: Paediatric Respiratory Medicine

465

Nutritional care

Kajsa Bohlin

Neonatal care has undergone a dramatic

interstitial fibroproliferation. Nutrition plays

development during the past decades.

an important role in normal lung maturation

Survival rates, particularly for those born

and development. Nutritional status may

very preterm, have increased remarkably and

directly modulate lung structure as general

there are growing numbers of preterm

undernutrition in humans leads to lung

survivors. Despite great progress with

emphysema and, in experimental settings,

improved ventilation strategies, antenatal

caloric restriction reduces alveolar number.

steroids and surfactant treatment,

Thus, sufficient nutrition is necessary for

bronchopulmonary dysplasia (BPD) remains

adequate lung growth and undernutrition

the most frequent adverse outcome

can compromise repair of ongoing lung

following very low birth weight. However,

injury. Nutritional care is therefore to be

the picture of BPD has changed from that of

considered a key factor, both in prevention

ventilator-induced lung injury to the so

and management of BPD.

called ‘‘new BPD’’, characterised by

impaired lung development with reduced

Growth failure and BPD

alveolarisation, dysplastic capillaries and

Many preterm infants with BPD become

growth restricted as sufficient nutrition is

often difficult to achieve. Several factors

contribute to the development of growth

Key points

failure during the first year of life. Early

challenges in the neonatal intensive care

N BPD is characterised by impaired lung

unit (NICU) are as follows:

growth and altered lung structure,

which may be further aggravated by

N Delayed time to establish adequate intake

poor nutritional status.

following delivery in the small sick infant

and frequent interruptions of enteral

BPD is associated with increased work

feeding because of feeding intolerance

of breathing and a higher resting

and clinical concerns.

metabolic state; therefore, energy

N Decreased nutritional intake secondary to

expenditure is high, making sufficient

fluid restriction.

nutrition a challenge and growth

N Dysfunction in other organ systems, such

restriction in preterm infants with

as heart failure secondary to large patent

BPD a common problem.

ductus arteriosus, renal insufficiency or

N The nutritional challenge continues

nerotising enterocolitis.

after discharge, the growth pattern of

N Medications, such as methylxanthines

infants with BPD must be closely

and b-sympathomimetics, may increase

monitored and, when needed,

energy consumption. Post-natal steroids

nutrition should be supplemented to

can impair growth and alter the

ensure adequate catch-up growth.

composition of weight gain by increasing

fat and decreasing protein accretion.

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ERS Handbook: Paediatric Respiratory Medicine

Later challenges after discharge from the

generally indicated in infants that are fed only

NICU are:

breast milk to ensure adequate intake for

sustained growth. Analysis of breast milk

N increased energy expenditure secondary

content will allow for individualised supple-

to increased work of breathing,

mentation and a close collaboration with a

tachypnoea, chronic hypoxia and anaemia

paediatric dietician is essential to optimise

of prematurity;

nutritional management in the NICU.

N poor feeding related to swallowing

dysfunction, fatigue or gastrointestinal

Fluid restrictions High fluid intake during the

reflux as well as oral aversion secondary

first days of life is associated with an

to repeated negative stimuli, such as

increased risk of developing BPD.

intubation and prolonged tube feeding;

Administration of excessive fluid can cause

N undernutrition contributing to an

pulmonary oedema through patency of the

increased risk of infections that further

ductus arteriousus. Data from the National

interfere with growth.

Institute of Child Health and Human

Development demonstrates a strong

In addition, dietary needs are not well

correlation of higher fluid intake and lower

established in preterm infants. The

post-natal weight loss during the first

fundamental principle is to provide a

10 days of life to BPD. A recent meta-

nutritional intake that meets the needs to

analysis also reports an association of

ensure optimal growth and development.

restricted fluid volume administration in

Compared with infants without BPD, infants

preterm infants with decreased incidence of

with BPD have increased energy expenditure

patent ductus and death, and a trend toward

of up to 25% above total caloric needs. This

reduced risk of BPD. For preterm infants

is partly explained by increased work of

with a birth weight ,1000 g or intrauterine

breathing, but also by a higher resting

growth restriction, it is recommended to

metabolic state, and needs to be taken into

start fluid administration at 80 mL?kg^-1?day^-1

account when determining target intake.

on the first day of life and then increase by

Nutritional management in BPD

10-20 mL?kg^-1?day^-1 increments to a

maintenance level of 120-150 mL?kg^-1?day^-1.

The overall goal of the nutritional

management of very preterm infants is to

Energy, protein and lipid intake As mentioned

support a rate of growth that approximates

above, the energy needs of infants with BPD

the intrauterine rate of growth. This may be

are higher than those of age-matched healthy

virtually impossible during the first weeks of

infants. To date, there are no randomised

life and later the recommended intakes are

controlled trials that examine the effects of

based on needs for maintenance and normal

increased versus standard energy intake for

growth; no allowance is generally made for

preterm infants with developing or

recovery or ‘‘catch-up’’.

established BPD. The European Society of

Paediatric Gastroenterology, Hepatology and

In clinical practice, very preterm infants are

Nutrition (ESPGHAN) have recently

often started on parenteral nutrition and

suggested that a reasonable range of energy

enteral feeding is initiated through a

intake for healthy growing preterm infants is

nasogastric tube as soon as the infant’s

110-135 kcal?kg^-1?day^-1. A higher caloric intake

condition is stable. Enteral nutrition may start

may be beneficial for children with BPD, but

as trophic feeds of very small volumes: 5-

may vary depending on respiratory status,

10 mL?kg^-1?day^-1. The transition from

clinical condition and activity level. Strict

parenteral to full enteral feedings may take

monitoring of growth and accordingly

many weeks. No specific feeding regimen has

adjusted energy intake is therefore required.

been proven superior in relation to BPD.

Breast milk has benefits over formula feeding

Proteins are essential for fetal growth and the

in reducing sepsis and necrotising enetero-

goal of post-natal protein administration is to

colitis, but does not affect the incidence of

match intrauterine growth and support

BPD. Caloric and protein supplementation is

protein accretion. Early intravenous

ERS Handbook: Paediatric Respiratory Medicine

467

administration of amino acids is usually well

outcome was found. Taken together with the

tolerated and side-effects, such as metabolic

need to administer vitamin A as

acidosis and hyperammonaemia, are rarely

intramuscular injections three times a week,

seen. However, to avoid amino acid toxicity

the use of vitamin A supplementation has not

the right amount of protein should be given at

been widely adopted.

the right time. ESPGHAN recommends

Catch-up growth and nutrition post-

aiming toward a higher intake for infants

discharge

weighing f1000 g (4.0-4.5 g

protein?kg^-1?day^-1) and less for infants

Despite good efforts, many preterm infants

weighing 1000-1800 g (3.5-4.0 g

with BPD will grow poorly and accrue

protein?kg^-1?day^-1). If the growth pattern of the

nutritional deficits during their long hospital

infants is adequate, with signs of catch-up

stay. Malnutrition leads to reduced brain

growth, protein intake can be reduced

size and impaired neurodevelopmental

towards discharge.

outcome. A clear relationship exists between

catch-up growth and development, but the

Lipids are necessary to provide energy,

time frame within which it needs to occur is

essential fatty acids and improve

not well delineated. There is a concern that

bioavailability of fat-soluble vitamins.

rapid growth will lead to later development

Moreover, lipid administration limits the

of insulin resistance and obesity. The

metabolic conversion of carbohydrates to

challenge is to ensure not only weight gain,

lipids, thereby decreasing carbon dioxide

but lean mass accretion. Mature human

production, which might be important in

breast milk is designed to meet the needs of

BPD. However, the role of lipid

the term infant and may not suffice for

administration in the development of BPD

catch-up growth of the preterm infant.

remains controversial. The current practice of

Therefore, all growth parameters, including

most centres is to initiate lipids at 0.5-

length and head circumference, should be

1 g?kg^-1?day^-1 by the second day of life and

closely monitored during the first year of life,

advance by increments of 0.5 to 1 g?kg^-1?day^-1

preferably in specialist clinics as part of a

up to 3-4 g?kg^-1?day^-1. However, ESPGHAN

standardised follow-up programme after

states that a reasonable range for most

prematurity. In infants with pathological

preterm infants is 4.8-6.6 g fat?kg^-1?day^-1,

growth patterns, fortification of the breast

corresponding to 40-55% of energy intake.

milk or supplementation with nutrient-

enriched formula should be considered to

Electrolytes and vitamins Infants with BPD

promote healthy development.

are often treated with diuretics to counteract

a tendency to accumulate interstitial lung

fluid. This, in combination with renal

Further reading

immaturity, makes them susceptible to

Agostoni C, et al. (2010). Enteral nutrient

sodium, potassium and chloride depletion

supply for preterm infants: commentary

and at increased risk for disturbed bone

from the European Society for Paediatric

mineralisation. Calcium, phosphate and

Gastroenterology,

Hepatology,

and

alkaline phosphatase must be closely

Nutrition Committee on Nutrition.

monitored and supplementation of vitamin

J Pediatr Gastroenterol Nutr; 50: 85-91.

D, calcium and phosphate provided through

Biniwale MA, et al. (2006). The role of

premature formula or fortified breast milk.

nutrition in the prevention and manage-

ment of bronchopulmonary dysplasia.

Vitamin A is an important antioxidant as well

Semin Perinatol; 30: 200-208.

as a key nutrient in maintaining lung

Cooke RJ (2011). Nutrition of preterm

epithelial cell integrity. In a recent meta-

infants after discharge. Ann Nutr Metab;

analysis, vitamin A has been shown to reduce

58: 32-36.

the incidence of death or BPD. The number

Dani C, et al.

(2012). Nutrition and

needed to treat was 12 to 13 infants to prevent

bronchopulmonary dysplasia. J Maternal

one case of BPD and no long-term positive

Fetal Neonatal Med; 25: 37-40.

effect on respiratory or neurodevelopmental

468

ERS Handbook: Paediatric Respiratory Medicine

Neurodevelopmental

assessment and outcomes

Charles C. Roehr, Lex W. Doyle and Peter G. Davis

The aim of this chapter is to review the

with BPD show characteristic radiographic

neurodevelopmental outcome of preterm

changes (fig. 1).

infants with bronchopulmonary dysplasia

The clinico-pathological problem of BPD

(BPD). We discuss the influence of neonatal

Despite the many advances, very preterm

intensive care on the development of

infants (defined as ,32 weeks of gestation)

chronic lung disease and neurological

still suffer from BPD, leading to long-term

development in preterm infants.

respiratory morbidity and oxygen

Mechanical ventilation (MV) and its adverse

dependency. Sadly, this morbidity is also

effects on the lungs

found in survivors of preterm birth who have

never been given MV. Our understanding of

Advances in respiratory support of the preterm

the underlying pathophysiology of BPD has

neonate The widespread use of antenatal

changed. It is thought that affected infants

corticosteroids and the introduction of

with BPD now primarily suffer from a

exogenous surfactant replacement therapy,

maturational arrest of alveolar

together with gentler MV, have led to better

differentiation (fig. 2).

outcomes for preterm infants. Alongside

Classification, incidence and disease burden of

these improvements came a change in

BPD According to the National Institutes of

characteristics of NICU patients. Whilst

Health consensus definition, BPD is graded as

most NICU patients in the 1960s were more

mild, moderate or severe on the basis of

than 32 weeks of gestation and weighed

oxygen requirements at 28 days and 36 weeks

.1500 g at birth, treatment is now offered

of corrected age. Despite many improvements

to many infants ,25 weeks of gestation and

in care, BPD still affects approximately 20-

with a birth weight ,500 g. Lungs of infants

40% of very preterm infants. Infants with BPD

are known to have a higher disease burden

than their non-BPD preterm peers. Even after

Key points

initial discharge, they require more adjunct

therapy and have more hospital readmissions

N BPD is a distinct disease entity of

in the first 2 years of life.

survivors of preterm birth.

Impact of premature birth and intensive

N The prevalence of BPD among

care treatment on neurodevelopmental

survivors of very preterm birth is

outcome

20-40%.

Effects of preterm birth and NICU admission

N BPD is associated with a risk for

on health The disruptive environment of

significant neurodevelopmental delay.

NICUs per se results in poorer growth and

Compared with non-BPD peers,

impaired neurosensory development.

infants with BPD may exhibit poorer

According to a recent meta-analysis, the

academic achievements and impaired

incidence of developmental delay or learning

emotional and physical development.

difficulties in very preterm infants is 60%,

cerebral palsy is 27%, impaired vision or

ERS Handbook: Paediatric Respiratory Medicine

469

Figure 2. A 1-year-old child with severe BPD

receiving respiratory support.

intensity of treatment and will therefore be

at increased risk for iatrogenic effects of

Figure 1. Chest radiograph of a ventilated infant

treatment. The post-natal administration of

with severe BPD.

corticosteroids has been linked to poorer

neurological outcome, as well as repeated

fluctuations in arterial oxygen concentration

blindness is 11%, gross motor and

and apnoea and bradycardia, both of which

coordination deficits is 10%, and deafness is

are commonly found in BPD infants.

7%. Preterm infants, compared with term-

born infants, are more likely to:

Testing the hypothesis that diagnosis of BPD

predicts negative neurological outcome To test

N have poorer overall academic

the hypothesis that BPD, defined as

achievement;

requirement of supplemental oxygen at

N exhibit specific challenges in

36 weeks of corrected age, predicted poor

mathematical abilities and social

neurological outcome, Davis et al. (2002)

relationships;

analysed data from 945 preterm infants born

N have impaired emotional and physical

with birth weights ,1000 g. The authors

development.

found poor neurosensory outcome at follow-

up in 34% of infants. Of these, 77% suffered

In general, the rate of developmental delay

cognitive delay, 37% cerebral palsy, 5%

increases with falling gestational age.

blindness and 7% severe hearing

Bassler et al. (2009) used severity of illness

impairment. However, this definition of BPD

as a predictor of neonatal outcome and

had a sensitivity of only 45% for predicting

established that a count of three neonatal

poor neurodevelopmental outcomes, and an

morbidities (BPD, brain injury and severe

overall accuracy of 63%.

retinopathy of prematurity) strongly predicts

the risk of death or neurosensory

Long-term studies on neurodevelopmental

impairment in extremely low birth weight

outcome in infants with BPD Long-term

infants. Male sex is increasingly recognised

neurodevelopmental impairment can affect:

as a predictor for poor outcome following

N cognitive development (including visual-

prenatal birth.

spatial perception);

Additive effect of BPD on neurological

N hearing;

outcome

N speech and language development;

N memory and learning capacity;

Preterm birth and BPD Preterm infants with

N gross and fine motor function.

BPD are likely to have been sicker than non-

BPD infants whilst in the NICU. They are

The Victorian Infant Collaborative Study

likely to have been subjected to a higher

Group has studied large geographical cohorts

470

ERS Handbook: Paediatric Respiratory Medicine

of preterm infants since 1979. Data from

Further reading

these studies and those of other groups

Bassler D, et al. (2009). Using a count of

indicate that preterm infants with BPD have

neonatal morbidities to predict poor

poorer outcomes than their non-BPD peers

outcome in extremely low birth weight

infants: added role of neonatal infection.

Prevalence of specific neurological

Pediatrics; 123: 313-318.

impairments For general cognitive function,

Davis PG, et al.

(2002). Evaluating

results from different studies suggest that

"old" definitions for the "new" broncho-

BPD infants were rated 0.25-0.66 standard

pulmonary dysplasia. J Pediatr;

140:

deviations lower for IQ than their non-BPD

555-560.

peers. For behaviour, the rate of attention

Davis PG, et al.

(2009). Non-invasive

deficit was 59% for BPD infants compared

respiratory support of preterm neonates

with 32% for non-BPD infants. Preterm

with respiratory distress: continuous

survivors with BPD performed between 0.5-1

positive airway pressure and nasal inter-

standard deviations below very low birth

mittent positive pressure ventilation.

weight infants (birth weight ,1500 g)

Semin Fetal Neonatal Med; 14: 14-20.

without BPD or term controls on tests of

Doyle LW, et al. (2004). Neonatal inten-

sive care at borderline viability

- is it

reading and mathematics. Poor memory

worth it? Early Hum Dev; 80: 103-113.

performance was significantly more common

Doyle LW, et al. (2009). Long-term out-

in BPD infants (65%) compared with 29% in

comes of bronchopulmonary dysplasia.

a non-BPD group, and language skills at

Semin Fetal Neonatal Med; 14: 391-395.

preschool and school age were found to be

Gregoire MC, et al. (1998). Health and

significantly delayed in BPD infants

developmental outcomes at 18 months in

compared with non-BPD controls. 49% of the

very preterm infants with broncho-

BPD infants tested at preschool age showed

pulmonary dysplasia. Pediatrics;

101:

significantly delayed receptive language

856-860.

development, and 43% had significantly

Jobe AH (2011). The new bronchopul-

delayed expressive language development.

monary dysplasia. Curr Opin Pediatr; 23:

167-172.

Conclusion

Morley CJ

(2012). Volume-limited and

volume-targeted

ventilation.

Clin

Preterm birth is strongly associated with

Perinatol; 39: 513-512.

abnormal neurodevelopmental outcome.

Mwaniki MK, et al.

(2012). Long-term

Preterm infants with BPD suffer from poorer

neurodevelopmental outcomes after

health and worse neurological outcome than

intrauterine and neonatal insults: a sys-

tematic review. Lancet; 379: 445-452.

their non-BPD peers. However, the

Peacock JL, et al. (2012). Neonatal and

diagnosis of BPD, given at the age of

infant outcome in boys and girls born

36 weeks of corrected gestation, is not a

very prematurely. Pediatr Res; 71: 305-310.

highly sensitive predictive measure for

Saigal S, et al.

(2008). An overview of

negative neurological outcome. The

mortality and sequelae of preterm birth

increasing survival rates of very preterm

from infancy to adulthood. Lancet; 371:

infants and concurrent numbers of children

261-269.

with BPD will lead to more children with

Victorian Infant Collaborative Study

neurological problems. Therefore, reducing

(VICS). www.vics-infantstudy.org.au Date

the rate of BPD will remain one of the

last accessed: December 12, 2012.

biggest challenges in neonatal care.

ERS Handbook: Paediatric Respiratory Medicine

471

Long-term respiratory

outcomes

Manuela Fortuna, Marco Filippone and Eugenio Baraldi

Chronic lung disease of infancy (CLDI)

comprises a heterogeneous group of

Key points

diseases that evolve as a consequence of a

neonatal respiratory disorder. The most

Survivors of extreme prematurity, and

common form of CLDI is

those with BPD in particular,

bronchopulmonary dysplasia (BPD). Due to

experience high rates of respiratory

the marked decline in mortality among very

symptoms (mainly cough and

immature, extremely low birth weight

wheeze) and hospital readmission in

infants in recent decades, there are

the early years of life.

increasing numbers of children and adults

Into mid-childhood and adolescence,

who have survived BPD. This means that

clinical symptoms become milder and

not only paediatricians, but also adult

less frequent, but spirometric studies

physicians, will have to deal more and more

show that many of those born very

often with the sequelae. Today, BPD is

prematurely have scarcely reversible

defined as the need for supplemental

airflow obstruction (mean FEV1 70-

oxygen for at least 28 days after birth, and

80% predicted).

its severity is graded according to the

respiratory support required near term.

Although BPD survivors frequently

suffer from asthma-like symptoms,

An important effort has been made to

BPD and asthma are distinct clinical

characterise the extent of pulmonary disease

entities resulting from different

and assess lung function in infants and

pathogenic mechanisms and caution

children born prematurely, generating

is needed when recommending

considerable information on the pulmonary

asthma treatments to BPD patients.

outcome of BPD into adolescence.

Due to the natural age-related decline

Less is known about the respiratory health of

in respiratory function, it is reasonable

adult survivors of BPD, since few studies are

to expect a phenotype resembling

available on this topic. The available data are

COPD to develop in some survivors of

based mainly on cohorts born in the late

BPD, so these patients should be

1970s and/or 1980s, and often include cases

followed up into adulthood and efforts

of ‘‘old’’ BPD, i.e. patients born before the

should be made to prevent them from

introduction of exogenous surfactant and

smoking.

antenatal corticosteroids, who usually

required prolonged mechanical ventilation.

Acute lung injury (causing airway

inflammation, bronchial smooth muscle

of BPD, which include much more

hypertrophy, emphysema and parenchymal

immature, smaller newborns, who are

fibrosis) has a major role in the resulting

treated very differently (with less ventilatory

chronic lung disease in such patients, so

support). This latter type of so-called ‘‘new’’

their functional outcome is not fully

BPD is a developmental disease of the

comparable with that of more recent cases

terminal airspaces, characterised mainly by

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ERS Handbook: Paediatric Respiratory Medicine

impaired alveolarisation. Although

use inhaled asthma medication more

symptoms in the newborn are usually milder

frequently than term-born controls.

than those of the old form of BPD, whether

or not patients with this new BPD will

Into adolescence, symptoms progressively

ultimately have better respiratory outcomes

subside in survivors of BPD too, and most

remains to be seen.

of them lead apparently normal lives. The

relationship between clinical symptoms and

Morbidity associated with BPD

lung function fades, and even patients with

severe airway obstruction detected by

Infants with BPD may require oxygen

spirometry may not have any clinically

supplementation on discharge from

significant respiratory symptoms.

neonatal intensive care units. However, very

few remain oxygen dependent beyond 1 year

Data on adult respiratory health are limited

of age, reflecting some lung growth.

and refer mainly to cases of old BPD in

patients studied in their twenties. These

Upper airway problems (laryngo-tracheal

patients seem to complain of more

stenosis, laryngomalacia, tracheomalacia

respiratory symptoms (especially shortness

and unilateral vocal cord paralysis) resulting

of breath and wheezing on exertion) than

from prolonged or reiterated intubation can

healthy controls. The same may not fully

worsen the respiratory course of infants with

apply to new BPD cases, however, so a long-

BPD, although the incidence of the more

term follow-up of well-characterised cohorts

severe forms of stenosis requiring

of children born in the post-surfactant era is

tracheostomy has fortunately declined in the

needed to ascertain the respiratory outcome

last decade.

after new BPD.

In the first 2 years after birth, infants born

Pulmonary arterial hypertension associated

before 33 weeks of gestational age, and

with stabilised BPD

survivors of BPD in particular, are very

susceptible to respiratory exacerbations,

The clinical course of extremely preterm

with higher rates of recurrent wheezing than

infants with BPD can be made worse by

in children born at term. Hospital

concomitant pulmonary arterial

readmissions for complications of

hypertension (PAH), defined as a mean

respiratory tract infections are also frequent

pulmonary artery pressure (Ppa) .25 mmHg

(up to 40% in the first 1-2 years), with a

at rest (measured by cardiac

relevant burden of disease for patients,

catheterisation), or an estimated systolic Ppa

parents and the healthcare system. Strict

.40 mmHg on echocardiography. PAH

measures to prevent viral infections (e.g.

arises from the combination of an altered

prophylaxis against respiratory syncytial

vascular development (normal lung

virus with monoclonal antibodies) and to

angiogenesis is disrupted by premature

avoid adverse environmental factors (e.g.

birth), function (hypoxia-related increases in

passive smoking) are of the utmost

vascular tone and reactivity) and structure

importance in this population.

(vascular remodelling with smooth muscle

cell proliferation). Although the true

Although respiratory symptoms (cough and

prevalence of PAH in infants with stabilised

wheeze) are very common at preschool age,

BPD is unknown, it has ranged between 17%

the clinical condition of BPD survivors

and 25% in individual studies. Sustained

generally improves with time and their

and severe PAH, and the resulting cor

respiratory symptoms become less severe.

pulmonale are linked to high mortality rates

By mid-childhood, respiratory exacerbations

in infancy (up to 40%), so it is very

become less frequent. During their years of

important to detect PAH, not only for the

schooling, most of these children appear to

purpose of prognostic considerations, but

live normally, although they experience more

also to ensure an appropriate treatment.

chronic coughing and wheezing (and other

Echocardiography is recommended as the

asthma-like symptoms), and they need to

main screening tool and should be

ERS Handbook: Paediatric Respiratory Medicine

473

performed in BPD infants whose clinical

N areas of reduced lung attenuation (due to

course is atypical (with high or increasing

small airway obstructions leading to

oxygen needs, recurrent cyanotic episodes

obstructive emphysema);

and/or a poor growth rate), arousing the

N linear and triangular opacities (due to

suspicion of underlying PAH. Cardiac

strands of atelectasis extending to the

catheterisation can assess the severity of

pleura);

PAH more precisely, but it is usually

N multifocal emphysema;

performed only in the more severe cases,

N bronchial wall thickening;

when vasodilators other than oxygen (such

N bullae and air trapping on expiratory

as phosphodiesterase-5 inhibitors or

scanning.

endothelin receptor antagonists) are

needed. Long-term supplemental oxygen

These pathological features are more

therapy with a target oxygen saturation in

pronounced in cases previously diagnosed

the range of 91-95% is considered the

with BPD. Some validated scoring systems

standard treatment for PAH associated with

are available for assessing the extent of

BPD, because it may reduce pulmonary

these structural abnormalities on HRCT;

vascular resistance. Patients should be

interestingly, a correlation has recently been

weaned off supplemental oxygen only

reported between HRCT scores, duration of

gradually, and monitoring Ppa with serial

neonatal oxygen exposure and FEV1 values

echocardiography after it has been

in a cohort of children and adolescents

discontinued is mandatory, because the Ppa in

surviving extremely preterm birth.

these patients may remain persistently higher

than normal in the early years of life despite

Radionuclide imaging is not usually part of

their clinical improvement. By the time they

the assessment of BPD patients, but it has

reach school age, pulmonary vascular

the potential to add additional information

resistance and Ppa appear to return to normal

about lung function. Single photon emission

in survivors, although pulmonary vascular

CT has recently been used to assess regional

reactivity to hypoxia may persist into

distribution of lung ventilation (V9) and

adolescence and adulthood. A tailored cardiac

perfusion (Q9) in a cohort of 30 BPD

and echocardiographic follow-up should then

preterm infants at a median post-menstrual

be assured for selected BPD survivors.

age of 37 weeks. Interestingly, in this study a

significant proportion of BPD infants (40%)

Long-term imaging anomalies in BPD

had an abnormal V9/Q9 distribution, and a

patients

correlation between V9/Q9 mismatch and

time spent on mechanical ventilation was

The radiographic pulmonary findings in

detectable.

survivors of BPD have changed. Traditional

chest radiograph findings in survivors of old

Lung function studies in BPD patients

BPD during their childhood include fibrosis,

patchy atelectasis and emphysema. Findings

Analysing forced expiratory flows (obtained

in new BPD are milder, with the chest

with forced expiratory manoeuvres) reveals

radiograph picture improving over time. The

substantial airflow limitation in BPD

sensitivity of radiography in diagnosing

survivors during the first 3 years of life, with

minor lung abnormalities is limited,

no significant improvements on serial

however. Although HRCT of the chest is not

measurements. The degree of airflow

performed routinely in BPD survivors, it can

limitation in the early years of life seems to

detect abnormalities in up to 80% of

predict pulmonary function later on: in a

survivors of extreme prematurity and

small group of BPD survivors followed from

provides important information on the

birth, forced expiratory flow at 2 years of age

airways and parenchymal structural

correlated closely with FEV1 at 8 years of

changes. Significant findings in children and

age, indicating a tracking of lung function

adolescents surviving extremely preterm

over time and a negligible ‘‘catch-up’’ in

birth include:

lung growth. This finding is suggestive of an

474

ERS Handbook: Paediatric Respiratory Medicine

irreversible early airway remodelling

of the predicted value, and the well-known

process.

natural decline in respiratory reserves with

ageing could mean that these individuals

Spirometric studies have often been used

reach a critical threshold for significant

for cross-sectional assessments of lung

respiratory symptoms in mid-adulthood.

function in school-age and older BPD

Given the lack of longitudinal studies into

survivors. Their findings often refer to

adulthood on survivors of prematurity and/

heterogeneous cohorts recruited mainly

or BPD, we still do not know whether their

among patients born in the pre-surfactant

natural age-related rate of decline in

era, and clearly indicate that BPD children of

respiratory function will be normal or

all ages have a significant airflow

accelerated, but it is reasonable to expect a

obstruction (generally achieving mean FEV1

new phenotype resembling COPD, but

values between 70% and 80% of the

related to premature delivery, to emerge

expected levels) that proves scarcely

over the coming years. This risk emphasises

reversible. Patients born prematurely but not

the need to follow up BPD survivors into

developing BPD usually fare better, but they

adulthood, and to minimise their exposure

too have airflow limitation at school age and

to risk factors associated with a faster

later. It is worth noting that recent cohort

decline of lung function, such as cigarette

studies on children born extremely

smoking.

prematurely in the post-surfactant era report

airflow limitations throughout their years of

Other major lung function anomalies

schooling. These studies found a clearly

reported in survivors of BPD during their

detectable trend toward an obstructive

childhood and adolescence include a higher

spirometric pattern even in very low birth

residual volume and a higher residual

weight children who did not develop BPD,

volume to TLC ratio, probably due to air

raising concern that premature birth may per

trapping. Exercise capacity (e.g. maximal

se impair lung maturation and growth, with

oxygen consumption) is also slightly

life-long detrimental effects on pulmonary

reduced, and gas exchange (e.g. TLCO) is

function. The benefits associated with better

impaired in BPD children. Finally, a

perinatal care may, therefore, be partially

significant airway hyperresponsiveness (to

masked by the gradual improvement in the

histamine, methacholine or physical

survival rates for the most immature infants.

exercise) is detectable in BPD survivors,

These preliminary findings also emphasise

although the mechanism(s) behind it is not

the need to develop novel therapies to

yet clear.

reduce the long-term pulmonary effects of

Airflow obstruction and asthma-like

extremely premature delivery.

symptoms in BPD patients

Only a few studies have been designed to

The real nature of the airflow limitation

provide longitudinal lung function data at

detected in survivors of prematurity and

multiple time-points in children with a

BPD has yet to be fully elucidated and

history of BPD. Data from some of them

morphologically characterised, since no

indicate that lung function may deteriorate

information is available on lung pathology in

throughout childhood and adolescence in

BPD patients beyond infancy. Airway

the more severe cases, suggesting that

obstruction has often been interpreted as

some forms of BPD may be progressive in

the result of stable, not progressive,

nature.

structural changes in the airways coupled

Persistent airway obstruction with a

with a poor or dysmorphic alveolar growth.

significantly lower FEV1/FVC ratio and a

In the new form of BPD, in particular,

forced expiratory flow at 25-75% of FVC

hypoalveolarisation would reduce the

(FEF25-75%) than controls is also

number of alveolar attachments per airway,

characteristic of BPD survivors in their

prompting a more limited airway-

twenties. In young adults, a history of BPD is

parenchymal coupling and predisposing to

often associated with a maximal FEV1 ,80%

airflow obstruction. A relevant question is

ERS Handbook: Paediatric Respiratory Medicine

475

whether the long-term pulmonary

have been no randomised controlled trials

consequences of prematurity and BPD

on these drugs for the treatment of BPD.

depend only on a non-progressive reduction

In conclusion, given the absence of

in airway calibre due to a stabilised airway

morphological information and randomised

disease, or whether they also reflect an

therapeutic trials, the pathogenesis of long-

ongoing active airway disease. A recent

term obstructive symptoms in survivors of

report of higher concentrations of 8-

prematurity remains elusive and their

isoprostane (a reliable biomarker of

treatment empirical.

oxidative stress in vivo) in the exhaled breath

condensate of adolescents born preterm in

comparison with healthy controls born at

Further reading

term suggests an ongoing oxidative stress in

Allen J, et al.

(2003). Statement on the

the airways of survivors of prematurity. This

care of the child with chronic lung disease

issue is important and warrants further

of infancy and childhood. Am J Respir Crit

investigation because the presence of

Care Med; 168: 356-396.

ongoing airway disease would point to a

Baraldi E, et al.

(2007). Chronic lung

greater risk of an accelerated age-related

disease after premature birth. N Engl J

decline in lung function; however, it opens

Med; 357: 1946-1955.

up the possibility of an active treatment with

Doyle LW, et al.

(2006). Broncho-

antioxidants.

pulmonary dysplasia in very low birth

weight subjects and lung function in late

Respiratory symptoms and the obstructive

adolescence. Pediatrics; 118: 108-113.

spirometric pattern encountered in BPD

Fawke J, et al. (2010). Lung function and

patients are often labelled as asthma, but

respiratory symptoms at

years in

caution is needed in dealing with this

children born extremely preterm. Am J

problem. Airflow obstruction in BPD

Respir Crit Care Med; 182: 237-245.

patients is only partially reversed by b₂-

Fibrun AG, et al.

(2011). Longitudinal

agonists, suggesting a stable remodelled

measures of lung function in infants with

airway condition. Moreover, in BPD

bronchopulmonary dysplasia. Pediatr

patients, unlike asthma sufferers, there is no

Pulmonol; 46: 369-375.

evidence of eosinophil-driven airway

Filippone M, et al.

(2009). Childhood

inflammation; in fact, exhaled nitric oxide (a

course of lung function in survivors of

biomarker of eosinophilic inflammation and

bronchopulmonary dysplasia. JAMA; 302:

response to corticosteroid therapy) is

1418-1420.

reportedly low in BPD survivors. HRCT

Filippone M, et al. (2012). Evidence of

studies have also documented

unexpected oxidative stress in airways of

morphological differences in the lungs

adolescents born very pre-term. Eur Respir J;

40: 1253-1259.

between children with asthma and cases of

Gough A, et al.

(2012). General and

BPD. Although airway wall thickening and

respiratory health outcomes in adult

areas of low attenuation may be seen in both

survivors of bronchopulmonary dysplasia.

diseases, scattered parenchymal fibrosis

Chest; 141: 1554-1567.

(linear opacities facing triangular subpleural

Kjellberg M, et al. Bronchopulmonary

opacities) and architectural distortion are

dysplasia: clinical grading in relation to

common findings in survivors of BPD but

ventilation/perfusion mismatch measure

unusual in children with asthma. Finally,

by single photon emission computed

individuals with a history of BPD do not

tomography. Pediatr Pulmonol

2013

[in

have a higher than normal prevalence of

press DOI: 10.1002/ppul.22751].

atopy (a major risk factor for childhood

Narang I, et al. (2006). Airway function

asthma). So, asthma and BPD are distinct

measurement and the long-term follow-

clinical entities resulting from different

up of survivors of preterm birth with and

pathogenic mechanisms, and care should be

without chronic lung disease. Pediatr

taken when treating BPD children with

Pulmonol; 41: 497-508.

inhaled asthma medication because there

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ERS Handbook: Paediatric Respiratory Medicine

Pleural effusion, chylothorax,

haemothorax and

mediastinitis

Juan Antón-Pacheco, Carmen Luna-Paredes and Antonio Martinez-Gimeno

Pleural effusion

Clinical picture There are two usual patterns

of presentation. In the first, the child has

The pleural space normally contains 0.3 mL

classic symptoms of pneumonia (fever,

per kg body weight of pleural fluid.

cough, breathlessness, abdominal pain and

Lymphatic vessels can cope with several

malaise) but they are usually more unwell

hundred millilitres of extra fluid per 24 h. An

than those with simple pneumonia alone,

imbalance between pleural fluid formation

with pleuritic chest pain and even cyanosis.

and drainage will result in a pleural effusion.

In the other clinical presentation, the child

In a previously well child, pleural effusions

has been diagnosed with pneumonia but

are usually secondary to acute bacterial

does not respond to 48 h of an appropriate

pneumonia and less often due to chronic

treatment. On examination, a pleural

infection such as pulmonary TB. Other

effusion is suggested by unilateral signs of

causes usually considered in adults, such as

decreased chest expansion and dullness to

malignancies, cardiovascular diseases, or

percussion, reduced or absent breath

systemic inflammatory conditions, are

sounds, and scoliosis.

uncommon in children.

Diagnosis Contrary to community-acquired

pneumonia (CAP), which may be diagnosed

on clinical grounds only, the diagnosis of

Key points

parapneumonic pleural effusion requires an

imaging technique to demonstrate the

N All children with parapneumonic

presence of fluid in the pleural space. The

pleural effusion or empyema should

first imaging technique should be a

be admitted to hospital and managed

posteroanterior chest radiograph. The

following local or national guidelines.

earliest sign of a pleural effusion is

obliteration of the costophrenic angle. A rim

Intravenous antibiotics and careful

of fluid may be seen ascending the lateral

consideration of pleural drainage

chest wall (meniscus sign). If the film is

procedures are the most important

taken in a supine position, the appearance

aspects of parapneumonic effusion/

can be of a homogeneous increase in

empyema management.

opacity over the whole lung field without

N Chylothorax is a rare condition in

blunting the costophrenic angle, or a classic

children usually caused by injury to

pleural-based shadow. A lateral chest

the thoracic duct; simple chest

radiograph rarely adds anything extra and

drainage and dietary modifications

should not be routinely obtained.

are the mainstay of treatment.

Once pleural effusion has been diagnosed or

When haemothorax is diagnosed,

suspected by a chest radiograph, chest

blood should be promptly drained

ultrasonography should be obtained to

from the pleural cavity with a chest

confirm the diagnosis, estimate the size of

tube.

the effusion, differentiate between free and

loculated pleural fluid and determine its

ERS Handbook: Paediatric Respiratory Medicine

477

local threshold, usually 92-94%), fluid

therapy if the child is dehydrated or unable/

unwilling to drink, pain control and

antipyretics.

Intravenous empirical antibiotic treatment

should begin as soon as possible. In the

most common setting of a pleural effusion

arising from CAP, empirical treatment must

cover Streptococcus pneumoniae, S. pyogenes

and Staphylococcus aureus. In most cases,

cefotaxime (150 mg?kg^-1?dose^-1), co-

amoxiclav or cefuroxime are appropriate.

Penicillin allergic patients can be treated

with clindamycin alone. If pneumatoceles

Figure 1. Chest ultrasound showing a loculated

are evident, anti-staphylococcal cover is

pleural effusion.

mandatory (cloxaciline or flucoxaciline).

However, in cases of hospital-acquired

pneumonia or following surgery, trauma or

aspiration, broader spectrum agents should

echogenicity (fig. 1). It may also be used to

be used to cover aerobic Gram-negative

guide chest drain insertion or thoracentesis.

rods.

Chest CT scans involve radiation exposure

Further blood diagnostic tests should be

that can be equivalent to 20-400 chest

obtained after diagnosis and before starting

radiographs depending on technical factors

antibiotic therapy: full blood count (for

and should not be performed routinely. It

anaemia, white cell count with differential

may have a role in complicated cases,

and platelet count), electrolytes (to detect

including immunocompromised children

inappropriate anti-diuretic hormone

where a CT scan can detect airway or

syndrome), C-reactive protein or other

parenchymal lung abnormalities, such as

acute-phase reactants and blood culture,

endobronchial obstruction or a lung

including anaerobic bottle. If available,

abscess, or before surgery to delineate the

sputum culture can also be useful.

anatomy.

An important issue is whether to insert a

Management Once the diagnosis of

pleural drain or not. It is generally accepted

parapneumonic effusion has been

that isolated pleural taps for diagnostic

established, the decisions on additional

purposes are not recommended in children

diagnostic tests and therapeutic

interventions should be conducted by

with a small, uncomplicated parapneumonic

following local guidelines. Several national

pleural effusion, except if there are any

atypical features suggesting the presence of

scientific societies have published their own

malignancy, such as the absence of acute

guidelines and every paediatric centre

fever or pneumonia and evidence of an

treating children with pleural effusions

underlying mediastinal mass or

should have their own protocol adapted to

lymphadenopathy. In these uncommon

local circumstances.

situations it is important to remember that

All children with parapneumonic effusion

large volume aspiration and general

should be admitted to hospital. Initial

anaesthesia pose a significant risk of

treatment should focus on general

sudden death in children with superior

supportive measures and prompt

mediastinal obstruction due to malignancy,

intravenous antibiotic administration.

therefore, the volume of aspirated pleural

General measures include assessing the

fluid should be small (5 mL) and general

need of supplemental oxygen (SpO₂ below

anaesthesia should be avoided.

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ERS Handbook: Paediatric Respiratory Medicine

Indications for pleural drain vary in different

All chest tubes should be connected to a

guidelines. As a general rule, there is a good

unidirectional flow drainage system with an

deal of evidence suggesting that a pleural

underwater seal, which must be kept below

drain is not always necessary and that

the level of the patient’s chest at all times.

antibiotics alone can be enough to provide

The indications for suction are unclear in the

excellent clinical outcomes when there is not

management of pleural effusion but it is

a clear indication for chest drainage. Tube

commonly believed that it improves

thoracostomy must be performed if the child

drainage. A low suction pressure (5-

is in respiratory distress due to lung

10 cmH₂O) is usually applied in the

compression by the pleural effusion, or if

underwater seal, and it is acceptable to stop

suction for short periods (such as for

toxic appearance and sepsis is suspected. It

radiographs or mobilisation). Regular

also may be considered if the effusion size is

flushing of small bore drains to prevent

large (definitions vary from 10 mm

blockage has been recommended. Patients

thickness in ultrasonography or radiography

with chest drains do not need to remain in

to one-third of the hemithorax in

the PICU for only this reason and they can

radiography) or is enlarging, and the child is

be managed on a ward by staff trained in

not responding after 48 h of antibiotic

chest drain management.

treatment.

The role of intrapleural fibrinolytics in the

Pleural drainage is rarely an emergency

management of parapneumonic pleural

procedure and must be carefully planned

effusion is not completely clear. Only two

and performed in the most appropriate

fibrinolytics are currently available in most

setting by trained personnel, according to

European countries (urokinase and

local guidelines. Two types of chest drains

alteplase) but only urokinase has been

are usually used. Paediatric surgeons usually

studied in a double-blind placebo-controlled

prefer large bore chest tubes (around 20 FG)

randomised clinical trial in children,

surgically inserted in the operating theatre

showing a significantly shorter hospital stay

with general anaesthesia and paravertebral

(7.4 versus 9.5 days) compared with placebo.

block with local anaesthetics to provide

Urokinase should be given twice daily for

post-operative pain relief. Respiratory

3 days (six doses in total) using 40 000

paediatricians, paediatric intensivists and

units in 40 mL 0.9% saline for children aged

interventional paediatric radiologists usually

o1 year, and 10 000 units in 10 mL 0.9%

prefer smaller drains (around 10 FG),

saline for children aged ,1 year. The

including pigtail catheters, inserted by the

summary of product characteristics of

Seldinger technique in paediatric intensive

alteplase does not include approval for

care units (PICU) or interventional radiology

empyema in adults or children, and only

rooms, with general anaesthesia or

case-series have been published.

sedation. These two options are both

appropriate and have the same outcomes,

The drain should be removed when there is

so the choice depends on local

clinical resolution. An obstructed drain that

circumstances. The drain should be inserted

cannot be unblocked should be removed

by well-trained personnel, or trainees under

too, but replaced if significant pleural fluid

expert supervision, to minimise the risk of

remains. Pain control is extremely important

during the time in which the chest drain

complications. Ultrasonography guiding is

remains in place.

mandatory and the appropriate site for chest

tube insertion should be marked with an X

Another pleural drainage method to be

when this test is being performed. Pleural

considered is surgery. Three surgical

fluid must be obtained during the procedure

methods are available.

and sent for microbiological and

cytochemical tests, including Gram staining,

N Video-assisted thoracoscopic surgery

culture for standard pathogens and

(VATS), which achieves debridement of

mycobacteria, PCR, glucose and pH.

fibrinous pyogenic material, breakdown

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479

of loculations and drainage of pus from

usually caused by an injury to the thoracic

the pleural cavity under direct vision,

duct during surgery. The thoracic duct

leaving two or three small scars.

collects lymph from the abdomen, lower

N Mini-thoracotomy, which procures

limbs, left thorax, head, neck and upper

debridement and evacuation in a similar

limbs. Disruption of the duct between the

way to VATS but as it is an open

diaphragm and T5 usually yields chylothorax

procedure leaves a small linear scar.

on the right side, while a left-sided

N Decortication, which involves an open

chylothorax can be seen when damage

posterolateral thoracotomy and excision

occurs above T5.

of the thick fibrous pleural rind with

Aetiology Most cases of chylothorax in

evacuation of pyogenic material.

children are acquired and of iatrogenic

Early VATS should be considered an

origin. According to some studies,

alternative to tube thoracostomy, with or

cardiothoracic surgery accounts for 65-80%

without fibrinolytics, when a loculated

of all paediatric chylous effusions.

effusion is present and its use will largely

Congenital presentation represents only a

depend on local availability and expertise. It

small percentage in the paediatric age

seems to offer the same clinical outcomes

group, although it is the most common type

compared to simple chest tube drainage.

of pleural effusion in the neonatal period

Mini-thoracotomy should be reserved for

(table 1).

more complex cases, and decortication

should be performed only in symptomatic

Diagnosis Antenatal chylothorax can lead to

children with organised empyema not

restriction of normal lung development and

responding to previous treatment or in

cause lung hypoplasia. For this reason,

cases of lung entrapment.

severe respiratory distress can be present in

some cases of congenital chylothorax.

Intravenous antibiotic treatment should

Respiratory symptoms depend on the size of

continue until the child is afebrile or the

the effusion and most patients will show

chest drain is removed. Oral antibiotics,

varying degrees of dyspnoea, cough or chest

such as co-amoxiclav, are then administered

discomfort. Large volumes of chyle can lead

for an additional 1-4 weeks after discharge

to significant cardiorespiratory compromise.

or even for a longer period of time if there is

residual disease.

A chest radiograph will demonstrate a

unilateral or bilateral pleural effusion

Follow-up and long-term outcome At

(fig. 2). Chylothorax should be suspected

discharge, most children will have abnormal

when an extensive pleural effusion occurs in

chest radiographs and clinical examination

a neonate with a lymphatic malformation,

(diminished breath sounds and some

some genetic syndromes, or after

dullness on the affected area due to pleural

cardiothoracic surgery (table 1).

thickening), which must not cause concern.

Most affected children will return to having

Although pleural fluid from chylothorax is

normal radiographs and clinical examination

typically milky it can appear completely clear

in 3-6 months and after 12-18 months they

when fasting. Definite diagnosis relies on

will have a full clinical recovery. Opposite to

the biochemical analysis of the fluid drained

what happens in adults, long-term

from the pleural space. This study will show

prognosis of parapneumonic pleural

an elevated level of triglycerides

effusion or empyema in children is excellent

.110 mg?dL^-1, and the presence of

and significant complications or sequelae

chylomicrons. A high lymphocyte count may

are uncommon.

also be present.

Chylothorax

Diferential diagnosis should be made with

Chylothorax is the accumulation of chyle in

empyema and pseudochylothorax, which

the pleural space and is an uncommon

develops when an exudative effusion

cause of pleural effusion in children. It is

remains in the pleural space for a long

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Table 1. Aetiology of chylothorax in children

Table 1. Continued

Traumatic

Infectious

Iatrogenic

Surgical

Filariasis

Cardiothoracic surgery

Histoplasmosis

Scoliosis or neck surgery

Malignancies

Invasive procedures

Lymphoma

Subclavian vein catheterisation

Teratoma

Non-iatrogenic

Sarcoma

Forceful emesis or cough

Neuroblastoma

Hyperextension of the neck or thoracic

Others

spine

Transdiaphragmatic movement of

Mechanism of birth

chylous ascites

Blunt trauma

Systemic disorders

Penetrating chest trauma

Cardiac failure

Non-traumatic

Benign tumours

Congenital

TORCH: toxoplasmosis, rubella, cytomegalovirus

Abnormalities of the lymphatic system

and herpes simplex virus.

Primary or secondary lymphangiectasis

period of time and gradually becomes

Lymphangiomatosis

enriched with cholesterol.

Lymphatic dysplasia syndrome

Management Chest drainage with tube

Genetic syndromes

thoracostomy, together with nutritional

Noonan syndrome

modifications, has been the mainstay of

Turner syndrome

treatment for many years. More recently, a

dietary approach alone has been suggested

Down syndrome

as the initial treatment option.

Infectious

Medical therapy Nutritional: the use of

TORCH infections

medium chain triglyceride milk formulas

Thoracic duct atresia/agenesia

decreases overall lymphatic flow through the

Congenital diaphragmatic hernia

thoracic duct, while allowing spontaneous

healing of the duct injury. Another option is

Congenital cystic malformation of the lung

total parenteral nutrition with bowel rest,

Congenital heart disease

although most reports indicate little

Congenital mediastinal/pleural tumours

difference in outcome compared to medium

Hydrops fetalis

chain triglyceride enteral nutrition. Chest

drainage cessation with this dietary

Idiopathic

approach ranges from 1 to 4 weeks.

Antenatal primary fetal hydrothorax

Medications: somatostatin and synthetic

Elevated venous pressure in the superior

analogues (octreotide) have been used in

vena cava

the treatment of chylothorax resistant to

Secondary to a Fontan-procedure

dietary modifications. Although their

Venous thrombosis

mechanism of action is not completely

understood, it seems that they reduce the

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481

Pleuroperitoneal shunt: persistent chylothorax

refractory to the standard medical or

surgical therapies can be managed with

pleuroperitoneal shunting. The pleural and

peritoneal cavities are communicated by a

valved catheter placed subcutaneously. Fluid

is pumped from the chest into the abdomen

where it is absorbed by peritoneal vessels.

Possible complications include malfunction

and infection.

If untreated, chylothorax can lead to

nutritional compromise and immunological

problems.

Haemothorax

Figure 2. Chest radiograph of a small infant with

Aetiology Haemothorax is a rare condition

bilateral chylothorax.

in children in which blood accumulates in

the pleural space. It is usually caused by

intestinal blood flow by vasoconstriction of

blunt or penetrating thoracic trauma and

the splachnic circulation with reduction of

may be life threatening if a large-volume

lymphatic fluid output. In addition, they

rapidly developing haemothorax occurs.

decrease gastrointestinal motility, and

Bleeding from lacerated intercostal vessels

gastric, pancreatic and biliary secretions,

or bone surfaces in rib fractures are the

significantly diminishing the lymphatic flow.

most common sources for haemothorax in

Dosage and method of delivery are not

children. Other less frequent lesions such as

definitely established. Other medications

pulmonary parenchymal lacerations or lung

such as nitric oxide, etilefrine and

contusions may cause persistent and

corticosteroids have been used in single

gradually increasing blood storage inside

case reports in adults.

the chest. Massive haemothorax with

Surgical therapy The main indication for

hypovolaemic shock is indicative of injury to

surgery is persistent chest drainage despite

a great vessel or the heart, and has a

nutritional modifications and bowel rest.

mortality rate of .60%.

The most frequently used surgical

techniques are described below.

Diagnosis Clinical symptoms depend on the

severity of haemothorax; tachypnoea, some

Pleurodesis: can be performed surgically or

degree of respiratory distress and decreased

using chemical agents. Sclerosing

oxygen saturation are usually observed. In

substances (tetracycline, povidone-iodide

those cases with massive bleeding a

and talc) can be administered directly

diminished level of consciousness and

through the thoracostomy tube or with the

clinical signs of haemodynamic instability

assistance of VATS. Chemical pleurodesis

are usually present. On auscultation,

with povidone-iodide has shown good

ventilation will be reduced or completely

tolerance and relative success in congenital

absent on the affected side. When two or

idiopathic chylothorax in neonates.

more rib fractures are present there is a high

Thoracic duct ligation: although direct

probability of multisystem injury including

surgical ligation of the thoracic duct at the

pulmonary contusion and haemothorax. As

rupture site would seem the most definitive

in adults, children with lung contusions

treatment, it has yielded variable results with

have the same incidence of serious

success rates between 25% and 100% in

complications associated to this condition,

different series including a small number of

such as pneumonia or acute respiratory

patients.

distress syndrome (ARDS).

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If haemothorax is suspected a chest

clamping of the chest tube may be of some

radiograph is the first image test to be

benefit in re-establishing the tamponade

performed. Due to the supine position, fluid

effect.

present in the pleural space will be diffusely

distributed across the lung field giving an

In most cases, bleeding will stop

image of generalised increased opacity.

spontaneously within a short period of time

Ultrasound is a quick and useful test in

without requiring any further surgical

demonstrating cardiac or lung injuries and

intervention. Drainage of the pleural cavity

haemothorax, but a chest CT scan is the

with effective lung expansion is all that is

most valuable diagnostic tool, especially if a

needed in this setting. Persistent bleeding in

great vessel injury is suspected (fig. 3).

an unstable patient is an indication for

urgent thoracotomy. Guidelines for

Management Management of significant

operative intervention are: a bleeding rate of

haemothorax must deal with two crucial

2-3 mL?kg^-1?h^-1 in a child over 4 h (200-

conditions:

300 mL per hour in an adolescent), or a

N increased intrapleural pressure with

return of 20-30% of the blood volume in a

secondary lung collapse,

child at chest tube placement (1000-

N reduced blood volume with possible

1500 mL in an adolescent). As a general

haemodynamic instability.

rule, the physiological response of the

patient to volume resuscitation is the best

Both situations can be severe enough to

guide in decision making and a prompt and

seriously compromise oxygenation and

sustained answer precludes surgical

cardiac output. Initial management

exploration. In selected cases of ongoing

measures must be directed to correct both

haemothorax, in an otherwise stable patient,

conditions by means of ensuring an

thoracoscopy (VATS) may be considered

adequate airway and restoring the

instead of thoracotomy in order to identify

intravascular volume. When diagnosed,

and control the source of the bleeding.

blood should be promptly removed from the

pleural cavity with tube thoracostomy. Large

Complications Hypovolaemic shock is the

catheters are preferable although they

most frequent complication when massive

should be matched to the patient’s age and

or persistent haemorrhage is present. Renal

size. In some cases, haemodynamic

failure, severe acidosis or cardiac ischaemia

collapse may occur with rapid evacuation of

may occur in this setting. When blood inside

the blood inside the chest. This is explained

the pleural space is not drained promptly it

because it may act as a tamponade reducing

may become clotted and organised.

ongoing blood loss from the intravascular

Reabsorption may take place in the

space. In this situation, intermittent

following weeks or months but in the

meanwhile empyema or fibrothorax may

develop. In order to prevent these

complications, a VATS procedure to

evacuate the retained haemothorax is

recommended within 1 week of injury.

Mediastinitis

Aetiology Mediastinitis is an infection of the

connective tissue of the mediastinum. Most

cases of acute mediastinitis usually occur

after sternotomy for cardiothoracic surgery

but it can also be caused by some

oesophagogastric diseases or injuries and

Figure 3. Chest CT showing bilateral haemothorax

from adjacent spread of retropharyngeal or

and lung contusion secondary to blunt trauma.

odontogenic infections. In children, an

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483

oesophageal perforation due to a foreign

be seen in granulomatous diseases, such as

body should be ruled out.

histoplasmosis, or infections like TB, and

after radiation therapy. Treatment remains

Diagnosis Although mediastinitis is a rare

controversial.

post-operative complication of median

sternotomy (0.1-5% of all paediatric

patients undergo this procedure), it

Further reading

represents a significant source of morbidity

Agrawal V, et al.

(2008). Lipid pleural

and mortality. Risk factors include: young

effusions. Am J Med Sci; 335: 16-20.

age, a high anaesthesiologist score, and a

Al-Sehly AA, et al.

(2005). Pediatric

long duration of the surgical procedure.

poststernotomy

mediastinitis.

Ann

Mediastinitis most often presents days to

Thorac Surg; 80: 2314-2320.

Asensio de la Cruz O, et al.

(2001).

weeks after cardiac surgery. Clinical signs

[Management of parapneumonic pleural

are variable, usually in the setting of an

effusions]. An Esp Pediatr; 54: 272-282.

unfavourable post-operative course. Sepsis,

Balfour-Lynn IM, et al. (2005). BTS guide-

pleural effusion, pneumothorax,

lines for the management of pleural

pneumomediastinum, thoracic pain,

infection in children. Thorax; 60: Suppl.

subcutaneous emphysema and

1, i1-i21.

odynophagia may be present in a patient

Bradley JS, et al. (2011). The management

with acute mediastinitis. Less frequently,

of community-acquired pneumonia in

cardiac arrhythmias may occur.

infants and children older than 3 months

of age: clinical practice guidelines by the

The most common organism isolated in

Pediatric Infectious Diseases Society and

children is Staphyloccus spp. but Gram-

the Infectious Diseases Society of

negative organisms account for up to one

America. Clin Infect Dis; 53: e25-e76.

third of cases in some series of post-

Caserío S, et al.

(2010). Congenital

operative mediastinitis. The microbiology of

chylothorax: from fetal life to adoles-

infection among heart and lung transplant

cence. Acta Paediatrica; 99: 1571-1577.

patients may differ depending on the

Cohen E, et al.

(2012). The long-term

underlying condition as well as the use of

outcomes of pediatric pleural empyema:

post-transplant immunosuppression.

a prospective study. Arch Pediatr Adolesc

Med; 166: 999-1004.

Management Treatment for acute

Crameri J, et al. Blunt thoracic trauma. In:

mediastinitis involves aggressive

Parikh DH, et al., eds. Pediatric Thoracic

intravenous antibiotherapy and surgical

Surgery. London, Springer-Verlag, 2009;

management. In post-operative

pp. 199-212.

mediastinitis the standard surgical approach

Lasko D, et al. Chylothorax. In: Parikh DH,

includes debridement followed by open

et al., eds. Pediatric Thoracic Surgery.

wound care with delayed closure. Other

London, Springer-Verlag, 2009; pp. 573-

surgical alternatives include: closed suction

577.

with antimicrobial irrigation, vacuum-

Sartorelli KH, et al. (2004). The diagnosis

assisted closure and muscle flap closure.

and management of children with blunt

These strategies have been initially

injury of the chest. Semin Pediatr Surg; 13:

developed for adults and later applied to

98-105.

children. Recently, some authors have

Shah SS, et al.

(2011). Comparative

suggested treating acute mediastinitis with

effectiveness of pleural drainage proce-

debridement and concomitant primary

dures for the treatment of complicated

closure without prolonged suction or

pneumonia in childhood. J Hosp Med; 6:

256-263.

irrigation.

Soto-Martínez M, et al.

(2009).

Chronic mediastinitis is characterised by

Chylothorax: diagnosis and management

diffuse fibrosis of the soft tissues of the

in children. Paediatr Respir Rev; 10: 199-207.

mediastinum. It is a very rare entity that can

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ERS Handbook: Paediatric Respiratory Medicine

Pneumothorax and

pneumomediastinum

Nicolaus Schwerk, Folke Brinkmann and Hartmut Grasemann

Pneumothorax

Epidemiology Epidemiological data in

children and adolescents are scarce. PSP in

Pneumothorax is defined as an

adults shows male predominance with a

accumulation of air in the pleural cavity. It

reported incidence of 18-28 cases per

can be classified as primary spontaneous

100 000 in males and 1.2-6 cases per

pneumothorax (PSP), secondary

100 000 in females. In children, a male

spontaneous pneumothorax (SSP) and

predominance is also consistently reported

traumatic or iatrogenic pneumothorax.

(65-80%), with a mean age at presentation

Whereas PSP occurs in the absence of an

of 14-16 years. While typically tall, thin boys

underlying disease, SSP is the result of pre-

with a below-average BMI are affected, it is

existing lung affection (table 1).

important to note that a pneumothorax can

occur in any age group. Smoking is a

recognised risk factor for PSP.

Key points

Pathogenesis Apical subpleural blebs and

The most common cause of

bullae are often found in patients with PSP

pneumothorax in paediatric patients

(55-88% at the ipsilateral side and 15-66%

is the rupture of bullae or blebs in the

at the contralateral side). Rupture of these

apex of the lung without an underlying

lung bullae or blebs that develop without an

predisposing lung disease or history

underlying lung disease or history of trauma

of trauma.

is generally considered to be the cause of

When pneumothorax is suspected,

PSP. The gradient of negative pleural

standard erect posterior to anterior

pressure increases from the lung base to the

chest radiograph in inspiration

apex, so that alveoli at the lung apex,

technique represents the diagnostic

especially in tall individuals, are subject to

gold standard.

significantly greater distending pressures

than those at the lung base. Presumably,

Patients with pneumothorax who

these pressure differences predispose to the

experience symptoms should be

development of apical subpleural blebs.

treated with oxygen supplementation

However, the presence of blebs is not a

and needle aspiration or chest

reliable predictor to estimate the recurrence

catheter insertion independent of the

risk in patients suffering from PSP, and

size of the pneumothorax.

apical subpleural blebs and bullae can also

In the setting of recurrent

be found in healthy subjects. In children

pneumothorax, surgical treatment is

with PSP and basilar subpleural bullae or

indicated. The preferred technique

blebs and a positive family history for PSP,

consists of the resection of the

Birt-Hogg-Dubé syndrome should be

causative bleb or bulla and a

considered. Blebs or bullae in the lower

pleurodesis procedure.

lobes can be detected in almost all patients

with this autosomal dominant disorder,

ERS Handbook: Paediatric Respiratory Medicine

485

Table 1. Causes of secondary and traumatic/iatrogenic pneumothorax

Congenital pulmonary malformations (congenital cystic adenomatoid malformation), congenital

emphysema and lung hypoplasia

Asthma

Bronchiolitis obliterans

Diffuse parenchymal lung diseases

Systemic inflammatory diseases, e.g. rheumatoid arthritis, systemic lupus erythematodes,

polymyositis and dermatomyositis

Sarcoidosis

Connective tissue diseases, e.g. Marfan syndrome and Ehlers-Danlos syndrome

Foreign body aspiration

Infections, e.g. Pneumocystis jirovecii, TB, parasitic necrotising pneumonia or abscess, and

bronchiolitis

Langerhans cell histiocytosis

Malignancies, e.g. lymphoma, pleuropulmonary blastoma and metastasis

Post-surgical trauma

Sjögren syndrome

Ventilator-associated interstitial emphysema

which is caused by a mutation in the

disease. Therefore, following the initial

folliculin gene, and 40% will develop PSP.

treatment, patients with SSP should be

transferred to a specialised centre whenever

A special form of pneumothorax is

possible.

ventilator-associated interstitial

emphysema. Rupture of alveoli during

Symptoms PSP can develop following

mechanical ventilation, especially in

manoeuvres that result in increased

neonates, can lead to air entry into

intrathoracic pressures (e.g. lifting) but most

perivascular connective tissue. Gas then

commonly occurs at rest. Typical symptoms

migrates into the interstitium and becomes

are chest pain and dyspnoea. Symptoms can

trapped within the pulmonary perivascular

be relatively minor and self-limiting within

sheaths, resulting in interstitial emphysema.

24 h so that a high index of initial diagnostic

Rarely, a pneumothorax results from

suspicion is required. In patients with SSP,

infection with gas-producing

clinical symptoms are usually more severe

microorganisms, penetrating tumours or

than those associated with PSP and may

chest wall defects. Chest wall defects can be

include severe breathlessness, even with

traumatic or iatrogenic. SSP constitute a

small pneumothoraces. Severity of clinical

threat in patients with pre-existing

symptoms is therefore an unreliable

underlying lung diseases and management

indicator of pneumothorax size.

in these individuals is potentially more

Characteristic signs on physical examination

challenging. SSP in patients with CF is

include:

associated with a significantly increased

mortality risk. Treatment for SSP should be

N diminished breath sounds,

more aggressive than for PSP (e.g. broad

N reduced lung expansion,

indication for a chest drain insertion) and

N decreased vocal fremitus,

special consideration may need to be

N hyperresonance on percussion at the side

given to the treatment of the underlying

of the pneumothorax.

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ERS Handbook: Paediatric Respiratory Medicine

These signs can be subtle or even absent,

especially in neonates or infants. As

pneumothorax in this younger age group is

potentially life threatening, a chest

radiograph in any situation of unexplained

cardiorespiratory symptoms is required to

rule out pneumothorax. At any age, in the

case of cardiorespiratory distress with

tachycardia, hypotension and/or cyanosis, a

tension pneumothorax must be considered

and rapid diagnosis and treatment is

mandatory (fig. 1).

Imaging Standard erect posterior to anterior

chest radiograph in inspiration technique

remains the diagnostic gold standard,

notwithstanding limitations including, for

Figure 2. Pneumothorax in CF.

instance, the problem of quantifying the size

of a pneumothorax. Typical radiological

justified when confirming the diagnosis is of

signs are displacement of the pleural line

clinical and therapeutic relevance.

and an air-fluid level visible in the

costophrenic angle (fig. 2). Supine and

There are numerous different approaches to

lateral decubitus chest radiographs are

calculate the size of a pneumothorax.

alternative options for patients who cannot

Commonly the erect radiograph has been

be moved safely. In patients with cystic lung

used for these quantifications. According to

lesions, such as congenital pulmonary

the British Thoracic Society (BTS) guidelines

malformations or Langerhans cell

a large pneumothorax is defined as a 2-cm

histiocytosis (fig. 3), the lesions can lead to

gap between the entire lateral lung edge and

diagnostic errors, with potentially fatal

the chest wall. In the guidelines of the

consequences for the patient. Therefore, in

American College of Chest Physicians

uncertain cases alternative techniques such

(ACCP) a large pneumothorax is defined as

as ultrasound or CT can be helpful. It is

an apical distance of 3 cm. However, since

important to note that CT scans are only

Figure 3. Pneumothorax in Langerhans cell

Figure 1. Tension pneumothorax.

histiocytosis.

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487

pneumothorax size does not closely

a single needle aspiration is not inferior to

correlate with its clinical manifestations, a

intercostal chest catheter (ICC) insertion

thorough clinical evaluation is probably

with respect to success and recurrence

more important for determining the proper

rates. Moreover, needle aspiration is less

management strategy than the estimation of

invasive, more cost-effective and associated

its actual size.

with lower complication rates compared to

ICC. Unfortunately, no randomised

Therapy There are no evidence-based

controlled trial comparing needle aspiration

guidelines for the treatment of

to ICC has been conducted in paediatric

pneumothorax in children, and

patients to date. In the BTS guidelines for

recommendations of different national and

adult patients it is recommended that

international guidelines for adult patients

aspiration of a maximum of 2.5 L should not

are controversial. Therefore, treatment

be exceeded in order to avoid re-expansion

decisions are often made on the basis of

oedema. Control radiographs are suggested

institutional guidelines. It is generally

after single aspiration to assess the

agreed that a patient with pneumothorax

presence of ongoing air leak. ICC insertion

who experiences symptoms should be

should be considered in the case of:

treated independently of the size of the

pneumothorax. Asymptomatic children

N age ,1 year,

should be observed in hospital for at least

N bilateral pneumothorax,

24 h. A repeat chest radiograph should be

N tension pneumothorax,

obtained prior to discharge to exclude

N evidence for a big air leak (although this

expansion of the pneumothorax.

may result in bronchopleural fistula),

N pneumothorax recurrence within the first

Observation only (watch and wait)

hours following aspiration,

Conservative treatment with observation

N co-existence of a pleural effusion

only in asymptomatic patients with small

especially in the case of haemothorax.

pneumothoraces has been shown to be safe.

Up to 80% of patients are estimated to have

Furthermore, chest drain insertion should

no active air leak, and recurrence in those

be performed in all children with iatrogenic

managed by observation only is equal or

and traumatic pneumothorax, SSP or co-

even less frequent than in those treated with

existing pneumomediastinum. The success

chest drainage. Nevertheless, a long time to

rates for small-bore ICCs are comparable to

resolution of up to 30 days has to be

large-bore ICCs while being less painful;

considered.

however, large-bore ICCs are indicated when

the rate of air leak exceeds the capacity of a

Supplemental oxygen at high concentrations

smaller ICC. Needle aspiration or ICC

generates a partial pressure gradient

insertion should only be performed by, or

between the pleural cavity and the capillary

under the supervision of, medical staff

blood by decreasing the partial pressure

experienced in the procedure. Initial chest

contribution of nitrogen. This accelerates

the absorption of gas from the pleural cavity.

radiograph imaging should guide the site of

placement. An appropriate approach in the

Small case series have shown a four-fold

increase in the rate of pneumothorax

majority of cases is the ‘‘triangle of safety’’,

resolution in patients treated with

which is bordered anteriorly by the lateral

supplemental oxygen compared to patients

edge of pectoralis major, laterally by the

managed by observation only. Therefore,

lateral edge of latissimus dorsi, inferiorly by

supplemental high-flow oxygen should be

the line of the fifth intercostal space and

given to all patients hospitalised for a

superiorly by the base of the axilla (fig. 4).

pneumothorax.

An alternative approach is the second

intercostal space in the mid-clavicular line.

Needle aspiration and intercostal chest

Proper sedation should be given in addition

catheter insertion There is an emerging body

to local anaesthetic. After insertion, ICCs

of evidence that, in adult patients with PSP,

should be connected to a Heimlich valve or

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ERS Handbook: Paediatric Respiratory Medicine

an underwater seal device. The benefit of

continuous suction is unclear. Since initial

suction might increase the risk of re-

expansion pulmonary oedema it is only

recommended if lung re-expansion has not

occurred at 48 h or if there is a persisting air

leak, which may indicate a

bronchopulmonary fistula. Optimal suction

should entail pressures of -10- -20 cmH₂O.

Surgical management The primary aim of a

surgical intervention is to prevent recurrence

of pneumothorax. Nevertheless, the

detection of blebs or bullae in patients with

their first PSP normally does not require

surgical intervention. Current indications for

surgical intervention include:

N second ipsilateral pneumothorax,

N first contralateral pneumothorax,

N bilateral pneumothorax,

N persistent air leak,

N associated haemothorax,

N following a first episode in professionals

at risk, including pilots and divers.

Surgical treatment consists of the resection

of the causative bulla or bleb associated with

Figure

5. Pneumomediastinum. a) Radiograph

some type of pleurodesis procedure, either

and b) CT.

pleurectomy or pleural mechanical abrasion.

Chemical pleurodesis is not used in children

because of its potentially severe side-effects.

Recurrence Whether children with PSP have

a higher rate of recurrence than adults

The current gold standard in the adult

remains unclear. Reported data from small

literature is blebectomy and apical parietal

case series range between 20% and 50%

pleurectomy. Newer surgical techniques

after first PSP and 1-15% after surgical

such as video-assisted thoracoscopic

treatment. Recurrence risk in paediatric

surgery (VATS) have also been shown to be

patients with SSP depends on the course of

safe and effective in children. Advantages of

the underlying disease.

VATS are decreased post-operative pain,

reduced length of hospital stay and

Pneumomediastinum and subcutaneous

improved lung function.

emphysema

Pneumomediastinum is defined as the

presence of free air in the mediastinum.

Epidemiology Currently there are no

epidemiological data in the paediatric

literature, but undoubtedly

pneumomediastinum is an exceedingly rare

condition in this age group.

Pathogenesis Rarely, pneumomediastinum

can occur as spontaneous

Figure 4. Schematic diagram of the triangle of safety.

pneumomediastinum (e.g. Hamman’s

ERS Handbook: Paediatric Respiratory Medicine

489

the underlying cause. While symptoms in

Table 2. Predisposing conditions for pneumomediasti-

children with spontaneous

num

pneumomediastinum can be mild,

Allergic bronchopulmonary aspergillosis

pneumomediastinum as a complication of

Asthma exacerbation

an underlying disease can be life threatening

Barotrauma

with reported mortality rates of up to 40%.

Typical clinical signs are chest pain,

Blunt or penetrating trauma of the chest wall

dyspnoea and cough. In 30-40%

Bronchiolitis obliterans

pneumomediastinum is associated with

Bronchopulmonary dysplasia/chronic lung

subcutaneous emphysema with soft tissue

disease

swelling of the neck, the face and sometimes

the whole chest wall in conjunction with

Central venous or cardiac catheterisation

characteristic subcutaneous crepitations.

Connective tissue diseases-related

interstitial lung disease

Imaging As for pneumothorax the diagnosis

of pneumomediastinum is made by

radiography. However, up to 30% of cases of

Diffuse parenchymal lung diseases

pneumomediastinum are missed on chest

Endoscopic/bronchoscopic interventions

radiographs, therefore CT has become the

gold standard for diagnosis, especially when

Foreign body aspiration

the underlying predisposing condition is

Infections, e.g. influenza A/B virus,

unknown.

Mycoplasma pneumoniae, Pneumocystis

jirovecii and Aspergillus fumigatus

Therapy In the adult literature, several

Mechanical ventilation

surgical techniques have been reported to

treat pneumomediastinum and

Oesophageal perforation

subcutaneous emphysema including

Penetrating tumours

mediastinal drain insertion, subcutaneous

Pneumothorax (PSP and SSP)

pigtail or large-bore drains with or without

suction. All of these methods are invasive and

Surgical interventions

have an increased risk of infection. The most

important therapeutic approach is the

syndrome) in the absence of a specific

treatment of the underlying cause. In addition

underlying disease. In these cases it is

to this, conservative treatment including

thought to be the result of a sudden increase

analgesics, bed rest and avoidance of Valsalva

in intrathoracic pressure (e.g. emesis,

manoeuvres may be beneficial. Symptoms

cough, physical activity or defecation) and

generally improve within 3-15 days without

subsequent alveolar rupture. Further leakage

sequelae. It is not clear whether preventive

of air throughout the interstitium and

antibiotic therapy can reduce the risk of

bronchovascular tissue follows a centripetal

secondary infections of the mediastinum.

pattern towards the mediastinum. In most

Nevertheless, antibiotic treatment should be

cases, however, pneumomediastinum is

initiated generously in patients with extended

thought to be a complication of a specific

trauma of the bronchial tree, the oesophagus,

underlying disease or the result of a specific

or a known infection as the underlying cause

pathological event leading to rupture of lung

of pneumomediastinum.

parenchyma or the bronchial tree (fig. 5).

Given the grave clinical consequences of

Further reading

pneumomediastinum and the necessity to

institute specific treatment of an underlying

Baumann MH, et al. (2001). Manage-

cause, responsible predisposing conditions

ment of spontaneous pneumothorax: an

have to be excluded (table 2).

American College of Chest Physicians

Delphi consensus statement. Chest; 119:

Symptoms The severity of symptoms

590-602.

depends on pneumomediastinum size and

490

ERS Handbook: Paediatric Respiratory Medicine

Bialas RC, et al.

(2008). Video-assisted

MacDuff A, et al. (2010). Management of

thoracic surgery for primary spontaneous

spontaneous pneumothorax: British

pneumothorax in children: is there an

Thoracic Society pleural disease guide-

optimal technique? J Ped Surg; 43: 2151-2155.

line. Thorax; 65: Suppl. 2, ii18-ii31.

Caceres M, et al. (2008). Spontaneous

Northfield TC (1971). Oxygen therapy for

pneumomediastinum: a comparative

spontaneous pneumothorax. Br Med J; 4:

study and review of the literature. Ann

86-88.

Thorac Surg; 86: 962-965.

O’Lone E, et al.

(2008). Spontaneous

Chan SS

(2008). The role of simple

pneumothorax in children: when is inva-

aspiration in the management of primary

sive

treatment indicated?

Pediatr

spontaneous pneumothorax. J Emerg

Pulmonol; 43: 41-46.

Med; 34: 131-138.

Ohata M, et al. (1980). Pathogenesis of

Elphick EO, et al.

(2008). Spontaneous

spontaneous pneumothorax. With special

pneumothorax in children: when is invasive

reference to the ultrastructure of emphy-

treatment indicated? Ped Pulm; 43: 41-46.

sematous bullae. Chest; 77: 771-776.

Giuliani S, et al.

(2010). Massive sub-

Robinson PD, et al.

(2009). Evidence-

cutaneous emphysema, pneumomedias-

based management of paediatric primary

tinum, and pneumopericardium in

spontaneous pneumothorax. Ped Respir

children. J Ped Surg; 45: 647-649.

Rev; 10: 110-117.

Guimaraes CV, et al. (2007). CT findings

Toro JR, et al.

(2007). Lung cysts,

for blebs and bullae in children with

spontaneous pneumothorax, and genetic

spontaneous pneumothorax and compar-

associations in

families with Birt-

ison with findings in normal age-matched

Hogg-Dube syndrome. Am J Respir Crit

controls. Pediatr Radiol; 37: 879-884.

Care Med; 175: 1044-1053.

Havelock T, et al. (2010). Pleural proce-

Vedam H, et al. (2003). Comparison of

dures and thoracic ultrasound: British

large- and small-bore intercostal cathe-

Thoracic Society pleural disease guide-

ters in the management of spontaneous

line. Thorax; 65: Suppl. 2, ii61-ii76.

pneumothorax. Intern Med J; 33: 495-499.

ERS Handbook: Paediatric Respiratory Medicine

491

Neuromuscular disorders

Anita K. Simonds

Prevalence

by variable combinations of reduced

inspiratory muscle strength, the presence of

While some neuromuscular diseases are

a thoracic scoliosis and reduced chest wall

very rare, as a group the neuromuscular

and pulmonary compliance - the latter

disorders in childhood are quite common,

caused by micro- or macro-atelectasis.

with an overall prevalence of about 1:3000.

Inspiratory and expiratory muscle strength

Most are inherited in origin, the commonest

mostly decrease in parallel, but when

being Duchenne muscular dystrophy, spinal

diaphragm strength is preserved expiratory

muscular atrophy, congenital muscular

muscle weakness may predominate e.g. in

dystrophies and myopathies. The probability

spinal muscular atrophy. Expiratory muscle

of respiratory complications varies

weakness combined with inspiratory muscle

according to diagnosis, genotype and age

weakness leads to poor cough efficacy and

(table 1) and in the past 20 years an

secretion clearance and can be measured by

increasing amount has been learned about

cough peak flow - values less than

genotype-phenotype correlations and

270 L?min^-1 in children aged approximately

respiratory management strategies. In some

10 years and above suggest reduced cough

conditions, the natural history has changed

power, and values less than 160 L?min^-1 are

significantly with the introduction of

associated with increased frequency of chest

ventilatory support.

infections. A vital capacity of f60%

Assessment of pathophysiology

predicted is predictive of the presence of

sleep disordered breathing, which initially

Children with neuromuscular weakness have

occurs in REM sleep and then spreads to all

a restrictive pattern of spirometry on

sleep stages. Usually this appears as

pulmonary function testing. This is caused

nocturnal hypoventilation, but obstructive

hypoventilation may be seen in some

conditions e.g. Duchenne muscular

Key points

dystrophy. Sleep studies should be carried

out routinely in these children or in any with

N Neuromuscular disorders are

sleep-related symptoms or recurrent chest

relatively common, with a prevalence

infections, in those requiring

of 1:3000.

hospitalisation, or in failure to thrive.

Sleep disordered breathing is likely

Scoliosis is common and will occur in

when vital capacity falls to ,60%

virtually all children with spinal muscular

predicted.

atrophy types 1 and 2, and in 70-90% of

those with Duchenne muscular dystrophy.

N NIV is indicated to control

Scoliosis progresses with the adolescent

symptomatic sleep disordered

growth spurt and transition to permanent

breathing.

wheelchair use. Use of steroid therapy and

Use of NIV in Duchenne muscular

preservation of standing using frames may

dystrophy may double life expectancy.

reduce scoliosis severity. Scoliosis surgery is

carried out to prevent progression of the

492

ERS Handbook: Paediatric Respiratory Medicine

curvature and achieve comfort rather than to

occur. In addition, mask rotation and

increase lung volumes.

avoidance of tight-fitting interfaces should

be employed to reduce the risk of pressure

Bulbar involvement is inevitable in type 1

over facial structures resulting in mid facial

spinal muscular atrophy and some

hypoplasia and pressure sores. Customised

conditions such as myotubular myopathy

masks reduce the occurrence of mask-

and myotonic dystrophy, but in others, e.g.

Further reading

muscular dystrophy patients by the mid-to-

late teenage years and should be treated

Hull J, et al.

(2012). British Thoracic

with angiotensin-converting enzyme

Society guideline for respiratory manage-

inhibitor and beta blocker. Cardiac

ment of children with neuromuscular

involvement is also highly prevalent in

weakness. Thorax; 67: Suppl. 1, 1-40.

Wang CH, et al.

(2010). Consensus

Becker muscular dystrophy, myotonic

statement on standard of care for con-

dystrophy and the lamininopathies such as

genital muscular dystrophies. J Child

Emery Dreyfuss muscular dystrophy. The

Neurol; 25: 1559-1581.

limb girdle muscular dystrophies are a very

Bushby K, et al. (2010). Diagnosis and

heterogenous group and cardiac

management of Duchenne muscular dys-

surveillance should be adapted to the

trophy, part 2: implementation of multi-

underlying disorder - for example cardiac

disciplinary care. Lancet Neurol; 9: 177-

disease is common in the

189.

sarcoglycanopathies (LGMD2C-F), but less

Simonds AK (2006). Risk management of

frequent in the dysferlinopathies (e.g.

the home ventilator dependent patient.

LGMD2B) and calpainopathies (e.g.

Thorax; 61: 369-371.

LGMD2A).

496

ERS Handbook: Paediatric Respiratory Medicine

Chest wall disorders

Daniel Trachsel, Carol-Claudius Hasler and Jürg Hammer

Paediatric chest wall disorders include the

Pathophysiology of respiratory compromise

congenital structural anomalies of the rib

in chest wall disorders and scoliosis

cage, spine, and thoracic musculature, and a

Long-term respiratory stability requires a

number of acquired chest wall diseases such

sufficient ventilatory reserve and the

as costal Ewing sarcoma. Congenital chest

expectoration of accumulating airway

wall diseases may be apparent at birth or

secretions. While infants are limited in their

become apparent with time, usually as a

respiratory stability by increased chest wall

result of disturbed growth and development.

compliance and collapsibility of the airways,

In this chapter, the most important features

older children with thoracovertebral

of congenital disorders will be highlighted; a

deformatities are more hindered by

discussion of acquired chest wall diseases is

abnormal stiffness of the chest. The

beyond its scope.

recruitment of inspiratory reserve to full

expansion of the thoracic cage depends on

Key points

the free mobility of the costo-vertebral and

costo-sternal articulations, and on a

Despite obvious deformations, lung

diagonal resting position of the rips on the

function remains surprisingly preserved

vertebrocranial to sternocaudal axis, which

in most individuals with adolescent

allows widening of the chest by lifting the

idiopathic scoliosis, pectus excavatum

ribs into a horizontal position. For this to be

and pectus carinatum.

accomplishable with minimal effort, the

In contrast, severe thoracic restriction

alignment of the respiratory muscles must

conveys a high risk of pulmonary

provide optimal leverage angles.

morbidity and respiratory failure in

The severity of a thoracovertebral

early-onset scoliosis and complex

malformation often correlates with the

syndromal thoracovertebral

degree at which these structural requisites

malformations.

for respiratory stability are lost in affected

N Surgical correction rarely improves lung

children who then become more and more

function but may significantly

exclusively dependent of diaphragmatic

deteriorate the natural history if young

breathing, which in turn can be hindered by

individuals undergo early fusion of the

distortion and flattening of the diaphragm.

thoracic spine.

Congenital chest wall and sternal defects

Recent developments in orthopaedic

techniques allow timely intervention in

Poland syndrome, or Poland sequence,

early-onset scoliosis promoting spinal

describes a unilateral hypoplasia or aplasia

and chest wall growth, but the potential

of the pectoral muscle which is associated

for improving lung function remains to

with a more or less pronounced

be clarified.

malformation of the ipsilateral upper

extremity, typically a synbrachydactyly, and

ERS Handbook: Paediatric Respiratory Medicine

497

occasionally absence of one or more ribs.

The majority of patients, anyhow, seek

Concomitant Moebius syndrome may be

correction for aesthetic reasons.

present. Poland syndrome does not usually

Sternal clefts Congenital sternal clefts can be

affect respiratory function but may have a

complete or partial. Partial superior clefts

significant psychosocial impact.

prevail; partial lower clefts are often

Pectus carinatum The pectus carinatum

associated with ectopia cordis or Cantrell

deformity is three times rarer than pectus

pentalogy. Other concurrent malformations,

excavatum, occurring sporadically, with a

e.g. midline defects, are found in up to three-

familial preponderance in 25% of cases, or

quarters of cases, but many individuals with

as part of genetically determined syndromes

sternal clefts are asymptomatic. Reported

such as Marfan syndrome, Noonan

complaints include exercise intolerance,

syndrome, prune belly syndrome or

cough and vulnerability to lower respiratory

homocysteinuria. In most affected

tract infections. Early surgical repair is often

individuals, cardiopulmonary function is not

recommended, the more theoretical

impaired, but many suffer from the

rationale being concerns about chest

psychosocial impact that may justify surgical

instability and risk of trauma.

correction.

Cantrell pentalogy Cantrell pentalogy is a

Pectus excavatum The pectus excavatum

rare, combined midline defect including the

deformity has a prevalence of 1 in 400 with a

pentade supra-umbilical abdominal wall

male preponderance of 3-5:1. As with the

defect with or without evisceration, inferior

carinatum deformity, its occurrence is

sternal cleft, pericardial defect or ectopia

sporadic, familial, or syndromic (Marfan or

cordis, median diaphragmatic defect, and

Noonan); in addition, it may be seen in

congenital heart defect, e.g. ventricular

survivors of congenital diaphragmatic

septal defect or tetralogy of Fallot. The

hernia, or secondary to longstanding

outcome depends on the extent of the

malformation and the complexity of the

significant upper airway obstruction. Pectus

congenital heart defect. Mortality in children

excavatum can become apparent at any age

with the complete pentalogy is high.

during growth and is not spontaneously

reversible except for the secondary form.

Thoracoverebral deformities

Significant pectus excavatum is associated

Isolated congenital scoliosis and adolescent

with mild restrictive lung function with a

idiopathic scoliosis The period of fastest

decrease in mean vital capacity (VC) to

spine growth is from birth to age 5 years

about 80-85% predicted. The probability of

(T1-L5 grows 2.2 cm per year), when spinal

significant restriction is four times higher if

length gain is almost 50%. Growth then

the Haller index, defined as the ratio

transiently slows to 1.1 cm per year, and re-

between the transverse thoracic diameter

accelerates again for the pubertal growth

and the narrowest distance between

spurt to 1.8 cm per year, starting at age 10-

sternum and vertebra, is .7. Significant

11 years in girls, and 2 years later in boys.

airway obstruction is rare. Although

The thoracic volume makes up about 6% of

measurable lung function abnormalities are

its adult size at birth, 30% at age 5 years and

usually mild, many affected individuals

50% at age 10 years.

complain about shortness of breath and

reduced exercise tolerance.

Early onset scoliosis (EOS) is defined as any

scoliosis manifesting before the age of

Available data report no benefit of corrective

5 years irrespective of its origin, i.e. a

surgery to lung function but a possible

congenital (thoraco-)vertebral

favourable effect on exercise capacity,

malformation, neuromuscular disease,

independently of the therapeutic approach,

specific syndrome or the infantile idiopathic

i.e. treatment with a vacuum bell, an open

type. 70% of EOS worsen over time and

surgical procedure, or minimally invasive

require treatment, approximately half by

repair of pectus excavatum (MIRPE).

surgical intervention. The hallmark of EOS is

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ERS Handbook: Paediatric Respiratory Medicine

its propensity to progressive respiratory

leverage vectors of the respiratory muscles,

failure and associated mortality. The overall

but likely also reflects a generalised muscle

prognosis is worse in the presence of

weakness that has repeatedly been found in

concomitant thoracic cage malformations or

AIS patients and might contribute to the

in neurogenic EOS. The best outcome may

pathogenesis of scoliosis.

be expected in cases of idiopathic scoliosis

Complex syndromal thoracovertebral

with little rotational deviation (Mehta rib

malformations The complex syndromal

angle difference of ,20u).

thoracovertebral malformations comprise a

Survival improves dramatically if idiopathic

heterogeneous group of combined

scoliosis is diagnosed between 5 and

malformations of the spine and thoracic

10 years of age, and is normal in adolescent

cage that lead to severe kyphoscoliosis and/

idiopathic scoliosis (AIS) patients.

or narrowing and stiffening of the thoracic

cage. Respiratory function of affected

Most individuals with AIS have normal lung

children is impaired by the thoracic

function. When scoliosis progresses,

restriction, reduced respiratory muscle

however, lung function decreases by the

function, weak cough and impaired airway

reduction of both the volume and the

clearance. Additional symptoms may arise

compliance of the chest, and by the change

from associated malformations, gastro-

of the lever arm vectors of the respiratory

oesophageal reflux and heart failure. These

muscles. TLC is preserved longer than VC,

malformations not only cause physical

resulting in an extrinsic (asymmetrical)

suffering but also enormous psychosocial

overinflation with an increased residual

stress from social marginalisation, school

volume/TLC ratio. Ventilation becomes

absenteeism and concerns about the future.

increasingly inhomogeneous, but bronchial

Medical care, therefore, requires a

obstruction is found in fewer than 20% of

multidisciplinary approach. Numerous

cases. The degree of pulmonary restriction

syndromes may manifest with complex

is underestimated if height-based reference

thoracovertebral malformations, including

values of normal lung function are used.

diastrophic dysplasia, infantile Marfan,

Klippel-Feil, Jeune, and Jarcho-Levin

The Cobb angle cannot reliably depict the

syndromes.

three-dimensionality of scoliosis, and it

correlates only moderately with the degree

Concept of thoracic insufficiency syndrome

of pulmonary limitation. A decrease of the

(TIS): The severe thoracic restriction is

FVC below 80% pred may be expected in AIS

associated with respiratory failure and lung

from Cobb angles of 70-100u onwards, but

hypoplasia. This common feature led

the variability of pulmonary restriction

Campbell et al. (2003) to propose the

remains significant. Rotation in the

concept of TIS in 2003, defined as the

transverse plane is an important feature of

inability of the thorax to allow normal

scoliosis, clinically manifesting as rib hump

respiration and lung growth. TIS has been

or lumbar hump depending of the height of

divided into 4 different types of volume

the scoliosis, and additionally impairs lung

depletion deformities (table 1).

function in patients with advanced scoliosis

or concomitant thoracic hypokyphosis. It is

Patients with unilateral absent ribs and

estimated that height and length of the

associated flail chest have a high mortality in

scoliotic curvature and the presence of

the first years of life. Death is usually caused

hypokyphosis (,10u sagittal angulation)

by respiratory failure and/or right heart

account for up to 20% of FVC reduction.

failure. The unilateral fused ribs type is the

most common form and typically leads to

AIS patients often complain about reduced

worsening of scoliosis and pulmonary

exercise tolerance. Maximum inspiratory

function with growth. The differentiation

and expiratory pressures (MIPS and MEPS)

into the four types of TIS guides the surgical

are about 70% pred on average, which is in

management. For the paediatric

part attributable to the disadvantaged

pulmonologist, it is important to recognise

ERS Handbook: Paediatric Respiratory Medicine

499

Table 1. Types of volume-deficiency deformities causing TIS

Type

Characteristics

Unilateral absent ribs with scoliosis and hemihypoplasia of the thorax

Unilateral fused ribs with scoliosis and hemihypoplasia of the thorax

IIIa

Vertebral malformation with loss of thoracic height and kyphosis

Bilateral longitudinal restriction of the lungs (e.g. Jarcho-Levin syndrome)

IIIb

Global thoracic hypoplasia with windswept deformity and lateral lung constriction on

both sides (e.g. Jeune syndrome)

that both chest radiography and lung

are at risk of developing end-stage renal

function testing do not reliably reflect the

disease.

degree of respiratory morbidity. Studies

Spondylocostal and spondylothoracic dysostosis

suggest that sleep studies may be more

(Jarcho-Levin syndrome/Lavy-Moseley

sensitive to detect respiratory limitation.

syndrome): The Jarcho-Levin syndrome

Asphyxiating thoracic dystrophy is a rare

encompasses individuals with a very short

osteochondrodysplasia with autosomal

spine and malformed vertebral bodies, and a

recessive inheritance and variable

dysplastic rip cage with fused, dysplastic or

expression that occurs in all ethnicities with

absent ribs. Various gene mutations have

an estimated incidence of 1 in 130 000. A

been found and underlie the phenotypic

narrow, bell-shaped and very stiff thorax with

variations. Spondylocostal dysostosis

an almost normal-sized vertebral column is

(Jarcho-Levin syndrome sensu stricto) may

the hallmark of the syndrome. Chest width is

be distinguished from spondylothoracic

reduced in both the sagittal and the coronal

dysostosis (Lavy-Moseley syndrome).

plane with shortened ribs typically bowed

Severe pulmonary restriction leads to

inwards at the tips, resulting in a cloverleaf

chronic respiratory failure, recurrent

appearance of the thoracic cage in the

pneumonias, and right heart failure.

transverse plane. Other skeletal features of

Spondylocostal dysostosis occurs both as

the pelvis and extremities are common and

autosomal recessive and autosomal

associated with short stature, and vertebral

dominant trait, and is mainly characterised

malformations of the neck need special

by:

attention for their potential to damage the

cervical medulla. One-third of affected

N an abnormal segmentation of at least 10

individuals have renal disease including

consecutive vertebral bodies,

cysts, tubular atrophy and renal failure.

N a costal malalignment, fused ribs and

Other frequently encountered organ

costal bifurcations, or occasionally absent

manifestations involve the liver, the

ribs,

pancreas, and the eyes. There is apparently

N a mild scoliosis with variable potential for

no correlation between the severity of

progression, depending on the

thoracic dystrophy and the extent of

asymmetry of the costal malformations

parenchymal involvement.

(TIS type II or type IIIa).

More than 120 cases have been described in

Multiple associated malformations are

the literature. Mortality is as high as 50%,

known. Without early thoracic expansion,

with up to 80% dying within the first 2 years

progression of scoliosis occurs in 75% of

due to respiratory failure and cor pulmonale.

cases. Mean survival has improved

Most survivors need some sort of ventilatory

significantly, but long term prognosis is as

support. Thorax-expansion surgery increases

yet unknown.

the transverse cross-sectional area, but its

effect on lung growth remains uncertain.

Spondylothoracic dysostosis is an

Jeune patients surviving into adolescence

autosomal recessive syndrome seen mostly

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ERS Handbook: Paediatric Respiratory Medicine

in individuals of Puerto Rican descent,

small steps and reducing anaesthetic and

characterised by an extremely short spine

infection risks.

with posteriorly fused rips giving a crab-like

Whether these interventions stimulate

appearance to the chest radiograph (TIS

pulmonary catch-up growth is not yet clear.

type IIIa). Among other malformations, it

CT scans have revealed a 25 -90% increase

may be associated with congenital

of the thoracic cage after VEPTR, likely

diaphragmatic hernia which further worsens

consequent to the enlargement of the

the prognosis of these children who are

coronal chest diameter and the stimulation

almost exclusively dependent on

of spinal growth. Reported clinical benefits

diaphragmatic breathing. Mortality is very

of expansion thoracoplasty include

high and generally attributable to respiratory

improved exercise tolerance, reduced

failure, pulmonary arterial hypertension and

ventilatory support, increased body weight,

heart failure.

and reduction of polyglobuly. Whether the

Orthopaedic treatment of scoliosis and

improvement of these surrogate markers

thoracovertebral malformations, and impact

results from improved breathing mechanics,

on lung function Early multiple-level

a larger chest volume or even alveolar catch-

vertebral fusions have been completely

up growth is a matter of debate. Preliminary

abandoned because they result in a short

longitudinal lung function studies failed to

straight or bent spine and a reduced growth

document any significant catch-up growth in

of the ribcage that is associated with

children with TIS after repeated thoracic

respiratory compromise and back and chest

expansion. It is not known whether an age

pain. Up to 50% or 10 cm of the spine

limit exists for possible pulmonary catch-up

length can be lost by spinal fusion before

growth, or whether VEPTR halts the

5 years of age, with a corresponding

progression of scoliosis and thoracic

significant loss of the thoracic volume. At

deformation in children with complex

least 22 cm length of the thoracic spine is

thoracovertebral malformations.

deemed necessary as a prerequisite for

Spinal fusion of AIS rarely leads to improved

satisfactory lung function.

lung function. Rib hump resection is even

In contrast, bilaterally implanted spine-

accompanied by a 15-20% decrease of FVC

based growing rods improve the scoliosis

in the first postoperative months that slowly

and stimulate the growth of the vertebral

recovers to the preoperative level within

column. They have no direct beneficial

2 years. In contrast, in patients with

neuromuscular disease, specifically in those

impact, however, on chest growth and are

with Duchenne muscular dystrophy, timely

therefore standard for treatment for EOS

spinal fusion seems to halve the rate of

without vertebral or costal malformations.

pulmonary function decline.

EOS that is associated with ribcage

malformations tends to progress rapidly and

to end in respiratory failure. The primary

Further reading

goal of therapy is thus to partially correct the

deformation and stabilise the correction,

Campbell RM Jr, et al.

(2003). The

characteristics of thoracic insufficiency

beginning usually at the age of 1.5-2 years.

syndrome associated with fused ribs

Rib-based implants such as the vertical

and congenital scoliosis. J Bone Joint

expandable prosthetic titanium rib (VEPTR)

Surg Am; 85-A: 399-408.

primarily focus on improving the space

Campbell RM Jr, et al. (2007). Thoracic

available for the lungs, thereby allowing lung

insufficiency syndrome and exotic scolio-

expansion and, hopefully, stimulating lung

sis. J Bone Joint Surg Am; 89: S108-S122.

growth. In the near future, new magnetically

Hasler CC, et al. (2010). Efficacy and safety

extensible rods may obviate the need for the

of VEPTR instrumentation for progressive

repeated surgical interventions required to

spine deformities in young children with

expand current VEPTR devices with growth,

rib fusions. Eur Spine J; 19: 400-408.

allowing lengthening of the rods in frequent

ERS Handbook: Paediatric Respiratory Medicine

501

Physiology and

pathophysiology of sleep

Sedat Oktem and Refika Ersu

The two-process model of sleep and

overview of basic sleep physiology and

wakefulness predicts the day-to-day

pathophysiology, and describes the

synchronisation of an organism with its

characteristics of rapid eye movement

environment by the interaction of a circadian

(REM) and non-REM (NREM) sleep. Sleep

(process C) and a homeostatic process

and circadian-generating systems are also

(process S). This section provides an

discussed.

Sleep may be defined as a state of natural

unconsciousness from which a person can

Key points

be aroused. Despite the advances that have

been made in related areas, sleep remains a

The two-process model of sleep and

complicated physiological entity that is not

wakefulness predicts the day-to-day

yet fully understood.

synchronisation of an organism to its

environment by the interaction of a

For many years, sleep was thought to be a

circadian (C) and a homeostatic

purely passive state. However, sleep is an

process (S).

active process and the brain is actually quite

busy during sleep. It is now known to affect

Circadian rhythms are driven by an

both physical and mental health, and is

endogenous circadian pacemaker,

essential for the normal functioning of all

located in the suprachiasmatic

the systems of the body. Since the body is

nucleus (SCN) of the hypothalamus.

known to require sleep as part of its

Circadian sleep rhythm controls the

homeostatic regulatory and repair

sleep-wake cycle, modulates physical

mechanisms, it seems logical that the body

activity and food consumption, and

can exert considerable influence on the

over the course of the day, regulates

sleep process.

body temperature, heart rate, muscle

tone and hormone secretion.

The physiology of sleep and sleep-wake

regulation

The SCN sets the body clock to ,24 h.

The main influence of the SCN on

Sleep is a part of the daily routine for

sleep is due to a series of relays

everyone, even when the ‘‘normal’’ sleep-

through the dorsomedial nucleus of

wake pattern is disrupted by outside factors.

the hypothalamus, which signals to

In humans, the circadian cycle operates in

the sleep-wake systems to coordinate

an ,24-h cycle, measured from awakening

their activity with day-night cycles.

after one sleep period to awakening from the

There are two types of sleep state,

next sleep period.

NREM and REM sleep.

The physiological mechanisms of circadian

NREM sleep is conventionally divided

rhythm begin when light strikes special cells

into three or four stages, each with its

within the retina of the eye, which, in turn,

own distinguishing characteristics.

causes these cells to secrete melatonin,

which causes an area of the brain known as

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the suprachiasmatic nucleus (SCN) to

None of these theories adequately explain all

signal the pineal body to stop secreting the

the facets of sleep as a phenomenon. It is

hormone melatonin, which has been shown

also just as likely that a single theory will

to reach its highest levels during sleep. As

never be proposed that will incorporate the

the day progresses, adenosine accumulates

ever-expanding knowledge base related to

within the brain as the level of melatonin

the physiology and function of sleep.

falls.

The two-process model of sleep and

As night falls, the inhibitory effects of the

wakefulness predicts the day-to-day

retinal secretions on the pineal body are

synchronisation of an organism to its

removed and this allows the pineal to begin

environment by the interaction of processes

secreting melatonin once again. It is the

C and S.

presence of higher melatonin levels within

Process C Most physiological and

certain areas of the brain (e.g. the thalamus

behavioural variables in humans, such as

and hypothalamus) that controls the urge to

heart rate, blood pressure, core body

sleep.

temperature (CBT), hormone levels, food

Body system changes during sleep are listed

consumption, muscle tone, cognitive

in table 1 (NHLBI, 2003; Douglas, 2005).

performance, subjective alertness and the

sleep-wake rhythm, undergo circadian

There have been several theories advanced

rhythms with an ,24-h periodicity.

concerning the biological function of sleep.

Circadian rhythms are driven by an

While no one theory can explain all the

endogenous circadian pacemaker, located in

observations that have been made regarding

the SCN of the hypothalamus. The SCN is

sleep, some are more widely accepted than

the master pacemaker in the mammalian

others.

brain that synchronises the circadian

oscillators of most neuronal cells and

The Restorative Theory of sleep holds that

peripheral tissues. The SCN sets the body

sleep is a time of growth and repair.

clock to ,24 h. Light is the strongest

Some have cited the rise in certain growth

zeitgeber for all species, synchronising the

hormones during periods of deeper sleep

endogenous circadian clock to the 24-h day

as supporting this hypothesis. However,

of the environment. Photobiotic activation is

no one has been able to demonstrate any

transmitted to the SCN via the

significant degradation of organ function

retinohypothalamic tract. When external

during periods of sleep deprivation. This

zeitgebers are absent, the endogenous

theory currently has very little support in

circadian clock ‘‘free-runs’’ with a period

the scientific community.

that is slightly different from 24 h in

The Preservation Theory states that our

humans.

sleep cycles are the result of an

evolutionary process that grew from our

The circadian profile of melatonin secretion

remote ancestors’ habits of resting/

and CBT are reliable physiological ‘‘hands of

sleeping at night, a time when predator

the clock’’ and good markers of the

species enjoyed an advantage in vision

circadian process in humans. Under

and stealth. Over time, the ‘‘sleep when

entrained conditions, the onset of melatonin

it’s dark’’ and ‘‘work in the daylight’’

secretion occurs ,13 h after habitual wake-

behaviors were amplified by natural

up time and CBT crests in the afternoon

selection and are present in the brain’s

with a nadir ,2 h before habitual wake time.

neurochemistry.

Sleep timing and structure are highly

The Memory Encoding explanation draws

dependent on circadian phase. It has been

upon the large body of evidence

shown that the circadian drive for sleep is

demonstrating that learning is facilitated

highest in the early morning, whereas the

when the body is well rested and that

circadian drive for wakefulness is highest in

memory retention is enhanced by resting

the late evening, shortly before bedtime. The

after some new lesson is learned.

paradoxical character of these two extremes

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Table 1. Physiological changes during sleep

Sleep

Physiological changes

periods

Cardiovascular

NREM

Overall reduction in heart rate, cardiac output and blood

system

pressure

REM

Variations in blood pressure and heart rate but, overall, the

rates are increased

Respiratory system

NREM

Slight hypoventilation

REM

Slight hypercapnia

Reduction in total ventilation

Reduction in sensitivity to inspired carbon dioxide

Reduction in tidal volume

Increase in respiratory rate

Reduction in rib cage movement

Increase in upper airway resistance

Nervous system

NREM

Overall, decreased discharge rate, brain metabolism and blood

flow

Active inhibition of the reticular activating system

Increase in parasympathetic activity similar to relaxed

wakefulness

Sympathetic drives remain at about the same level as during

relaxed wakefulness

REM

Total blood flow and metabolism in REM sleep are comparable

to wakefulness

Metabolism and blood flow increase in certain brain regions

during REM sleep compared to wakefulness, e.g. limbic system,

visual association areas

During tonic REM sleep, sympathetic activity decreases,

resulting in an overall predominance of parasympathetic activity

During phasic REM sleep, both sympathetic and

parasympathetic activity increase

Sympathetic activation is generally favored

Endocrine system

Stage 3 sleep is associated with increased secretion of growth

hormone, thyroid hormone, melatonin and prolactin

Sleep onset inhibits the release of cortisol

Gastrointestinal tract

Motility and gastric acid secretion decrease during sleep

Swallowing reflex slows down during sleep.

Kidney

Decrease in excretion of Na⁺, K⁺, Cl^- and Ca2+ during sleep that

allows for more concentrated and reduced urine flow

Secretion of aldosterone increases, as does ADH, both of which

contribute to the decreased production of urine

Decrease in glomerular filtration rate and renal plasma flow

Thermoregulation

At sleep onset, body temperature set point is lowered and body

temperature falls

ADH: antidiuretic hormone.

of the circadian system can be explained by

homeostatic sleep pressure increases, a

the interaction of process S with process C.

stronger wake-promoting signal is needed in

In the course of a normal 16-h day, when

the evening than in the morning, when sleep

ERS Handbook: Paediatric Respiratory Medicine

505

pressure is low, to counteract upcoming

pathways. The first pathway, which

physiological and behavioural decrements.

originates from cholinergic neurons in the

In contrast, throughout the night-time sleep

upper pons, activates parts of the thalamus

episode, when homeostatic sleep pressure

that are responsible for maintaining the

dissipates, a circadian sleep-promoting

transmission of sensory information to the

signal is necessary to prevent premature

cerebral cortex (Saper et al., 2005). The

waking and to maintain sleep. This concept

second pathway, which originates in cell

is drawn from studies with nonhuman

groups in the upper brainstem that contain

primates and indicates that one function of

the monoamine neurotransmitters

the circadian system is to provide an alerting

(norepinephrine, serotonin, etc.), enters the

stimulus, which opposes the accumulating

hypothalamus, rather than the thalamus,

homeostatic sleep drive during waking

where it picks up inputs from nerve cells

hours. Besides the circadian, there are also

that contain peptides (orexin or hypocretin

.24-h and ,24-h processes, which oscillate

and melanin-concentrating hormone).

in or out of phase with the endogenous

These inputs then traverse the basal

circadian pacemaker and have additional

forebrain, where they pick up additional

modulatory influences on sleep-wake

inputs from cells containing acetylcholine

rhythms in humans (Dijk et al., 1995).

and c-aminobutyric acid (GABA).

Ultimately, all of these inputs enter the

Process S Process S was originally assumed

cerebral cortex, where they diffusely activate

to be global, and its parameters were mainly

the nerve cells, and prepare them for the

gleaned from central or fronto-central

interpretation and analysis of incoming

derivations. The general view is that the

sensory information.

amount of sleep pressure accumulated

during wake time is reflected in the amount

Arousal from sleep could be an important

of slow-wave sleep (SWS) that occurs during

defence mechanism against potentially

the following period of sleep. Process S

dangerous situations during sleep. Such

depends on prior sleep and wakefulness,

situations include severe obstructive

and reflects the need for or pressure of

apnoea, oesophageal reflux, cardiac rhythm

sleep. Sleep pressure rises during waking,

abnormalities and external suffocation.

declines during sleep and increases with

Arousal from sleep that is triggered by

sleep deprivation. The build-up or

abnormal levels of carbon dioxide and

dissipation of sleep pressure is usually

oxygen is essential for the initiation of

represented by an exponential function.

protective airway responses; indeed, head

Slow-wave activity serves as a marker for

turning and escape to fresh air are critical

sleep homeostasis and, thus, for modelling

for survival from an asphyxial

of process S. Slow-wave activity shows a

microenvironment. Arousal involves a

decline in the course of sleep that can be

progressive activation of specific

approximated by an exponential decrease

subcortical-to-cortical brain structures, and

across NREM sleep episodes (Achermann et

consists of ascending and descending

al., 2011). The level of slow-wave activity in

components that mediate cortical and

the first NREM sleep episode is dependent

subcortical arousal, respectively, with

on the duration of prior waking and is best

feedback loops between them. Cortical

described with a saturating exponential

arousal involves noradrenergic,

function.

serotonergic, dopaminergic, cholinergic and

histaminergic neurons in the brain stem,

The central nervous system regulation of

basal forebrain and hypothalamus, which

sleep

excite the cerebral cortex and cause cortical

Wakefulness and arousal from sleep Waking

activation. Subcortical arousal, however, is

and consciousness depend on the activity

mediated mainly by brain-stem pathways

of neurons in the ascending reticular

that increase heart rate, blood pressure,

activating system of the brainstem.

respiration and postural tone without

Specifically, there are two ascending

changes in cortical activity.

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ERS Handbook: Paediatric Respiratory Medicine

NREM and REM sleep The transition

catecholamines, acetylcholine, histamine,

between wakefulness and sleep occurs

glutamate and aspartate, that are localised

through a process of reciprocal inhibition

within the reticular formation and have

between arousal- and sleep-promoting

important roles in cortical activation and

neurons by way of a ‘‘flip-flop’’ switch.

arousal.

The ‘‘switch’’ for sleep is considered to be

NREM sleep The thalamus, dorsal raphe,

the ventrolateral pre-optic nucleus (VLPO)

nucleus tractus solitarius, anterior

of the anterior hypothalamus. This area

hypothalamus and adjacent forebrain areas

becomes active during sleep and uses the

are important in producing NREM sleep.

inhibitory neurotransmitters GABA and

Neurotransmitters such as serotonin and

galanin to initiate sleep by inhibiting the

GABA, which may be important in sleep

arousal regions of the brain. The VLPO

mechanisms, are located in these brain

innervates and can inhibit the wake-

regions and play an important role in sleep.

promoting regions of the brain including the

Serotonin (5-hydroxytryptamine), found in

tuberomammillary nucleus, lateral

raphe neurons of the brainstem, may be

hypothalamus, locus coeruleus, dorsal

involved in sleep onset. Insomnia occurs

raphe, laterodorsal tegmental nucleus and

when serotonergic cells of the dorsal raphe

pedunculopontine tegmental nucleus. The

are lesioned. In addition, there is evidence

hypocretin (orexin) neurons in the lateral

that substances in the biosynthetic pathway

hypothalamus help stabilise this switch.

of serotonin (such as tryptophan and

REM sleep occurs with activation of

vitamin B₆) may facilitate sleep (Jones,

cholinergic neurons in the laterodorsal and

1989). However, in spite of all the evidence

pedunculopontine tegmental nuclei. This

supporting the role of serotonin in sleep

cholinergic activation occurs when

onset, there are studies that suggest that the

withdrawal of the aminergic arousal systems

role of serotonin in sleep is not clear.

(noradrenergic neurons in the locus

coeruleus and serotonergic neurons in the

The inhibitory neurotransmitter GABA is

dorsal raphe nuclei) produces disinhibition.

released in its highest concentrations during

This causes the release of acetylcholine,

NREM sleep. GABAergic neurons are

which triggers the increased neural activity

located throughout the brain, including the

that is a feature of REM sleep. Suppression

basal forebrain, hypothalamus, thalamus,

of motor activity, the other marker of REM

brainstem and cortex. Hypnotics, such as

sleep, is generated by glutamate-mediated

benzodiazepines and barbiturates, tend to

activation of descending medullary reticular

work by potentiating GABA-mediated

formation relay neurons. The activity of

inhibitory processes. They may shut off

these neurons is inhibitory to spinal motor

neurons in the reticular activating system

neurons via the release of glycine, and to a

and inhibit transmission and activity of

lesser extent, GABA.

neurons that project to the cortex and

thalamus.

Neurochemistry of sleep Sleep results from

the complex interaction of multiple

Overall, hypnotics increase total sleep time,

neurotransmitter systems, as well as the

decrease sleep latency, decrease the number

influence of other physiological or

of awakenings, decrease the amount of time

psychological states.

spent in NREM sleep stage 3 and, in some

cases, REM sleep.

Wakefulness Waking and consciousness

depend on the activity of neurons in the

REM sleep Acetylcholine is located within

ascending reticular activating system of the

neurons in the pontine tegmentum and is

brainstem. These neurons project into the

involved in REM sleep generation. ‘‘REM-

thalamus, hypothalamus and basal

on’’ cells are cholinergic cells in the lateral

forebrain, and eventually send projections to

pontine and medial medullary reticular areas

the cortex. There are particular

that innervate the thalamus, hippocampus

neurotransmitters, such as the

and hypothalamus. These cells discharge at

ERS Handbook: Paediatric Respiratory Medicine

507

high rates during REM and show little or no

standard of 1968. The American Academy of

activity during NREM. Physostigmine, which

Sleep Medicine (AASM) has discontinued

inhibits catabolic enzymes, precipitates the

the use of stage 4, such that the previous

appearance of REM sleep during NREM. The

stages 3 and 4 now are combined as stage 3.

injection of carbachol, a muscarinic agonist,

Slow wave sleep usually lasts between 70

into the pontine tegmentum induces REM

and 90 min in normal individuals. REM

sleep. Blocking muscarinic receptors will

sleep in the first cycle of the night is usually

retard the appearance of REM sleep.

short-lived (1-5 min). Stage 3 sleep occupies

less time in the second cycle, and might

‘‘REM-off’’ cells are noradrenergic and

disappear altogether from later cycles, as

serotonergic cells found in the locus

stage 2 sleep expands to occupy the NREM

coeruleus and raphe. These cells are slow or

portion of the cycle. The NREM-REM cycles

silent during REM sleep. Affecting levels of

vary in length from 70-100 min initially to

noradrenaline or serotonin can have an

90-120 min later in the night. Across the

effect on REM sleep. In general,

night, the average period of the NREM-REM

antidepressants have the effect of

cycle is approximately 90-110 min

decreasing REM sleep, which is elevated in

(Carskadon et al., 2011).

human endogenous depression.

The three stages of NREM sleep are each

Sleep architecture

associated with distinct brain activity and

Stages of sleep Sleep is staged in 30-s

physiology. As one progresses through

epochs. Sleep begins in NREM and

stages 1-3, sleep gets deeper and waves

progresses through deeper NREM stages

become more synchronised.

(stages 1-3), before the first episode of REM

Stage 1 sleep is a very light stage of sleep with

sleep occurs approximately 80-100 min

a low arousal threshold. Aside from

later. Thereafter, NREM sleep and REM

newborns and those with narcolepsy and

sleep cycle with a period of ,90 min. NREM

other specific neurological disorders, the

and REM sleep alternate cyclically. The

average individual’s sleep episode begins in

function of alternations between these two

NREM stage 1. It generally lasts for ,10 min,

types of sleep states is not yet understood,

constituting 2-5% of total sleep, and is

but irregular cycling and/or absent sleep

easily interrupted by a disruptive noise.

stages are associated with sleep disorders.

Electroencephalography (EEG) is

NREM and REM sleep cycles NREM sleep

characterised by low-voltage, mixed-

constitutes about 75-80% of the total time

frequency activity (4-7 Hz). Stage 1 is scored

spent asleep and REM sleep constitutes the

when ,50% of an epoch contains a-waves

remaining 20-25%. REM sleep follows

and the criteria for deeper stages of sleep

NREM sleep and occurs four or five times

are not met. a-waves are associated with a

during a normal 8-h sleep period. The first

wakeful relaxation state and are

REM period of the night may be ,10 min in

characterised by a frequency of 8-13 Hz.

duration, while the last may exceed 60 min.

Well-developed a-wave activity is present in

The NREM-REM cycles vary in length from

most normal children by 8 years of age

70-100 min initially to 90-120 min later in

(fig. 1). Slow rolling eye movements are

the night.

often present in the tracings, and the level of

muscle tone is equal or diminished

The first cycle of sleep in the normal young

compared to that in the awake state. Vertex

adult begins with stage 1 sleep, which

waves are common in stage 1 sleep and are

usually persists for only 1-7 min at the onset

defined by a sharp configuration with a

of sleep. Stage 2 NREM sleep follows this

maximum over the central derivations

brief episode of stage 1 sleep and continues

(fig. 2).

for approximately 10-25 min. Slow-wave

sleep (SWS), often referred to as deep sleep,

Stage 2 sleep lasts approximately 10-25 min

consists of stages 3 and 4 of NREM sleep,

in the initial cycle and lengthens with each

according to the Rechtschaffen and Kales

successive cycle, eventually constituting

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ERS Handbook: Paediatric Respiratory Medicine

Left EOG

Right EOG

~.C3M2

~.C4M1

~.O1M2

~.O2M1

~.F3M2

~.F4M1

Chin EMG

Stage W

W W W W W W W W W W W W W W W W W W W W W W W W W W

Time s

Figure 1. 30-s epoch of wakefulness. During eyes-open wake, the EEG is characterised by high-frequency,

low-voltage activity. Electro-oculography (EOG) shows REM and the chin EMG activity is relatively high.

During eyes-closed wake, the EEG is characterised by prominent a-wave activity. The amplitude of the

channels is 70 mV. W: wake.

between 45% and 55% of the total sleep

with durations of 0.5-1.5 s. The K-complex is

episode. An individual in stage 2 sleep

a high-amplitude, biphasic wave of o0.5 s

requires more intense stimuli than in stage 1

duration. A K-complex consists of an initial

to awaken. The EEG during stage 2 sleep

sharp, negative voltage (by convention, an

shows relatively low-voltage, mixed-

upward deflection) followed by a positive

frequency activity characterised by the

deflection (down) slow wave. Spindles are

presence of sleep spindles and K-complexes.

frequently superimposed on K-complexes

Sleep spindles are oscillations of 12-14 Hz

(fig. 3).

Left EOG

Right EOG

~C3M2

~C4M1

~O1M2

~O2M1

~.F3M2

~.F4M1

Chin EMG

107

Time s

Figure 2. 30-s epoch of stage 1 sleep. EEG is characterised by low-voltage, mixed-frequency activity. Slow

rolling eye movements often are present. Vertex waves are common in stage 1 sleep (arrow). The

amplitude of the channels is 70 mM. EOG: electro-oculogram.

ERS Handbook: Paediatric Respiratory Medicine

509

Left EOG

Right EOG

~C3M2

~C4M1

~O1M2

~O2M1

~F3M2

~F4M1

Chin EMG

315

Time s

Figure 3. 30-s epoch of stage 2 sleep. Stage 2 sleep is characterised by the presence of one or more K-

complexes (arrow) or sleep spindles (arrowheads). The amplitude of the channels is 70 mM. EOG: electro-

oculogram.

During stage 3 sleep (SWS), the EEG is

arousal threshold, especially in children

synchronised. Stage 3 lasts approximately

(fig. 4).

20-40 min in the first cycle and makes up

about 14-32% of sleep. This stage is

REM sleep is defined by the presence of

characterised by increased amounts of high-

desynchronised (low-voltage, mixed-

voltage, slow-wave activity on the EEG.

frequency) brain wave activity, muscle

d-wave (slow wave) activity is defined as

atonia and bursts of REMs. ‘‘Sawtooth’’

waves slower than 2 Hz (.0.5 s duration)

wave forms, h-wave activity (3-7 Hz) and

with a peak-to-peak amplitude .75 mV.

slow a-wave activity also characterise REM

During SWS, we see the highest auditory

sleep. During the initial cycle, the REM

Left EOG

Right EOG

~C3M2

~C4M1

~O1M2

~O2M1

~F3M2

~F4M1

Chin EMG

208

Time s

Figure 4. 30-s epoch of stage 3 sleep. Stage 3 NREM sleep is called slow-wave, d-wave or deep sleep. Stage

3 is scored when slow-wave activity (frequency ,2 Hz and amplitude .75 mV peak to peak) is present for

.20% of the epoch. The amplitude of the channels is 70 mM. EOG: electro-oculogram.

510

ERS Handbook: Paediatric Respiratory Medicine

period may last only 1-5 min; however, it

the total sleep duration in a day can be 14-

becomes progressively prolonged as the

16 h. Over the first several months of life,

sleep episode progresses. REM sleep

sleep time decreases; by age 5-6 months,

generally makes up 20-25% of total sleep

sleep consolidates into an overnight period

time in adults. In infants, REM sleep may

with at least one nap during the day. Total

account for up to 50% of sleep. REM sleep

sleep time continues to decrease during

consists of tonic and phasic characteristics.

childhood as nap duration and frequency

Tonic characteristics are persistent

decrease.

throughout the entire REM sleep period,

In newborns, sleep can be categorised into

while phasic characteristics appear

two main patterns, active sleep (REM

intermittently during the REM sleep period.

precursor), and quiet sleep (NREM

Tonic characteristics include a

precursor), but a proportion of sleep time is

desynchronised EEG, muscle atonia and a

not attributable to either of these patterns

lack of thermoregulation. Phasic

and is accordingly classed as indeterminate.

characteristics include REMs, clitoral and

Non-EEG correlates are very helpful in

penile tumescence, and dreams (fig. 5).

recognising NREM and REM sleep in infants

Typically, stage 3 sleep is present more in

6 months post-term or younger. These

the first third of the night, whereas REM

correlates in REM sleep include the

sleep predominates in the last third of the

presence of irregular respiration, chin

night. This can be clinically helpful, as

electromyogram (EMG) atonia and REMs.

NREM parasomnias such as sleep walking

In NREM sleep, correlates include regular

typically occur in the first third of the night

respiration, no or rare vertical eye

with the presence of stage 3 sleep. This

movements and preserved chin EMG tone.

contrasts with REM sleep behaviour

REM sleep in infants represents a larger

disorder, which typically occurs in the last

percentage of the total sleep (newborn to

half of the night. There are numerous

3 months, 50%; by 3-5 months, 40%; by the

physiological differences between NREM

end of the first year, 30% of total sleep

and REM sleep (table 1).

time). After 3 months, NREM sleep begins to

dominate. The percentage of REM sleep is

Important developmental changes occur in

reduced to adult levels by 10 years of age.

sleep over an individual’s lifetime. In newborns,

Until the age of 3 months, newborns

Left EOG

Right EOG

~C3M2

~C4M1

~O1M2

~O2M1

~F3M2

~F4M1

Chin EMG

623

Time s

Figure 5. 30-s epoch of REM sleep. REM sleep is characterised by a low-voltage, mixed-frequency EEG, the

presence of episodic REMs, and a relatively low-amplitude chin EMG. ‘‘Sawtooth’’ waves also may occur

in the EEG. The amplitude of the channels is 70 mM. EOG: electro-oculogram.

ERS Handbook: Paediatric Respiratory Medicine

511

transition from wake into REM sleep.

morning after sleep restriction. In addition,

However, sleep-onset REM may continue up

children do not show recovery rebound of

to ,6 months of age. Thereafter, sleep

SWS and REM sleep similar to that reported

starts with NREM sleep. At 3 months of age,

for adults. Children seem to require more

clear differentiation of NREM sleep states by

time to recuperate fully from nocturnal sleep

EEG criteria is quite difficult. By 6 months,

restriction than adults. The effect of sleep

NREM sleep can typically be differentiated

restriction on daytime sleepiness,

into three distinct states (stages 1 and 2,

performance of children in school and

and SWS) (Anders et al., 1995).

behaviour is prominent.

Effects of sleep deprivation

Sleep disorders

As the function of sleep has not been fully

A sleep disorder is loosely defined as any

determined, the absolute number of hours

condition or process that alters the patient’s

necessary to fulfil its function is still

previously established sleep-wake cycle.

unknown. Some individuals claim full

Sleep disorders are divided into two general

effectiveness with only 3-5 h of sleep per

classes: dyssomnias and parasomnias.

night, while others claim to need o8 h of

Dyssomnias are conditions that manifest

sleep per night to perform effectively. Sleep

themselves as either hypersomnia

deprivation is a relative concept. Small

(abnormal sleep cycles causing the urge to

amounts of sleep loss (e.g. 1 h per night over

sleep at times when the circadian cycle

many nights) have subtle cognitive costs,

would suggest that wakefulness was

which appear to go unrecognised by the

appropriate) or insomnia (the inability to

individual experiencing the sleep loss. More

sleep). The dyssomnias can be further

severe restriction of sleep for a week leads to

subdivided into three classes that are

profound cognitive deficits similar to those

dependent on the source of the sleep

seen in some stroke patients. Glucose

interference.

positron emission tomography (PET)

studies in individuals deprived of sleep have

N Intrinsic (arising within the body):

shown that after 24 h of sustained

primary insomnia, OSA, restless leg

wakefulness, the metabolic activity of the

disorder and unspecified limb

brain decreases significantly. In humans,

movements.

sleep deprivation also results in a decrease

N Extrinsic (arising outside the body):

in core body temperature, a decrease in

environmental conditions not conducive

immune system function as measured by

to uninterrupted sleep, such as noise or

white blood cell count and activity, and a

ambient temperature.

decrease in the release of growth hormone.

N Alteration or interference with the

Sleep deprivation has also been implicated

circadian rhythm: jet lag or variations in

as a cause of increased heart rate variability

occupational schedules (shift work).

(Banks et al., 2007).

Parasomnias include sleep terror (sudden

Short-term sleep deprivation has been

awakening and unreasonable fear),

implicated in contributing to obesity as well

bedwetting, somnambulism (sleep walking)

as glucose dysregulation contributing to

and somniloquy (talking in one’s sleep)

poor control of type II diabetes.

(American Academy of Sleep Medicine,

2005).

Children differ from adults in their response

to acute restriction in sleep. When sleep has

This AASM classifies sleep disorders into

been restricted by o4 h, there is a decrease

eight major categories:

in all stages of sleep (except SWS), a

reduction in sleep onset latency, stage 3

insomnia,

latency and REM latency. Multiple sleep

sleep-related breathing disorders,

latency tests show a significant increase in

hypersomnias of central origin,

daytime sleepiness, which persists into the

circadian rhythm sleep disorders,

512

ERS Handbook: Paediatric Respiratory Medicine

parasomnias,

Achermann P, et al. Sleep homeostasis

sleep-related movement disorders,

and models of sleep regulation. In: Kryger

isolated symptoms and normal

MH, et al., eds. Principles and Practice of

variants,

Sleep Medicine.

5th Edn. Philadelphia,

other sleep disorders.

Elsevier Saunders, 2011; pp. 431-444.

Carskadon M, et al. Normal human sleep:

Conclusion

an overview. In: Kryger MH, et al., eds.

Principles and Practice of Sleep Medicine.

Humans spend about one-third of their lives

4th Edn. Philadelphia, Elsevier Saunders,

asleep, yet most individuals know little

2005; pp. 13-23.

about sleep. Although its function remains

Dijk DJ, et al. (1995). Contribution of the

to be fully elucidated, sleep is a universal

circadian pacemaker and the

sleep

need of all higher life forms including

homeostat to sleep propensity, sleep

humans, absence of which has serious

structure, electroencephalographic slow

physiological consequences. Sleep is divided

waves, and sleep spindle activity in

into two periods: NREM sleep and REM

humans. J Neurosci; 15: 3526-3538.

sleep. NREM sleep is conventionally divided

Dijk DJ, et al.

(2002). Integration of

into three or four stages, each with its own

human sleep-wake regulation and circa-

distinguishing characteristics. Sleep begins

dian rhythmicity. J Appl Physiol; 92: 852-

in NREM and progresses through deeper

862.

NREM stages (stages 1-3) before the first

Douglas NJ. Respiratory physiology: con-

episode of REM sleep occurs approximately

trol of ventilation. In: Kryger MH, et al.,

eds. Principles and Practice of Sleep

80-100 min later. Thereafter, NREM sleep

Medicine. 4th Edn. Philadelphia, Elsevier

and REM sleep cycle with a period of

Saunders, 2005; pp. 224-229.

,90 min. NREM and REM sleep alternate

Iber C, et al. The AASM Manual for the

cyclically. The function of alternations

Scoring of Sleep and Associated Events:

between these two types of sleep states is

Rules, Terminology and Technical

not yet understood but irregular cycling and/

Specifications. Westchester, American

or absent sleep stages are associated with

Academy of Sleep Medicine, 2007.

sleep disorders.

Jones BE. Basic mechanisms of sleep-

wake states. In: Kryger MH, et al., eds.

Principles and Practice of Sleep Medicine.

Further reading

4th Edn. Philadelphia, Saunders,

2005;

American Academy of Sleep Medicine.

pp. 136-153.

International Classification of Sleep

National Heart, Lung and Blood Institute.

Disorders: Diagnostic and Coding

Sleep, Sleep Disorders, and Biological

Manual. 2nd Edn. Westchester, American

Rhythms: NIH Curriculum Supplement

Academy of Sleep Medicine, 2005.

Series, Grades 9-12. Colorado Springs,

Anders TF, et al. Normal sleep in

Biological Sciences Curriculum Study,

neonates and children. In: Ferber RKM,

2003.

ed. Principles and Practice of Sleep

Vitaterna M, et al. Molecular genetic

Medicine in the Child. Philadelphia,

basis for mammalian circadian rhythms.

Saunders, 1995; pp. 7-18.

In: Kryger MH, et al., eds. Principles and

Banks S, et al.

(2007). Behavioral and

Practice of Sleep Medicine.

4th Edn.

physiological consequences of sleep

Philadelphia, Elsevier Saunders,

2005;

restriction. J Clin Sleep Med; 3: 519-528.

pp. 363-374.

ERS Handbook: Paediatric Respiratory Medicine

513

OSAS and upper airway

resistance syndrome

Maria Pia Villa and Silvia Miano

OSAS in children is defined as a disorder of

breathing during sleep characterised by

Key points

prolonged partial upper airway obstruction

and/or intermittent complete obstruction

N OSAS in children is a complex, multi-

(obstructive apnoea), which disrupts normal

organ syndrome consisting of

ventilation during sleep and normal sleep

habitual snoring, witnessed apnoea,

patterns. Prevalence ranges from 1.2% to

sleep fragmentations and diurnal

5.7%. Although no specific genes have been

consequences.

identified for OSAS to date, it has become

N The most frequent cause is adeno-

apparent that OSAS is probably a polygenic

tonsillar hypertrophy and treatment

disease. Specific genes impacting on factors

involves adeno-tonsillectomy;

such as oral mucosa thickness and facial

however, many children do not

structure may play a deterministic role in

resolve and need further therapy, such

OSAS.

as orthodontic therapy.

Diagnosis

Signs and symptoms Paediatric OSAS is

Other rare conditions include foreign body

accompanied by habitual snoring

aspiration, vascular haemangioma or other

(o3 nights?week^-1) and major nocturnal and

tumours.

diurnal symptoms and signs (table 1). Other

conditions that may be associated with OSA

One of the mechanisms implicated in the

are:

pathogenesis of OSAS is increased

collapsibility of the upper airway during

N allergic rhinitis,

sleep, because the activity of the upper

N asthma,

airway dilator muscles is not enough to

N Down syndrome,

compensate for an anatomically small upper

N nasoseptal obstruction,

airway. Children with OSAS often have

N cleft palate repair and velopharyngeal

significantly large adenoids and tonsils,

flap,

causing the upper airway to collapse.

N craniofacial syndromes (Treacher-

However, enlarged adeno-tonsillar tissues

Collins, midfacial hypoplasia, Crouzon

may not always lead to OSAS. A complex

syndrome, Apert syndrome, Pierre Robin

interaction between the anatomical

sequence, etc.),

component and other elements, such as

N achondroplasia,

upper airway tone, respiratory drive, etc., has

N mucopolysaccharidoses,

been postulated. Several anatomical and

N macroglossia,

functional mechanisms may lead to OSAS in

N sickle-cell disease,

children and in adults, one being a smaller

N myelomeningocele,

upper airway, which predisposes subjects to

N cerebral palsy,

airway collapse during sleep in all age

N prematurity,

groups. Orthodontic and craniofacial

N neuromuscular disorders.

abnormalities associated with OSAS are,

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Major signs, symptoms and other conditions accompanying paediatric OSAS

Symptoms

Signs

Other conditions

Laboured breathing during sleep Underweight or overweight African-American

Gasps/observed episodes of

Tonsillar hypertrophy

Allergic rhinitis

apnoea

Sleep enuresis

Adenoidal facies

Asthma

Sleeping in a seated position or

Micrognathia

Prematurity

with the neck hyperextended

Cyanosis

Retrognathia

Neurological conditions

(cerebral palsy or

neuromuscular diseases)

Headaches on awakening

High-arched palate

Craniofacial syndromes

Daytime sleepiness

Failure to thrive

Down syndrome

Attention deficit/hyperactivity

Hypertension

Rare diseases such as

disorder and or learning

achondroplasia or

problems

mucopolysaccharidoses

Data from Marcus et al. (2012) and Bhattacharjee et al. (2009).

despite their impact on public health, widely

low-grade inflammatory condition. The

ignored. A narrow upper airway with

induction of systemic inflammatory

maxillary constriction and/or some degree of

responses is most likely related to the

mandibular retrusion is a common

generation of systemic oxidative stress

paediatric phenotype of OSAS. In such

secondary to the recurrent hypoxic

cases, children are typically described as

and arousal episodes that characterise

having a narrow, long face, they may have

OSAS.

retrognathic mandibles and increased

posterior facial height associated (or not)

Failure to thrive was extremely frequent and

with severe tonsillar hypertrophy. Whether

attributed to increased metabolic

this skeletal conformation is genetically

expenditure caused by the elevated work of

determined or influenced by the early onset

breathing during sleep, reduced nutrient

of habitual snoring has yet to be assessed.

intake due to tonsillar hypertrophy and,

Another common abnormality in patients

most likely, to disrupted growth hormone-

with OSAS is a high arched (ogival) palate,

insulin growth factor pathways in the

which results in posterior tongue

presence of recurrent hypoxaemia and

displacement forcing the lateral palatine

disturbed sleep patterns. In more recent

processes to expand over the abnormally

years, however, obesity has emerged as a

placed tongue.

frequent finding and it is likely to amplify the

morbidities of OSAS and obesity alone. The

Comorbidities Paediatric OSAS is associated

concomitant presence of OSAS in obese

with a multitude of end-organ morbidities,

children further amplifies the risk for lipid

such as daytime sleepiness, neurocognitive

disturbances and reveals the presence of an

impairment, behavioural problems, failure

interaction between adiposity and insulin

to thrive, hypertension, cardiac dysfunction

resistance. Adipokines, including leptin, are

and systemic inflammation.

cytokines released from adipose tissue that

In recent years, research from many

are important in the regulation of appetite,

paediatric sleep centres has accumulated

metabolic homeostasis, sleep and

substantial evidence suggesting that

respiratory control. A recent study reported

paediatric OSAS constitutes a systemic

on the elevation of circulating leptin levels in

ERS Handbook: Paediatric Respiratory Medicine

515

children with OSAS, independent of the

that have evaluated autonomic dysfunction

degree of obesity.

reported an increase in diastolic blood

pressure, both during wakefulness and

The exact prevalence of excessive daytime

sleep, as well as an increase in sympathetic

sleepiness (EDS) in paediatric OSAS is

activity demonstrated by peripheral arterial

unclear and, when objective measurements

tonometry and catecholamine concentration

on sleep propensity are used (i.e. multiple

measurements in plasma and urine. An

sleep latency test), the prevalence of EDS in

increase in basal sympathetic activity during

paediatric OSAS ranged from 13% to 20%.

wakefulness has been demonstrated in

Furthermore, the presence of obesity

patients with OSAS. In children with OSAS,

appeared to increase the likelihood of EDS.

an increase in the baseline systolic and

diastolic blood pressure and heart rate has

It is estimated that 30% of all children with

been observed, whereas the autonomic

frequent and loud snoring will manifest

cardiovascular tests revealed a greater

significant hyperactivity and inattention

variability of blood pressures during the

(attention deficit-hyperactivity disorder

supine-to-orthostatic posture change, as

(ADHD)), and learning problems. Moreover,

well as less heart rate variability during deep

children with OSAS have a lower global

breathing. Cardiovascular diseases reported

intelligence compared to controls, with

in patients with moderate-to-severe OSAS

positive correlations between sleep

also include pulmonary hypertension with

fragmentations and global intelligence and

cor pulmonale, left ventricular (LV)

ADHD scores, while a positive correlation

hypertrophy or dysfunction, cardiac

was found between ADHD scores and oxygen

arrhythmias, atherosclerosis and coronary

saturation during the night. This study

artery disease. A common

indicated that arousal is a protective

pathophysiological aspect of these

mechanism to preserve cognitive function by

alterations is the presence of a condition of

counteracting the respiratory events, at the

oxidative stress and increased reactive

expense of sleep maintenance. A study

oxygen species generation, which directly or

previously reported a high prevalence of

indirectly promotes the development and

paroxysmal activity in a population of

progression of LV dysfunction or

children with OSAS (14.3% of the sample

hypertrophy and vascular remodelling.

investigated). Interictal epileptiform

Oxidative stress and asymptomatic

discharges (IEDs) mostly occurred over the

(subclinical) proinflammatory state, as

centro-temporal regions, suggesting some

demonstrated by the higher serum levels of

similarities with IEDs of benign epilepsy with

high-sensitivity C-reactive protein (hsCRP),

central temporal spikes. Since the occurrence

have been observed in adults and children

of IEDs during sleep may disrupt cognitive

with OSAS and have been interpreted as

abilities and impair learning and memory in

pathogenetic factors that promote cardiac

children, the findings may represent a new

remodelling and LV structural and

possibility to explain the neurocognitive

functional adaptations in these patients. The

dysfunction in children with OSAS.

presence of both left and right ventricular

Of particular interest are the cardiovascular

hypertrophies, as well as diastolic

complications that may develop in children

abnormalities, detected by means of

with OSAS, since they may have not only an

conventional Doppler examination of LV

immediately significant impact on

filling patterns, in children with severe

cardiovascular health during childhood, but

OSAS, hypertension or obesity have been

may also affect cardiovascular outcomes

demonstrated. A two-dimensional colour

during adult life. Studies in children with

Doppler cardiac examination with LV mass

OSAS have reported increased blood

assessment and systolic and diastolic

pressure, changes in cardiac structure and

function evaluation revealed that LV

function, increased fasting insulin and lipid

diastolic dysfunction was significantly more

levels, and endothelial dysfunction as signs

frequent in patients with severe OSAS,

of cardiovascular damage. The few studies

associated with higher hsCRP levels.

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ERS Handbook: Paediatric Respiratory Medicine

Sleep polysomnography analysis The

airflow signal amplitude compared with the

American Academy of Pediatrics

pre-event baseline amplitude for at least

recommends that if a child or adolescent

90% of the duration of the event; the event

snores on a regular basis and has any of the

had to last at least two missed breaths and

major symptoms then clinicians should

be associated with an arousal, awakening or

obtain a polysomnograph (PSG). Although

a .3% desaturation (fig. 1). The AHI is

history and physical examination are useful

defined as the average number of apnoeas,

to screen patients and determine which

hypopneas and respiratory event-related

patients need further investigation for

arousals per hour of sleep. The diagnosis is

OSAS, the sensitivity and specificity of the

defined by an obstructive AHI .1 event?h^-1.

history and physical examination are poor.

As part of the OSAS spectrum of severity,

Recently, a simple Sleep Clinical Record

upper airway resistance syndrome and

based on physical examination, subjective

another PSG feature of obstructive alveolar

symptoms and clinical history has been

hypoventilation constitute mild forms of

validated. In children with a score less than

OSAS, characterised by an increased

6.5 PSG is not performed.

number of arousals that can be attributed to

increased respiratory effort (upper airway

However, the gold standard test remains

resistance syndrome) and increased end-

overnight, attended, in-laboratory PSG

tidal carbon dioxide levels during sleep.

(sleep study). This is a noninvasive test

involving the measurement of a number of

If PSG is not available, then clinicians may

physiological functions overnight, typically

perform alternative diagnostic tests, such as

including electroencephalography (EEG),

nocturnal video recording, nocturnal

pulse oximetry, oronasal airflow, abdominal

oximetry, daytime nap PSG or ambulatory

and chest wall movements, partial pressure

PSG, although they have weaker positive-

of carbon dioxide, oxygen saturation and

and negative-predictive values than PSG. If

video recording. Specific paediatric

an alternative test fails to demonstrate

measuring and scoring criteria should be

OSAS in a patient with signs and symptoms,

used. Central, obstructive and mixed apnoea

a full PSG should be performed with

events were counted according to the

extended EEG montage in order to exclude

criteria established by the American

the presence of IEDs.

Academy of Sleep Medicine (AASM).

Obstructive apnoea was scored when there

Treatment

was a .90% drop in the signal amplitude of

Adeno-tonsillectomy is recommended when

airflow for .90% of the entire event,

a child with OSAS has a clinical examination

compared with the pre-event baseline

consistent with adeno-tonsillar hypertrophy

amplitude with continued chest wall and

and does not have a contraindication to

abdominal movement for a duration of at

surgery. Clinical judgment is required to

least two breaths. Central apnoea was

determine the benefits of adeno-

defined as the absence of airflow, with the

tonsillectomy compared with other

cessation of respiratory effort, lasting .20 s

treatments in obese children with varying

or at least two missed breaths (or the

degrees of adeno-tonsillar hypertrophy.

duration of two baseline breaths),

Other treatment options, such as anti-

associated with an arousal, an awakening or

inflammatory medications, weight loss or

a .3% desaturation. Central apnoea

tracheostomy, are less effective. Risk factors

occurring after gross body movements or

for post-operative complications of adeno-

after sighs was not considered a

tonsillectomy are:

pathological finding. Mixed apnoea was

defined as apnoea that usually began as

N children ,3 years of age,

central and ends in obstruction, according

N severe OSAS on PSG,

to changes in the chest, abdominal and flow

N cardiac complications,

traces. An event could be scored as

N failure to thrive,

hypopnoea if there was a .50% drop in

N obesity,

ERS Handbook: Paediatric Respiratory Medicine

517

C4-A1

C3-A2

D2-A1

D1-A2

LOC

ROC

Chin

ECQ

Nasal

cannula

Effort

Chest

Nasal

cannula

Abdomen

Chest

Abdomen

SaO2

Pulse

C4-A1

C3-A2

D2-A1

D1-A2

LOC

ROC

Chin

ECQ

Effort

Nasal

cannula

Chest

Abdomen

SaO2

Figure 1. Examples of a) obstructive apnoea, b) central apnoea, c) mixed apnoea and d) hypopnea sleep

epochs of 120 s. ROC: right electro-oculogram; LOC: left electro-oculogram.

N craniofacial anomalies,

or supplementary treatment in children

N neuromuscular disorders,

presenting with OSAS. Although the use of

N current respiratory infection.

oral appliances has received relatively little

attention in the literature, interest in this

It is also recommended that all patients with

approach is growing rapidly. Oral appliances

an oxygen saturation ,80% and an AHI

may improve upper airway patency during

o24 events?h^-1 should be observed as

sleep by enlarging the upper airway and/or by

inpatients.

decreasing upper airway collapsibility, thereby

Clinicians should refer patients for CPAP

improving upper airway muscle tone. The

management if symptoms and signs or

treatment options available for growing

objective evidence of OSAS persists after

children are rapid maxillary expansion,

adeno-tonsillectomy or if adeno-

mandibular retropositioning and a modified

tonsillectomy is not performed. There is no

monobloc. Rapid maxillary expansion, which is

clear advantage of using bilevel pressure

a dentofacial orthopaedic treatment procedure

over CPAP. Clinicians should recommend

routinely used in young patients .4 years with

weight loss in addition to other therapy if a

constricted maxillary arches, is considered to

child/adolescent with OSAS is overweight or

be an effective treatment for OSAS.

obese. Clinicians may prescribe topical

Conclusion

intranasal corticosteroids for children with

mild OSAS in whom adeno-tonsillectomy is

There is a great need for further research

contraindicated or for children with mild

into the prevalence of OSAS, consequences

post-operative OSAS (AHI ,5 events?h^-1).

of OSAS and the best treatments. In

Orthodontic treatment by means of oral

particular, randomised controlled trials of

devices is considered to represent a potential

treatment are needed. Figure 2 shows an

518

ERS Handbook: Paediatric Respiratory Medicine

Sleep-disordered breathing:

multidisciplinary approach

Paediatrician, ORL, orthodontist,

sleep record

Diagnostic evaluation?

Refer to paediatrician

YES

High risk or <2 years

Overnight pulse oximetry

YES

Positive?

YES

Attended video PSG

Adenotonsillectomy or

or unattended PSG

craniofacial surgery or

orthodontic treatment, CPAP

Refer to paediatrician, follow-up

Positive?

YES

YES#

Signs and symptoms

Drug therapy, plus orthodontic

after therapy?

Surgical intervention?

therapy and/or diet, or CPAP

YES

Symptoms?

Signs and symptoms

Adenotonsillectomy or

after 6 months?

YES

craniofacial surgery

Adjusting therapy and or CPAP

YES

Clinical evaluation and or

Signs and symptoms?

overnight pulse oximetry

YES

Signs and symptoms?

YES

Positive?

Clinical evaluation and/or

Clinical evaluation

PSG after 6 months

and/or PSG after 6 months

YES

Positive?

Refer to paediatrician

Refer to paediatrician, follow-up

Figure 2. Algorithmic approach to the diagnosis and treatment of paediatric OSAS. ORL:

otoringolarhingologic examination; PSG: polysomnography.^#: refer to the orthodontist for ORL, assess

for obesity, and perform cardiologic (ECG, blood pressure holter) and neuropsychological assessment.

algorithm for the diagnosis and treatment of

Bhattacharjee R, et al.

(2010). Adeno-

paediatric OSAS using a multi-step

tonsillectomy outcomes in treatment

approach. As multi-therapies might act

of obstructive sleep apnea in children:

synergistically, a greater degree of

a multicenter retrospective study.

Am J Respir Crit Care Med;

182:

collaboration between sleep medicine, ENT

676-683.

specialists and orthodontists is warranted to

Gozal D, et al.

(2008a). Metabolic

establish the contribution of each therapy to

alteration and systemic inflammation

the outcome of paediatric OSAS.

in obstructive sleep apnea among non-

obese and obese prepubertal children.

Further reading

Am J Respir Crit Care Med; 177: 1142-

1149.

Amin RS, et al. (2008). Activity-adjusted 24-

Gozal D

(2008b). Obstructive sleep

hour ambulatory blood pressure and cardiac

apnea in children: implications for the

remodelling in children with sleep disor-

developing central nervous system.

dered breathing. Hypertension; 51: 84-91.

Semin Pediatr Neurol; 15: 100-106.

ERS Handbook: Paediatric Respiratory Medicine

519

Iber C, et al., eds. The AASM manual

Tresaco B, et al.

(2005). Homeostatic

for the scoring of sleep and associated

model assessment (HOMA) index cut-off

events: rules, terminology, and tech-

values to identify the metabolic syndrome

nical

specifications.

Westchester,

in children. J Physiol Biochem; 61: 381-388.

American Academy of Sleep Medicine,

Villa MP, et al.

(2012a). Early cardiac

2007.

abnormalities and increased C-reactive

Marcus CL, et al.

(2012). American

protein levels in a cohort of children with

Academy of Pediatrics. Diagnosis and

sleep disordered breathing. Sleep Breath;

management of childhood obstructive

16: 101-110.

sleep apnea syndrome. Pediatrics;

130:

Villa MP, et al. (2012b). Mandibular advance-

714-755.

ment devices are an alternative and valid

Miano S, et al.

(2011). Neurocognitive

treatment for pediatric obstructive sleep

assessment and sleep analysis in children

apnea syndrome. Sleep Breath; 16: 971-976.

with sleep-disordered breathing. Clin

Villa MP, et al. Mandibular Advancement

Neurophysiol; 122: 311-319.

Devices in Sleep Disordered Breathing in

Montesano M, et al. (2010). Autonomic

Children A Comprehensive Clinical Guide

cardiovascular tests in children with

to Evaluation and Treatment. Heidelberg,

obstructive sleep apnea syndrome.

Humana Press, 2012c; pp. 542-551.

Sleep; 33: 1349-1355.

Villa MP, et al.

(2013). Sleep clinical

Tauman R, et al. (2004). Peripheral ar-

record: an aid to rapid and accurate

terial tonometry events and electroence-

diagnosis of paediatric sleep disordered

phalographic arousals in children. Sleep;

breathing. Eur Respir J 41: 1335-1361.

27: 502-506.

Waters KA, et al.

(2007). Structural

Tauman R, et al. (2007). Adipokines in

equation modeling

of sleep apnea,

children with sleep disordered breathing.

inflammation, and metabolic dysfunction

Sleep; 30: 433-449.

in children. J Sleep Res; 16: 388-395.

520

ERS Handbook: Paediatric Respiratory Medicine

Central sleep apnoea and

hypoventilation syndromes

Malin Rohdin and Hugo Lagercrantz

Sleep alters the function and control of the

cessation of breathing for at least two

respiratory system. These changes may result

breaths. Central sleep apnoea can be

in clinically significant abnormalities in upper

idiopathic but it can also occur secondary to

airway function and pulmonary gas exchange

another medical condition. Central apnoeas

among healthy children as well as those with

are common in the neonatal period,

an underlying disease. Sleep disordered

particularly among pre-term newborns, and

breathing (SDB) is a common cause of

this is viewed as a physiological immaturity of

morbidity in childhood that can result in

breathing control and ceases spontaneously

severe complications if left untreated. Central

around term post-conceptional age. Central

sleep apnoea, hypoventilation syndromes and

hypoventilation is caused by an inability of the

OSA are sleep-related breathing disorders,

central nervous system to maintain

and this section will focus on the first two

ventilation sufficient to overcome the

conditions. Central sleep apnoea is

respiratory load. Alveolar hypoventilation

characterised by a decreased or absent

syndromes are often caused by an abnormal

respiratory drive that results in reduction or

central integration of chemoreceptor signals

and can be primary, as in congenital central

hypoventilation syndrome (CCHS), or

Key points

secondary to diseases of the central nervous

system or neuromuscular disorders. Early

diagnosis and comprehensive treatment will

N Central sleep apnoea and

hypoventilation syndromes are causes

minimise the number of sequelae and

of morbidity in childhood that may

improve individual outcomes.

result in severe complications if left

Clinical features

untreated.

Sleep apnoea should be considered in

N Complications of sleep apnoea

children of all ages who present with

include pulmonary hypertension, cor

nonspecific symptoms of daytime

pulmonale, systemic hypertension,

dysfunction. More specific signs and

cardiac arrhythmias, hypoxic cerebral

symptoms of SDB include nocturnal or

injury and seizures.

early-morning headache, poor sleep quality

PSG is the gold standard test for SDB

with nocturnal awakenings, failure to thrive,

and is required to diagnose sleep-

and daytime breathing disturbances.

related disorders.

Children with daytime sleepiness due to

N Treatments include supplementary

SDB often ‘‘act out’’ behaviourally (e.g.

oxygen, caffeine (apnoea of

hyperactivity, impulsivity and increased

prematurity), diaphragm pacing,

aggression) rather than complaining

CPAP, BiPAP and mechanical

verbally. Younger children are less likely than

ventilation via tracheostomy.

older children to show signs of tiredness

(e.g. yawning and rubbing eyes).

ERS Handbook: Paediatric Respiratory Medicine

521

Sequelae of SDB The reason why some

syringobulbia, Chiari malformation, high

children become hypoxic and others arouse

cervical spinal cord injuries, encephalitis,

from sleep in response to respiratory

multiple system atrophy, and autonomic

compromise is unclear. Intermittent hypoxia

disorders such as Rett syndrome and

is an important mediator of neurocognitive

familial dysautonomia. Respiratory

deficit in children. Animal models

dysfunction constitutes an early and

simulating isolated intermittent hypoxia

relatively major manifestation of several

have shown neuronal cell loss in brain areas

neurological disorders, and may be due to

critical for executive function and memory,

an abnormal breathing pattern generation

namely the pre-frontal cortex and

due to involvement of the cardiorespiratory

hippocampus.

network or more frequently to respiratory

muscle weakness.

Sleep-related hypoxaemia in children is

associated with neurobehavioral, cognitive

Apnoea of prematurity is a common problem

and cardiovascular morbidities. Other

affecting pre-term infants and probably

sequelae in infants and young children

secondary to a physiological immaturity of

include pulmonary hypertension, failure to

respiratory control. The incidence of apnoea

thrive, cor pulmonale, systemic

is inversely correlated with gestational age

hypertension, cardiac arrhythmias, hypoxic

and birth weight. During rapid eye

cerebral injury and seizures. Perturbation in

movement (REM) sleep, these infants have

neonatal respiratory control and chronic

more paradoxical breathing with a less

intermittent hypoxia in premature infants

stable baseline oxygen saturation. Therefore,

may contribute to later SDB.

apnoeas occur more frequently in REM sleep

than in quiet sleep. Apnoea of prematurity

Severe apnoea that lasts .20 s is usually

may be exacerbated by diseases such

associated with bradycardia or desaturation,

as infections, intracranial haemorrhage,

which may lead to disturbances of cerebral

hypoxic-ischaemic encephalopathy,

haemodynamics and possibly affect

seizures, patent ductus arteriosus, and

neurodevelopmental outcome. However, it is

glucose or electrolyte imbalance. Resolution

difficult to demonstrate a link between apnoea

of apnoea and establishment of a normal

and poor neurodevelopmental outcome due

respiratory pattern is a major developmental

to a number of comorbidities and

milestone for many pre-term infants.

confounding factors affecting neurological

development. In addition, reports of severity

Rett syndrome is a severe

may be unreliable, and impedance monitoring

neurodevelopmental disorder that almost

techniques may fail to identify mixed and

exclusively affects females. After Down

obstructive events. Therefore, evaluating the

syndrome, Rett syndrome is the most

consequences of apnoea and hypoventilation

common specific cause of severe cognitive

on long-term neurological development

impairment in females, affecting one in

remains a challenge.

10 000. Rett syndrome causes severe

Central sleep apnoea The word ‘‘apnoea’’

autonomic dysregulation, probably due to

comes from the Greek word meaning

brainstem dysfunction. The patients have

‘‘without wind’’. The brainstem respiratory

severely disturbed breathing and heart rate

network contains neurons critical for

both when awake and when asleep (Rohdin

respiratory rhythmogenesis (pre-Botzinger

et al., 2007). The cardiorespiratory morbidity

complex). This network receives inputs from

is characterised by hypoventilation, central

peripheral and central chemoreceptors, and

apnoea, episodic hyperventilation,

from forebrain structures. Manifestations

tachycardia, bradycardia and poor peripheral

associated with disorders of this network

circulation. A mouse model of Rett

include sleep apnoea and dysrhythmic

syndrome revealed breathing disturbances

breathing. Common disorders associated

that probably originate from a deficiency in

with impaired cardiorespiratory control

noradrenergic and serotonergic modulation

include brainstem stroke or compression,

of the medullary respiratory network.

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ERS Handbook: Paediatric Respiratory Medicine

Familial dysautonomia is a

ventilation during wakefulness, to complete

neurodevelopmental disorder that affects

apnoea during sleep and severe

autonomic and sensory functions. Familial

hypoventilation during wakefulness. CCHS

dysautonomia is caused by mutations in the

is, however, far more complex than a simple

IKBKAP gene on chromosome 9 and

orphan disorder of respiratory control.

transmitted as an autosomal recessive

Patients with CCHS also have disturbances

disorder. Patients with familial

of autonomic nervous system regulation.

dysautonomia have SDB with both central

Characteristically, patients have diminutive

and obstructive apnoea. Many individuals

tidal volumes and monotonous respiratory

with familial dysautonomia initially increase

rates both while awake and asleep, although

ventilation during shorter periods of hypoxia

more profound alveolar hypoventilation

but have a decreased ventilatory drive

primarily occurs during sleep. Furthermore,

during prolonged hypoxia. It follows that

CCHS patients display a reduced influence

familial dysautonomia patients must be

of breathing on cardiac rate variation as well

cautious in settings where the partial

as a range of disturbances in both

pressure of oxygen is decreased, such as at

sympathetic and parasympathetic nervous

high altitudes or during aeroplane travel.

system control. Despite reduced ventilatory

responses to hypercapnia and hypoxaemia,

Alveolar hypoventilation syndromes are often

peripheral chemoreceptor responses are

caused by an abnormal central integration

partially preserved, particularly among

of chemoreceptor signals and could be

children who are able to sustain near-

primary, as in CCHS and Prader-Willi

adequate ventilatory output during

syndrome (PWS), or secondary to diseases

wakefulness. There is stage-related

of the spinal cord or brainstem. The

cardiorespiratory and autonomic regulation

respiratory deficit is typically more severe

that can be learned from the care of infants

during sleep than wakefulness and is

with CCHS (fig. 1). Polysomnography (PSG)

characterised by alveolar hypoventilation,

often shows different ventilatory responses

resulting in hypoxaemia and hypercarbia.

depending on sleep stage, with more severe

The goddess Ondine and her curse According

hypoventilation during non-REM sleep than

to a Medieval folk tale, the water nymph

during REM sleep in CCHS patients. Huang

Ondine would became mortal only when she

et al. (2008) speculated that this

fell in love with a human. She sacrifices her

phenomenon may be due to increased

immortality by marrying a knight, Sir

excitatory inputs to the respiratory system

Lawrence, and bearing his child. Sir

during REM sleep. CCHS appears to be the

Lawrence promises Ondine that his every

only respiratory disorder in which breathing

waking breath will be a testimony of his love,

is better during REM than during non-REM

but he is soon unfaithful to her. Witnessing

sleep (Huang et al., 2008).

Sir Lawrence’s adultery, the king of the

nymphs curses the knight. The king’s curse

In most cases, CCHS is diagnosed in the

makes the mortal responsible for

newborn infant, although an increasing

remembering to perform all bodily

number of patients are diagnosed after the

functions. When Sir Lawrence falls asleep,

neonatal period and even up to adulthood

he ‘‘forgets’’ to breathe and dies.

(late-onset CCHS). An increased clinical

awareness of CCHS may prevent potential

‘‘Ondine’s curse’’ is a term used to denote

life-threatening decompensation or

CCHS, a rare neurological condition

neurocognitive impairment. Clinical

causing lifelong failure of respiratory

suspiciousness towards unexplained

regulation. CCHS is characterised by sleep-

alveolar hypoventilation is likely to identify

related, life-threatening hypoventilation

a higher incidence of milder cases of

requiring lifetime mechanically assisted

CCHS.

ventilation during sleep. The severity of

ventilatory dysregulation ranges from

A mutation in the disease-defining gene

hypoventilation during sleep and adequate

PHOX2B (paired-like homeobox) is a

ERS Handbook: Paediatric Respiratory Medicine

523

mmHg kPa

Prader-Willi syndrome is a complex disorder

with hypothalamic dysfunction where the

clinical features vary with age. Early

●

symptoms include hypotonia, feeding

●

Quiet sleep

difficulties and failure to thrive, and later

●

Active sleep

symptoms are hypogonadism, hyperphagia-

●

obesity, and behavioural and cognitive

problems. PWS is a genetic disorder where a

●

Awake state

●

majority (70-75%) of the affected

individuals have a deletion in the paternally

derived chromosome 15q11-q13. Individuals

with PWS are at risk for a variety of

abnormalities of breathing during sleep,

including alveolar hypoventilation, central

apnoeas and OSA. The incidence and

severity of alveolar hypoventilation are

related to the degree of obesity. Individuals

Time months

with PWS may have a restrictive lung

disease due to muscle weakness or

) in

Figure 1. End-tidal carbon dioxide tension (PCO2

scoliosis. They also have impaired

a toddler (3-year-old girl) with CCHS. End-tidal

ventilatory control during sleep with

PCO₂ was highest during quiet sleep and lowest

abnormal ventilatory responses to

during wakefulness, while it was moderately

hypercapnia and hyperoxia, and reduced

elevated during active (REM) sleep. It illustrates

arousal responses to hypoxia. Excessive

how the suprapontine respiratory drive can sustain

daytime sleepiness is a common feature and

ventilation during wakefulness and, to some extent,

during REM sleep, but not during quiet sleep.

is suggested to be a primary feature of PWS

rather than a consequence of insufficient

sleep quantity or quality.

requisite to the diagnosis of CCHS. The

Patients with PWS, particularly if they are

PHOX2B gene promotes neuronal

obese or have symptoms suggestive of SDB,

differentiation and development of the

require a PSG to exclude or characterise

autonomic nervous system. Knowledge of

abnormal breathing. An early diagnosis of

the specific PHOX2B mutation aids in

SDB and appropriate treatment may delay or

anticipating CCHS phenotype severity

prevent the development of cor pulmonale.

(Weese-Mayer et al., 2010). CCHS is

Secondary hypoventilation syndromes

associated with an increased risk of

Alveolar hypoventilation syndromes can be

Hirschsprung’s disease and tumours of

secondary to an underlying disease and

neural crest origin. A fairly recent study

therefore cause an abnormal central

from the French CCHS registry estimates

integration of chemoreceptor signals.

an incidence of one per 200 000 live births

Examples include diseases affecting the

(Trang et al., 2005). PHOX2B mutation-

central nervous system (trauma, tumours

confirmed CCHS confers a risk of adverse

and cerebrovascular incidents),

neurocognitive outcome, though the range

neuromuscular disorders, chest wall

of observed functioning raises questions

deformities and obesity. This is a

about factors that may contribute to

heterogeneous group of diseases and

neurocognitive variability. The

incurs variable degrees of damage to the

recommended management options in

respiratory control centres.

optimising CCHS patient care and

neurocognitive outcome are summarised

Neuromuscular disorders SDB is now well

in an official American Thoracic Society

recognised in children with neuromuscular

clinical policy statement (Weese-Mayer

disorders and may lead to significant

et al., 2010).

morbidity and increased mortality.

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ERS Handbook: Paediatric Respiratory Medicine

Predisposing factors include reduced

PSG in children. Overnight PSG studies are

ventilatory responses, reduced activity of

preferred because negative nap studies

respiratory muscles during sleep and poor

have been shown not to exclude the

lung mechanics due to the underlying

possibility of SDB. Studies should be

neuromuscular disorder. Children with

performed without sedation in order to

different neuromuscular disorders are at

most accurately mimic the child’s normal

risk of developing both central and

sleep. PSG requires an overnight stay at a

obstructive apnoea and hypoventilation

sleep laboratory and the attachment of

during sleep. These neuromuscular

multiple sensors to the patient. Qualitative

disorders include Duchenne muscular

respiratory effort is detected using thoracic

dystrophy, myotonic dystrophy, spinal

and abdominal belts, which is essential in

muscular atrophy, cerebral palsy,

distinguishing between central and

poliomyelitis, myasthenia gravis, peripheral

obstructive respiratory events. Sleep stages

neuropathies, metabolic myopathies and

can be assessed by behavioural criteria

congenital muscle diseases (Arens et al.,

using video recording or determined using

2010). Symptoms of SDB in children with

electroencephalography (EEG), chin

neuromuscular diseases may be subtle.

electromyography (EMG) and electro-

The physician should be especially vigilant

oculography (EOG). Gas exchange is

for any of the following complaints:

assessed by monitoring SpO₂ and end-tidal

snoring, increasing numbers of nocturnal

or transcutaneous carbon dioxide. Airflow

awakenings, daytime sleepiness, or

can be assessed with a thermistor, nasal

morning headache that may be caused by

pressure or capnography. ECG is essential

cerebral vasodilation due to

to evaluate cardiorespiratory regulation, as

hypoventilation and carbon dioxide

respiratory events may be associated with

retention. Additional symptoms, such as

different heart rate regulation. Audio and

fatigue, exertional dyspnoea, orthopnoea,

digital video recordings are useful in

swallowing difficulties, weakened cough,

documenting snoring, body position and

weight loss and frequent respiratory

movements.

infections, could suggest progression of

Respiratory events during PSG Apnoea is

the underlying respiratory muscle disorder

often defined as a cessation or decrease in

and worsening of nocturnal ventilation and

airflow by o90% compared to the baseline

SDB. Abnormal respiration during sleep in

flow observed before the event when the

these disorders is often not predicted by

event meets duration and respiratory effort

awake pulmonary function testing, arterial

criteria for an obstructive, mixed or central

blood gases or the degree of muscle

apnoea (Berry et al., 2012). Partial airway

involvement.

obstruction is characterised by shallower or

Polysomnography

slower breathing, and has been described by

the term ‘‘hypopnoea’’. Hypopneas are

PSG is the gold-standard test for SDB in

defined as a o30% reduction in airflow, for

infants and children. It is a noninvasive

the duration of two or more breaths in

method to diagnose sleep-related

association with either o3% oxygen

hypoventilation due to central mechanisms

desaturation or an arousal. The apnoea-

or upper airway obstruction, or mixed

hypopnoea index (AHI), expressed as the

apnoeas. This in-laboratory, multichannel

number of apnoeas and hypopneas per hour

method obtains information about sleep

of sleep, is an important measure for

architecture, respiratory effort, movements

quantifying disease severity. Apnoeas and

during sleep, respiratory events and gas

hypopnoeas can be further classified as

exchange, facilitating the evaluation of

being central, obstructive or mixed in

children with suspected SDB. Children should

nature.

preferably be studied in a sleep laboratory

equipped for, and staffed with personnel

A central apnoea is when the event meets

comfortable with and experienced in,

criteria for an apnoea, there is an absence of

ERS Handbook: Paediatric Respiratory Medicine

525

inspiratory effort throughout the event and

unfortunately, only symptomatic treatments

at least one of the following conditions is

exist, including positive pressure ventilation

met:

via tracheostomy, BiPAP, negative pressure

ventilation or diaphragm pacing. It is of

N the event is o20 s in duration,

utmost importance to select the best mode

N the event is associated with an arousal or

of artificial ventilatory support for each

o3% oxygen desaturation,

individual patient. CCHS does not seem to

N in infants (,1 year of age) only, the event

improve with age, except in rare anecdotal

is associated with a decrease in heart rate

cases.

to ,50 beats per minute for o5 s or ,60

beats per minute for 15 seconds (Berry

et al., 2012).

Further reading

The respiratory pause in central apnoea is

American Thoracic Society

(1996).

not associated with a physical attempt to

Standards and indication for cardiopul-

breathe: the PSG shows no breathing

monary sleep studies in children. Am J

movements from the thoracic cage or

Respir Crit Care Med; 153: 866-878.

abdomen. Obstructive apnoea is a cessation

Arens R, et al.

(2010). Sleep, sleep

disordered breathing, and nocturnal

of airflow at both the nose and mouth

hypoventilation in children with neuro-

associated with out-of-phase movements of

muscular diseases. Paediatr Respir Rev; 11:

the rib cage and abdomen. A mixed apnoea

24-30.

has no inspiratory effort in the initial portion

Beck SE, et al. (2009). Pediatric polysom-

of the event, followed by resumption of

nography. Sleep Med Clin; 4: 393-406.

inspiratory effort before the end of the event.

Berry RB, et al. (2012). Rules for scoring

Periodic breathing is defined as more than

respiratory events in sleep: update of the

three episodes of central apnoea lasting

2007 AASM Manual for the Scoring of

.3 s separated by f20 s of normal

Sleep and Associated Events. Deliberations

breathing. Alveolar hypoventilation is when

of the Sleep Apnea Definitions Task Force

PaCO₂ (or a surrogate measure) is

of the American Academy of Sleep

.50 mmHg for .25% of total sleep time.

Medicine. J Clin Sleep Med; 8: 597-619.

Surrogates of PaCO₂ are end-tidal or

Bixler EO, et al. (2009). Sleep disordered

transcutaneous carbon dioxide tension.

breathing in children in a general popula-

tion sample: prevalence and risk factors.

Treatments for SDB

Sleep; 32: 731-736.

Bourke R, et al.

(2011). Cognitive and

Clinical management of apnoea of

academic functions are impaired in

prematurity includes continuous positive or

children with all severities of sleep-

nasal intermittent positive pressure

disordered breathing. Sleep Med;

12:

ventilation to prevent pharyngeal collapse

489-496.

and alveolar atelectasis. Methylxanthine

Huang J, et al. (2008). Effect of sleep

compounds such as caffeine, theophylline

stage on breathing in children with

and aminophylline stimulate the central

central hypoventilation. J Appl Physiol;

nervous system and respiratory muscle

105: 44-53.

function, and probably reduce apnoea by

Iber C, et al. The AASM manual for the

multiple physiological and pharmacological

scoring of sleep and associated events:

mechanisms.

rules, terminology, and technical specifi-

cations. 1st Edn. Westchester, American

Other treatments for SDB include

Academy of Sleep Medicine, 2007.

supplementary oxygen, CPAP, bi-level

Lal C, et al.

(2012). Neurocognitive

positive pressure ventilation (BiPAP) and

impairment in obstructive sleep apnea.

mechanical ventilation via tracheostomy. In

Chest; 141: 1601-1610.

hypoventilation syndromes, the primary

Lesser DJ, et al.

(2009). Congenital

goals are often to secure the airway, and

hypoventilation syndromes. Semin Respir

ensure optimal ventilation and oxygenation

Crit Care Med; 30: 339-347.

with artificial ventilation. For CCHS,

526

ERS Handbook: Paediatric Respiratory Medicine

Impact of obesity on

respiratory function

Andrea Bon, Martina Tubaro and Mario Canciani

Obese children present different lung

defined as: mass (kg)/[height (m)]². In

anatomy and function and have more

adults, a BMI .30 kg?m^-2 defines obesity,

respiratory symptoms than their normal-

but as the normal BMI changes throughout

weight peers. Paediatric obesity is now

childhood and is age- and sex-specific, a

considered a major public health problem

centile chart has to be used in children. In

and data from many observational studies

UK centile charts, overweight is taken as a

show an increase of this disease in recent

BMI .91st centile and obesity a BMI .98th

decades, in all age-groups: about 7% of the

centile. Other methods of assessment

world population is obese. In Europe the

include Ideal Body Weight (IBW), waist

prevalence of childhood obesity ranges from

circumference, waist/hip ratios, skinfold

10-20% in the north to 20-40% in the cities

thickness, abdominal fat from CT/MRI

of the Mediterranean basin. In the USA, the

scans, bioelectrical impedance and dual

prevalence of overweight children has tripled

energy X-ray absorptiometry (DEXA).

in the past 20 years. Globally, an estimated

Lung function in obesity

43 million preschool children (under age

5 years) were overweight or obese in 2010, a

There are limited data on obese children,

60% increase since 1990.

but studies on adults show that obesity has

a profound effect on the anatomy and

The commonest and simplest method of

physiology of breathing (table 1).

measuring and determining obesity is BMI,

The upper airways may be directly narrowed

by fatty infiltration of muscles and

Key points

subcutaneous fat deposits.

An important respiratory abnormality in

N Obesity is defined as BMI .98th

obesity is a decrease in total respiratory

centile according to age- and sex-

system compliance. The primary reason is a

specific centile charts.

decrease in chest wall compliance

Obesity is associated with a change in

associated with the accumulation of fat.

static and dynamic lung volumes.

Lung compliance is decreased as well and

may relate to the increased pulmonary blood

N Obese children experience more

volume seen in obese individuals. Total

respiratory symptoms compared to

respiratory compliance is reduced markedly,

their normal-weight peers.

mainly in supine position. This reduction

There is a parallel increase in asthma

increases the work of breathing, along with

and obesity prevalence, but a true

an increase in nonelastic work and

relationship is controversial.

inefficiency of respiratory muscles. The

nonelastic work comes from the raised

N Obese children should be screened at

upper and lower airway resistance, the latter

routine visits for the presence of

resulting from a reduction in lung volumes

snoring, apnoea, sleep disordered

due to obesity. Moreover, studies suggest

breathing and daytime drowsiness.

that the pressures generated by the

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ERS Handbook: Paediatric Respiratory Medicine

decreased lung volumes with increasing

Table 1. Main changes in lung physiology in obesity

obesity.

Q Total respiratory compliance

Q chest wall compliance

Finally, gas exchange, assessed by the

Q lung compliance

carbon monoxide diffusion capacity (DLCO),

q Work of breathing

is increased in obesity. This may be

q nonelastic work

explained by increased pulmonary blood

Q muscle efficiency

volume and flow. This rise has been

Change in static lung volumes

observed without evidence of pulmonary

Q ERV

congestion or heart disease.

Q FRC

Asthma and obesity

Change in dynamic lung volumes

Q FEV1

The relationship between asthma and

Q FVC

obesity in children is controversial. The

q Gas exchange

increasing prevalence of asthma in children

in recent decades, demonstrated by several

Q: decrease; q: increase.

epidemiological studies, goes hand in hand

with the rise in obesity, making these

diseases among the top priorities in

childhood health both in Western countries

respiratory muscles in obese patients are

and in the developing world. The definition

lower than those of nonobese patients at all

of asthma is crucial if we are to find any

lung volumes. This may result from

definite correlation with obesity. Asthma is

diaphragm dysfunction due to increased

characterised by increased airway

abdominal and visceral adipose tissue

responsiveness with chronic inflammation,

deposition, or from overstretching of

resulting in reversible airway obstruction.

diaphragm fibres leading to length-tension

The criteria for asthma diagnosis and

disadvantage.

asthma definition vary between studies and

frequently rely on self-reported symptoms

In obese individuals, there are changes in

(or on physician diagnosis based solely on

static and dynamic lung volumes. Among

self-reported symptoms). Review of the

the static lung volumes, expiratory reserve

evidence suggests that a higher BMI in

volume (ERV) and functional residual

children is associated with a higher

capacity (FRC) are decreased, and this is

prevalence of symptoms commonly

more evident in the supine position due to

attributed to asthma, such as wheeze, but

the increased gravitational effects of the

not a higher prevalence of objective

abdomen. TLC and vital capacity (VC) may

asthma. Obese children are less fit and

be reduced, while residual volume (RV) is

may have more symptoms of

usually maintained. These changes

breathlessness on exertion than their peers.

influence ventilation:perfusion ratio mainly

An increased perception of symptoms in

at the bases, where airway closure and

the obese may further complicate

alveolar collapse are responsible for

this issue.

underventilation. Dynamic lung volumes

are affected only in morbidly obese

However the parallel increases in prevalence

subjects. An increase in body mass

suggest a link between the two conditions,

correlates with reduced FEV1 and FVC.

even if the pathophysiological basis of this

Generally, in mild obesity, spirometry is

relationship remains unclear. Correlation

normal. Patients with mild-to-moderate

mechanisms seem to be possible: sedentary

obesity present a restrictive pattern whereas

lifestyle, dietary factors, systemic

with severe and morbid obesity spirometry

inflammation, reduced chest wall

is more likely to show true airflow

compliance, insulin resistance, the presence

obstruction. One mechanism may be

of comorbidities and common genetic

related to small airway collapse due to

predispositions.

ERS Handbook: Paediatric Respiratory Medicine

529

Cross-sectional studies show a weak link

children with mild or moderate asthma have

between asthma and obesity. However, a

a significant risk of becoming overweight.

number of longitudinal studies in children

and adolescents show a positive

Paediatricians should be cautious about

association, in particular supporting the

diagnosing asthma in an obese child on the

correlation between overweight and future

basis of self-reported symptoms alone, and

should seek objective evidence from peak-

risk of developing asthma. In addition,

flow recordings, exercise tests or laboratory

obesity may be associated with asthma

measurement of airway reactivity.

severity and/or poor asthma control. Studies

in adult asthma patients show that obese

Obstructive sleep apnoea syndrome

patients are more symptomatic, require

more medications and make more

OSAS is a disorder of breathing during sleep

emergency department visits than their

characterised by prolonged partial upper

nonobese counterparts. However, such

airway obstruction and/or intermittent

reports in the paediatric population are

complete obstruction (obstructive apnoea)

controversial.

that disrupts normal ventilation during sleep

and normal sleep patterns. Obese children

Asthma and obesity are both characterised

have a 4.5-fold increased risk for OSAS

by chronic inflammation. Asthma is, by

compared with the general population. In the

definition, a chronic inflammatory disease.

pathophysiology of OSAS in obese children,

Obese patients show a low degree of

anatomical and functional factors play a role.

systemic inflammation involving a number

In the first group, adenoid and tonsillar

of mediators, known as adipokines. The

hypertrophy is found in 45% of obese children

adipokines include tumor necrosis factor-a,

with OSAS. However, after

interleukin-6, eotaxin, vascular endothelial

adenotonsillectomy OSAS persists in nearly

growth factor and chemotactic proteins for

half of obese paediatric patients, compared to

monocytes. These factors have been

10-20% residual OSAS in nonobese children.

associated with asthma and may play a role

Other anatomical factors, such as fat pads,

in the common state of inflammation.

soft palate, lateral pharyngeal wall, and

Leptin, one of the main hormones involved

tongue may restrict upper airway size. A

in the regulation of inflammation in obesity,

recent study suggests that the development

is potentially relevant in asthma as well.

of OSAS in obese children is linked to marked

High levels of leptin are associated with an

visceral adiposity, increased parapharyngeal

increased prevalence of asthma during life,

fat pads and upper airway lymphoid

especially nonatopic asthma. Leptin serum

hypertrophy, even if the size of these tissues

levels in asthmatic patients are high

do not correlate with the BMI. Obese children

independently of BMI, possibly because

have an increased incidence of both the

leptin contributes to the typical

presence and marked enlargement of the

inflammatory cascade of asthma.

lingual tonsils. This enlargement can be

responsible for persistent OSAS after

Obesity is often associated with sedentary

adenotonsillectomy and require specific

lifestyle leading to dyspnoea and

treatment. In obese children, as previously

breathlessness during exercise, which could

stated, there is a change in chest wall

be interpreted easily as asthma or wheezing.

mechanics, reducing compliance and FRC,

These symptoms lead to a further reduction

leading to hypoventilation, atelectasis, and

in physical activity and increase in body

ventilation:perfusion mismatch. Functional

weight in a vicious circle. Poorly controlled

factors leading to airway collapsibility may be

exercise-induced asthma as well may

neuromotor tone, tissue properties and

contribute to reduction in physical activity

increased resistance. Studies on obese adults

and to weight gain, showing an overlap

with OSAS have demonstrated higher critical

among obese and asthmatic phenotypes.

closing pressure of the pharynx, a direct sign

The Childhood Asthma Management

of increased airway collapsibility. It is possible

Program (CAMP) Study has shown that

that obese children have altered ventilatory

530

ERS Handbook: Paediatric Respiratory Medicine

responses, although the role of the ventilatory

the respiratory system with muscular

drive in OSAS in children is unclear.

exhaustion leading to chronic hypoxia and

hypercapnia, with blunting of chemo-

Although true cardiovascular diseases are

receptor responsiveness in susceptible

not detected in young children with OSAS,

individuals. The chronic fatigue, daytime

predisposing conditions such as the

sleepiness and headaches of these patients

dysregulation of blood pressure, cardiac

are associated with hypercapnia and

function, autonomic function and

hypoxaemia; with time these patients

endothelial function are independently

develop polycythaemia, pulmonary

associated with it. Studies suggest OSAS as

hypertension and later right ventricular

a possible independent cause of metabolic

failure. The most appropriate treatment

syndrome, augmenting insulin resistance,

includes weight loss and nocturnal NIV.

dyslipidaemia, hypertension and

inflammation through increased

Breathing disorders in obesity-associated

sympathetic tone, intermittent hypoxaemia,

syndromes

sleep fragmentation and insufficient sleep.

Prader-Willi syndrome Commonly

Obese children should be screened at

associated characteristics of this syndrome

routine visits for the presence of snoring,

include neonatal hypotonia, obesity due to

apnoea, disordered breathing during sleep

excessive intake and inactivity, mental

and daytime drowsiness. Polysomnography

retardation, short stature, scoliosis,

is considered the gold standard for the

hypogonadotropic hypogonadism,

diagnosis of OSAS. Other methods, such

strabismus, and small hands and feet.

nocturnal pulse oximetry or daytime nap

Typically these children may present a

polysomnography are specific but need

variety of abnormalities of breathing,

confirmation if negative. Weight loss is

including OSAS and sleep-related alveolar

associated with a significant reduction in

hypoventilation. Although the abnormal

sleep apnoea and is the most effective long-

response to hypercapnia is probably related

term treatment, but the least likely to take

to obesity, there is an altered ventilatory

place. However, the majority of patients

response to hypoxaemia and chemoreceptor

continue to experience sleep disordered

responsiveness both in obese and nonobese

breathing. In obese children with OSAS and

patients with Prader-Willi syndrome. They

adenotonsillar hypertrophy, adenotonsill-

may not arouse normally following

ectomy is an important option, with effective

prolonged airway obstruction, leading to

resolution of symptoms in about 50%. CPAP

increased risk of morbidity, including

is considered in patients without

sudden death. Severely obese patients with

adenotonsillar hypertrophy or ineffective

respiratory impairment receiving human

adenotonsillectomy. Other treatments

growth hormone are potentially at risk of

include oral appliances, uvulopalato-

sudden death especially in the first 12-

pharyngoplasty and positional therapy, with

18 months of therapy.

variable results.

The treatment of OSA in Prader-Willi

Obesity hypoventilation syndrome

patients includes weight loss, which is

particularly difficult for these patients,

Obesity hypoventilation syndrome (OHS),

adenotonsillectomy, and NIV, which could

also known as Pickwickian syndrome, is

be challenging with the behavioural

defined as a combination of obesity and

problems associated with this syndrome.

awake arterial hypercapnia (arterial carbon

dioxide tension .45 mmHg) in the absence

Down syndrome Many features that

of other causes of hypoventilation. This

characterise this syndrome, such as

disorder is associated with gross obesity,

micrognathia, hypotonia, macroglossia,

with only few case reports in children. The

midfacial hypoplasia, along with obesity,

pathophysiology is thought to be the

increase the risk of airway obstruction. The

exasperation of the mechanical loading of

first-line treatment is adenotonsillectomy.

ERS Handbook: Paediatric Respiratory Medicine

531

Further reading

De Onis M, et al. (2010). Global pre-

valence and trends of overweight and

American Academy of Pediatrics (2012).

obesity among preschool children. Am J

Diagnosis and management of childhood

Clin Nutr; 92: 1257-1264.

obstructive sleep apnea syndrome.

Deane S, et al. (2006). Obesity and the

Pediatrics; 130: 576-584.

pulmonologist. Arch Dis Child; 91: 188-191.

Arens R, et al.

(2011). Upper airway

Koenig SM. (2001). Pulmonary complica-

structure and body fat composition in

tions of obesity. Am J Med Sci;

321:

obese children with obstructive sleep

249-279.

apnea syndrome. Am J Respir Crit Care

Parameswaran K, et al. (2006). Altered

Med; 183: 782-787.

respiratory physiology in obesity. Can

Black MH, et al. (2012). Higher preva-

Respir J; 13: 203-210.

lence of obesity among children with

Raanan A, et al.

(2010). Childhood

asthma. Obesity; 20: 1041-1047.

obesity and obstructive sleep apnea

Costa DJ, et al.

(2009). Adenoton-

syndrome. J Appl Physiol; 108: 436-444.

sillectomy for obstructive sleep apnea

Redline S, et al.

(2007). Association

in obese children: a meta-analysis.

between metabolic syndrome and sleep-

Otolaryngol Head Neck Surg;

140:

disordered breathing in adolescents. Am J

455-460.

Respir Crit Care Med; 176: 401-408.

532

ERS Handbook: Paediatric Respiratory Medicine

Lung injury

Andreas Schibler

A multitude of endogenous and exogenous

ventilation/perfusion mismatch exists (a

factors can cause acute lung injury in infants

false low PaO₂/FIO₂ ratio). Lung injury can be

and children. The clinical picture is

seen as part of a systemic inflammatory

characterised by an increased work of

process (sepsis, pancreatitis and post-blood

breathing and impaired gas exchange.

transfusion), or directly related to local

Depending on the severity of the lung injury

injury caused by infection, aspiration or toxic

mechanical respiratory support is needed.

gas inhalation. The histopathological

An adult-based definition for acute lung

characteristics are a widespread destruction

injury (ALI) or acute respiratory distress

of the capillary endothelium, extravasation

syndrome (ARDS) has been developed for

of protein-rich fluid and interstitial oedema

the purpose of clinical trials. The definition

followed by damage to the alveolar

of ALI or ARDS has changed little over the

membrane, and fluid leaks into the alveolar

past 20 years and is mainly defined by a

space.

bilateral pulmonary infiltrate on chest

radiography (fig. 1), a pulmonary capillary

ARDS is characterised by two distinct

wedge pressure of ,18 mmHg (for

stages. The acute phase is defined by

paediatric purpose excluding heart failure

disruption of the alveolar-capillary

due to congenital heart disease or

membrane with leakage of protein-rich fluid

cardiomyopathy) and a PaO₂/inspiratory

in interstitial and alveolar space combined

oxygen fraction (FIO₂) ratio ,200 or ,300

by release of cytokines and inflammatory

for ARDS and ALI, respectively. A recent

cells. This leads to a secondary leakage of

review of the ARDS and ALI criteria defines

inflammatory proteins into the circulation

severe ARDS as a PaO₂/FIO₂ ratio ,100 and

(systemic inflammatory response syndrome

moderate ARDS as a PaO₂/FIO₂ ratio 100-

(SIRS)). The second reparative stage shows

200. ALI is defined as a PaO₂/FIO₂ ratio 200-

fibroproliferative changes with organisation

300. This definition doesn’t consider the

of lung tissue. Although any lung injury is a

considerable large range of possible causes

diffuse process, it is also a heterogeneous

for lung injury and fails to accurately

disease and not all lung units are affected

characterise the severity if significant

equally. This causes two different

pathophysiological outcomes. First,

ventilation-induced lung injury (VILI) is

Key points

more likely to affect the open and less

injured lung unit than the closed and hardly

N ALI can be caused by endogenous or

aerated diseased lung. Secondly, the

exogenous factors.

ventilation/perfusion mismatch increases

intrapulmonary shunting, which decreases

N VILI causes additional harm in the

oxygen delivery. Hence the corner stone of

presence of lung injury.

optimal mechanical support is to open the

Protective ventilation strategies have

previously closed lung units and have them

reduced the mortality of ARDS.

participating in the gas exchange. In

achieving this, airway pressures are more

ERS Handbook: Paediatric Respiratory Medicine

533

man-made disease. Avoiding high airway

pressures and potentially even avoiding

invasive mechanical ventilation may

improve outcome of patients with ARDS.

Human and experimental studies in healthy

lungs have shown that the mechanical

stress inflicted on the tissue and skeleton of

the lung during positive pressure

ventilation can be seen within 20 min of

ventilation. For a better understanding of

the differences between healthy and sick

lungs knowledge of ventilation distribution

is important. In healthy lungs the alveolar

structure hardly changes its geometry

during tidal breathing and volume changes

occur mainly in the peripheral airways and

alveolar ducts. The alveolar structure is

maintained by the elastic stretch and recoil

forces of the lung parenchyma and the

presence of surfactant within the alveoli.

Figure 1. Chest radiograph from a 5-year-old girl

Hence the lung parenchyma does not

with sepsis-induced ARDS. Note, the bilateral

experience significant mechanical stress

chest infiltrate affecting the majority of the lung

fields.

during regular tidal breathing. This delicate

balance and geometry is destroyed in lung

disease and alveoli may additionally be

evenly distributed throughout the lung and

filled with secretion containing loose

less damage is seen to the healthier parts of

alveolar or epithelial cells, neutrophils,

the lung. Intrapulmonary shunts are

macrophages, lymphocytes and airway

decreased and oxygen uptake improved.

secretion. This then leads to collapse or

The two-hit model

atelectasis, especially of the dependent lung

regions. Gas exchange is consequently

For a comprehensive understanding of the

impaired and these so-called closed lung

characteristics of lung injury the concept of

regions experience significant shunting of

the ‘‘two-hit’’ model needs to be discussed.

pulmonary blood flow, which adds to low

The initial primary hit consists of the

systemic oxygen saturation. Mechanical

underlying pathological process such as

ventilation directs positive pressure into

hyaline membrane disease, bacterial or viral

these affected lung regions and causes

infection, or aspiration of meconium or

cyclic opening and closing of the alveoli.

water in drowning. In case mechanical

Alveoli do not tolerate these extreme stress

ventilatory support is required for adequate

forces and the previously mentioned

gas exchange a secondary hit may occur,

rupture of the alveolar-capillary membrane

previously described as VILI. This

occurs. In the past, rather large tidal

secondary hit causes an augmentation of

volumes were delivered during mechanical

the already pre-existing inflammatory

ventilation (10-15 mL?kg^-1), which were

response of the lung, which is commonly

detrimental to the lung and led to

defined as biotrauma caused by positive

significant secondary lung injury. The newer

pressure ventilation. Most of the recent

approach of mechanical ventilation these

research efforts aimed to reduce and

days is to reopen and stabilise the

minimise this secondary insult have

collapsed lung regions and expose the lung

improved ventilation strategies with

to small tidal volumes (protective

significantly better outcomes and reduced

ventilation). This is mainly achieved by

morbidity and mortality. Many experts in

using recruitment manoeuvres of the lung

the field even argue that ARDS is a partially

and the use of high positive end-expiratory

534

ERS Handbook: Paediatric Respiratory Medicine

pressures (PEEP). Studies using CT-guided

N an increase in airway calibre and length,

lung recruitment have shown significantly

N development of the immune system,

improved respiratory mechanics and gas

including the plasticity of T-helper cell

exchange, but this has not yet translated

response,

into reduced mortality. The concept of

N exposure to a range of pathogens and

protective ventilation with high PEEP and

viruses, in particular for the first time.

low tidal volumes as a general strategy has

The interaction of the disease process with

improved outcome overall (mainly studied

normal lung development may have long

in adult patients with ARDS). In clinical

lasting impact on lung function. It is

practice, however, we lack good monitoring

therefore not surprising that the impact of

tools indicating optimal lung recruitment

positive pressure ventilation in addition to

and mechanical support. In general, tidal

the interactions mentioned above further

volumes of 6 mL?kg^-1 and generous PEEP

augments the potential for more severe lung

have been accepted also in paediatric

injury. Another important factor is that

ventilation. The personal experience of

during invasive ventilation, secondary lung

many ventilation experts is that the severity,

infections (ventilator-associated pneumonia

morbidity and mortality of children with

(VAP)) and aspiration of saliva and acidic

ARDS have been reduced. Mortality of

fluids from gastro-oesophageal reflux occur.

ARDS has been reported for infants and

children to as high as 40%

Respiratory causes are responsible for

and, for ALI, 20%. The availability of

,25% of all admissions to paediatric

extracorporeal membrane oxygenation

intensive care units. Bronchiolitis and

(ECMO) in combination with the use of

pneumonia are the most common among

protective ventilation has further improved

respiratory causes but with a relative low

outcome. Newer adult figures show an

mortality (1.9%). All common respiratory

ARDS mortality of 25% and it is suspected

viruses, such as RSV, HMV and influenza,

that the current paediatric figure is well

can cause ARDS similar to any bacterial

below 25%. Most of the patients die

infection. Other exogenous causes are fresh

because of the associated multiorgan

water aspiration during drowning, inhalation

failure and not lung failure. Pulmonary

of toxic fumes in a house fire or aspiration of

oedema can present clinically and on

gastric content in the unconscious or

radiography is very similarly to ARDS.

seizing patient (table 1). In cases of smoke

Hence, in all patients echocardiography of

inhalation injury, carbon monoxide and

the heart needs to be performed.

cyanide poisoning complicate the care of the

patient. Transfusion-related acute lung

Cause and pathophysiology of ALI needs to

injury (TRALI) is a potentially fatal side-

be discussed based on the following three

effect of blood transfusion. It is now

factors: stage of lung development at which

considered to be the most frequent cause of

the insult occurred, and endogenous or

transfusion-related morbidity and mortality

exogenous cause for the injury.

and is under-reported and underdiagnosed.

TRALI is thought to develop via transfusion

Insult during lung development

of either an anti-leukocyte antibody or a

biological response modifier. Transfusion of

There are fundamental differences in the

blood products in a patient with an already

remodelling process during and after lung

existing ALI may aggravate the lung disease.

injury between adults and children despite

Conservative blood transfusion

similarities in the structural changes of the

management in ARDS is suggested.

disease process. In adults, the lung injury

occurs in a fully developed lung whereas, in

A few ARDS/ALI-specific treatment options

contrast, in infants and young children

will be briefly discussed. Most evidence is

,3 years of age airway and lung tissue

adult-based as there are only a few

development still occurs. The changes in the

paediatric ARDS trials. The general concept

developing lung include:

of a high PEEP (10-15 cmH₂O) and low tidal

ERS Handbook: Paediatric Respiratory Medicine

535

ARDS if they are treated with NIV at an early

Table 1. Causes of lung injury

stage. Further to the appropriate

Exogenous

antimicrobial therapy, surfactant

Sepsis

replacement has been successfully used in

paediatric ARDS. The key to success is to

Pneumonia

use surfactant in the early stage to keep the

Aspiration and drowning

lung open for adequate ventilation. Inhaled

Meconium aspiration syndrome

nitric oxide to treat hypoxaemia and reverse

Inhalation of noxious fumes

the associated pulmonary hypertension has

been widely used but the sobering fact is

Endogenous

that nitric oxide has not had any impact on

TRALI

outcome. Currently, nitric oxide should only

Pancreatitis

be offered in desperate cases before transfer

Burns

to ECMO and if the patient doesn’t respond

then nitric oxide should be ceased. The use

Poisoning

of steroids is also controversial. It is

suggested that the use of steroids in a low

dose and mainly during the early stage of

volume ventilation (6 mL?kg^-1) strategy is

ARDS may be beneficial. Steroids may have

mostly accepted in paediatric intensive care,

a short-term benefit in improving gas

despite the lack of paediatric-specific data.

exchange and lung function, and even

With the use of low tidal volumes clinicians

ventilator-free days in adults but long-term

accept higher PaCO₂ levels as long as the pH

outcome i.e. discharge to home, was not

is .7.2 (permissive hypercapnia). Lung

necessarily improved in all studies. Prone

recruitment using either a sustained

positioning is one of the simple means to

inflation manoeuvre (i.e. maintaining an

improve gas exchange in children with ARDS

inspiratory pressure as high as 40 cmH₂O

and adult studies have shown improved

for 20-40 s) or a staircase PEEP trial have

outcomes and reduced mortality. The

shown improved gas exchange and lung

concept of changing the body position

compliance in most human and

between supine and prone is to redistribute

experimental studies, but only a few studies

pulmonary fluids, reopening of the collapsed

have reported better outcomes. Not all

lung regions in the previously dependent

patients with ARDS have recruitable lungs.

lung regions and improving chest wall

Patients with a pulmonary cause of ARDS

mechanics. Because of the ease of

are less likely to benefit from lung

repositioning an infant or child compared to

recruitment in the early stage of the disease.

adults, prone positioning is widely used in

High-frequency oscillatory ventilation

paediatric intensive care settings. ECMO is

(HFOV) is commonly used in severe

used as a rescue treatment if conventional

paediatric ARDS. There are only a few, and

treatment or HFOV fails. The international

small, controlled trials demonstrating a

ECMO database reports an ,50% ECMO

benefit of HFOV in children. A recent adult

success rate for patients who otherwise

trial using HFOV in ARDS has shown a

would have died on conventional ventilation.

higher morbidity and mortality in the HFOV

arm. Like many diseases, early detection and

Further reading

treatment is key to a good outcome. Hence,

there is a similar shift in the paradigm to

Amato MB, et al.

(1998). Effect of a

support any acute lung failure. With the use

protective-ventilation strategy on mortal-

of NIV and CPAP in the very early stage of

ity in the acute respiratory distress

lung injury we may see a significant

syndrome. N Engl J Med; 338: 347-354.

reduction in the severity of many patients

Arnold JH (2000). High-frequency venti-

with ARDS. Some adult and paediatric trials

lation in the pediatric intensive care unit.

are already reporting a significant reduction

Pediatr Crit Care Med; 2: 93-99.

in mortality and morbidity in patients with

536

ERS Handbook: Paediatric Respiratory Medicine

Acute and chronic respiratory

failure

Robert I. Ross-Russell and Colin Wallis

Acute respiratory failure

in the Blood gas assessment and oximetry

section.

Acute respiratory failure occurs when the

lungs are unable to adequately deliver

Acute respiratory failure (ARF) can occur as

oxygen to the arterial blood or clear carbon

a result of several different causes including

dioxide from the blood. Although there are

hypoxaemia, hypoventilation, diffusion

no formal definitions, a PaO₂ ,50 mmHg or

impairment or shunt. Diffusion problems

a PaCO₂ .60 mmHg is generally considered

can be observed due to direct impairment of

an appropriate threshold. Measurement of

the movement of gas between alveoli and

arterial blood gas is critical to the

blood (such as is seen in interstitial lung

determination of respiratory failure.

disease), or due to changes in the balance of

Interpretation and analysis of blood gas

ventilation/perfusion (V9/Q9) in different

results have been covered in this Handbook

parts of the lung. Of these, V9/Q9 inequality

is the most common and important in the

majority of clinical conditions.

Key points

Definition and physiology Acute hypoxic (Type

I) respiratory failure is a common

There are a wide range of causes of

presentation in children with severe

both acute and chronic respiratory

respiratory disease. It is important, as

failure in children.

reduced oxygen delivery to the rest of the

body can lead to tissue hypoxia, which can,

Blood gas analysis remains the central

in turn, cause organ dysfunction or injury.

investigation when assessing

Severe hypoxia is therefore a potentially

respiratory failure.

critical situation and can lead to

Methods of support, and particularly

neurological, renal, cardiac and other organ

noninvasive techniques, have allowed

failure. However, such findings are

a much greater ability to avoid

uncommon, and mild or moderate hypoxia

prolonged intensive care.

is well tolerated in the short term. Most

Improvements in technology,

hypoxic respiratory failure in children will

intensive care and the provision of

occur as a result of acute parenchymal

home care for children in chronic

disease caused by infection.

respiratory failure have led to

In most cases the hypoxia is related to

increasing numbers of these children

abnormalities in V9/Q9 matching and in

being cared for in the community.

particular to areas of low V9/Q9. If an area of

Early recognition of chronic

the lung has a blood flow but no ventilation

respiratory failure should lead to

(V9/Q950) this allows deoxygenated blood

interventions that will correct gas

to pass directly through to the systemic

exchange as far as possible before

circulation, and is termed a shunt. In normal

secondary complications develop.

circumstances we have an effective (virtual)

shunt of 3-4%, but if this increases, SaO₂ is

538

ERS Handbook: Paediatric Respiratory Medicine

unable to reach 100% and the plateau of the

Type I failure can give rise to significant

oxygen dissociation curve (ODC) is

organ dysfunction and injury, but this is not

depressed. Conversely, if there is reduced

usually an immediate effect (unless the

(but measurable) ventilation to a well

failure is coupled with systemic shock).

perfused area (low V9/Q9), the alveolar gas

Blood gas results will therefore tend to show

tends to contain increased levels of carbon

an isolated hypoxia but without much

dioxide and PaO2 is reduced, as predicted by

change in pH. The development of a

the alveolar gas equation. This will also tend

significant acidosis (often seen as a

to reduce the saturation of arterial blood,

metabolic acidosis) implies that organ

but (unlike shunt) can be overcome by

perfusion has been compromised, and may

indicate the severity of the problem.

increasing oxygen concentration. The effect

on the ODC is therefore to move the curve

Acute hypercarbic (Type II) respiratory failure

to the right (fig. 1). Areas that are well

is less common in paediatric practice. It can

ventilated but poorly perfused will generate

be seen in children with underlying

well-oxygenated blood, but the reduced flow

neuromuscular disease or major skeletal

limits their contribution to the overall blood

abnormality such as severe scoliosis. Acute

gases.

presentation in such cases would be rare but

can follow intercurrent infection (acute on

In many diseases, such as acute asthma,

chronic). Unusual causes include Guillain-

chronic lung disease and bronchiolitis, there

Barré syndrome, acute upper airway

are significant changes to V9/Q9 throughout

obstruction (e.g. foreign body) or over

the lung, due to areas of hyperinflation and

sedation, which may be witnessed following

atelectasis. This causes some shunting as

administration of anticonvulsants.

well as significant areas of low V9/Q9

matching and it is this that causes SaO₂ to

Unlike Type I failure, carbon dioxide

fall. This becomes more evident when we

retention will produce a rapid fall in pH

consider that children with lung aplasia, or

(respiratory acidosis). Measurement of

following lobar resection, will have entirely

carbon dioxide and pH is more difficult than

normal blood gases despite the loss of lung

saturation, and although there are some

volume.

noninvasive techniques (such as end-tidal or

100

10 kPa

15%

20 kPa

25%

30 kPa

35%

FIO2

Figure 1. The effect of a) low V9/Q9 and b) shunt on the ODC. Note that reduced (but not absent) ventilation

will tend to move the curve to the right, and can be overcome with additional inspired oxygen. However, in

pure shunt the maximal saturation that can be reached is reduced. FIO₂: inspiratory oxygen fraction.

ERS Handbook: Paediatric Respiratory Medicine

539

transcutaneous monitoring), Type II failure

with falling consciousness, and urine output

can be easily missed or overlooked.

may decrease.

Consideration of this possibility in patients

Hypoventilation can be much more difficult

at risk is therefore critical and measurement

to assess clinically and measurement of

of a blood gas (capillary of arterial) is

arterial saturations may miss significant

important. This will show a low pH and

problems, particularly if additional oxygen is

raised carbon dioxide, but even pure

being administered. In more chronic

respiratory acidosis may involve some

conditions, headaches and other

lowering of the bicarbonate (and hence the

neurological changes can be seen. If

base excess) due to the intimate

acidosis is significant (,7.25), cellular

relationship between carbon dioxide and

enzyme systems start to be affected. In

bicarbonate levels.

particular contraction of myocardial cells

starts to decrease, causing reduced cardiac

It is also important to understand the role of

output with implications for organ

muscle fatigue in the presentation of

perfusion.

children with ARF. The diaphragm, just like

other skeletal muscle within the body, is

Investigation of ARF Faced with a child with

unable to indefinitely sustain a workload

respiratory problems in whom ARF is

that is .40% of its maximal capacity. When

possible, the immediate concerns should be

this occurs, the metabolic demands of the

to address the ABC of resuscitation:

muscle result in cellular energy failure and

an inability to maintain contraction. This

N oxygen should be administered;

energy failure is usually quite sudden,

N support summoned and;

particularly in children, and so children with

N the patient’s airway and breathing

significantly increased work of breathing can

evaluated in a systematic manner.

deteriorate and decompensate very rapidly.

However, once the immediate issues have

been addressed a more measured

Another clinical situation where respiratory

assessment can be made. A clear history

failure can present rapidly is in acute lung

must be obtained, including the duration of

injury (sometimes referred to as acute

symptoms, previous medical problems,

respiratory distress syndrome (ARDS)). In

family history, etc. A thorough clinical

this situation, which may follow sepsis

examination aims to determine the cause of

aspiration or trauma amongst other things,

the failure and the acute consequences.

interstitial fluid and alveolar oedema

develop rapidly causing significant

The mainstay of investigation in ARF is the

difficulties in oxygenation. It is unusual for

measurement of arterial blood gases.

this to present de novo and usually occurs in

Clinical assessment or SpO₂ alone are unable

a child who is already unwell from one of the

to provide a complete picture of the

underlying causes, such as a severe

respiratory and metabolic components

pneumonia. However, it is a devastating

involved. As an example, a patient with

disease with a high mortality. High

diabetic ketoacidosis may present with

ventilatory pressures are often required that,

tachypnoea, increased work of breathing but

in turn, further damage the lung and often

normal oxygenation. Immediate physical

lead to interstitial fibrosis and lung scarring.

examination may show dehydration, but

may not demonstrate any indication of

Clinical effects of respiratory failure: Increasing

metabolic acidosis and it may initially

hypoxaemia stimulates increased respiratory

appear as though the patient is suffering

drive and together with the underlying cause

from a respiratory problem. However, blood

of the hypoxia will present clinically as an

gas analysis would rapidly show that the pH

increase in respiratory effort and distress.

was low but so was the carbon dioxide, and

Symptoms from other organ involvement

that the respiratory effort was a response to

become more apparent with increasing

a metabolic problem and not the underlying

hypoxia. Neurological status can be affected

cause of distress.

540

ERS Handbook: Paediatric Respiratory Medicine

A chest radiograph may be very helpful in

dioxide levels can be missed if blood gases

the acute setting. In patients with extensive

are not obtained.

shadowing, consideration of an ultrasound

Delivery of additional oxygen can be via a

should be made as pulmonary effusions can

mask, nasal cannula or a head box. Masks

otherwise be missed, and management

are easily tolerated but can entrain air at

would be altered if a large effusion were

higher inspiratory airflows, and so a

present. The exception to this may be a child

reservoir bag is needed to deliver high

with bronchiolitis, where the diagnosis is

concentrations. Delivery of oxygen via nasal

clinical and chest radiographs are not

cannula or head box has been shown to be

recommended routinely. Radiographs are of

equally effective, and the choice of method

limited value in assessing a child with

is mostly down to tolerability and personal

hypoventilation.

preference.

Lung function testing may be useful to

Maintaining a high level of inspired oxygen

document recovery from an acute event or

is important, but other factors may also

track a slow deterioration. Measurements of

affect delivery of oxygen to the tissues.

flow and volume (peak expiratory flow rate,

Cardiac output, haemoglobin concentration

FEV1 and FVC) are valuable in asthma, and

and local blood flow need to be considered.

can help to determine the degree of

obstruction. They can also be useful in

Noninvasive pressure support: Applying a flow

patients with acutely progressing Guillain-

of gas to the upper airway, often with an

Barré syndrome, as FVC has been used as a

increased positive airway pressure, has been

marker of disease severity, and as an

used to support ventilation for many years.

indication for intubation.

Pressure can be delivered via a mask to the

nose or face or with nasal prongs in the

Management of ARF The prerequisites of

small child. There are several mechanisms

respiratory support are to improve the

by which this may help.

oxygenation and the clearance of carbon

dioxide. This can be managed through

N Increased pressure in the airway may be

improving oxygen delivery (increasing

transmitted to the lung. In a lung with

inspired oxygen concentration, using

reduced compliance this may move the

positive pressure ventilation, relieving

pressure-volume curve to a more

obstruction), or by reducing demand

compliant phase, allowing better air entry

(reducing work of breathing and reducing

for the same effort, and reducing work of

metabolic demand).

breathing.

N Pressure in the upper airways may help

Oxygen administration: The simplest way to

reduce resistance to airflow. This may be

improve arterial oxygen levels is to increase

especially useful in patients with

the partial pressure of inspired oxygen

neuromuscular disease who can develop

(PiO₂). The rate of gas diffusion across the

obstruction due to weak pharyngeal

alveolar basement membrane is directly

muscles, or in patients with obstructive

related to the concentration gradient, and so

sleep apnoea.

a higher inspired PiO₂ will lead to greater

N High flow nasal oxygen (see below) may

absorption. The effect that increasing PiO₂

also reduce dead space. Normally, air

will have on blood gases will depend, to

within the oropharynx constitutes part of

some extent, on the underlying disease. If

the anatomical dead space but high flow

there is significant shunt, then the effect will

gas will remove this component of the

be small, but for patients with

dead space, which can reduce the work of

hypoventilation or with V9/Q9 inequality,

breathing.

oxygen administration should be effective at

improving the abnormality. This is

Noninvasive support may be delivered either

important, as oxygen administration can

through a tight fitting mask (nasal mask or

readily correct arterial saturation values in a

full facial mask), or through nasal catheters.

hypoventilating patient, and high carbon

Proper sizing and fitting of the mask is

ERS Handbook: Paediatric Respiratory Medicine

541

essential. Support may be CPAP, with a

Another critical factor when instituting

single pressure (designed to reduce work of

ventilation in patients is the effect that

breathing, but not directly contributing to

positive pressure ventilation will have on the

ventilation), or biphasic positive airway

cardiovascular system. Cardiac output is

pressure (BiPAP), where bilevel support

integrally tied to venous return. Positive

enables direct ventilation.

pressure ventilation (especially in

noncompliant lungs) will lead to a

High flow oxygen, such as the Optiflow

restriction on venous return to the heart,

(Fisher and Paykel, Auckland, New Zealand)

and this can act to reduce cardiac output

and Vapotherm (Stevensville, MD, USA)

and organ perfusion. High airway pressure

systems, are a recent innovation. Heated

will also affect lung perfusion and affect V9/

and humidified gas is passed through nasal

Q9 ratios. Hypoxia and hypercarbia in the

cannulae at high flow rates (,5 L?min^-1 in

pulmonary circulation further contribute to

neonates and up to 70 L?min^-1 in adults).

vasoconstriction. Recognising these factors

Although the exact mechanism is uncertain,

and adjusting cardiorespiratory parameters

it is a technique that is simple to use and

accordingly usually requires the skills of an

there is increasing evidence of its

anaesthetist or intensivist.

effectiveness in neonatal, paediatric and

Chronic respiratory failure

adult practice. Reduction of dead space and

airway resistance, or an increase in airway

There is no satisfactory definition of chronic

pressure, has been postulated as a potential

respiratory failure in children. In practice

benefit.

one encounters chronic respiratory failure in

two different scenarios:

Intubation and ventilation remains the

definitive method of supporting respiratory

N the child with an underlying chronic

failure. The securing of a clear airway is

condition who, as part of the natural

obtained by passing an endotracheal tube

history of the disorder, is developing a

through the vocal cords and into the central

slow failure of ventilation or oxygenation;

trachea. A detailed discussion of the

N the child who has been on ventilatory

management of ventilated patients is

support for an acute respiratory insult

beyond the scope of this Handbook, but

and then fails to wean and will require

basic physiological principles apply. The

long-term ventilation or supplemental

settings used need to allow adequate oxygen

oxygen. For the purposes of audit and

delivery and carbon dioxide removal. Oxygen

census the following definition of long-

delivery requires adequate pressures to

term ventilation is often accepted: ‘‘Any

deliver gas to the alveoli, and for the partial

child who, when medically stable,

pressure of inspired oxygen (PIO₂) to be

continues to need a mechanical aid for

sufficient that oxygen will diffuse across to

breathing which may be acknowledged

the blood. Carbon dioxide removal depends

after a failure to wean or a very slow

on adequate alveolar ventilation, but

wean, 3 months after the institution of

diffusion is rarely a problem (carbon dioxide

ventilation.’’ Some of these children will

have had an underlying incipient

and so tidal volume and rate become the

respiratory failure and represent as

critical factors. In simplistic terms, oxygen

‘‘acute-on-chronic’’ respiratory failure.

delivery is often increased by adjusting the

airway pressures, whereas carbon dioxide

For children with an evolving underlying

removal is effected by adjusting the rate.

disorder, unlike ARF, characterised by life-

Inevitably things are more complex than

threatening derangements in arterial blood

this, and proper lung expansion is critical to

gases and acid-base status, the

both, but the differing factors involved in

manifestations of chronic respiratory failure

determining gas exchange for each gas need

are less apparent or dramatic. Acute

to be understood when interpreting and

respiratory failure develops over minutes to

reacting to blood gas results.

hours with a commensurate drop in pH.

542

ERS Handbook: Paediatric Respiratory Medicine

Chronic respiratory failure develops over a

Table 1. Examples of causes of chronic respiratory failure

much longer period, allowing time for renal

in children

compensation and an increase in

Loss of central respiratory drive to breathe

bicarbonate concentration with a normal or

near normal pH.

Congenital central hypoventilation

syndrome

Causes of chronic respiratory failure There are

Acquired central hypoventilation

many causes of chronic respiratory failure in

syndrome

children. Any aetiological classification

results in artificial ‘‘lumping’’ especially

Post-infectious encephalopathy

where dual pathology exists. However, for

Non-accidental injury

epidemiological studies and audit it is

High spinal injury

useful to consider three main categories:

Birth injury

N a loss of central respiratory drive to

Vascular malformations

breathe;

Post-neurosurgery

N ineffective thoracic musculoskeletal

function;

Ineffective thoracic musculoskeletal

function

N disorders of the respiratory tract.

Spinal muscular atrophy

Examples from each of these broad

Congenital myopathy

categories are listed in table 1.

Duchenne muscular dystrophy

Assessment for chronic respiratory failure For

Kyphoscoliosis

children with an underlying condition who

are at risk of developing chronic respiratory

Neurometabolic conditions

failure, assessments should be designed to

Skeletal dysplasia

determine the earliest signs of failure so that

Mucopolysaccharidosis

appropriate intervention can be introduced

before secondary complications develop. As

Thoracic dystrophy

with acute failure there will be those who will

Phrenic nerve damage

predominantly have hypoxic Type I failure

Disorders of the respiratory tract

(e.g. a child with severe CF) and those with

Conditions of the upper airways

hypercapnic Type II failure (e.g. a boy with

Duchenne muscular dystrophy).

Craniofacial disorders

Achondroplasia

For children with CF, spirometry will give an

indication that chronic respiratory failure

Tracheo-bronchomalacia

may be developing. When the FEV1 falls

Acquired: prematurity, post-surgery to

below 30-40% predicted, oxygen saturation

the trachea

will often begin to decrease with exercise or

Congenital: following repair of tracheo-

physiotherapy and additional oxygen may be

oesophageal fistula or vascular ring

required. This may progress to overnight

Disorders of pulmonary parenchyma

decline in oxygen saturation with an

eventual rise in carbon dioxide, triggering

Pulmonary hypoplasia

discussion about the use of overnight NIV.

Chronic lung disease of prematurity

Failure to notice chronic failure can lead to

Progressive lung diseases such as CF

increasing lethargy, failure to clear

or interstitial lung diseases

secretions, increased propensity to chest

infections and even cor pulmonale and signs

Recurrent aspiration

of carbon dioxide retention.

For children with Duchenne muscular

notice early signs of respiratory failure so

dystrophy, and other slowly progressive

that additional respiratory support can be

neuromuscular disorders, it is important to

introduced in a timely fashion; not too soon

ERS Handbook: Paediatric Respiratory Medicine

543

before it is required, but not too late so that

in the pattern of work for many respiratory

complications have developed.

paediatricians. Contributing factors to this

change in practice include:

Regular assessments will include a history of

decreasing cough efficacy, fatigue, weight

N the development of portable ventilators

loss, poor appetite and morning headaches.

that can be used in the home setting;

Lung function can provide important clues

N the use of paediatric noninvasive

as to the likelihood of impending respiratory

interfaces to deliver ventilation, either in

failure; an FVC ,40%, FEV1 ,40%, a poor

the form of CPAP or BiPAP;

peak cough flow and a specialised test of

N increasing acceptance on the use of a

respiratory muscle strength, such as the

tracheostomy in the home setting;

maximal inspiratory and expiratory efforts.

N improvements in intensive care allowing

for the survival of children with

It is now known that a sleep study is

life-threatening illness but ending in

essential in the early assessment for chronic

incomplete recovery and a chronic

respiratory failure in progressive

ventilatory need;

neuromuscular weakness. Measurement of

N a growing experience (especially in

overnight oxygen and carbon dioxide can

children with neuromuscular conditions)

allow categorisation of incipient respiratory

that long-term ventilatory support

failure into three levels:

improves quality of life and even alters

the natural history of some conditions;

N level I: intermittent rapid eye movement

N enthusiastic internet-based organisations

(REM) sleep, hypercapnia and

and support groups advocating the value

hypoxaemia;

and gain of moving children from the

N level II: nocturnal hypoventilation in REM

hospital to home setting.

and non-REM sleep;

N level III: hypoventilation during all sleep

and wakefulness.

Further reading

The documentation of these changes during

Fauroux B, et al. (2008). NIV and chronic

sleep provides early evidence of a need for

respiratory failure in children. Eur Respir

additional respiratory support. If missed, the

Monogr; 41: 272-284.

neuromuscular patient may lose carbon

Hull J, et al.

(2012). British Thoracic

dioxide sensitivity in their respiratory drive

Society guideline for the respiratory man-

and run carbon dioxide levels at a chronically

agement of children with neuromuscular

weakness. Thorax; 67: Suppl. 1, i1-40.

high level. The patient now has little

Simonds AK. Non-invasive Respiratory

respiratory reserve and relies entirely on a

Support. A Practical Handbook.

2nd

hypoxic drive to breathe, making them very

Edn. London, Arnold, 2001.

vulnerable to acute on chronic deterioration.

Wallis C, et al. (2011). Children on long-

Conclusion

term ventilatory support:

years of

progress. Arch Dis Child; 96: 998-1002.

The number of children using long-term

West J. Respiratory Physiology

- The

ventilatory support for chronic respiratory

Essentials. 8th Edn. Lippincott, Williams

failure has increased significantly over the

& Wilkins, 2011.

past decade and constitutes a major change

544

ERS Handbook: Paediatric Respiratory Medicine

Home oxygen therapy,

invasive ventilation and NIV,

and home ventilatory support

Brigitte Fauroux, Adriana Ramirez and Sonia Khirani

The ability to sustain spontaneous

oxygen. The second type of respiratory

ventilation can be viewed as a balance

failure, ‘‘ventilatory/pump failure’’, is the

between neurological mechanisms

result of an imbalance of the respiratory

controlling ventilation together with

system. In normal individuals, central

respiratory muscle strength on the one

respiratory drive and ventilatory muscle

hand, and the respiratory load, determined

power exceed the respiratory load, thus

by lung, thoracic and airway mechanics, on

explaining the ability to maintain adequate

the other hand.

spontaneous ventilation during different

physiological conditions such as

Chronic respiratory failure is constituted by

wakefulness, sleep and exercise. However,

two different types of respiratory failure,

significant dysfunction of any of these three

which have a distinct pathophysiological

components of the respiratory system may

background and therapeutic implication

impair the ability to generate spontaneously

(fig. 1). The first type of respiratory failure,

efficacious breaths. Indeed, if the

‘‘lung failure’’, is characterised by an

respiratory load is too high and/or

abnormality of the alveolar-capillary

ventilatory muscle power or central

membrane, as observed in interstitial lung

respiratory drive is too low or inefficient,

diseases. In this type of failure, the different

ventilation may become insufficient. This

components of the ventilatory balance are

type of respiratory failure is characterised by

globally normal, with the main abnormality

alveolar hypoventilation with hypercapnia

being the transfer of the gases from the

and hypoxaemia.

alveoli through the alveolar capillary

membrane, resulting primarily in

The treatment of respiratory failure is

hypoxaemia due to the greater diffusion

determined by the type of respiratory failure.

capacity of carbon dioxide compared to

In the case of an abnormality of the

alveolar-capillary membrane, the treatment

is oxygen. Oxygen therapy, by increasing the

Key points

oxygen concentration within the alveolar

space, will increase the alveolar-capillary

N The main objective of oxygen therapy

gradient and, as a consequence, the arterial

and mechanical ventilation is to

oxygen concentration. While in the case of

restore a normal nocturnal and

an imbalance of the ventilatory balance, the

daytime gas exchange and a normal

aim of the treatment is to correct the

sleep quality.

disequilibrium, by either unloading the

respiratory muscles in the case of an

N LTOT is the treatment of choice of

increase in respiratory load (as observed in

chronic hypoxaemia.

CF), or by replacing them in the case of

Mechanical ventilation is the

respiratory muscle weakness (as observed in

treatment of choice of chronic

neuromuscular diseases). In the rare cases

hypercapnia.

of a failure of central drive (as in Ondine’s

curse) the aim of the treatment is to replace

ERS Handbook: Paediatric Respiratory Medicine

545

the brain. Ventilatory assistance,

Oxygen therapy

preferentially by a noninvasive route such as

NIV, represents the treatment of choice for

The aim of LTOT is to prevent or correct the

deleterious consequences of chronic

this type of respiratory failure, by

hypoxaemia, such as pulmonary

maintaining sufficient minimal ventilation.

hypertension and heart failure. But in

Besides these two types of respiratory failure,

children, in the absence of validated markers

children may present with structural or

of end-organ morbidity, the minimal level

anatomical upper airway obstruction,

(and duration) of hypoxaemia that may be

exposing them to recurrent episodes of upper

safely tolerated is not known. Moreover, it is

airway closure, which are responsible for

probable that the consequences of chronic

apnoeas or hypopnoeas, especially during

hypoxaemia vary according to age, with

sleep. These children do not present with

younger children being more susceptible,

overt respiratory failure as the bypass of the

and to the type of underlying disease.

obstruction restores normal breathing. In

In clinical practice, recommendations for

these patients, CPAP delivered by a

LTOT derive from the normal SpO₂ values

noninvasive interface, such as a nasal mask,

observed in healthy children. As such,

is the technique of choice, with a

nocturnal SpO₂ should not fall below 90%

tracheostomy being reserved for CPAP failure.

without any desaturation (rapid drops in

During sleep, the breathing process is less

SpO₂ of o3%). Thus, the oxygen flow should

efficient. Indeed central drive,

be adapted to reach this target, without any

chemoreceptor and mechanoreceptor

excessive correction in order to avoid the

sensitivity are less performant during sleep

potential side-effects of hyperoxia. The

than during wakefulness with a relationship

harmful consequences of hyperoxia have

to the depth of sleep, with stages 3 and 4

been well documented in the premature

sleep being the least responsive. Sleep is

child, with retinopathy being one of the most

also associated with changes in respiratory

important side-effects. The deleterious

consequences of hyperoxia have not been

mechanics with an increase in ventilation

documented in the older child and in other

(functional residual capacity). Although the

diseases, but an SpO₂ target between 94%

activity of the diaphragm is preserved, those

and 96% is safe and largely sufficient.

of the intercostal and the upper airway

muscles decrease significantly. All these

The most common paediatric diseases that

abnormalities explain a physiological degree

may need LTOT are bronchopulmonary

of nocturnal hypoventilation causing a 2-3%

dysplasia (BPD), interstitial lung disease and

fall in SpO₂ and an increase in PaCO₂ of up to

CF. BPD is probably the disease in which the

3 mmHg (0.4 kPa) in healthy adults. In

consequences and benefits of LTOT have

children with moderate abnormal gas

been studied the most extensively. As such, it

exchange during wakefulness, these

has been shown that oxygen therapy

physiological modifications may precipitate

decreases central sleep apnoeas and

respiratory failure during sleep, underlining

improves sleep quality in infants with BPD. A

the importance of systematic sleep studies

sleep SpO₂ level .91-92% is also associated

in all children who present with, or who are

with a better weight gain compared to lower

suspected of, respiratory failure. This

SpO₂ levels. In CF, nocturnal desaturation,

worsening of breathing abnormalities during

but not the minimal nocturnal SpO₂, has been

sleep is of major importance for the

shown to be associated with pulmonary

diagnosis and treatment of all types of

hypertension. No information on the

respiratory failure. Indeed, the criteria to

deleterious consequences of chronic

start long-term oxygen therapy (LTOT) and

hypoxaemia is available for children with

NIV will be based on overnight parameters

interstitial lung disease.

such as SpO₂ and transcutaneous oxygen

and carbon dioxide pressure (PtcO₂ and

The choice of the oxygen source depends on

PtcCO₂, respectively).

the daily duration of LTOT (sleep only or

546

ERS Handbook: Paediatric Respiratory Medicine

Abnormalities of the

respiratory mechanics

alveolar-capillary barrier

Respiratory

Capillary

control

Respiratory

muscle capacity

Alveolus

Respiratory

load

Neuromuscular

diseases

Lung and airway

diseases

PaCO

PaO2

Figure 1. The two different types of respiratory failure: ventilatory imbalance (left) and abnormalities of the

alveolar-capillary membrane (right).

also during daily activities), the cost and

The most common diseases that may need

local facilities. An oxygen concentrator is a

NIV are neuromuscular disorders,

cheap and safe source but does not allow

hypercapnic lung diseases, such as

ambulation. When LTOT is required during

advanced CF or COPD, and central

the daytime, and especially during daily

hypoventilation if the patient has a minimal

activities, gaseous or liquid oxygen is

respiratory autonomy while awake. The

preferred. The efficacy of LTOT should be

criteria to start NIV are not validated in

checked by overnight gas recording to check

children but most experts recommend NIV

the SpO₂ but also the carbon dioxide level, in

when nocturnal PtcCO₂ exceeds 50 mmHg

order to detect hypercapnia, especially in

despite optimal medical treatment. The aim

patients with lung diseases such as CF, and

of NIV is to maintain the maximal PtcCO₂

the possibility of NIV should be discussed.

below 50 mmHg, by providing a sufficient

tidal volume and V9E.

Noninvasive ventilation

Numerous ventilators are available for home

The aim of NIV is to correct alveolar

ventilation but few have been specifically

hypoventilation, i.e. chronic hypercapnia.

designed for children. However,

Even if the deleterious consequences of

manufacturers have improved the

chronic hypoxaemia are not well documented

performances of the most recent devices

in children, our knowledge is even more

with some ventilators being as performant

limited with regard to the consequences of

as intensive care ventilators. The ventilatory

long-term hypercapnia. Besides systemic

modes have improved significantly over

hypertension, very few side-effects have been

recent years. Initially, two modes were

objectively reported in children. Again, in

available, a volume-target and a pressure-

clinical practice, the target values are derived

target mode, with the former being

from the values observed in healthy children.

preferentially prescribed for patients with a

As such, most authors and experts

restrictive lung disease, such as patients

recommend that the maximal (nocturnal)

with a neuromuscular disease, and the latter

PtcCO₂ should not exceed 50 mmHg.

being preferentially prescribed for patients

ERS Handbook: Paediatric Respiratory Medicine

547

with a lung disease such as CF or COPD.

obstruction. These diseases may be

But presently, new ‘‘dual control’’ modes,

congenital and/or acquired, and may require

combining a volume- and a pressure-

CPAP in order to prevent airway closure and,

targeted mode are being increasingly used,

thus, the consequent apnoeas and

even if they have not been validated

hypopneas. Indeed, by maintaining a normal

specifically for the paediatric population. In

airway patency during the entire breathing

practice, in the case of chronic alveolar

cycle, CPAP may improve alveolar

hypoventilation, the main objective is to

ventilation. CPAP may also prevent the

maintain a sufficient minimal tidal volume

decrease of functional residual capacity by

to correct chronic hypercapnia. This may be

delivering a continuous distending pressure.

achieved by setting a sufficient tidal volume,

Common diseases that may cause severe

inspiratory pressure and inspiratory time,

upper airway obstruction are craniofacial

without forgetting a back-up rate for patients

malformations, such as Crouzon and Apert

at risk for sleep apnoeas or those who are

disease, Franceschetti syndrome, Pierre

not able to trigger the ventilator, such as

Robin syndrome, achondroplasia, and other

patients with neuromuscular disease. As a

congenital bone diseases, as well as

consequence, the adjustment of the

metabolic disorders such as

ventilator will thus be based on the

mucopolysaccharidoses, and Down

combined recording of SpO₂ and PtcCO₂.

syndrome. The maintenance of airway

patency throughout the entire breathing

The NIV interface is as important as the

cycle restores normal ventilation with

ventilator. Indeed, the patient will not be

correction of the OSA. The criteria to start

able to tolerate the NIV if there is

CPAP have not been validated in children. In

discomfort, pain or leaks due to a non-

the absence of reliable markers of end-organ

adapted interface. A large number of

morbidity of OSA, the indication is based on

industrial interfaces are available for long-

the association of clinical and

term NIV in children, even if the range is

polysomnographic parameters.

smaller for children compared to adults.

Adenotonsillectomy is the treatment of first

The choice will be guided by the age of the

choice followed, eventually, by an anti-

patient, the underlying disease and the

inflammatory treatment in the case of

ventilatory mode (allowing an interface with

moderate residual OSA. If the OSA persists

or without a manufacturer leak) and, most

and is associated with abnormal gas

importantly, the facial physiognomy of the

exchange, CPAP should be initiated. If the

child. The majority of children are ventilated

residual OSA is less severe, without

with a nasal mask. A facial mask is reserved

significant abnormalities in gas exchange, a

for those who have mouth leaks during

1-month trial, followed by an objective and

sleep. Nasal prongs or cannula are relatively

subjective sleep evaluation, may be

new interfaces available for older children

proposed.

that have minimal contact with the patient’s

face. Of note, because of the cutaneous and

Numerous simple CPAP devices are

facial side-effects, such as facial flattening

available but most do not have an internal

or maxilla retrusion, which may be observed

battery and alarms adapted for young

with all types of interfaces in young

children. Numerous new ‘‘automatic’’ CPAP

children, a systematic and close follow-up

modes are available for adult patients. These

by a paediatric maxillofacial team is

new modes are based on the analysis of the

mandatory.

flow pattern of the patient with the aim to

automatically adapt the level of CPAP to a

Continuous positive airway pressure

change in airflow. However, it is not known

Obstructive diseases of the upper airways

if these devices are able to detect the

are not rare in children. Apart from nasal

changes in airflow in young children and, in

obstruction and tonsils and adenoids

a recent clinical study, the use of such a

hypertrophy, children may present with

mode was not associated with an increase in

numerous causes of chronic upper airway

CPAP efficacy or compliance.

548

ERS Handbook: Paediatric Respiratory Medicine

The CPAP mode requires a vented interface

exchange and a normal sleep quality, by

with a manufacturer leak, allowing carbon

means of the least invasive treatment, in

dioxide clearance through the constant leak.

order to preserve the best quality of life for

The choice of vented interfaces is much

the child and their family.

broader than for nonvented interfaces. The

side-effects of CPAP interfaces are similar to

that of NIV interfaces, justifying the same

Further reading

maxillofacial follow-up.

Bersanini C, et al.

(2012). Nocturnal

Tracheotomy

hypoxemia and hypercapnia in children

with neuromuscular disorders. Eur Respir

Tracheotomy represents the treatment of

J; 39: 1206-1212.

last resort for severe airway obstruction that

Bhattacharjee R, et

al.

(2010).

may not be successfully relieved by CPAP,

Adenotonsillectomy outcomes in treat-

and for persistent nocturnal hypoventilation

ment of OSA in children: a multicenter

despite NIV or when NIV is not possible, e.g.

retrospective study. Am J Respir Crit Care

Med; 82: 676-683.

in patients with advanced neuromuscular

Clinical indications for noninvasive posi-

disease or in very young infants. In the case

tive pressure ventilation in chronic

of isolated upper airway obstruction, the

respiratory failure due to restrictive lung

patient will not need simultaneous

disease, COPD, and nocturnal hypoventi-

ventilatory assistance, whereas in the case of

lation - a Consensus Conference Report.

lung or neuromuscular disease, the patient

Chest 1999; 116: 521-534.

will need ventilatory assistance by means of

Damy T, et al. (2012). Pulmonary accel-

a tracheostomy.

eration time to optimize the timing of

lung transplant in cystic fibrosis. Pulm

Tracheotomy is associated with a significant

Circ; 2: 75-83.

morbidity and discomfort and may impair

Dempsey JA, et al. (2010). Pathophysiology

normal development and, particularly,

of sleep apnea. Physiol Rev; 90: 47-112.

language development. Discomfort and

Essouri S, et al.

(2005). Noninvasive

social life and family disruption are common

positive pressure ventilation in infants

in patients with a tracheostomy. Indeed,

with upper airway obstruction: compar-

although tracheotomised children may be

ison of continuous and bilevel positive

safely discharged home after careful family

pressure. Intensive Care Med; 31: 574-580.

education and training, home treatment

Fauroux B, et al. (2001). Chronic stridor

may be difficult or even unfeasible for some

caused by laryngomalacia in children.

families.

Work of breathing and effects of non-

invasive ventilatory assistance. Am J

Numerous different tracheostomy tubes are

Respir Crit Care Med; 164: 1874-1878.

available for children; the size and format

Fauroux B, et al.

(2003). Long-term

should be adapted individually. The aims of

noninvasive mechanical ventilation for

a tracheotomy are the same as for the other

children at home: a national survey.

ventilatory assistance equipment; nocturnal

Pediatr Pulmonol; 35: 119-125.

and diurnal gas exchange together with

Fauroux B, et al.

(2005). Facial side

normalised sleep quality.

effects during noninvasive positive pres-

sure ventilation in children. Intensive Care

The necessity to maintain the tracheostomy

Med; 31: 965-969.

should be evaluated on a regular basis, in

Fauroux B, et al. (2008). Performance of

order to decannulate or switch the patient to

ventilators for noninvasive positive-pres-

NIV or CPAP whenever possible.

sure ventilation in children. Eur Respir J;

31: 1300-1307.

In conclusion, oxygen therapy, NIV, CPAP

Fauroux B, et al. (2012). Sleep quality and

and tracheotomy are complementary

nocturnal hypoxaemia and hypercapnia in

treatments for children with chronic

children and young adults with cystic

respiratory failure. The main objective is to

fibrosis. Arch Dis Child; 97: 960-966.

restore a normal nocturnal and daytime gas

ERS Handbook: Paediatric Respiratory Medicine

549

Gallagher TQ, et al.

(2010). Pediatric

Marcus CL, et al. (2012). Randomized,

tracheotomy. Adv Otorhinolaryngo;

73:

double-blind clinical trial of two different

26-30.

modes of positive airway pressure ther-

Giovannini-Chami L, et al. (2012). Work of

apy on adherence and efficacy in children.

breathing to optimize noninvasive venti-

J Clin Sleep Med; 8: 37-42.

lation in bronchiolitis obliterans. Intensive

Moyer-Mileur LJ, et al. (1996). Eliminating

Care Med; 38: 722-724.

sleep-associated hypoxemia improves

Groothuis JR, et al. (1987). Home oxygen

growth in infants with bronchopulmonary

promotes weight gain in infants with

dysplasia. Pediatrics; 98: 779-783.

bronchopulmonary dysplasia. Am J Dis

Paiva R, et al.

(2009). Carbon dioxide

Child; 141: 992-995.

monitoring during long-term noninvasive

Guilleminault C, et al. (1986). Alternative

respiratory support in children. Intensive

treatment to tracheostomy in obstructive

Care Med; 35: 1068-1074.

sleep apnea syndrome: nasal continuous

Pérez-Ruiz E, et al.

(2012). Paediatric

positive airway pressure in young chil-

patients with a tracheostomy: a multi-

dren. Pediatrics; 78: 797-802.

centre epidemiological study. Eur Respir J;

Julliand S, et al.

(2012). Lung function,

40: 1502-1507.

diagnosis and treatment of sleep-disor-

Ramirez A, et al. (2012). Interfaces for

dered breathing and in children with

long term noninvasive positive pressure

achondroplasia. Am J Clin Genetics;

ventilation in children. Intensive Care Med;

158A: 1987-1993.

38: 655-662.

Kerbl R, et al. (1996). Congenital central

Rutgers M, et al.

(1996). Respiratory

hypoventilation syndrome

(Ondine’s

insufficiency and ventilatory support.

curse syndrome) in two siblings: delayed

39th European Neuromuscular Centre

diagnosis and successful noninvasive

International workshop. Neuromuscul

treatment. Eur J Pediatr; 155: 977-980.

Disord; 6: 431-435.

Kheirandish L, et al. (2006). Intranasal

Sekar KC, et al. (1991). Sleep apnea and

steroids and oral leukotriene modifier

hypoxemia in recently weaned premature

therapy in residual sleep-disordered

infants with and without bronchopulmon-

breathing after tonsillectomy and adenoi-

ary dysplasia. Pediatr Pulmonol; 10: 112-116.

dectomy in children. Pediatrics;

117:

Sullivan CE, et al.

(1981). Reversal of

e61-e66.

obstructive sleep apnea by continuous

Leboulanger N, et al.

(2010). Physio-

positive airway pressure applied through

logical and clinical benefits of noninva-

the nares. Lancet; 1: 862-865.

sive respiratory support in infants with

Ward S, et al.

(2005). Randomised

Pierre Robin sequence. Pediatrics;

126:

controlled trial of non-invasive ventilation

1056-1063.

(NIV) for nocturnal hypoventilation in

Management of pediatric patients requir-

neuromuscular and chest wall disease

ing long-term ventilation. Chest 1998; 113:

patients with daytime normocapnia.

322S-336S.

Thorax; 60: 1019-1024.

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ERS Handbook: Paediatric Respiratory Medicine

Primary ciliary dyskinesia

Deborah Snijders, Serena Calgaro, Massimo Pifferi, Giovanni Rossi and

Angelo Barbato

Primary ciliary dyskinesia (PCD) is

from a European Respiratory Society Task

predominantly inherited as an autosomal

Force on PCD in children, a prevalence of

recessive disorder leading to recurrent and

diagnosed cases in 5-14-year-olds was found

chronic upper and lower respiratory tract

to be between one in 10 000 and one in

infection and, in 40-50% of cases, mirror

20 000.

image organ arrangement and other forms

of heterotaxy. Ciliary dysfunction is also

In clinical samples of patients with diffuse

bronchiectasis, PCD is naturally more

implicated in a wider spectrum of diseases,

common. It might account for up to 13% of

such as polycystic liver and kidney disease,

all patients with bronchiectasis, being

biliary atresia, and central nervous system

relatively more common in North African

abnormalities including retinopathy and

patients than European patients. The

hydrocephalus.

average age at diagnosis, in a paediatric

The prevalence of PCD is very difficult to

case series by Coren et al. (2002), was

estimate accurately. In a European survey

4.4 years (6 years for those without situs

inversus). More recent data showed a

median age at diagnosis of 5.3 years, lower

Key points

in those with situs inversus (3.5 versus

5.8 years).

N The gold standard for the diagnosis of

Cilia structure

PCD is a combination of ciliary beat

pattern and frequency analysis and

Normal cilia structure The epithelial lining of

electron microscopy in patients with

the large airways and contiguous structures,

upper or lower airway disease.

including the paranasal sinuses, middle ears

and Eustachian tubes, consists of ciliated

N Specific ultrastructural defects

pseudostratified columnar epithelium.

responsible for PCD result in specific

Ciliated cells are also found in the

abnormalities in beat frequency and

ependymal lining of the brain and fallopian

pattern; however, a small number of

tubes. In addition, the spermatozoal flagella

milder phenotypes may appear with

(tail of spermatozoa) has a core structure

subtle or no apparent structural

that is identical to cilia.

defects or ciliary dysfunction.

N When diagnosis by ultrastructural

Each matured ciliated cell has up to 200

analysis or beating patterns analysis is

cilia. Each cilium has an array of longitudinal

not conclusive, but the suspicion of

microtubules arranged as nine doublets

PCD is high, further testing should be

formed in an outer circle around a central

performed in order to find the right

pair. The main structural protein of these

diagnosis, such as nasal nitric oxide,

doublets is tubulin. The microtubules are

immunofluorescent microscopy and

anchored by a basal body in the apical

genetic analysis.

cytoplasm of the cell. Radial spokes connect

the outer microtubular doublets with a

ERS Handbook: Paediatric Respiratory Medicine

551

central sheath of proteins around the central

stasis of the respiratory tract secretions,

tubules.

which will be responsible for the clinical

manifestations of the disease.

Cross-section of the cilia (fig. 1) reveals

inner and outer dynein arms (IDA and ODA,

Genetics of PCD

respectively), which are attached to a

Inheritance PCD (MIM#242650) is a

subunit A of each microtubule doublet. The

genetically heterogeneous disorder, which is

microtubules are interconnected by nexin

predominantly inherited as an autosomal

links, radial spokes and dynein arms. Cilia

recessive trait. To date, the majority of the

beating originates from the sliding of

genes identified for autosomal recessive

microtubule doublets, which is generated by

PCD variants (DNAI1, DNAI2, DNAH5,

the ATPase activity of the dynein arms.

DNAH11 and TXNDC3) encode ODA

The dynein arms are periodically distributed

components while KTU and LRRC50 are

along the axoneme; ODAs with a 24-nm

required for cytoplasmic pre-assembly of

periodicity and IDAs with a 96-nm

axonemal dyneins (table 1). In addition,

periodicity. The dynein arms are

mutations in the two genes RSPH9 and

multiprotein complexes that project from

RSPH4A have been reported in PCD patients

the microtubule A of every outer doublet.

with abnormalities of the central

The outer arms face towards the boundary

microtubular pair. Molecular defects

of the axoneme and the inner arms face the

affecting dynein regulatory complexes (DRC)

central sheath.

and IDAs are characterised by the absence

of GAS11 (a DRC component) and the IDA

Ciliary movement involves two phases:

component DNALI1 from the ciliary

axoneme (CCDC38 and CCDC40). In a

N an effective stroke phase that sweeps

minority of cases, other inheritance patterns

forward,

have been recognised.

N a recovery phase during which the cilia

bend backward and extend into the

Genetic analyses may help to assess the

starting position for the stroke phase.

carrier status of family members and

provide tools for informed reproductive

The mucous lining present on the

choices, although this is only currently

respiratory epithelium has an inner serous

possible for a minority of families. They may

layer called the sol phase, in which the cilia

also become more important diagnostically

recover from their active beat, and an outer,

as ,35% of PCD patients carry either

more viscous layer, the gel phase. The tips

DNAH5 or DNAI1 mutations (hot spots and

of the cilia are in contact with the gel layer

founder mutations are worthy of analysis in

during the stroke phase in order to propel

patients with ODA).

the secretions forward. During the recovery

phase the cilia lose contact with the mucus

Clinical aspects of PCD

layer, reinforcing the forward thrust of the

mucus.

Children with PCD often have a clinical

history of lower airway disease, manifested

Normal ciliary beat frequency is 1000-

by a chronic ‘‘wet’’ sounding cough and

1500 beats?min^-1. The frequency is slower in

occasionally wheeze or shortness of breath.

the peripheral airways (e.g. bronchioles)

compared to the larger airways (e.g.

Moreover, .75% of full-term neonates with

trachea). The ciliary motility is maintained in

PCD have neonatal respiratory distress

the same plane along the length of the

requiring supplemental oxygen for days to

airways and results in mucociliary transport

weeks.

rates up to 20-30 mm?min^-1.

Complications of chronic lower airway

Whenever there is an alteration in ciliary

infections, such as bronchiectasis, can be a

structure or function, there will be an

sign of detoriation of lung function and are

alteration in mucociliary clearance, with

more frequent in adults.

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ERS Handbook: Paediatric Respiratory Medicine

Ciliary membrane

Peripheral microtubule doublet

Radial spoke

ODA

Nexin link

IDA

Central microtubule pair

Central sheath

Figure 1. Cross section of the cilia. a) Schematic diagram of a cilium revealing 9+2 arrangement of nine

peripheral microtubule doublets surrounding a central microtubule pair. b, c) Transmission electron

microscopy of normal cilia (b) and absent IDA and ODA (c). Reproduced from Becker-Heck (2012).

In addition, virtually all subjects have evidence

Ear symptoms (recurrent otitis media and

of chronic upper airway symptoms such as

glue ear) are a frequent complication that

chronic rhinitis (nasal discharge, episodic

can require multiple interventions, including

facial pain and anosmia). This may be

repeated courses of antibiotics.

confirmed by either physical examination and/

or sinus imaging. Continuous rhinorrhoea can

PCD should be suspected in cases of situs

be present from the first day of life.

inversus totalis or heterotaxy; ,25% of

ERS Handbook: Paediatric Respiratory Medicine

553

individuals with situs inversus totalis have

PCD. Prevalence of PCD within the

heterotaxy subclass is unknown. In PCD

patients, 40-50% present with situs inversus

totalis (Kartagener’s syndrome) and 6%

have heterotaxy (situs ambiguus).

Adult males with PCD may be infertile due

to impaired sperm motility because the

flagella of the sperm and cilia often, but not

always, have the same ultrastructural and

functional defects. Some females with PCD

have normal fertility, but others have

impaired fertility and an increased risk for

ectopic pregnancy because of impaired

ciliary function in the oviduct.

The clinical aspects of PCD are shown

according to the different age groups in

table 2. A positive family history of PCD is

an indication to undergo diagnostics, as this

accounted for 10% of cases in one series.

Also siblings of probands should have PCD

excluded.

Diagnosis of PCD is frequently delayed, in

part, because it presents with symptoms

(rhinitis, secretory otitis media, cough and

recurrent bronchitis) that are common in

healthy children.

PCD as an associated diagnosis Beside the

classical signs and symptoms, we

recommend that PCD should be at least

considered when the following diagnoses

are made, in particular if there is a family

history of more than one of these

conditions, or if the patient has other

features of PCD.

N Complex congenital heart disease,

especially with disorders of laterality,

such as atrial isomerism, transposition of

the great vessels, double outlet right

ventricle, anomalous venous return,

interrupted inferior vena cava and

bilateral superior vena cava.

N Asplenia (predominant bilateral right-

sidedness (right isomerism)), or

polysplenia (predominant bilateral left-

sidedness (left isomerism)). This is

present in at least 6% of individuals with

PCD.

N Polycystic kidney or liver disease.

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Clinical presentation of symptoms

Antenatal period

Situs inversus totalis or heterotaxy on antenatal ultrasound

scanning

Mild fetal cerebral ventriculomegaly

Newborn period

Neonatal respiratory distress in full-term neonates

Continuous rhinorrhoea from the first day of life

Mirror image organ arrangement and other forms of heterotaxy

Hydrocephalus may occur in some individuals with PCD and may

reflect dysfunctional ependymal cilia

Childhood

Chronic productive or wet sounding cough, associated or not

with recurrent atelectasis or pneumonia

Atypical asthma

Idiopathic bronchiectasis

Daily rhinitis, without remission

Severe chronic sinusitis in older children

Otitis media with effusion/hearing loss

Adolescence and adulthood

Same as for childhood

Bronchiectasis, more evident in adulthood

Chronic mucopurulent sputum production

Digital clubbing

Pulmonary function tests with progressive obstructive or mixed

pattern

Nasal polyposis and halitosis

Infertility

N Hydrocephalus.

Samples of ciliated cells can be obtained by

N Biliary atresia.

nasal brushing or bronchoscopic samples.

N Severe oesophageal disease

With the only notion that patients should be

(oesophageal atresia or severe reflux).

free from an acute upper respiratory tract

N Retinal degeneration, including retinitis

infection for 4-6 weeks to help minimise

pigmentosa.

poorly ciliated samples or secondary

N Oral-facial-digital syndrome type 1.

dyskinesia, avoiding complication of the

analysis.

Diagnostic testing

Ciliary beat pattern and frequency analysis

The diagnosis of PCD should be based on

Analysis of ciliary beat pattern using a slow

the presence of a typical clinical phenotype

motion replay videotape recorder and a

and appropriate diagnostic testing. PCD is a

digital high speed video camera is

rare disease and diagnostic analysis and

recommended as part of the diagnostic

interpretation is difficult. There is no one

testing for PCD. Ciliated samples at 37uC are

gold standard test, a combination of ciliary

observed using a 6100 objective. A digital

function and ultrastructural analysis is

high speed video camera mounted on a

recommended. Screening tests may precede

conventional microscope allows over 500

ciliary analysis, such as nasal nitric oxide

frames per second to be recorded. These are

measurement, saccharin test and

played back in slow motion allowing ciliary

radioaerosol mucociliary clearance tests

beat pattern to be assessed. A permanent

ERS Handbook: Paediatric Respiratory Medicine

555

recording can be made for audit purposes

that do not have significant secondary

and beat frequency can also be measured by

damage can be difficult. This may lead to

directly observing the beating cilia in slow

erroneous reports of new cases of PCD.

motion. In PCD, all of the cilia are seen to be

Various methods to improve analysis of

dyskinetic on slow motion replay. Analysis

images from electron microscopy have been

also allows measurement of ciliary beat

suggested. Some patients with PCD may not

frequency. Specific beat patterns have been

have an obvious ultrastructural defect;

shown to be related to particular

however, normal ciliary ultrastructure

ultrastructural defects. This analysis is

should always prompt a full diagnostic

particularly useful in identifying patients

review.

who have ciliary dyskinesia due to an

ultrastructural defect where beat frequency

Other techniques to assist diagnosis are

is normal: for example, in those with a

ciliated cell culture to improve diagnostic

central microtubular defect such as ciliary

certainty of PCD and to confirm less

common phenotypes, such as ciliary

transposition or central microtubular

disorientation, ciliary aplasia, central

agenesis. A major advantage is that videos

microtubular agenesis and IDA defects.

may be stored as a permanent record,

allowing reassessment if the clinical picture

In addition, the analysis of dynein protein

changes.

localisation by immunofluorescent

Until recently, prior to advances in high-

microscopy may help in the clinical

speed video analysis, ciliary beat frequency

diagnosis of PCD. Not only can it diagnose

without assessment of beat pattern was

ODA but it can also diagnose IDA

common. When the beat frequency is low,

abnormalities in the various genetic

suspicion of PCD is high. It had been

mutations. In addition, the

recommended that if the ciliary beat

immunofluorescent microscopy method is

frequency was above a certain threshold

not altered by secondary ciliary

further tests, such as electron microscopy,

abnormalities.

were not indicated. However, in the

Genetic analysis for some cases of PCD is

experience of some ciliary diagnostic

possible, but it is not recommend as part of

centres, using ciliary beat frequency

initial diagnostic testing. After a clinical

readings to reject the diagnosis of PCD will

diagnosis has been ascertained genetic

result in 10-15% of patients with the disease

testing may be directed according to the

being missed, since these have beat pattern

specific PCD variant (i.e. DNAH5 and DNAI1

abnormalities despite normal beat

testing in PCD patients with ODA defects or

frequency.

DNAH11 testing in a special functional defect).

Electron microscopy is important in the

Respiratory treatment

diagnosis of PCD, and is always performed

when there is any suspicion of the diagnosis.

As with all chronic respiratory diseases, the

However, specialist knowledge is required to

aim of therapy for PCD is to prevent

interpret the various ultrastructural defects

bronchiectasis and to restore or maintain

responsible for PCD and it is acknowledged

normal lung function for as long as possible,

that ultrastructural analysis has limitations.

based on early detection and vigorous

In particular, IDA defects are difficult to

treatment of complications. There are no

determine because they are less electron

randomised trials of PCD treatment and

dense and less frequent along the ciliary

consequently all treatment

axoneme. In addition, it has been shown

recommendations are based on very low

that the dynein motor protein composition

level evidence, or extrapolated from CF

varies along the ciliary length meaning that

guidelines.

ultrastructural defects depending on the site

of the ciliary cross-section can be missed by

Management of PCD involves aggressive

electron microscopy. Obtaining samples

treatment of upper and lower airways

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ERS Handbook: Paediatric Respiratory Medicine

infections and airway clearance by

b₂-agonist in PCD. Exercise is encouraged at

combinations of physiotherapy and physical

all ages to promote general health and

exercise.

wellbeing.

Antibiotics Airway infection with

Surgical procedures Complications of

Haemophilus influenzae, Staphylococcus

bronchiectasis and chronic lung disease

aureus and Streptococcus pneumoniae

become more prominent with age. The role

frequently occur, but Pseudomonas aeruginosa

of lobectomy in advanced bronchiectasis is

and non-tuberculous mycobacteria have also

similar to that in other aetiologies, and can

been reported, usually in adults. The use of

rarely be recommended. Although

antibiotic prophylaxis should be considered

stabilisation or improvement of lung disease

when repeated courses of antibiotics are

is expected with institution of modern

necessary. At the first sign of worsening

treatment, there are reports of PCD patients

respiratory symptoms or deterioration in lung

going on to lung transplantation, both living

function, high-dose oral antibiotics should be

related and cadaveric. This underlines that

administered, even better if the evidence is

PCD is a serious condition, from which

based on sputum or cough swab culture.

adults die, and that paediatricians are

mandated to treat children aggressively to

If P. aeruginosa is isolated, an eradication

retard later lung deterioration.

regime similar to CF should be used,

although evidence of efficacy has yet to be

Environmental exposures Preventive

obtained in PCD patients.

counselling should include:

Other inhaled medications Regular

N the avoidance of active and passive

bronchodilators do not seem to be very

smoking;

effective. The role of nebulised recombinant

N minimisation of exposure to respiratory

human DNase (Pulmozyme; Genentech Inc.,

pathogens;

San Francisco, CA, USA) in PCD patients

N minimisation of exposure to indoor and

remains unproven. However, anecdotally

environmental pollutants.

some patients show an improvement in

respiratory symptoms. As for the use of

Cough suppressant medications must be

nebulised normal or hypertonic saline, it may

avoided.

theoretically be effective in increasing mucus

clearance. N-acetylcysteine has been shown

Immunisations PCD patients should receive

not to be useful.

all childhood immunisations, as well as

pneumococcal and influenza immunisation.

Anti-inflammatory strategies There are no

data on which to recommend or avoid

Outpatient follow-up

inhaled corticosteroids; although the

PCD patients should be managed in

neutrophillic profile of sputum is similar to

specialised centres, in which they have regular

CF. Corticosteroids are probably best

access to respiratory paediatricians,

avoided unless they can be shown to be of

audiology, ENT specialists and respiratory

definite benefit in an individual patient.

physiotherapists. Some patients need access

Airway clearance techniques Airway clearance

to clinical psychology and social work services.

is widely used in PCD patients. Since cough

In addition to general paediatric care, each

clearance is intact, techniques promoting

patient should have regular visits to a

cough seem helpful. Physiotherapy varies

with age, the changing clinical state and

tertiary centre to check growth, lung

local expertise and resources.

function (including pulse oximetry) and

hearing function. Regular sputum or cough

The effect of physical exercise on airway

swab cultures should be performed. Chest

clearance in PCD may help sputum

radiographs are probably relatively

clearance. Exercise has been shown to be a

insensitive. HRCT of the lungs is used to

better bronchodilator than the use of a

define the extent of bronchiectasis, and can

ERS Handbook: Paediatric Respiratory Medicine

557

be repeated to monitor the progression of

Bush A, et al.

(2007). Primary ciliary

the disease when necessary.

dyskinesia: current state of the art. Arch

Dis Child; 92: 1136-1140.

Ferkol T, et al. (2006). Current issues in

the basic mechanisms, pathophysiology,

Further reading

diagnosis and management of primary

Afzelius BA (1976) A human syndrome

ciliary dyskinesia. Eur Respir Monogr; 37:

caused by immotile cilia. Science;

193:

291-313.

317-319.

Engesaeth VG, et al. (1993). New associa-

Armengot M, et al. (2010). Cilia motility

tions of primary ciliary dyskinesia syn-

and structure in primary and secondary

drome. Pediatr Pulmonol; 16: 9-12.

ciliary dyskinesia. Am J Rhinol Allergy; 24:

Kuehni CE, et al. (2010). Factors influen-

175-180.

cing age at diagnosis of primary ciliary

Barbato A, et al. (2009). Primary ciliary

dyskinesia in European children. Eur

dyskinesia: a consensus statement on

Respir J; 36: 1248-1258.

diagnostic and treatment approaches in

Midulla F, et al.

(2003). Flexible endo-

children. Eur Respir J; 34: 1264-1276.

scopy of paediatric airways. Eur Respir J;

Becker-Heck A, et al. Dynein dysfunction

22: 698-708.

as a cause of primary ciliary dyskinesia

Noone PG, et al. (2004). Primary ciliary

and other ciliopathies. In: King SM, ed.

dyskinesia: diagnostic and phenotypic

Dyneins: Structure, Biology and Disease.

features. Am J Respir Crit Care Med; 169:

London, Academic Press, 2012: pp. 602-

459-467.

628.

O’Callaghan C, et al. (2007). Diagnosing

Brueckner M (2007). Heterotaxia, con-

primary ciliary dyskinesia. Thorax;

62:

genital heart disease, and primary ciliary

656-657.

dyskinesia. Circulation; 115: 2793-2795.

Strippoli MP, et al. (2012). Management

Bush A, et al.

(1998). Primary ciliary

of primary ciliary dyskinesia in European

dyskinesia: diagnosis and standards of

children: recommendations and clinical

care. Eur Respir J; 12: 982-988.

practice. Eur Respir J; 39: 1482-1491.

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Gastro-oesophageal reflux-

associated lung disease and

aspiration syndrome

Osvaldo Borrelli, Efstratios Saliakellis, Fernanda Cristofori and Keith J. Lindley

Chronic pulmonary aspiration (CPA)

common in pre-term infants, it remains a

syndrome is defined as the entry of food

major health risk throughout infancy and

materials, gastric contents and/or saliva into

childhood.

the subglottic airways in a manner sufficient

to induce chronic or recurrent respiratory

Different physiological mechanisms have

symptoms (Boesch et al., 2006). These

been suggested to be involved in the

symptoms include:

pathogenesis of CPA, including swallowing

dysfunction, salivary aspiration and gastro-

N cough,

oesophageal reflux (GOR). Swallowing

N asthma and wheezing,

dysfunction during feeding commonly

N recurrent pneumonia,

occurs in neurologically impaired children as

the different phases of the swallowing

N choking, failure to thrive,

process require complex coordination

N apnoea of prematurity,

between voluntary and involuntary actions,

N acute life-threatening events,

although it should be also considered in

N bronchiectasis/pulmonary fibrosis, and

neurologically normal infants with recurrent

N delayed resolution of chronic neonatal

pneumonia, wheezing, chronic cough and

lung disease.

stridor. Chronic aspiration of saliva is the

CPA constitutes one of the most serious

least commonly recognised form of

threats to the normal development of the

aspiration and is usually diagnosed after the

respiratory tract and, although more

development of significant lung injury. It

generally occurs in children with

neurological impairment as a consequence

Key points

of their swallowing dysfunction and

abnormal laryngeal sensation rather than

N CPA constitutes one of the most

abnormal production of saliva. Finally, GOR

serious challenges to the normal

has been implicated in the pathogenesis of

development of the respiratory tract,

CPA, although their relationship is still

and it represents a major health risk

matter of debate.

throughout infancy and childhood.

GOR is a physiological phenomenon

Several studies have reported an

occurring in healthy infants and children

association between GOR and CPA.

several times daily. In contrast, gastro-

oesophageal reflux disease (GORD) is

N Both acid and nonacid reflux are

defined as a condition in which the reflux of

implicated in the pathophysiology of

gastric contents causes troublesome

parenchymal lung disease.

symptoms and/or complication, and

The diagnosis of GOR-related

represents one of the most common causes

aspiration remains challenging

of foregut symptoms in children (Sherman

because of the absence of sensitive

et al., 2009). Although several studies in

and specific tests.

children have emphasised the role of GOR

in the pathogenesis of upper and lower

ERS Handbook: Paediatric Respiratory Medicine

559

airway respiratory disorders, the likelihood

Although a significant body of literature in

of interactions between GOR and the

children has emphasised the role of GOR in

respiratory system remains an area of

the pathogenesis of lower airway respiratory

controversy in paediatric GORD (Tolia et al.,

disorders, it should be stressed that the

2009). It is now generally agreed that certain

range of methodologies used hampers the

underlying disorders predispose children to

interpretation of the results. Examples

higher risk of severe GORD, and thus to

include the lack of standardised definitions

higher risk of GOR-induced respiratory

for respiratory symptoms and/or diseases,

manifestations. These include neurological

and the lack of temporal relationships

disorders, such as cerebral palsy, metabolic

between the onset of respiratory symptoms

or genetic diseases (e.g. Pierre Robin

and/or signs and GORD symptoms and/or

syndrome), congenital abnormalities, (e.g.

signs. Moreover, it is difficult to evaluate

oesophageal atresia with tracheo-

whether GORD children are at increased risk

oesophageal fistula), chronic lung disease

of respiratory disorders in studies that do

(e.g. CF), and anatomical abnormalities

not assess the prevalence of same disorders

characterised by a direct connection

in a representative control group. Similarly,

between the oesophagus and airway. For

the estimation of the prevalence of GORD in

instance, while type III tracheo-oesophageal

children with respiratory disorders using

fistulas are often apparent at birth, H-type

investigational tools cannot be extrapolated

fistulas may be more difficult to detect.

to the general population, as the children are

investigated by a paediatric

gastroenterologist after the failure of

The relationship between GORD and CPA

conventional therapy. Finally, although it is

has been the subject of a number of

now generally agreed that the presence of

epidemiological and clinical studies. In

abnormal GOR extending into the proximal

children with severe neurodisability, severe

oesophagus and cricopharyngeal region is a

lower respiratory infections are associated

risk factor for aspiration, its finding does not

with severe GOR only with coexistence of

inevitably imply aspiration.

swallowing dysfunction (Morton et al.,

1999). GOR seems to be involved in the

Pathophysiology of GOR-induced CPA

pathogenesis of recurrent pneumonia in

,6% of cases (Owayed et al., 2000).

Proximal reflux episodes followed by direct

However, the prevalence of pneumonia

irritation of the airway epithelium are the

and bronchiectasis among children with

pathophysiological mechanism of GOR-

GORD without neurological disability or

related CPA. Through elaborate reflex

congenital oesophageal anomalies is also

mechanisms, a close functional relationship

increased between three and six times over

exists between the oesophagus and the

that among controls (El-Serag et al., 2001;

airway, which ensures the safety of the

Piccione et al., 2012). Finally, several

airway against aspiration of material during

studies have reported an association

an episode of GOR. For instance,

between GORD and CF. The prevalence of

microaspiration of gastric contents into the

GORD in children with CF ranges between

lung can be prevented by protective

25% and 100%, which is six to eight times

mechanisms such as oesophageal clearance

the rate of GORD in the non-CF

and reflex closure of the upper oesophageal

population. One-fifth of newly diagnosed

sphincter and/or vocal cords. However, even

infants and 25-55% of CF children older

if aspiration occurs, gastric aspirate may be

than 1 year show pathological reflux when

rapidly cleared from the lung. In

investigated (Mousa et al., 2012). GOR

experimental animals, acute instillation of

may contribute to poor CF control at the

gastric contents into the main bronchi leads

end stage of disease, and may cause

to a wide array of histopathological changes

bronchiolitis obliterans syndrome (BOS)

both in areas directly in contact with acid as

after lung transplantation (D’Ovidio et al.,

well as in distant areas, including alveolar

2006).

haemorrhage and pulmonary oedema

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ERS Handbook: Paediatric Respiratory Medicine

(Sherrington, 2006). These changes seem

not to be related to direct tissue damage

induced by acid, but to the inflammatory

cascade triggered by release of preformed

cytokines from damaged cells, such as

leukotriene B₄ and thromboxane A₂. These

in turn stimulate the synthesis of other

cytokines, including interleukin (IL)-1,

tumour necrosis factor (TNF)-a and IL-8,

followed by neutrophil recruitment.

Repetitive chronic aspiration induces loss of

parenchymal architecture, collagen

deposition with fibrosis, bronchiectasis and

Figure 1. Fluid from BAL stained with Oil Red O.

obliterative bronchiolitis.

The lipid is seen within the cytoplasm of alveolar

macrophages. Image courtesy of F. Midulla

Several experimental and clinical data have

(Paediatric Emergency Department, Policlinico

suggested the role of acid microaspiration in

Umberto I, Sapenzia University of Rome, R0me,

Italy; personal communication).

the pathophysiology of bronchial

inflammation and bronchoconstriction.

However, recent studies also emphasise the

Biomarkers Ideally, a biomarker for

role of nonacid reflux in the pathophysiology

aspiration should be a noninvasive measure

of some parenchymal lung diseases in both

of a quantifiable marker within the lung,

adult and children. Bile acids and pepsin

specific for reflux aspiration and reliably

from patients on antisecretory therapy

detectable over a sustained period after

stimulate the production of transforming

aspiration.

growth factor (TGF)-b via a p38 mitogen-

activated protein (MAP) kinase-dependent

Lipid-laden macrophages (LLMs) in the

pathway, connective tissue growth factor

bronchoalveolar lavage (BAL) have been

and IL-8 secreted by bronchial epithelial

reported as useful markers of GOR-related

cells, suggesting their ability to provoke a

pulmonary aspiration. The amount of lipid

significant bronchial reaction (Mertens et

per single macrophage is determined after

al., 2010). Moreover, it has been recently

Oil Red O staining of BAL using a

shown that nonphysiological levels of pepsin

semiquantitative method, which assigns to

and acid are able to induce inflammation

each cell a score ranging from 0 to 4

and death of airway epithelial cells with an

according to the amount of lipid in the

effect inversely related to the acid

cytoplasm (fig. 1). The number of cells

concentration.

graded 0, 1, 2, 3 and 4 is calculated for each

patient, and the final LLM index (LLMI) is

Diagnosis

determined by evaluating 100 cells, with the

highest possible score being 400 (Corwin et

Before considering GOR as cause of CPA,

al., 1985). A LLMI of 165 is considered to be

the clinician needs to rule out the presence

consistent with aspiration (Furuya et al.,

of swallowing dysfunction and,

consequently, a direct aspiration of fluid/

2007). A rapid increase in LLMs occurs after

food with swallowing. The following steps

intratracheal milk instillation, lasting for

are to determine whether pathological GOR

o2 days after a single instillation and longer

is occurring, with gastric contents entering

with recurrent instillation. LLMI seems to

the lungs, and to assess the likelihood of an

correlate with total number of nonacid reflux

association between GOR and respiratory

episodes and the number of nonacid reflux

symptoms and/or signs. Unfortunately, at

episodes reaching the proximal oesophagus

the present time, there is no sensitive,

(Borrelli et al., 2010). However, these

specific test for GOR-related aspiration, and

findings are highly debated. The role of LLMI

the diagnosis is made combining clinical,

as a standard test for aspiration is widely

laboratory and radiological tests.

disputed, as studies have shown significant

ERS Handbook: Paediatric Respiratory Medicine

561

5000

Time

Figure 2. Example of acid reflux episodes reaching the proximal oesophagus. Impedance measurements from

the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as acid

because of the presence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).

variation in its sensitivity (57-100%) and

before and after lung transplantation

specificity (57-89%) (Colombo et al., 2012).

(Blondeau et al., 2008). Though a promising

An increase in LLMs has been described in

investigative measure, the detection of

pulmonary conditions other than aspiration,

pepsin in BAL fluid as a marker of gastric

such as CF, infections, use of intravenous

aspiration has a number of concerns. Firstly,

lipid infusion and pulmonary fat embolism

early cross-sectional studies only provide a

in sickle cell disease, suggesting that any

snapshot in time of its presence, and there

pulmonary insult severe enough to cause

are no data on how pepsin concentrations

tissue destruction may result in an increase

change over time following aspiration or

in LLMs by releasing lipids from cell

with frequency of aspiration events.

membranes (Knauer-Fischer et al., 1999).

Secondly, alterations in content and

However, despite these significant

concentrations may be dependent on BAL

limitations, an elevated LLMI may provide

technique. However, based on current data,

supporting evidence of aspiration in a

the specificity of the pepsin makes this

selected group of children.

biomarker highly appealing.

Pepsin is a proteolytic enzyme of gastric

Radiology An upper gastrointestinal contrast

origin and should not be detectable in the

study is not a reliable test for discriminating

lower respiratory tract. Therefore, its

between physiological and pathological

detection in the BAL fluid should be a highly

GOR. However, it is useful to confirm or rule

sensitive and specific marker for GOR-

out anatomical abnormalities of the upper

related aspiration. The presence of pepsin in

gastrointestinal tract that may predispose to

the BAL is detected in a high percentage of

GOR-related aspiration. Scintigraphy has

children with GORD and chronic respiratory

been widely used for the evaluation of GOR

symptoms (83%) and its level correlates

in children. However, its low sensitivity and

with proximal acid GOR (Starosta et al.,

specificity compared with 24-h oesophageal

2007). Pepsin has been used as a marker of

pH monitoring makes this test unsuitable

aspiration in both preterm infants and

for the routine diagnosis and management

children ventilated in the intensive care

of GOR in infants and children. Evidence of

setting. Finally, increased BAL pepsin has

pulmonary aspiration during the test is

been found in adults and children with CF,

usually assessed through images obtained

562

ERS Handbook: Paediatric Respiratory Medicine

up to 24 h after administration of the

there is a degree of subjectivity in the

radionuclide. However, a negative test does

interpretation of the results, but

not exclude the possibility of infrequent

improvements in automated software

aspiration. Furthermore, even in the

analysis will help to overcome this pitfall.

presence of aspiration, the technique is not

Secondly, a positive test in a child with

able to discriminate between aspiration due

symptoms and signs of aspiration does not

to swallowing dysfunction and GOR-related

inevitably imply a cause-effect relationship,

aspiration.

and negative test does not exclude the

possibility of GOR-related aspiration. Finally,

Oesophageal studies Although oesophageal

the results of MII-pH monitoring are still

pH monitoring has been regarded for many

difficult to interpret given the absence of

years as the most sensitive and specific

normal paediatric reference values.

diagnostic tool for diagnosing GORD, its

Treatment

sensitivity and specificity are not well

established. In fact, pH monitoring has

Medical and conservative therapies are the

significant limitations because of its inability

initial choice for children with GORD and

to detect nonacidic retrograde bolus

features of aspiration, including thickened

movement in the oesophagus, and in

feeds, prokinetics and acid secretion

particular in infants who are frequently fed

inhibitors. Proton pump inhibitors (PPIs)

milk and/or milk-based formulas.

have been widely used to decrease acid

Multichannel intraluminal impedance (MII)

reflux and the perceived risks of PPIs are

monitoring is a new clinically available tool

low. Although the efficacy of PPIs has been

able to detect anterograde or retrograde

shown for the treatment of patients with

bolus movement into the oesophagus in a

oesophageal symptoms and signs, no data

pH-independent fashion. MII and pH (MII-

are available for GORD-related respiratory

pH) monitoring combined can characterise

symptoms. This is especially true in children

the reflux episodes as acid or nonacid (figs 2

with chronic pulmonary aspiration due to

and 3) and determine the composition

GORD who do not seem to benefit from

(liquid, gas or mixed) and height reached by

medical therapy in terms of improving lower

the refluxate. However, there are some

respiratory tract injury. Moreover, it is

limitations of MII-pH monitoring. First,

important to point out that although PPIs

5000

Time

Figure 3. Example of nonacid reflux episode reaching the proximal oesophagus. Impedance measurements from

the proximal, intermediate and distal oesophagus, and pH are shown. The episode is categorised as nonacid on

the absence of a pH drop to ,4 during the impedance-detected episode (arrow and shaded area).

ERS Handbook: Paediatric Respiratory Medicine

563

change the gastric pH, they do not prevent

Further reading

episodes of reflux-related microaspiration.

Blondeau K, et al. (2008). Gastro-oeso-

phageal reflux and gastric aspiration in

Naso- or gastrojejunal feeding provides an

lung transplant patients with or without

approach to prevent reflux-related

chronic rejection. Eur Respir J; 31: 707-713.

pneumonia, especially in children with

Boesch RP, et al. (2006). Advances in the

severe neurological impairment; sometimes,

diagnosis and management of chronic

it needs to be combined with

pulmonary aspiration in children. Eur

fundoplication.

Respir J; 28: 847-861.

Borrelli O, et al. (2010). Non-acid gastro-

Fundoplication has become the surgical

oesophageal reflux in children with sus-

antireflux procedure of choice in children with

pected pulmonary aspiration. Dig Liv Dis;

severe and persistent respiratory symptoms

42: 115-121.

due to GOR refractory to the medical

Colombo JL, et al. (2012). Aspiration: a

treatment. It represents one of the three most

common event and a clinical challenge.

commonly performed major operations in

Pediatr Pulmonol; 47: 317-320.

childhood. Resolution or improvement of

Corwin RW, et al. (1985). The lipid-laden

respiratory symptoms after fundoplication

alveolar macrophage as a marker of

occurs in 48-92% of patients. It has been

aspiration in parenchymal lung disease.

demonstrated that fundoplication could

Am Rev Respir Dis; 132: 576-581.

reverse bronchiolitis obliterans syndrome in

D’Ovidio F, et al. (2006). The effect of

some lung transplant recipients with

reflux and bile acid aspiration on the lung

allograft and its surfactant and innate

pathological reflux. Unfortunately, in children

immunity molecules SP-A and SP-D. Am J

with neurological impairment, who represent

Transplant; 6: 1930-1938.

the group with greatest incidence of GOR-

El-Serag HB, et al. (2001). Extraesophageal

related aspiration, symptom relapse has been

associations of gastroesophageal reflux

reported in up to 60% of them following the

disease in children without neurologic

first antireflux surgery and a high failure rate

defects. Gastroenterology; 121: 1294-1299.

even after redo Nissen (Pacilli et al., 2007).

Furuya ME, et al. (2007). Cutoff value of

For this reason, the selection of patients to

lipid-laden alveolar macrophages for

undergo Nissen fundoplication needs to be

diagnosing aspiration in infants and

accurate and alternative surgical strategies,

children. Pediatr Pulmonol; 42: 452-457.

such as jejunostomy feeding, need to be

Knauer-Fischer S, et al.

(1999). Lipid-

considered. The insertion of a

laden macrophages in bronchoalveolar

gastrojejunostomy has the advantage of

lavage fluid as a marker for pulmonary

allowing gastric venting as well as

aspiration. Pediatr Pulmonol; 27: 419-422.

establishing jejunal feeding. However, the

Krishnan U, et al. (2002). Assay of tracheal

tendency for accidental displacement renders

pepsin as a marker of reflux aspiration. J

Pediatr Gastroenterol Nutr; 35: 303-308.

this option impractical for long-term use, and

Mertens V, et al. (2010). Gastric juice from

surgical jejunostomy represents a more

patients ‘‘on’’ acid suppressive therapy can

permanent solution. Although with either

still provoke a significant inflammatory

type of jejunal feeding, aspiration of gastric

reaction by human bronchial epithelial

juice may still occur, they show a similar rate

cells. J Clin Gastroenterol; 44: e230-e235.

of aspiration pneumonia and mortality

Morton RE, et al. (1999). Respiratory tract

compared with fundoplication (Srivastava et

infections due to direct and reflux aspira-

al., 2009). Finally, in children with severe,

tion in children with severe neurodisa-

irreversible neurological impairment and

bility. Dev Med Child Neurol; 41: 329-334.

intractable aspiration despite medical and

Mousa HM, et al.

(2012).

surgical treatments previously described, a

Gastroesophageal reflux in cystic fibrosis:

more aggressive surgical approach, such as

current understandings of mechanisms

oesophagogastric disconnection with

and management. Curr Gastroenterol Rep;

oesophagojejunal anastomosis, may be

14: 226-235.

required.

564

ERS Handbook: Paediatric Respiratory Medicine

Owayed AF, et al.

(2000). Underlying

Sherrington CA. Pediatric aspiration syn-

causes of recurrent pneumonia in chil-

drome. In: Laurent GJ, et al., eds.

dren. Arch Pediatr Adolesc Med; 154: 190-

Encyclopedia of Respiratory Medicine.

194.

Waltham, Elsevier, 2006; pp. 309-312.

Pacilli M, et al. (2007). Factors predict-

Srivastava R, et al. (2009). Impact of fundo-

ing failure of redo Nissen fundoplica-

plication versus gastrojejunal feeding tubes

tion in children. Pediatr Surg Int;

23:

on mortality and in preventing aspiration

499-503.

pneumonia in young children with neurologic

Piccione JC, et al. (2012). Bronchiectasis

impairment who have gastroesophageal

in chronic pulmonary aspiration: risk

reflux disease. Pediatrics; 123: 338-345.

factors and clinical implications. Pediatr

Starosta V, et al. (2007). Bronchoalveolar

Pulmonol; 47: 447-452.

pepsin, bile acids, oxidation, and inflam-

Sherman PM, et al. (2009). A global,

mation in children with gastroesophageal

evidence-based consensus on the

reflux disease. Chest; 132: 1557-1564.

definition of gastroesophageal reflux

Tolia V, et al. (2009). Systematic review: the

disease in the pediatric popula-

extra-oesophageal reflux symptoms of gas-

tion. Am J Gastroenterol;

104:

1278-

troesophageal reflux disease in children.

1295.

Aliment Pharmacol Ther; 29: 258-272.

ERS Handbook: Paediatric Respiratory Medicine

565

Foreign body aspiration

Iolo Doull

Foreign body aspiration (FBA) is a serious

airflow, so even small foreign bodies can be

and potentially fatal condition in infants and

dangerous. Compared to adults the larynx is

children. Choking may occur due to an

in a relatively high position in infants with

obstruction in the oral cavity, and insertion

the epiglottis close to the root of the tongue,

injuries may occur when foreign objects are

increasing the risk of aspiration. Infants

present in either the nose or nasopharynx.

have gag, cough and glottic closure reflexes

Ingestion injuries occur due to foreign

to protect against aspiration, but they may

bodies in the oesophagus or stomach.

not always be fully developed from birth, and

Depending on the age of the child and the

swallowing, in particular, may be delayed.

size of the foreign body, airway obstruction

Children with developmental delay are at

and aspiration can occur anywhere in the

increased risk of aspiration.

respiratory tract. Large airway obstruction

Incisors are necessary to bite through food,

preventing adequate ventilation can be fatal,

and molars are necessary to masticate the

while more distal obstruction can lead to

food in preparation for swallowing.

emphysema, atelectasis and subsequent

However, incisors erupt approximately

chronic changes including bronchiectasis.

6 months before molars and so food may

Aetiology and predisposing factors

not be appropriately pulped, remaining as a

small smooth or rounded mass, the ideal

Children ,3 years of age are at greatest risk.

shape to obstruct an airway if aspirated.

Infants have smaller airways than adults.

Infants and children are less able to cough

Flow through an airway is inversely

out foreign bodies aspirated into the airway;

proportional to the radius to the fourth

peak cough flows at 4 years of age are

power, thus small changes in airway radius

approximately a quarter of that of adults.

lead to proportionately greater changes in

Once lodged in an airway, mucus and local

inflammation will quickly result in complete

airway obstruction, thus diminishing the

Key points

possibility of forced clearance. Finally

infants are easily distracted and often

Children ,3 years of age are at

inattentive, are more likely to talk and run

greatest risk of FBA.

around while chewing, and more likely to put

a small non-organic foreign body in their

N FBA must be suspected for any

mouth while playing.

witnessed choking episodes.

N FBA cannot be excluded on either

Epidemiology

normal physical examination or chest

The exact incidence of fatal and non-fatal

radiograph.

FBA and choking-related injuries in children

Removal of the foreign body is the

is unclear; the available data are probably an

primary objective and mainstay of

under-representation, and international

treatment.

comparisons are difficult. Analysis of the US

National Electronic Injury Surveillance

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ERS Handbook: Paediatric Respiratory Medicine

System in 2001 identified 17 537 children

Respiratory distress and/or cyanosis suggest

aged f14 years treated in emergency

obstruction to a large airway and warrants

departments for choking related episodes

emergency treatment. Laryngeal obstruction

(rate 29.9 per 100 000 population). Rates

may cause a hoarse voice or aphonia,

were highest for infants (140.4 per 100 000)

drooling, stridor and/or wheezing and

decreasing with each successive age cohort

respiratory distress. Tracheal obstruction

to a rate of 4.6 per 100 000 for those aged

may present with biphasic or monophonic

10-14 years. Many choking-related episodes

wheeze and bilaterally decreased breath

were mild and included minor pharyngeal

sounds and respiratory distress. More distal

irritation without FBA, but ,10% required

obstruction may result in unilateral

hospitalisation and for every 110 children

monophonic wheeze and unilateral

treated there was one death. The

decreased breath sounds. Cough and

commonest food substance was sweets/

wheeze are the most sensitive signs, while

chewing gum (19%) while the commonest

stridor and cyanosis are the most specific.

non-food item was coins (12.7%). In Italy

there are about 400 children admitted per

Late presentations may be misdiagnosed as

year who require removal of a foreign body.

pneumonia, asthma or laryngitis presenting

with decreased chest movement, decreased

A review of 13 266 cases (91 reports) of FBA

breath sounds, wheezing and possibly

from high-income countries and 24 731

crackles and pyrexia.

cases (83 reports) from low-/medium-

income countries (total 37 997)

Investigations

demonstrated similar demographics in both

A chest radiograph is mandatory for all

populations. 60% of subjects were male and

cases of suspected FBA to localise potential

40% were female, and the majority were

foreign bodies and assess chest asymmetry,

aged f3 years (high-income countries 75%,

but also to exclude other causes for

low-/middle-income countries 60%). The

respiratory distress. Flat objects such as

diagnosis of inhaled foreign bodies was

coins tend to align in the sagittal plane in

delayed by more than 24 h in approximately

the trachea whereas objects in the

60% of the cases.

oesophagus tend to align in the coronal

In a review of 30 reports comprising 12 979

plane. Lateral chest radiographs can

children with suspected FBA; of whom

sometimes be helpful.

11 145 had aspirated an object (14% false

negative rate), over 80% of foreign bodies

Chest radiograph abnormalities may include

were organic materials, with nuts and seeds

asymmetry, such as air trapping and

being the most common. Approximately

emphysema, infiltrates and possibly

90% were lodged in the bronchial tree, with

mediastinal shift. For older children who are

the remainder in the larynx or trachea.

able to co-operate, a combination of

Foreign bodies were more likely to lodge on

inspiratory and expiratory films should be

the right side (52%) than the left (33%),

obtained. Partial airway obstruction may

while a small number of objects fragmented

cause a valve-like effect resulting in air

and lodged in different parts of the airways.

trapping and mediastinal shift being more

prominent on expiratory films. The majority

Presentation

of foreign bodies are organic materials and

are not usually radio opaque. Only 10% of

A history of a witnessed choking event is

foreign bodies will be visible on a chest

very suggestive of FBA, a child aged

radiograph. Pneumothorax and

,3 years is rarely able to give a clear history,

pneumomediastinum are infrequent

and an adult is present in over half of such

findings. Chest radiographs may be normal

cases.

in approximately 17% of children

The clinical findings will depend on the level

subsequently shown to have FBA. Later

at which obstruction has occurred, although

radiographic features include segmental

most patients will have a paroxysmal cough.

collapse, consolidation or atelectasis.

ERS Handbook: Paediatric Respiratory Medicine

567

CT and generation of virtual bronchoscopy

rare circumstance where the foreign body is

can be useful in assessment of FBA in stable

too large to pass through the subglottic

children, offering greater sensitivity than

space (the so-called monkey trap

plain radiographs.

phenomenon) a temporary tracheostomy

may be required.

Treatment

Although the vast majority of foreign bodies

Immediate treatment of FBA by parents or

are removed with rigid bronchoscope, there

carers may dislodge the foreign body. In

is increasing evidence for the use of flexible

infants, back slaps in a head down position

bronchoscopy. In a study of .1000 children,

with or without chest thrusts are the

foreign bodies were successfully removed by

treatment of choice. Abdominal thrusts

flexible bronchoscopy in .90%. Flexible

including the Heimlich manoeuvre appear

bronchoscopy may be superior to rigid

more appropriate for older children.

bronchoscopy in the removal of foreign

Foreign body aspiration must be suspected

bodies from distal airways and, particularly,

the upper lobe bronchi.

for any witnessed choking episodes.

Although a history of inhalation can be

There is lack of consensus on the best

elicited from the parent in many cases, FBA

anaesthetic regime with some authors

cannot be excluded on either normal

advocating paralysis, while others advocate

physical examination or chest radiograph.

spontaneous ventilation. Positive airway

Removal of the foreign body is the primary

pressure during the procedure and

objective and mainstay of treatment. Rigid

particularly afterwards is useful for re-

bronchoscopy is the classical investigation

inflation of atelectatic lung areas. It is

and treatment of choice, although a

important that after removal of a foreign

common strategy is to use rigid

body the rest of the airways are checked to

bronchoscopy for children with convincing

ensure there are no smaller objects. If there

evidence of FBA, while children with a less

is significant bleeding during the procedure,

clear-cut history or findings undergo flexible

dilute (100 mg?L^-1) adrenaline can be

bronchoscopy. The majority of cases of FBA

administered topically. Pre-operative

antibiotics are usually administered and

in Europe are treated in ENT departments. A

continued for a 5-day course. Corticosteroids

number of negative bronchoscopies are

may be beneficial following removal of a

required, with the reported incidence varying

foreign body to decrease airway oedema.

between 9% and 16.5%.

Rigid bronchoscopy requires general

For patients presenting with respiratory

anaesthesia but allows control of the airway

distress or cyanosis, emergency

at the same time, as instruments can be

bronchoscopy is essential. However for

advanced to remove the foreign body in a

patients who are clinically stable without

safe way, while also facilitating removal of

respiratory compromise, it is reasonable to

mucous plugging and installation of saline

take the child to theatre in a planned

or mucolytics to areas of lung collapse.

manner during normal working hours, even

Removal is completed most often either

if this incurs a delay. It is unlikely that a

delay of ,24 h in removal of the foreign

with an alligator jaw or cup forceps. Balloon

body will have any significant long-term

tipped catheters can be used, particularly for

effects on the lung. A review of over 3000

round foreign bodies, to dislodge foreign

FBAs suggested that sequelae were more

bodies that may be lodged with surrounding

common where a foreign body had been

granulation tissue. For organic material in

present for .1 week: 27.2% versus 6.7% for

particular, considerable care is required to

those ,1 week.

prevent disintegration of the foreign body

resulting in multiple smaller foreign bodies.

Complications

Once manoeuvred to the larynx it should be

removed via the lower triangle of the glottis

In a meta-analysis of 26 studies where major

to avoid trauma to the vocal cords. In the

complications were specified, deaths

568

ERS Handbook: Paediatric Respiratory Medicine

occurred in 43 (0.42%) out of 10 236 cases.

Fidkowski CW, et al. (2010). The anes-

Death rates in individual studies varied

thetic considerations of tracheobronchial

between 0.21% and 0.94% with

foreign bodies in children: a literature

approximately a third presenting with

review of 12,979 cases. Anesth Analg; 111:

hypoxic arrest and a third arresting during

1016-1025.

Foltran F, et al.

(2011). Foreign bodies

the procedure. Major non-fatal

inhalation as a research field: what can

complications occurred in 0.96% and

we learn from a bibliometric perspective

included severe laryngospasm or

over 30 years of literature? Int J Pediatr

bronchospasm requiring tracheostomy or

Otorhinolaryngol; 75: 721-722.

intubation, pneumothorax or

Foltran F, et al.

(2013). Inhaled foreign

pneumomediastinum. Approximately a third

bodies in children: a global perspective

required thoracotomy to remove the foreign

on their epidemiological, clinical, and

body.

preventive aspects. Pediatr Pulmonol; 48:

344-351.

Prevention

Gang W, et al. (2012). Diagnosis and

treatment of tracheobronchial foreign

Public health strategies can reduce the risk

bodies in 1024 children. J Pediatr Surg;

of FBA in children. There are European and

47: 2004-2010.

US recommendations about the types of

Gregori D, et al. (2010). Ingested foreign

food that are inappropriate for younger

bodies causing complications and requir-

children, and choking hazard warnings on

ing hospitalization in European children:

small toys that pose particular risks of FBA.

results from the ESFBI study. Pediatr Int;

Parents can receive education and basic

52: 26-32.

instructions on what to do in an emergency

Mani N, et al. (2009). Removal of inhaled

situation.

foreign bodies - middle of the night or

the next morning? Int J Pediatr

Otorhinolaryngol; 73: 1085-1089.

Mantor PC, et al. (1989). An appropriate

Further reading

negative bronchoscopy rate in suspected

Adaletli I, et al. (2007). Utilization of low-

foreign body aspiration. Am J Surg; 158:

dose multidetector CT and virtual

622-624.

bronchoscopy in children with suspected

Martinot A, et al. (1997). Indications for

foreign body aspiration. Pediatr Radiol; 37:

flexible versus rigid bronchoscopy in

33-40.

children with suspected foreign-body

Altkorn R, et al. (2008). Fatal and non-

aspiration. Am J Respir Crit Care Med;

fatal food injuries among children (aged

155: 1676-1679.

0-14 years). Int J Pediatr Otorhinolaryngol;

Pinzoni F, et al. (2007). Inhaled foreign

72: 1041-1046.

bodies in pediatric patients: review of

CDC (2002). Non fatal choking-related

personal experience. Int J Pediatr

episodes amongst children

- United

Otorhinolaryngol; 71: 1897-1903.

States,

2001. Morb Mort Week Rep; 51:

Righini CA, et al.

(2007). What is the

945-948.

diagnostic value of flexible bronchoscopy

Cohen S, et al. (2009). Suspected foreign

in the initial investigation of children with

body inhalation in children: what are the

suspected foreign body aspiration? Int J

indications for bronchoscopy? J Pediatr;

Pediatr Otorhinolaryngol; 71: 1383-1390.

155: 276-280.

Sersar SI, et al. (2006). Inhaled foreign

Committee on Injury, Violence and

bodies: presentation, management and

Poison Prevention (2010).Prevention of

value of history and plain chest radio-

choking among children. Pediatrics; 125:

graphy

delayed

presentation.

601-607.

Otolaryngol Head Neck Surg; 134: 92-99.

ERS Handbook: Paediatric Respiratory Medicine

569

Bronchiolitis obliterans

Francesca Santamaria, Silvia Montella and Salvatore Cazzato

Bronchiolitis obliterans, or constrictive

bronchiolitis, is a rare chronic obstructive

Key points

lung disease, which follows a severe insult

to the respiratory tract and results in

Bronchiolitis obliterans is a rare

narrowing and/or complete obliteration of

paediatric chronic obstructive lung

the small airways. Although the term

disease, which follows a severe insult

describes a pathology confined to small

to the respiratory tract and results in

airways, inflammation and fibrosis may

narrowing and/or complete

extend to the alveoli and interstitium.

obliteration of the small airways.

In children, bronchiolitis obliterans is a long-

The most common cause is severe

term sequela of severe infections occurring

lower airway infection, followed by

most commonly after acute pneumonia or

bone marrow or lung transplantation,

bronchiolitis. Other causes include

drug toxicity, noxious inhalation

transplantation of bone marrow or lung,

injury, vasculitis and autoimmune

drug toxicity, noxious inhalation injury,

disorders.

vasculitis and autoimmune disorders.

Open lung biopsy for histological

The onset of bronchiolitis obliterans is

confirmation of the diagnosis is rarely

frequently insidious and symptoms may be

necessary. In the appropriate setting,

misinterpreted, thus resulting in delayed

after the exclusion of other chronic

diagnosis. Mortality remains high and most

obstructive lung disease, HRCT

patients die of respiratory failure

provides adequate evidence for a

complicated by additional infections.

correct diagnosis.

Epidemiology

Lung function is characterised by a

moderate-to-severe fixed airflow

Although childhood post-infectious

obstruction unresponsive to

bronchiolitis obliterans is rare, its

bronchodilators that may slowly

prevalence seems greater than previously

progress to fatal deterioration even a

thought, particularly in South America,

few months after diagnosis. Mortality

Europe, USA, India, East Asia, New Zealand

rates range from 3.2% to 16.7%,

and Australia. Although the prevalence of

depending on bronchiolitis obliterans

post-infectious bronchiolitis obliterans is

severity.

unknown, its epidemiology is directly related

to severe viral respiratory infections in young

The treatment of bronchiolitis

children, mainly adenovirus. Race has also

obliterans is often unsuccessful

been suggested as a predisposing factor for

because patients are referred to

post-infectious bronchiolitis obliterans.

specialised centres when irreversible

However, while an Argentinean group found

fibrotic changes and airway

that their post-infectious bronchiolitis

obliteration have already occurred.

obliterans patients had an increased

frequency of an allele highly expressed in an

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ERS Handbook: Paediatric Respiratory Medicine

Amerindian population, 70% of the post-

N Influenza virus,

infectious bronchiolitis obliterans children

N Parainfluenza virus,

followed up by a Brazilian centre were

N Measles virus,

Caucasian. This suggests that a different

N Varicella virus,

distribution may be found among centres

N Mycoplasma pneumoniae,

according to the local racial composition.

N Chlamydophilia pneumoniae,

N Staphylococcus aureus,

In long-term lung transplant survivors,

N Streptococcus pneumoniae,

bronchiolitis obliterans represents the

N Bordetella pertussis.

leading cause of morbidity and mortality,

and occurs in 60-70% of patients surviving

Although respiratory syncytial virus (RSV) is

at 5 years, whereas in allogeneic

frequently associated with bronchiolitis,

haematopoietic stem-cell transplantation

evidence for a causative role of it in

(HSCT) incidence ranges from 0% to 48%.

determining post-infectious bronchiolitis

obliterans is lacking. Increased serum

Pathology

interleukin (IL)-6, IL-8 and tumour necrosis

Bronchiolitis obliterans is primarily a lesion

factor (TNF)-a in children with adenovirus

of the membranous and respiratory

infection suggest that the host

bronchioles with fibrosing inflammatory

immunological response may play an

process surrounding the lumen, which

important role in the development of post-

results in progressive airways narrowing,

infectious bronchiolitis obliterans.

distortion and obliteration. Histological

The acute infection leading to post-

features have a wide spectrum from chronic

infectious bronchiolitis obliterans usually

inflammation to bronchiolar scarring

requires hospital admission for oxygen

without extensive changes in alveolar ducts

therapy and sometimes requires mechanical

or walls, and show a patchy distribution.

ventilation. Despite appropriate initial

The term bronchiolitis obliterans organising

treatment, hypoxaemia, cough,

pneumonia (BOOP) identifies an airspace

breathlessness, wheezing, tachypnoea,

filling process with granulation tissue plugs

exercise intolerance and crackles on

extending to small airways, and is

auscultation are common clinical findings.

distinguished from bronchiolitis obliterans

Oxygen may be required for months or years

on the basis of clinical, functional and

after the acute infection. Failure to thrive,

radiographic features, including response to

clubbing, chest deformity and pulmonary

corticosteroids and prognosis. It was long

arterial hypertension are reported in severe

considered a small airways disease, but

cases.

current classification lists BOOP among

Bronchiolitis obliterans following bone marrow

interstitial pneumonias.

transplant Bronchiolitis obliterans is the

most common late, non-infectious

Clinical entities

pulmonary complication of allogeneic

Post-infectious bronchiolitis obliterans Post-

HSCT. Generally, bronchiolitis obliterans

infectious bronchiolitis obliterans should

does not develop after autologous HSCT.

always be suspected in previously healthy

Although there are reports of bronchiolitis

children who develop chronic respiratory

obliterans as early as 30 days following

symptoms lasting for longer than 4-8 weeks

HSCT, 80% of cases present 6-12 months

after an episode of acute, usually severe,

post-transplantation.

infection at preschool age.

The presentation is usually insidious, and

Several pathogens are associated with

main symptoms include dry cough (60-

paediatric post-infectious bronchiolitis

100% of cases) and dyspnoea (50-70% of

obliterans, and adenovirus (serotypes 3, 7, 11

patients). Wheezing and sinusitis are also

and 21) is most frequently implicated. Other

frequent, while fever is rare unless there is a

microorganisms include:

concomitant infection. Approximately 20%

ERS Handbook: Paediatric Respiratory Medicine

571

of patients are asymptomatic, and diagnosis

disease process or the medication used as

may be suspected based on lung function.

treatment.

In the advanced stages, patients are

Risk factors

physically limited because of severe airway

obstruction and may require home oxygen.

Pathogen load, immunological response,

Some patients may develop bronchiectasis

and genetic and environmental factors may

with recurrent respiratory infections and

be associated with bronchiolitis obliterans.

colonisation by Pseudomonas spp., S. aureus

However, it is still unknown why some

and, occasionally, Aspergillus spp. Usual

children, but not all, develop bronchiolitis

examination features are decreased breath

obliterans.

sounds, wheezing, inspiratory squeaks and

Possible risk factors for post-infectious

signs of hyperinflation, while basal crackles

bronchiolitis obliterans are prolonged

are rare. However, thoracic examination may

hospitalisation, multifocal pneumonia, need

be normal in early stages. Almost all

for mechanical ventilation and hypercapnia.

patients also have symptoms and signs of

It remains unclear whether the need for

chronic graft versus host disease (GVHD),

mechanical ventilation is an indicator of

especially skin changes and sicca syndrome,

disease severity or is responsible for the

with dryness in the eyes and mouth.

direct induction of airway injury. Moreover,

Bronchiolitis obliterans following lung

bilateral pulmonary involvement is

transplantation Lung transplantation

associated with more severe post-infectious

recipients often have a variable period of

bronchiolitis obliterans.

good graft function, followed by insidious

Recurrent acute cellular rejection (ACR)

onset of symptoms. Clinical presentation of

episodes following lung transplantation, as

bronchiolitis obliterans may vary from

well as high-grade ACR, are primary risk

asymptomatic disease to nonspecific

factors for bronchiolitis obliterans. However,

symptoms as dyspnoea, cough and exercise

a single episode of minimal ACR without

intolerance, while wheezing and chest pain

recurrence or progression to rejection is also

are less common. Chest auscultation

a significant independent predictor of

includes expiratory wheezing and occasional

bronchiolitis obliterans. As a result, early

crackles, as well as distant breath sounds

and aggressive treatment of ACR represents

with only mild expiratory prolongation.

an important preventive strategy. Indeed,

Digital clubbing rarely occurs.

recognition and treatment of ACR are often

delayed, as patients may be stable.

Compared to deceased donor transplant,

Moreover, ischaemia-reperfusion injury

the incidence of bronchiolitis obliterans is

after transplantation or primary graft

lower in living donor lobar transplant

dysfunction are associated with bronchiolitis

recipients, probably due to less frequent and

obliterans, and the risk depends on the

less severe rejection episodes. Moreover,

severity of graft dysfunction. Ischaemia and

children aged ,3 years undergoing lung

reperfusion, or other insults, may damage

transplantation show lower risk of

the respiratory epithelium with resulting

bronchiolitis obliterans, probably because of

exposure of hidden epitopes of collagen type

decreased incidence of acute rejection.

V, which may result in bronchiolitis

obliterans secondary to autoimmune injury.

Bronchiolitis obliterans following autoimmune

Furthermore, leukocyte antigen mismatches

disorders or vasculitis The majority of

following lung transplantation might

described cases with collagen-vascular

promote bronchiolitis obliterans, but this is

diseases and associated bronchiolitis

controversial.

obliterans (i.e. rheumatoid arthritis,

scleroderma, systemic lupus erythematosus,

The presence of chronic GVHD is the most

Crohn’s disease and Stevens-Johnson

important, but not the 9 unique, risk factor

syndrome) are adults. It remains unclear

for bronchiolitis obliterans in HSCT. Other

whether this association is due to the

frequent risk factors include:

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ERS Handbook: Paediatric Respiratory Medicine

N airflow obstruction (FEV1/FVC ratio ,0.7)

Pulmonary function tests (PFTs) provide

prior to HSCT;

information about disease severity and

N recipient’s age .20 years;

progression over time. Infant PFTs, when

N viral infections (e.g. influenza,

available, indicate severe obstruction,

parainfluenza and RSV) within 100 days

diminished lung distensibility and increased

following HSCT;

airway resistance since a few months after

N busulfan-based conditioning regimen;

the disease onset. Older children exhibit

severe and irreversible airflow obstruction

N mismatched or unrelated donor;

and the greater the air-trapping, the greater

N hypogammaglobulinaemia (especially

the compromise during exercise. The

IgG and IgA);

decrease in forced expiratory flow at 25-75%

N methotrexate prophylaxis against GVHD;

of FVC (FEF25-75) is the typical functional

N older age of the donor;

marker of the disease, often associated with

N HSCT for chronic myelogenous

reduced FEV1 and FVC. Increased residual

leukaemia;

volume (RV) and RV/TLC ratio indicate

N blood-derived stem cells;

hyperdistension. A positive methacholine

N interval from diagnosis of leukaemia to

challenge test following transplant is a risk

transplantation .14 months;

to developing bronchiolitis obliterans at an

N female donor to male recipient;

accelerated rate. Single-breath nitrogen

N prior interstitial pneumonitis;

washout may reveal heterogeneous

N low pre-transplant serum surfactant

ventilation and alteration in expiratory flow

protein D levels;

rates 6-12 months before conventional

N nucleotide-binding oligomerisation

PFTs. The lung clearance index (LCI) is

domain 2/caspase recruitment domain 15

increasingly used to detect the earliest

variants.

bronchiolitis obliterans abnormalities. The

first evidence of its effectiveness in detecting

In lung or bone marrow graft recipients,

post-bone marrow transplant bronchiolitis

nonimmunological factors leading to

obliterans in adults and children was

bronchiolitis obliterans include Epstein-Barr

reported by Khalid et al. (2007). In that

virus reactivation and infection of the lung

study, paediatric patients demonstrated an

allograft by cytomegalovirus, adenovirus,

increased LCI from an early stage of

influenza and parainfluenza viruses, RSV,

bronchiolitis obliterans compared to healthy

fungi and bacteria. The lung transplantation

controls. This finding has been recently

type may also be a risk factor, with single

confirmed in Australian adults who

transplant recipients being at higher risk

underwent repeated LCI measurements after

than bilateral. Gastro-oesophageal reflux

HSCT (Lahzami et al., 2011). Finally, in

may contribute to allograft rejection, and

children with post-infectious bronchiolitis

bile acids and pepsin in bronchoalveolar

obliterans the impairment of TLCO related to

lavage fluid (BALF) from lung transplant

poorly ventilated lung units with marked

recipients indicate aspiration.

small airways obstruction may be helpful in

Diagnosis

the differential diagnosis with severe

asthma, which often shows normal or even

Although diagnosis is based on clinical,

increased TLCO due to hypervascularity.

functional and radiographic criteria, lung

biopsy remains the gold standard to

Chest radiographs are often unspecific or

diagnose bronchiolitis obliterans. Since

even normal, but may reveal bilateral

parenchymal involvement is patchy,

peribronchial thickening and/or

transbronchial biopsy has a small yield.

hyperinflation with or without opacities,

Transthoracic biopsy from two sites is

sometimes with associated pneumothorax

recommended. One of the major challenges

or pneumomediastinum. Rarely there is

for paediatricians is the search less

predominant unilateral hyperlucency

invasive diagnostic methods for

(Swyer-James or McLeod’s syndrome), with

bronchiolitis obliterans.

the affected lung being smaller on

ERS Handbook: Paediatric Respiratory Medicine

573

inspiration and the mediastinum shifted on

inspiratory scan. Indeed, the extent of air-

expiration towards the controlateral lung

trapping may correlate with bronchiolitis

because of air-trapping.

obliterans severity. The severity of HRCT

within the first 2 years after the acute

HRCT is extremely helpful for diagnosis, and

event seems to predict the subsequent

structural changes include:

lung function evolution. Furthermore, the

characteristic mosaic perfusion on HRCT,

N mosaic perfusion,

due to areas of attenuated density

N air-trapping,

alternating with areas of increased

N bronchial wall thickening,

attenuation with a patchy distribution,

N bronchiectasis,

may be useful in discriminating between

N thickening of septal lines,

patients with bronchiolitis obliterans and

N narrowing of the pulmonary vessels due

those with severe asthma and irreversible

to reflex vasoconstriction secondary to

obstruction. For all the above mentioned

tissue hypoxia,

reasons and given the relative risk of lung

N tree-in-bud pattern (fig. 1).

biopsy, it has been emphasised that in the

Expiratory scans are helpful in identifying

appropriate setting, once other congenital

air-trapping that may be missed on an

or acquired disorders have been excluded

(e.g. CF, primary ciliary dyskinesia,

immunodeficiency, bronchopulmonary

dysplasia, congenital heart disease, severe

asthma, inhaled foreign body, extrinsic

bronchial compression and a₁-antitrypsin

deficiency), HRCT provides clear evidence

for a correct diagnosis without the need

for biopsy. Thus, lung biopsy is

recommended if HRCT is inconclusive or

not available, or when severe progression

and gradual deterioration occur despite

treatment.

Ventilation-perfusion scintigraphy with the

typical matched ventilation/perfusion defect

in one or more pulmonary segments

provides a valuable assessment of

extension, distribution and severity of lung

involvement that correlates with the number

of exacerbations.

BALF neutrophilia in the absence of an

identifiable pathogen might be a

reproducible marker of bronchiolitis

obliterans as it increases with the severity of

Figure 1. a) HRCT scan of a 4-year-old boy with

bronchiolitis obliterans stage.

bronchiolitis obliterans following Mycoplasma

pneumoniae infection. Bilateral areas of

Finally, in severe bronchiolitis obliterans

increased and decreased parenchymal attenuation

oximetry may reveal overnight

(mosaic perfusion), bronchiectasis and air-

hypoxaemia that should prompt

trapping can be seen. b) Bronchiolitis obliterans in

a 13-year-old boy 2 years after bone marrow

a thorough cardiovascular assessment,

transplantation for acute lymphoblastic

including electrocardiogram,

leukaemia. The HRCT scan shows a bilateral

echocardiogram and cardiac

mosaic perfusion pattern, air-trapping and

catheterisation, if necessary, to detect

bronchial dilatation.

pulmonary arterial hypertension.

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ERS Handbook: Paediatric Respiratory Medicine

Treatment

bronchiolitis obliterans, but should be

discontinued in the absence of benefits.

Patients should be treated by a

multidisciplinary team with:

In lung transplant and bone marrow

transplant recipients, azithromycin may

N a paediatric pulmonologist,

improve bronchiolitis obliterans symptoms,

N a paediatric cardiologist,

lung function and exercise tolerance, probably

N a physical therapist,

because it exerts anti-inflammatory and

N a nutritionist,

immunomodulatory activity through

N a psychologist,

neutrophil chemotaxis inhibition and

N a social worker.

proinflammatory cytokine reduction.

Bronchiolitis obliterans treatment for

Empirical monthly intravenous Ig

children has not been clearly defined, and

administration was used in few cases. There

pharmacological approaches are often

are also some anecdotal reports of symptom

based on the clinical experience of different

improvement after chloroquine and

healthcare workers.

hydroxychloroquine in bronchiolitis obliterans,

and after TNF-a monoclonal antibodies

The treatment of bronchiolitis obliterans is

(infliximab) in bronchiolitis obliterans

often unsuccessful because patients are

complicating bone marrow transplantation.

referred to specialised centres when airway

Finally, in bronchiolitis obliterans following

changes are irreversible. It is mainly

lung transplantation the addition of

supportive, including prolonged oxygen

montelukast to immunosuppressive drugs

supplementation, particularly during the

was reported to decrease lung function

first period of the disease, antibiotics,

decline over 6 months.

annual influenza vaccination and chest

physiotherapy for cases complicated by

In localised bronchiectasis or atelectasis

bronchiectasis. Adequate nutritional

unresponsive to pharmacological therapy,

support is fundamental as up to 20% of

surgical resection is indicated. Severe cases

children with bronchiolitis obliterans may

with oxygen dependency, important physical

have some degree of malnutrition. Gastro-

limitation and extremely impaired lung

oesophageal reflux must be adequately

function should be referred for lung

treated.

transplantation.

Although frequently used in the clinical

Prognosis

practice, corticosteroids in post-infectious

bronchiolitis obliterans are controversial

The long-term prognosis of bronchiolitis

because no trials have confirmed their

obliterans is variable and depends on

efficacy. There are only clinical reports of

several factors, including the underlying

beneficial effects of pulse

causes and the speed of development. In

methylprednisolone (25-30 mg?day^-1 for

most cases, post-infectious bronchiolitis

3 days) in children with post-infectious

obliterans is chronic and nonprogressive, in

bronchiolitis obliterans. Conversely, in

contrast with bronchiolitis obliterans

GVHD occurring after HSCT high-dose

occurring after Stevens-Johnson syndrome

systemic prednisone (1-1.5 mg?kg^-1?day^-1 for

or bone marrow transplantation. Most

2-6 weeks) or methylprednisolone

patients with post-infectious bronchiolitis

(10 mg?kg^-1?day^-1 for 3 days on monthly

obliterans improve slowly and progressively,

basis for 1-6 cycles) should be prescribed,

but this may be due to airways growth rather

and immunosuppressive therapy should be

than to resolution of inflammation.

reinstituted or augmented. In paediatric

Nevertheless, most patients continue to

lung transplant recipients, the development

have mild symptoms especially during

of bronchiolitis obliterans should lead to

exercise. Neutrophils, CD8⁺ T-cell

augmentation of immunosuppression.

lymphocytes, activated T-cells (CD3⁺HLA-

Inhaled corticosteroids and/or

DR⁺) and IL-8, a potent chemoattractant and

bronchodilators may be considered in

activator for neutrophils, are increased in

ERS Handbook: Paediatric Respiratory Medicine

575

the BALF several years after the initial insult,

Camargos P, et al. Bronchiolite oblitérante

suggesting that lung inflammation persists.

post-infectieuse. In: de Blic J, ed.

Pneumologie Pédiatrique. Paris, Médecine-

In most bone marrow transplant recipients,

Sciences Flammarion, 2009; pp. 72-76.

bronchiolitis obliterans progressively leads

Cazzato S, et al. (2008). Airway inflam-

to irreversible airflow obstruction over

mation and lung function decline in

months to years because of frequent

childhood post-infectious bronchiolitis

exacerbations. The mortality is 9% at

obliterans. Pediatr Pulmonol;

43:

381-

3 years, 12% at 5 years and 18% at 10 years.

390.

Patients with advanced bronchiolitis

Champs NS, et al. (2011). Post-infectious

obliterans usually die from pneumonia.

bronchiolitis obliterans in children. J

Factors associated with mortality include

Pediatr (Rio J); 87: 187-198.

rapid FEV1 deterioration (.10% per year),

Fischer GB, et al. (2010). Post infectious

progressive chronic GVHD, underlying

bronchiolitis obliterans in children.

Paediatr Respir Rev; 11: 233-239.

disease relapse, respiratory viral infections,

Khalid Y, et al.

(2007). Obliterative

airflow obstruction within 150 days following

bronchiolitis after stem cell transplanta-

transplantation, and no response to the

tion: inert gas washout makes early

primary treatment.

diagnosis of this serious complication

Chronic bacterial airway colonisation in lung

possible. Lakartidningen; 104: 3373-3376.

Kurland G, et al.

(2005). Bronchiolitis

transplant recipients with bronchiolitis

obliterans in children. Pediatr Pulmonol;

obliterans is commonly associated with

39: 193-208.

poor outcome. Moreover, bronchiolitis

Lahzami S, et al. (2011). Small airways

obliterans, or its complications, are the

function declines after allogeneic haema-

single most common cause of death in lung

topoietic stem cell transplantation. Eur

transplant recipients, accounting for 40% of

Respir J; 38: 1180-1188.

deaths .1 year later.

Mallory GB, et al. (2004). Paediatric lung

transplantation. Eur Respir J; 24: 839-845.

Morbidity due to frequent obstructive

Moonnumakal SP, et al.

(2008).

exacerbations and infections requiring

Bronchiolitis obliterans in children. Curr

hospitalisations is high in bronchiolitis

Opin Pediatr; 20: 272-278.

obliterans. Mortality rates range from 3.2%

Pandya CM, et al. (2010). Bronchiolitis

to 16.7%. Fatal course may occur secondary

obliterans following hematopoietic stem

to progressive respiratory failure.

cell transplantation: a clinical update. Clin

Transplant; 24: 291-306.

Robertson AGN, et al. (2009). Targeting

Further reading

allograft injury and inflammation in the

Boehler A, et al.

(2000). Obliterative

management of post-lung transplant

bronchiolitis after lung transplantation.

bronchiolitis obliterans syndrome. Am J

Curr Opin Pulm Med; 6: 133-139.

Transplant; 9: 1272-1278.

Bosa VL, et al. (2008). Assessment of

Teper AM, et al.

(2004). Association

nutritional status in children and adoles-

between HLA and the incidence of

cents with post-infectious bronchiolitis

bronchiolitis obliterans in Argentina. Am

obliterans. J Pediatr; 84: 323-330.

J Respir Crit Care Med; 169: A382.

Bowdish ME, et al.

(2004). Surrogate

Williams KM, et al. (2009). Bronchiolitis

markers and risk factors for chronic lung

obliterans after allogeneic hematopoietic

allograft dysfunction. Am J Transplant; 4:

stem cell transplantation. JAMA;

302:

1171-1178.

306-314.

576

ERS Handbook: Paediatric Respiratory Medicine

Plastic bronchitis

Bruce K. Rubin and William B. Moskowitz

Plastic bronchitis is an uncommon disease

characterised by the presence of cohesive

Key points

branching casts filling the airways. This

disease has been recognised for thousands

Plastic bronchitis in children is usually

of years and was first described by Galen

associated with congenital heart

who believed that patients were

disease post-surgery with Fontan

expectorating pulmonary veins; venae

physiology.

arteriosae expectoranti. Plastic bronchitis has

Cast formation appears to be related

had many names through the years although

to poor cardiac output, lymphatic

the terms plastic bronchitis, fibrinous

abnormalities, inflammation, and

bronchitis and cast bronchitis are most

tissue factor activation.

commonly used.

There is no proven therapeutic value

Diagnosis

in using hypertonic saline,

salbutamol, corticosteroids,

Plastic bronchitis is part of the secretory

acetylcysteine, dornase alfa,

hyperresponsiveness disease spectrum.

antibiotics or expectorants.

The diagnosis of plastic bronchitis is

confirmed by identifying the cohesive,

There is some evidence to support the

branching airways casts that are

use of low-dose azithromycin and

expectorated by the patient or removed

aerosol heparin to prevent casts, and

bronchoscopically (fig. 1). Bronchoscopic

tPA can help mobilise casts in situ but

removal is most common in young children

can be very irritating to the airway.

with severe, life-threatening respiratory

Airway clearance therapy, such as high

distress due to both the cast and the

frequency chest wall compression, is

underlying cardiac disease. These casts

strongly recommended.

contain an abundance of mucin but unlike

Thoracic duct ligation and cardiac

normal mucin polymers that are linearly

transplantation appear to reduce or

joined, there is significant cross-linking

eliminate cast formation in some

between adjacent mucin strands. The casts

patients.

contain variable amounts of fibrin with

many patients having only small amounts

of fibrin in expectorated casts.

bronchitis casts further distinguishing them

In patients with bronchiectasis and CF there

from mucus plugging. Plastic bronchitis

are large amounts of polymeric DNA and F-

also appears to be different from the mucus

actin as the principal polymer gel substance.

plugging associated with fungal

These mucus (sputum) plugs have low

inflammation of the airway, as noted in

cohesivity and rarely, if ever, develop into

allergic bronchopulmonary aspergillosis. It

solid cohesive complex branching casts

is not clear if plastic bronchitis can be part

diagnostic of plastic bronchitis. There is also

of the asthma spectrum in patients with

no polymeric DNA or F-actin in plastic

severe asthma and secretory

ERS Handbook: Paediatric Respiratory Medicine

577

exacerbations of plastic bronchitis varies

markedly among patients with congenital

heart disease; sometimes first appearing

years after surgery. Some patients may have

subclinical disease with the expectoration of

small casts or resolution of casts between

exacerbations. It is not clear which patients

with single ventricle physiology are most

likely to develop plastic bronchitis, although

there are associations with protein losing

enteropathy, poor cardiac function, central

venous pressure elevation, arrhythmias and

low cardiac output. The cardiac and

Figure 1. Typical expectorated branching cast from

pulmonary interaction leading to plastic

a child with plastic bronchitis and congenital heart

bronchitis is not known, but may be

disease.

associated with abnormalities in tissue

factor.

hyperresponsiveness. These patients

Plastic bronchitis has been associated with

probably should not be classified as having

lymphatic abnormalities both in patients

plastic bronchitis.

with congenital heart disease and in patients

with primary abnormalities of lymphatic

We have examined plastic bronchitis casts

flow. Case reports suggest that thoracic duct

from more than 50 adults and children with

ligation can attenuate, or even cure, plastic

a variety of associated conditions and all

bronchitis in some patients. A plastic

show the presence of inflammatory cells.

bronchitis-like condition can be triggered by

Although plastic bronchitis was once

the inhalation of toxic gases such as sulfur

classified as Type 1 or Type 2 (cellular and

mustard. In experimental animals that have

acellular) the consistent appearance of

inhaled sulfur mustard there is extensive

inflammatory cells, predominantly

plugging of the airway with fibrin rich casts

lymphocytes with a minor component of

that appear similar to those seen in humans

macrophages, makes this classification of

limited therapeutic or prognostic value.

with plastic bronchitis.

Inflammatory cells are more commonly

Plastic bronchitis is also associated with

seen in association with asthma and allergy

sickle cell disease acute chest syndrome. It

and other non-cardiac associated

is not known if development of casts in

conditions.

sickle cell disease leads to areas of

hypoxaemic sickling within the lung

Plastic bronchitis is probably under

producing the symptoms of acute chest

diagnosed. The diagnosis is often made at

syndrome, or if the acute chest syndrome

autopsy after death from respiratory failure.

itself predisposes to cast formation. Plastic

Patients with milder forms of plastic

bronchitis is not associated with pulmonary

bronchitis probably undergo spontaneous

bacterial infection and, in general,

recovery. Thus, identified patients probably

antibiotics are not recommended as part of

represent the most severe cases with

therapy. However, plastic bronchitis has

dramatic branching casts, airway

been shown to be associated with influenza

obstruction and extensive atelectasis.

A infection in children and similar cast

Disease associations

formation has been described in birds who

have been experimentally infected with avian

Plastic bronchitis in young children is

influenza.

primarily associated with congenital heart

disease, particularly in children with single

It is controversial as to whether severe asthma

ventricle Fontan physiology (table 1). The

and airway plugging should be considered a

occurrence, severity and the frequency of

plastic bronchitis-like disease. Fatal asthma

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ERS Handbook: Paediatric Respiratory Medicine

or hypertonic saline, or mucolytics, such as

Table 1. Conditions associated with plastic bronchitis

N-acetylcysteine. These medications

Proven

should only be used with caution as some

Congenital heart disease with Fontan

can induce mucus secretion or increase

physiology

airway inflammation.

Sickle cell disease acute chest syndrome

There have been several case reports that

Pulmonary lymphatic abnormalities

the inhalation of tissue plasminogen

Influenza A pulmonary infection

activator (tPA) can improve plastic

bronchitis, most probably through fibrin

Toxic inhalation

depolymerisation. tPA is extremely

Possible

expensive and can be irritating to the

airway with haemoptysis or dyspnoea

Other congenital cyanotic cardiac disease

being reported after inhalation. In patients

Non-pulmonary lymphatic abnormalities

with severe plastic bronchitis a trial of

Hypersecretory and near-fatal asthma

aerosol tPA should be considered at a dose

(eosinophilic casts)

of 0.7-1.0 mg?kg^-1 every 4 h. Inhaled

Allergic bronchopulmonary aspergillosis

heparin has also been effective in patients

Unlikely

with plastic bronchitis. Heparin has no

effect on preformed fibrin but has been

shown to reduce mucin secretion and

COPD

prevent tissue factor activation of the fibrin

Bronchiectasis

pathway. Heparin also has anti-

inflammatory properties and is far less

Bacterial pneumonia

irritating to the airway and dramatically

less expensive than some of the other

agents. A trial of aerosolised heparin at a

secretions are extremely cohesive and when

dose of 5000 units every 4 h should be

extracted from the airway appear to have a

considered.

formation of branching casts; and in that

respect they more closely resemble plastic

Isolated reports suggest that inhaled

bronchitis than mucus plugging.

anticholinergics may reduce cast

formation. Although there has been

Therapy

concern that inhaled anticholinergics may

‘‘thicken’’ secretions, this has not been the

Because plastic bronchitis is an

case when these have been used to treat

uncommonly reported condition, most

asthma, CF or COPD. There is no role for

reports of ‘‘effective’’ therapy are isolated

the use of antibiotics to treat bacterial

case reports or small case series.

infection in plastic bronchitis. However,

Furthermore, most patients reported in

low-dose macrolides can decrease mucin

these case studies have received a number

production by inhibiting extracellular

of different medications making it difficult

regulated kinase (ERK)1/2. There are case

to ascertain which of these therapies, if

reports suggesting that low-dose

any, are effective (table 2). Evaluation of

macrolides, similar to their use in CF or

data from the International Plastic

diffuse panbronchiolitis, can attenuate the

Bronchitis Registry suggests no benefit

severity of plastic bronchitis.

from the use of asthma medications, such

as short-acting b-agonists or inhaled

In patients with documented lymphatic

corticosteroids. There is no therapeutic

abnormalities, thoracic duct ligation may be

benefit from using inhaled dornase alfa

of benefit. There is limited evidence that

(Pulmozyme; Roche, San Francisco, CA,

improving cardiac physiology by fenestrated

USA) as plastic bronchitis casts do not

Fontan has a beneficial effect on the severity

contain polymeric DNA. There is no benefit

or resolution of plastic bronchitis.

in using expectorants, such as guaifenesin

Improving cardiac output, when possible,

ERS Handbook: Paediatric Respiratory Medicine

579

The future

Table 2. Recommendations for therapy

Good evidence

Through the US National Institutes of

Airway clearance including physical

Health, Office of Rare Diseases we have

therapy and devices such as high-

established an International Plastic

frequency chest compression vest

Bronchitis Registry to collect data on

patients worldwide (www.clinicaltrials.gov

Aerosol heparin

identifier NCT01663948). This will help us

Aerosol tPA

to generate hypotheses that can be tested

Cardiac transplantation

clinically and will, potentially, allow us to

Anecdotal or case report evidence

use genome or inflammasome screening to

interrogate potential causes for this

Hyperosmolar saline

devastating disease. Through the Office of

Low-dose oral macrolides (clarithromycin

Rare Diseases we have also set up a

or azithromycin)

tissue repository of expectorated bronchial

Oral or inhaled corticosteroids (only for

casts and, with an approved protocol,

eosinophilic casts)

we will make these available to

Thoracic duct ligation

investigators interested in studying

this devastating disease. Information

Modifications of Fontan (fenestration or

can be accessed through www.clinicaltrials.

take down)

gov.

No evidence

b-agonist aerosol

Further reading

Dornase alfa (Pulmozyme)

Akhter J, et al. (2004). Flexible fiberscope

Mucolytics such as N-acetylcysteine

directed removal of mucus plugs in a child

Expectorants such as guaifenesin

with plastic bronchitis. J Bronchol; 11: 112-114.

Non-macrolide antibiotics

Deng J, et al. (2010). Plastic bronchitis in

three children associated with

2009

influenza A(H1N1) virus infection..

Chest; 138: 1486-1488.

can reduce the severity of plastic bronchitis.

Eason DE, et al.

(2013). Aerosolized

There are reports that cardiac

heparin in the treatment of Fontan

transplantation in children and young adults

related plastic bronchitis. Cardiol Young

with heart failure can cure plastic bronchitis

23: 1-3.

when medical management is ineffective.

Goldberg DJ, et al. (2010). Rare problems

associated with the Fontan circulation.

Airway clearance appears to be among the

Cardiol Young; 20: 113-119.

safest and most effective therapy. Once

Heath L, et al. (2011). Prospective, long-

plastic bronchitis has been diagnosed,

itudinal study of plastic bronchitis cast

starting the routine with daily use of a

pathology and responsiveness to tissue

plasminogen activator. Paediatr Cardiol;

high-frequency chest compression vest, for

32: 1182-1189.

those with an effective cough, or the

Kanoh S, et al. (2010). Macrolides as

CoughAssist device (Philips Respironics,

immunomodulatory

medications.

France), for those with impaired cough, can

Mechanisms of action and clinical

prevent cast re-accumulation. We also

applications. Clin Microbiol Rev;

23:

recommend exercise, if possible, and good

590-615.

nutrition, which can consist of protein

Laubisch JE, et al. (2011). Treatment of

repletion in children with protein losing

plastic bronchitis by orthotopic heart

enteropathy or, sometimes, weight loss,

transplantation. Pediatr Cardiol; 32: 1193-

especially in obese adults with plastic

1195.

bronchitis (table 2).

580

ERS Handbook: Paediatric Respiratory Medicine

Haemangiomas,

lymphangiomas and

papillomatosis

Thomas Nicolai

Haemangiomas

4-12 weeks of life, depending on the size of

the haemangioma and its rate of growth.

Airway haemangiomas are benign capillary

Quite often an acute viral airway infection

tumours. Generally, benign capillary

will acutely increase the pre-existing airway

tumours occur in 1-2% of newborns, usually

obstruction caused by a haemangioma. The

involving the skin. However, haemangiomas

most common differential diagnosis is

may also occur in the airways and ,25% of

croup or laryngomalacia. In contrast to

these cases also have haemangiomas of the

croup the symptoms caused by a laryngeal

skin.

or tracheal haemangioma exacerbated by a

The most common benign capillary tumours

viral infection will not disappear fully after

in the paediatric airway are subglottic and

the acute phase of the respiratory infection

glottic haemangiomas, which may be

and may actually progress to overt

present at birth and usually grow for the next

respiratory insufficiency. Often, an

4-6 months. Haemangiomas of the lower

expiratory component of the stridor

airways have been described but are rare.

becomes apparent with critical obstruction,

Laryngeal haemangiomas can also be part of

and the voice or cry is changed in quality

larger haemangiomas that may extend into

and loudness.

the intrathoracic cavity.

Diagnosis The diagnosis is suspected by a

Clinical signs Sometimes, the haemangioma

typical history and an inspiratory and,

may be present at birth leading to neonatal

sometimes, also expiratory noise. A very

inspiratory stridor. However, this early

useful instrument for diagnosis is

presentation is rare. In a typical case,

ultrasound, which can define the typical

inspiratory stridor develops over the first

subglottic tumour structures. In addition, an

MRI scan can show the typical blood filled

glottic or subglottic rounded object.

Key points

However, care must be taken as children

may need sedation for MRI scans, and when

Haemangiomas are benign and

these children are intubated for this purpose

respond to propranolol.

the haemangioma will be compressed by the

N Lymphangiomas may need to be

endotracheal tube and may then be missed.

resected if they obstruct the airway;

Also, the intubation itself can be quite

the clinical course is less predictable.

dangerous with damage to the subglottic

area or even bleeding. Therefore,

N Papillomatosis of the larynx may

laryngotracheoscopy (usually performed

require repeated surgical resection

with a flexible endoscope) is often the

and often responds to cidofivir.

easiest way to diagnosis when ultrasound

N Newer therapies are currently being

has failed to rule out haemangioma.

explored for lymphangiomas and

Subglottic haemangiomas have a quite

papillomas.

typical appearance and may form a rounded

unilateral or bilateral structure in the

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ERS Handbook: Paediatric Respiratory Medicine

Various methods of surgically removing the

haemangioma have been described. Careful

endoscopic laser resection has been

reported to be quite successful in avoiding

tracheotomy in almost all cases, and will, in

my view, remain a good option in

nonresponders to propranolol. Before these

therapeutic options became available many

children had to remain tracheotomised for

2-3 years until the size of the malformation

had become small enough to allow

decannulation.

However, recently it was found, by a

serendipitous discovery, that propranolol

will shrink haemangiomas and arrest further

growth (fig. 1). Therefore, today, therapy

consists of the administration of

propranolol, sometimes accompanied by

initial short-term steroid therapy. With this

strategy it is usually possible to avoid

tracheotomy, as only about 14% of infants

with airway haemangioma are

nonresponders. The optimal duration of

propranolol therapy has not been

established, and it is recommended to treat

until the involution phase of the

haemangioma is reached (usually at 6-

8 months of age but some authors advocate

12 months). Catch-up growth of airway

haemangioma in infants after cessation of

propranolol has been reported in about 7%

of children and may need extended therapy.

Refractoriness of the regrowth to

Figure

a) Subglottic haemangioma almost

propranolol has been described. The long-

totally obstructing the airway. b) Subglottic

time prognosis of this tumour is excellent.

haemangioma that is reduced in size after 1 week of

treatment with propranolol (2 mg?kg^-1?day^-1).

Lymphangiomas

Lymphangiomas are not neoplastic growing

subglottic area (fig. 1). The surface is

lesions, but malformations of the lymphoid

smooth and often has a reddish colour. In

tissues. It is assumed that these

malformations originate from primitive

very rare cases a biopsy may be needed and

lymphatic sacks formed of mesenchymal or

histology and staining for glucose

epithelial embryonic tissue. Dysplastic

transporter 1 (GLUT1) will establish the

lymph capillaries do not allow normal

diagnosis.

drainage of interstitial fluid and lead to

Therapy Mortality without treatment has

tissue swelling and cystic transformation of

been reported to be ,50%. Therapy used to

the affected structures. This malformation is

rely on long-term systemic steroids with all

usually not confined to specific organs and

their known side-effects. Intra-lesional local

may involve larger regions of the body. This

application of steroids was also tried, with

explains the changeable course of the size

only limited success; almost two-thirds of

with, for example, sudden increases of

the children were eventually tracheotomised.

pharyngeal masses in size during viral

ERS Handbook: Paediatric Respiratory Medicine

583

infections or with bleeding into the

lymphangioma. It also explains why

therapeutic options are sometimes limited:

total resection of the affected tissue is not

always possible and remaining (often

clinically unapparent) malformed regions

may later expand in size when drainage of

the lymphatic fluid is obstructed. Other

manifestations of lymphatic malformations

may concern the whole lung and or

mediastinum and lead to chylothorax and

respiratory failure.

Lymphangioma

Clinical signs Lymphangiomas can involve

the pharynx and larynx and lead to severe

airway compromise (fig. 2). Sometimes the

Figure 3. MRI scan of a lymphangioma of the

lymphangioma may be present at birth,

larynx.

being visible as a cranial, pharyngeal or neck

N interferon-a2b,

mass, and/or leading to neonatal inspiratory

N laser resection.

stridor. Clinical manifestations may also

occur later in life, e.g. with swelling due to an

However, the optimal selection of therapy

acute viral infection or when bleeding into

requires considerable experience. The

the lymphangioma leads to an abrupt

natural history of lymphangiomas is less

increase in lesion size.

benign than that of haemangioma, as

involution is not seen regularly.

Diagnosis Airway endoscopy shows an

obstructing mass that may have a typical

Future developments Recently, the use of

multicystic appearance, and allow for

sildenafil has been described in case reports

biopsy. MRI scans will delineate the

and seems to open up a promising new

extension of the lymphangioma into

therapeutic approach, but controlled studies

adjacent tissues (fig. 3).

are only currently under way. Another

promising therapeutic agent in complicated

Therapy Therapeutic options include:

refractory lymphangioma seems to be

N surgical resection,

sirolimus.

N infiltration with sclerosing agents,

Papillomas

Recurrent respiratory papillomatosis (RRP)

of the larynx of children is the most common

tumour of the paediatric larynx, and

involvement of the lower airways does occur.

Its incidence has been estimated to be two

to four cases per 100 000. The papilloma

viruses most frequently seen in the aetiology

are human papilloma virus (HPV) type 6

and 11; however, there are more than 100

types of HPV. The infection is caused by

transmission during birth from the mother’s

genital lesions to the child’s airways.

Caesarean section can reduce but not totally

eliminate the infection risk. However, only

very few children born to mothers with

Figure 2. Lymphangioma of the larynx infiltrating

genital HPV infections later develop airway

the right dorsal aspect.

papillomatosis; therefore, individual risk

584

ERS Handbook: Paediatric Respiratory Medicine

factors have to play a role in disease

normal larynx. However, surgery sometimes

manifestation. Subtle complex

leads to highly dangerous laryngeal scarring

abnormalities of the immune response to

at the level of the vocal fold, in particular if

HPV in these patients have been found.

the resection of the papillomas has been

either too aggressive, including more than

Clinical signs The usual time-point of clinical

one vocal cord during one session, or

manifestation is 3-4 years of age. Clinical

resection was close to the anterior

signs include:

commissure of the vocal folds. The use of

laser surgery may lead to heating structures

N progressive dyspnoea,

below the level of the papillomas, such as

N hoarseness,

the vocal fold, and thereby cause damage

N stridor.

with scar formation. These scars can lead to

Papillomas can grow quite large and

complete airway obstruction and

obstruct the laryngeal opening completely.

tracheostomy. Children with airway

papillomatosis and tracheostomy are at risk

Diagnosis Laryngotracheoscopy will show

of generalisation of the papillomatosis to

the typical cauliflower-like appearance of

the lower airways (trachea and bronchi)

growth, usually above the vocal folds, a

where an eradication of the papillomas is

biopsy will allow the identification of the

usually impossible.

virus type (fig. 4).

A therapeutic modality used widely is the

Clinically an aggressive form can be

virustatic cidofovir. This antiviral has shown

observed with HPV type 6, while the milder

clinical effectiveness in treating adults with

course seems to be associated with HPV

AIDS and systemic HPV infection, and is

type 11. Manifestation before the age of

also widely used to infiltrate papillomas

3 years and more than four surgical

locally. At present there are no good

procedures to remove airway-obstructing

randomised studies, but well-documented

papillomas are associated with a more

case series in children and adults with

aggressive clinical form, which may not

aggressive papillomatosis show that ,60-

resolve spontaneously.

80% of patients will respond, with the

therapy either leading to less frequent

Therapy Therapy may include resection of

the papillomas either surgically or with a

interventions for papilloma resection or

microdebrider or laser. However, utmost

even disappearance of the lesions.

care must be taken not to cause secondary

From experiments in cell cultures and

airways stenosis. It must be kept in mind

marker expression studies some concern

that papillomatosis itself does not lead to

has been voiced that cidofovir may increase

scarring and once overcome will leave a

the risk for laryngeal cancer. However, such

cancer has never been clearly attributed to

cidofovir use, and papillomatosis itself can

lead to airway cancer when it is present for

many years. A recent paper assessing its

safety in a large number of patients found

no increased laryngeal malignancies.

Therefore, in cases with aggressive diseases,

cidofovir may be useful and sometimes the

only option available. However, parents have

to be informed about their choices and the

conceivable side-effects of the drug and the

infection itself.

In rare cases, a generalised HPV infection

Figure 4. Papillomatosis of the larynx with

of the lung follows tracheobronchial

obscured vocal folds.

dissemination, resulting in cavitation.

ERS Handbook: Paediatric Respiratory Medicine

585

This is more frequent in adult patients and it

Lucs AV, et al. (2012). Constitutive over-

may be difficult to differentiate this from

expression of the oncogene Rac1 in the

carcinoma formation.

airway of recurrent respiratory papilloma-

tosis patients is a targetable host-sus-

Future developments Recent research has

ceptibility factor. Mol Med; 18: 244-249.

elucidated that in many people HPV is

Meeuwis J, et al.

(1990). Subglottic

present in the airway mucosa without overt

haemangioma in infants: treatment with

papillomatosis and that the oncogene Rac1

intralesional corticosteroid injection and

is overexpressed in the epithelium of these

intubation. Int J Pediatr Otorhinolaryngol;

individuals. The downstream product of

19: 145-150.

Rac1, COX-2, can be blocked with a COX-2

Nicolai T, et al. (2005). Subglottic hae-

inhibitor, which leads to diminished HPV

mangioma: a comparison of CO(2) laser,

Neodym-Yag laser, and tracheostomy.

transcription in cell culture. One study has

Pediatr Pulmonol; 39: 233-237.

treated three patients with the COX-2

Pransky SM, et al. (1999). Intralesional

inhibitor celecoxib and achieved disease

cidofovir for recurrent respiratory papillo-

remission in all. A prospective study has

matosis in children. Arch Otolaryngol

been initiated. Other agents tried for

Head Neck Surg; 125: 1143-1148.

papillomatosis, but for which no clear

Richter GT, et al. (2012). Haemangioma

benefit has as yet been demonstrated

and vascular malformations:et al current

convincingly include avastin, artemisinin

theory and management. Int J Pediatr;

and propranolol, while interferon seems

645678.

effective but has had unacceptable side-

Rozman Z, et al. (2011). Lymphangioma:

effects in some children.

is intralesional bleomycin sclerotherapy

effective? Biomed Imaging Interv J; 7: e18.

Vaccination programmes against HPV will

Sherrington CA, et al. (1997). Subglottic

hopefully reduce the frequency of this

haemangioma. Arch Dis Child; 76: 458-

worrisome disease. In established disease

459.

the currently available vaccinations cannot

Sie KC, et al. (1994). Subglottic haeman-

be expected to be effective, but a therapeutic

gioma: ten years’ experience with the

carbon dioxide laser. Ann Otol Rhinol

DNA vaccine is currently being developed.

Laryngol; 103: 167-172.

Snoeck R, et al.

(1998). Treatment of

severe laryngeal papillomatosis with

intralesional injections of cidofovir. J

Further reading

Med Virol; 54: 219-225.

Swetman GL, et al. (2012). Sildenafil for

Bonagura VR, et al.

(2010). Recurrent

severe lymphatic malformations. N Engl J

respiratory papillomatosis: a complex

Med; 366: 384-386.

defect in immune responsiveness to

Tjon Pian Gi RE, et al. (2013). Safety of

human papillomavirus-6 and -11. APMIS;

intralesional cidofovir in patients with

118: 455-470.

recurrent respiratory papillomatosis: an

Grasso

DL,

al.

(2008).

international retrospective study on 635

Lymphangiomas of the head and neck

RRP patients. Eur Arch Otorhinolaryngol;

in children. Acta Otorhinolaryngol Ital; 28:

270: 1679-1687.

17-20.

Vlastarakos PV, et al. (2012). Propranolol is

Hammill AM, et al. (2011). Sirolimus for

an effective treatment for airway haeman-

the treatment of complicated vascular

giomas: a critical analysis and meta-

anomalies in children. Pediatr Blood

analysis of published interventional stu-

Cancer; 57: 1018-1024.

dies. Acta Otorhinolaryngol Ital; 32: 213-221.

Laranne J, et al.

(2002). OK-432

Wierzbicka M, et al. (2011). Effectiveness

(Picibanil) therapy for lymphangiomas in

of cidofovir intralesional treatment in

children. Eur Arch Otorhinolaryngol; 259:

recurrent respiratory papillomatosis. Eur

274-278.

Arch Otorhinolaryngol; 268: 1305-1311.

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ERS Handbook: Paediatric Respiratory Medicine

Interstitial lung diseases

Annick Clement, Guillaume Thouvenin, Harriet Corvol and Nadia Nathan

Interstitial lung disease (ILD) in infants and

Key points

children represents a heterogeneous group

of respiratory disorders that are mostly

ILD in children represents a

chronic and impair the respiratory function

heterogeneous group of respiratory

of the lung. In pathology, the term ILD

disorders that are mostly chronic and

describes structural alterations of the lung

impair the respiratory function of the

interstitium. However, in clinical practice, it

lung.

refers to processes that affect the lung

parenchyma, which include the alveolar

The term ILD has been replaced by

structure (i.e. the alveolar epithelium, the

the term DPLD, thus covering all

interstitium and the pulmonary capillary

pathological entities affecting lung

endothelium), as well as the terminal

homeostasis and remodelling

bronchioles. Based on these anatomic and

following injury.

functional considerations, a new term

The mechanisms underlying disease

diffuse parenchymal lung diseases (DPLD)

development are dependent on the

has recently been introduced to more

type of DPLD; the common basis is

accurately describe these diseases.

the interaction between injurious

Therefore, the term DPLD will be used in

environmental triggers and genetic

this chapter instead of ILD.

predisposition.

DPLD covers a large number of disorders

The presenting clinical manifestations

characterised by inflammation and/or

are often subtle and nonspecific,

remodelling of the lung parenchyma. They

therefore, a two-step diagnosis

include rare diseases with established

approach is required: 1) diagnosis of

diagnosis criteria (such as genetic disorders

DPLD syndrome; 2) diagnosis of

of the surfactant system), as well as

specific DPLD.

pathological conditions with uncertain

Treatment protocols remain difficult

diagnosis and/or unknown causes. This

to produce but the overall strategies

explains the fact that the estimated

include general measures and

incidences of the various forms of DPLD are

pharmacological therapy,

difficult to establish, especially in children.

mainly anti-inflammatory and

Indeed, in the paediatric population, disease

immunosuppressive

expressions are dynamically influenced by

molecules.

the ongoing process of lung growth and

maturation. Several reports in the literature

A favourable response to anti-

have provided information on a national

inflammatory therapy can be expected

survey of paediatric DPLD. An estimated

in almost two-thirds of cases,

prevalence of 3.6 per million cases was

although significant sequelae are

reported in immunocompetent children in

often observed.

the UK and Ireland. In Germany, a rate of

1.32 new cases per 1 million children per

ERS Handbook: Paediatric Respiratory Medicine

587

year has been observed. These numbers are

member 3 (ABCA3) and the thyroid

certainly underestimated due to the lack of

transcription factor (TTF)-1. More than 30

standardised definitions, the absence of

SFTPB mutations have been identified

organised reporting systems and the variety

among patients with a congenital deficiency

of pathological conditions. In addition,

in SP-B. For SFTPC, at least 35 mutations

clinical presentation is nonspecific,

have been reported, localised primarily in the

contributing to a poor recognition of the

COOH- terminal Brichos domain.

disorders that may be confused with other

Alterations in this domain can lead to

diseases. Nevertheless, it seems that DPLD

diseases via mechanisms related to

is more frequently observed in the younger

abnormal protein processing and cell

age and in males. In addition, nearly 10% of

toxicity. Recently, several studies have

cases appear to be familial.

described genetic variations of ABCA3 in

DPLD, with the information that ABCA3 plays

Pathophysiology

an important role in the transport of

DPLD can be caused by a number of factors

surfactant lipids into lamellar bodies.

with distinct prognosis and natural history.

Another molecular contributor of surfactant

Agents responsible for initiation of the

homeostasis is TTF-1, a regulator of

pathological process can be introduced

transcription for SP-B and SP-C. Other

through the airways and the circulation, or

genetic factors/predispositions currently

can occur as a result of sensitisation.

being discussed include genes associated

Consequently, the mechanisms underlying

with lung development and embryonic

disease progression will be influenced by the

pathways, and those involved in the

causative event, as well as by the host and

telomerase system. Telomerases are

the environment. These mechanisms are

important regulators of the re-population of

developed through interactions of multiple

the damaged epithelium, partly through

pathways.

activation and proliferation of tissue-

resident stem cells and their differentiation

Based on results from experimental models

leading to replacement of the injured cells.

and patient lung tissue analysis, it is

Telomere shortening has been linked to

proposed that injury of the respiratory

decreased activity of telomerase and a

epithelium is the key determinant of the

reduced capacity for stem cell renewal.

disorders. Repeated multi-focal epithelial

Several studies have also indicated that

micro-injury and/or delayed surface

telomerase is mainly expressed during lung

regeneration lead to epithelial cell apoptosis

development with a peak expression before

and altered epithelial-mesenchymal

birth followed by a decrease to nearly

interactions, with consequently disturbed

undetectable levels in mature alveolar

epithelium homeostasis, dysregulated

epithelium. Interestingly, exposure of

inflammatory response and lung

normal quiescent alveolar cells to injury

remodelling.

induces induction of telomerase expression

The mechanisms underlying disease

and activity. The contribution of telomerase

development are dependent on the type of

mutation and/or dysfunction in the

DPLD, with the common basis being the

progression of paediatric DPLD remains to

interaction between injurious environmental

be explored.

triggers (which include oxidants and toxic

DPLD seems to be observed less frequently

agents, immune complexes, viruses and

in children than in adults. In addition, the

gastro-oesophageal reflux) and genetic

overall outcome and prognosis of the

predisposition.

disease are thought to be less severe in

Genetic defects of the surfactant system are

paediatric patients. These differences may

increasingly described in paediatric DPLD.

be explained by the types of initial injury

They include variations in genes encoding

(which might not be similar due to changes

the surfactant protein (SP)-B (SFTPB), SP-C

in the host environment), as well as

(SFTPC), ATP-binding cassette, sub-family A,

modifications of the process of wound

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ERS Handbook: Paediatric Respiratory Medicine

healing after injury with age. Recent

Diagnosis of DPLD ‘‘syndrome’’

experimental studies have shown that a

The diagnosis of DPLD is established on

single episode of lung injury by either

presenting history and clinical, radiological

bleomycin or virus can induce pulmonary

and functional findings. Major criteria

fibrosis only in aged wild-type mice and not

include dyspnoea, diffuse infiltrates on chest

in young animals, supporting the view that

radiographs and abnormal pulmonary

age-related physiological changes contribute

function tests (PFTs) with restrictive

to distinct disease expressions. Several

ventilatory defect and/or impaired gas

factors may participate in the altered

exchange with hypoxaemia.

response to wound with ageing. One of

these is the progressive modification in cell

The presenting clinical manifestations are

renewal capacity due to increased epithelial

often subtle and nonspecific. The onset of

cell apoptosis and accumulation of

symptoms is, in most cases, insidious and

senescent stem cells. Apoptosis is necessary

many children may have had symptoms for

for the removal of inflammatory cells

months before the diagnosis of DPLD is

following injury, but this process requires a

confirmed. Common symptoms at

complex balance between the various

presentation include:

parenchyma cell types. In several models of

lung fibrosis, an abnormal pattern of

N tachypnoea/dyspnoea (observed in 80%

enhanced apoptosis of alveolar epithelial

of patients),

cells in combination with a decreased

N cough (present in almost 75% of the

capacity of fibroblast to apoptosis has been

patients),

documented, leading to insufficient surface

N exercise limitation,

re-population and fibrotic tissue

N frequent respiratory infections.

development. Studies of the molecular

mechanisms have recently led to targeting

Failure to thrive (37%), tiring during feeding

of the endoplasmic reticulum and the

and weight loss are also common

transforming growth factor (TGF)-b

symptoms, mainly in young patients.

pathways. Dysregulation of these pathways

Unexplained fever is also reported in infants.

is increasingly observed in ageing tissues

The past medical history should be deeply

with abnormal scar formation. Among the

reviewed for precipitating factors such as

other contributors to altered healing with

feeding history, infections or exposure to

ageing are the increased burden of oxidative

environmental agents and drugs. In

stress and epigenetic changes. Several

addition, family history needs to be

recent studies tend to suggest that ageing is

investigated for relatives or siblings with

associated with a general relaxation of

similar lung conditions.

epigenetic control, including progressive

changes in DNA methylation and histone

The frequent clinical findings are inspiratory

modifications, with consequently impaired

crackles, tachypnoea and retraction. In a

renewal capacity of the stem/progenitor cells

child with a normal birth history, these are

of the lung parenchyma.

strongly suggestive of DPLD. Other findings

observed in older patients include finger

Clinical approach and diagnosis

clubbing and cyanosis during exercise or at

The number of separate disorders under the

rest. Depending on the types of DPLD,

DPLD umbrella implicates selected

associated nonrespiratory symptoms may

investigation strategies. However, despite

be observed, such as cutaneous rashes,

the differences in causes and outcomes, the

joint manifestations, uveitis and recurrent

clinical presentation of the majority of DPLD

fever in situations of collagen-vascular

is globally similar. Therefore, a two-step

disorders.

diagnosis approach is required:

Chest imaging is an essential contributor for

N Step 1: diagnosis of DPLD ‘‘syndrome’’,

the diagnosis. Plain radiographs are usually

N Step 2: diagnosis of specific DPLD.

performed at first presentation. In almost all

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589

cases, abnormalities are documented but

defined by a reduced resting SaO₂ or a

the information provided is often limited

reduced resting PaO₂, is often present.

and the key chest imaging tool for diagnosis

Hypercapnia occurs only late in the disease

is HRCT. The most common HRCT feature

course. During exercise the previously

of paediatric DPLD is widespread ground-

described dysfunctions become even more

glass attenuation, with some observations

pronounced, and gas exchange during

of intralobular lines and irregular

exercise might be a more consistent and

interlobular septal thickening. Large

sensitive indicator of early disease.

subpleural air cysts in the upper lobes

adjacent to areas of ground-glass opacities

Bronchoalveolar lavage (BAL) and lung

are also reported in young patients (fig. 1).

tissue analysis are not commonly proposed

These cysts are interpreted as paraseptal or

in the first-step diagnostic approach.

irregular emphysema. HRCT is useful not

Besides infections, BAL can be of diagnostic

only for diagnosis, but also for selection of

value in specific situations, which include

lung area to be biopsied.

pulmonary alveolar haemorrhage,

Langerhans cell histiocytosis, lipid disorders

PFT represents a useful investigation for

with lung involvement, or alveolar

both the diagnosis and the management of

proteinosis. In other pathological situations,

DPLD in children and adolescents. In

BAL can usefully serve to direct further

preschool children, the techniques currently

investigations, by providing specimens for

available are limited. Common pulmonary

cytological examination, microbial cultures

function abnormalities reflect a restrictive

and molecular analysis.

ventilatory defect with reduced lung

compliance and decreased lung volumes.

Histological evaluation of lung tissue

Vital capacity (VC) is variably diminished

usually represents the final step in a series

and the decrease in TLC in general is

of diagnostic approaches. Different methods

relatively less than in VC. Functional residual

of biopsy are reported, based on expertise of

capacity (FRC) is also reduced but relatively

the surgical teams and the balance between

less than VC and TLC, and residual volume

procedure invasiveness and the potential for

(RV) is generally preserved; thus, the ratios

obtaining adequate and sufficient tissue

of FRC/TLC and RV/TLC are often increased.

material for diagnosis. The techniques of

Airway involvement is observed in only a

choice are open lung biopsy and video-

minority of patients. TLCO is often markedly

assisted thoracoscopy biopsy. The other

reduced and may be abnormal before any

methods, such as transbronchial lung

radiological findings. However, TLCO

biopsy, are less frequently proposed. The

corrected for lung volume may also be

lung histological patterns observed in

normal in many children. Hypoxaemia,

various forms of DPLD have been reviewed

in several reports. The most common

abnormalities include thickening of alveolar

interstitial walls, accumulation of

inflammatory cells, fibrotic components,

epithelial cell hyperplasia, and alveolar

spaces filled with inflammatory cells, hyaline

membranes containing surfactant proteins

or cellular debris.

Specific diagnosis of DPLD and

classification

Figure 1. HRCT scan of a 2-year-old girl with

There have been many different approaches

surfactant protein C deficiency (I73T mutation in

to the classification of paediatric DPLD;

SFTPC gene). The scan shows diffuse ground-glass

several of them are now being reconsidered.

attenuations with parenchymal cysts and

It is believed that some forms are more

interlobular septal thickening.

prevalent in very young children. However,

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ERS Handbook: Paediatric Respiratory Medicine

increasing reports in older patients and

tests focus on the search for serum-

adults have documented genetic causes

precipitating IgG antibodies against the

previously documented in infants, such as

offending antigen. Other exposure-related

mutations in the genes encoding proteins of

diseases are those caused by radiation and

the surfactant system. In addition, along

drugs including anti-inflammatory agents

with the continuous improvement of

(e.g. aspirin and etanercept),

investigation procedures, diseases

immunosuppressive and chemotherapeutic

associated with lung parenchyma structural

agents (e.g. azathioprine, methotrexate and

abnormalities have been reported in

cyclophosphamide), and illicit drugs in

patients beyond infancy. Another important

teenagers.

issue relates to the inclusion of some forms

Systemic disease-associated DPLD comprises

of bronchopulmonary dysplasia (BPD) in the

a complex group of disorders requiring

list of causes. The debate, with the expertise

specific investigations oriented by the

of clinicians and pathologists, is still

clinical expression. They mainly include:

ongoing. Indeed, BPD may favour repeated

insults of the lung parenchyma with delayed

N granulomatous diseases,

surface regeneration early in life. Also, the

N metabolic disorders,

question of the role of chronic aspiration

N connective tissues disorders (CTD),

syndromes as a causal or precipiting factor

N pulmonary vasculitis,

is increasingly being addressed and will

N Langerhans cell histiocytosis.

require further prospective studies.

In situations of granulomatous diseases, the

From a clinical point of view, a step-by-step

discussed diagnoses are mainly sarcoidosis,

aetiological search is critical, starting with a

infections and disorders of neutrophil

clinical evaluation requiring careful attention

function. Sarcoidosis is relatively

to exposure and environment, systemic

uncommon among children. Its diagnosis is

manifestations and family disorders. This

based on a combination of suggestive

clinical approach will lead to determining

clinical features, with histologically

the specific investigations, which will be

documented noncaseating granuloma, in

performed according to the following

the absence of other known causes of

grouping:

granuloma formation. Its incidence seems

to be influenced by age, race and geographic

N exposure-related DPLD;

localisation. Most of the cases in children

N systemic disease-associated DPLD;

occur in pre-adolescents and adolescents,

N lung-restricted DPLD;

with more observations documented in

N DPLD specific to infancy (table 1).

Black children than Caucasian children.

Exposure-related disease refers to diseases

DPLD in metabolic disorders are reported in

caused by a sufficient level of exposure

lysosomal diseases such as Gaucher’s

(dose) to components with target organ

disease, Niemann-Pick diseases and

contact, and subsequent biologic changes

Hermansky-Pudlak syndrome. CTD refers to

and clinical expression. Many agents have

any disease that has the connective tissues

been associated with pulmonary

of the body as a primary target of pathology

complications of various types, including

and whose development implicates genetic,

DPLD. In children, this diagnosis is certainly

constitutional and environmental elements.

underestimated, as paediatricians do not

The main disorders to be considered during

usually have the expertise necessary to

childhood are rheumatoid arthritis, systemic

obtain an environmental history. The

sclerosis and systemic lupus erythematosus.

diagnoses most commonly reported include

Pulmonary vasculitis is observed in

hypersensitivity pneumonitis, a cell-

vasculitic syndromes that preferentially

mediated immune reaction to inhaled

affect small vessels (arterioles, venules, and

antigens in susceptible persons, e.g. bird

capillaries): anti-neutrophil cytoplasmic

fancier’s diseases, humidifier lung diseases

antibody-associated vasculitis

and chemical lung diseases. Laboratory

(granulomatosis with polyangiitis

ERS Handbook: Paediatric Respiratory Medicine

591

disorders and lymphatic system dysfunction.

Table 1. DPLD diagnosis in children

As mentioned previously, some forms of

Exposure-related DPLD

chronic neonatal lung diseases associated

Hypersensitivity pneumonitis

with BPD and pulmonary hypertension may

also be discussed.

Radiation exposure

Drugs

The role of infections, mainly viral, in DPLD

Systemic disease-associated DPLD

is sustained by a number of human and

experimental studies documenting targeted

Granulomatous diseases

injury of the alveolar epithelium. The list of

Metabolic disorders

viruses comprises adenovirus, members of

Connective tissue disorders

the herpes virus family (Epstein-Barrr virus

Pulmonary vasculitis

and cytomegalovirus) and respiratory

syncytial virus. Among the other pathogens,

Langerhans cell histiocytosis

Chlamydophila pneumoniae and Mycoplasma

DPLD-associated with other organ

pneumoniae are currently drawing increasing

diseases

consideration.

Lung-restricted DPLD

Surfactant disorders include genetic

Infections

surfactant protein disorders and pulmonary

Surfactant disorders

alveolar proteinosis. Mutations in SFTPC are

Pulmonary alveolar proteinosis

currently the main reported genetic

Diffuse alveolar haemorrhage

disorders with the most prevalent mutation

being I73T (c.218 T.C). The phenotype

Eosinophilic lung diseases

associated with SFTPC mutations is

Diffuse developmental disorders

extremely heterogeneous, from neonatal

Lymphatic system disorders

fatal respiratory failure to DPLD children and

adults. The deficiency in SP-B is a rare

DPLD specific to infancy

autosomal recessive condition known to be

Neuroendocrine cell hyperplasia

mainly responsible for lethal neonatal

Pulmonary interstitial glycogenosis

respiratory distress. Recessive mutations in

Chronic pneumonitis in infancy

the ABCA3 gene were first attributed to fatal

respiratory failure in term neonates but are

increasingly being recognised as a cause of

DPLD in older children and young adults.

(Wegener’s granulomatosis), Churg-Strauss

Mutations in the TTF-1 gene are associated

syndrome and microscopic polyangitis);

with ‘‘brain-lung-thyroid syndrome’’ which

anti-glomerular basement membrane

combines congenital hypothyridism,

disease; Henoch-Schönlein purpura and

neurological symptoms (hypotonia and

cryoglobulinemia vasculitis.

chorea) and lung diseases.

In addition to Langerhans cell histiocytosis,

Pulmonary alveolar proteinosis is a rare lung

other causes of systemic disease-associated

disorder characterised by alveolar filling with

DPLD include inflammatory bowel diseases

floccular material derived from surfactant

(Crohn’s disease), liver and neurocutaneous

phospholipids and protein components.

disorders, and amyloidosis.

Pulmonary alveolar proteinosis is described

Lung-restricted DPLD include disorders

as primary or secondary to lung infections,

primarily affecting the components of the

haematological malignancies and inhalation

distal parenchyma. The main diagnosis is

of mineral dusts. Abnormalities in

infections, surfactant disorders, pulmonary

granulocyte/macrophage colony-stimulating

alveolar proteinosis, diffuse alveolar

factor are increasingly reported in

haemorrhage and eosinophilic lung

pulmonary alveolar proteinosis

diseases, as well as diffuse developmental

pathogenesis.

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ERS Handbook: Paediatric Respiratory Medicine

Diffuse alveolar haemorrhage syndromes

hyperplasia of infancy is a non-lethal disease

are caused by the disruption of alveolar-

characterised by tachypnoea without

capillary basement membrane as a

respiratory failure. On lung biopsy, the

consequence of injury to the alveolar septal

histological abnormality is hyperplasia of

capillaries, and less commonly to the

neuroendocrine cells within bronchioles

arterioles and veinules. The hallmarks are

documented by bombesin

intra-alveolar accumulation of red blood

immunohistochemistry. In some cases, the

cells, fibrin and haemosiderin-laden

follow-up reveals the persistence of

macrophages. In approximately one-third of

tachypnoea and oxygen requirement for

patients, diffuse alveolar haemorrhage does

several months. Usually, there is a good

not manifest haemoptysis, and BAL can be

prognosis. Pulmonary interstitial

extremely helpful by documenting the

glycogenosis is also a non-lethal disease

presence of siderophages or red blood cells

reported in neonates with respiratory

within the alveoli. Diffuse alveolar

distress syndrome that develops shortly

haemorrhage can be observed in the

after birth. The histological hallmark is the

absence of systemic diseases or in the

accumulation of monoparticulate glycogen

context of other diseases, which include

in the interstitial cells on lung biopsy. It is

pulmonary hypertension, congenital heart

thought to represent a maturation defect of

diseases, pulmonary veno-occlusive disease,

interstitial cells that causes them to

arteriovenous malformations, hereditary

accumulate glycogen within their cytoplasm.

haemorrhagic telangiectasia, coagulation

Treatment strategies and outcome

disorders and coeliac disease.

The diversity of DPLD conditions and the

Eosinophilic lung diseases constitute a

lack of randomised clinical trials in groups

diverse group of disorders of various

of well-phenotyped paediatric patients

origins. The diagnosis is suggested by

explain the difficulty to propose treatment

increased peripheral eosinophilia and

strategies. Longitudinal care of these

confirmed by the presence of eosinophils in

children needs to be organised in

BAL and/or lung tissue. Eosinophilic lung

specialised centres. In this section, general

diseases of known cause in children mainly

include allergic bronchopulmonary

management with the most usual

aspergillosis, parasitic infections and drug

pharmacological therapies is indicated.

reactions. Eosinophilic lung diseases of

General measures are essential and mainly

unknown cause comprise Loeffler syndrome

include administration of oxygen for chronic

(characterised by migrating pulmonary

hypoxaemia and maintenance of nutrition

opacities), acute eosinophilic pneumonia

with an adequate energy intake.

and chronic eosinophilic pneumonia.

Immunisation with the influenza vaccine on

Among the diffuse developmental disorders is

an annual basis is recommended along with

alveolar capillary dysplasia, a rare disorder

other routine immunisations against major

presenting with persistent pulmonary hyper-

respiratory pathogens. In addition, aggressive

tension of the newborn. A definitive diagnosis

treatment of intercurrent infections and strict

can only be made by histological examination,

avoidance of tobacco smoke and other air

documenting poor capillary apposition and

pollutants are strongly recommended.

density, allied with medial arterial hypertrophy

Pharmacological therapy includes anti-

and misalignment of pulmonary vessels.

inflammatory and immunosuppressive

Interestingly, capillary proliferation in the

molecules. Steroids are the preferred choice,

alveolar wall has been reported in hereditary

administered orally and/or intravenously.

haemorrhagic telangiectasia.

Oral prednisolone is most commonly

DPLD specific to infancy includes

administered at a dose of 1-2 mg?kg^-1?day^-1.

neuroendocrine cell hyperplasia, pulmonary

Children with significant disease are best

interstitial glycogenosis and chronic

treated with pulsed methylprednisolone, at

pneumonitis in infancy. Neuroendocrine cell

least initially. This is usually given at a dose

ERS Handbook: Paediatric Respiratory Medicine

593

of 10-30 mg?kg^-1?day^-1 for 3 consecutive

Lung transplantation is a viable option in

days at monthly intervals. When the disease

children of all ages, even in young infants,

is under control, the dosage of

and lung or heart-lung transplantation may

methylprednisolone can be reduced or the

be offered as an ultimate therapy for end-

time between cycles can be spaced out. An

stage DPLD. The outcome and survival do

alternative to steroids is hydroxychloroquine

not seem to be different from those reported

with a recommended dose of 6-

in other pulmonary conditions. Among other

10 mg?kg^-1?day^-1. Individual case reports

specific treatments is whole lung lavage in

have described a response to

situations of pulmonary alveolar proteinosis.

hydroxychloroquine, even in the presence of

steroid resistance. Some groups have

The prognosis of children with DPLD is

proposed to base the decision as to which

extremely variable. It is highly dependent on

agent to use on the lung biopsy findings,

the cause, the expertise and environment of

with a preference for steroids in the case of

the patient care system, and the individual

large amounts of desquamation and

response to treatment. It is also very difficult

inflammation, but for hydroxychloroquine if

to predict: some children with relatively

increased amounts of collagen representing

severe fibrosis on lung biopsy make good

pre-fibrotic change are found. However, as

progress, whereas others with mild

documented in the European Respiratory

desquamation have a poor outcome.

Society Task Force on paediatric ILD, the

Overall, a favourable response to anti-

preferred choice between steroids or

inflammatory therapy can be expected in

hydroxychloroquine in children is highly

almost two-thirds of cases, although

dependent on the expertise of the centre in

significant sequelae, such as limited exercise

charge of the patient, and does not seem to

tolerance or the need for long-term oxygen

be oriented by the histopathological pattern.

therapy, are often observed. Reported

In the case of severe disease, steroids and

mortality rates are approximately 15%.

hydroxychloroquine may be associated. In

situations of inefficiency of steroids and

Conclusion

hydroxychloroquine, other

DPLD in children comprises a large

immunosuppressive or cytotoxic agents,

spectrum of disorders, resulting from

such as azathioprine, cyclophosphamide,

interactions between injurious

cyclosporine, or methotrexate, may be used.

environmental triggers and genetic

Other therapeutic options include

predisposition. Although much effort has

macrolides. Indeed, these antibiotics have

been made in the clinical approach, there is

been shown to display a number of anti-

still a lack in disease characterisation,

inflammatory and immunomodulatory

identification of specific phenotypes linked

actions. Of interest is the ability of

to documented molecular mechanisms, and

macrolides to accumulate in parenchymal

proposals of novel therapeutic interventions.

cells including epithelial cells and

The current development of international

phagocytes. New therapeutic strategies

collaborations, including European and

currently proposed in adult patients target

North American teams, with the aim of

fibrogenic cytokines. Antagonists to TGF-b

sharing cohorts of well-phenotyped

include pirfenidone and decorin. The use of

paediatric patients is a major opportunity to

molecules directed against tumour necrosis

efficiently progress in DPLD understanding

factor (TNF)-a, such as the soluble TNF-a

and management.

receptor agent etanercept, is also under

investigation. In the future, it is probable

Further reading

that an expanding number of molecules

aimed at favouring alveolar surface

Clement A (2004). Task force on chronic

regeneration and repair through activation

interstitial lung disease in immunocom-

and proliferation of tissue-resident

petent children. Eur Respir J; 24: 686-697.

(progenitor) cells will be discovered.

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ERS Handbook: Paediatric Respiratory Medicine

Clement A, et al. (2008). Interstitial lung

Kapetanaki MG, et al. (2013). Influence of

diseases in infants and children. Eur

age on wound healing and fibrosis. J

Respir J; 31: 658-666.

Pathol; 229: 310-322.

Clement A, et al. (2010). Interstitial lung

Langston C, et al. (2009). Diffuse lung

diseases in children. Orphanet J Rare Dis;

disease in infancy: a proposed classifi-

5: 22.

cation applied to 259 diagnostic biop-

Costabel U

(2011). Emerging potential

sies. Pediatr Dev Pathol;

12:

421-

treatments: new hope for idiopathic

437.

pulmonary fibrosis patients? Eur Respir

Nathan N, et al. (2011). Interstitial lung

Rev; 20: 201-207.

disease: physiopathology in the context of

Dinwiddie R, et al.

(2002). Idiopathic

lung growth. Paediatr Respir Rev; 12: 216-

interstitial pneumonitis in children: a

222.

national survey in the United Kingdom

Nathan N, et al.

(2012). A national

and Ireland. Pediatr Pulmonol; 34: 23-29.

internet-linked based database for

Driscoll B, et al. (2000). Telomerase in

pediatric interstitial lung diseases: the

alveolar epithelial development and

French network. Orphanet J Rare Dis; 7:

repair. Am J Physiol Lung Cell Mol

40.

Physiol; 279: L1191-L1198.

Popler J, et al. (2012). New coding in the

Epaud R, et al. (2012). Genetic disorders

International Classification of Diseases,

of surfactant. Arch Pediatr; 19: 212-219.

Ninth Revision, for children’s interstitial

Flamein F, et al. (2012). Molecular and

lung disease. Chest; 142: 774-780.

cellular characteristics of ABCA3

muta-

Thouvenin

al.

(2010).

tions associated with diffuse parenchy-

Characteristics of disorders associated

mal lung diseases in children. Hum Mol

with genetic mutations of surfactant

Genet; 21: 765-775.

protein C. Arch Dis Child; 95: 449-454.

Griese M, et al. (2009). Incidence and

Tuder RM, et al. (2011). Stress responses

classification of pediatric diffuse parench-

affecting homeostasis of the alveolar

ymal lung diseases in Germany. Orphanet

capillary unit. Proc Am Thorac Soc;

J Rare Dis; 4: 26.

485-491.

Guillot L, et al. (2009). New surfactant

van Moorsel CH, et al. (2010). Surfactant

protein C gene mutations associated with

protein C mutations are the basis of a

diffuse lung disease. J Med Genet; 46:

significant portion of adult familial pul-

490-494.

monary fibrosis in a Dutch cohort. Am J

Guillot L, et al. (2010). NKX2-1 mutations

Respir Crit Care Med; 182: 1419-1425.

leading to surfactant protein promoter

Wuyts WA, et al. (2010). Azithromycin

dysregulation cause interstitial lung dis-

reduces pulmonary fibrosis in a bleomy-

ease in ‘‘Brain-Lung-Thyroid Syndrome’’.

cin mouse model. Exp Lung Res;

36:

Hum Mutat; 31: E1146-E1162.

602-614.

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595

Surfactant dysfunction and

alveolar proteinosis

Armin Irnstetter, Carolin Kröner, Ralf Zarbock and Matthias Griese

Pulmonary surfactant is a complex mixture

Detailed molecular knowledge of these

of the surfactant proteins (SP)-A, B, C and D

components led to the discovery of primary

and lipids, and a is key component of

disorders of the surfactant system.

alveolar integrity and function. These

Deficiencies of SP-B and SP-C, the lipid

proteins are essential for lowering surface

transporter ABCA3 located in type II

tension (mainly SP-B/C) and play a major

pneumocytes, and the transcription factor

role in innate immunity (mainly SP-A/D).

TTF1, which regulates expression of SP-B

and SP-C, lead to clinical entities that are

summarised here as surfactant dysfunction

Key points

mutations. On histopathological

examination characteristic features include

Two major groups of disorders are

interstitial widening, hyperplasia of type II

associated with the surfactant system:

alveolar epithelial cells and proteinaceous

surfactant dysfunction mutations and

material in the distal airspaces. Of interest,

PAP.

association with a deficiency of surfactant or

its components, such as SP-B-deficiency and

Surfactant dysfunction mutations

other surfactant deficiency syndromes, may

include diseases caused by mutations

show a pulmonary alveolar proteinosis

in the genes coding for SP-B, SP-C, the

(PAP)-like pattern on histology. This

lipid transporter ABCA3 and the

accumulation of surfactant is the result of an

transcription factor TTF1.

impaired surfactant metabolism leading to

Although these entities may show a

local surfactant accumulation; the extent of

PAP-like pattern on histology, the

alveolar filling is much less than in PAP. In

extent of alveolar filling is much less

the past this has contributed to some

than in PAP and this term should be

confusion and we suggest not using the

avoided when naming the surfactant

term ‘‘congenital alveolar proteinosis’’ to

dysfunction mutations.

describe newborns with surfactant

dysfunction.

Hereditary deficiency of the a-chain of

the receptor for GM-CSF is

In contrast to a deficiency of surfactant and

responsible for increased

its components, other clinical entities lead

accumulation of surfactant in the

to a surplus of surfactant, because its

alveolar space and resulting PAP.

removal from the alveolar space is deficient.

Surfactant dysfunction mutations may

Such accumulation of surfactant material in

present at birth as respiratory distress

the alveolar space is called PAP. The primary

syndrome or later in infancy as

pathomechanism responsible for PAP in

chronic dyspnoea and hypoxia (chILD

children is hereditary deficiency of the a-

syndrome), whereas mutations in the

chain of the receptor for granulocyte-

a-chain of the receptor for GM-CSF

macrophage colony-stimulating factor (GM-

present only as chILD syndrome.

CSF). GM-CSF is responsible for the

metabolism and degradation of surfactant

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ERS Handbook: Paediatric Respiratory Medicine

by alveolar macrophages. Disruption of its

evaluated by an experienced

receptor leads to PAP. Several other

histopathologist.

diseases are known to cause PAP. These, as

Clinical course and therapeutic strategies SP-B

well as secondary surfactant deficiency

deficiency: Two decades ago Nogee et al.

syndromes, have to be included in the

(1994), first described a mutation in SP-B

differential diagnosis of patients with

disturbance of the surfactant system.

causing a severe neonatal respiratory

distress syndrome in term infants ultimately

Surfactant dysfunction mutations

leading to death. SP-B deficiency is a very

rare disease affecting approximately one

Deficiencies of SP-B and SP-C, the lipid

child in every 1 000 000 live births. The

transporter ABCA3 located in type II

mode of inheritance is autosomal recessive,

pneumocytes, and the transcription factor

the most common mutation is the insertion

TTF1 are caused by mutations in the SFTPB-,

of two amino acids (121ins2). All mutations

SFTBC-, ABCA3- and NKX2-1 genes. The

lead to an absolute or partial loss of SP-B.

resulting diffuse parenchymal lung diseases

clinically present with two major

The diagnosis is confirmed by sequencing of

phenotypes, although other modes of

SP-B (SFTPB). Currently, there are no

presentation (e.g. as an asthma syndrome)

therapeutic options, except lung

have also been observed.

transplantation. Experimental therapy with

Clinical presentation At birth children with

inhaled RNA was shown to be successful in

dysfunction mutations typically manifest

animals. Palliative therapy is indicated for

with idiopathic respiratory distress

children with classic mutation.

syndrome or idiopathic pulmonary

SP-C deficiency: Inheritance of this disease,

hypertension without being preterm or

which occurs more frequently than SP-B

having other explanations for their clinical

deficiency, is autosomal dominant. The

manifestations (i.e. infections, congenital

clinical syndromes described above will

heart defects, blood vessel abnormalities or

lead to sequencing of the candidate gene.

other anatomic abnormalities). The

pulmonary symptoms are often so severe

In early stages of the disease the

that the children require mechanical

radiological findings are similar to those in

ventilation. Depending on the underlying

PAP with the typical alveolar filling pattern

mutation the clinical course is variable,

and ground-glass opacities (fig. 1). Further

ranging from rapid disease progression and

in the disease course increased interstitial

death to mild forms. Transient response to

markings are seen with distinct triangular

medication, such as systemic steroids or

shaped subpleural or interlobar septa,

administration of surfactant, may be

which develop into multiple subpleural,

observed.

interstitial bullae. If biopsy is performed, an

experienced paediatric pathologist should

The other clinical manifestation, the so-

evaluate the specimen in order to ensure

called chILD-syndrome (Children’s

the correct diagnosis. Therapeutic options

Interstitial Lung Disease), is characterised

may include anti-inflammatory therapy

by an insidious start of dyspnoea, dry

(corticosteroids) or treatment with

coughing, fine crackles and failure to thrive.

hydroxychloroquine or azithromycin.

Such clinical symptoms together with a

Additional treatment with

familial history of fatal or chronic lung

immunosuppressants has anecdotally been

diseases or presence of consanguinity must

described for these and other entities. To

lead to specific genetic testing for the

date, no controlled trials have been

conditions that are potentially disease

performed; all treatments should be tried

causing.

and assessed in the framework of a registry

If the diagnosis cannot be established, open

for ILD (www.childeu.net) in order to

or thoracoscopic lung biopsy should be

systematically record these rare

performed. The lung biopsy should be

experiences.

ERS Handbook: Paediatric Respiratory Medicine

597

ranging from neonatal respiratory distress

syndrome to typical manifestations of chILD

syndrome. Furthermore, recurrent

bronchopulmonary infections are seen in

childhood. About 40% of the cases present

with respiratory symptoms alone. To date

there is still relatively little experience

concerning the treatment of the disease.

Thus, empiric therapy should be evaluated

and registered prospectively in order to

establish and compare different therapeutic

options.

Figure 1. HRCT scan of an infant with SP-C

deficiency and presentation of chILD syndrome at

Pulmonary alveolar proteinosis

6 months of age. Note the crazy paving pattern in

both lower lobes.

PAP represents a group of rare diseases that

are characterised by an accumulation of

periodic acid-Schiff (PAS) reaction-positive

ABCA3-transporter deficiency: ABCA3 is a lipid

granular eosinophilic material in the alveolar

transfer protein which is essential for the

space. As mentioned previously, PAP is a

biogenesis of lamellar bodies of type 2-

histological diagnosis. In paediatrics, the

pneumocytes. More than 100 different

classic form of PAP is due to GM-CSF-

mutations with autosomal recessive

receptor-a deficiency. The other forms must

inheritance mode have been described. As

be differentiated and include a large number

heterozygous frequency in the population is

of causes leading to this group of diseases

relatively high, ABCA3-transporter deficiency

(table 1). An imbalance between the

represents one of the most frequent genetic

synthesis and secretion of surfactant from

changes detected in interstitial lung

type II pneumocytes, its intra-alveolar

diseases in children and adolescents. The

metabolism and surfactant recycling, and

clinical course and prognosis are highly

elimination, mainly by macrophages, leads

variable depending on the mutations

to the accumulation of surfactant material in

present, may begin at birth or later, and are

the alveolar space. GM-CSF is a key

difficult to foresee. Effective therapeutic

regulatory cytokine for the catabolism of

interventions should be determined

surfactant by alveolar macrophages.

empirically, evaluated systematically and

Although other primary forms of PAP in

registered prospectively. In addition to

paediatrics have been described, the

diverse systemic steroid therapy regimes,

underlying mutations have yet to be

hydroxychloroquine or azithromycin are

characterised.

used.

Clinical manifestations and diagnosis The

Brain-thyroid-lung syndrome: this disease,

alveolar accumulation of surfactant leads to

also called thyroid transcription factor-1

impaired gas exchange, detected early

deficiency-syndrome or NKX2-1, is caused by

during exercise. Carbon dioxide transfer is

haplo-insufficiency of the transcription

usually not affected. Therefore, the clinical

factor TTF1. This factor modulates the

course typically starts insidiously at various

expression of SP-B, SP-C and ABCA3 in the

ages ranging from infancy to young

lung and other proteins in the thyroid and

adulthood. The diagnosis is frequently made

basal ganglia. The clinical trials of

in the context of an acute respiratory

congenital hypothyroidism, neurological

infection that does not resolve appropriately

syndromes (muscular hypotonia, which

or has a very severe course. Primary

develops to benign hereditary chorea after

presenting symptoms include exercise-

infancy) and symptoms of chronic

induced non-productive cough, at times

respiratory insufficiency represent the full

developing into coughing with expectoration

disease spectrum of pulmonary symptoms

of whitish surfactant material. Other

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Conditions associated with PAP due to a reduction in the number and function of alveolar macrophages

Autoimmune PAP due to GM-CSF autoantibodies that block macrophages (overall most frequent

form .90%, especially in adults)

Hereditary GM-CSF receptor a/b chain mutations

Inhalation exposure to aluminium, cement, silica, titanium, indium, tin, organic dust, sawdust,

fertiliser/agricultural dust, bakery flour, fumes, gasoline, chlorine and petroleum

Infections including Cytomegalovirus, Mycobacterium tuberculosis, Nocardia, Pneumocystis jirovecii,

HIV

Haematological disorders including myelodysplastic syndrome, acute lymphatic leukaemia,

acute myeloid leukaemia, chronic myeloid leukaemia, hairy cell leukaemia, Hodgkin’s and non-

Hodgkin’s lymphoma, multiple myeloma, essential thrombocythemia, polycythemia vera,

amyloidosis and Fanconi’s anaemia

Other malignancies including adenocarcinoma, glioblastoma and melanoma

Immunological diseases including monoclonal gammopathy, selective IgA deficiency and severe

combined immunodeficiency

Metabolic diseases such as Niemann-Pick disease type C2 and type B, and lysinuric protein

intolerance

Others including membranous nephropathy, dermatomyositis and lung transplantation

Data from Bonella et al. (2012).

symptoms include exercise intolerance,

as siblings of affected children) or suffer

weight loss or failure to thrive. The physical

from dyspnoea and oxygen

examination may reveal dyspnoea with

supplementation, initially during exercise

intercostal retractions, digital clubbing and

and later at rest. Chest CT scans showed

sometimes fine crackles and reduced

abnormalities in all cases and lavage

breathing sounds. Chest radiographs

samples suggest PAP due to whitish

typically show bilateral alveolar filling

recovered fluid in some cases. GM-CSF

pattern, which are often more prominent in

auto-antibodies are usually not detectable;

the perihilar regions, the so-called bat wing

serum levels of GM-CSF are elevated.

pattern. HRCT initially shows a diffuse

distribution of interstitial markings and,

Whole lung lavage represents the most

subsequently, the so-called crazy paving

important therapeutic option which has

pattern. The most common abnormalities in

clearly shown to be effective. In older

pulmonary function tests are significant

children, a double lumen endotracheal tube

restrictive patterns and a reduction in the

is used to ventilate one lung while lavaging

diffusion capacity. Bronchoalveolar lavage

the other. In young children, where this

(BAL) fluids show typically extracellular PAS-

procedure is not feasible, other strategies

positive material and frequently oval bodies.

are applied, such as using an inflatable

Diagnosis is made genetically or by open

catheter. Lavaging of both lungs is

lung biopsy, because in infants and children

performed sequentially using total volumes

the typical BAL fluid features are sometimes

of 50-200 mL?kg^-1 body weight of normal

not as prominent. GM-CSF auto-antibodies

saline.

are rarely elevated in children, but should be

The time required for lavaging one lung is

assessed to exclude this condition.

,4-6 h. If the child is in a good clinical

Clinical course and therapeutic strategies GM-

condition, lavaging the other lung is

CSF-receptor-a mutations: The age of

possible in the same session. It is important

diagnosis ranges from 2 to 11 years. Patients

to take care to ensure a balanced recovery

may have no clinical symptoms (diagnosed

and avoid electrolyte displacements.

ERS Handbook: Paediatric Respiratory Medicine

599

Injection or inhalation of recombinant GM-

Many other conditions associated with

CSF is ineffective and therefore not

alveolar proteinosis must be differentiated;

recommended. In several cases the patients

almost all are due to a reduced number or

have to undergo whole lung lavage at regular

function of alveolar macrophages (table 1).

intervals for long periods in order to enable

physiologic gas exchange and development.

Further reading

Such a therapy should be performed in

specialised centres to offer a good long-term

Bonella F, et al. (2012). Wash out kinetics

prognosis.

and efficacy of a modified lavage techni-

que for alveolar proteinosis. Eur Respir J;

Differential diagnosis of PAP in children

40: 1468-1474.

Niemann-Pick disease type C2: This disease

Gower WA, et al.

(2011). Surfactant

often manifests with respiratory distress

dysfunction. Paediatr Respir Rev; 12: 223-

during infancy and childhood. The average

229.

age of death from respiratory insufficiency is

Griese M, et al.

(2010). Respiratory

8 months. The accumulation of PAS-positive

disease in Niemann-Pick type C2

lipid material which, in contrast to normal

caused by pulmonary alveolar proteino-

sis. Clin Genet; 77: 119-130.

surfactant, also contains high

Griese M, et al. (2011). Long-term follow-

concentrations of ceramids,

up and treatment of congenital alveolar

glucosylceramids and SP-A, is at the centre

proteinosis. BMC Pediatr; 11: 72.

of the respiratory distress syndrome.

Kormann MS, et al. (2011). Expression of

Furthermore, the widened interstitium is

therapeutic proteins after delivery of

characterised by progressive fibrosis und

chemically modified mRNA in mice. Nat

lipoid pneumonia. Therapeutically whole

Biotechnol; 29: 154-157.

lung lavages have been tried without

Martinez-Moczygemba M, et al. (2008).

success at late disease stages.

Pulmonary alveolar proteinosis caused by

deletion of the GM-CSFR alpha gene in

Lysinuric protein intolerance: This is an

the X chromosome pseudoautosomal

autosomal recessive disorder caused by

region 1. J Exp Med; 205: 2711-2716.

defective plasma membrane transport of

Nogee LM, et al. (1994). A mutation in

cationic amino acids in epithelial cells of the

the surfactant protein B gene responsible

gastrointestinal tract and kidneys, due to a

for fatal neonatal respiratory disease in

mutation in the SLC7A7 gene. So far, most

multiple kindreds. J Clin Invest; 93: 1860-

cases have been reported in Finland, Italy and

1863.

Japan. While major focus is put on renal and

Notarangelo LD, et al.

(2008). Out of

breath: GM-CSFR alpha mutations dis-

gastrointestinal manifestations (e.g.

rupt surfactant homeostasis. J Exp Med;

pancreas insufficiency), pulmonary affection

205: 2693-2697.

in the sense of interstitial lung disease is

Suzuki T, et al. (2008). Familial pulmon-

highly variable and can lead to respiratory

ary alveolar proteinosis caused by muta-

insufficiency. In these cases, this is often due

tions in CSF2RA. J Exp Med; 205: 2703-

to PAP, probably caused by reduced

2710.

expression of SLC7A7 by GM-CSF. A

Suzuki T, et al. (2010). Hereditary pul-

therapeutic approach that has been tried with

monary alveolar proteinosis: pathogen-

variable success includes whole lung lavages,

esis,

presentation, diagnosis, and

inhaled GM-CSF or lung transplantation.

therapy. Am J Respir Crit Care Med; 182:

However, recurrence of PAP after lung

1292-1304.

transplantation has been reported.

600

ERS Handbook: Paediatric Respiratory Medicine

Pulmonary vascular disorders

Andrea McKee and Andrew Bush

The cardinal manifestation of pulmonary

present. There are no data to define

vascular disorders is pulmonary

pulmonary hypertension on exercise.

hypertension. The international definition of

Classification of pulmonary hypertension in

pulmonary hypertension is a pulmonary

children

arterial pressure (PAP) .25 mmHg. For pre-

capillary pulmonary hypertension,

There are significant differences in the

pulmonary capillary wedge pressure must be

pathophysiology of pulmonary hypertension

,15 mmHg and cardiac output normal or

in children and adults. Abnormalities of

reduced. Post-capillary pulmonary

growth and development are more likely in

hypertension (usually due to left heart

paediatric cases; so, for example, infants

disease) wedge pressure is .5 mmHg and

with pulmonary hypertension may have

cardiac output normal or reduced. If the

failed to reduce the antenatally

transpulmonary pressure gradient is

physiologically high pulmonary vascular

.12 mmHg with an elevated wedge

resistance (PVR) during the post-natal

pressure, then a reactive component is

period. Abnormalities of vasculogenesis and

angiogenesis have increasingly been

implicated in paediatric pulmonary

hypertension. A recent proposed

classification of pulmonary hypertension in

Key points

children is given in table 1; this differs from

the World Health Organization (WHO)

N The symptoms of pulmonary

classification (table 2), which has been

hypertension are nonspecific and the

criticised as less applicable to children (e.g.

possibility of the condition should

pulmonary hypertension secondary to

always be remembered. Syncope on

bronchopulmonary dysplasia and congenital

exercise should never be ignored.

diaphragmatic hernia do not fit neatly into

If pulmonary hypertension is

the WHO classification). Pulmonary

secondary to lung disease, this is

hypertension does not, of itself, mean the

usually obvious from the chest

child has pulmonary vascular disease; a high

radiograph.

pulmonary venous pressure and a high

pulmonary blood flow can both elevate PAP

N In a child with pulmonary

without there necessarily being any

hypertension and a normal chest

pulmonary vascular disease. Although the

radiograph, remember OSA and

WHO definition does not include

occult interstitial lung disease are

measurement of PVR (pulmonary blood

possible causes.

flow/transpulmonary vascular pressure

Children with pulmonary hypertension

gradient; normal range ,3 Wood units), in

should be referred to specialist

paediatric practice, it is wise to include a

centres for consideration of emerging

PVR .3 Wood units as part of the definition,

therapies.

particularly in children with left-to-right

shunts and anaemia. Functional classes of

ERS Handbook: Paediatric Respiratory Medicine

601

Table 1. A practical approach to pulmonary hypertension in children: 10 basic categories of paediatric pulmonary

hypertensive disease

Pre-natal or developmental pulmonary hypertensive vascular disease

Perinatal pulmonary vascular maladaptation

Paediatric cardiovascular disease

Bronchopulmonary dysplasia

Isolated paediatric pulmonary hypertensive vascular disease (isolated paediatric pulmonary

arterial hypertension)

Multifactorial pulmonary vascular disease in congenital malformation syndromes

Paediatric lung disease

Paediatric thromboembolic disease

Paediatric hypobaric hypoxic exposure

Pulmonary vascular disease associated with other system disorders

severity are given in table 3; these are largely

of pulmonary hypertension with a normal

adult based and there is a need for a specific

chest radiograph are interstitial lung disease

paediatric classification.

and sleep disordered breathing, usually

OSA. Hence, every case of apparently

Epidemiology

idiopathic pulmonary hypertension should

Pulmonary hypertension may present at any

have these conditions excluded. The

age. Paediatric pulmonary hypertension is

management of secondary pulmonary

ceasing to be an orphan disease; there are

hypertension is largely of the underlying

increasing numbers of national and

respiratory conditions, and this will not be

international specifically paediatric

discussed further. If secondary pulmonary

registries, which have increased our

hypertension is thought to be

information base. The incidence and point

disproportionate to the severity of lung

prevalence of isolated pulmonary

disease, then consideration should be given

hypertension are less than one and five

to the use of therapies used in primary

cases per million children, respectively. The

pulmonary hypertension (PPH) (see later),

number of cases of pulmonary hypertension

probably best as part of a randomised

secondary to congenital heart disease is of a

controlled trial. Any child thought to have

similar order of magnitude. The prevalence

primary pulmonary vascular disease should

of pulmonary hypertension in

have Eisenmenger’s syndrome and other

bronchopulmonary dysplasia is probably

cardiological conditions excluded by a

underestimated due to ascertainment bias.

careful cardiological evaluation. The

management of this latter group is usually

Pulmonary hypertension secondary to

medical in specialist paediatric cardiological

respiratory disease is usually dominated by

centres and discussions of these conditions

obvious features of the underlying cause, for

are beyond the scope of this chapter.

example, very severe bronchiectasis in CF.

The underlying mechanism is intermittent or

Normal pulmonary vascular development

continuous alveolar hypoxia leading to

pulmonary vasoconstriction and ultimately

The pulmonary arteries develop

vascular remodelling. Systemic arterial

embryologically from the sixth bronchial

hypoxaemia in the absence of alveolar

arches. The pre-acinar vessels follow the

hypoxia (for example, due to multiple

airway development and are largely

pulmonary arteriovenous malformations)

complete by the end of the first 16 weeks of

does not lead to pulmonary hypertension.

pregnancy, the end of the pseudoglandular

Two important ‘‘occult’’ respiratory causes

phase. Blood vessels form by

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Updated clinical classification of pulmonary hypertension (PH)

PAH

Idiopathic PAH

Heritable: BMPR2, ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia),

unknown

Drug and toxin induced

APAH: connective tissue diseases, HIV infection, portal hypertension, congenital heart

disease, schistosomiasis, chronic haemolytic anaemia, persistent PH of the newborn

PVOD and/or pulmonary capillary haemangiomatosis

PH due to left heart disease

Systolic dysfunction

Diastolic dysfunction

Valvular disease

PH due to lung diseases and/or hypoxia

COPD

Interstitial lung disease

Other pulmonary diseases with mixed restrictive and obstructive pattern

Sleep disordered breathing

Alveolar hypoventilation disorders

Chronic exposure to high altitude

Developmental abnormalities

CTEPH

PH with unclear and/or multifactorial mechanisms

Haematological disorders: myeloproliferative disorders, splenectomy.

Systemic disorders, sarcoidosis, pulmonary Langerhans cell histiocytosis,

lymphangioleiomyomatosis, neurofibromatosis, vasculitis

Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

PAH: pulmonary arterial hypertension; APAH: associated PAH; CTEPH: chronic thromboembolic PH.

Reproduced from Simonneau et al. (2009) with permission from the publisher.

Table 3. Functional classes of pulmonary hypertension

Functional class

Status

No limitation of physical activity

Ordinary activity does not cause dyspnoea, fatigue, chest pain or near

syncope

Slight limitation of physical activity

Comfortable at rest; ordinary physical activity causes undue dyspnoea,

fatigue, chest pain or near syncope

III

Marked limitation of physical activity

Comfortable at rest; less than ordinary physical activity causes undue

dyspnoea, fatigue, chest pain or near syncope

Symptomatic on any physical activity

Signs of right heart failure

May have dyspnoea and fatigue at rest; discomfort increased by physical

activity

This classification may be more appropriate to adults; for example, adults are more prone to right heart failure

earlier in the disease.

ERS Handbook: Paediatric Respiratory Medicine

603

vasculogenesis (de novo formation of

underlying cause is found. It is thought to be

vessels in the mesenchyme) with the airways

related to failure of regression of the

acting as a template for vascular

antenatal physiologically hypertensive

development. Acinar vessels develop in

pulmonary circulation. Although

parallel with the terminal bronchioles and

anecdotally, some cases respond to medical

alveoli. Alveolar development is largely a

management, generally the prognosis is

post-natal phenomenon and capillaries form

poor.

by angiogenesis (sprouting from existing

Alveolar capillary dysplasia spectrum is an

vessels). Uniquely, the lung has no function

overlapping group of diseases, comprising

as it develops in the intrauterine

acinar dysplasia, alveolar capillary dysplasia,

environment. It is a fluid-filled, fluid-

and alveolar capillary dysplasia with

excreting organ with a very low blood flow

misalignment of the pulmonary veins,

and no role in gas exchange. At birth, the

considered by some to be part of the

most profound adaptations must take place

spectrum of paediatric interstitial lung

if the baby is to survive. The lung absorbs

disease. Mutations in the FOXF1 (forkhead

fluid and becomes ‘‘dry’’; the alveoli expand,

box F1) and STRA6 (stimulated by retinoic

PVR falls and the pulmonary blood flow rises

acid 6) genes should be sought.

from ,5% to equal that of the systemic

Presentation is usually in a term baby with

circulation. The arterial duct and the oval

relentlessly progressive respiratory distress.

foramen become functionally, and later

These conditions should be distinguished

structurally, closed. In the subsequent weeks,

from disease due to mutations in SFTPB

there is thinning of the alveolar capillary

(surfactant protein B), SFTPC (surfactant

membrane and profound increases in the

protein C), ABCA3 (ATP-binding cassette

number of alveoli, produced by secondary

sub-family A member 3) and TTF1 (thyroid

septation and modulated through elastin and

transcription factor 1), which may present in

the retinoic acid pathways. Post-natally,

a similar way (see the section on Interstitial

alveolar development was thought to be

lung diseases). Diagnosis is on lung biopsy

largely complete by 2 years of life, but recent

or at autopsy. There is no treatment and

work in rhesus monkeys and also using

prognosis is poor.

hyperpolarised helium to measure alveolar

size in humans has shown that alveolar size

Presentation of pulmonary hypertension

is largely stable during the phase of somatic

due to pulmonary vascular disease

growth, implying neoalveolarisation, and by

The symptoms of pulmonary hypertension

implication pulmonary capillary growth,

are nonspecific and the condition can be

continues to puberty.

missed initially. Breathlessness may be

Abnormal pulmonary vascular development

attributed to airway disease and early

cyanosis may be difficult to detect. Syncope,

Most of these conditions present to the

particularly on exercise, is an ominous

neonatologist and are only briefly discussed

symptom that should never be ignored.

here.

Once suspected, ECG, or better

echocardiography, confirms the diagnosis. If

Persistent fetal circulation is the most

there is tricuspid or pulmonary

dramatic example of failure of normal

regurgitation, PAP can be estimated

developmental homeostasis. Shortly after

reasonably accurately from the Bernoulli

birth, the baby becomes deeply cyanosed

equation. The gold standard is right heart

and very difficult to oxygenate. This is a

catheterisation, which also allows cardiac

neonatal intensive care unit emergency and

output and pulmonary capillary wedge

will not be discussed further here.

pressure to be measured.

Early-onset ‘‘primary’’ pulmonary

Primary pulmonary vascular disease

hypertension comprises babies presenting at

a few weeks of age with very severe

The three main causes encountered in

pulmonary hypertension for which no

paediatrics are PPH, pulmonary

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ERS Handbook: Paediatric Respiratory Medicine

veno-occlusive disease (PVOD) and pulmonary

of vasoconstrictor and pro-proliferative

embolism (thrombotic and nonthrombotic).

agents, such as endothelin-1 and

Each will be considered in turn.

thromboxane A₂, but multiple other

mediators are probably involved.

Primary pulmonary hypertension is a

diagnosis of exclusion, requiring the

The most common genetic mutation is in

documentation of pulmonary hypertension

the BMPR2 (bone morphogenetic protein

and an elevated PVR, and the exclusion of

receptor II) gene, found in ,70% of familial

any secondary cause of the condition

PPH. BMPR2 is part of the transforming

(table 4). Pulmonary hypertension and other

growth factor (TGF)-b superfamily and,

vascular disease secondary to liver disease

among other properties, contributes to the

are described in more detail in the section

modulation of vascular proliferation.

on Systemic disorders with lung

Mutations in other receptors for these

involvement.

polypeptides are associated with familial

pulmonary hypertension, including activin

The pathophysiology of PPH is unclear.

receptor-like kinase 1 (encoded by the ALK1

Important components are vasoconstriction

gene) and endoglin, both of which are also

(which may be related to potassium channel

associated with hereditary haemorrhagic

dysfunction), obstructive remodelling of the

telangiectasia.

pulmonary circulation, thrombosis and

inflammation. Histopathology reveals

Symptoms are nonspecific but fainting

combinations of arterial medial hypertrophy,

during exercise should always be taken

concentric laminar fibroelastosis, plexiform

seriously. Infants typically present with right

lesions, necrotising vasculitis and fibrosis.

heart failure and cyanosis. There may be

There may be increased neuroendocrine cell

suggestive physical signs such as a loud

numbers and positive endothelial staining

pulmonary component of the second heart

for endothelin-1 immunoreactivity. Children

sound, the murmurs of pulmonary or

tend to have more medial hypertrophy, less

tricuspid insufficiency, a parasternal heave

intimal fibrosis and fewer plexiform lesions

or, in advanced cases, the signs of right

than adults. The clinical correlate may be

heart failure. Blood tests should be directed

greater pulmonary vascular reactivity and a

to eliminating any underlying cause of the

propensity to sudden death from pulmonary

pulmonary hypertension, as well as

hypertensive crises, especially in infants.

excluding thyroid disease, which is not

Endothelial dysfunction manifests as

uncommon in PHT. Elevated N-terminal

reduced production of vasodilator and

pro-brain natriuretic peptide and brain

antiproliferative mediators, such as nitric

natriuretic peptide have been reported in

oxide and prostacyclin, and overproduction

children with pulmonary hypertension, and

are likely to be increasingly used in the

future as biomarkers. Chest radiography

Table 4. Differential diagnosis of apparent PPH

may lead to suspicion of the diagnosis if

HIV infection

there is peripheral oligaemia and enlarged

Substance abuse: smoking crack cocaine,

central pulmonary arteries. The ECG may

amphetamine ingestion

show signs of right ventricular hypertrophy

and strain, and right atrial dilatation and

Liver disease leading to pulmonary

right axis deviation, but these signs should

hypertension

not be relied upon. Echocardiography is

Connective tissue disease, especially

mandatory to exclude occult cardiac disease

scleroderma

and to estimate PAP, most easily using the

Pulmonary vasculitis

Bernoulli equation, if pulmonary or tricuspid

Metabolic: Gaucher disease, Niemann-Pick

insufficiency is present. The 6-min walk test

disease

may give useful functional information. The

decision to proceed to the definitive

Sarcoidosis

diagnostic investigation, right heart

ERS Handbook: Paediatric Respiratory Medicine

605

catheterisation and measurement of

bronchoconstriction when nebulised.

vascular reactivity, is taken in conjunction

Subcutaneous and inhaled treprostinil are

with a paediatric cardiologist; the procedure

other options.

is not without risk, especially in children

The first ever randomised controlled trial in

with suprasystemic PAP. Overall, children

children with pulmonary hypertension

appear to have a better preserved cardiac

showed that sildenafil reduced PVR and

output than adults and go into right

improved survival. Sildenafil is thus the only

ventricular failure later in the course of the

soundly evidence-based treatment for

disease.

paediatric patients. There is emerging, but

Any underlying condition, such as HIV or

currently less strong, evidence that

connective tissue disease, should be treated

vardenafil may be a better agent. Tadalafil

as usual. Oxygen should be given to prevent

may also offer further advantages but the

hypoxaemia, even this is of controversial

evidence base is more flimsy.

benefit. A single, nonrandomised study of

pulmonary hypertension in children with

Endothelin-1 is a potent vasoconstrictor and

congenital heart disease suggested oxygen

mitogen for fibroblasts and smooth muscle

had a beneficial effect on survival. Calcium

cells. There are two isoforms of the

channel antagonists are prescribed only for

endothelin receptor found in pulmonary

those children with marked vascular

vascular smooth muscle cells, ET_A and ET_B.

reactivity; the exact definition of this is

ET_B receptors are also found in the

unclear. Anticoagulation should be

endothelium and are involved in endothelin

considered in selected children, usually

clearance and release of nitric oxide leading

those with right heart dysfunction,

to vasodilatation. However, despite these

indwelling lines or a hypercoaguable state,

physiological differences, dual-receptor and

but is used much less often with the advent

selective ET_A receptor antagonists are

of advanced therapies (see later). There are

equally effective. Bosentan, a dual-receptor

no paediatric studies suggesting benefit

antagonist, is not licensed in children but

from anticoagulation. Blade atrial

observational studies suggest it may be

septostomy may help symptomatically by

beneficial. However, 10-15% of children

decompressing the right-sided circulation

discontinue therapy because of side-effects,

but may be associated with significant

including abnormal liver function tests.

mortality. Patients with end-stage disease

There may be additional benefit with the

should be considered for heart-lung

addition of ambrisentan, a specific ET_B

transplantation.

antagonist.

There are three groups of compounds that

Novel innovative therapies may include the

may be used to treat pulmonary

use of Rho kinase inhibitors, vasoactive

hypertension. These are prostacyclin and its

intestinal peptide (VIP), oestrogen

derivatives, phosphodiesterase-5 inhibitors

derivatives, modulation of the serotonin

(e.g. sildenafil), and the endothelin receptor

pathway, L-arginine and therapies (including

antagonists. Their use has led to enhanced

gene therapy) that may modulate apoptosis

survival.

to attenuate vascular remodelling.

Continuous intravenous infusion of

In general, these new options are expensive

prostacyclin has been associated with

and potentially toxic medications that are

improved survival in children as well as

best utilised in centres accredited for the

adults but the logistic challenge of this

care of pulmonary hypertension. There is a

treatment is considerable. The benefit may

scarcity of randomised controlled trials in

be not only by vasodilation but also

children and treatment algorithms are

restoration of endothelial function. Inhaled

unfortunately extrapolated from adult

iloprost has also been used but the need for

studies; this is dangerous, because the

six to eight nebulisations a day has limited

pathophysiology of pulmonary hypertension

its value in children; it may also cause

may not be the same. It is likely in the future

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ERS Handbook: Paediatric Respiratory Medicine

that combinations of these medications will

underdiagnosed in children because it is

be prescribed. They are also increasingly

frequently not considered. Presentation may

used in pulmonary vascular disease

be with acute collapse due to a massive

complicating congenital heart disease.

embolism or the more subtle onset of

breathlessness due to repeated small

Prognosis is usually poor in children,

emboli. There are four important questions

although the suggestion that it is worse than

if pulmonary embolic disease is suspected

in adults has not been confirmed. However,

(table 6).

children are often sicker at presentation. 5-

year survival is of the order of 75%. Factors

The factors predisposing to

carrying a poor prognosis include WHO

thromboembolism are intravascular foreign

functional class III/IV, poor nutrition and

body (e.g. a portacath), a sluggish

older age at presentation, and lower mixed

circulation, coagulopathy and immobility.

venous oxygen saturation and higher PVR.

More than one factor may be operative.

Typical causes of a sluggish circulation

Pulmonary veno-occlusive disease

include the post-Fontan situation and left

Presentation is indistinguishable from PPH.

atrial dilatation secondary to

Physical examination may reveal digital

cardiomyopathy. Numerous congenital and

clubbing (unusual in other forms of PAH

acquired prothrombotic disorders have been

than cyanotic congenital heart disease) and

implicated in pulmonary embolism or in situ

crackles. Chest radiograph and HRCT will

thrombosis. Membranous

show signs of pulmonary venous

glomerulonephritis is a notorious source of

congestion. The diagnostic gold standard is

pulmonary thromboemboli from the renal

open-lung biopsy but noninvasive testing

veins.

may obviate the need for this. If lung tissue

is obtained, the pulmonary veins and

There are numerous causes of

venules contain organised and recanalised

nonthrombotic emboli. Tumour emboli

thrombi with intimal fibrous pads and

originating from Wilm’s, hepatoblastoma or

medial hypertrophy. The veins may show

testicular teratoma are among the

medial hypertrophy and arterialisation.

commonest. In tropical regions,

There may be similar changes in pulmonary

schistosomal ova are an important cause of

capillaries and the pre-capillary circulation,

pulmonary hypertension. Talc emboli from

including fibrinoid necrosis in the latter. If

injecting crushed up tablets as a form of

cardiac catheterisation is undertaken, wedge

substance abuse is another cause. The

pressure is often normal because the large

presentation of infected emboli, another

pulmonary veins are not affected and

complication of intravenous drug abuse, is

pulmonary vasodilator trials may precipitate

usually dominated by a septic picture.

pulmonary oedema. There is no medical

Since these conditions are so rare in

therapy and referral to the local transplant

childhood, there is usually insufficient

centre is indicated at diagnosis.

experience to rely on noninvasive diagnosis,

The majority of cases are idiopathic; rare

for example with D-dimer. Suspicion may be

familial cases are described, and cases

aroused by a ventilation/perfusion scan, which

secondary to chemotherapy, bone marrow

typically shows normal ventilation but marked

transplantation and congenital heart disease

perfusion defects. Contrast-enhanced CT

have been described. Differential diagnosis

scanning will demonstrate filling defects in the

includes congenital absence or stenosis of

proximal pulmonary arteries. If distal disease

the pulmonary veins and pulmonary venous

not visible on CT scanning is suspected and,

obstruction due to mediastinal pathology

in particular, if nonthromboembolic disease is

such as fibrosing mediastinitis.

a diagnostic consideration, then a lung biopsy

may be indicated.

Pulmonary embolic disease Causes of

pulmonary embolic disease are summarised

Management is of the underlying cause, for

in table 5. This is undoubtedly

example, removal of the indwelling line.

ERS Handbook: Paediatric Respiratory Medicine

607

Table 5. Causes of pulmonary embolic disease

Thromboembolic disease

Nonthrombotic embolic disease

Indwelling venous catheters (.25% cases)

Tumour emboli

Low flow states

Right atrial myxoma

Cardiac failure

Liver, renal or testicular tumours

Fontan circulation

Tropical

Dilated cardiomyopathy

Schistosomiasis

Coagulopathy

Fat embolism

Factor V Leiden

Trauma

Protein C deficiency (congenital or

Burns

acquired)

Cardiopulmonary bypass

Protein S deficiency (congenital or

Acute pancreatitis (always consider an

acquired)

underlying diagnosis of CF if no other

Antithrombin III

obvious cause)

Dysfibrinogenaemias

Adolescent issues

Miscellaneous, including oral

Pregnancy complications (amniotic fluid

contraception

embolism)

Immobility

Intravenous drug abuse (talc emboli from

Blunt thoracic trauma

injecting crushed up tablets)

Axillary vein thrombosis

May be associated with acquired

lymphangiectasia and chylothorax

Renal vein thrombosis

Membranous nephropathy, may also

have a coagulopathy

More than one cause may be operative in a given child; for example, a boy with Duchenne muscular dystrophy

has immobility and cardiomyopathy as predisposing factors.

For an otherwise well child who has had a

Given that heritable coagulopathies may

pulmonary thromboembolism and is

present with thromboembolic disease,

clinically stable, anticoagulation with

consideration should be given to screening

heparin and warfarin is indicated. If there is

the child and first-degree relatives for at

an underlying coagulopathy, the advice of a

least for protein C, protein S and

paediatric haematologist should be sought.

antithrombin III deficiency, given the risk of

If the child is critically unstable, then

thromboembolic events in these conditions.

consideration should be given to

Invasive pulmonary capillary

thrombolysis and even embolectomy, in

haemangiomatosis This rare condition is

consultation with a paediatric cardiologist

characterised by proliferating sheets of thin-

and cardiothoracic surgeon.

walled vessels, which infiltrate the

pulmonary circulation leading to vascular

Table 6. Four clinical questions if pulmonary embolic

occlusion. The condition behaves like a low-

disease is suspected

grade vascular neoplasm. Rarely, there is

extrathoracic spread of the abnormal

Has there been embolic occlusion of part of

vasculature. Presenting features include

the pulmonary arterial tree?

dyspnoea, thrombocytopenia and

Is the child cardiovascularly stable or is

haemoptysis, and symptoms of pulmonary

urgent intervention required?

hypertension. There may be digital clubbing

What is the material embolised?

and pleural and pericardial effusions.

Familial and congenital cases have been

What has predisposed to the embolic event?

described. HRCT differentiates the

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ERS Handbook: Paediatric Respiratory Medicine

condition from other causes of pulmonary

Cerro MJ, et al.

(2011). A consensus

hypertension. The distinction is important

approach to the classification of pediatric

because vasodilator trials may cause

pulmonary hypertensive vascular disease:

pulmonary oedema in this condition.

report from the PVRI Pediatric Taskforce.

Typically, there is diffuse bilateral

Pulm Circ; 1: 286-298.

thickening of the interlobular septa and

Galiè N, et al. (2009). Guidelines for the

small centrilobular opacities, which are

diagnosis and treatment of pulmonary

poorly defined. There may also be diffuse

hypertension: the Task Force for the

Diagnosis and Treatment of Pulmonary

ground-glass opacities. Definitive diagnosis

Hypertension of the European Society of

is by lung or other tissue biopsy.

Cardiology

(ESC) and the European

Occasional children have an associated

Respiratory Society

(ERS), endorsed by

connective tissue disease or other

the International Society of Heart and

comorbidity. Localised forms may be

Lung Transplantation (ISHLT). Eur Heart

treated surgically, disseminated disease

J; 30: 2493-2537.

with interferon-a2a or heart-lung or

Gatzoulis MA, et al. (2009). Pulmonary

bilateral-lung transplant. However, most

arterial hypertension in paediatric and

affected children die quickly.

adult patients with congenital heart dis-

ease. Eur Respir Rev; 18: 154-161.

Holzhauser S, et al.

(2012). Inherited

Further reading

thrombophilia in children with venous

Abman SH, et al. (2011). Recent progress

thromboembolism and the familial risk of

in understanding pediatric pulmonary

thromboembolism: an observational

hypertension. Curr Op Pediatr; 23: 298-

study. Blood; 120: 1510-1515.

304.

Ivy D

(2012). Advances in pediatric

Adatia I, et al. (2010). The role of calcium

pulmonary arterial hypertension. Curr

channel blockers, steroids, anticoagula-

Opinion Cardiol; 27: 70-81.

tion, antiplatelet drugs, and endothelin

Janda S, et al. (2010). HIV and pulmonary

receptor antagonists. Pediatr Crit Care

arterial hypertension: a systematic review.

Med; 11: Suppl., S46-S52.

HIV Med; 11: 620-634.

Barst RJ, et al. (2011). Pulmonary arterial

Kirkpatrick EC. Echocardiography in pedia-

hypertension: a comparison between

tric pulmonary hypertension. Paediatr

children and adults. Eur Respir J;

37:

Respir Rev 2013 [In press DOI: 10.1016/

665-677.

j.prrv.2012.12.008].

Barst RJ, et al.

(2012). A randomized

Roofthooft MTR, et al. (2010). Management

double-blind placebo-controlled dose-ran-

of pulmonary arterial hypertension in chil-

ging study of oral sildenafil citrate in the

dren. Paediatr Respir Rev; 11: 240-245.

treatment of children with pulmonary

Simonneau G, et al.

(2009). Updated

arterial hypertension. Circulation;

125:

clinical classification of pulmonary hyperten-

324-334.

sion. J Am Coll Cardiol; 54: Suppl., S43-S54.

ERS Handbook: Paediatric Respiratory Medicine

609

Eosinophilic lung diseases

and hypersensitivity

pneumonitis

Carlo Capristo, Giuseppina Campana, Francesca Galdo, Emilia Alterio and

Laura Perrone

Eosinophilic lung diseases

disease, such as Churg-Strauss syndrome

and hypereosinophilic syndrome.

Eosinophilic lung diseases are a diverse

group of disorders characterised by

Based on aetiology, eosinophilic lung

pulmonary opacities associated with tissue

diseases are generally classified as those of

or peripheral eosinophilia. The diagnosis of

unknown cause (idiopathic

eosinophilic lung disease can be made if any

hypereosinophilic syndrome) and those of

of the following findings is present:

known cause (ABPA, bronchocentric

granulomatosis, parasitic infection and drug

N pulmonary opacities with peripheral

reactions), as well as eosinophilic vasculitis.

eosinophilia,

Diagnosis The diagnostic methods consist

N tissue eosinophilia confirmed at lung

biopsy, and

of a detailed medical history and physical

examination. The duration and severity of

N increased eosinophils in bronchoalveolar

symptoms are also of critical importance.

lavage (BAL) fluid.

Testing for potential helminth infections,

Eosinophilic lung diseases are generally

including stool examination and serology,

classified in terms of presentation (clinical

should be guided by the exposure history. If

or radiological) and aetiology. Clinical and

no inciting drug or infection is identified, a

radiological presentations can include

thorough investigation for allergic/atopic or

simple pulmonary eosinophilia, chronic

autoimmune disorders, blood cell disorders

eosinophilic pneumonia, acute eosinophilic

and other neoplastic conditions should be

pneumonia, allergic bronchopulmonary

initiated. A history of asthma may raise

aspergillosis (ABPA) and pulmonary

suspicion of Churg-Strauss syndrome,

eosinophilia associated with a systemic

ABPA, or bronchocentric granulomatosis.

Pulmonary infiltrates, characterised by foci

Key points

of air-space consolidation and focal ground-

glass opacities, can be seen in pulmonary

N Eosinophilic lung diseases are a

eosinophilia of all causes. Cavitation can

diverse group of disorders

occur in certain cases of ABPA and Churg-

characterised by pulmonary opacities

Strauss syndrome, as well as in certain

associated with tissue or peripheral

parasitic infections.

eosinophilia.

Important initial parameters that can be

Hypersensitivity pneumonitis, or

obtained from routine laboratory testing

extrinsic allergic alveolitis, is a diffuse

include:

granulomatous ILD caused by

inhalation of various antigenic organic

N a complete blood count with differential

particles or low molecular weight

counts (confirmed by microscopy),

chemicals.

N routine chemistries (including tests of

hepatic and renal function),

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ERS Handbook: Paediatric Respiratory Medicine

N levels of inflammatory markers and

diagnosis of pulmonary eosinophilia. Biopsy

autoantibodies, and

is performed to rule out the hypotheses of

N serum IgE,

infection and neoplasia, as well as to make a

N vitamin B₁

2 and

differential diagnosis with other interstitial

N tryptase levels.

diseases and cryptogenic organising

pneumonia, or to confirm Churg-Strauss

Bone marrow investigations should also

syndrome. Histopathological findings that

include a core biopsy with histology and

are common to virtually all causes include

immunohistochemistry, including CD34,

intra-alveolar exudation of histiocytes and

CD117, tryptase and CD25. In addition,

eosinophils, also present in the interstitium,

cytogenetics, FISH (fluorescent in situ

and eosinophilic microabscesses,

hybridisation) and molecular analyses

macrophages containing Charcot-Leyden

should be performed. Bone marrow

crystals and findings of bronchiolitis

investigation is warranted in all patients in

obliterans or organising pneumonia. Small

whom hypereosinophilia remains

focal areas of interstitial fibrosis, as well as

unexplained or if a haematopoietic

intra-alveolar necrosis and even a certain

neoplasm is suspected. Haematopoietic

degree of vasculitis, can occur, although

malignancies typically accompanied by

without granulomas. Granulomas, as well as

eosinophilia are myeloproliferative

being present in ABPA, are indicative of

neoplasms (MPNs), certain variants of

parasitic infections and Churg-Strauss

acute myeloid leukaemia (AML), a smaller

syndrome.

subset of patients with myelodysplastic

syndromes (MDS), some MDS/MPN

Eosinophilic lung diseases of unknown cause

overlap disorders, several (mostly T-cell

Simple pulmonary eosinophilia, or Löffler

derived) lymphoproliferative disorders and

syndrome, was originally reported as a

(advanced) systemic mastocytosis.

benign acute eosinophilic pneumonia of

Finally, lymphocyte (T-cell) phenotyping (by

unknown cause characterised by increased

flow cytometry) should be performed in

peripheral blood eosinophils, minimal or no

patients with hypereosinophilia to identify

pulmonary symptoms, and spontaneous

aberrant populations, most commonly CD3^-

resolution. In some patients, these clinical

CD4⁺ T-cells, which have been associated

characteristics may prove to be secondary to

with eosinophilopoietic cytokine production.

the presence of parasites, ABPA or drugs.

Pathological specimens show oedema and

Peripheral eosinophilia occurs in virtually all

accumulation of eosinophils in the alveolar

cases, either in the initial presentation or

septa and interstitium.

during the course of the disease.

Eosinophilia is not always severe in blood

The radiographic manifestations consist of

samples, with eosinophil counts of 500-

transient and migratory areas of

1000 cells?mm^-3, or it can even be absent

consolidation. These consolidations are

from the initial clinical presentation, thereby

non-segmental, may be single or multiple,

making diagnosis difficult.

usually have ill-defined margins, and often

have a predominantly peripheral

Increased eosinophil counts in the air

distribution. The prognosis is excellent. The

spaces, common to various causes of

use of corticosteroids is rarely necessary,

pulmonary eosinophilia, result in severe

and spontaneous resolution occurs within

eosinophilia in the BAL fluid and are the

30 days.

principal method of confirming the

diagnosis of acute and chronic eosinophilic

Acute eosinophilic pneumonia presents

pneumonia. In such cases, eosinophils

frequently in young smokers as acute

account for .25% of the cells in the BAL

hypoxaemic respiratory failure. These

fluid.

patients present without peripheral

Lung biopsy (transbronchial or by thora-

eosinophilia but usually have .25%

cotomy) is not a prerequisite for the

eosinophils in bronchoalveolar fluid.

ERS Handbook: Paediatric Respiratory Medicine

611

Acute eosinophilic pneumonia may be

There are two variants of idiopathic

secondary to a number of causes, such as

hypereosinophilic syndrome:

vaccinations (BCG (bacille Calmette-

myeloproliferative and lymphocytic. The

Guérin) vaccination and minocycline) and

myeloproliferative variant is a

drugs (fludarabine, progesterone and

haematological disorder that belongs to the

sertraline), infections (Aspergillus and

leukaemia group, and is accompanied by

Coccidioides) or environmental factors

dysplasia, hepatosplenomegaly and

(smoking, tear gas, gasoline and demolition

increased vitamin B₁₂ level. The lymphocytic

dust). It is important to rule out fungi

variant results from a proliferation of T-

infection.

helper (Th) type 2 cells with overexpression

of the cytokines interleukin (IL)-3,

The principal histological finding in acute

granulocyte-macrophage colony-stimulating

eosinophilic pneumonia is diffuse alveolar

factor (GM-CSF) and, especially, IL-5. In the

damage associated with interstitial

lymphocytic variant, as in allergic disorders

eosinophilia. The predominant radiographic

(IgE levels are usually increased), the three

findings are bilateral reticular densities (with

sites most commonly involved are the

or without areas of patchy consolidation)

respiratory tract, gastrointestinal tract and

and pleural effusion.

skin. Treatment includes corticosteroids,

and other agents, such as anti-IL-5, have

Chronic eosinophilic pneumonia is an

been considered.

idiopathic condition characterised by

chronic and progressive clinical features

Eosinophilic lung diseases of known cause

and specific pathological findings. The

ABPA is a hypersensitivity reaction to

clinical manifestation is usually insidious

Aspergillus antigens. ABPA is typically seen in

and the patient experiences symptoms for

patients with long-standing asthma or CF. It

an average of 7.7 months before the

is usually suspected on clinical grounds, and

diagnosis is made. Most patients are

the diagnosis is confirmed by radiology and

middle aged and ,50% have asthma.

serological testing. Diagnostic criteria

Females are more frequently affected than

include the presence of:

males. Pulmonary function tests can be

normal in mild cases but usually show

N asthma,

restrictive defects.

N peripheral blood eosinophilia,

an immediate positive skin test for

Idiopathic hypereosinophilic syndrome is a rare

Aspergillus antigens,

disorder characterised by marked,

N increased serum IgE levels, and

prolonged idiopathic eosinophilia and

N pulmonary opacity on chest radiographs.

variable organ dysfunction related either to

The IgE level is probably the most useful

infiltration by eosinophils or secondarily

laboratory test for ABPA, as it correlates well

eosinophil-associated tissue damage.

with disease activity. Lung biopsies are

The diagnosis is based on three criteria

rarely performed for diagnosis.

established by Chusid et al. (1975):

Bronchocentric granulomatosis is a rare

disorder characterised by a necrotising

N persistent eosinophilia (eosinophil count

granulomatous inflammation of bronchial

.1500 cells?mm^-3) for o6 months or

and bronchiolar epithelium with chronic

death within 6 months due to the signs

inflammatory changes in the surrounding

and symptoms related to eosinophilia;

lung parenchyma. Approximately one-third

N eosinophilia-related involvement of at

of affected patients have tissue eosinophilia

least one organ; and

and tend to have asthma, peripheral

N absence of a known causes of

eosinophilia and positive sputum cultures

eosinophilia, such as drugs, parasites,

for Aspergillus organisms.

malignancy, vasculitis, chronic

eosinophilic pneumonia and Churg-

Many parasites can cause pulmonary

Strauss syndrome.

opacities with blood or tissue eosinophilia.

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ERS Handbook: Paediatric Respiratory Medicine

Because the prevalence of individual

syndrome, confirmation of at least four

parasitic infections varies from one

being necessary: asthma; eosinophilia

geographic region to another, familiarity

(eosinophil count .1500 cells?mm^-3);

with the common parasites in one’s

paranasal sinus involvement; transient

geographic area of practice is critical to

pulmonary infiltrates; mononeuropathy or

arriving at a correct diagnosis.

polyneuropathy; and biopsy findings of

vasculitis. Therefore, the histopathological

A wide variety of drugs and toxic substances

criterion of small vessel biopsy findings of

are important causes of pulmonary

extravascular eosinophils can be dispensed

eosinophilic infiltrates. Patients with drug-

with if the other clinical criteria are present.

induced eosinophilic lung disease can

present with a variety of pathologic

With these new criteria, a diagnosis of

conditions ranging from a mild, simple

Churg-Strauss syndrome has come to be

pulmonary eosinophilia-like syndrome to a

more common. Skin, muscle and sural nerve

fulminant, acute pulmonary eosinophilia-like

biopsy can reveal perivascular eosinophilic

syndrome. Pulmonary involvement by

inflammation and confirm the diagnosis.

cutaneous adverse drug reactions is rare

Lung biopsy is considered the gold

and is considered to be a severity factor.

standard, although transbronchial biopsy is

Many patients with drug-induced

typically insufficient. Chief among biopsy

eosinophilic lung disease will improve by

findings is small vessel vasculitis associated

simply discontinuing the medication; in

with positivity for antineutrophil cytoplasmic

severe or persistent cases, however, short

antibody (ANCA), perinuclear ANCA test

courses of corticosteroids appear to hasten

results being positive in 50-70% of cases.

recovery. The diagnosis is usually made on

The combination of Churg-Strauss

the basis of clinical history and blood

syndrome and positive ANCA test results

eosinophilia rather than imaging findings.

represents a more significant form of

vasculitis and has therapeutic implications.

Churg-Strauss syndrome was first described

A study evaluating the radiological test

in 1951 by Churg and Strauss on the basis of

results of nine patients revealed bilateral foci

the histologic criteria necrotising vasculitis,

of non-segmental consolidation in most of

tissue infiltration by eosinophils and

the cases.

extravascular granulomas.

Currently, the mean survival among Churg-

This syndrome is characterised by three

Strauss syndrome patients is 9 years. Doses

phases.

of prednisone (40-60 mg?day^-1) for several

weeks are usually necessary in order to

N Allergic phase: presence of asthma or

control vasculitis and should be followed by

rhinitis.

a maintenance regimen for 1 year.

N Eosinophilic phase: presence of severe

persistent peripheral eosinophilia

Hypersensitivity pneumonitis

(eosinophil count .1500 cells?mm^-3) for

Hypersensitivity pneumonitis, or extrinsic

.6 months.

allergic alveolitis, is a diffuse granulomatous

N Vasculitic phase: presence of systemic

interstitial lung disease (ILD) caused by

manifestations and small vessel

inhalation of various antigenic organic

vasculitis, represented by the

particles or low molecular weight chemicals.

involvement of two or more

Because the resulting inflammatory

extrapulmonary organs.

response involves not only the alveoli but

However, the three phases can be

the terminal bronchioli and the interstitium,

dissociated and asthma is present in 100%

the term ‘‘hypersensitivity pneumonitis’’

of cases.

may be more correct than ‘‘extrinsic allergic

alveolitis’’.

In 1990, the American College of

Rheumatology established the following

The prevalence and incidence of

criteria for the diagnosis of Churg-Strauss

hypersensitivity pneumonitis vary

ERS Handbook: Paediatric Respiratory Medicine

613

considerably depending upon disease

chronic, resulting in fibrosis. It is

definitions, methods used to establish the

characterised by an insidious onset of

diagnosis, intensity of exposure,

dyspnoea, fatigue and cough. Because the

environmental conditions and host/genetic

respiratory symptoms are usually mild or

risk factors that remain poorly understood.

absent in subacute hypersensitivity

The disease may also arise in children.

pneumonitis, infectious pneumonia or

Clinical behaviour in children is similar to

noninfectious ILD is the important

adult cases.

differential diagnosis.

Occupational and environmental exposures A

Chronic hypersensitivity pneumonitis may

number of occupations have been

result from continuous, low-level exposure

associated with the risk of hypersensitivity

to inhaled antigens. Bird antigen exposure

pneumonitis, including farmers, mushroom

is the most common in this form of

and tobacco workers, woodworkers, maple

disease. The onset of chronic

bark strippers, stucco workers, malt

hypersensitivity pneumonitis is insidious,

workers, millers, machinists, foundry

with slowly increasing dyspnoea, dry

workers, office workers, etc., or hobbyists

cough, fatigue and weight loss. Digital

such as bird fanciers.

clubbing may be present in 20-50% of

patients and predicts clinical deterioration.

Clinical features The spectrum of clinical

Chronic hypersensitivity pneumonitis often

features varies and has been conventionally

develops progressive fibrosis with cor

classified into acute, subacute and chronic

pulmonale and mimics idiopathic

forms. The interval between sensitisation by

pulmonary fibrosis (IPF) or fibrotic

antigen inhalation and the symptomatic

nonspecific interstitial pneumonia (NSIP)

onset of HP is unknown. It seems to be

in the advanced stage. This form of

variable and may range from several months

disease, therefore, often leads the

to several years after the antigen exposure.

physician to mistake the disease for other

chronic ILDs. The auscultatory findings

Acute hypersensitivity pneumonitis is

include bibasilar crackles and,

characterised by an influenza-like syndrome

characteristically, inspiratory squeaks

(fever, chills, malaise, myalgia and

resulting from the coexisting bronchiolitis.

headache) and respiratory symptoms (dry

cough, dyspnoea, tachypnoea and chest

Acute exacerbation of chronic hypersensitivity

tightness). However, respiratory symptoms

pneumonitis is an emerging concept

in acute hypersensitivity pneumonitis are

showing an accelerated respiratory

sometimes absent. The disease onset is

deterioration with the presence of new

abrupt and usually occurs 4-12 h after

bilateral ground-glass opacities on HRCT.

antigen exposure. In general, acute

The pathogenesis of acute exacerbations in

hypersensitivity pneumonitis is non-

chronic hypersensitivity pneumonitis is

progressive and spontaneously improves

unknown.

within a few days after antigen avoidance.

The disease often recurs after re-exposure to

Diagnosis Several diagnostic criteria for

antigen. Clinical examination shows

hypersensitivity pneumonitis have been

bibasilar crackles and occasional cyanosis,

recommended. However, none of these

whereas finger clubbing is rare. Patients with

criteria has been validated. The diagnosis of

recurrent acute farmer’s lung may

hypersensitivity pneumonitis relies on a high

sometimes develop an obstructive lung

level of clinical suspicion, the recognition of

disease with centrilobular emphysema

antecedent antigen exposure, and a

instead of fibrosis.

constellation of clinical, radiological,

laboratory and pathological findings.

Subacute hypersensitivity pneumonitis may be

associated with repeated low-level exposure

A large prospective multicentre cohort study

to inhaled antigens. After recurrent acute

(116 patients with hypersensitivity

episodes, this form may also become

pneumonitis and 284 control subjects with

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ERS Handbook: Paediatric Respiratory Medicine

other ILD) showed that the diagnosis of

lymphocytic interstitial pneumonitis; minor

hypersensitivity pneumonitis could be made

degrees of organising pneumonia, when

with six significant predictors:

present, also can contribute to this

appearance. The poorly defined centrilobular

N exposure to a known offending antigen;

nodules may be caused by cellular

N positive precipitating antibodies;

bronchiolitis, the predominantly

N recurrent episodes of symptoms;

peribronchiolar distribution of interstitial

N inspiratory crackles;

pneumonitis or focal areas of organising

N symptoms 4-8 h after exposure; and

pneumonia. The lobular areas of decreased

N weight loss.

attenuation and air trapping are presumably

caused by small-airway obstruction by

If all six predictors are present, the

cellular bronchiolitis or by constrictive

probability of having hypersensitivity

bronchiolitis.

pneumonitis is 98%. If none of the six

predictors is present, the probability is 0%.

Chronic hypersensitivity pneumonitis is

characterised by the presence of reticulation

Careful history taking is mandatory.

and traction bronchiectasis and

Clinicians should have specific expertise

bronchiolectasis on HRCT, due to fibrosis

concerning the antigens relevant to

superimposed on findings of acute or

hypersensitivity pneumonitis. Important

subacute hypersensitivity pneumonitis. The

factors are hay feeding, bird keeping, feather

reticulation in chronic hypersensitivity

duvets and pillows in the home, air

pneumonitis can be patchy or random or

conditioning or ventilators in the buildings,

have a predominantly subpleural and

and formation of mould on room walls or in

peribronchovascular distribution but

cellars.

typically tends to spare the lung bases. In a

Important diagnostic tools include BAL,

small percentage of cases, chronic

HRCT, provocation tests and lung biopsies.

hypersensitivity pneumonitis results in

subpleural honeycombing.

The most sensitive diagnostic test is BAL. In

our experience and based on a literature

Acute hypersensitivity pneumonitis is

review, a normal BAL widely excludes the

characterised histologically by the presence

diagnosis of hypersensitivity pneumonitis.

of neutrophilic infiltration of the respiratory

The characteristic finding is a lymphocytosis

bronchioles and alveoli. A pattern of diffuse

in the subacute and chronic forms. In

alveolar damage and temporally uniform,

asymptomatic sensitised individuals

nonspecific, chronic interstitial

(subclinical alveolitis), BAL lymphocytosis is

pneumonitis may also be seen. Subacute

also apparent. BAL lymphocytosis .30% is

hypersensitivity pneumonitis is

recommended as a discriminative factor of

characterised histologically by the presence

chronic hypersensitivity pneumonitis from

of cellular bronchiolitis, noncaseating

IPF, showing usual interstitial pneumonia

granulomas and bronchiolocentric

(UIP) pattern on HRCT.

interstitial pneumonitis with a

predominance of lymphocytes. Areas of

The radiological manifestations of acute

organising pneumonia (bronchiolitis

hypersensitivity pneumonitis are those of

obliterans with organising pneumonia) may

acute pulmonary oedema. The characteristic

be identified. These findings, however, are

HRCT manifestations of subacute

not present in all cases. Furthermore, in

hypersensitivity pneumonitis consist of

some patients, the predominant histologic

patchy or diffuse bilateral ground-glass

pattern is NSIP or UIP.

opacities, poorly defined small centrilobular

nodules, and lobular areas of decreased

Although lung function may be normal in

attenuation and vascularity on inspiratory

acute hypersensitivity pneumonitis,

images and of air trapping on expiratory

abnormal lung function is common in most

images. The ground-glass opacities

patients with chronic hypersensitivity

primarily reflect the presence of diffuse

pneumonitis. The most frequent functional

ERS Handbook: Paediatric Respiratory Medicine

615

abnormalities are a restrictive impairment

Further reading

and/or an impaired gas exchange (decreased

Allen JN, et al. (1994). Eosinophilic lung

diffusing capacity or increased alveolar/

diseases. Am J Respir Crit Care Med; 150:

arterial oxygen gradient). Only a few patients

1423-1438.

with farmer’s lung show obstructive

Bain GA, et al. (1996). Pulmonary eosi-

impairment resulting from emphysema.

nophilia. Eur J Radiol; 23: 3-8.

However, these changes are not

Bosken CH, et al.

(1988). Pathologic

characteristic of chronic hypersensitivity

features of allergic

bronchopulmonary

pneumonitis but are found in any type of

aspergillosis. Am J Surg Pathol; 12: 216-222.

ILD. Therefore, these abnormalities are not

Bourke SJ, et al.

(1989). Longitudinal

diagnostic for hypersensitivity pneumonitis.

course of extrinsic allergic alveolitis in

Although hypoxaemia is common in

pigeon breeders. Thorax; 44: 415-418.

hypersensitivity pneumonitis, patients with

Bourke SJ, et al. (1997). Pigeon fanciers

mild-to-moderate disease may lack this

lung. BMJ; 315: 70-71.

Bourke SJ, et al. (2001). Hypersensitivity

symptom and only present hypoxaemia with

pneumonitis: current concepts. Eur Respir

exercise.

J; 18: Suppl. 32, 81s-92s.

The functional impairment is not well

Campos LE, et al.

(2009). Pulmonary

eosinophilia. J Bras Pneumol; 35: 561-573.

correlated with the severity of radiological

Carrington CB, et al.

(1969). Chronic

abnormalities. The importance of pulmonary

eosinophilic pneumonia. N Engl J Med;

function tests is to evaluate the severity of

280: 787-798.

the physiological impairment at diagnosis

Cheon JE, et al. (1996). Acute eosinophilic

and during follow-up.

pneumonia: radiographic and CT findings

in six patients. AJR Am J Roentgenol; 167:

Treatment Antigen avoidance is the key

1195-1199.

element in the treatment of hypersensitivity

Choi YH, et al. (2000). Thoracic manifes-

pneumonitis and complete cessation of

tation of Churg-Strauss syndrome: radi-

exposure to the provoking antigen is the

ologic and clinical findings. Chest;

117:

safest advice for these patients.

117-124.

Churg J, et al. (1951). Allergic granuloma-

Although there is often an apparent

tosis, allergic angiitis, and periarteritis

beneficial response to corticosteroids in

nodosa. Am J Pathol; 27: 277-301.

hypersensitivity pneumonitis, it is difficult to

Chusid MJ, et al. (1975). The hypereosi-

distinguish between the effects of treatment,

nophilic syndrome: analysis of fourteen

the natural course of the disease and the

cases with review of the literature.

effect of antigen avoidance. A randomised,

Medicine (Baltimore); 54: 1-27.

double-blind, placebo-controlled study of

Cordier JF. Eosinophilic pneumonias. In:

corticosteroids in patients with acute

Schwarz M, et al., eds. Interstitial Lung

farmer’s lung found that patients given

Disease. 4th Edn. Toronto, Decker, 2003;

prednisolone showed more rapid

pp. 657-700.

improvement in lung function, with a

Durieux P, et al. (1981). Poumon éosino-

significantly higher diffusing capacity at

phile conceptions actuelles, démarches

1 month, compared to the control group, but

diagnostique et thérapeutique [Pulmonary

eosinophilia: current concepts, diagnostic

there was no difference in the long-term

and therapeutic advances]. Rev Fr Mal

outcome between the two groups.

Respir; 9: 5-26.

Recurrence of acute farmer’s lung was more

Fink JN, et al.

(1968). Pigeon breeders

common among corticosteroid-treated

disease: a clinical study of a hypersensitivity

patients than among controls if they had

pneumonitis. Ann Int Med; 68: 1205-1219.

continuing antigen exposure, raising the

Fink JN, et al.

(2005). Needs and

possibility that corticosteroid treatment was

opportunities for research in hypersensi-

also suppressing the counter-regulatory

tivity pneumonitis. Am J Respir Crit Care

aspects of the immune response in these

Med; 171: 792-798.

patients.

616

ERS Handbook: Paediatric Respiratory Medicine

Ford RM (1996). Transient pulmonary

Mohr LC (2004). Hypersensitivity pneu-

eosinophilia and asthma: a review of 20

monitis. Curr Opin Pulm Med; 10: 401-411.

cases occurring in

5,702

asthma suf-

Ohshimo S, et al. (2009). Significance of

ferers. Am Rev Respir Dis; 93: 797-803.

bronchoalveolar lavage for the diagnosis

Fox B, et al. (1980). Chronic eosinophilic

of idiopathic pulmonary fibrosis. Am J

pneumonia. Thorax; 35: 570-580.

Respir Crit Care Med; 179: 1043-1047.

Grech V, et al. (2000). Pigeon breeder’s

Ohtani Y, et al.

(2005). Chronic bird

lung in childhood: varied clinical picture

fancier’s lung: histopathological and clin-

at presentation. Pediatr Pulmonol;

30:

ical correlation

- an application of the

145-148.

2002 ATS/ERS consensus classification of

Hansell DM, et al.

(1996). Hypersen-

the idiopathic interstitial pneumonias.

sitivity pneumonitis: correlation of indivi-

Thorax; 60: 665-671.

dual CT patterns with functional abnorm-

Patel RA, et al. (2000). Hypersensitivity

alities. Radiology; 199: 123-128.

pneumonitis: patterns on high-resolution

Horny HP, et al.

(2011). Eosinophil,

CT. J Comput Assist Tomogr; 24: 965-970.

basophil, and mast infiltrates in the bone

Peters MS, et al. (1988). Ultrastructural

marrow: crossing the boundaries of

study of eosinophils from patients with

diagnosis. J Hematopathol; 4: 101-111.

the hypereosinophilic syndrome: a mor-

Jederlinic PJ, et al.

(1988). Chronic

phological basis of hypodense eosino-

eosinophilic pneumonia: a report of 19

phils. Blood; 71: 780-785.

cases and a review of the literature.

Radu AS, et al.

(2005). Antineutrophil

Medicine; 67: 154-162.

cytoplasmic antibodies. J Bras Pneumol;

Jeong YJ, et al. (2007). Eosinophilic lung

31: Suppl. 1, S16-S20.

diseases: a clinical, radiologic, and patho-

Ricketti AJ, et al. (1984). Serum IgE as an

logic overview. Radiographics; 27: 617-639.

important aid in management of allergic

Johkoh T, et al. (2000). Eosinophilic lung

bronchopulmonary aspergillosis. J Allergy

diseases: diagnostic accuracy of thin-

Clin Immunol; 74: 68-71.

section CT in

111

patients. Radiology;

Robinson

RG, et

al.

(1982).

216: 773-780.

Bronchocentric granulomatosis: roent-

Katzenstein AL, et al.

(1975). Broncho-

genographic manifestations. Am Rev

centric granulomatosis, mucoid impac-

Respir Dis; 125: 751-756.

tion and hypersensitivity reaction to

Rosenberg M, et al. (1977). Clinical and

fungi. Am Rev Respir Dis; 111: 497-537.

immunologic criteria for the diagnosis of

King MA, et al. (1997). Acute eosinophilic

allergic bronchopulmonary aspergillosis.

pneumonia: radiologic and clinical fea-

Ann Intern Med; 86: 405-414.

tures. Radiology; 203: 715-719.

Roufosse F, et al.

(2000). Clonal Th2

Kokkarinen JI, et al.

(1992). Effect of

lymphocytes in patients with the idio-

corticosteroid treatment on the recovery

pathic hypereosinophilic syndrome. Br J

of pulmonary function in farmers lung.

Haematol; 109: 540-548.

Am Rev Respir Dis; 145: 3-5.

Roufosse

al.

(2006).

Lacasse Y, et al. (2003). Clinical diagnosis

Hypereosinophilic syndrome: lymphoproli-

of active hypersensitivity pneumonitis.

ferative and myeloproliferative variants.

Am J Respir Crit Care Med; 168: 952-958.

Semin Respir Crit Care Med; 27: 158-170.

Lalancette M, et al. (1993). Farmer’s lung.

Selman M, et al. (2012). Hypersensitivity

Long-term outcome and lack of predictive

pneumonitis: insights in diagnosis and

value of bronchoalveolar lavage fibrosing

pathobiology. Am J Respir Crit Care Med;

factors. Am Rev Respir Dis; 148: 216-221.

186: 314-324.

Liebow AA

(1973).

The J. Burns

Simon HU, et al. (1999). Abnormal clones of

Amberson lecture: pulmonary angiitis

T cells producing interleukin-5 in idiopathic

and granulomatosis. Am Rev Respir Dis;

eosinophilia. N Engl J Med; 341: 1112-1120.

108: 1-18.

Tazelaar HD, et al. (1997). Acute eosino-

Martinet Y, et al. (1984). Les poumons

philic pneumonia: histopathologic find-

éosinophiles [The eosinophilic pneumo-

ings in nine patients. Am J Respir Crit Care

nias]. Presse Med; 30: 1833-1837.

Med; 155: 296-302.

ERS Handbook: Paediatric Respiratory Medicine

617

Travis WD, et al.. Idiopathic interstitial

Wang JL, et al. (1978). Serum IgE and IgG

pneumonitis and other diffuse parenchy-

antibody activity against Aspergillus fumi-

mal lung diseases. In: Atlas of Nontumor

gatus as a diagnostic aid in allergic

Pathology Non-Neoplastic Disorders of

bronchopulmonary aspergillosis. Am Rev

the Lower Respiratory Tract. Washington,

Respir Dis; 117: 917-927.

American Registry of Pathology and the

Wechsler ME (2007). Pulmonary eosino-

Armed Forces Institute of Pathology,

philic syndromes. Immunol Allergy Clin

2002: 115-123.

North Am; 27: 477-492.

Valent P, et al.

(2012). Contemporary

Winn RE, et al. (1994). Pulmonary invol-

consensus on criteria and classification

vement in the hypereosinophilic syn-

of eosinophil disorders and related syn-

drome. Chest; 105: 656-660.

dromes. J Allergy Clin Immunol; 130: 607-

Wolkenstein P, et al. (2003). Toxidermies

612.

avec atteinte pulmonaire

[Cutaneous

Valent P (2009). Pathogenesis, classifica-

adverse drug reaction with pulmonary

tion, and therapy of eosinophilia and

involvement]. Rev Mal Respir;

20:

719-

eosinophil disorders. Blood Rev; 23: 157-165.

726.

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ERS Handbook: Paediatric Respiratory Medicine

Pulmonary haemorrhage

Robert Dinwiddie

Pulmonary haemorrhage can occur at any

,1%. The underlying causes are shown in

age in childhood, from birth through to

table 1.

adolescence. The presentation can be acute

The underlying mechanism is thought to be

or chronic, clinically obvious or covert and

due to capillary leakage into the interstitium.

subtle over a period of time. Presenting

Haemorrhagic fluid can also leak directly

features can vary from the acute and life-

threatening to chronic ill health secondary to

into the alveolar spaces and then into the

small and large airways. Neonatal

iron deficiency anaemia. The aetiology is

pulmonary haemorrhage has also been

best divided into two age groups: neonatal

associated with the administration of

and childhood.

exogenous surfactant. Other predisposing

Neonatal

factors include birth asphyxia, excessive

fluid administration, hypoglycaemia,

Neonatal pulmonary haemorrhage most

coagulation defects, intercurrent infection,

commonly occurs in preterm infants

hypothermia and cardiac failure.

secondary to severe pulmonary oedema in

association with respiratory distress

Frothy haemorrhagic fluid appears through

syndrome and patency of the arterial duct

the nose and mouth or via the endotracheal

(patent ductus arteriosus). The incidence is

tube. In its most acute form it is associated

with the sudden onset of shock and can be

life-threatening. Chest radiographs show

diffuse interstitial shadowing throughout

Key points

both lung fields. Treatment includes the use

of high levels of positive end-expiratory

N Pulmonary haemorrhage can occur at

pressure (PEEP), replacement of blood loss

any age.

but with overall fluid restriction and

Presentation varies from the acute

correction of coagulation deficiencies. If

and life-threatening to ‘‘hidden’’, with

there is an associated patent ductus

no obvious haemoptysis.

arteriosus then this should be closed as

soon as possible.

N Many cases are idiopathic but a

number of clear underlying causes

Infancy and childhood

can be recognised by selective

investigations.

Pulmonary haemorrhage in infancy and

childhood can occur due to a variety of

N Known complications include chronic

causes. They are best divided into those

iron deficiency anaemia and

which result in diffuse or focal areas of

pulmonary fibrosis.

bleeding. These are shown in table 2.

Systemic corticosteroids are the most

Consideration should also be given to the

effective treatment in the majority of

possibility that bleeding from the nose or

cases.

mouth can be due to other causes, such as

epistaxis or haematemesis.

ERS Handbook: Paediatric Respiratory Medicine

619

diagnostic tests is shown in table 3 and an

Table 1. Causes of pulmonary haemorrhage in the

algorithm for diagnosis is shown in figure 1.

neonatal period

Respiratory distress syndrome

Lung function tests may demonstrate

Patent arterial duct (patent ductus

evidence of airflow obstruction, reduced

arteriosus)

lung volumes and functional residual

capacity and associated hypoxaemia with

Fluid overload

reduced oxygen saturation levels in air. The

Cardiac failure, left-to-right shunt

diffusion of carbon monoxide is also

Birth asphyxia

reduced over the longer term if progressive

lung damage occurs. This parameter is

Administration of surfactant

difficult to measure in young children.

Coagulation disorders

Neonatal sepsis

Radiological changes include bilateral

patchy interstitial infiltrates throughout one

or both lungs. In the longer term the chest

Clinical presentation

radiograph may develop more chronic

changes including reticulo-nodular

The most obvious clinical presentation of

shadowing due to pulmonary fibrosis.

diffuse or focal pulmonary haemorrhage is

with clinically apparent bleeding manifesting

Depending on the severity, a CT scan of the

itself as haemoptysis. However, only a

chest will show patchy interstitial infiltrates

proportion of children present in this way

in one or both lung fields. More generalised

and many present with less specific

areas of consolidation may also be evident

symptoms such as cough, breathlessness,

(fig. 2). In those with prolonged disease,

wheezing and exercise limitation. In some

changes of pulmonary fibrosis can develop.

cases, in which the underlying condition has

Any associated bronchiectasis will also be

been present over a longer period of time, a

seen.

faltering growth pattern is seen. A few

Histopathology

patients with focal intrapulmonary

haemorrhage, such as in CF, complain of a

When acute pulmonary haemorrhage occurs

localised ‘‘bubbling sensation’’ within the

red blood cells are seen in large numbers in

chest. At the other extreme, major acute

the alveoli and interstitial spaces. Within

cases may present with massive

48-72 h many alveolar macrophages are

haemoptysis, profound anaemia and shock,

seen which have phagocytosed red blood

which can be life-threatening.

cells and are in the process of digesting

them. These cells are called siderophages

Physical examination may reveal pallor,

and stain positive with Prussian blue. A

tachycardia, fever, tachypnoea and

specific parameter used for reporting

dyspnoea, with indrawing of the chest

alveolar haemorrhage in bronchoalveolar

muscles and cyanosis. Localised chest signs

lavage specimens is the Golde score. This

include focal or generalised areas of

gives a ranking score of 0-4 depending on

decreased air entry and crackles or wheeze.

the density of haemosiderin in the cells. 100

Finger clubbing is also seen but is

cells are counted and the Golde score is

uncommon.

reported. In normal individuals this is ,20.

Diagnostic work-up

A score of 20-70 is found in those with

significant alveolar haemorrhage. Other

As shown in table 2 the differential

pathology groups have used a cut-off of

diagnosis is extensive. A carefully

.20% of siderophages present among the

considered diagnostic work-up exploring

total number of alveolar macrophages as

known causes is warranted in every case,

diagnostic for haemorrhage.

bearing in mind that a significant proportion

are ‘‘idiopathic’’ and no specific underlying

Lung biopsy is rarely indicated but if

condition will be found. A suggested list of

undertaken may show abnormalities of the

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ERS Handbook: Paediatric Respiratory Medicine

alveolar capillary endothelial basement

Table 2. Causes of pulmonary haemorrhage in infants

membrane and, in cases of repeated

and children

bleeding episodes, early pulmonary fibrosis.

Diffuse

Haemosiderosis

Diffuse pulmonary haemorrhage

IPH

Idiopathic pulmonary haemosiderosis (IPH) is

Goodpasture syndrome

a rare condition in children with a variable

and, at times, severe prognosis. It can

Cow‘s milk protein allergy, Heiner

appear at any age throughout childhood but

syndrome

its onset is more common in the early years.

Systemic vasculitis

It varies in severity and presents when there

Granulomatosis with polyangiitis

is active bleeding into the lung tissue itself.

(Wegener’s)

This can take the form of haemoptysis, from

Henoch-Schonlein purpura

small amounts to massive acute life-

threatening episodes, or the gradual onset

Churg-Strauss syndrome

of severe anaemia without any clinically

Microscopic angiitis

obvious haemoptysis. Patients can become

Collagen vascular

breathless and occasionally wheezy or may

Systemic lupus erythematosis

be asymptomatic. If haemoptysis does occur

it is manifested by cough and small or large

Cardiac

amounts of blood which may continue over

Left-to-right shunt

several days or weeks. The full blood count

Left-sided obstruction

shows an acute reticulocyte response and

Cardiac failure

evidence of iron deficiency anaemia.

Diagnosis is made by the finding of

Coeliac disease

haemosiderin laden macrophages in

Alveolar injury

bronchoalveolar lavage fluid, gastric

Bleeding diatheses

aspirates or on lung biopsy in the absence of

Focal

any other known aetiology for pulmonary

haemorrhage.

Viral or bacterial lung

infection

Other associations with pulmonary

haemorrhage include acute

Atypical mycobacterial

glomerulonephritis and Goodpasture’s

infection

syndrome. These patients also present with

haematuria and proteinuria. Antibodies to

Bronchiectasis

glomerular and alveolar basement

membranes can be detected in the blood.

Non-CF bronchiectasis

Renal biopsy, which is rarely indicated,

Primary ciliary dyskinesia

demonstrates specific antibodies to basement

membrane and disruption of the underlying

Immunodeficiency

vascular endothelial membrane. Similar

Foreign body

changes have been demonstrated in the lung.

Vascular

Chest radiography findings are similar to IPH

with patchy interstitial infiltrates seen

Haemangiomas

bilaterally, increasing in severity during

Arterio-venous malformations

episodes of active bleeding. Over the longer

Neoplasms

term, if this is recurrent, pulmonary fibrosis

Tracheostomy

occurs and the changes, which are initially

ground-glass in appearance, become more

Fabricated or induced illness

reticular and nodular.

ERS Handbook: Paediatric Respiratory Medicine

621

Table 3. Possible diagnostic tests for cases of pulmonary haemorrhage

Full blood count

ECG

Coagulation studies

Echocardiogram

Erythrocyte sedimentation rate

Pulmonary function tests

C-reactive protein

Chest radiograph

Serum iron and ferritin

CT scan of the chest

Renal function tests

Sputum culture and sensitivity

Immune deficiency screen including HIV/AIDS Mantoux test

Total IgE

Viral antibodies

Cow’s milk protein antibodies

CF mutation analysis

Anti-neutrophil cytoplasmic antibodies

Ciliary biopsy and electron microscopy

Antinuclear antibodies

Bronchoalveolar lavage

Anti-glomerular basement membrane

Lung biopsy (rarely necessary)

antibodies

IgA anti-tissue transglutaminase antibodies

Pulmonary haemorrhage is also associated

to cor pulmonale. Chest radiographs show

with allergy to cow’s milk protein, i.e. Heiner

patchy bilateral infiltrates. Blood counts

syndrome. Apart from acute episodes of

show a marked eosinophilia and elevated

pulmonary haemorrhage it most commonly

levels of IgE. Antibodies to cow’s milk

presents in children under the age of three

protein are diagnostic. A cow’s milk-free diet

with clinical signs of cow’s milk protein

results in the disappearance of symptoms.

intolerance including vomiting, diarrhoea,

Pulmonary haemorrhage occurs in cardiac

gastrointestinal bleeding, rhinorrhoea and

failure, particularly where there is a left-sided

faltering growth. Some patients develop

obstructive lesion or a large left-to-right

significant lymphoid hyperplasia of the

shunt. Such conditions are usually evident

upper airway, specifically, adenotonsillar

clinically before a bleeding episode occurs.

hypertrophy, which in severe cases can lead

Diffuse pulmonary haemorrhage is also a

Algorithm for the diagnosis

of pulmonary haemorrhage

Idiopathic

Immune mediated

Cardiac

Infection

Focal

Chest radiograph

Review upper airway

Chest CT

Chest radiograph

Bronchoscopy

Chest CT

BAL

CF screen

Haematology

Autoantibodies

ECG

Virology Non-CF bronchiectasis screen

Immunology screen

Echo

Bacteriology

Ciliary biopsy

Renal function

TB screen

Factitious

Induced

Figure 1. Algorithm for the diagnosis of pulmonary haemorrhage. BAL: bronchoalveolar lavage; Echo:

echocardiography.

622

ERS Handbook: Paediatric Respiratory Medicine

conditions heavily blood-stained sputum is

more common than the major bleeding

episodes which can occur in IPH and CF.

Localised lesions such as haemangiomas

and arteriovenous malformations can also

be the cause of acute bleeding episodes.

Bleeding can occur as a complication of an

underlying clotting disorder. Pulmonary

haemorrhage can be real or imagined as

part of the spectrum of factitious or induced

illness in childhood.

Management

Figure 2. CT scan of 5-year-old boy with diffuse

bilateral alveolar haemorrhage.

Major bleeding episodes can occur without

warning and may be fatal. Chronic covert

known complication of systemic lupus

haemorrhage also occurs over a period of

erythematosis, Henoch-Schonlein purpura,

several weeks and may present only with

granulomatosis with polyangiitis

chronic but sometimes severe anaemia.

(Wegener’s), microscopic polyangiitis,

Management of the acute situation requires

coeliac disease and diffuse alveolar injury

oxygen therapy and other respiratory

from exposure to external toxic agents.

support including bronchodilators, blood

transfusion and ventilation in severe cases.

Focal pulmonary haemorrhage CF is the

Corticosteroids such as pulsed

most common cause of massive pulmonary

methylprednisolone 10-30 mg?kg^-1?day^-1 for

haemorrhage in older children. Many

3 days are given at monthly intervals. In less

episodes are precipitated by an acute

severe cases oral prednisolone is given at

exacerbation of long-term infection.

2 mg?kg?^-1?day^-1 for a minimum of 5-7 days

Bleeding can be exacerbated in individual

following which the dose is titrated to the

cases by the use of over aggressive chest

lowest level that controls symptoms. In a

physiotherapy techniques, high-

number of cases oral steroids may only be

concentration mucolytic agents and,

necessary for short periods while in others a

occasionally, as a complication of rhDNase

continuing dosage on a daily basis or

therapy.

preferably on alternate days is required to

control symptoms. Other

Management includes reduction of physical

immunosuppressive agents such as

activity, adaptation of chest clearance

hydroxychloroquine, azathioprine and

techniques to less physically stressful

cyclophosphamide have been used. If there

methods and appropriate intensification of

is evidence of cow’s milk allergy then a milk

antibiotic therapy. Should this be

free diet is indicated. Inhaled corticosteroids

unsuccessful then bronchial artery

have also been used in an attempt to reduce

embolisation is indicated. This is not

underlying inflammation. Plasmapheresis

without risk as embolisation of an adjacent

has been used in Goodpasture’s syndrome.

anterior spinal artery with paraplegic

consequences is a known complication. This

Prognosis

procedure is, however, successful in the

The natural history of most causes of

majority of cases. Limited lung resection is

pulmonary haemorrhage is to wax and wane

the final option if other procedures fail to

control the bleeding.

over a period of time. Because of the rarity of

these conditions there are no formal clinical

Pulmonary haemorrhage can occur as a

trials of any the above treatments. The

complication of non-CF bronchiectasis, with

overall prognosis is therefore variable, in

or without immunodeficiency, TB and

severe cases of IPH, mortality rates as high

primary ciliary dyskinesia. In these

as 50% over a 5-year period have been

ERS Handbook: Paediatric Respiratory Medicine

623

reported in the past. Results with recent

Brunner J, et al.

(2009). Successful

more intensive treatment regimens have

treatment of severe juvenile microscopic

reduced this to around 14%. Those who

polyangiitis

with

rituximab.

Clin

have major haemorrhagic episodes are most

Rhematol; 28: 997-999.

at risk. Other patients may show only small

Esposito S, et al.

(2010). Wegener’s

granulomatosis presenting with life threa-

episodes of a milder degree and in these

tening lung haemorrhage in a 7-year-old

cases there is a tendency to improve with

child. Rheumatol Int; 30: 1665-1668.

age, especially during adolescence and early

Godfrey S

(2004). Pulmonary hemor-

adult life.

rhage/hemoptysis in

children. Pediatr

Pulmonol; 37: 476-484.

Further reading

McCoy KS. Hemosiderosis. In: Pediatric

Respiratory Medicine.

1st Edn. Taussig

Boat TF. Pulmonary hemorrhage and

LM, et al., eds. St Louis, Mosby, 1999;

hemoptysis. In: Chernick V, et al., eds.

pp. 835-841.

Kendig’s Disorders of the Respiratory

Roberton NRC. Pulmonary oedema/pul-

Tract in Children.

7th Edn. Philadel-

monary haemorrhage. In: Greenough A, et

phia, Saunders Elsevier,

2006; pp.

al., eds. Neonatal Respiratory Disorders. 1st

676-685.

Edn. London, Arnold, 1996; pp. 375-385.

624

ERS Handbook: Paediatric Respiratory Medicine

Sickle cell disease

Tobias Ankermann

The term sickle cell disease (SCD) is used to

the rheological properties of the erythrocyte

refer to a haemoglobinopathy that results

leads to dysfunction in the microcirculation

from a genetic variant giving rise to sickle

with vaso-occlusive crises. Vascular

haemoglobin (HbS). This includes the

occlusions can occur in almost all organs

homozygote SCD (HbSS, previously named

(e.g. skin, lung, liver, spleen, bone, kidney

sickle cell anaemia) and compound

and brain). The clinical consequences of this

heterozygote haemoglobinopathies (HbS-b-

are acute and chronic pain, hyposplenism

thalassaemias, HbSC disease, etc.). In

(or functional asplenia in older children

Europe, ,1300 children will be born with

following splenic infraction and splenic

SCD per year. 60-70% of these children

sequestration) with secondary

suffer from HbSS.

immunodeficiency, osteonecrosis,

nephropathy and cerebral infarction. The

HbS-haemoglobinopathies cause a chronic

most common causative organisms of

haemolytic anaemia and a disease of the

infectious complications following

blood vessels. HbS is caused by a mutation

secondary immunodeficiency are

in the b-globin locus on chromosome 11;

Streptococcus pneumoniae, Salmonella,

HbSS leads to polymerisation and a loss of

Haemophilus influenzae type b, Neisseria

solubility of the haemoglobin during

meningitidis and Mycoplasma. In acute chest

deoxygenation. The subsequent change in

syndrome (ACS) of infectious origin, the

most commonly identified agents are

atypical bacteria and viruses.

Key points

The chronic disease of the vessels results in

priapism, cerebrovascular disease,

SCD includes HbS-

hypercoagulability and inflammation of

haemoglobinopathies, which lead to

endothelial structures.

haemoglobin polymerisation with

subsequent vaso-occlusion, a chronic

In the lungs and airways, SCD leads to acute

haemolytic anaemia and endothelial

manifestations (acute pulmonary vascular

damage in blood vessels, with

occlusions, ACS and acute lower respiratory

consequent chronic organ failure.

tract infections (LRTIs)), and a chronic lung

disease with lung fibrosis and secondary

N In the lungs and airways, SCD induces

pulmonary hypertension with cor

acute pulmonary vascular occlusions,

pulmonale. Children with SCD frequently

ACS, LRTIs, and chronic lung disease

exhibit bronchial hyperresponsiveness and

with lung fibrosis and pulmonary

bronchial asthma. The comorbidity of SCD

hypertension.

and asthma is associated with a two-fold

Important pulmonary comorbidities

increased mortality and a reduced life span

of children with SCD are bronchial

of patients with asthma and SCD compared

hyperresponsiveness, atopy and

to patients with SCD without asthma. The

asthma.

role of OSAS is not yet clearly defined.

Pulmonary complications are the most

ERS Handbook: Paediatric Respiratory Medicine

625

frequent reason for death in children with

haemoglobin concentration decreases

SCD.

(,2 g?dL^-1 of individual baseline) or the

PaO₂ decreases ,70 mmHg below the

Keystones of care are:

normal range during oxygen therapy, then

blood transfusion is indicated. One small

N protection against infections (e.g.

trial (DeNOVO) suggested that patients

vaccination against pneumococci,

with ACS and early transfusion had an

H. influenzae B, Neisseria, influenza A, and

improved outcome, when compared with

antibiotics (prophylactic penicillin in

historical data. In very severe cases or when

small children continued until the

transfusion fails to reduce the HbSS to

immunisation series is complete, with

,30%, an exchange transfusion should be

pneumococcal polysaccharide vaccine

considered. Extracorporeal membrane

with HbSS and HbS-b⁰-thalassaemia),

oxygenation (ECMO) and nitric oxide are

N early intervention to prevent disease

therapy options in very severe cases but are

progression if pain or fever occurs,

not standard therapies.

N optimal asthma therapy, and

N together with haematologists,

The application of glucocorticoids is

hydroxyurea, folic acid and occasionally a

controversial. In mild ACS, positive effects

transfusion regimen.

have been described, but there are reports

In acute vaso-occlusive crisis and ACS,

that administration of glucocorticoids in

oxygen, hydration, analgesia, antibiotics and

ACS leads to relapse after sudden

incentive spirometry are required.

termination, reactive vaso-occlusive disease

and longer hospitalisation. In children with

Acute chest syndrome

ACS on artificial ventilation, it may be

necessary to perform bronchoscopy and to

ACS is an acute lung injury and is caused by

apply DNase to remove mucus and/or

infection, fat embolism, vaso-occlusion or a

bronchial casts. Figure 3 delineates the

combination of these factors. It is defined as

therapy of ACS.

respiratory signs and/or symptoms (cough,

tachypnoea, chest pain, retractions, rales,

Chronic lung disease in SCD

crackles, wheezing and hypoxaemia) and/or

new infiltrates on the chest radiography and

Fibrotic remodelling of the lung occurs due

fever (.38.5uC) (fig. 1). One-third of children

to changes in the structure and function of

with ACS complain about abdominal pain

and pain in their extremities. Figure 2 shows

a practical approach to the diagnosis of

A new pulmonary infiltrate detected by chest

ACS. The discrimination of ACS from

radiograph involving at least one complete

pneumonia or other LRTIs is often difficult

lung segment that is not consistent with the

but not essential for treatment. Children

appearance of atelectasis

with suspected or manifest ACS should be

and

admitted to hospital for close observation of

one or more of the following signs

their clinical and respiratory status. The

or symptoms:

treatment should be initiated early and is

• cough

based on the administration of oxygen to

• signs of increased work of breathing

counter the polymerisation of HbS.

(retractions, tachypnoea)

• chest pain

Furthermore, antibiotic treatment (third-

• wheezing

generation cephalosporin or amoxicillin/b-

• rales

lactamase inhibitor plus a macrolide; if

• body temperature >38.5°C

methicillin resistant Staphylococcus aureus

• hypoxaemia relative to baseline

(MRSA) is suspected, consider

measurement

vancomycin), inhalation of b₂-

sympathomimetics, intravenous hydration,

analgesia and incentive spirometry are

Figure 1. Clinical criteria for diagnosis of ACS in

keystones of the therapy of ACS. If the

children with SCD.

626

ERS Handbook: Paediatric Respiratory Medicine

Fever

and/or

Cough

and/or

Respiratory distress (tachypnoea, chest retractions)

and/or

SaO

2 ≤95%

and/or

Chest pain

Rales?

Yes

Acute chest syndrome

Reduced breath sound?

Start therapy

Percussion dullness?

Chest radiography

Yes

Acute chest syndrome

Infiltrates?

Start therapy

Monitoring clinical course and SaO

If pain present: optimise analgesia

Other cause?

Figure 2. Practical approach if criteria for ACS are met in children with SCD. Reproduced and modified

from Miller (2011) with permission from the publisher.

the endothelium and the metabolism of

pulmonologist should examine children with

nitric oxide. ACS and asthma are important

SCD when they are well on an individual

risk factors for this process. Lung function

basis (every 4 months in small children; up

tests in preschool children mostly

to 6-12 months in older children with HbSS

demonstrate an obstructive pattern. A

and HbS-b⁰-thalassemia). Integral parts of

restrictive pattern occurs beginning in the

the consultation are:

second decade. In the third decade, there

can be a progressive decline in TLC and

N history,

diffusion capacity. CT may show interstitial

N recording of room-air oxygen saturation,

lung disease.

N lung function testing (according to age,

including diffusion capacity in older

Atopy, asthma and bronchial

children),

hyperresponsiveness are important

N allergy tests (skin-prick test or specific

comorbidities in children with SCD. The

IgE), and

prevalence of asthma in children with SCD is

N checking for signs and symptoms of OSA.

between 20% and 48%. Children with SCD

and asthma and/or specific sensitisation

If, in asthma, a decline in lung function or a

suffer more frequent and earlier episodes of

specific sensitisation is detected, lung

ACS. A possible explanation is the

function should be tested every 6 months.

ventilation/perfusion mismatch in asthma

with local tissue hypoxia in the lung

Children with abnormal overnight oxygen

following sickling and vaso-occlusion, and

saturation (,95%) and/or abnormal lung

the higher incidence of LRTIs in children

function test should be screened for OSA,

with atopy and asthma. The paediatric

interstitial lung disease and pulmonary

ERS Handbook: Paediatric Respiratory Medicine

627

Markers of inflammation (CRP, sedimentation rate)

Blood gas analysis

Complete blood count, reticulocytes

Markers of haemolysis (haptoglobin, LDH, bilirubin direct + total), electrolytes, creatinine, BUN,

Blood culture, sputum culture, urine culture

Pulse oximetry, ECG and respiratory rate, repeated clinical examination

Oxygen

Antibiotics (third-generation cephalosporin (or ampicillin + β-lactamase inhibitor)

+ macrolide)

Inhalation with β₂-sympathomimetics

Balanced i.v. hydration

Analgesia

Physiotherapy (PEP, incentive spirometry)

Yes

Hb 2 g·dL-1 < baseline

Transfusion

PaO

2 <70 mmHg

Deterioration over 6-12 h

Mechanical ventilation, exchange transfusion (ECMO)

Figure 3. Procedure and therapy if criteria for ACS are met in children with SCD. CRP: C-reactive protein;

LDH: lactate dehydrogenase; BUN: blood urea nitrogen; PEP: positive expiratory pressure. Reproduced

and modified from Miller (2011) with permission from the publisher.

hypertension. At present, there is no specific

disease and early mortality. With optimal

therapy for chronic lung disease in SCD.

care, children with SCD are able to reach the

Asthma in SCD is associated with ACS,

sixth decade of life. Without structured care,

faster decline in lung function and mortality,

many children will not reach adulthood.

and should therefore be managed based on

established asthma guidelines. In

Further reading

childhood, pulmonary hypertension is less

common. Therefore, evidence-based

Colombatti R, et al.

(2011). Pulmonary

recommendations for the treatment of

hypertension in sickle cell disease chil-

pulmonary hypertension in children with

dren under 10 years of age. Br J Haematol;

SCD are lacking. The application of

150: 601-609.

sildenafil, bosentan and prostacyclins has

Gladwin MT, et al.

(2008). Pulmonary

been reported.

complications of sickle cell disease. N

Engl J Med; 359: 2254-2265.

Course of lung disease in SCD

Kavanagh PL, et al. (2011). Management

of children with sickle cell disease: a

Children with SCD demonstrate a decline in

comprehensive review of the literature.

lung function with increasing age,

Pediatrics; 128: e1552-e1574.

accompanied by decreasing exercise

Knight J, et al. (1999). The lung in sickle

tolerance. The incidence of ACS and

cell disease. Pediatr Pulmonol; 28: 205-

comorbidity with asthma are important risk

216.

factors for the development of chronic lung

628

ERS Handbook: Paediatric Respiratory Medicine

Lung and mediastinal

tumours

Amalia Schiavetti

Benign or malignant paediatric chest

tumours can originate from the lung

Key points

parenchyma, mediastinum, pleura or chest

wall.

Primary pulmonary neoplasms are

rare in childhood; metastatic disease

Primary lung tumours

or inflammatory/congenital diseases

are more frequently recognised.

Primary pulmonary neoplasms are rare in

children, whilst metastatic disease or

The most common primary lung

inflammatory/congenital diseases are more

malignancies in children are

frequently recognised. The ratio of primary

pleuropulmonary blastoma and

to metastatic to inflammatory/congenital

carcinoid tumour; bronchogenic

tumours is reported to be 1:5:60. In a

carcinomas are exceptionally rare.

published large series of childhood lung

Symptoms of primary lung tumours in

tumours, 16.7% were primary and 83.3%

childhood are nonspecific (cough,

reflected metastatic disease or secondary

haemoptysis, chest pain or shortness

involvement by a haematolymphoid or

of breath); persistent symptoms or

histiocytic process.

persistent radiographic findings

Clinical picture Primary pulmonary tumours

despite therapy require a CT scan and/

in children present with nonspecific

or a MRI of the chest.

symptoms. Some lesions are found

Tumours arising in the anterior

incidentally on radiological studies

mediastinum are most commonly due

requested for unrelated medical diseases.

to lymphoma followed by germ cell

Common presenting symptoms include

tumours; large masses present life-

cough, chest pain, haemoptysis or shortness

threatening airway compromise,

of breath and they may mimic common

especially during anaesthesia.

entities. Due to the paucity of primary

pulmonary malignancies in paediatric and

adolescent patients, delays in diagnosis are

provides better visualisation of soft tissue

common. At least half of these lesions can

lesions, vascular anatomy and masses of the

present with advanced stage disease. Most

mediastinum. The presence of a suspicious

patients are initially diagnosed as having

mass lesion can require bronchoscopy for

pneumonia that contributes to a delay in

central lesions and thoracoscopic or image-

diagnosis.

guided biopsy for peripheral lesions.

Diagnosis Initial workup consists of baseline

Bronchoscopic evaluation should consist of

laboratory and chest radiography. Persistent

gross inspection. Tracheal and

symptoms or persistent radiographic

endobronchial tumours are most likely to be

findings despite therapy require a CT scan

carcinoid tumours or mucoepidermoid

and/or MRI of the chest, as well as

carcinomas; both are malignant processes.

evaluation by a pulmonologist. CT is most

Tissue biopsy of endobronchial lesions can

useful for parenchyma lesions, whereas MRI

be performed, although this procedure is

630

ERS Handbook: Paediatric Respiratory Medicine

opposed by some authors because of the

survival is 63% (type I 80%; type II 73%; type

risk of fatal haemorrhage. If attempted,

III 48%). Although PPB has not been

endobronchial biopsy should be performed

identified as part of a specific syndrome, it is

in a setting where thoracic surgery is

a strikingly familial cancer with genetic

immediately available. A history of a

implications for others in the immediate and

congenital cystic malformation of the lung

extended families. In fact, in ,25% of cases,

has been reported to increase the risk of

PPB is associated with other extrapulmonary

lung malignancy. It is thought that these

lesions in the same patient or family

malformations may undergo malignant

members.

degeneration with time.

Carcinoid tumour is considered a low-grade

Prognosis and treatment The frequency of the

neuroendocrine carcinoma due to its

various histology types and the outcome for

potential for locally aggressive growth and

children with pulmonary malignancies is

low potential for metastasis. These lesions

different to adults. In adults, ,80% of the

are typically obstructive endobronchial

lung tumours are adenocarcinoma, small

masses in older children and adolescents

cell carcinoma or squamous cell carcinoma

and have been reported to account for 50-

and the 5-year overall survival for all patients

80% of primary malignant lung tumours in

is very poor. In children, pleuropulmonary

children. These lesions tend to be

blastoma, inflammatory myofibroblastic

endobronchial and this probably explains

tumour and carcinoid tumour are frequently

the presentation with haemoptysis. Patients

recognised. The prognosis is dependent on

with carcinoid tumours seem to have the

the histology and stage. All patients with

best prognosis. No adjuvant therapies are

localised disease are treated with surgical

recommended for paediatric pulmonary

resection. Some patients with advanced

carcinoid tumours. The outcome is related

disease can be treated with chemotherapy,

to the extent of disease at presentation and

radiotherapy and selective surgery either

to the tumour resection.

independently or in combination.

Mucoepidermoid carcinoma is typically an

Malignant tumours

exophytic polypoid mass that causes

bronchial obstruction (80% of cases).

Primary lung tumours are mostly malignant.

Treatment is primarily surgical, with

Pleuropulmonary blastoma (PPB) is a rare

chemotherapy and radiotherapy reserved for

malignant embryonal mesenchymal

those tumours with incomplete resection.

neoplasm of the lung and pleura described

The prognosis in children appears to be

in 1988 as a unique entity distinct from

more favourable than in adults.

pulmonary blastoma. This tumour occurs

Inflammatory myofibroblastic tumour (IMT)

almost exclusively in children ,6 years of

has traditionally been considered benign

age. Three subtypes of PPB have been

and is known by many names including

described; defined grossly:

plasma cell granuloma and inflammatory

N type I is cystic and lacks solid

pseudotumour. More recently, the World

component,

Health Organization recognised IMT as a

N type III is solid without a cystic

low-grade mesenchymal malignancy. These

component,

nodular lesions are rarely endobronchial,

N type II consists of a mixture of solid and

and more frequently intraparenchymal.

cystic components.

Surgical resection is the treatment of choice,

although chemotherapy and radiation have

PPB has a propensity to metastasis to the

been proposed as adjuvant therapy.

brain. The differential diagnosis for type I

PPB includes more common benign cystic

Among the rare epithelial lung cancers most

lung malformations. Treatment is based on

paediatric cases are adenocarcinomas. The

aggressive surgery followed by multimodal

actual incidence in children is difficult to

chemo-radiotherapy. The overall 2-year

determine and is limited to individual case

ERS Handbook: Paediatric Respiratory Medicine

631

reports and small case series. These

excised for diagnosis and staging purposes,

tumours may occur in children at any age,

others are removed as a part of oncological

but they are more usually found during

management to achieve long-term survival

adolescence. The adenocarcinomas in these

and cure. Conversely, surgical management

patients are histologically similar to

of metastatic disease is not used for

conventional pulmonary adenocarcinomas

chemosensitive and radiosensitive

of adults and should be managed according

malignancies. Wilms tumour and

to reasonable adult guidelines with surgical

osteosarcoma are the two most common

resection of operable tumours. Radiation

solid tumours leading to surgical excision of

therapy and chemotherapy may be of some

isolated metastatic lung nodules.

benefit to patients with unresectable

Secondary involvement of the lung in

tumours. Delay in diagnosis and metastasis

systemic diseases

at presentation has led to generally poor

survival in the few cases of bronchogenic

Langerhans cell histiocytosis presents in

carcinoma in children.

multiple organs including lungs. The lung is

considered a high-risk organ, but is less

Benign tumours

frequently involved in children than in

Among benign lung tumours, hamartomas

adults. Chest radiographs may show a

may present as large parenchymal masses

nonspecific interstitial infiltrate. A chest CT

with respiratory distress. Chest CT

is needed to visualise the cystic/nodular

classically shows fat and ‘‘popcorn’’

pattern of the Langerhans cell histiocytosis,

calcifications, which suggest the diagnosis.

which leads to the destruction of lung

tissue. Medical treatment following

Metastatic lung tumours

Histiocyte Society clinical trials is

recommended.

Metastases to the lung are more common

than primary lung malignancies in children,

Leukaemia and lymphoma Leukaemic

and they may be excised for diagnosis,

infiltration of the lung may cause a pattern

staging or therapeutic purposes. Most

that is radiographically similar to primary

malignant lung lesions are metastases from

infections. Lung involvement by leukaemia

distant organs or direct invasions from

usually manifests as patchy interstitial,

adjacent structures. Metastatic tumours

septal or pleural infiltrates in contrast to

account for ,80% of all lung tumours in

non-Hodgkin and Hodgkin lymphoma,

children and .95% of malignant tumours of

which tend to form larger, well-

the lung in this population. Wilms tumour,

circumscribed nodules. An associated

lymphoma, hepatoblastoma,

mediastinal mass or hilar adenopathy are

rhabdomyosarcoma, Ewing sarcoma,

variable features. Leukaemia and

osteosarcoma and gonadal tumours can

lymphoma are closely related and patients

produce metastases in the lungs, both

with leukaemia may present with an

isolated and multiple (fig. 1). Although a

anterior mediastinal mass and pleural

wide variety of childhood tumours produce

effusions. The distinction between the two

lung metastases, Wilms tumour and

is arbitrarily based on the degree of bone

osteosarcoma are the most frequent.

marrow involvement such that patients

Metastases to the lung can be seen on chest

with o25% marrow blasts are designated

radiography, but CT frequently identifies

as having leukaemia. The differential

small pulmonary nodules that are occult on

diagnosis for lymphoma involving the lung

conventional chest radiography. It is difficult

in children primarily includes Hodgkin

to distinguish benign from malignant

lymphoma and non-Hodgkin lymphoma.

pulmonary nodules in children based on CT

Associated pulmonary nodules and pleural

imaging features. Pulmonary metastases

effusions occur in only ,5% of patients

often appear as round, sharply marginated

with Hodgkin lymphoma, whereas

nodules, but they may be also ill-defined.

effusions occur in 50-75% of those with

While some metastatic lung nodules are

non-Hodgkin lymphoma.

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ERS Handbook: Paediatric Respiratory Medicine

metastatic tumours and primary tumours

such as lymphomas, germ cell tumours,

carcinoid and thymoma.

Lymphoma Lymphoma accounts for ,13%

of all childhood cancers and is the most

common cause of a mediastinal mass in

children. 60% of all lymphomas in this age

group are non-Hodgkin lymphomas while

Hodgkin lymphoma makes up the

remainder (fig. 2).

Diagnosis The growth rate in non-Hodgkin

lymphoma is often more rapid than in

Hodgkin lymphoma. Non-Hodgkin

lymphomas have a rapidly growing tumour

mass that can cause life-threatening

complications. In particular, children with

anterior mediastinal masses are at high risk

of life-threatening airway compromise

during anaesthesia. Large mediastinal

masses can cause compression of

surrounding mediastinal structures and

patients may have symptoms of airway

obstruction or cardiovascular compromise.

The additive effects of an anaesthetic with

paralysis and positioning during biopsy can

lead to acute airway obstruction and death.

The least invasive procedure should be used

Figure

1. Metastatic Wilms tumour in a 9-year-old

to establish the diagnosis. Lymph nodes in

girl. a) A chest axial CT scan showing bilateral,

areas outside the mediastinum provide

large, hilar nodes and multiple round lung lesions

access for tissue diagnosis; in the other

with right pleural thickening. b) A chest axial CT

cases, a diagnostic and management

scan performed after chemotherapy showing a

challenge arises for paediatric surgeons.

dramatic decrease in parenchyma lesions and hilar

Some patients at greatest risk require pre-

nodes. There is no pleural involvement.

treatment of the mass before tissue

diagnosis. Anterior mediastinal masses in

Mediastinal tumours

children should be approached in a step-

wise fashion with multi-disciplinary

Tumours in the mediastinum are best

involvement, starting with the least invasive

characterised by the compartment in which

techniques and progressing cautiously.

they arise. Malignant tumours arising in the

Biopsy may be obtained by trans-thoracic

anterior mediastinum are most commonly

puncture under CT or ultrasound guidance

due to lymphoma followed by germ cell

and it can be considered a viable, safe and

tumours. Tumours of the posterior

accurate method of reaching a diagnosis in

mediastinum are usually of neurogenic

the paediatric population. If these children

origin with neuroblastoma being most

require general anaesthesia for diagnosis, the

common.

surgeon should have a well-defined and pre-

Benign tumours are typically teratomas

operatively established contingency plan. Of

localised in the anterior mediastinum. About

the many clinical, functional and radiological

half of mediastinal tumours in childhood

criteria used to identify the children at

occur in the anterior mediastinum .The

greatest risk for anaesthetic complications,

majority of these are malignant, including

the peak expiratory flow rate (PEFR)

ERS Handbook: Paediatric Respiratory Medicine

633

Figure 2 Hodgkin lymphoma in 7-year-old boy. a) Anteroposterior and b) lateral chest radiographs

demonstrate a large anterior mediastinal mass lesion.

and the tracheal cross-sectional area seem to

infancy and young childhood, the

be the most reliable. General anaesthesia

histological subtypes are restricted to

should not be administered to children if the

benign teratoma and yolk sac tumour. In

PEFR and tracheal cross-sectional area are

adolescence, histological subtypes most

both ,50% predicted. If both are .50%

commonly include yolk sac tumour,

pred, general anaesthesia can be

seminoma, teratoma and immature

administered safely.

teratoma. Seminomas lack serological

markers, whereas non-seminomatous

Treatment After diagnoses and staging

tumours are often associated with increased

evaluation by imaging, chemotherapy is the

serum b-human chorionic gonadotropin or

main component of treatment for childhood

alpha-fetoprotein levels. Adolescents may be

non-Hodgkin lymphoma, while the majority

relatively asymptomatic, whereas infants

of patients with Hodgkin lymphoma are

may have severe respiratory symptoms.

currently managed with combined modality,

Surgical excision is the therapy of choice in

incorporating radiotherapy and

benign tumours such as teratomas.

chemotherapy.

Malignant germ cell tumours are

Germ cell tumours/teratomas

chemosensitive tumours.

About 20% of mediastinal germ cell

Posterior mediastinum Approximately 90%

tumours are malignant and include

of posterior mediastinal masses in children

seminomas and non-seminomatous

are of neurogenic origin. These include

tumours, such as teratocarcinoma, yolk sac

ganglion cell tumours and nerve tumours.

tumour, embryonal carcinoma,

Most are ganglion cell tumours that arise

choriocarcinoma and mixed types, the

from sympathetic chain ganglia and form a

others are teratomas. Malignant germ cell

spectrum of disease ranging from the most

tumours are generally a complex tumour,

aggressive, neuroblastoma, to the less

often containing coexisting benign

aggressive, ganglioneuroblastoma and

components. There are two age peaks for

benign ganglioneuroma. About 30% of

mediastinal germ cell tumours at about

these contain calcifications on radiological

2 years of age and at adolescence. During

imaging.

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ERS Handbook: Paediatric Respiratory Medicine

Tumours of the pleura

partially calcified soft-tissue mass arising

from one or more ribs, with associated

Mesothelioma of the pleura is primarily a

destruction and distortion of the bone.

tumour of the adult, .90% of

Although these features suggest an

mesothelioma are diagnosed after the fifth

aggressive process, mesenchymal

decade of life; the prognosis is dismal.

hamartomas are benign lesions, with no

Pleural involvement by malignant tumours

reports of recurrence or metastasis

in children is typically from metastatic

following complete surgical resection.

diseases, invasive chest wall neoplasms,

lymphoma or pleuropulmonary blastoma.

Further reading

Chest wall tumours

Dishop MK, et al. (2008). Primary and

The most common malignant primary

metastatic lung tumors in the pediatric

tumours of the chest wall arise from bone or

population: a review and 25-year experi-

soft tissue. They are mostly commonly of the

ence at a large Children’s Hospital. Arch

Ewing types (Askin or primitive

Pathol Lab Med; 132: 1079-1103.

neuroectodermal tumour) or

Garey CL, et al. (2011). Management of

anterior mediastinal masses in children.

rhabdomyosarcoma; others include

Eur J Pediatr Surg; 21: 310-313.

fibrosarcoma or osteosarcoma. Non-

Jaggers J, et al.

(2004). Mediastinal

malignant chest wall tumours are

masses in children. Semin Thorac

neurofibroma, haemangiomas and

Cardiovasc Surg; 16: 201-208.

osteochondromas. Imaging findings that

Lal DR, et al. (2005). Primary epithelial

suggest a malignant chest wall mass include

lung malignancies in the pediatric popu-

rib destruction, pleural extension and large

lation. Pediatr Blood Cancer; 45: 683-686.

size. The prognosis is dependent on the

McCarville MB

(2010). Malignant pul-

total resection, as well as on the histology

monary and mediastinal tumors in chil-

and stage. Small-cell malignant tumours,

dren: differential diagnoses. Cancer

such as Ewing’s sarcoma and Askin’s

Imaging; 10: 35-41.

tumour, should be treated with an

Petroze R, et al. (2012). Pediatric chest II:

aggressive multimodality approach

benign tumors and cysts. Surg Clin North

combining chemotherapy, radiation therapy

Am; 92: 645-658.

and surgery.

Priest JR, et al. (1996). Pleuropulmonary

blastoma: a marker for familial disease. J

Mesenchymal hamartomas of the chest wall

Pediatr; 128: 220-224.

are unusual rib lesions most commonly

Yu DC, et al. (2010). Primary lung tumors

affecting infants. The typical radiographic

in children and adolescents: a

90-year

manifestation of a chest wall mesenchymal

experience. J Pediatr Surg; 45: 1090-1095.

hamartoma is that of a large, extrapleural,

ERS Handbook: Paediatric Respiratory Medicine

635

Systemic disorders with lung

involvement

Andrew Bush

The lung can be affected by systemic disease

An extrapulmonary disease may itself be

in a number of ways, which are not

a single-organ disease but the

necessarily mutually exclusive.

consequence of that disease (causing

dysfunction of that organ) affects the

N The underlying condition has both

lung either through relatively specific

systemic and pulmonary specific

(e.g. hepatopulmonary syndrome) or

manifestations, for example ciliopathy, in

nonspecific mechanisms (e.g.

which ciliary disease can cause

pulmonary oedema secondary to renal

combinations of upper and lower

or cardiac failure), or by causing

respiratory disease, complex congenital

dysfunction in an another

heart disease, retinitis pigmentosa, and

organ.

renal, hepatic and pancreatic cystic

Lung disease or its treatment may affect

disease. Only those diseases not covered

another organ and dysfunction of that

elsewhere in this Handbook will be

organ may create a positive feedback

discussed in this section.

loop, worsening lung disease. An obvious

example is OSA leading to congestive

cardiac failure and secondary pulmonary

Key points

oedema.

The treatment of a systemic disorder may

Although individual rare diseases are,

affect the lungs (e.g. chemotherapy with

by definition, rare, taken together,

bleomycin leading to pulmonary fibrosis).

they are sufficiently common that they

Finally, apparent associations that are in

need to be considered in paediatric

fact artefacts of receiving medical

respiratory differential diagnosis.

attention for another condition must not

Respiratory paediatricians need to be

be confused with real connections

aware that multisystem diseases may

between diseases.

present with respiratory signs and

symptoms.

This section will give a brief overview of the

lung manifestations of liver, kidney and

Respiratory paediatricians also need

heart disease; haemoglobinopathy,

to be ready to advise specialists in

excluding sickle cell disease, which is

other fields, especially cardiology,

discussed elsewhere; connective tissue

nephrology and hepatology, about

disorders (both acquired inflammatory (e.g.

respiratory complications of their

systemic lupus erythematosus (SLE)) and

disease specialities.

inherited (e.g. Ehlers-Danlos syndrome)),

Ciliary dysfunction, far from being a

metabolic diseases and miscellaneous

purely respiratory issue, affects

disorders (e.g. familial dysautonomia and

multiple organs. The basic science

lymphangiomatosis). Pulmonary

and clinical aspects of ciliopathy are a

manifestations of congenital and acquired

huge growth area.

immunodeficiencies are discussed

elsewhere.

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ERS Handbook: Paediatric Respiratory Medicine

Table 1. Diseases affecting the liver and lung

Disease

Liver manifestations

Lung manifestations

Fatty liver

Chronic infection and

Biliary cirrhosis

inflammation

Portal hypertension

Pneumothorax

Gall stones

Haemoptysis

Allergic bronchopulmonary

aspergillosis

a₁-antitrypsin deficiency

Cirrhosis

Bronchiectasis and

emphysema

Ciliopathy

Biliary atresia

Recurrent infections

Cystic liver disease

Bronchiectasis

Chest wall deformity (Jeune’s

and other syndromes)

Granulomas

Fibrosis

Bronchiectasis

Lymphadenopathy

Pleural effusion

Sarcoidosis

Hepatosplenomegaly

Granulomas

Lymphadenopathy

Pulmonary fibrosis

Gaucher disease

Hepatosplenomegaly

Pulmonary infiltration with

Gaucher cells

Mucopolysaccharidoses

Hepatosplenomegaly

Upper airway obstruction

Skeletal malformations leading

to extrapulmonary restrictive

lung disease

Niemann-Pick disease

Hepatosplenomegaly

Pulmonary infiltrates

Extensive bronchial casts

Lung manifestations of liver disease

ventilation/perfusion mismatch and,

possibly, the creation of a functional

Diseases affecting the liver and the lungs The

diffusion barrier; it must be distinguished

more important of these are summarised in

from hypoxia as a nonspecific complication

table 1.

of liver disease due to ascites, pulmonary

Effects of liver dysfunction on the lung The

oedema or pleural effusion. Pulmonary

definition of hepatopulmonary syndrome

angiogenesis may also be a feature.

(HPS) in children is the presence of:

Prevalence is reported as up to 35% in

cirrhotic children but the syndrome may be

N liver disease;

seen even with relatively mild disease. There

N hypoxaemia (alveolar-arterial oxygen

will be signs of liver disease, especially

tension gradient .15 mmHg or PaO₂

spider naevi, and platypnoea (worsening

,80 mmHg while breathing room air);

hypoxaemia ongoing from the supine to the

N evidence of intrapulmonary shunting; and

erect position). Digital clubbing is common.

N no other cause of hypoxaemia.

Spirometry and lung volumes are usually

normal, with reduced diffusion capacity; in

HPS is manifest by profound hypoxaemia

severe disease, restrictive physiology may be

due to intrapulmonary right-to-left shunting,

seen. Cases have been described in

ERS Handbook: Paediatric Respiratory Medicine

637

association with noncirrhotic portal

Hepatocellular failure may lead to ascites

hypertension and otherwise uncomplicated

and, in theory, large volumes of intra-

viral hepatitis. The pathophysiology is not

abdominal fluid may splint the diaphragm

known but the physiological abnormality is

causing respiratory impairment. In fact, old

usually due to dilatation of pulmonary

studies looking at lung function before and

capillaries; occasionally, the syndrome

after tapping even huge volumes of ascites

arises as a result of the development of

(a practice now known to be dangerous)

anastomoses between pulmonary and

showed remarkably little change in lung

systemic veins, in the portal or

function. However, if there are

paraoesophageal regions. This syndrome

discontinuities in the diaphragm, pleural

should be remembered in children with

effusions may result. Hepatorenal syndrome

diseases affecting liver and lung (e.g. CF) if

is a serious consequence of advanced

there is hypoxaemia disproportionate to the

ascites, due to systemic and splanchnic

apparent severity of the lung disease. The

vasodilatation, and renal vasoconstriction,

abnormal shunting may be detected by

leading to multiorgan (including lung)

contrast echocardiography (peripheral

failure. There are two types of HPS. Type 1

injection of saline containing microbubbles,

presents as acute renal failure, type 2 as

which rapidly appear in the left atrium); a

reduced glomerular filtration rate and

perfusion scan, which will show

refractory ascites. Pulmonary oedema may

accumulation of technetium that has

be exacerbated by hypoalbuminaemia and

bypassed the lungs in the brain and kidneys,

cirrhotic cardiomyopathy, the latter of which

and can be used to quantify shunt; and

is characterised by diastolic dysfunction.

contrast HRCT. Technetium scanning may

Treatment of these serious complications

be the most sensitive test. Contrast

should be in a specialist liver unit. Another

echocardiography may be positive even in

indirect mechanism of lung disease is

nonhypoxaemic liver disease, suggesting

pulmonary compression by a hugely

that subclinical HPS is common. Treatment

involved liver and spleen; partial and total

is of the underlying liver disease, if this is

excision of a huge spleen has been reported

susceptible to medical management, which

in CF with at least transient benefit. Finally,

may resolve HPS. Nonspecific measures

there may be dilation of bronchial veins in

include supplemental oxygen but the child is

children with portal hypertension, similar to

likely eventually to undergo liver

oesophageal varices. If there is haemoptysis

transplantation due to rapidly progressive

as well as haematemesis complicating

hypoxaemia. Hypoxaemia related to

portal hypertension, bronchial embolisation

pulmonary angiogenesis (see earlier) may

may be considered as well as variceal

not respond to liver transplantation. The

banding.

rare cases with large shunts may benefit

Lung manifestations of kidney disease

from coil embolisation. Medical

management is anecdotal; for example, case

Diseases affecting the kidney and the lungs

series of the use of methylene blue and

The more important of these are

antibiotics. Untreated the prognosis is poor

summarised in table 2.

(23% 5-year survival versus 69% in patients

matched for severity of liver disease but

Effects of renal dysfunction on the lung

without HPS).

Pulmonary oedema and pleural effusion are

the most common pulmonary

Pulmonary hypertension is covered in more

manifestations of renal disease. ‘‘Uraemic

detail in the section on Pulmonary vascular

lung’’, manifested by pulmonary oedema, is

diseases; it is far less common than HPS and,

multifactorial in origin and is not a simple

rarely, features of both may co-exist.

transudate. Aetiological factors in a given

Presentation is as with primary pulmonary

individual may include fluid overload,

hypertension. The reasons why some patients

hypoproteinaemia, myocardial dysfunction

develop HPS while others develop severe

and increased pulmonary capillary

pulmonary hypertension are not known.

permeability. Pleural effusion is also

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Diseases affecting the kidney and lung

Disease

Kidney manifestations

Lung manifestations

Acute and chronic renal failure

Chronic infection and

Renal stones

inflammation

Renal amyloid

Pneumothorax

Haemoptysis

Allergic bronchopulmonary

aspergillosis

Ciliopathy

Cystic kidney disease

Recurrent infections

Nephronophthisis

Bronchiectasis

Renal dysplasia

Chest wall deformity (Jeune’s

and other syndromes)

Wilm’s tumour

Renal mass

Pulmonary metastases

Pulmonary embolism

Tuberose sclerosis

Angiolipoma

Lymphangioleiomyomatosis

Renal cystic disease

Renal carcinoma

Goodpasture’s syndrome

Glomerulonephritis

Pulmonary haemorrhage

Renal failure

Granulomatosis with

Glomerulonephritis

Pulmonary haemorrhage

polyangiitis (Wegener’s)

Renal failure

(Upper airway disease)

SLE

Glomerulonephritis

Interstitial lung disease

Renal failure

Pleuritis and pleural effusion

Acute pneumonitis

Pulmonary haemorrhage and

increased risk of infection

Henoch-Schönlein purpura

Glomerulonephritis

Pulmonary haemorrhage

Renal failure

Scleroderma

Renal failure

Pulmonary fibrosis

Aspiration

Pulmonary vasculopathy and

pulmonary hypertension

Glomerulonephritis

Nephrotic syndrome

Pulmonary embolism

(especially membranous)

Potter’s syndrome

Renal agenesis

Pulmonary hypoplasia

multifactorial, including fluid overload and

index of suspicion should be maintained

uraemic pleuritis.

because presentation may be atypical.

Other indirect effects include opportunistic

Side-effects of medications used to treat

infection secondary to immune suppression,

renal disease may affect the lung, including

urinothorax secondary to obstructive

iatrogenic immunosuppression, the

uropathy, respiratory muscle dysfunction,

consequences of plasmapheresis, and

and dystrophic calcification secondary to

medications used to treat hypertension,

chronic acidosis and abnormal calcium and

including angiotensin-converting enzyme

phosphate homeostasis. Calcification is

(ACE) inhibitors causing chronic cough.

frequently an asymptomatic finding.

Immunosuppression leads to a higher than

Haemodialysis complications include the

expected prevalence of TB, for which a high

potential for silicone emboli and activation

ERS Handbook: Paediatric Respiratory Medicine

639

of the complement cascade and other

Primary respiratory disease may have a

immunological issues of dialysis

cardiovascular presentation; for example,

membranes causing hypoxaemia.

apparent dilated cardiomyopathy may be a

Hypoventilation secondary to carbon dioxide

presentation of OSA, and ‘‘primary pulmonary

loss across the dialysis membrane may

hypertension with a normal chest radiograph’’

contribute to hypoxaemia. Peritoneal

may be the presentation of OSA, interstitial

dialysis may cause pleural effusions if there

lung disease and pulmonary embolism.

are diaphragmatic defects. The volumes of

fluid used for peritoneal dialysis have little

The child in a paediatric intensive care unit

(PICU) after cardiac surgery presents

acute effect on lung function.

particular challenges to the paediatric

Lung manifestations of cardiac disease

pulmonologist. Respiratory failure and acute

respiratory distress syndrome (ARDS) are

Respiratory paediatricians inevitably interact

well-described complications of

with paediatric cardiologists and, often, the

cardiopulmonary bypass, and activation of

debate is whether respiratory issues are

complement and other immunological

primary or secondary to heart disease. In my

cascades by the membrane oxygenator is

experience, the clinical scenario ‘‘the child

thought to be responsible. Ventilator-

has a respiratory problem and it’s not the

acquired pneumonia is an important

heart’’ is usually resolved when it is

complication of especially prolonged

discovered that it is the heart.

ventilation and must be distinguished from

other causes of new infiltrates, such as

Diseases affecting the heart and the lungs The

more important of these are summarised in

atelectasis and pulmonary oedema. Another

common referral is the ventilated child who

table 3.

weans to minimal support but then fails

Effects of cardiac dysfunction on the lung

extubation. Significant pulmonary

Respiratory diseases may be the first

parenchymal disease is excluded by a low

presentation of an underlying cardiovascular

oxygen requirement. The differential

abnormality. Steroid-resistant asthma may

diagnosis lies between upper airway

be the presentation of a vascular ring or

obstruction (usually subglottic stenosis or

pulmonary artery sling; the latter may also

vocal cord paralysis secondary to recurrent

be associated with complete cartilage rings,

laryngeal nerve damage) and respiratory

complicating assessment. Diagnosis of

muscle disease (usually due to phrenic

vascular compression is with contrast-

nerve damage, occasionally an intensive

enhanced CT or MRI. ‘‘Exercise-induced

care unit myopathy). If upper airway

asthma’’ in young adults who have had

obstruction is suspected, bronchoscopy

ligation of the arterial duct as part of the

should be performed with the child being

management of lung disease of prematurity

extubated for the purpose, under a formal

may, in fact, be a late complication of

general anaesthetic. Another common

recurrent laryngeal nerve damage. The

referral is a unilateral, post-cardiac surgical

breathless child may have pulmonary

whiteout. Fluid (pleural effusion, chylothorax

oedema secondary to a hitherto

or haemothorax) is excluded with thoracic

unsuspected congenital cardiac lesion

ultrasound. The differential diagnosis then

(pulmonary venous hypertension or high

lies between extrinsic compression of the

pulmonary blood flow due to left-to-right

airway by an enlarged cardiac chamber,

shunting), or a congenital or acquired

surgically placed shunt or great vessel,

cardiomyopathy. Enlarged cardiac chambers

airway malacia (which is relatively common

secondary to these conditions may cause

in cardiac patients), and airway plugging by

airway compression and localised

mucus or a blood clot. A particularly difficult

atelectasis or pneumonia. Recurrent

issue to deal with is the airway compression

multifocal consolidation may be the

by the hugely enlarged pulmonary arteries

presentation of increased pulmonary blood

seen in absent pulmonary valve syndrome,

flow due to left-to-right shunts.

usually associated with tetralogy of Fallot.

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ERS Handbook: Paediatric Respiratory Medicine

Table 3. Diseases affecting the heart and lung

Disease

Cardiac manifestations

Lung manifestations

Down syndrome

Congenital heart disease

Gastro-oesophageal reflux

Incoordinate swallowing

OSA

VATER, VACTER, and

Congenital heart disease,

Tracheo-oesophageal fistula

VACTERL syndromes

especially ventricular and atrial

Vertebral abnormalities

septal defects

leading to scoliosis

Tetralogy of Fallot

William’s and Noonan’s

Aortic and pulmonary stenosis

Pulmonary lymphangiectasia

syndromes

Cardiomyopathy

Chest wall deformity

Ciliopathy

Complex congenital heart

Recurrent infections

disease, especially with

Bronchiectasis

heterotaxic syndromes

Chest wall deformity (Jeune’s

and other syndromes)

Pericardial effusion

Ghon focus

Constrictive pericarditis

Pleural effusion

Lung cavities and fibrosis

Sarcoidosis

Cardiomyopathy

Lung granulomas

Arrhythmia

Pulmonary fibrosis

Neurological disease

Cardiomyopathy

Inspiratory and expiratory

muscle dysfunction

Incoordinate swallowing

Upper airway obstruction

Impaired function and

Chronic infection and

tamponade due to air leaks

inflammation

Pneumothorax

Haemoptysis

Allergic bronchopulmonary

aspergillosis

Mucopolysaccharidoses

Cardiomyopathy

Upper airway obstruction

Restrictive lung disease

Chest wall deformity

Recurrent respiratory

infections

SLE

Myocarditis

Interstitial lung disease

Pericarditis

Pleuritis and pleural effusion

Endocarditis

Acute pneumonitis

Pulmonary haemorrhage

Increased risk of infection

Scleroderma

Cardiomyopathy

Pulmonary fibrosis

Aspiration

Pulmonary vasculopathy

Pulmonary hypertension

VATER: vertebral anomalies, anal atresia, tracheo-oesophageal fistula, renal and/or radial anomalies; VACTER:

vertebral anomalies, anal atresia, cardiovascular anomalies, tracheo-oesophageal fistula, renal and/or radial

anomalies; VACTERL: vertebral anomalies, anal atresia, cardiovascular anomalies, tracheo-oesophageal

fistula, renal and/or radial anomalies, and limb defects.

ERS Handbook: Paediatric Respiratory Medicine

641

Very rarely, a pneumonia involving all lobes

gastro-oesophageal reflux disease and CF,

of the lung is the cause of a complete

which are discussed in detail elsewhere.

whiteout; in such cases, the child is

Inflammatory bowel disease Pulmonary

obviously septic.

manifestations are rare. In ulcerative colitis,

Further reading

tis: new insights and a classification

Al-Hussaini A, et al. (2010). Long-term

scheme. Paediatr Respir Rev; 6: 292-300.

outcome and management of hepatopul-

Maldonado F, et al. (2009). Yellow nail

monary syndrome in children. Pediatr

syndrome. Curr Op Pulm Med;

15:

Transplant; 14: 276-282.

371-375.

ERS Handbook: Paediatric Respiratory Medicine

645

Miller AC, et al.

(2012). Pulmonary

Sari S, et al.

(2012). Hepatopulmonary

complications of sickle cell disease. Am

syndrome in children with cirrhotic and

J Respir Crit Care Med; 185: 1154-1165.

non-cirrhotic portal hypertension: a

Milliner DS, et al.

(1990). Soft tissue

single-center experience. Dig Des Sci; 57:

calcification in pediatric patients with end-

175-181.

stage renal disease. Kidney Int; 38: 931-936.

Torok KS (2012). Pediatric scleroderma:

O’Sullivan PP (2012). Pulmonary compli-

systemic or localised forms. Pediatr Clin

cations of systemic vasculitides. Paediatr

North Am; 59: 381-405.

Respir Rev; 13: 37-43.

Turcios NL (2012). Pulmonary complica-

Rabinovitch CE (2012). Pulmonary com-

tions of renal disease. Paediatr Respir Rev;

plications of childhood rheumatic dis-

13: 44-49.

ease. Paediatr Respir Rev; 13: 29-36.

Von Vigier RO, et al. (2000). Pulmonary

Rodriguez-Roisin R, et al.

(2004).

renal syndrome in childhood: a report of

Pulmonary hepatic vascular disorders

twenty-one cases and a review of the

(PHD). Eur Respir J; 24: 861-880.

literature. Pediatr Pulmonol; 29: 382-388.

646

ERS Handbook: Paediatric Respiratory Medicine

Lung transplantation and

management of post-lung

transplant patients

Paul Robinson and Paul Aurora

Lung transplantation is now a well-

Key points

established treatment for children with

end-stage lung disease, with .120

Short- and long-term outcomes have

paediatric lung transplantations now

improved but still lag behind other

performed worldwide each year, across

solid-organ transplant groups.

40-50 centres (Benden et al., 2012).

Chronic graft rejection remains a

The majority of centres (.80%) perform

significant barrier to further

fewer than five transplantations a year,

improvements in survival.

with only two or three centres performing

.10 procedures each year .

Donor organ shortage remains a

Infant lung transplantation has been

critical issue. Given this limited

established at centres in North America

resource, optimal timing of

but this remains a small proportion of

transplantation is both essential and

total paediatric transplantations (only

challenging, especially in conditions

eight performed in 2010).

where survival can be difficult to

Procedures performed have changed:

predict.

bilateral single sequential lung

A lifelong regimen of triple

transplantation now is preferred to

immunosuppression is used,

heart-lung transplantation, with the

consisting of a CNI, a cell cycle

latter reserved mainly for cases with

inhibitor (or antimetabolite) and a

significant left heart dysfunction (e.g.

corticosteroid. Important drug

idiopathic pulmonary arterial

interactions exist with CNIs which the

hypertension (IPAH) and congenital

physician must be aware of.

heart disease).

Post-transplantation management

Single-lung transplantation is rarely

focuses on ongoing rehabilitation,

performed in the paediatric age range,

careful surveillance, and treatment of

mainly reflecting its contraindication in

acute and chronic complications,

suppurative lung disease, such as CF.

including infection and graft rejection.

Indications for lung transplantation

The most common indication for lung

transplantation in the paediatric age range

Selection for lung transplantation

is CF, although the indications are age

dependent (table 1). CF is the most

Current international guidelines for referral

common indication from school age,

and selection of lung transplant recipients

whereas in younger children, other

(Orens et al., 2006) are based upon limited

pathologies such as IPAH, congenital heart

paediatric data and the decision to list a

disease, idiopathic pulmonary fibrosis and

child for lung transplant is often based on a

surfactant protein dysfunction are the

multidisciplinary team consensus within the

indications.

individual centre. Potential survival and

ERS Handbook: Paediatric Respiratory Medicine

647

N No specific contraindications (table 2).

Table 1. Common indications for lung transplantation

Relative contraindications are assessed

by age group

on a case-by-case basis.

Indication

Cases %

An acceptable psychological profile.

Infancy (age ,1 year)

N Fully informed commitment by the child

Surfactant protein B deficiency

and family. This includes good social

support to aid rehabilitation following

Congenital heart disease

transplantation surgery and a

IPAH

commitment to the procedure involved,

Preschool (age 1-5 years)

the required lifestyle adjustments and

strict adherence to the medication

IPAH

regimen.

Idiopathic pulmonary fibrosis

Bronchiolitis obliterans

Life expectancy criteria also account for the

probable waiting period for a suitable organ

Early school age (6-11 years)

to become available and may vary

depending on the centre. Existing survival

IPAH

prediction models for CF are only

estimations and have limitations: changing

Bronchiolitis obliterans

CF survival rates over time, lack of

Adolescence (12-17 years)

paediatric-specific validation and lack of

validation in children being assessed for

IPAH

transplantation. The referral criterion of

FEV1 ,30% predicted is widely quoted but

Bronchiolitis obliterans

important exceptions, where referral should

Data from Benden et al. (2012).

be considered at higher FEV1 due to an

increased risk of accelerated future decline,

exist:

quality of life (QoL) benefits are offset

against an individual’s risk of perioperative

N females;

mortality and both short- and long-term

N very young patients;

complications of transplantation. Early

N subjects declining quickly;

referral is preferable, as late referral

N subjects with a history of massive

potentially affects not only the ability of the

haemoptysis, pneumothorax or

family to make a carefully considered

increasing acute exacerbation frequency.

decision about whether they want a

transplant, but also because poor clinical

Donor allocation

status may adversely affect suitability for

listing. Lung transplantation is indicated in

N Standard donor criteria exist but have

children where lung function parameters

been criticised for being too restrictive.

and QoL are declining despite maximal

Only 20-30% of lungs offered for

medical therapy (Aurora, 2004). Broad

use in organ transplantation are

criteria for listing are as follows.

usable.

‘‘Marginal donors’’ are considered but

N Predicted life expectancy, without

only used with informed consent from the

transplantation, of f2 years.

recipient and family.

N Poor QoL, which is likely to be improved

N Organs procured from brain-dead

by transplantation. Assessment of QoL is

donors, the use of non-heart beating

taken ideally from the child’s perspective,

donors (used in other solid-organ

and details their ability to complete daily

transplant groups successfully) and ex

routine activities, participate in school

vivo lung perfusion attempt to address

and social activities, and the time spent

this imbalance, with encouraging results

in hospital.

(Cypel et al., 2012).

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ERS Handbook: Paediatric Respiratory Medicine

Table 2. Specific contraindications to lung transplantation in children

Absolute

Relative

Active malignancy

Pan-resistant bacterial infection

Active TB

Nontuberculous mycobacterial infection

Major psychiatric illness

Other organ failure

Hepatic, renal and left ventricular failure^#

HIV infection

Irreversible and significant respiratory muscle

Nonadherence to treatment

dysfunction

Invasive ventilation

Long-term high-dose steroid therapy

Hepatitis B or C

Burkholderia cenocepacia (genomovar III)

Severe scoliosis or thoracic rib cage deformity

Severe tracheomegaly and/or tracheomalacia

Severe transpleural systemic to bronchial artery

collateral arteries

Contraindications vary between transplant centres and the referring physician should always check with their

own centre.^#: multiorgan transplantation (e.g. lung-liver, heart-lung or lung-kidney) may be considered in

this situation.

N Living-related lobar lung transplantation

oxygenation, is controversial and not

has decreased in recent years, in part due

universally adopted. Despite demonstrated

to the potential 300% mortality risk.

feasibility in paediatric patients (Schmidt

N The lung allocation score (LAS) allocates

et al., 2012), post-transplantation

organs to recipients based on calculated

outcomes remain inferior. The projected

survival benefit but is not appropriate for

timeframe of bridging until suitable donor

use in children due to a lack of paediatric

organ availability is an unknown

data. Paediatric allocation is based upon

factor.

donor-recipient blood group

compatibility, size matching and the

The early post-transplant period is

current clinical conditions of individual

characterised by establishment of effective

waiting list patients at that centre.

immunosuppression (started immediately

prior to surgery), minimisation of infection

Management following referral

risk, rehabilitation, and protection of both

the newly implanted donor organ and other

Changes in clinical status during the pre-

important organ systems.

transplant period may affect suitability,

necessitating regular review. Optimisation

A lifelong regimen of triple

of current management during the pre-

immunosuppression is used, consisting of

transplantation period is an essential

the following.

component of managing future

transplantation risk. This includes:

N A calcineurin inhibitor (CNI), most

commonly Tacrolimus. CNIs act by

N maintaining good nutrition and bone

binding to calcineurin in the cytoplasm

density;

and interfere with the transcription of

N optimising anti-infective and anti-

important cytokine genes, thereby

inflammatory therapies;

inhibiting T-cell stimulation. Tacrolimus

N screening for and treatment of associated

is favoured over cyclosporin in paediatric

respiratory failure with NIV.

centres due to its more favourable side-

The use of more invasive ‘‘bridging’’

effect profile, aiding compliance (less

measures to transplantation, such as

hirsuitism and gingivism, but a greater

ventilation and extracorporeal membrane

incidence of diabetes).

ERS Handbook: Paediatric Respiratory Medicine

649

N A cell cycle inhibitor (or antimetabolite),

CMV-negative recipient) or medium risk

most commonly mycophenolate mofetil.

(donor and recipient both CMV positive);

Cell cycle inhibitors inhibit the

and valaciclovir in those at increased

proliferation of T- and B-cells by

risk of herpes simplex virus (HSV)

interrupting DNA, RNA and purine

re-activation.

synthesis.

N Prophylaxis against Pneumocystis jirovecii:

N Corticosteroids: initially high-dose

co-trimoxazole.

methylprednisolone, subsequently

Ventilation is weaned as rapidly as can be

weaned to oral prednisolone.

tolerated, with extubation often occurring

Many centres further augment this with

within the first 24 hours. Inotropic support

‘‘induction therapy’’ at the time of

may be brief, particularly if transplantation

transplantation, namely a monoclonal

occurs on cardiopulmonary bypass. A

antibody such as basiliximab or daclizumab,

relative hypovolaemia strategy protects the

which bind irreversibly to T-cell interleukin

lung from ischaemia-reperfusion injury and

(IL)-2 receptors. Increasing levels of

pulmonary oedema.

immunosuppression must be balanced

Primary graft failure:

against increased risk of severe infection or

later malignancy (e.g. Epstein-Barr virus

N occurs in ,10% and resembles the

(EBV)-driven post-transplant

clinical appearance of acute respiratory

lymphoproliferative disease (PTLD)).

distress syndrome (ARDS);

Anti-infective prophylaxis starts with

N is a risk with marginal donors and longer

attempts to minimise bacterial load prior to

graft ischaemia times (.6 h);

transplantation, and extends through

N is managed supportively.

stringent surgical aseptic techniques and, in

In CF subjects, regular aperients (e.g.

some cases, thoracic cavity washout with

lactulose, N-acetylcysteine and magrocol)

weak antibiotic solutions prior to organ

and early introduction of enteral feeds are

implantation. Other aspects after lung

used to prevent distal ileal obstruction

transplantation include the following.

syndrome (DIOS), which may occur in 10%.

Intravenous antibiotics based on the

Physical mobilisation following chest drain

sensitivities of organisms present before

removal aids respiratory secretion clearance

transplantation, especially in CF, are

in conjunction with regular chest

given until the patient is mobilising and

physiotherapy. The typical in-patient stay in

able to clear secretions. Nebulised

uncomplicated cases is 64 weeks.

antibiotics are often continued for a

Ongoing management

prolonged period if the recipient lungs

are chronically infected with Pseudomonas

Management focuses on ongoing

aeruginosa before transplantation, as it is

rehabilitation, and surveillance for and

assumed that the sinuses will remain

treatment of acute complications, including

chronically infected.

infection and graft rejection, and education

Antifungal prophylaxis in children with CF

regarding transplant-orientated medication

and others in whom pre-transplantation

and follow-up regimens.

fungal colonisation is suspected: oral

nystatin during the first 6-12 months; and

N Careful surveillance and monitoring of

either oral itraconazole or voriconazole,

both immunosuppression (using

or nebulised amphotericin for

tacrolimus trough levels) and graft

o6 months.

function (using daily home spirometry)

Antiviral prophylaxis in patients at

aims to maintain adequate

increased risk: prophylactic valganciclovir

immunosuppression and protect the

in those at high risk for cytomegalovirus

graft from both immune and nonimmune

(CMV) disease reactivation (transplant

insults to prevent rejection (both cellular

from a CMV-positive donor to a

and antibody-mediated).

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ERS Handbook: Paediatric Respiratory Medicine

Bronchoscopy and transbronchial biopsy

N Adopting a strict routine of drug timing,

is performed in almost all transplant

administration and compliance is a key

recipients, across centres, at defined

element to better outcomes.

surveillance points during the first year

Graft rejection The clinical picture of early

following transplantation and additionally

acute rejection is nonspecific and may be

as clinically indicated, based on

difficult to distinguish from infection. As a

respiratory symptom monitoring and

result, periods of coughing, malaise, low-

daily home spirometry readings, with

grade pyrexia or a minor drop in lung

drops of .10% triggering urgent clinical

function should be thoroughly evaluated (De

review.

Vito Dabbs et al., 2004).

CNIs operate within a narrow therapeutic

window, which gradually shifts to lower

N Chest radiography may be normal and

targeted trough levels during the first year

does not distinguish the two pathologies.

before plateauing at a suitable level

N Urgent flexible bronchoscopy,

dictated by the relative balance of

bronchoalveolar lavage and

episodes of rejection, infection and CNI

transbronchial biopsy are indicated.

side-effects.

Minimising the risk of infection and other

The presence and severity of rejection in

unwanted side-effects of

biopsy specimens is classified on the

immunosuppressive therapy (in

presence of perivascular and interstitial

particular renal dysfunction).

mononuclear cell infiltrates in alveolar tissue

Specific drug-related side-effects and

(from grade A0, for no acute rejection, to

medication interactions must be

grade A4, for severe rejection), with an

monitored for and considered (tables 3

additional classification for associated

and 4).

airway inflammation (from B0, for no airway

Table 3. Common side-effects of maintenance immunosuppression

Drug

Side-effect

Tacrolimus

Nephrotoxicity

Tremor

Paraesthesia/hypersensitivity

Hypertension

Hypercholesterolaemia

Neurotoxicity

Diabetes mellitus

Alopecia

MMF

Bone marrow suppression

Nausea, dyspepsia, diarrhoea, constipation

Hyperglycaemia

Hypercholesterolaemia

Prednisolone

Cushing’s syndrome

Dyspepsia

Peptic ulceration

Osteoporosis

Proximal myopathy

Increased appetite

Neuropsychiatric effects

Glaucoma, papilloedema, cataracts

Skin atrophy, striae, bruising, acne

MMF: mycophenolate mofetil.

ERS Handbook: Paediatric Respiratory Medicine

651

Table 4. Agents interacting with CNIs

CYP3A inhibitors (increase CNI levels)

CYP3A inducers

(decrease CNI levels)

Antibiotics

Erythromycin

Rifampicin

Clarithromycin

Clindamycin

Chloramphenicol

Ethambutol

Ciprofloxacin (rare)

Antifungals

Caspofungin

Itraconazole

Antiepileptics

Fluconazole

Phenytoin

Voriconazole

Phenobarbitone

Imidazoles (e.g. ketoconazole)

Carbamazepine

Triazoles (e.g. posaconazole)

Others

Cardiovascular drugs

Cigarette smoking

Amiodarone

St John’s wort

Calcium channel blockers (e.g. verapamil, diltiazem, felodipine)

Nifedipine (rare)

Gastrointestinal

Cimetidine

Omeprazole (rare)

Other

Grapefruit juice

Antiretrovirals (e.g. atazanavir, nelfinavir and ritonavir)

Danazol

This is not intended to be an exhaustive list. CYP: cytochrome P450.

inflammation, to B4, for severe airway

N Many centres use specific therapies like

inflammation).

ribavirin for proven cases of lower

respiratory tract infection (LRTI) with

N The clinical relevance of A1 rejection is

respiratory syncytial virus (RSV) and

unclear, although frequent A1 episodes

paramyxoviruses (e.g. parainfluenza and

have been linked to a greater risk of

human metapneumovirus).

chronic graft rejection in adults (Benden

N The role of viral infections in acute and

et al., 2010; Hopkins et al., 2004). At

chronic refection remains more

present, A1 is not usually treated.

controversial (Vu et al., 2011; Liu et al.,

N More severe episodes (A2-A4) are

2009), and is particularly relevant in

managed with a 3-day course of high-

children given the increased frequency,

dose methylprednisolone (typically

particularly in the infant-preschool age

10 mg?kg^-1?day^-1), though some centres

range. Day-care is discouraged,

will occasionally treat A2 rejection with

compliance with active immunisation is

oral corticosteroids.

critical and prophylactic palivizumab may

N Steroid-resistant rejection is exceptionally

be considered in infants.

rare, although true cases may require

second-line therapy such as polyclonal

The histological diagnosis of chronic

anti-lymphocyte antibodies (anti-

rejection (or bronchiolitis obliterans) is

thymocyte globulin).

challenging due to the patchy distribution of

N The clinical relevance of airway

disease; therefore, a clinical diagnosis based

inflammation and optimal method of

on the pattern of lung function seen following

treatment remains unclear.

transplantation has been developed, termed

N Patients with positive bacterial or fungal

‘‘bronchiolitis obliterans syndrome’’ (BOS)

cultures should be treated.

(table 5) (Estenne et al., 2002).

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ERS Handbook: Paediatric Respiratory Medicine

Table 5. Grading of BOS

Grade

Definition

BOS 0

FEV1 .90% of baseline and FEF25-75% .75% of baseline

BOS 0-p

FEV1 81-90% of baseline and/or FEF25-75% f75% of baseline

BOS 1

FEV1 66-80% of baseline

BOS 2

FEV1 51-65% of baseline

BOS 3

FEV1 f50% of baseline

Baseline lung function is defined as the average of the two highest values achieved after transplantation,

recorded o3 weeks apart. FEF25-75%: forced expiratory flow at 25-75% of FVC. Reproduced and modified from

Estenne et al. (2002) with permission from the publisher.

BOS is defined by an irreversible fall in

spirometry and CT data suggest the lungs

lung function when other causes have

continue to grow with age (Cohen et al.,

been excluded, such as infection.

1999).

Important potential contributing factors

Complications A variety of noninfectious

include gastro-oesophageal reflux disease

complications may be encountered

(GORD) or airway infection (e.g. RSV or

subsequent to lung transplantation

Pseudomonas), and should be treated

(table 6).

aggressively to reverse this dysfunction.

GORD is common in transplant

Early surgical complications, beyond the

recipients (Benden et al., 2005), and

immediate post-transplantation period,

emerging data in adults appear to

include:

support early surveillance and

fundoplication, although equivalent

N bronchial anastomosis stenosis,

paediatric data are lacking.

managed with balloon dilatation with or

Low-dose macrolide therapy appears to

without laser treatment (repeated as

be beneficial in those with neutrophilic

necessary);

inflammation.

N damage to the phrenic nerve affecting

In general, advanced BOS is poorly

diaphragmatic function;

responsive to therapy and interventions

N damage to the vagus nerve causing

aim to stabilise and prevent ongoing lung

delayed gastric emptying.

function decline. Other BOS therapeutic

Common later complications include the

options include leukotriene receptor

following.

antagonists, augmentation of

immunosuppression, total body

N Hypertension, ,70% at 5 years; typically

lymphoid irradiation or photopheresis.

managed with calcium channel blockers

Retransplantation is offered in some

such as amlodipine.

centres but the risks are often increased

N BOS, ,50% at 5 years.

due to previous thoracotomy, making

N Diabetes mellitus, approximately one-

explantation more challenging, and the

third at 5 years; corticosteroids and CNIs

increased prevalence of other

are major risk factors.

complications such as renal dysfunction.

N CNI-induced nephropathy, approximately

Graft monitoring by spirometry is

one-third at 5 years; due to the prevalence

challenging in the preschool age range due

of renal dysfunction in survivors,

to the cooperation and coordination

exposure to other agents associated with

required. Modification of reported indices

potential renal toxicity are minimised or

may be required (e.g. FEV0.75 rather than

avoided (e.g. nonsteroidal anti-

FEV1). The use of age-appropriate reference

inflammatory drugs (NSAIDs),

equations is essential, and longitudinal

amphotericin and aminoglycosides).

ERS Handbook: Paediatric Respiratory Medicine

653

Table 6. Common noninfectious complications after lung transplantation

Time

Complication

Early

Anastomotic dehiscence or stenosis

Pulmonary vein or artery stenosis

Nerve damage (phrenic or vagal nerve injury, loss of cough reflex,

swallowing difficulty)

Intermediate and late

Malignancy (e.g. lymphoproliferative disease)

Nephrotoxicity

Hypertension

Hyperlipidaemia

Osteopenia and osteoporosis

Avascular necrosis of the femoral head

Growth failure

Diabetes mellitus

Hyperuricaemia/gout

Viral papillomatosis

Cytopaenias (anaemia, leukopaenia, thrombocytopaenia)

Thromboembolism

GORD

N Increased malignancy risk due to ongoing

around the world. Long-term outcomes are

immunosuppression, with PTLD

steadily improving for paediatric patients but

(typically EBV-driven B-cell expansion)

have yet to reach those achieved by other

and skin cancers being the most relevant

solid-organ transplants. There are many

to the paediatric population; advice about

similarities in management between adult and

sunlight exposure is important.

paediatric subjects but several differences

N CF children continue to be at risk of

unique to the paediatric age range exist.

nonrespiratory complications of their

Future work to improve the availability and

underlying disease (e.g. DIOS,

allocation of suitable organs will hopefully see

malabsorption and bone disease).

this therapeutic option offered to a greater

proportion of children who are eligible.

Long-term outcomes

Median survival after lung transplantation is

Further reading

now ,5 years, and is identical in children and

adults. Better survival of recipients aged 1-

Aurora P (2004). When should children

11 years is seen compared with those aged 12-

be referred for lung or heart-lung trans-

17 years (Benden et al., 2012). The onset of

plantation? Pediatr Pulmonol Suppl; 26:

puberty and adolescence brings with it several

116-118.

challenges, including risk-taking behaviour

Benden C, et al. (2005). High prevalence of

and noncompliance, with adverse effects on

gastroesophageal reflux in children after

post-transplantation outcomes. While there is

lung transplantation. Pediatr Pulmonol; 40:

little evidence of how best to manage this,

68-71.

Benden C, et al. (2010). Minimal acute

most centres encourage adolescents to take

rejection in pediatric lung transplantation

increasing responsibility for their own care,

- does it matter? Pediatr Transplant; 14:

maintain adherence to therapy, and develop

534-539.

long-term goals and ambitions.

Benden C, et al. (2012). The registry of the

Conclusion

international society for heart and lung

transplantation: fifteenth pediatric lung

Lung transplantation is now an established,

and heart-lung transplantation report-2012.

accepted treatment option for children with

J Heart Lung Transplant; 31: 1087-1095.

end-stage lung disease at many centres

654

ERS Handbook: Paediatric Respiratory Medicine

Cohen AH, et al. (1999). Growth of lungs

Kirk R, et al. (2011). Fourteenth Pediatric

after transplantation in infants and in

Heart Transplantation Report - 2011. J

children younger than 3 years of age. Am J

Heart Lung Transplant; 30: 1095-1103.

Respir Crit Care Med; 159: 1747-1751.

Liu M, et al. (2009). Respiratory viral infec-

Cypel M, et al. (2012). Experience with the

tions within one year after pediatric lung

first 50 ex vivo lung perfusions in clinical

transplant. Transpl Infect Dis; 11: 304-312.

transplantation. J Thorac Cardiovas Surg;

Orens JB, et al. (2006). International guide-

144: 1200-1207.

lines for the selection of lung transplant

De Vito Dabbs A, et al.

(2004). Are

candidates: 2006 update - a consensus

symptom reports useful for differentiat-

report from the Pulmonary Scientific

ing between acute rejection and pulmon-

Council of the International Society for

ary infection after lung transplantation?

Heart and Lung Transplantation. J Heart

Heart Lung; 33: 372-380.

Lung Transplant; 25: 745-755.

Estenne M, et al. (2002). Bronchiolitis

Schmidt F, et al.

(2012). Concept of

obliterans syndrome 2001: an update of

‘‘awake venovenous extracorporeal mem-

the diagnostic criteria. J Heart Lung

brane oxygenation’’ in pediatric patients

Transplant; 21: 297-310.

awaiting lung transplantation. Pediatr

Hopkins PM, et al. (2004). Association of

Transplant; 17: 224-230.

minimal rejection in lung transplant

Vu DL, et al. (2011). Respiratory viruses in

recipients with obliterative bronchiolitis.

lung transplant recipients: a critical

Am J Respir Crit Care Med; 170: 1022-

review and pooled analysis of clinical

1026.

studies. Am J Transplant; 11: 1071-1078.

ERS Handbook: Paediatric Respiratory Medicine

655

Rehabilitation programmes

and nutritional management

Andreas Jung

Targets of rehabilitation programmes in

Key points

childhood and adolescence

Rehabilitation programmes in children

Pulmonary rehabilitation is defined as ‘‘an

and adolescents with chronic respiratory

evidence-based multidisciplinary and

disorders:

comprehensive intervention for patients

with chronic respiratory diseases who are

aim at preventing worsening of the

symptomatic and often have decreased daily

disease, improving self-management

life activities. Integrated into the

and restoring quality of life in order to

individualised treatment of the patient,

enable full participation in daily life,

pulmonary rehabilitation is designed to

including school, and social and

reduce symptoms, optimise functional

physical activities,

status, increase participation, and reduce

health care costs through stabilising or

consist of standardised

reversing systemic manifestations of the

multidisciplinary interventions,

disease’’ (Nici et al., 2006). Rehabilitation

include diagnostic procedures,

programmes in children and adolescents

specific medical care and nursing,

target preventive measures, which aim to

nutritional and psychological

stop the disease worsening, improve self-

counselling and educational

management and restore quality of life. It is

interventions,

anticipated that the child, or the adolescent,

will be able to fully participate in daily life,

address a broad spectrum of chronic

such as school, social activities and sports,

respiratory conditions and can

in the same ways as their healthy peers.

contribute efficiently to a general

Today, rehabilitation programmes have been

improvement in morbidity and

developed in many countries in inpatient

mortality, in the context of a complex

and outpatient settings. Inpatient

disease management.

programmes are often more standardised

Advanced lung disease results in

than outpatient programmes, as the latter

increased energy expenditure, an

are often tailored to meet local needs. In

augmented level of inflammation and

addition, inpatient programmes provide the

diminished appetite, contributing to a

possibility of individual, daily monitoring of

loss of body weight and requiring

patients over several weeks in specific

specific nutritional management,

institutions in order to optimise therapeutic

including counselling, installation of a

interventions and complete diagnostic

daily nutrition plan, high-protein

procedures that are beyond the possibilities

calorie supplementation and

of an outpatient setting. Independent of the

substitution of vitamins and

rehabilitation setting, objectives of current

micronutrients.

rehabilitation programmes include a

number of specific considerations, as shown

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ERS Handbook: Paediatric Respiratory Medicine

in table 1. Rehabilitation centres and

A multidisciplinary team closely follows each

sponsors of healthcare systems have

patient or family during the whole

defined criteria for the eligibility of an

interventional period. This approach

individual intending to participate in a

facilitates an individual treatment in the

rehabilitation programme (table 2). If the

context of an often group-based

criteria of the rehabilitation institution, the

rehabilitation programme. As patients can

patient and their family are met, the most

be monitored intensively over a longer

important preconditions for successful

period of time, individual symptoms and

pulmonary rehabilitation are given.

risk factors, as well as psychological aspects,

can be evaluated continuously and, as a

Elements of paediatric rehabilitation

result, specific diagnostic procedures can be

programmes for respiratory diseases

applied. In the same way, treatment

modifications can be carried out and the

Pulmonary rehabilitation programmes

subsequent course of the disease can be

consist of standardised, multidisciplinary

observed over time.

interventions performed by a range of highly

qualified health professionals. Depending

Patient education: a core element of

on the disease spectrum and the severity

rehabilitation programmes

addressed by rehabilitation centres,

Educational programmes are important

potentially essential components include a

components of contemporary rehabilitation

wide range of actions, such as diagnostic

programmes, featuring theoretical

procedures, specific medical care,

instructions accompanied by practical

educational interventions and a

exercises. Knowledge is disseminated to

multidisciplinary team approach (table 3).

promote disease understanding, and

Standardised care may also include

recognition of individual risk-factors and

consultation of specific medical

coping strategies. Practical training is

professionals in case of multi-organ or

provided to improve medication application

psychiatric symptoms and diseases. In

skills and techniques. Written action plans

inpatient programmes, children and

foster the adherence to the individual

adolescents often participate in educational

treatment strategy. As a result, compliance,

preschool or school activities for the

self-management and outcome of the

duration of the hospitalisation period. Some

disease are often significantly increased.

rehabilitation centres offer a family-oriented

intervention and treat parents and other

Educational programmes for children and

family members together with their children.

adolescents have been developed for various

diseases in many countries. In the

respiratory field, the most wide-spread and

Table 1. Goals of pulmonary rehabilitation programmes

in children and adolescents

best standardised protocols exist for

asthma. Asthma education programmes

Maintenance and restoration of social and

have often been developed independently of

professional activities

pulmonary rehabilitation programmes and

Improvement of health condition

are often performed in an outpatient setting.

Preventive measures of disease worsening

Inpatient rehabilitation programmes have

or progression

integrated sections or whole protocols of

national or regional asthma education

Amendment of disease perception and

programmes, resulting in standardised en

management

bloc interventions.

Improvement of compliance

Disease-specific rehabilitation programmes

Restoration of quality of life

Change of lifestyle

A vast spectrum of chronic respiratory

conditions are addressed by paediatric

Reproduced from Jung et al. (2012) with

rehabilitation programmes, including

permission from the publisher.

asthma, CF, bronchopulmonary dysplasia,

ERS Handbook: Paediatric Respiratory Medicine

657

Table 2. General criteria for children and adolescents to participate in rehabilitation programmes

Ability for rehabilitation is fulfilled: willingness to actively participate in the programme, capacity

to fulfil rehabilitation aims and ability to integrate into groups

Improvement of prognosis can be achieved: improvement of health and restoration of

professional and/or social activity

Measures of outpatient care are exhausted but not sufficient to adequately ameliorate health or

suspend health impairment

Secondary health damage is imminent or has already occurred

Psychosomatic or psychosocial problems are difficult to address in an outpatient setting

(demarcation from the social environment)

Interventions to promote coping and to adhere to treatment are necessary

Reproduced from Jung et al. (2012) with permission from the publisher.

primary ciliary dyskinesia, neuromuscular

N increase a child’s locus of control,

disorders, interstitial lung diseases,

N improve self-efficacy and attitude to

cardiovascular diseases and pre- and post-

disease,

lung transplantation. A recent joint

N improve asthma-related behaviour and

statement of the American Thoracic Society

pulmonary function measures,

and the European Respiratory Society on

N improve metered-dose inhaler technique.

pulmonary rehabilitation highlights the huge

progress that has been made in evidence-

Furthermore, asthma camps decrease

based support for pulmonary rehabilitation

anxiety, symptoms, exacerbations, school

in the management of patients with chronic

absences, emergency department visits and

respiratory disease, focusing on adults with

hospitalisations. Although asthma camps

COPD. Similarly, there is a growing body of

also exist in Europe, standardised inpatient

evidence that rehabilitation programmes for

asthma rehabilitation programmes in

chronic respiratory diseases in the paediatric

specialised hospitals are predominant.

population are efficient in terms of health

Nevertheless, the literature on protocols and

improvement. Most published studies

outcome of the intervention is relatively

investigated protocols and outcome in

limited. Studies found significant

patients with asthma and CF, as these

improvements in pulmonary function and

disorders constitute the majority of

bronchial inflammation, as well as a

indications for pulmonary rehabilitation in

decrease in days absent from school and in

the first two decades of life. In future,

visits to a physician, supporting the

structured interventions before and after

importance of multidisciplinary

lung transplantation will become more and

rehabilitation programmes for disease

more important in light of a growing

management and compliance modification.

number of patients on the transplantation

Long-term effects following an inpatient

waiting list, as well as a rapidly increasing

intervention in terms of better lung function

number of transplanted individuals.

parameters, less asthma-related school

absence, and improved asthma

Asthma In the USA, asthma camps often

management and quality of life compared to

focus on health education and interaction

an outpatient reference group have been

with peers. Despite the fact that asthma

documented.

camps cannot replace specific rehabilitation

programmes, there is evidence that these

Several studies have implicated lifestyle

interventions can:

changes, specifically decreased physical

activity, as a contributor to the increase in

N improve the parent’s and child’s

asthma prevalence and severity. Moreover,

knowledge of asthma,

the capacity for asthmatic subjects to

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ERS Handbook: Paediatric Respiratory Medicine

Table 3. Essential components of a comprehensive paediatric pulmonary rehabilitation programme

Respiratory diagnostics including body plethysmography

Comprehensive allergy testing including provocation tests

Routine laboratory including blood gas analysis

(Chest) radiograph

Disease-specific nursing

Separation of patients according to microbiological profile

Monitoring of vital parameters and possibility of oxygen application

Physiotherapy

Physical exercise training and sports therapy

Occupational therapy

Nutritional intervention and advice by a dietician

Psychological counselling and family support

Standardised specific education in disease understanding and management

Advice in matters of financial, educational and occupational aspects

Reproduced from Jung et al. (2012) with permission from the publisher.

exercise safely and to significantly improve

therefore, exceed the general requirements

their cardiovascular fitness and quality of life

of pulmonary rehabilitation programmes.

has been demonstrated. From this

Physiotherapists, sports therapists,

perspective it seems logical to subject

psychologists, dieticians, diabetologists,

asthmatic patients to exercise training to

gastroenterologists, pulmonologists and

increase fitness and strength. Indeed, many

other healthcare specialists need to work

rehabilitation centres focus on exercise

closely together in a multidisciplinary

interventions with remarkable success on

setting. If this aspect is properly addressed,

quality of life and exercise capacity, leading

rehabilitation programmes are likely to

to the assumption that exercise training

significantly ameliorate the short- and long-

should be part of all asthma rehabilitation

term quality of life of affected individuals

programmes.

and improve symptom score, pulmonary

function, grade of inflammation and weight.

Cystic fibrosis During the past decades the

Exercise and endurance training results in

fear of cross-infection, especially for

significant improvements in exercise

Pseudomonas aeruginosa, has determined the

tolerance, aerobic fitness, peak work

evolution of rehabilitation programmes for

capacity, strength, coordination and

CF patients. To date, rigorous hygiene

ventilation parameters. Moreover, clinical

standards addressing disinfection and

experience demonstrates a remarkable

segregation (spatial and temporal) are a

improvement in treatment adherence after

widely accepted prerequisite to qualify

rehabilitation as a result of educational

centres for inpatient CF rehabilitation

activities, possibly leading to longer periods

programmes. Still, in the view of potential

of mild symptoms and prolonging the time

cross-infections, close contact between the

between intravenous antibiotic cycles, thus

CF centres and the rehabilitation clinics is

demonstrating the importance of such

advisable to foster mutual trust, minimise

programmes in CF care.

risk for the patient and optimise intervention

outcome. To achieve this goal, structured

Pre- and post-lung transplantation Published

interventions need to take into account all

data on protocols and outcome of

aspects of CF multi-organ disease and,

rehabilitation programmes for patients with

ERS Handbook: Paediatric Respiratory Medicine

659

chronic lung diseases pre- and post-lung

literature in this field focuses on the

transplantation are largely lacking. However,

pancreatic insufficient type of CF. However,

with the increasing number of paediatric

advanced lung disease in many other

and adult transplanted patients, specific

conditions can lead to an enhanced calorie

rehabilitation programmes will have to be

need and, subsequently, to a decreased

established. The majority of the transplanted

BMI. This process is often a result of

paediatric population consists of patients

increased energy expenditure due to

with CF, followed by pulmonary fibrosis.

respiratory work, as well as of a general

Rehabilitation programmes for severely

augmented level of inflammation and/or

affected individuals clearly exceed the

regular use of systemic corticosteroids.

general requirements for pulmonary

Diminished appetite and a consequently

rehabilitation. Next to medical experience

decreased energy intake might contribute to

and know-how, specific psychological and

a loss of body weight. If weight gain cannot

educational conditions have to be provided

be achieved by regular nutrition,

by the rehabilitation centre. Access to acute

coordinated actions need to be

interventions and intensive care units

implemented to improve the patient’s

should be available, as well as an emergency

condition. These potentially include

laboratory and advanced respiratory

intensive counselling by a dietician,

diagnostics, such as bronchoscopy.

installation of a daily nutrition plan,

prescription of high-protein calorie

Major objectives for programmes pre-

supplementation or substitution of vitamins

transplantation are the stabilisation of

and micronutrients. In case of progressive

general and pulmonary health in

weight loss or failure to regain weight over a

conjunction with psychological priming with

longer period of time, insertion of a

respect to the intervention. The effect of

percutaneous, gastrointestinal tube and

rehabilitation for adults awaiting lung

subsequent additional feeding might

transplantation has been demonstrated by a

become indispensable. The specific

significant increase in physical efficiency and

nutritional management of CF patients with

endurance.

pancreatic insufficiency leading to

malnutrition, which includes regular

Rehabilitation programmes following lung

counselling by a nutritionist, oral

transplantation have to consider various

substitution of pancreatic enzymes and fat-

complex aspects, from education in

soluble vitamins, and high-protein calorie

adherence to treatment to early recognition

supplementation, is discussed elsewhere in

of organ rejection and, at the same time,

this Handbook.

promoting physical fitness to prepare the

individual for re-entry into the social

When respiratory disease leads to general

community, including school or workplace.

inactivity, uncontrolled weight gain and

Next to inpatient interventions, protocols for

obesity can result. Prevention of becoming

outpatient rehabilitation programmes have

overweight is, therefore, an important

been established, with reported success in

element of the management of chronic

terms of patient satisfaction. Nevertheless,

respiratory disorders such as asthma. As

both inpatient and outpatient interventions

well as encouraging patients to exercise

need to be scientifically evaluated and better

regularly and supporting their sportive

standardised in future to meet the

ambitions, it is crucial to provide individuals

complexity of the requirements of paediatric

and their families with specific education on

transplant rehabilitation programmes and to

the prevention of and behaviour in

improve their outcome.

emergency situations. This includes

Nutritional management In many chronic

knowledge about individual risk factors,

respiratory disorders, nutritional

awareness of the available rescue

interventions are mandatory to improve

medication and an action plan, which the

respiratory function and ameliorate disease

patient needs to follow in the case of severe

symptoms and outcome, although available

respiratory symptoms. The goal is to foster

660

ERS Handbook: Paediatric Respiratory Medicine

trust of the patient and the families in their

Coffman JM, et al.

(2008). Effects of

self-management skills and in the

asthma education on children’s use of

implemented treatment strategies in order

acute care services: a meta-analysis.

to overcome the fear of respiratory

Pediatrics; 121: 575-586.

symptoms in situations of increased

Jung A, et al. (2012). Inpatient paediatric

physical activity. At the same time,

rehabilitation in chronic respiratory dis-

orders. Paediatr Respir Rev; 13: 123-129.

nutritional education should be

Moeller A, et al. (2010). Effects of a short-

implemented to support the efforts of

term rehabilitation program on airway

physical activity, especially when excess

inflammation in children with cystic

weight is already an issue and weight

fibrosis. Pediatr Pulmonol; 45: 541-551.

reduction is desired. This might include

Nesvold JH, et al. (2006). Assessing the

shopping and cooking guidance, education

value of children’s asthma camps. J

in nutritional components and meal plans,

Asthma; 43: 273-277.

and even in offering temporary household

Nici L, et al. (2006). American Thoracic

support, where available.

Society/European Respiratory Society

Statement on Pulmonary Rehabilitation.

In situations where increased physical

Am J Respir Crit Care Med; 173: 1390-1413.

activity is not or is hardly possible, such as

Poustie VJ, et al.

(2000). Oral protein

neuromuscular disorders, optimisation of

calorie supplementation for children with

the nutritional management by the families

chronic disease. Cochrane Database Syst

is of general importance, especially because

Rev; 3: CD001914.

many parents tend to allow their sick or

Scaparrotta A, et al.

(2012). Growth

disabled children any desired foods that are

failure in children with cystic fibrosis. J

Pediatr Endocrinol Metab; 25: 393-405.

high in carbohydrates as comfort. Empathic

Schmitz TG, et al. (2006). The effect of

nutritional guidance, e.g. by a dietician, can

inpatient rehabilitation programmes on

often strengthen awareness of the families

quality of life in patients with cystic

of a more reasonable food composition, and

fibrosis: a multi-center study. Health

must include regular and thorough diet

Qual Life Outcomes; 4: 8.

education and advice.

Smith JR, et al.

(2005). A systematic

review to examine the impact of psychoe-

ducational interventions on health out-

Further reading

comes and costs in adults and children

Abrams SA (2001). Chronic pulmonary

with difficult asthma. Health Technol

insufficiency in children and its effects on

Assess 9: iii-iv, 1-167.

growth and development. J Nutr;

131:

Spindler T (2010). Was kann und muss

938S-941S.

eine Rehabilitation bei Kindern und

Basaran S, et al.

(2006). Effects of

Jugendlichen mit schweren Atemwegserk-

physical exercise on quality of life, exer-

rankungen leisten? Kinder-und Jugendarzt;

cise capacity and pulmonary function in

41: 28-32.

children with asthma. Rehabil Med; 38:

Stachow R, et al.

(2006). Medication

130-135.

behaviour of children and adolescents

Bauer CP, et al. (2002). Long-term effect

with asthma before and after inpatient

of indoor rehabilitation on children and

rehabilitation

- a multicenter study.

young people with moderate and severe

Rehabilitation; 45: 18-26.

asthma. Pneumologie; 56: 478-485.

Van Doorn N (2010). Exercise programs

Burton JH, et al. (2009). Rehabilitation

for children with cystic fibrosis: a sys-

and transition after lung transplantation

tematic review of randomized controlled

in children. Transplant Proc; 41: 296-299.

trials. Disabil Rehabil; 32: 41-49.

ERS Handbook: Paediatric Respiratory Medicine

661

Prevention of indoor and

outdoor pollution

Giuliana Ferrante, Velia Malizia, Roberta Antona and Stefania La Grutta

Asthma is a multifactorial disease affected by

biological, environmental and social factors.

Key points

Consequently, reducing asthma morbidity

requires management that addresses the

N Environmental triggers, such as in-

several contributing factors and not only the

and outdoor allergens and irritants,

clinical aspects. It is well known that

can elicit and exacerbate acute attacks

environmental triggers, such as in- and

in asthmatic children.

outdoor allergens and irritants, can elicit and

N Children are particularly susceptible to

exacerbate acute attacks in asthmatic

air pollution because of their higher

children. Many studies have demonstrated

ventilation rate, with an increased risk

the effectiveness of environmental trigger

of medication use and hospitalisation.

reduction in lowering the burden of the

disease at the individual level (table 1).

N Interventions must be addressed to

multiple triggers through multiple

Today, children spend most of the day in

intervention components.

indoor environments. The most common

N Simple measures (mattress covers,

indoor allergens and irritants are dust mites,

HEPA filters, air filtration, home repairs,

pets, mould and environmental tobacco

and limiting levels of exertion in

smoke (ETS) (Crocker et al., 2011).

outdoor activities when pollutant

Dust mites

concentrations are elevated) may

protect children’s respiratory health,

House dust mite (HDM) is considered one of

reducing asthma symptom-days, school

the most common indoor allergens and the

days missed and healthcare utilisation.

main trigger for allergic asthma. Dust mites are

prevalent in rural and in tropical areas

of the studies (sample size, multiple

compared to urban centres and areas with a

sensitisation and exposures) (Rao et al., 2011).

temperate climate. Temperatures ranging

between 15uC and 30uC and relative humidity of

Pets

60-80% represent the ideal parameters for

their development and survival. The home

Cat and dog dander are well-known asthma

represents an optimal environment for dust

triggers in sensitised individuals. In

mites as it is a source of food with good

particular, Fel d 1, the major cat allergen, is

microclimate conditions (Brunetto et al.,

widespread in homes as well as in public

2009). Easy measures are suggested to reduce

places (schools). There is conflicting

the risk of mite exposure (allergen-

evidence whether pet elimination prevents

impermeable pillow and mattress covers;

childhood asthma development. The current

washing bedding in hot water; removing

standard of care, including pet removal in

carpet, upholstered furniture and stuffed toys;

patients with a proven allergy, is reported to

and reducing humidity levels to ,60%), but

reduce the need for medication, even if the

evidence of a reduction in asthma morbidity is

efficacy of this recommendation is still

controversial, mainly due to the inhomogeneity

unclear (Rao et al., 2011).

662

ERS Handbook: Paediatric Respiratory Medicine

Table 1. Essential measures to reduce the exposure to main in- and outdoor allergens and pollutants

Allergen/pollutant

Measures to reduce exposure

Comments

HDM

Allergen-impermeable pillow and

Evidence is controversial

mattress covers

Washing bedding in hot water

Removing carpet, upholstered furniture

and stuffed toys

Reducing humidity levels to ,60%

Fel d 1

Pet removal in patients with a proven

Cat owners may diffuse cat

allergy

allergen through their clothes,

making it ubiquitous

Mould

Removing mould from surfaces

Reduction in emergency

Discarding mould-contaminated

department visits and

materials

hospitalisation after home

Addressing the source of moisture

renovations

responsible for mould growth

ETS

Counselling to encourage parents to quit

Ineffectiveness of most of the

smoking

intervention studies in lowering

Use of HEPA air cleaners

ETS exposure in children

Outdoor

Limiting level of exertion in outdoor

Decreasing levels of PM10 were

pollutants (PM,

activities when pollutants concentrations

associated with reduced

NO_x, VOCs,

are elevated

prevalence of respiratory

ozone)

Breathing through the nose, at rest or at

symptoms in children

low level of exertion

Exercising early in the morning, when air

pollution levels are lower

Indoor pollutants

HEPA filters

Interventions to address multiple

(PM, NO_x, VOCs)

Air filtration/ventilation

triggers through multiple

Home repair

interventions are suggested

Mould

smoking cessation and use of high-

efficiency particulate air (HEPA) air cleaners

Early exposure to mould or damp is strongly

to lower airborne particles in the air

related to asthma in children and

(Crocker et al., 2011). The education of

adolescents. Mould remediation includes

children with asthma, including avoidance

removing mould from surfaces, discarding

of asthma triggers, showed an association

mould-contaminated materials and

between ETS exposure reduction and fewer

addressing the source of moisture

episodes of poorer asthma control,

responsible for mould growth (Crocker et al.,

respiratory-related emergency department

2011). A study reported an important

visits and hospitalisations (Gerald, 2009).

reduction in emergency department visits

A recent Cochrane review showed the

and hospitalisation after home renovations

ineffectiveness of most of the intervention

such as leak repair, removal of water-

studies in lowering ETS exposure in

damaged materials and improvements of

children (Priest et al., 2008). Finally, ETS

damp basements (Rao et al., 2011).

should be an integral part of the standard

environmental assessment, education

ETS and exposure to air pollutants

and evaluation components in home-

Interventions to reduce ETS exposure focus

based environmental interventions (Crocker

on counselling to encourage parental

et al., 2011).

ERS Handbook: Paediatric Respiratory Medicine

663

Children are more susceptible to air

Further reading

pollution because of their higher relative

Brunetto B, et al. (2009). Differences in

ventilation, with an increased risk of

the presence of allergens among several

medication use and hospitalisation

types of indoor environments. Ann Ist

(Laumbach, 2010). Exposure to outdoor air

Super Sanità; 4: 409-414.

pollution has been associated with

Clark NM

(2012). Community-based

respiratory outcomes in children. Asthmatic

approaches

to controlling childhood

people are considered to be especially

asthma. Ann Rev Public Health; 33: 193-208.

vulnerable because outdoor pollutants, such

Crocker DD, et al. (2011). Effectiveness of

as particulate matter, nitrogen oxides (NO_x),

home-based, multi-trigger, multicompo-

volatile organic compounds (VOCs) and

nent interventions with an environmental

ozone, can trigger exacerbations. Recently, it

focus for reducing asthma morbidity. A

has been demonstrated that decreasing

community guide systematic review. Am J

Prev Med; 41: S5-S32.

levels of particulate matter ,10 mm in

Gerald LB, et al.

(2009). Changes in

diameter (PM10) were associated with

environmental tobacco smoke exposure

reduced prevalence of respiratory symptoms

and asthma morbidity among urban

in children. Simple recommendations to

school children. Chest; 135: 911-991.

reduce exposure and prevent health effects

Gilliland FD (2009). Outdoor air pollu-

might be to: avoid heavy traffic areas, if

tion, genetic susceptibility, and asthma

possible; spend less time outdoors and limit

management: opportunities for interven-

level of exertion in outdoor activities when

tion to reduce the burden of asthma.

pollutants concentrations are elevated;

Pediatrics; 123: S168-S173.

breathe through the nose at rest or at low

Priest N, et al. (2008). Family and carer

levels of exertion to reduce the amount of

smoking control programmes for redu-

pollutants reaching the lung; and exercise

cing children’s exposure to environmen-

early in the morning, when air pollution

tal tobacco smoke. Cochrane Database

levels are lower (Laumbach, 2010).

Syst Rev; 4: CD001746.

Laumbach RJ (2010). Outdoor air pollu-

Interventions aimed at limiting exposure to

tants and patient’s health. Am Fam

indoor pollutants may be more easily

Physician; 81: 175-180.

applicable, less costly and more effective in

Rao D, et al. (2011). Impact of environ-

mental controls on childhood asthma.

reducing respiratory health outcomes.

Curr Allergy Asthma Rep; 11: 414-420.

Recent studies suggest that interventions

Rosen LJ, et al. (2012). Parental smoking

that address a single trigger may not be as

cessation to protect young children: a

effective as those that address multiple

systematic review and meta-analysis.

triggers through multiple intervention

Pediatrics; 129: 141-152.

components (Crocker et al., 2011). Since

Sauni R, et al. (2011). Remediating build-

single preventive measures are seldom

ings damaged by dampness and mould

effective, comprehensive strategies

for preventing or reducing respiratory tract

combining the most appropriate measures

symptoms, infections and asthma.

are recommended. In fact, a large number

Cochrane Database Syst Rev; 9: CD007897.

of environmental variables can affect the

Sublett JL (2011). Effectiveness of air filters

patterns of exposure as well as

and air cleaners in allergic respiratory

sensitisation, development of symptoms

diseases: a review of the recent literature.

and exacerbations. Even if attempting to

Curr Allergy Asthma Rep; 11: 395-402.

Sundell J, et al. (2011). Ventilation rates

control every possible kind of exposure may

and health: multidisciplinary review of the

be difficult, simple measures (mattress

scientific literature. Indoor Air; 21: 191-204.

covers, HEPA filters, air filtration and home

USEnvironmentalProtectionAgency.Asthma

repairs) may protect children’s respiratory

home environmental checklist. www.epa.gov/

health, reducing asthma symptom-days,

asthma/pdfs/home_environment_checklist.

school days missed and healthcare

pdf

utilisation.

664

ERS Handbook: Paediatric Respiratory Medicine

Respiratory physiotherapy

Beatrice Oberwaldner

Paediatric respiratory physiotherapy has

some origins in the attempt to clear

Key points

tenacious secretions from the airways of

children with CF by simple mechanical

Paediatric respiratory physiotherapy

means. From this starting point, it has

has developed into a wide field,

developed into a broad spectrum of

encompassing airway clearance,

techniques and a wide field of therapeutic

rehabilitation, aerosol treatment,

approaches to various disease entities and

tracheostomy management and long-

patients. It should, therefore, be understood

term home ventilation programmes.

as a rapidly developing area of knowledge-

Paediatric respiratory physiotherapy is

and skill-based competencies with

a special therapeutic approach to

considerable potential for further growth.

respiratory disorders in newborns,

Most of these competencies have been

infants, children and adolescents. As

developed at the bedside by trial and error,

such it needs a profound

but more recently there has been interest in

understanding of the structure and

establishing a scientific basis for paediatric

the function of the growing respiratory

respiratory physiotherapy and to understand

tract and the necessary competencies

how these mechanical interventions work.

required for working with paediatric

Aims and general principles

patients.

An individualised approach to the

Aims vary with the patients treated and

treatment of a specific patient is

pathophysiology encountered. However,

preferable to any kind of rigid

there are a few general principles that

therapeutic routine.

constitute the basis of every therapeutic

approach. A detailed knowledge of the

Airway clearance employs basic

structure and function of the immature and

mechanisms like expiratory airflow,

growing respiratory tract of the premature,

forced expiration and gas-liquid

newborn, infant, toddler, schoolchild and

pumping. It might, therefore, be

adolescent are fundamental. Based on a

considered as a therapeutic

careful analysis of prevailing

application of respiratory physiology.

pathophysiology, as derived from history,

clinical investigation, imaging, lung function

testing and other relevant investigations, a

predominant principle when planning

therapeutic goal and a treatment plan

treatment. In situations where cooperation

should be defined for any individual patient.

of the patient is required, an age-dependent

An individualised approach to the patient is

psychological approach is a prerequisite.

preferable to any kind of routine that uses

Furthermore, involving parents and

standardised techniques for the

caregivers in the therapeutic management is

management of certain disease entities.

essential for young patients, but also helps

Depending on the vulnerability of the

to provide a supportive environment for

patient, avoiding unwanted side-effects is a

older ones.

ERS Handbook: Paediatric Respiratory Medicine

665

Airway clearance therapy

autogenic drainage, PEP therapy, oscillating

PEP, hi-PEP and various combinations of

Aims Airway clearance therapy (ACT) aims at

these. They are of special interest for

preventing, treating or alleviating the

patients with bronchiectasis-effected airway

mechanical (atelectasis, local hyperinflation,

wall instability, where a subtle balance

ventilation/perfusion imbalance and

between sustained expiratory airflow and

increased work of breathing) and biochemical

moderate airway compression is found on

(increased proteolytic stress on the airway

one side and the avoidance of compression-

walls, local proliferation of infectious agents

effected airway closure on the other.

and mechanisms) consequences of

intrabronchial retention of secretions.

Mechanisms The physiology of cough, which

Sometimes ACT also has diagnostic aims,

mobilises and transports secretions, serves

such as the need for bacteriological analysis

as a model for all these techniques.

of mucus from the lower airways.

Expiratory airflow transports material

towards the airway opening; its effectiveness

Techniques One can distinguish between

depends on airflow velocity, bronchial

therapist-applied and self-applied

calibre and viscoelasticity of secretions. The

techniques.

physiology of a forced expiration combines

Therapist-applied techniques: Chest-clapping,

expiratory airflow with the upstream

vibration and compression, all in

migration of bronchial choke-points, thereby

combination with assisted coughing, are

catching material in a stenosis through

traditional therapeutic approaches that are

which it is blown downstream. In the airway

still valid for uncooperative patients such as

periphery, where airflow is almost negligible,

newborns and infants, as well as the

gas-liquid pumping takes over for

unconscious. Suction techniques for

mobilising secretions. This incompletely

patients with and without an artificial airway

understood mechanism is based on

remove secretions that have been mobilised

breathing-effected lung volume changes,

and transported by the former interventions.

mixing secretions and air. All these key

Lung volume management (manual

mechanisms, in combination with posture-

hyperinflation/bagging and CPAP) is a

effected redistribution of ventilation, are

complementary approach for patients

modified and combined in different ways in

unable to inspire sufficiently to bring air

the various techniques mentioned above.

behind the obstructing secretions.

Physical exercise and sports often contain

Positioning effects redistribution of

some of these key mechanisms; in

ventilation; by locally changing lung

particular, exercise-induced hyperventilation

distension and ventilator excursions, it may

may effect significant gas-liquid pumping.

serve as a means to target gas-liquid

Consequently, physical activity must be seen

pumping and opening airways. For patients

as a complementary means for ACT and

who require ACT in the long term, parents

thus should constitute an important

and other caregivers are trained in these

element in the long-term management of

techniques by the therapist.

patients with bronchiectasis.

Some techniques, originally developed for

Patients and disease entities Patients with

self-application, can also be used by

bronchiectasis (CF, primary ciliary

therapists, such as assisted autogenic

dyskinesia and localised bronchiectasis)

drainage and positive expiratory pressure

require ACT in the long term. In any kind of

(PEP) techniques, for infants and severely ill

atelectasis that is caused by airway

and weak patients.

occlusion (after removal of a foreign body or

Self-applied techniques: These are taught to

mucoid impaction), therapeutic ACT is

cooperating patients who require ACT

indicated. Due to an immature respiratory

regularly over several months and years.

tract with a very special physiology, the term

Several techniques have been developed,

newborn, and especially the preterm

e.g. the active cycle of breathing techniques,

newborn, is particularly prone to airway

666

ERS Handbook: Paediatric Respiratory Medicine

obstruction by mucus impaction and other

capacity, and a gain in muscle strength and

respiratory complications. This highly

motor skills, as well as more effective ACT

vulnerable patient group requires

are important components. Clearly the

specialised therapeutic approaches in order

medical management of these patients

to achieve the desired therapeutic effects

must be optimised in order to provide a

with a minimum of risk. Paediatric patients

solid basis for any rehabilitation effort.

undergoing thoracic surgery are also prone

to airway occlusion and therefore often need

Rehabilitation is an option for all paediatric

ACT post-operatively. The special group of

patients with chronic respiratory disorders,

children with neuromuscular disorders

malformations or severe respiratory

suffer from an unstable chest in

complications and side-effects from other

combination with small breathing

disorders and/or treatments.

excursions and a weak cough and, therefore,

Aerosol therapy

require long-term support from paediatric

respiratory physiotherapy.

Aims Aerosol therapy is a targeted approach

to the inner surface of the respiratory tract

Rehabilitation

and thereby offers itself as a means to

Aims Rehabilitation aims at preventing and

deliver medication topically. In contrast to

alleviating disease-inflicted disabilities that

this simple and convincing principle, the

interfere with the age-specific activities of

technical details of aerosol therapy are

childhood and adolescence. Paediatric

complex and complicated. Paediatric

respiratory physiotherapists, by their

expertise in working with children of all ages,

competence in working with the breathing

may design, organise and conduct

patterns of their patients, may serve as

rehabilitation programmes.

teachers and trainers, thereby providing the

necessary quality assurance. The aim is to

Techniques, mechanisms and patients

provide optimised aerosol therapy to the

Endurance training has been proven to be a

individual patient.

valuable component of rehabilitation for

patients with chronic respiratory disorders.

Techniques, mechanisms and patients

Strength training may prevent disease-

Depending on the disorder, disease

inflicted abnormalities of posture, thoracic

situation, prevailing pathophysiology, age

mobility, breathing excursions and body

and psychosocial profile of the child,

image. Breathing exercises and respiratory

nebulisers and metered-dose inhalers with

muscle training may be desirable additions

or without spacers, as well as powder

in special cases.

inhalers may be the ideal choice. Interfaces

(masks and mouthpieces) are dependent on

It is of note that the effective application of

age and cooperation. The required breathing

these principles in paediatric patients

manoeuvres have to be demonstrated,

requires an age-specific approach, which

taught and optimised. Patients with an

considers the special characteristics of

artificial airway require specific approaches.

children such as shorter attention span and

enjoyment of games/playing, as well as a

The paediatric asthma spectrum is a wide

general tendency towards increased mobility.

field for aerosol therapy, but, beyond that, all

Programmes designed for adults may work in

other respiratory disorders may also require

adolescents but are rarely suitable for younger

aerosol medication either intermittently or

children. In these, fun group activities and

in the long term.

competitions are more important than strict

adherence to formal training plans.

Management of the technology-dependent

child

The effective mechanisms for the

rehabilitation of paediatric patients with

Aims The long-term management of children

chronic respiratory disorders are complex.

with a tracheostomy and those on home

Improved aerobic fitness and exercise

ventilation calls for a highly specialised,

ERS Handbook: Paediatric Respiratory Medicine

667

multidisciplinary approach and the paediatric

respiratory physiotherapist, while always

respiratory physiotherapist may be an

considering infection control issues and

important member of this team. Aims range

guidelines. Last but not least, by their

from maintenance of upper airway patency to

familiarity with chronically diseased patients,

the mechanical substitution of inefficient

therapists may grow into the role of a trusted

breathing movements, and in all those cases

confidant of the patient and their family in

successful management is characterised by

various psychosocial situations.

achieving these aims while avoiding

Evidence

tracheostomy- and ventilation-related

complications, as well as respiratory

There is a certain discrepancy between a

inefficiency.

paucity of studies and the wide clinical

application of paediatric respiratory

Techniques, mechanisms and patients The

physiotherapy. Some studies document

respiratory physiotherapist may have a

beneficial effects of ACT techniques in chronic

crucial role in selecting the appropriate

respiratory disorders. Such studies, however,

tracheal cannula, choosing the optimal

are difficult to conduct since outcomes are

home ventilator and interface, training

multifactorial and patients, as well as disease

patients and parents and monitoring the

situations, vary considerably. Studies

entire long-term management.

comparing different ACTs are, at least in part,

The patient spectrum is wide, ranging from

contradictory. Such comparisons are based

children with severe upper airway stenosis and

on the potential misconception that one ACT

infants with bronchopulmonary dysplasia, to

is superior to another; maybe, however, there

children with central hypoventilation

is no ‘‘best technique’’ that is equally effective

syndrome and those with severe and

in all patients. An individualised approach

progressive neuromuscular disease.

employing key components of several

Furthermore, home ventilation is a means to

techniques, skilfully tailored to the prevailing

bridge the time-span to lung transplantation

disease situation, may be superior to any rigid

for patients with end-stage lung disease. All

application of therapeutic protocols. Another

these disease situations require a highly

interesting analytic approach is the attempt to

individualised approach where, again, careful

more profoundly understand the basic

analysis of the prevailing pathophysiology is a

physiologic mechanisms behind various

prerequisite for successful management.

ACTs. This means asking the question ‘‘how’’

paediatric respiratory physiotherapy works.

Other aspects

Today, leading experts consider airway

clearance in paediatric respiratory

Occasionally there are other disease

physiotherapy as a therapeutic application of

situations and problems where the expertise

respiratory physiology.

of the paediatric respiratory physiotherapist

may be of significant benefit for patient and

Organisational aspects

disease management. For patients

undergoing any kind of surgery, the therapist

The role of the paediatric respiratory

may provide valuable help in pre-surgical

physiotherapist in the caregiving team varies

respiratory optimisation, early extubation and

widely across Europe and worldwide

post-operative respiratory care and return to

depending on local traditions, formal

baseline function. In paediatric intensive care

training, specialisation and professional

the therapist may assist in the weaning

expertise, as well as the legal and

process from mechanical ventilation.

administrative background and framework.

Therapists can help in adapting the home

Authorities responsible for hospital structure

environment for long-term ventilation and

and function must provide appropriate

they may also offer home visits in special

professional positions of respiratory

cases. Group events, like training classes and

physiotherapists in caregiving teams, thus

rehabilitation camps, may be planned,

ensuring maximum effectiveness within a

organised and conducted by the paediatric

multidisciplinary care. General training in

668

ERS Handbook: Paediatric Respiratory Medicine

physiotherapy, however, rarely suffices to

McIlwaine M

(2007). Chest physical

provide enough competencies to manage

therapy; breathing techniques and exer-

patients with chronic, complex and severe

cise in children with CF. Paediatr Respir

respiratory disorders. Lack of sufficient

Rev; 8: 8-16.

expertise carries the risk of side-effects and

Oberwaldner B (2000). Physiotherapy for

complications. It follows that specialised

airway clearance in paediatrics. Eur Respir

training is required and should be available

J; 15: 196-204.

across Europe and internationally. At present

Oberwaldner B, et al.

(2006).

this is not the case and different countries

Tracheostomy care in the home.

Paediatr Respir Rev; 7: 185-190.

have different concepts and traditions (or

Pryor JA, et al. (2010). Beyond postural

lack thereof) in their paediatric respiratory

drainage and percussion: airway clear-

physiotherapy training. Scientific medical

ance in people with cystic fibrosis. J Cyst

societies like the European Respiratory

Fibros; 9: 187-192.

Society are called upon to provide trans-

Zach MS, et al. Chest physiotherapy. In:

European harmonisation and

Taussig LM, et al., eds. Pediatric

standardisation of training and standards.

Respiratory Medicine. St. Louis, Mosby

Inc., 1999; pp. 299-311.

Zach MS, et al. Paediatric mucus clear-

Further reading

ance by chest physiotherapy - principles

Lannefors L, et al. (2004). Physiotherapy

and practice. In: Rubin BK, et al., eds.

in infants and young children with cystic

Therapy for Mucus-Clearance Disorders.

fibrosis: current practice and future devel-

Vol.191. New York, Marcel Dekker, Inc.,

opments. J R Soc Med; 97: Suppl. 44, 8-24.

2004; pp. 471-502.

ERS Handbook: Paediatric Respiratory Medicine

669

Fitness-to-fly testing

Mary J. Sharp and Graham L. Hall

Aircraft cabins are pressurised to 1500-

and 6 months of age little is known about

2400 m, resulting in an oxygen tension

oxygen saturation levels during flight.

(PO₂) of 15 kPa (112 mmHg), which is

The normal physiological compensation to

equivalent to an ambient oxygen level of 15-

this hypoxia is an increase in V9E, mostly by

17%. At sea level the alveolar oxygen tension

increasing tidal volume, and a moderate

(PAO₂) is ,98 mmHg while at the maximum

tachycardia. A patient with pulmonary disease

cruising altitude the PAO₂ drops to

may not be able to increase V9E enough to

55 mmHg, which corresponds to an oxygen

compensate for the fall in PAO₂ and their PAO₂

saturation of 90%. In healthy passengers

may end up on the steep part of the oxygen

.6 months of age, SpO₂ declines to 89-94%

dissociation curve resulting in low oxygen

during flight without changes in clinical

saturation. Physiological factors such as lower

status, whereas 35% of healthy ex-preterm

respiratory system compliance, more

infants flying near term exhibit significant

horizontal rib placement, higher airways

desaturation (SpO₂ ,85%). Figure 1 shows

resistance and fewer alveoli in infants and

the SpO₂ for a term and pre-term infant

young children mean they are more at risk

during air travel. In infants between birth

than adults of developing hypoxaemia in

aircraft. In addition, infants are at risk of even

greater hypoxaemia due to fetal haemoglobin,

increased pulmonary vascular reactivity and

Key points

biphasic hypoxic ventilation response.

N Infants and children with chronic lung

The aim of this chapter is to highlight the key

disease are at risk of developing

points for paediatricians and neonatologists

hypoxia and respiratory symptoms

considering the safety of air travel in

during air travel.

newborns and young infants. Readers

seeking more detailed information relating to

N The hypoxia challenge test is the

the broader changes that occur during air

currently recommended tool for the

travel and the most appropriate approach in

identification of at-risk indviduals.

older children are directed to the recent

N The hypoxia challenge test does not

guidelines from the British Thoracic Society

predict the incidence of in-flight

(BTS) on identifying which patients with lung

hypoxia in infants born preterm and

disease are at risk during air travel.

travelling by air at near term.

Methods of pre-flight testing for infants and

The accuracy of the hypoxia challenge

children

test in infants and young children has

The hypoxia challenge test was first reported

not been assessed.

by Gong et al., (1984) and subsequently

Further research into the prediction of

validated in a variety of adult populations

in-flight hypoxia is required in infants

with chronic respiratory disease. The

and young children.

primary aim of the hypoxia challenge test is

to identify patients prior to flight who are at

670

ERS Handbook: Paediatric Respiratory Medicine

100

Ascent commenced

Descent commenced

23:30

00:00

00:30

01:00

01:30

02:00

02:30

100

Ascent commenced

Oxygen commenced Descent commenced

00:30

01:00

01:30

02:00

02:30

03:00

03:30

Flight time

Figure 1. Recording of in-flight SpO₂ in a) a 7 month-old term born infant and b) a 9.6 month-old preterm

infant (corrected post-natal age 27 weeks). The red dotted line indicates a SpO2 of 85%. The term infant

maintained their SpO2 above 90% for the majority of the flight. The SpO2 of the preterm infant decreased

to 85-90% once cruising altitude was reached and remained stable for approximately half of the flight

before decreasing to ,85%. Supplemental oxygen was commenced at this time for the remainder of the

flight. Reproduced from Withers (2011) with permission from the publisher.

risk of significant in-flight respiratory

to predict in-flight hypoxia in children aged

symptoms. During the hypoxia challenge

11-16 years with CF; however, in a larger

test the infant or young child sits on a carers

study of children with CF the hypoxia

lap in a body plethysmograph and 100%

challenge test predicted in-flight hypoxia in

nitrogen is introduced to reduce the

only two out of 10 cases. One study has

inspiratory oxygen fraction (FIO₂) to 14-15%.

reported that the hypoxia challenge test is not

Alternatively, the infant can have a face mask

accurate in ex-preterm infants flying near

placed over their nose and mouth through

term. These studies imply there may be a

which high flow 14% oxygen is administered.

developmental trajectory for the hypoxia

The typical duration of the test is 20 min.

challenge test. In addition, there have been

Oxygen saturations are monitored

no studies between the body box and face

throughout but, unlike in adults, arterial gas

mask technique to compare whether they

samples are not routinely collected and ECGs

give similar results. The cut-off for normal

are not monitored. Nasal cannulas are worn

and abnormal hypoxia challenge test results

so that if SpO₂ decreases supplemental

is also unclear. The BTS guidelines

oxygen can be commenced and titrated to an

recommend that infants ,1 year of age with

appropriate level.

a hypoxia challenge test result of ,85%

Whilst the hypoxia challenge test is a valuable

should fly with supplemental oxygen but in

tool there are a number of unanswered

children .1 year of age the cut-off is 90%.

questions, including how reliable is the test

There are no studies supporting the choice of

in infants and children? A preliminary study

85% or 90% in children .1 year of age. One

reported the hypoxia challenge test was able

study compared hypoxia challenge test cut-off

ERS Handbook: Paediatric Respiratory Medicine

671

levels of 85% and 90% and found that the

to be restricted to those individuals with

90% cut-off in children ,2 years of age did

severe airway obstruction. In infants the

not discriminate between healthy children

primary risk group is those born preterm or

and those with a history of neonatal chronic

with chronic lung disease requiring

lung disease whereas the 85% cut-off did.

supplemental oxygen. While the hypoxia

However, this study did not report whether

challenge test is the currently recommended

the hypoxia challenge test results predicted

tool for the identification of at-risk

in-flight oxygen saturation levels.

indviduals it does not predict the incidence

of in-flight hypoxia in infants born preterm

The European Lung Foundation (www.

and travelling by air near term and its

european-lung-foundation.org) has

accuracy in older infants and young children

developed a database that provides

has not been established.

information facilitating the organisation of

air travel and supplemental oxygen for

respiratory patients and healthcare

Further reading

providers. The most relevant guidelines are

Audley AM, et al. (2010). The European

from the BTS and these are briefly

Lung Foundation database on airlines’

summarised below. Readers are directed to

policies for patients who require oxygen

the guidelines for detailed information.

supplementation during air travel. Prim

Care Respir J; 19: 284.

Healthy term infants should delay air

Buchdahl RM, et al. (2001). Predicting

travel for 7 days after the expected term

hypoxaemia during flights in children

date.

with cystic fibrosis. Thorax; 56: 877-879.

Preterm infants that have not yet reached

Dine CJ, et al. (2008). Hypoxia altitude

their expected date of delivery should fly

simulation test. Chest; 133: 1002-1005.

with supplemental oxygen available,

Gong H Jr, et al. (1984). Hypoxia-altitude

should respiratory symptoms develop.

simulation test. Evaluation of patients

Infants and children receiving

with chronic airway obstruction. Am Rev

supplemental oxygen at the time of air

Respir Dis; 130: 980-986.

travel should have their oxygen flow

Hall GL, et al. (2007). Assessing fitness

doubled.

to fly in young infants and children.

Young infants (,1 year of age) with a

Thorax; 62: 278-279.

Lee AP, et al. (2002). Commercial airline

neonatal lung disease should be referred

travel decreases oxygen saturation in

to a paediatric respiratory physician and a

children. Pediatr Emerg Care; 18: 78-80.

hypoxia challenge test performed.

Martin AC, et al.

(2008). Definition of

Supplemental oxygen should be available

cutoff values for the hypoxia test used for

if the hypoxia challenge test results in a

preflight testing in young children with

SpO₂ ,85% or if SpO₂ is 85-90% and

neonatal chronic lung disease. Chest; 133:

there is physician doubt.

914-919.

Infants and children with recent long-

Oades PJ, et al.

(1994). Prediction of

term oxygen therapy (in the past

hypoxaemia at high altitude in children

6 months) should have a hypoxia

with cystic fibrosis. BMJ; 308: 15-18.

challenge test.

Resnick SM, et al. (2008). The hypoxia

Children with chronic lung disease (such

challenge test does not accurately predict

as CF) with a FEV1 ,50% predicted

hypoxia in flight in ex-preterm neonates.

should have a hypoxia challenge test and

Chest; 133: 1161-1166.

in-flight oxygen should be used if the

Shrikrishna D, et al.

(2011). Managing

hypoxia challenge test result is ,90%.

passengers with stable respiratory disease

planning air travel: British Thoracic Society

In summary, infants and children with

recommendations. Thorax; 66: 831-833.

chronic lung disease are at risk of the

Withers A, et al. (2011). Air travel and the

development of respiratory symptoms and

risks of hypoxia in children. Paediatr

signs, including hypoxia when undertaking

Respir Rev; 12: 271-276.

air travel. In older children the risk appears

672

ERS Handbook: Paediatric Respiratory Medicine

Sports medicine

Giancarlo Tancredi, Giovanna De Castro and Anna Maria Zicari

Definition

When considering sports activity, it is

possible to differentiate between

Sports medicine concerns scientific and

‘‘competitive’’ and ‘‘non-competitive’’ or

medical aspects of physical activity, physical

leisure-time sports. According to a scientific

fitness, and sports performance. The World

statement of the American Heart

Health Organization defines physical activity

Association (2005), a competitive athlete is

as any bodily movement produced by

defined as one who participates in an

skeletal muscles that requires energy

organised team or individual sport that

expenditure and physical fitness as the ability

requires systematic training and regular

to perform muscular work satisfactorily.

competition against others and that places a

high premium on athletic excellence and

achievement.

Key points

Pre-competition medical assessment and

screening is an important part of preventive

A physically active lifestyle including

measures to detect compromising health

sports and supervised conditioning

conditions in competitive athletes. The

programmes provides physiological

physical examination should include, but

improvements in muscle function,

not be limited to, cardiovascular,

cardiopulmonary efficiency, immune

pulmonary, and musculoskeletal

system function, obesity prevention

assessment.

and self-esteem.

Since 1982, Italian law has mandated that

Cardiopulmonary exercise testing

every participant engaged in competitive

provides a global assessment of the

sports must undergo a clinical evaluation to

integrative exercise responses

obtain eligibility. Furthermore, a medical

involving the pulmonary,

history, physical examination, and any

cardiovascular, and skeletal muscle

required additional assessments are

systems.

recommended for all subjects who practice

V9O₂max

reflects the maximal ability of

physical activity.

the body to take in, transport and

Benefits of sports programmes

utilise oxygen and it is the best single

measure of aerobic fitness.

Participation in sports programmes

Exercise prescriptions to improve

provides an opportunity for children to

cardiopulmonary fitness in patients

increase their physical activity and develop

with chronic health diseases are based

physical and social skills.

on the initial level of fitness and

In particular, the American Academy of

include the modalities of physical

Pediatrics recommends that organised

activity as well as the frequency,

sports programmes for pre-adolescents

intensity and duration of the training.

should complement, not replace, the regular

physical activity that is a part of free play,

ERS Handbook: Paediatric Respiratory Medicine

673

child-organised games, recreational sports,

include musculoskeletal injuries, which can

and physical education programmes at

occur from excessive amounts of activity or

school.

sudden beginning of an activity for which

the body is not conditioned. These include

Inactivity is a risk factor for many chronic

muscle tears, acute damage to joints and

diseases such as hypertension, diabetes,

ligaments, fractures, and overuse injuries.

obesity, depression, cancer and cardiovascular

However, many injuries associated with

disease. Conversely, a physically active lifestyle

physical activity may be prevented by

helps to maintain body weight, and leads to

gradually increasing the level of activity and

favourable health habits, such as not smoking

avoiding excessive amounts of activity.

and a healthy diet.

Doping in sports is a big social problem.

The numerous benefits of regular physical

Adolescents employ a wide variety of drugs

activity include physiological improvements

hoping to improve their athletic

in skeletal muscle function,

performance and to look better. Studies

cardiopulmonary efficiency, immune system

report that 3-12% of male adolescents admit

function, obesity prevention, self-esteem

they have used an anabolic-androgenic

and psychological and social conditions. In

steroid.

particular, physical activity may induce

beneficial immune system changes with a

‘‘Female athlete triad’’ is a syndrome

reduction in pro-inflammatory cytokines of

characterised by the presence of disordered

allergic inflammation.

eating, amenorrhoea, and osteopenia or

osteoporosis. The prevalence of this

Risks of physical activity

syndrome is unknown but it will probably

continue to grow because of the increased

The most significant, but extremely rare, risk

number of girls participating in sports such

associated with exercise in youth is a sudden

as cross-country running, gymnastics, and

death event. Among children and

figure skating.

adolescents, cardiovascular causes of death

include hypertrophic cardiomyopathy,

Adolescents engaged in contact sports after

myocarditis, anomalous coronary artery

having infectious mononucleosis are at

anatomy, Marfan syndrome and commotio

potential risk of splenic rupture secondary to

cordis. Exercise-induced arrhythmias - with

abdominal trauma. It is safe to allow these

or without pre-existing anomalies of cardiac

athletes to return to contact sports after a

electrical excitation and repolarisation - may

period ranging from 3-6 months.

also lead to death.

Physical activity in children with chronic

Becker et al. (2004) reported that sudden

pulmonary diseases

fatal asthma can occur in competitive and

Asthma The prevalence of bronchial asthma

recreational athletes during sporting

in children is about 10%, and 40-90% of

activities. These subjects were usually white

these patients have exercise induced asthma

male subjects in the age range of 10-

(EIA), a manifestation that is frequently

20 years, and many of them had mild

undiagnosed. EIA is defined as a condition

asthma. The possible causes of this type of

in which physical activity triggers acute

fatal asthma attack include sudden severe

airway narrowing in people with heightened

asphyxia as well as a reduced

airway reactivity. The exact mechanisms of

chemosensitivity to hypoxia and blunted

how exercise may trigger an asthmatic

perception of dyspnoea by the patient. In

attack in susceptible people are still a matter

this study, only three subjects were reported

of research. It is likely that cytokine release

to be using long-term control medications.

and parasympathetic nerve reflexes

It is essential to ensure that an athlete with

triggered by water and heat loss from the

asthma is receiving proper care and therapy.

respiratory epithelium associated with the

Sports injuries are other common problems

exercise-induced increase in ventilation play

associated with physical activity; they

a key role.

674

ERS Handbook: Paediatric Respiratory Medicine

The diagnosis of EIA is suggested by the

There is good evidence suggesting that

symptoms of cough, wheezing, chest

children with mild-to-moderate CF can

tightness or dyspnoea during or shortly after

benefit in terms of pulmonary function from

exercise, and demonstrated by a decrease of

either an aerobic or resistance training

12-15% in forced expiratory volume in 1 s

programme. Moreover, team sports are

(FEV1). EIA is usually studied with

important for the social integration of any

ergometers such as the treadmill and cycle

child with a chronic disease.

ergometer, or free running. These tests are

complex, expensive or require a large space.

Specific sports such as scuba diving and

The current authors have found that the step

sports at high altitude should be

discouraged for children with CF with

test is a quick, economical, reproducible and

significant air trapping. In both types of

portable alternative procedure for identifying

activity, unfavourable situations can happen

EIA in out-patients and epidemiological

in which oxygen becomes limited and severe

studies.

desaturation can occur over longer time-

Moreover, it is necessary to underline that

periods.

exercise testing is less sensitive but more

Pulmonary barotrauma is relevant in scuba

specific than pharmacological challenges

diving. The lung injury is caused by

(histamine, methacholine) in detecting EIA.

overdistention of alveoli and rupture of

In a systematic review of 16 studies and 516

alveolar walls as a consequence of

subjects, Crosbie (2012) evaluated the effect

expanding gases during ascent.

of physical training in children with asthma.

This review confirms that there is an

Further reading

Janssen I, et al.

(2010). Systematic

review of the health benefits of physical

American College of Sports Medicine.

activity and fitness in school-aged

ACSM’s Guidelines for Exercise Testing

children and youth. Int J Behav Nutr

and Prescription. 9th Edn. Philadelphia,

Phys Act; 7: 40.

Lippincott Williams & Wilkins, 2013.

Longmuir PE, et al. (2013). Promotion of

American Academy of Pediatrics,

physical activity for children and adults

Committee on Sports Medicine and

with congenital heart disease. A Scientific

Fitness and Committee on School

Statement from the American Heart

Health

(2001). Organized Sports for

Association. Circulation; 127: 2147-2159.

Children and Preadolescents. Pediatrics;

Lubrano R, et al.

(2012). Influence of

107: 1459-1462.

physical activity on cardiorespiratory fit-

Becker JM, et al. (2004). Asthma deaths

ness in children after renal transplanta-

during sports: report of a 7-year experi-

tion. Nephrol Dial Transplant;

27:

ence. J Allergy Clin Immunol; 113: 264-267.

1677-1681.

Crosbie A (2012). The effect of physical

Palange P, et al.

(2007). Recom-

training in children with asthma on

mendations on the use of exercise testing

pulmonary function, aerobic capacity

in clinical practice. Eur Respir J;

29:

and health-related quality of life: a sys-

185-209.

tematic review of randomized control

Rogol AD (2010). Drugs of abuse and the

trials. Pediatr Exerc Sci; 24: 472-489.

adolescent athlete. Ital J Pediatr; 36: 19.

Deimel JF, et al.

(2012). The female

Tancredi G, et al. (2004). 3-min step test

athlete triad. Clin Sports Med; 31: 247-254.

and treadmill exercise for evaluating

Del Giacco SR, et al. (2012). Allergy and

exercise-induced asthma. Eur Respir J;

sports in children. Pediatr Allergy

23: 569-574.

Immunol; 23: 11-20.

Tancredi G, et al.

(2011). Cardio-

Farley DR, et al.

(1992). Spontaneous

pulmonary response to exercise and

rupture of the spleen due to infectious

cardiac assessment in patients with

mononucleosis. Mayo Clin Proc;

67:

Turner syndrome. Am J Cardiol;

107:

846-853.

1076-1082.

ERS Handbook: Paediatric Respiratory Medicine

677

Index

obesity in 530, 531

adeno-tonsillectomy

ABCA₃ gene/protein 6, 588, 592, 597, 598

OSAS 62, 517-518, 531

abdominal pain 237, 410

polysomnography 122

abdominal tuberculosis 290-291

post-operative complications 517-518

aberrant innominate artery 455, 458f, 459

adenovirus(es) 10, 214, 570, 571

aberrant subclavian artery 454, 457, 459

adipokines 530

absent pulmonary valve syndrome 640

adolescent(s)

acaricides 385

asthma severity 325t

acetylcholine, REM sleep 507

bronchopulmonary dysplasia survivors 473

N-acetylcysteine 424-425

cystic fibrosis signs/symptoms 398t

acidaemia 94, 94t

physical activity risks

674

acid-base disorders/disturbances 93, 94t

primary ciliary dyskinesia 555t

mixed 93

tuberculosis 273

acidosis 94, 539

adolescent idiopathic scoliosis (AIS) 498-499, 501

acinar region 2

adrenaline

acinus 5, 8f

anaphylaxis 349, 351, 352, 352t

acrocyanosis (peripheral cyanosis) 39

bronchiolitis

307

action plans

croup 56, 231

asthma 324-325

food allergy 374

food allergy 373-374

inspiratory stridor

active sleep, newborns 511

adults

actual base excess (base excess of the extracellular

bronchopulmonary dysplasia survivors 473

fluid)

cystic fibrosis, nutritional status

411

acute cellular rejection (ACR) 572

adult-type tuberculosis 272, 273

acute eosinophilic pneumonia 611-612

adventitious sounds 37-39

acute glomerulonephritis 621

continuous (musical) see wheeze/wheezing

acute hypercarbic (type II) respiratory failure 539-540

discontinuous (nonmusical) see crackles

acute hypoxic (type I) respiratory failure 538-539, 539f

aegophony 39

acute lung injury (ALI) 472, 533, 535-536, 540

aerosol 199

acute-on-chronic respiratory failure 542

aerosol therapy 198-206, 667

acute otitis media (AOM) 215, 228-229

adherence 204-205

acute pancreatitis 642

aims 667

acute respiratory distress syndrome (ARDS) 533, 540,

delivery devices 199-204

640

choice of 199-200, 200f

causes 535, 536t

“five Ds” for prescribing 198

imaging 533, 534f

indications 198

lung recruitment 536

inhalation instructions 204-205

outcomes 534, 535

mechanisms 667

pathophysiological outcomes 533-534

particle deposition 199

phases 533

patients 667

treatment 535-536

techniques 667

acute respiratory failure (ARF) 538-542

technology 199

causes 538

air filtration

385

clinical effects

540

air inflammation modulation, CF 424-425

cystic fibrosis

406

air pollution

definitions 538-540

anthropogenic 30

history taking 540-541

bronchial hyperresponsiveness 87

investigations 540-541

cough 46

management 541-542

lung function growth 30

physiology 538-540