Chapter 13 - Pleural, mediastinal and chest wall diseases

Pleural effusion

428

Robert Loddenkemper

Pneumothorax and pneumomediastinum

432

Paul Schneider

Mediastinitis

439

Pierre-Emmanuel Falcoz, Nicola Santelmo and Gilbert Massard

Neuromuscular disorders

443

Andrea Vianello

Chest wall disorders

448

Pierre-Emmanuel Falcoz, Nicola Santelmo and Gilbert Massard

Chapter 14 - Thoracic tumours

Pathology and molecular biology of lung cancer

451

Sylvie Lantuéjoul, Lénaïg Mescam-Mancini, Barbara Burroni and

Anne McLeer-Florin

Lung cancer: diagnosis and staging

455

Johan Vansteenkiste, Sofie Derijcke and Inge Hantson

Chemotherapy and molecular biological therapy

460

Amanda Tufman and Rudolf M. Huber

Surgical treatment for lung cancer

466

Gilbert Massard, Nicola Santelmo and Pierre-Emmanuel Falcoz

Radiotherapy for lung cancer

472

Luigi Moretti and Paul Van Houtte

Contributors

Chief Editors

Paolo Palange

Anita K. Simonds

Department of Public Health and

NIHR Respiratory Disease Biomedical

Infectious Diseases

Research Unit

Sapienza University of Rome

Royal Brompton and Harefield NHS

Rome, Italy

Foundation Trust

paolo.palange@uniroma1.it

London, UK

a.simonds@rbht.nhs.uk

Authors

Nicolino Ambrosino

Peter J. Barnes

Cardio-Thoracic Dept

National Heart and Lung Institute

University Hospital

Imperial College

Pisa, Italy

London, UK

n.ambrosino@ao-pisa.toscana.it

p.j.barnes@imperial.ac.uk

Isabella Annesi-Maesano

Bianca Beghé

Université Pierre et Marie Curie -

Section of Respiratory Diseases

Paris 6

Department of Oncology

Medical School Saint-Antoine

Haematology and Respiratory

UMR S 707: EPAR

Diseases

Paris, France

University Policlinic of Modena

isabella.annesi-maesano@inserm.fr

University of Modena and Reggio

Emilia

Andrea Antonelli

Modena, Italy

Allergologia e Fisiopatologia

bianca.beghe@unimore.it

Respiratoria, ASO S. Croce e Carle

Cuneo, Italy

Francesco Blasi

andrea-antonelli@tiscali.it

Respiratory Medicine Section

Dipartimento Toraco-Polmonare e

Bruno Balbi

Cardiocircolatorio

Fondazione Salvatore Maugeri

Università degli Studi di Milano and

IRCCS

IRCCS Fondazione Cà Granda

Veruno, Italy

Milan, Italy

bruno.balbi@fsm.it

francesco.blasi@unimi.it

Sandra Baldacci

Konrad E. Bloch

Pulmonary Environmental

Pulmonary Division

Epidemiology Unit, Institute of

University Hospital of Zurich

Clinical Physiology National Research

Zurich, Switzerland

Council

konrad.bloch@usz.ch

Pisa, Italy

baldas@ifc.cnr.it

xiv

Annette Boehler

Barbara Burroni

University Hospital of Zurich

Département de Pathologie

Zurich, Switzerland

Pôle de Biologie et de Pathologie

capybara@compuserve.com

Centre Hospitalier Universitaire A.

Michallon

Chris T. Bolliger^†

INSERM U 823 - Institut A. Bonniot

Université J. Fourier

Philippe Bonniaud

Grenoble, France

Department of Pulmonary Medicine

BBurroni@chu-grenble.fr

and Intensive Care

CHU Dijon

Andrew Bush

Dijon, France

Imperial College and Royal Brompton

philippe.bonniaud@chu-dijon.fr

Hospital

London, UK

Aik Bossink

a.bush@rbht.nhs.uk

Diakonessenhuis

Utrecht, the Netherlands

Philippe Camus

aikbossink@mac.com

Department of Pulmonary Medicine

and Intensive Care

Julia Bott

CHU Dijon

Virgin Care

Dijon, France

Chertsey, UK

ph.camus@chu-dijon.fr

Julia.Bott@virgincare.co.uk

Emilio Canalis

Arnaud Bourdin

Thoracic Surgery Service

Department of Respiratory Disease

Hospital Universitari Joan XXIII

CHU Arnaud de Villeneuve

IISPV

Montpellier, France

URV

a-bourdin@chu-montpellier.fr

Tarragona, Spain

emilio.canalis@urv.cat

Thomas Brack

Cantonal Hospital Glarus

Kai-Håkon Carlsen

Glarus, Switzerland

Institute of Clinical Medicine,

thomas.brack@ksgl.ch

University of Oslo

Dept of Paediatrics, Oslo University

Hospital

Norwegian School of Sport Science

Oslo, Norway

k.h.carlsen@medisin.uio.no

Sonia Cerrai

Marco Chilosi

Pulmonary Environmental

Department of Pathology

Epidemiology Unit

Università di Verona

Institute of Clinical Physiology

Veronica, Italy

National Research Council

marco.chilosi@univr.it

Pisa, Italy

sonia.cerrai@ifc.cnr.it

Luke Clancy

TobaccoFree Research Institute

Stefania Cerri

Ireland

Centre for Rare Lung Disease

Dublin, Ireland

Dept of Medical and Surgical

lclancy@tri.ie

Sciences

University of Modena and Reggio

Amelia Clive

Emilia

North Bristol Lung Centre

Modena, Italy

University of Bristol

stefania.cerri@unimore.it

Bristol, UK

Amelia.Clive@nbt.nhs.uk

Pascal Chanez

Service de Pneumo-Allergologie et

Robert P. Coppes

Laboratoire d’Immunologie INSERM

Depts of Cell Biology and Radiation

U600

Oncology

Université de la Méditerranée

University Medical Center Groningen

AP-HM

University of Groningen

Marseille, France

Groningen, the Netherlands

pascal.chanez@univmed.fr

r.p.coppes@umcg.nl

Francesca Cherubino

Jean-François Cordier

Pneumology Unit, Fondazione

Department of Respiratory Diseases

Salvatore Maugeri

CHU de Lyon

IRCCS

Lyon, France

Tradate, Italy

jean-francois.cordier@chu-lyon.fr

francesca.cherubino@fsm.it

Ulrich Costabel

Sara Chiesa

Dept of Pneumology and Allergy

Department of Clinical and

Ruhrlandklinik

Experimental Medicine

Essen

University of Parma

Germany

Parma, Italy

ulrich.costabel@ruhrlandklinik.uk-

sara.chiesa@hotmail.it

essen.de

xvi

Vincent Cottin

Sofie Derijcke

Department of Respiratory Diseases

Respiratory Oncology Unit

CHU de Lyon

Dept of Pulmonology

Lyon, France

University Hospital Leuven

vincent.cottin@chu-lyon.fr

Leuven, Belgium

sofie.derijcke@azgroeninge.be

Jane C. Davies

Imperial College and Royal Brompton

Walter De Wever

Hospital

University Hospitals Leuven

London, UK

Leuven, Belgium

j.c.davies@imperial.ac.uk

walter.dewever@uz.kuleuven.be

Wilfried De Backer

Maria Anna Digiulio

Dept of Pulmonary Medicine

Dept of Clinical Medicine

University of Antwerp

Reference Centre for Primary

Antwerp, Belgium

Immunodeficiencies

wilfried.debacker@ua.ac.be

Sapienza University of Rome

Rome, Italy

Marc Decramer

mariaanna.digiulio@gmail.com

Respiratory Rehabilitation and

Respiratory Division

Antonino Di Stefano

University Hospital Leuven

Fondazione Salvatore Maugeri

Leuven, Belgium

IRCCS

marc.decramer@uzleuven.be

Veruno, Italy

antonino.distefano@fsm.it

Giovanni Della Casa

Division of Radiology

Lieven Dupont

Dept of Diagnostic and Imaging

Department of Respiratory Medicine

Services

University Hospital Gasthuisberg

University of Modena and Reggio

KU Leuven

Emilia

Leuven, Belgium

Modena, Italy

lieven.dupont@uzleuven.be

giodc@libero.it

Oliver Eickelberg

Sabrina Della Patrona

Comprehensive Pneumology Center,

Pneumology Unit

Ludwig-Maximilians-University and

Fondazione Salvatore Maugeri

Helmholtz Zentrum München

IRCCS

Munich, Germany

Tradate, Italy

oliver.eickelberg@helmholtz-

sabrina.dellapatrona@fsm.it

muenchen.de

xvii

Santiago Ewig

Alessandro Maria Ferrazza

Thoraxzentrum Ruhrgebiet

Dept of Public Health and Infectious

Kliniken für Pneumologie und

Diseases

Infektiologie

Sapienza University of Rome

Evangelisches Krankenhaus Herne

Rome, Italy

und Augusta-Kranken-Anstalt

ale.ferrazza@libero.it

Bochum

Bochum, Germany

Thomas Fuehner

ewig@augusta-bochum.de

Dept of Respiratory Medicine

Hanover Medical School

Leonardo M. Fabbri

Hanover, Germany

Section of Respiratory Diseases

fuehner.thomas@mh-hannover.de

Department of Oncology

Haematology and Respiratory

Mina Gaga

Diseases

Asthma Centre and 7th Respiratory

University Policlinic of Modena

Medicine Dept

University of Modena and Reggio

Athens Chest Hospital

Emilia

Athens, Greece

Modena, Italy

minagaga@yahoo.com

fabbri.leonardo@unimo.it

Stefano Gasparini

Pierre-Emmanuel Falcoz

Pulmonary Diseases Unit

Université Louis Pasteur and

Dept of Immunoallergic and

Hôpitaux Universitaires de

Respiratory Diseases

Strasbourg

Azienda Ospedaliero-Universitaria

Strasbourg, France

“Ospedali Riuniti”

pierre-emmanuel.falcoz@wanadoo.fr

Ancona, Italy

s.gasparini@fastnet.it

Ramon Farré

Unitat de Biofisica i Bioenginyeria,

Mari Carmen Gilavert

Facultat de Medicina, Universitat de

Intensive Care Unit

Barcelona

Hospital Universitari Joan XXIII

CIBER Enfermedades Respiratorias

IISPV

Institut de Investigacions

URV

Biomèdiques August Pi Sunyer

Tarragona, Spain

Barcelona, Spain

mcgilavert.hj23.ics@gencat.cat

rfarre@ub.edu

Rik Gosselink

Faculty of Kinesiology and

Rehabilitation Sciences

Dept of Rehabilitation Sciences

Katholieke Universiteit Leuven

Leuven, Belgium

xviii

Rik.Gosselink@faber.kuleuven.be

Patricia L. Haslam

Jens Gottlieb

National Heart and Lung Institute

Dept of Respiratory Medicine

and Royal Brompton Hospital

Hanover Medical School

Imperial College

Hanover, Germany

London, UK

gottlieb.jens@mh-hannover.de

p.haslam@imperial.ac.uk

Mark Greer

Allan F. Henderson

Dept of Respiratory Medicine

Norfolk and Norwich University

Hanover Medical School

Hospital

Hanover, Germany

Norwich, UK

greer.mark@mh-hannover.de

afhenderson@live.com

Fabio Guarracino

Jeroen M. Hendriks

Cardio-Thoracic Dept

Department of Thoracic and Vascular

University Hospital

Surgery

Pisa, Italy

Antwerp University Hospital

f.guarracino@ao-pisa.toscana.it

Antwerp, Belgium

jeroen.hendriks@uza.be

Federico Gumiero

Department of Clinical and

Matthew Hind

Experimental Medicine

Royal Brompton Hospital

University of Insubria

London, UK

Varese, Italy

M.Hind@rbht.nhs.uk

federico.gumiero@fsm.it

Clare Hooper

Inge Hantson

Worcestershire Royal Hospital

Respiratory Oncology Unit

Worcester, UK

Dept of Pulmonology

clarehooper@doctors.org.uk

University Hospital Leuven

Leuven, Belgium

Rudolf M. Huber

inge.hantson@uzleuven.be

Division of Respiratory Medicine

and Thoracic Oncology, Hospitals

Sylvia Hartl

of Ludwig-Maximilians-University -

Dept of Respiratory and Critical Care

Campus Innenstadt, and Thoracic

Otto Wagner Hospital

Oncology Centre of Munich

Vienna, Austria

Munich, Germany

sylvia.hartl@wienkav.at

huber@med.uni-muenchen.de

J. Mike Hughes

National Heart and Lung Institute

Imperial College

London, UK

mike.hughes@imperial.ac.uk

xix

Marc Humbert

Melanie Königshoff

Université Paris-Sud

Comprehensive Pneumology Center

INSERM U999

Ludwig-Maximilians-University and

Assistance Publique-Hôpitaux de

Helmholtz Zentrum München

Paris

Munich, Germany

Service de Pneumologie

melanie.koenigshoff@helmholtz-

Hôpital Bicêtre

muenchen.de

Paris, France

marc.humbert@bct.aphp.fr

Helen J. Lachmann

UK National Amyloidosis Centre

Magareta Ieven

Division of Medicine

Laboratory of Medical Microbiology,

University College London Medical

University Hospital Antwerp,and

School

Dept of Medical Microbiology,

London, UK

Vaccine and Infectious Disease

h.lachmann@ucl.ac.uk

Institute, Faculty of Medicine,

University of Antwerp

Daniel Langer

Antwerp, Belgium

Faculty of Kinesiology and

Greet.Ieven@uza.be

Rehabilitation Sciences

Dept of Rehabilitation Sciences

Zubair Kabir

Katholieke Universiteit Leuven

TobaccoFree Research Institute

Leuven, Belgium

Ireland

Daniel.Langer@faber.kuleuven.be

Dublin, Ireland

zkabir@tri.ie

Sylvie Lantuéjoul

Département de Pathologie

Christian Karagiannidis

Pôle de Biologie et de Pathologie

Abteilung für Pneumologie und

Centre Hospitalier Universitaire A.

Internistische Intensivmedizin

Michallon

Krankenhaus Oststadt-Heidehaus

INSERM U 823-Institut A.

Klinikum Region Hannover

Bonniot-Université J. Fourier

Hanover, Germany

Grenoble, France

KaragiannidisC@kliniken-koeln.de

SLantuejoul@chu-grenoble.fr

Coenraad F.N. Koegelenberg

Patrick Lauwers

Division of Pulmonology

Dept of Thoracic and Vascular

Dept of Medicine

Surgery

University of Stellenbosch and

Antwerp University Hospital

Tygerberg Academic Hospital

Antwerp, Belgium

Cape Town, South Africa

patrick.lauwers@uza.be

coeniefn@sun.ac.za

Pierantonio Laveneziana

Maurizio Luisetti

Equipe de Recherche ER 10 UPMC

University of Pavia

Laboratoire de Physio-Pathologie

SC Pneumologia

Respiratoire

Dip. di Medicina Molecolare

Faculté de Médecine Pierre et Marie

IRCCS Policlinico San Matteo

Curie

Pavia, Italy

Université Pierre et Marie Curie

m.luisetti@smatteo.pv.it

(Paris VI)

Paris, France

Alexander J. Mackay

pier_lav@yahoo.it

Academic Unit of Respiratory

Medicine

Romain Lazor

UCL Medical School

Interstitial and Rare Lung Disease

London, UK

Unit

alexander.mackay@ucl.ac.uk

Lausanne University Hospital

Lausanne, Switzerland

Sara Maio

romain.lazor@huv.ch

Pulmonary Environmental

Epidemiology Unit

Wei Shen Lim

Institute of Clinical Physiology

Respiratory Medicine

National Research Council

Nottingham University Hospitals

Pisa, Italy

NHS Trust

saramaio@ifc.cnr.it

Nottingham, UK

WeiShen.Lim@nuh.nhs.uk

Adel H. Mansur

Birmingham Heartlands Hospital

Marc C.I. Lipman

Birmingham, UK

University College London Medical

adel.mansur@heartofengland.nhs.uk

School and Royal Free London NHS

Foundation Trust

Georgios Margaritopoulos

London, UK

Interstitial Lung Disease Unit

marclipman@nhs.net

Royal Brompton Hospital

London, UK

Robert Loddenkemper

gmargaritop@yahoo.gr

Dept of Pneumology II

Lungenklinik Heckeshorn

Yves Martinet

HELIOS Klinikum Emil von Behring

University of Nancy Henri Poincaré

Berlin, Germany

Nancy, France

rloddenkemper@dzk-tuberkulose.de

y.martinet@chu-nancy.fr

xxi

Nick Maskell

Giovanni Battista Migliori

North Bristol Lung Centre

WHO Collaborating Centre for TB

University of Bristol

and Lung Diseases

Bristol, UK

Fondazione S. Maugeri

nick.maskell@bristol.ac.uk

Care and Research Institute

Tradate, Italy

Gilbert Massard

giovannibattista.migliori@fsm.it

Dept of Thoracic Surgery

Hôpitaux Universitaires de

Cinzia Milito

Strasbourg

Dept of Molecular Medicine

Strasbourg, France

Reference Centre for Primary

Gilbert.Massard@chru-strasbourg.fr

Immunodeficiencies

Sapienza University of Rome

Anne McLeer-Florin

Rome, Italy

Plateforme de Génétique Moléculaire

cinzia.milito@uniroma1.it

des Cancers

Pôle de Biologie et de Pathologie

Rob F. Miller

Centre Hospitalier Universitaire A.

University College London Medical

Michallon

School, and London School of

INSERM U 823-Institut A.

Hygiene and Tropical Medicine

Bonniot-Université J. Fourier

London, UK

Grenoble, France

robert.miller@ucl.ac.uk

AFlorin@chu-grenoble.fr

Marc Miravitlles

Andrew Menzies-Gow

Pneumology Dept

Royal Brompton and Harefield NHS

Hospital Universitari Vall d’Hebron

Foundation Trust

Barcelona, Spain

London, UK

marcm@separ.es

a.menzies-gow@rbht.nhs.uk

Luigi Moretti

Lénaïg Mescam-Mancini

Dept of Radiation Oncology

Département de Pathologie et

Institut Jules Bordet

Plateforme de Génétique Moléculaire

Université Libre de Bruxelles

des Cancers

Brussels, Belgium

Pôle de Biologie et de Pathologie

luigi.moretti@bordet.be

Centre Hospitalier Universitaire A.

Michallon

Alyn H. Morice

INSERM U 823-Institut A.

Hull York Medical School

Bonniot-Université J. Fourier

University of Hull

Grenoble, France

Hull, UK

LMescam@chu-grenoble.fr

a.h.morice@hull.ac.uk

xxii

Jean-François Muir

Dario Olivieri

Respiratory Dept and Respiratory

Department of Clinical and

Intensive Care Unit

Experimental Medicine

Rouen University Hospital

University of Parma

Rouen, France

Parma, Italy

Jean-Francois.Muir@chu-rouen.fr

dario.olivieri@unipr.it

Bruno Murer

Paolo Onorati

Surgical Pathology Unit

Department of Public Health and

Department of Clinical Pathology

Infectious Diseases

Ospedale dell’Angelo

Sapienza University of Rome

Venice, Italy

Rome, Italy

bruno.murer@ulss12.ve.it

paolo.onorati@fastwebnet.it

Daniel Navajas

Antonio Palla

Unitat de Biofisica i Bioenginyeria,

Cardiothoracic and Vascular Dept

Facultat de Medicina, Universitat

University of Pisa

de Barcelona, CIBER Enfermedades

Pisa, Italy

Respiratorias, and Institut de

a.palla@med.unipi.it

Bioenginyeria de Catalunya

Barcelona, Spain

Martyn R. Partridge

dnavajas@ub.edu

Imperial College, London, UK and

Lee Kong Chian School of Medicine,

Benoit Nemery

Singapore

Research Unit of Lung Toxicology,

m.partridge@imperial.ac.uk

Occupational, Environmental and

Insurance Medicine

Riccardo Pellegrino

KU Leuven

Allergologia e Fisiopatologia

Leuven, Belgium

Respiratoria

Ben.Nemery@med.kuleuven.be

ASO S. Croce e Carle

Cuneo, Italy

Marc Noppen

pellegrino.r@ospedale.cuneo.it

University Hospital Brussels

Brussels, Belgium

Claudio Piersimoni

Marc.Noppen@uzbrussel.be

Regional Reference Mycobacteriology

Unit

Yvonne Nussbaumer-Ochsner

Clinical Pathology Laboratory

University Hospital Zurich

Azienda Ospedaliera-Universitaria

Zurich, Switzerland

Ospedali Riuniti

yvonne.nussbaumer@swissonline.ch

Ancona, Italy

c.piersimoni@ospedaliriuniti.

marche.it

xxiii

Patrizia Pignatti

Federica Pulvirenti

Allergy and Immunology Unit

Dept of Clinical Medicine

Fondazione Salvatore Maugeri

Reference Centre for Primary

IRCCS

Immunodeficiencies

Pavia, Italy

Sapienza University of Rome

patrizia.pignatti@fsm.it

Rome, Italy

federica.pulvirenti@hotmail.it

Massimo Pistolesi

Section of Respiratory Medicine

Isabella Quinti

Dept of Experimental and Clinical

Dept of Molecular Medicine

Medicine

Reference Centre for Primary

University of Florence

Immunodeficiencies

Florence, Italy

Sapienza University of Rome

massimo.pistolesi@unifi.it

Rome, Italy

isabella.quinti@uniroma1.it

Riccardo Pistelli

Catholic University

Elisabeth Quoix

Columbus Hospital

University of Strasbourg

Rome, Italy

University Hospital

riccardopistelli@h-columbus.it

Strasbourg, France

equoix@gmail.com

Alessandro Pitruzzella

Fondazione Salvatore Maugeri

Klaus F. Rabe

IRCCS

Centre for Pneumology and Thoracic

Veruno, Italy

Surgery

alexpitruzzella@libero.it

Grosshansdorf Hospital

Grosshansdorf, Germany

Giovanni Poletti

k.f.rabe@kh-grosshansdorf.de

Hematology Laboratory Area Vasta

Romagna

Anna Rask-Anderson

Pievesestina, Italy

Uppsala University

gpoletti1958@gmail.com

Uppsala, Sweden

anna.rask-andersen@medsci.uu.se

Venerino Poletti

Department of Diseases of the

Luca Richeldi

Thorax

Centre for Rare Lung Disease

Ospedale GB Morgagni

Dept of Medical and Surgical

Forlì, Italy

Sciences

venerino.poletti@gmail.com

University of Modena and Reggio

Emilia

Modena, Italy

luca.richeldi@unimore.it

xxiv

Josep Roca

Paul Schneider

Hospital Clinic

DRK Kliniken Berlin

IDIBAPS

Thoracic Surgery

CIBERES

Berlin, Germany

University of Barcelona

p.schneider@drk-kliniken-berlin.de

Barcelona, Spain

jroca@clinic.ub.es

Bernd Schönhofer

Abteilung für Pneumologie und

Gernot Rohde

Internistische Intensivmedizin

Dept of Respiratory Medicine

Krankenhaus Oststadt-Heidehaus

Maastricht University Medical Centre

Klinikum Region Hannover

Maastricht, the Netherlands

Hanover, Germany

g.rohde@mumc.nl

Bernd.Schoenhofer@t-online.de

Nicola Santelmo

Macé M. Schuurmans

Université de Strasbourg and

University Hospital

Hôpitaux Universitaires de

Zurich, Switzerland

Strasbourg

mschuurmans@me.com

Strasbourg, France

Nicola.Santelmo@chru-strasbourg.fr

Martina Sester

Dept of Transplant and Infection

Giuseppe Sarno

Immunology

Pulmonary Environmental

Institute of Virology

Epidemiology Unit

University of the Saarland

Institute of Clinical Physiology

Homburg, Germany

National Research Council

Martina.Sester@uniklinikum-

Pisa, Italy

saarland.de

sarnogiu@ifc.cnr.it

Pallav L. Shah

Giorgio Scano

Royal Brompton Hospital

Dept of Internal Medicine

London, UK

Section of Immunology and

pallav.shah@ic.ac.uk

Respiratory Medicine

University of Florence

Nikolaos M. Siafakas

Florence, Italy

Dept of Thoracic Medicine

gscano@unifi.it

Medical School

University of Crete

Arnaud Scherpereel

Heraklion, Greece

Faculté de Médecine, Université de

siafak@med.uoc.gr

Lille Nord de France, CHRU de Lille,

and INSERM unit 1019, CIIL, Institut

Torben Sigsgaard

Pasteur de Lille

Aarhus University

Lille, France

Aarhus, Denmark

arnaud.scherpereel@chru-lille.fr

Sigsgaard@dadlnet.dk

xxv

Marzia Simoni

Nick ten Hacken

Pulmonary Environmental

University Medical Center Groningen

Epidemiology Unit

Groningen, the Netherlands

Institute of Clinical Physiology

n.h.t.ten.hacken@umcg.nl

National Research Council

Pisa, Italy

Einar Thorsen

marzia_simoni@libero.it

University of Bergen

Bergen, Norway

Gérald Simonneau

einar.thorsen@helse-bergen.no

National Reference Center for

Pulmonary Hypertension Hôpital

Pietro Torricelli

Antoine Béclère

Division of Radiology

Paris, France

Dept of Diagnostic and Imaging

France

Services

gerald.simonneau@abc.aphp.fr

University of Modena and Reggio

Emilia

Giovanni Sotgiu

Modena, Italy

Epidemiology and Medical Statistics

pietro.torricelli@unimore.it

Unit

Department of Biomedical Sciences,

Thierry Troosters

University of Sassari

Respiratory Rehabilitation and

Sassari, Italy

Respiratory division, University

gsotgiu@uniss.it

Hospital Leuven, and Faculty of

Kinesiology and Rehabilitation

Paolo Spagnolo

Sciences, Dept of Rehabilitation

Centre for Rare Lung Disease

Sciences, KU Leuven

Dept of Medical and Surgical

Leuven, Belgium

Sciences

Thierry.Troosters@med.kuleuven.be

University of Modena and Reggio

Emilia

Amanda Tufman

Modena, Italy

Division of Respiratory Medicine

paolo.spagnolo@unimore.it

and Thoracic Oncology, Hospitals of

Ludwig-Maximilians-University, and

Antonio Spanevello

Thoracic Oncology Centre of Munich

Pneumology Unit, Fondazione Sal-

Munich, Germany

vatore Maugeri, IRCCS Tradate, and

Amanda.Tufman@med.uni-

Dept of Clinical and

muenchen.de

Experimental Medicine, University of

Insubria, Varese, Italy

Panagiota Tzani

antonio.spanevello@fsm.it

Department of Experimental and

Clinical Medicine

University of Parma

Parma, Italy

panagiotat@yahoo.com

xxvi

Eleni G. Tzortzaki

Johan Vansteenkiste

Dept of Thoracic Medicine

Respiratory Oncology Unit

Medical School

Dept of Pulmonology

University of Crete

University Hospital Leuven

Heraklion, Greece

Leuven, Belgium

tzortzaki@med.uoc.gr

johan.vansteenkiste@uzleuven.be

Davide Vallese

Johny A. Verschakelen

Fondazione Salvatore Maugeri

University Hospitals Leuven

IRCCS

Leuven, Belgium

Veruno, Italy

Johny.Verschakelen@uzleuven.be

vallese.dav@gmail.com

Andrea Vianello

Paul Van Houtte

Respiratory Pathophysiology and

Dept of Radiation Oncology

Intensive Care Division

Institut Jules Bordet

University City Hospital of Padua

Université Libre de Bruxelles

Padua, Italy

Brussels, Belgium

avianello@qubisoft.it

paul.vanhoutte@bordet.be

Chiara Vicari

Peter van Luijk

Fondazione Salvatore Maugeri

University Medical Center Groningen

IRCCS

University of Groningen

Veruno, Italy

Groningen, the Netherlands

chiaravicari@libero.it

p.van.luijk@umcg.nl

Giovanni Viegi

Hans Van Remoortel

Pulmonary Environmental

Faculty of Kinesiology and

Epidemiology Unit, Institute of

Rehabilitation Sciences

Clinical Physiology, National

Dept of Rehabilitation Sciences

Research Council, Pisa and

KU Leuven

A. Monroy Institute of Biomedicine

Leuven, Belgium

and Molecular Immunology, National

hans.vanremoortel@faber.kuleuven.

Research Council, Palermo, Italy

viegig@ifc.cnr.it

Paul E. Van Schil

Duccio Volterrani

Dept of Thoracic and Vascular

Nuclear Medicine

Surgery

University of Pisa

Antwerp University Hospital

Pisa, Italy

Antwerp, Belgium

duccio.volterrani@med.unipi.it

Paul.VanSchil@uza.be

xxvii

Florian von Groote-Bidlingmaier

Nathalie Wirth

Division of Pulmonology

University of Nancy Henri Poincaré

Dept of Medicine

Nancy, France

University of Stellenbosch and

n.wirth@chu-nancy.fr

Tygerberg Academic Hospital

Cape Town, South Africa

Mark Woodhead

florianv@sun.ac.za

Dept of Respiratory Medicine

Manchester Royal Infirmary

Susan A. Ward

Manchester, UK

Human Bio-Energetics Research

mark.woodhead@cmft.nhs.uk

Centre

Crickhowell, UK

Andrea Zanini

saward@dsl.pipex.com

Pneumology Unit, Fondazione

Salvatore Maugeri, IRCCS, Tradate,

Jadwiga A. Wedzicha

Italy and Dept of Clinical and

Academic Unit of Respiratory

Experimental Medicine, University of

Medicine

Insubria, Varese, Italy

University College London

andrea.zanini@fsm.it

London, UK

w.wedzicha@ucl.ac.uk

Jean-Pierre Zellweger

Swiss Lung Association

Athol U. Wells

Berne, Switzerland

Interstitial Lung Disease Unit

zellwegerjp@swissonline.ch

Royal Brompton Hospital

London, UK

Eleftherios Zervas

Athol.Wells@rbht.nhs.uk

7th Pulmonary Dept

Athens Chest Hospital

Tobias Welte

Athens, Greece

Dept of Respiratory Medicine

lefzervas@yahoo.gr

Hannover Medical School

Hanover, Germany

Gernot Zissel

Welte.Tobias@mh-hannover.de

Dept of Pneumology

University Medical Centre Freiburg

Brian J. Whipp^†

Freiburg, Germany

gernot.zissel@uniklinik-freiburg.de

xxviii

‘To study the phenomenon of disease without books is to sail an

Preface

uncharted sea, while to study books without patients is not to go

to sea at all.’ ‘Too many men slip early out of the habit of studious

reading, and yet that is essential.’

William Osler

Eight years ago, the ERS School started a very ambitious project to harmonise

education in respiratory medicine for European specialists (HERMES). A

preliminary survey among 29 European countries showed considerable

variation in postgraduate training. Based on these findings, the ERS School

developed a range of consensus documents: a core syllabus describing the

competencies required, a curriculum of recommendations indicating how

competencies should be taught and learned, an accreditation methodology

for training centres, and a voluntary European examination to assess whether

specialists have acquired the knowledge-based component of competence. The

Handbook, together with a vast array of educational material, such as lectures,

articles published in Breathe and the European Respiratory Monograph, and other

lectures and courses, all available on the ERS School website, together comprise

an unrivalled educational resource for anyone preparing for the European

Examination in Adult Respiratory Medicine.

The first edition of the ERS Handbook of Respiratory Medicine was published

in 2010 with the aim of providing state-of-the-art summaries in all areas of

respiratory medicine. This second edition of the Handbook has been extensively

peer review and revisited, and includes new sections on

•

cytology of the lung

•

HRCT of the chest

•

long-term ventilation

•

opportunistic infections in the immunocompromised host

•

the pharmacology of asthma and COPD

•

HRCT in the diagnosis of interstitial lung disease

•

pathology and molecular biology of lung cancer

•

palliative care

The Handbook is a comprehensive, easily accessible source of the essentials

of respiratory medicine for senior medical staff requiring revalidation, and

nursing and allied healthcare professionals at all levels who wish to keep

their knowledge up to date. All readers can be assured that as they set sail to

manage patients across the spectrum of respiratory disorders, they are armed

with the best information, access to multiple-choice questions to check their

knowledge, and a source guide for more in-depth study.

We are particularly indebted to the ERS School Committee, the ERS Publications

Office who curated the entire contents of the Handbook, and all the

contributors.

Paolo Palange, Anita K. Simonds

Chief Editors

xxix

Get more from this Handbook

By buying the ERS Handbook of Respiratory 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 inside of the

front cover of the book.

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

ERS Handbook: Self-Assessment in Respiratory Medicine

Edited by Konrad E. Bloch, Paolo Palange and

Anita K. Simonds

Self-Assessment in Respiratory Medicine is an invaluable

tool for any practitioner of adult respiratory medicine.

The 111 multiple-choice questions cover the full breadth

of the specialty, using clinical vignettes that test not only

readers’ knowledge but their ability to apply it in daily

practice.

To buy a copy of this Handbook for €50 (€40 for ERS members) plus postage,

please contact sales@ersj.org.uk

xxx

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

xxxi

Genetics

Gernot Zissel

Genetics addresses the composition,

Genes are transcribed to RNA and

function and transmission of inherited

subsequently translated into proteins.

entities (genes) summing up to the genome

Genes do not code for ‘diseases’. Every

of an individual. Generally, the term ‘gene’ is

genetic disease is based on an altered or

understood as a unit coding for a single

missing protein. Because we are all

RNA that gives rise to a single and specific

equipped with a double set of

protein. However, due to alternative

chromosomes, in the vast majority of cases,

splicing, one gene may code for different

a dysfunctional gene is corrected by its

proteins. There are also genes not coding for

counterpart with normal function. A

proteins but for catalytic RNAs (tRNA,

deficiency occurs only when the respective

rRNA) or regulatory RNAs (microRNA

gene is dysfunctional on both

(miRNA)). The genotype is the specific

chromosomes, or the gene product is either

composition of genes of an individual that

missing or does not perform its task.

influences its phenotype. However, in

Diseases caused by the alteration of a single

contrast to the genotype, which is simply

gene with relevance for pulmonologists are

inherited, a phenotype is shaped by

CF and a1-proteinase inhibitor (PI) deficiency

epigenetic phenomena, environment,

(formerly a1-antitrypsin (AT) deficiency). In

climate, nutrition and other external factors.

other diseases such a clear-cut relationship

between a gene and a disease is not evident,

although facts, such as geographical

Key points

distribution or familial clusters, indicate a

genetic background. This is the case in

N A few respiratory diseases, such as CF

asthma, sarcoidosis, pulmonary fibrosis and

and a1-Pi deficiency, are single-gene

primary pulmonary hypertension. Table 1

conditions.

shows examples of mutated genes involved

in respiratory disorders.

N A large range of respiratory diseases,

including asthma, COPD, sarcoidosis,

There are also numbers of gene variations

IPF and primary pulmonary

that are regarded as neutral variations of the

hypertension, may have a genetic

human gene pool. These variations are not

background.

harmful per se, but together with distinct

external stimuli they foster the development

N Non-harmful gene variants can

of certain diseases. Glutamine at position

nonetheless confer susceptibility to

69 in the human leukocyte antigen (HLA)-

conditions such as chronic beryllium

DPB1 gene does not cause an illness;

disease.

however, when in contact with beryllium

The role of epigenetic regulatory

dust, carriers of Glu69+ HLA-DPB1 are at an

mechanisms in respiratory disease is

increased risk of developing chronic

likely to be very significant.

beryllium disease (CBD). Up to 97% of CBD

patients are Glu69+ HLA-DPB1 positive.

Another example is the lack of functional

ERS Handbook: Respiratory Medicine

Table 1. Examples of mutated genes involved in respiratory disorders

Disease

Gene

Gene product

Mutation(s)

CFTR

Cystic fibrosis transmembrane

.1500

conductance regulator

Emphysema SERPINA1

Serpin peptidase inhibitor,

SNP G-342A .90% of cases

clade A (a-1 antiproteinase,

antitrypsin)

Chronic

HLA-DPB1

Histocompatibility antigen,

Glutamine at position 69

beryllium

DP(W2) b-chain

disease

Sarcoidosis

BTNL2

Butyrophilin-like 2

rs2076530 SNP G-11084A

causing premature stop codon

ANXA11

Annexin A11

rs1049550 SNP CRT, arginine

to cysteine

TNF

SNP G-308A

TLR

SNPs in various TLR genes

influence disease course

Cancer

c-Myc

Promoter translocation

Ras

Family of GTPases

Various SNPs induce

permanent activation

EGFR

Epidermal growth factor

Deletions, SNPs leading

receptor

to over expression and

permanent activation

SNP: single-nucleotide polymorphism.

receptors for interferon-c or interleukin-12.

which is subsequently not translated. Cytosine

In these cases the individuals grow up

methylation is important in promoter

normally and reach adolescence; however,

silencing and inactivation of the

after the BCG (Bacillus Calmette-Guérin)

X chromosome.

vaccination or when they encounter

Histone modifications are an additional

environmental mycobacteria (e.g.

form of epigenetic regulation. Histones are

Mycobacterium fortuitum, Mycobacterium

protein spheres that bind DNA. There are

chelonae), these individuals develop severe

four different histones, two of each histone

and sometimes fatal disease.

together with the bound DNA build a

Epigenetics and regulatory genes

nucleosome, the core of a chromosome.

Histones can be modified, mainly by

The genome is not a static blueprint of the

acetylation, methylation and various other

phenotype as it was regarded in the past.

mechanisms. Generally, acetylation of

Several mechanisms of genetic regulation,

histones opens the nucleosome structure

epigenetics and regulatory genes, have been

and the gene becomes accessible for

discovered in recent years. The term

transcription. In contrast, histone

epigenetics describes a wide field of DNA and

methylation leads to the accumulation of

histone modifications that contribute to the

additional histone proteins in turn leading

regulation of gene transcription. One of these

to a compacted nucleosome and

modifications is the methylation of the

subsequently inhibiting gene transcription.

nucleobase cytosine. Cytosine is methylated

only in CG ‘islands’; single cytosines are not

The miRNAs are short, highly conserved,

methylated. Cytosine methylation inhibits

noncoding RNAs that bind to

binding of RNA polymerases to the gene,

39-untranslated regions (39-UTR) of mRNAs.

ERS Handbook: Respiratory Medicine

Incomplete binding leads to silencing and

proteases, such as neutrophil elastase,

complete binding to degradation of the

cathepsin G and proteinase 3, all released

RNA. In fact, miRNAs are powerful

by neutrophils and is, therefore, renamed

regulators. Activation of transcription

as a1-PI. The lack of a1-PI leads to an

factors, such as nuclear factor (NF)-kB leads

incomplete or absent containment of

to the transcription of a variety of immune

proteinases resulting in severe organ

mediator genes. Simultaneous activation of

damage (e.g. emphysema), mostly in

miRNAs suppresses certain mediators,

the lung.

giving rise to a specific pattern of mediator

There are several known mutations in the

activation. miRNAs are of strong

a1-PI gene, such as base substitutions, in-

importance in cancer and pulmonary

frame deletions, frame-shift mutations and

fibrosis; however, one might expect that

exon deletions. More than 90% of cases are

transcriptional regulation by miRNAs is also

caused by single amino acid exchange at

important in other diseases. The pattern of

position 342 (glycine to lysine), which is

miRNAs expressed in several diseases and

called Z mutation. The Z mutation results in

tumours is highly specific and might be

a structural alteration that inhibits post-

used as a biomarker.

translational modifications and secretion.

Genetics in CF

Patients bearing the Z allele demonstrate

,15% of the normal a1-PI level in serum,

CF is caused by the dysfunction of the cystic

which additionally seems to be non-

fibrosis transmembrane conductance

functional.

regulator (CFTR) gene, which codes for a

chloride channel. However, although in all

The gene frequency of the Z allele is rather

CF patients the CFTR is dysfunctional, there

common in Europe, with up to 4% of the

are .1 500 different mutations known to

population being heterozygotic. However,

affect CFTR and lead to a dysfunctional

the frequency declines to ,1% in southern

chloride channel. CF inheritance follows an

Europe. The lowest frequency is found in

autosomal recessive heredity, i.e. the

African-Americans (0.4%).

disease becomes manifest only when CFTR

genes on both chromosomes are mutated,

Genetics in interstitial lung diseases

albeit not necessarily by the same mutation.

The most common defect is the deletion of a

There is some indication that interstitial

phenylalanine at position 508 (DF508),

lung diseases, such as sarcoidosis, CBD or

which is responsible for up to 70% of all CF

idiopathic pulmonary fibrosis (IPF), are

cases. Interestingly, there is a marked

based on a specific genetic background.

difference in the frequency of this disease in

Familial clusters are seen in sarcoidosis and

different populations. It is most common in

IPF. In Europe, sarcoidosis frequency

Caucasians (1:2000 being highest in

increases from South to North. This might

Scotland and the Faroe Islands (1:500)) but

also be a matter of climate, as the same

lower in descendants from Africa (1:15 000);

distribution is seen in Japan. However, the

and lowest in Asians (1:30 000). CFTR

Swedish population encounters the highest

mutations can be grouped into classes

prevalence in Europe (55-64 per 100 000).

In contrast, in the Finnish population living

based on their functional consequences on

at the same latitude, the prevalence is just

the CFTR within the cell: CFTR is either not

half of the Swedish (28 per 100 000). This

synthesised, inadequately processed, not

difference points to a strong genetic

regulated, shows abnormal conductance,

background in the pathogenesis of

discloses partially defective production or

sarcoidosis.

shows accelerated degradation.

Genetics of proteinase inhibitors

An inherited pre-disposition for

sarcoidosis is also indicated by an

The PI a1-antitrypsin belongs to a family of

increased risk of sarcoidosis in close

serine PIs (serpins) and blocks serine

relatives of patients. The percentage of

ERS Handbook: Respiratory Medicine

patients with a positive family history

more polymorphic and sACE levels are not

ranges from 2.7% in Spain to 17% in

linked with the deletion/insertion

African-Americans. Analysis of familial

polymorphism.

sarcoidosis suggests that multiple small or

moderate genetic effects cause a

Familial pulmonary fibrosis is frequently

predisposition for sarcoidosis.

linked with two mutations in the surfactant

protein C (SP-C) gene resulting either in a

Genes of high interest are the HLA class II

splice deletion of exon 4 in a SP-C variant

antigens. Although some of these linkages

that cannot be processed and accumulates

are largely dependent on the population

as pro-SP-C in the cell causing cell stress

investigated, several associations seem to

be preserved, e.g. HLA-DRB1*03

and apoptosis. The pathological pattern of

associates with spontaneous resolution

fibrosis is in both forms consistent with

and mild disease, as demonstrated in

non-specific interstitial pneumonitis in

Swedish, Polish, Croatian and Czech

younger patients and usual interstitial

populations.

pneumonia in the elderly. A recent report

points to a mutation in the telomerase

Using different methods, a variety of

reverse transcriptase (TERT) causing short

candidate genes were identified and found

ends in the telomeres and bone marrow

to be associated with the susceptibility or

hypocellularity. But also mutations in

the natural course of the disease. This

genes regulating cell cycle like TP53 and

included genes for co-stimulatory

CDKN1A are found to influence survival

molecules (e.g. butyrophilin-like 2

times in IPF.

(BTNL2)), genes involved in cell cycle (e.g.

annexin A11 (ANXA11)), and genes involved

Genetics in asthma

in immune regulation (e.g. CD40),

mediators (e.g. tumour necrosis factor

There is a plethora of work related to the

(TNF)-a (TNFA2) or Toll-like receptors

genetics of asthma. The idea of a genetic

(TLR)). These genes may alter the reactivity

basis for asthma is supported by the fact

of the respective cells to external stimuli

that there are familial clusters of asthma

which subsequently initiate an inadequate

and differences of asthma frequency in

immune response.

different populations (highest at the South

Angiotensin-converting enzyme (ACE) is

Atlantic island Tristan da Cunha affecting

often used in the diagnosis and clinical

.20% of the population). However, no

monitoring of sarcoidosis. However,

single gene is responsible for the

serum levels of ACE (sACE) are highly

development or the clinical course of

variable, which impairs the clinical use of

asthma; instead, several genes are regarded

ACE as a marker. The variability of sACE is

as risk genes for developing asthma. The

based on a deletion/insertion in intron 16

gene products of these genes are involved

of the ACE gene. The homozygote deletion

in T-cell activation, cytokine release and

variant is associated with higher sACE,

balance, epithelial function and repair or

whereas homozygote insertion is

smooth muscle contractility. Again, new

associated with lower levels.

genes involved in asthma susceptibility

Heterozygotes exhibit intermediate values.

might be expected.

Therefore, in populations of Caucasian

origin, the knowledge of the zygosity of the

Nevertheless, although there are

deletion/insertion variants allows the

predisposing genes in asthma, the influence

application of genotype-corrected

of lifestyle on the development of asthma is

reference values of sACE, which leads to an

also evident. There is a clear increase in

improvement of the clinical application of

asthma incidences in developing countries.

this marker. However, this is not

Therefore, asthma might be an elucidating

applicable in populations of African origin;

example for the complex genotype/

the ACE gene in these populations is much

phenotype relationship.

ERS Handbook: Respiratory Medicine

Genetics in cancer

Further reading

Mutations and epigenetic modifications are

Al-Muhsen S, et al. (2008). The genetic

heterogeneity of mendelian susceptibility

passed to the offspring as far as the germ cells

to mycobacterial diseases. J Allergy Clin

are concerned. However, there are also

Immunol; 122: 1043-1051.

mutations outside the germ line: so-called

Biller H, et al. (2006). Genotype-corrected

somatic mutations. As these mutations

reference values for serum angiotensin-

accumulate over years, a growing organism

converting enzyme. Eur Respir J;

28:

resembles merely a genetic mosaic rather than a

1085-1090.

unique clone of the germ cell it is derived from.

Blumenthal MN (2012). Genetic epige-

netic, and environmental factors in

Most of these somatic mutations are silent

asthma and allergy. Ann Allergy Asthma

and either do not cause any defect or are

Immunol; 108: 69-73.

corrected by its respective counterpart.

Bogunia-Kubik K, et al. (2001). HLA-DRB1*03,

However, there is a variety of somatic

DRB1*11 or DRB1*12 and their respective

mutations that finally cause tumour genesis.

DRB3 specificities in clinical variants of

An example of such a somatic mutation

sarcoidosis. Tissue Antigens; 57: 87-90.

involved in cancer is a mutation in the MYC

Coakley RJ, et al.

(2001). a1-antitrypsin

gene, leading to the over-expression of c-Myc.

deficiency: biological answers to clinical

The regulatory protein c-Myc binds to

questions. Am J Med Sci; 321: 33-41.

Cottle LE (2011). Mendelian susceptibility

enhancer boxes in regulatory gene sequences

to mycobacterial diseases. Clin Genet; 79:

inducing enhanced gene expression. In

17-22.

addition, it recruits histone acetylases leading

Gooptu B, et al. (2009). Mechanisms of

to histone hyperacetylation. Approximately

emphysema in a1-antitrypsin deficiency.

15% of the human genes are affected by c-Myc

molecular and cellular insights. Eur Respir J;

regulation. Over-expression of c-Myc is an

34: 475-488.

important factor in the pathogenesis genesis

Grunewald J.

(2010). Review role of

of small cell lung cancer (SCLC). However, no

genetics in susceptibility and outcome

single event, like the mutation of c-Myc, is

of sarcoidosis. Semin Respir Crit Care

responsible for tumour genesis. In general,

Med; 31: 380-389.

tumours like SCLC or nonsmall cell lung

Kass DJ

(2011).

Evolving genomic

cancer present with a large variety of genetic

approaches to idiopathic pulmonary

alterations, like DNA methylation, alternative

fibrosis: moving beyond gene. Clin

splicing, histone modifications or altered

Transl Sci; 4: 372-379.

Lommatzsch ST (2009). Genetics of

miRNA patterns, which all might be involved

cystic fibrosis. Semin Respir Crit Care Med;

in oncogenesis.

30: 531-538.

As genetic tools become more common, the

Maier LA, et al. (2003). Influence of MHC

analysis of the individual pathways involved

class II in susceptibility to beryllium

in the individual cancer pathogenesis might

sensitization and chronic beryllium

help to develop individual targets for therapy.

disease. J Immunol; 171: 6910-6918.

Müller-Quernheim J, et al.

(2008).

Conclusion

Genetics of sarcoidosis. Clin Chest Med;

29: 391-414.

Genetic aspects have to be considered in all

Postma DS (2009). Genetics of asthma

areas of pulmonary medicine. As physicians

where are we and where do we go? Proc

are faced with phenotypes, the underlying

Am Thorac Soc; 6: 283-287.

degree of genetic influence is not always

Rowe SM, et al. (2005). Cystic fibrosis. N

obvious. The knowledge of the genotype

Engl J Med; 352: 1992-2001.

causing a respective phenotype might be a

Selroos O. Differences in sarcoidosis

promising tool to predict outcome or

around the world: what they tell us. In:

therapeutic options, and would enable

Baughman RP, ed. Sarcoidosis. New

individual genotype/phenotype-based

York, Informa, 2006; pp. 47-64.

therapies.

ERS Handbook: Respiratory Medicine

Molecular biology of the lung

Melanie Königshoff and Oliver Eickelberg

Understanding lung disease at the cellular

The extracellular matrix

and molecular level is crucial to developing

Components of the extracellular matrix

new approaches for the diagnosis, treatment

(ECM) surround and support the cell and

and prevention of lung disease. Although our

cell-cell interaction. In the lung, the ECM

knowledge at the molecular level is steadily

around the conducting airways, alveolar and

increasing, we still have a limited

understanding of the molecular events

interstitial cells, and the vascular system has a

major impact on lung architecture and

underlying lung diseases, which is reflected by

function, particularly gas exchange. All lung

very few therapies targeting specific defects.

cell types interact and signal through the ECM

The field of molecular biology focuses on the

via adhesion molecules, surface receptors or

interactions between various systems of a

growth factors (Suki et al., 2008).

cell and between cells, and particularly

includes:

The lung fibroblast is the main producer of

pulmonary ECM, which consists of:

N gene structure, expression, replication

and recombination

N collagens

N structure, function, modification, and

N elastins

processing of proteins and nucleic acids

N proteoglycans

N cellular and developmental biology

N genetics, structure and growth cycles of

The interstitium of the lung parenchyma

viruses, bacteria and bacteriophages

contains mostly collagen types I and III,

which are mainly responsible for tensile

The following paragraphs focus on selected

strength.

(signalling) molecules and structures, all of

which are altered in various lung disease and

The pulmonary ECM is subjected to a

are important topics in the field of molecular

continuous turnover of .10% of the total

biological research in respiratory medicine.

ECM per day. Thus, a dynamic equilibrium

between synthesis and degradation of the

pulmonary ECM maintains a physiological

balance. This balance is tightly controlled by

Key points

three regulatory mechanisms: 1) de novo

Major features of lung diseases are:

synthesis and deposition of ECM components

such as collagens, mainly by interstitial

altered deposition of extracellular

fibroblasts; 2) proteolytic degradation of

matrix,

existing ECM by matrix metalloproteinases

(MMPs), a family of zinc-dependent enzymes;

N impaired surfactant metabolism,

and 3) inhibition of MMP activity by specific

Distorted endogenous defence

endogenous antiproteases, the tissue

mechanisms.

inhibitors of metalloproteinases (TIMPs)

(Mocchegiani et al., 2011).

ERS Handbook: Respiratory Medicine

Excessive or inappropriate expression of

Surfactant abnormalities have been

MMPs and impaired expression of TIMPs

described in many infant and adult lung

are related to the pathogenesis of many

diseases, such as respiratory distress

chronic lung diseases, such as MMP-12 in

syndrome, bronchiolitis, COPD and

emphysema or MMP-7 in lung fibrosis

interstitial lung disease.

(Churg et al., 2011).

Defense and clearance mechanisms

The impact of the altered matrix or cell-

SP-A and SP-D are involved in innate host

matrix interaction within the diseased lung

defence of the lung. In addition, antimicrobial

represents an active area of investigation.

peptides, such as defensins, cathelicidins

While most research in the past focused on

and or lactoferrin, are present in the airway

the effect of signalling molecules and

and prevent infection. Moreover, cellular

pathways on matrix deposition and

defense mechanisms include macrophage-

turnover, recent studies aimed to

and neutrophil-mediated cytokine release,

understand how the lung matrix influences

such as interleukin (IL)-1, IL-8, tumour

cell differentiation and behaviour, and,

necrosis factor (TNF)-a and granulocyte-

subsequently, signal transduction

macrophage colony-stimulating factor

(Fernandez et al., 2012).

(GM-CSF) (Suzuki et al., 2008).

The surfactant system

Pulmonary alveolar proteinosis is caused by

disruption of GM-CSF signalling. Loss of

The maintenance of normal lung function

GM-CSF signalling in macrophages results in

throughout the life of an organism is ensured

an impaired ability to catabolise surfactant

largely by alveolar epithelial cells, which form a

proteins. Abnormal surfactant accumulation

tight functional barrier essential for gas

leads to respiratory insufficiency.

exchange. The alveolar epithelium is

composed of alveolar type I (ATI) and type II

Mucociliary clearance represents the

(ATII) cells. These cells produce and secrete

primary physiological defense mechanism.

components of the ECM and growth factors

The ciliated airway cells clear mucus, which

thereof, which facilitates restoration of the

is produced by secretory cells, by forcing the

interstitium and, subsequently, functional

mucus toward the larynx for elimination.

alveolar structure. ATII cells serve as

Impaired mucociliary clearance is the main

progenitor cells for ATI cells, which largely

feature of CF.

cover the alveolus and are the primary cell

The transforming growth factor-b pathway

responsible for gas exchange. ATII cells are

cuboidal secretory cells mainly responsible for

The transforming growth factor (TGF)-b

surfactant secretion (Herzog et al., 2008).

superfamily is critically involved in embryonic

Pulmonary surfactant is a complex mixture of

development, organogenesis and tissue

phospholipids and proteins, with surfactant

homeostasis (Bartram et al., 2004). TGF-b

protein (SP)-A, SP-B and SP-C constituting

superfamily members act as multifunctional

10% of surfactant. Its main role is to reduce

regulators of cell growth and differentiation. The

surface tension in the alveoli following the

TGF-b superfamily includes .40 members,

onset of breathing, thereby leading to lung

including the various isoforms of TGF-b itself.

expansion. Mechanical stretch of the lung

Three different TGF-b isoforms have been

forces the secretion of lamellar bodies, the

characterised so far: TGF-b1, TGF-b2 and TGF-

intracellular storage granules of surfactant,

b3. TGF-b1 is the most important isoform in the

which form tubular myelin. The surfactant film

cardiopulmonary system, as it is ubiquitously

stabilises the alveolar-air interface with low

expressed and secreted by several cell types, such

surface tension and prevents lung collapse. SP-

as endothelial, epithelial and smooth muscle

B and SP-C are the main protein components.

cells, as well as fibroblasts and most cells of the

Following secretion, both surfactant proteins

immune system. TGF-b is secreted in covalent

and lipids are recycled by the respiratory

association with the latent TGF-b binding

epithelium (Marraro et al., 2008).

protein, thus providing a reservoir in the ECM.

ERS Handbook: Respiratory Medicine

LTBP

Latent

Active

TGF-β

LAP

TGF-β

BMP

TβRI

TβRII

BMPR

MAPK

Smad2/3

pathway

Smad

pathway

Smad1/5/8

Ras/Rho

Smad6/7

Smad2/3

Smad4

Smad1/5/8

Smad2/3

Smad4

AP1

DNA

Transcriptional regulation

Figure 1. The TGF-b pathway. LTBP: latent TGF-b binding protein; LAP: latency-associated peptide; TbR:

TGF-b receptor; P: phosphoryl group; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-

regulated kinase; JNK: Janus kinase; AP: activator protein; BMP: bone morphogenetic protein; BMPR: BMP

receptor. Reproduced and modified from Königshoff M et al. (2009) with permission from the publisher.

For active signalling, TGF-b needs to be cleaved

nuclear translocation and regulation of gene

from the complex by a mechanism that involves

transcription. These receptor-regulated Smads

various proteases, such as plasmin or MMPs, as

(Smad2 and Smad3), in combination with the co-

well as interaction with integrins. Active TGF-b

Smad Smad4, positively regulate TGF-b-induced

ligands bind to the type II TGF-b receptor, which

effects, while the inhibitory Smads (Smad6 and

subsequently forms heterotetrameric complexes

Smad7) negatively regulate TGF-b signalling

with the type I TGF-b receptor. Subsequent

(fig. 1).

transphosphorylation of the type I receptor

results in recruitment of specific intracellular

Increased TGF-b signalling is the key

signal mediators called Smad proteins. Smad2

pathophysiological mechanism that leads to

and Smad3 have been shown to be

fibrotic lung disease, which is characterised

phosphorylated by the type I receptor, followed by

by an increase in activated (myo)fibroblasts

complex formation with Smad4 and, finally,

and excessive deposition of ECM.

ERS Handbook: Respiratory Medicine

Wnt

LRP 5/6

Membrane

CK-1γ

GSK-β

FZD

DSH

Axin

APC

DSH

Axin

GSK-β

Cytoplasm

APC

β-catenin

Degradation of β-catenin

Nucleus

TCF/LEF

β-catenin

Target gene expression

1) Initial failure signal

1) Initial injury

Wnt proteins

Wnt regulators

Type II

Type I

2) Multistep tumorigenesis

2) Attempted regeneration

Wnt

Dysplasia

Carcinogenesis

Hyperplasia

EMT

ECM deposition

EMT/metastasis

Paracrine:

Autocrine:

side-effects

survival signal

Figure 2. The Wnt/b-catenin pathway. The pathway is shown in the a) ‘off’ and b) ‘on’ states, and in lung

c) cancer and d) fibrosis. DSH: Dishevelled; GSK: glycogen synthase kinase; APC: adenomatous polyposis

coli protein; P: phosphoryl group; CK: casein kinase; TCF: T-cell-specific transcription factor; LEF: lymphoid

enhancer-binding factor family protein; EMT: epithelial-mesenchymal transition. Reproduced and

modified from Königshoff M et al. (2010) with permission from the publisher.

ERS Handbook: Respiratory Medicine

Furthermore, there is emerging interest in the

p50, p65 and the inhibitory protein IkBa.

role of TGF-b in the pathogenesis of COPD,

Upon activation, the IkBa protein undergoes

particularly since genetic studies have

phosphorylation, ubiquitination and

demonstrated an association of gene

degradation. p50 and p65 are then released

polymorphisms of the TGF-b superfamily

for translocation to the nucleus, bind specific

with COPD. In addition, increased expression

DNA sequences present in the promoters of

of TGF-b1 in COPD was reported, suggesting

target genes and initiate transcription. IkBa

an impact of TGF-b signalling in the

kinase (IKK) is responsible for the initial

development and progression of COPD

phosphorylation. Several different kinases

(Königshoff et al., 2009).

have been shown to activate IKK, such as Akt,

MEKK1 and protein kinase C. In the nucleus,

The Wnt/b-catenin pathway

NF-kB induces the expression of a variety of

The Wnt/b-catenin signalling pathway was

genes, particularly mediators of

originally identified as a developmental

inflammation, cell proliferation, metastasis

signalling pathway. It constitutes a large family

and angiogenesis (Sun et al., 2008).

of secreted glycoproteins that signal via a

Many potentially noxious substances related

variety of membrane-bound receptors. Wnt

to lung disease, such as cigarette smoke,

ligands bind to the membrane receptors

radiation, chemotherapeutic agents,

Frizzled (FZD) and low-density lipoprotein

cytokines and growth factors, activate NF-

receptor-related protein (LRP)5/6, resulting in

kB, and increased NF-kB signalling has

the phosphorylation of LRP6, which

been associated with COPD and asthma

subsequently leads to the recruitment of

cytosolic proteins that are part of the so-called

(Edwards et al., 2009).

b-catenin destruction complex. Subsequently,

the central mediator b-catenin is

Further reading

dephosphorylated and its degradation

attenuated. Accumulated b-catenin then

Bartram U, et al.

(2004). The role of

undergoes nuclear translocation and regulates

transforming growth factor beta in lung

target gene expression via interaction with

development and disease. Chest;

125:

members of the T-cell-specific transcription

754-765.

factor/lymphoid enhancer-binding factor family

Churg A, et al. (2012). Matrix metallopro-

teinases in COPD. Eur Respir J;

39:

(fig. 2) (Moon et al., 2004).

197-209.

Impaired Wnt/b-catenin signalling has been

Edwards MR, et al. (2009). Targeting the

implicated in a variety of chronic lung diseases,

NF-kB pathway in asthma and chronic

such lung cancer, fibrosis and COPD/

obstructive

pulmonary

disease.

emphysema. In particular, active Wnt/b-catenin

Pharmacol Ther; 121: 1-13.

signalling has been linked to lung epithelial cell

Fernandez IE, et al. (2012). New cellular

and molecular mechanisms of lung injury

repair and survival mechanisms.

and fibrosis in idiopathic pulmonary

Importantly, Wnt/b-catenin signalling is

fibrosis. Lancet; 380: 680-688.

tightly regulated during lung homeostasis.

Herzog EL, et al. (2008). Knowns and

Several Wnt inhibitors, such as Dickkopf and

unknowns of the alveolus. Proc Am

secreted FZD-related proteins, are

Thorac Soc; 5: 778-782.

Königshoff M, et al.

(2009). TGF-b

differentially expressed during chronic lung

signaling in COPD: deciphering genetic

disease, thereby impacting proper Wnt/b-

and cellular susceptibilities for future

catenin signalling (Königshoff et al., 2009).

therapeutic regimen. Swiss Med Wkly;

Nuclear factor-kB

139: 554-563.

Konigshoff M, et al. (2010). WNT signal-

Nuclear factor (NF)-kB is a ubiquitous

ing in lung disease: a failure or a

transcription factor present in all cell types. In

regeneration signal? Am J Respir Cell

its resting stage, this factor resides in the

Mol Biol; 42: 21-31.

cytoplasm as a heterotrimer consisting of

ERS Handbook: Respiratory Medicine

Marraro GA (2008). Surfactant in child and

Suki B, et al. (2008). Extracellular matrix

adult pathology: is it time to review our

mechanics in lung parenchymal dis-

acquisitions? Pediatr Crit Care Med; 9: 537-538.

eases. Respir Physiol Neurobiol; 163: 33-

Mocchegiani E, et al. (2011). Metalloproteases/

43.

anti-metalloproteases imbalance in chronic

Sun SC, et al. (2008). New insights into

obstructive pulmonary disease: genetic

NF-kB regulation and function. Trends

factors and treatment implications. Curr

Immunol; 29: 469-478.

Opin Pulm Med; 17: Suppl. 1, S11-S19.

Suzuki T, et al.

(2008). Role of innate

Moon RT, et al. (2004). WNT and b-

immune cells and their products in lung

catenin signalling: diseases and thera-

immunopathology. Int J Biochem Cell Biol;

pies. Nat Rev Genet; 5: 691-701.

40: 1348-1361.

ERS Handbook: Respiratory Medicine

Anatomy of the respiratory

system

Pallav L. Shah

Pleura

costal and mediastinal pleura, and is found

behind the sternum and costal cartilages.

The lungs are covered by a fine membrane

known as the pleura. The parietal pleura is

The pleura is supplied by its regional blood

the outer layer and the visceral pleura is

vessels. Hence, the cervical pleura is

adherent to the lungs. The two are in

supplied by branches of the subclavian

continuity with each other and there is a very

artery, the costovertebral pleura by the

fine space between the two, the pleural

intercostal arteries and the diaphragmatic

cavity. The parietal pleura is described

pleura from the vascular plexus from the

according to the surface that it is adjacent to:

surface of the diaphragm. The venous

costovertebral, diaphragmatic, cervical and

drainage occurs into the corresponding

mediastinal. There are also pleural recesses

veins, which then drain into the vena cava.

where the two different pleural surfaces are

The lymphatic drainage is into the

situated next to each other without any

corresponding lymph nodes, e.g. the

intervening lung in normal respiration. The

intercostal lymphatics drain into the

costodiaphragmatic recesses are a thin area

posterior lymph nodes and then into the

between the costal and diaphragmatic pleura.

thoracic duct. The visceral pleura is supplied

The costomediastinal recess is between the

by the bronchial vessels and the lymphatics

drain into the intercostal and peribronchial

lymphatics. The parietal pleura is supplied

Key points

by the regional nerves and contains the pain

fibres. The costal and peripheral aspects of

The anatomy of the thorax can be

the diaphragmatic pleura are supplied by the

divided broadly into the pleura, lungs,

corresponding intercostal nerves, whereas

mediastinum, diaphragm and heart.

the diaphragmatic and mediastinal pleura

are supplied by the phrenic nerves.

N The lungs can be further subdivided

into lobes, segments, trachea and

Lungs

bronchi.

The apex of the lung extends into the

N The mediastinal space contains

thoracic inlet and on the anterior aspect lies

structures including the thymus

above the first costal cartilage. On the

gland, thoracic lymph nodes, thoracic

posterior aspect, the apex of the lung is level

duct, vagus nerve and autonomic

with the neck of the first rib. At its highest

nerve plexus.

position it is ,2.5 cm above the clavicle.

The thoracic structures include the

The base of the lung is a concave structure

vital organs for respiration and

and lies over the diaphragm. The main

circulation. This section will focus on

surface of the lung is the costal surface,

the pleura, lungs, mediastinum and

which is smooth and shaped according to

diaphragm. The anatomy of the heart

the chest wall. The medial surface of the

is not discussed.

lung is shaped posteriorly according to the

vertebral column and medially by the heart.

ERS Handbook: Respiratory Medicine

The lungs are also indented by the

oblique fissure separates the upper lobe

numerous vascular structures, such as the

from the lower lobe.

aorta, that are in contact with them.

Bronchopulmonary segments

The right lung consists of upper, middle and

lower lobes (fig. 1a). The left lung is

The main bronchi divide into lobar bronchi

composed of an upper and lower lobe

that, in turn, divide into segmental bronchi.

(fig. 1b). In the right lung there are two

Each divides into a structurally and functionally

fissures. The oblique fissure separates the

independent unit of tissue. The right lung

lower lobe from the upper and middle lobes.

consists of 10 bronchopulmonary segments:

The smaller horizontal fissure separates the

three in the upper lobe, two in the middle lobe

upper and middle lobes. In the left lung, the

and five in the lower lobe.

Right upper lobe

Apex

Anterior barrier

Hilum

Horizontal

fissure

Cardiac

impression

Right middle

lobe

Groove for

inferior vena

cava

Oblique fissure

Right lower lobe

Left lower lobe

Groove for

Oblique fissure

subclavian

artery

Groove for

aortic arch

Hilum

Left lower lobe

Figure 1. Medial aspect of a) right and b) left lung.

P.L. Shah.

ERS Handbook: Respiratory Medicine

The left lung comprises nine segments: five

in the upper lobe, including two within the

lingula, and four in the lower lobes. There is

no true medial segment in the left lower lobe

as this area is occupied by the heart.

Each bronchus continues to subdivide into

smaller, narrower airways until they finally form

terminal bronchioles and then respiratory

bronchioles, which are devoid of cartilage.

These in turn lead to several alveolar ducts,

which in turn end in several alveoli. The

collective structure is termed an acinus. The

secondary pulmonary lobule is the smallest

part of the peripheral lung bounded by

connective tissue, and usually consists of three

to six pulmonary acini forming a hexagonal

pattern with a central artery, lymphatic and

peripheral veins.

Trachea and bronchi

The trachea (figure 2) is 100 mm long and

made up of anterolateral cartilage rings with

a fibromuscular posterior wall. The trachea

divides at the level of the fourth vertebral

Figure

2. The trachea and bronchi.

P.L. Shah.

body (level with the aortic arch) into the right

and left bronchi. The right main bronchus is

upper lobe and the inferior division, which

,25 mm long and divides into the right

supplies the superior segment of the lingula

upper lobe at the level of the fifth thoracic

and inferior segment of the lingula. The left

vertebra. It then continues as the bronchus

lower lobe descends posterolaterally and

intermedius, which is ,20 mm in length.

first gives off a posteriorly located branch to

The right main bronchus is wider, shorter and

the apical segment of the lower lobe and

more vertical than the left main bronchus

then gives branches to anteromedial, lateral

and, hence, foreign bodies tend to lodge

and posterior basal bronchi.

more frequently into the right main bronchus.

The bronchus intermedius then branches

The trachea is supplied superiorly by

into the middle and lower lobes. The right

branches of the inferior thyroid arteries and

middle lobe is formed on the anterior aspect

more inferiorly by branches of the bronchial

of the bronchus intermedius. The right lower

arteries. The venous drainage tends to be

lobe bronchus gives off a branch to the

towards the inferior thyroid venous plexus

superior segment and continues to descend

and the lymphatic drainage to the pre-

posterolaterally, giving off branches to the

tracheal and para-tracheal lymph nodes. The

medial, anterior, lateral and posterior

bronchi and the airways are supplied by the

segments of the lower lobe.

bronchial arteries, which originate from the

systemic circulation and arise either directly

The left main bronchus is longer, measuring

from the descending thoracic aorta or

,40 mm in length, and enters the hilum of

indirectly via the intercostal arteries. The

the left lung at approximately the level of the

venous drainage of the airways is more

sixth thoracic vertebra. It divides into the left

complicated and consists of deep bronchial

upper lobe and left lower lobe bronchus; the

veins that communicate with pulmonary

left upper lobe bronchus in turn gives off the

veins that drain back into the left atrium.

superior division and supplies the apical

There are also superficial bronchial veins that

posterior and anterior branches of the left

drain into the azygos or the intercostal veins.

ERS Handbook: Respiratory Medicine

The innervation of the endobronchial tree is

border is the vertebral column. It is divided

via the anterior and posterior pulmonary

into the superior, anterior, middle and

plexus, which include branches from the

posterior mediastinum. The mediastinum

vagus, recurrent laryngeal and sympathetic

contains numerous structures, such as the

nerves.

thymus gland, thoracic lymph nodes,

thoracic duct, vagus nerve and autonomic

Hila

nerve plexus.

The pulmonary hila join the medial aspect of

The thymus gland lies in the superior and

the lung to the heart and the trachea. In

anterior mediastinum. The lower border is

each hilum, there are a number of structures

down to the fourth costal cartilage. Its blood

either entering or leaving the structure. They

supply is derived from a branch of the

include the main bronchi, pulmonary artery,

internal thoracic artery and the inferior

superior pulmonary vein, inferior pulmonary

thyroid artery. The thymic veins drain into

vein, bronchial artery, bronchial vein,

the left brachial cephalic vein and internal

pulmonary autonomic neural plexus,

thoracic veins. The lymphatic drainage is

lymphatics and loose connective tissue.

into the tracheobronchial lymph nodes.

Pulmonary vasculature and lymphatic

The mediastinum lymph nodes have special

drainage

significance in the staging of lung cancer.

They are found in the pre-tracheal, para-

The pulmonary artery carries deoxygenated

tracheal, subcarinal and para-oesophageal

blood to the alveoli and the oxygenated

positions. They are classified according to the

blood then returns via the pulmonary veins

International Association for the Study of

to the left atrium. The pulmonary arteries lie

Lung Cancer (IASLC) lymph node map into

anterior to the carina and the corresponding

lymph node stations (e.g. station 4 is the right

main bronchi. The artery then enters the

paratracheal lymph node). The thoracic duct

lung via the hilum. On the right side, the

starts at the lower level of the 12th thoracic

upper lobe branch of the pulmonary arteries

vertebra and enters the mediastinum through

is anterior and lateral to the right upper lobe

the aortic opening of the diaphragm. It runs

whereas the inferior branch of the

in the posterior aspect of the mediastinum

pulmonary artery passes laterally and

just right of the midline between the aorta

posterior to the lower lobe bronchus. On the

and the azygos vein. In the superior

left side, both upper and lower lobe

mediastinum, it ascends onto the left side

pulmonary artery branches are lateral and

adjacent to the oesophagus. It finally

posterior to the corresponding airways. The

terminates into one of the subclavian veins or

descending branch of the left pulmonary

the internal jugular vein.

artery passes behind the left upper lobe and

travels laterally and inferior to the left lower

The vagus nerve on the right side is found

lobe bronchi.

lateral to the trachea and posterior medial to

the right brachiocephalic vein and super

There are two pulmonary veins on each side

vena cava. It then passes behind the right

(superior and inferior pulmonary veins) that

main bronchus and continues to the

pass anterior and inferior to the pulmonary

posterior aspect of the right atrium. Here it

artery and bronchi. The lymphatic vessels

divides into braches, which form the

drain into the hilar and subsequently into

pulmonary autonomic plexus. The left vagus

the tracheobronchial lymph nodes.

nerve is found between the left common

Mediastinum

carotid and subclavian artery and behind the

left brachiocephalic vein. It crosses the

The mediastinum is the space between the

aortic arch and passes behind the left hilum.

two lungs. The superior extent of the

Here, it divides and forms the pulmonary

mediastinum is the thoracic inlet and the

plexus. The autonomic nervous plexus in the

inferior extent the diaphragm. The anterior

mediastinum is formed from the vagus

border is the sternum and the posterior

nerve, thoracic sympathetic chain and the

ERS Handbook: Respiratory Medicine

autonomic plexus (cardiac, oesophageal and

and C6 cervical nerve root (the course of

pulmonary plexus).

which is described previously).

The right phrenic nerve descends laterally to

the super vena cava anterior to the

Development

pulmonary hilar and then along the

The development of the respiratory system

pericardium (over the right atrium) before

occurs at ,26 days of gestation with

reaching the diaphragm. The left phrenic

proliferation of a diverticulum that

nerve runs anteromedially to the vagus

originates from the foregut. The

nerve above the aortic arch and then

laryngotracheal tube and main bronchi are

anteriorly to the left hilum. It then runs

formed first. Over the next 10 weeks, the

along the pericardium (covering the left

lower conducting airways develop and,

ventricle) before supplying the diaphragm.

finally, the acinar structures develop. The

Diaphragm

alveoli and interstitial tissue are then

formed. Alveolar development occurs from

The diaphragm is a musculofibrous sheet

28 weeks gestation and continues during

that separates the thorax and abdomen. It

early childhood.

has an important role in the mechanism of

breathing and coughing. It has a convex

upper surface and is circumferentially

Further reading

attached to the lower aspect of the thorax by

Shah PL. Pleura, lungs, trachea and

muscle fibres that converge to a central

bronchi. In: Standring S, ed. Gray’s

tendon. The diaphragm has three openings

Anatomy. 40th Edn. London, Churchill

within it through which pass the inferior

Livingstone, 2008; pp. 989-1006.

vena cava (at the level of eighth thoracic

Shah PL. Diaphragm and phrenic nerve.

vertebra, T8), the oesophagus (T10) and the

In: Standring S, ed. Gray’s Anatomy. 40th

aorta (T12). Its blood supply is from the

Edn. London, Churchill Livingstone,

lower five intercostal arteries, the subcostal

2008; pp. 1007-1012.

artery and the phrenic arteries. The venous

Shah PL, et al. Mediastinum. In:

drainage is from the phrenic veins, which

Standring S, ed. Gray’s Anatomy. 40th

drain into the inferior vena cava. The

Edn. London, Churchill Livingstone,

diaphragm is supplied by the phrenic nerve,

2008; pp. 939-957.

which primarily originates from the C4, C5

ERS Handbook: Respiratory Medicine

Respiratory physiology

Susan A. Ward

The appropriateness of the ventilatory (V9E)

Ventilatory requirements

response to challenges, such as hypoxia or

Alveolar, and hence arterial, carbon dioxide

altered metabolic rate, depends on V9E and

and oxygen tensions (PACO₂, PAO₂, PaCO₂ and

on whether the pulmonary gas-exchange and

PaO₂, respectively) can only be regulated if

acid-base requirements are achieved: i.e.

alveolar ventilation (V9A) increases in an

regulation of PaCO₂, arterial pH (pHa) and

appropriate proportion to V9CO₂ and V9O₂,

PaO₂ within the relatively narrow range for

respectively. For carbon dioxide exchange

optimal functioning. This involves a cascade

(Fick’s principle):

of mechanisms: airflow and volume

generation; pulmonary oxygen uptake (V9O₂)

V9A5863?V9CO₂/PACO₂

(1)

and carbon dioxide output (V9CO2); and V9E

where 863 is the constant that corrects for

control with its associated respiratory

the different conditions of reporting gas

perceptions. Each of these mechanisms can

volumes (i.e. standard temperature and

be adversely affected in pulmonary disease,

pressure, dry; body temperature and

with impaired respiratory-mechanical and

pressure, saturated) and the transformation

gas-exchange function increasing the V9E

of fractional concentration to gas tension.

demands of the task and, in turn, the costs

of meeting these demands in terms of

Similarly, for oxygen:

respiratory-muscle work, perfusion and

V9A5863?V9O₂/(PI*O₂-PAO₂)

(2)

oxygen consumption.

where PIO₂ is inspiratory oxygen tension

(PO₂) and * is a relatively small correction

Key points

factor (FAN₂/FIN₂, where FAN₂ and FIN₂ are

alveolar and inspiratory nitrogen fractions,

The mechanical work of breathing

respectively) that takes account of inspired

comprises elastic (volume-related)

ventilation normally being slightly greater

and resistive (flow-related)

than the expired. This reflects the body’s

components.

metabolic processes releasing less carbon

N With expiratory efforts causing PIP to

dioxide relative to the oxygen used for a

become positive, an EPP is created

normal western diet, with a respiratory

that results in expiratory flow

quotient (RQ5metabolic carbon dioxide

limitation.

production/metabolic oxygen consumption)

of ,0.8.

Arterial hypoxaemia can result from

alveolar hypoventilation, diffusion

As V9A is common to equations 1 and 2,

limitation, V9A/Q9 mismatch and/or

then:

right-to-left shunt. Only the latter

(863?V9CO₂)/PACO₂rV9AR(863?V9O₂)/

three mechanisms also lead to a

(PI*O₂-PAO₂)

(3)

widened PA-aO₂ (i.e. inefficient

pulmonary oxygen exchange).

If V9CO₂ and V9O₂ are equal (i.e. respiratory

exchange ratio (R)51), both PACO₂ and PAO₂

ERS Handbook: Respiratory Medicine

can be regulated. However, both cannot be

Thus, log[HCO_3-]a/25.6 represents the set

regulated if V9CO₂ and V9O₂ differ, e.g. when:

point, V9E/V9CO₂ the ‘control’ term and 1-VD/

VT represents gas exchange efficiency.

1) RQ changes as a result of dietary- or

activity-related alterations in metabolic

Respiratory mechanics

substrate utilisation; or

A particular V9E requirement can, in theory,

2) there are transient variations in body gas

be accomplished with an infinite

stores (particularly the carbon dioxide

combination of VT and respiratory frequency

stores) as metabolic rate changes.

(fR). The VT-fR combination, in turn,

influences the inspiratory-muscle pressure

Under such conditions, V9A changes in

(Pmus) needed to effect inspiration:

closer proportion to V9CO₂ than to V9O₂, with

PACO₂ consequently being more closely

Pmus5E?V+R?v9+I?v99

(7)

regulated than PAO₂; as these associated PO₂

where V, v9 and v99 are volume, air (and

changes normally occur over the relatively

pulmonary tissue) flow and acceleration,

flat region of the oxygen dissociation curve,

and E, R and I are the pulmonary elastance,

arterial oxygen content (CaO₂) is not greatly

resistance and inertance, respectively.

affected. However, the regulatory outcome

Normally, the inertance-related term makes

is more complex if, for example:

an insignificant contribution, i.e. although

1) significant arterial hypoxaemia develops,

the acceleration of the air can be large, its

causing V9A to increase out of proportion to

mass is small, and while the mass of the

V9CO₂ (hyperventilation) so as to constrain

thorax is relatively large, its acceleration is

the fall in PAO₂; or

small (c.f. conditions such as obesity having

an abnormally increased thoracic mass).

2) with metabolic acid-base disturbances

Thus, Pmus has static (volume-related, with

that evoke compensatory respiratory

no associated air flow) and resistive (flow-

responses to ameliorate the pHa change.

related) components.

Importantly, it is the total V9E, rather than

The static component of Pmus equals the

V9A, that is controlled to effect these

increment in transpulmonary pressure (Ptp)

regulatory functions. Substituting V9E?(1-VD/

required to effect the required degree of lung

VT) for V9A in equation 1 (where VD is the

distension under static conditions:

physiological dead space volume, VT is the

tidal volume and VD/VT is the physiological

Ptp5Palv-PIP5V/CL

(8)

dead space fraction of the breath), and

where Palv and PIP are alveolar and

assuming PACO₂ to equal to PaCO₂ yields:

intrapleural pressures, respectively, and C

V9E5(863?V9CO2)/(PaCO2?(1-VD/VT))

(4)

is lung compliance. CL is determined by the

elastic properties of the lung parenchyma

Thus, the V9E requirement is determined by

and the surface-active forces operating at

PaCO₂, V9CO₂ and VD/VT. Furthermore, the

the alveolar air-liquid interface, which are

influence of metabolic acid-base

constrained by the influence of surfactant.

disturbances can be accommodated by

substituting PaCO₂ from equation 4 into the

The normal static V-Ptp relationship (line 2

Henderson-Hasselbalch equation, i.e.

in fig. 1) shows CL to be largely independent

of V over the tidal range but to decline as

pHa5pK9+log([HCO_3-]a/a?PaCO₂)

(5)

TLC is approached. When CL is decreased

(e.g. restrictive lung disease), a greater than

where [HCO_3-]a is the arterial bicarbonate

normal increase in Ptp is required to effect a

concentration and a is the carbon dioxide

given lung inflation (line 1 in fig. 1); an

solubility coefficient relating PaCO₂ to carbon

increased CL (e.g. emphysema) requires a

dioxide content. This yields:

smaller Ptp increment (line 3 in fig. 1). Also,

pHa5pK9+(log([HCO_3-]a/25.6))?(V9E/

as functional residual capacity (FRC) and

V9CO₂)?(1-VD/VT)

(6)

the associated PIP are determined by the

ERS Handbook: Respiratory Medicine

number (Re) exceeds a value of ,2000. As

Re5v?2r?r/g, where v is the linear velocity and

r is gas density, turbulent flow will

predominate when v is high, at branch points

or across constricted regions. Hence,

(3)

reducing r, for example by breathing high

concentrations of helium instead of nitrogen

(2)

(heliox), makes turbulence less likely.

The thoracic expansion that occurs during

inspiration causes Palv to become negative

● FRC

(i.e. below Patm) and flow to occur, until the

(1)

●

end of inspiration, when Palv again equals

●

× TLC

Patm (fig. 2a). Thus, the pressure

●

requirements for inspiratory flow and

volume generation are reflected in PIP: under

Ptp

static conditions, volume changes are

simply related to changes in PIP through the

Figure 1. CL curve between FRC and TLC for

static CL relationship (as Palv is zero) while,

increased (1) and decreased (3) lung recoil relative

during a normal inspiration, the additional

to normal (2). The slope at any point represents

muscular force needed to overcome R

CL, i.e. change in V induced by change in Ptp.

causes a greater negativity of PIP at any

given lung volume. The difference between

magnitude of the opposing chest wall and

the PIP change needed to provide v9 and that

lung recoil forces, FRC is smaller and PIP

required to distend the lung statically is

more subatmospheric under conditions of

represented by the blue area in figure 2a,

increased recoil (line 1 in fig. 1) than when

and is consequently greatest when v9 is

recoil is reduced (line 3 in fig. 1).

greatest. The respiratory-muscle work (W)

performed in producing the inspiration can

The resistive component of Pmus is the

thus be calculated as: DV?DPIP (fig. 2b),

increment in ‘driving’ pressure required to

where D represents a change, i.e. the sum of

effect air flow, i.e. the difference between Palv

the elastic work required to overcome the

and pressure at the airway opening

static lung recoil forces (red area) and the

(atmospheric pressure (Patm)):

resistive work (blue area). When breathing is

Palv-Patm5v9?R5k₁?v9+k₂?v9²

(9)

stimulated (e.g. in exercise), the greater Palv

required to generate the increased v9

The major site of this resistance lies in the

amplifies the dynamic component of the

segmental bronchi and larger-sized small

V-P relationship (right-hand panels of

bronchi. The bronchioles, although

fig. 2a) and, therefore, increases W. A similar

individually constituting sites of high

effect is seen in patients with an abnormally

resistance because of their very small radius,

increased R, in whom a greater Palv is

collectively contribute relatively little to the

required to achieve a particular v9.

overall resistance as they are very numerous

Expressing W relative to time yields the

(only around 10-20% of the airway resistance

power output (W9) of the inspiratory

being related to airways ,2 mm in diameter).

muscles that, when related to their oxygen

The term k₁?v9 reflects the ‘laminar’

consumption (Q9O₂), allows considerations

component of airflow, with k₁58gl/r⁴, where l

of overall respiratory muscle efficiency. It is

is airway length, r is airway radius and g is gas

only at very high levels of V9E (e.g. at peak

viscosity. The term k₂?v9² reflects the

exercise in very fit endurance athletes) or

‘turbulent’ component, which imposes a

when respiratory impedance is abnormally

greater demand on pressure generation

high (as in pulmonary disease) that W, W9

because of the squaring of the v9 term.

and Q9O₂ can become significant,

Turbulent flow develops when the Reynolds

predisposing to respiratory muscle fatigue.

ERS Handbook: Respiratory Medicine

1.5

1.0

0.5

-5

-10

-15

ΔPIP

-1

-2

Figure 2. a) VT, PIP and v9 changes for normal resting and exercising breaths. The dashed line on the PIP

curve represents pressure needed to produce lung inflation statically. The blue area is the extra PIP required

to generate flow. b) Dynamic inspiratory V-PIP curve. The red area represents static inspiratory work of

breathing; the blue area is the dynamic component. I: inspiration; E: expiration.

When V9E is low, expiration can be achieved

The term R?CL is the mechanical time

entirely through the recoil pressure (PREC)

constant (t) of the respiratory system, and

generated in the elastic structures of the

has the unit of time, i.e.

lungs during the previous inspiration, i.e.

(cmH₂O?L^-1?s)?(L?cmH₂O^-1)5s. Thus, if R or

providing the necessary driving pressure by

CL (or both) are large, then v9 will be low for

increasing Palv (left-hand panels of fig. 2a):

a given lung volume. Complete passive

emptying (i.e. down to FRC) for a

Ptp5PREC5Palv-PIP5R?v9

(10)

spontaneous expiration requires expiratory

duration to be sufficiently long (i.e.

Flow at any point in expiration is thus

effectively 4?t for an exponential process).

determined by the interplay between static

With a normal t of ,0.4 s (R and CL being

lung recoil, PIP and R:

,2 cmH₂O?L^-1?s and 0.2 L?cmH₂O^-1,

v95PREC+PIP/R

(11)

respectively), this minimum period is ,1.6 s

and translates to a total breath time (ttot) of

Furthermore, the equality for PREC deriving

,3 s, assuming an inspiratory duty cycle (tI/

from equations 8 and 9 yields:

ttot, where tI is inspiratory time) of ,0.4.

Thus, if fR exceeds ,20 breaths?min^-1,

V/CL5R?v9

(12)

complete emptying requires expiratory flow

which can be rearranged as:

to be augmented by expiratory muscle

action; without this, end-expiratory lung

v9/V51/R?CL

(13)

volume will be greater than FRC. Such

ERS Handbook: Respiratory Medicine

However, the effects of PIP on expiratory v9

are not quite as straightforward as those of

R and PREC (equation 13). PIP is an index of

the effort transmitted from the respiratory

muscles to the lungs via the chest wall.

During expiration, PIP can become positive

-2

as a function of the applied expiratory effort,

-4

i.e. the chest wall volume decreases faster

-6

than the lungs’ intrinsic recoil. This results

in a compressive force being applied to the

-8

V L

intrapleural space. As Palv5PIP+PREC

(equation 10), Palv will be more positive than

Figure 3. Inspiratory (downwards) and expiratory

PIP by an amount equal to PREC. Airway

(upwards) flow-volume curves at rest, maximal

exercise and with maximal volitional effort for a) a

pressure (Paw) declines from the alveolar

normal subject and b) a patient with COPD.

value down to zero at the mouth as a result

Reproduced from Klas et al. (1989), with

of frictional losses along the airways. At the

permission from the publisher.

point where Paw5PIP (i.e. the transmural

pressure across the airway is zero) (fig. 4),

an equal pressure point (EPP) results.

dynamic hyperinflation is a hallmark of the

In normal subjects, the EPP occurs in the

exercising COPD patient (fig. 3b), where

large airways (lower trachea or main stem

disease-related increases in R and/or CL can

bronchi), which, despite the tendency to

lower this limiting fR quite considerably.

become compressed, are prevented from

collapsing by their cartilaginous support.

That the maximal volitionally generated

Thus, the EPP becomes the limiting point

expiratory v9 is greater at high than at low

for expiratory flow generation, dictating the

lung volumes (fig. 3) is, of course, implicit in

maximum expiratory flow (v9max):

equation 11. That is, R and PREC are each

volume-dependent: at high volumes, R is

v9max5PREC/Rus

(14)

relatively low, reflecting a modest degree of

airway distension (whose effect is amplified

where Rus is the resistance of the upstream

through the r⁴ term) while PREC is relatively

segment of the airways (between the

high. Indeed, for a given t, v9 decreases as a

alveolus and the EPP) (fig. 4). This explains

linear function of V (equation 13),

why progressively greater expiratory efforts,

accounting for the descending limb of the

maximal expiratory flow-volume curve

normally being so linear (fig. 3a).

Rus

In COPD, however, the lower maximal v9 at

PIP = 20

TLC, despite the higher absolute lung

volume (line 3 in fig. 1), is indicative of an

increased R and, for emphysema, decreased

PREC (fig. 3b), and thus v9 at a particular lung

Palv

volume is lower than normal. In contrast, for

= 30

restrictive lung disease, while maximal v9 at

TLC is low owing to poor distensibility (line 1

in fig. 1), v9 at a particular lung volume can

PREC = 10

even be slightly higher than normal owing to

an increased PREC. Furthermore, when there

EPP

is regional nonuniformity of t, for example,

as in COPD, this can contribute to the

Figure 4. Airflow limitation in expiration. An EPP

typically ‘scooped’ maximal expiratory v9

results when Paw declines to a value equal to PREC.

profile (fig. 3b).

Values are expressed in cmH₂O.

ERS Handbook: Respiratory Medicine

although leading to a progressively more

Reduced RQ Recalling that V9E operates to

positive PIP, do not lead to a progressively

regulate PaCO₂ by responding in a

greater v9; greater expiratory effort simply

proportional fashion to V9CO₂, when the RQ

compresses the airways more, raising

of the dietary substrate is reduced (i.e. by

downstream R in proportion to the

ingestion of a high-fat diet), the associated

increased effort. Therefore, v9 becomes

reduction in metabolic carbon dioxide

maximised at a constant value (at that lung

production requires less ventilation to

volume), independent of effort.

maintain a stable PaCO₂ (equation 3). This

leads to hypoventilation relative to oxygen,

With the loss of lung recoil and/or increases

i.e. V9E is normal relative to V9CO₂ but low

in small airway resistance, however, the EPP

relative to V9O₂. Thus, PAO₂ and PaO₂ will fall.

migrates upstream. If it encroaches into the

small unsupported airways, airways collapse

Alveolar hypoventilation can occur in

occurs - with profound effects on v9max

diseases or with drugs that affect the

(equation 14).

medullary respiratory-integrating centres or

respiratory neuromuscular function and,

Pulmonary gas exchange

therefore, reduce the level of respiratory

motor output. It may also be seen in severe

The effectiveness of pulmonary oxygen

COPD, consequent to increased small

exchange is conventionally judged by the

airway resistance and a high resistive work

magnitude of the alveolar-arterial oxygen

of breathing. Arterial hypoxaemia and

tension difference (PA-aO₂), using PAiO₂,

hypercapnia result (equations 2 and 1,

which is the PAO₂ of the ‘ideal lung’ (one that

respectively), with the fall of PaO₂ being

hypothetically exchanges gases ideally).

related to the rise of PaCO₂ through R

PAiO₂ thus circumvents the difficulty of

(equation 17). When R51, the increase in

providing a single representative value for

PACO₂ and fall in PAO₂ that result from a

PAO₂ when there are regional variations in

reduction in V9A are equal, as notionally are

gas-exchange efficiency. It can be derived by

the corresponding changes in PaCO₂ and

re-arranging and amalgamating equations 1

PaO₂. However, as R is normally ,0.8 at

and 2:

rest, for each 10-mmHg decrease in PaO

that results from a fall of V9A, PaCO₂ will

V9CO₂/V9O₂5R5(V9A?((PIO₂?FAN₂/FIN₂)-

increase by only 8 mmHg. It should be noted

PAiO₂))/(V9A?PACO₂)

(15)

that the hypoxaemia can be offset by

PAiO₂5PIO₂-PaCO₂/R+(PaCO₂?FIO₂?(1-R)/R) (16)

administration of supplementary oxygen.

where FIO₂ is the inspiratory oxygen fraction.

Diffusion impairment Fick’s law indicates that

It is common practice to neglect the term

impairments in the pulmonary diffusive flux of

PaCO₂?FIO₂?(1-R)/R, as it is zero when R51,

oxygen (or carbon dioxide) can result from

and only contributes a few mmHg or so

1) a reduction in the driving pressure (for

when R?1. Therefore:

oxygen, DPO₂),

PAiO₂5PIO₂-PaCO₂/R

(17)

2) a reduction in the available surface area

for diffusion (A) and/or

Impairments of pulmonary gas exchange

typically result in arterial hypoxaemia and, in

3) an increased path length for diffusion (l):

some instances, arterial hypercapnia. Six

mechanisms can be identified as

V9O₂5A/l?d?DPO₂

(18)

independent causes of arterial hypoxaemia:

three of these affect PAO₂ (ambient hypoxia

where d, the diffusion coefficient for oxygen,

as with ascent to altitude, reduced RQ and

is inversely proportional to gas molecular

alveolar hypoventilation) and three affect

weight (MW) in the gas phase (d51/!MW),

PA-aO₂ (diffusion limitation, increased right-

while directly proportional also to gas

to-left shunt and V9A/perfusion (Q9)

solubility (s) in the blood phase (d5s/!MW).

maldistribution).

Hence, as oxygen is lighter than carbon

ERS Handbook: Respiratory Medicine

dioxide, it diffuses 18% more rapidly in the

TLO₂ can be usefully subdivided into its

gas phase for the same gas tension gradient.

functional components: the ‘membrane’

In the blood phase, however, carbon dioxide

component (TMO₂) and that due to chemical

is 20 times more diffusible than oxygen,

combination:

owing to its greater solubility.

1/TLO₂51/TMO₂+1/h?Vc

(21)

During inspiration, oxygen is transported

down the tracheobronchial tree by

where h is the reaction rate coefficient for

convective or bulk flow. At the level of the

chemical combination of oxygen with

alveolar ducts, owing to the large overall

haemoglobin and Vc is pulmonary capillary

cross-sectional area of the airways and the

blood volume. Because of technical

resulting reduction in linear velocity of the

limitations associated with estimating PcO₂,

inspired gas, movement to the alveolar-

it is conventional to determine transfer

capillary membrane relies on diffusion.

factors of the lung and membrane for

Diffusion through the alveolar gas space

carbon monoxide (TLCO and TMCO,

does not normally limit gas transfer into

respectively), as the high affinity of

pulmonary capillary blood. Thus, as the

haemoglobin for carbon monoxide ensures

average alveolar diameter is normally only

that the pulmonary capillary carbon

,100 mm, diffusion equilibrium (i.e.

monoxide tension (PCO) is effectively zero.

DPO₂50) throughout the alveolus is

attained rapidly: this is normally 80%

The initial driving pressure across the

complete within ,0.002 s, which is several

alveolar-capillary membrane (i.e. at the

entrance to the capillary bed) is given by the

orders of magnitude less than the time for

which pulmonary capillary blood is exposed

difference between PAO₂ (normally

to the alveolar gas-exchange surface (i.e. the

,100 mmHg) and mixed venous PO₂ (PvO₂)

pulmonary-capillary transit time (tTR),

(normally ,40 mmHg at rest, although

which is ,0.8 s at rest). In conditions such

decreasing in exercise). The rate at which

oxygen is taken up into the blood as it

as emphysema, air-sac enlargement

traverses the capillary declines, reflecting the

increases intra-alveolar diffusion distances,

increasing PcO₂ (and consequent decrease in

predisposing to less efficient oxygen and

PAO₂), which in turn reduces the

carbon dioxide exchange.

instantaneous DPO₂. Diffusion equilibrium

More commonly, however, diffusion

is normally reached within 0.25-0.3 s (i.e.

limitation reflects exchange impairments

well before blood reaches the end of the

between alveolar gas and pulmonary

capillary); thus, pulmonary end-capillary PO₂

capillary blood. The rate of diffusive uptake

(Pc9O₂)5PAO₂. This large safety margin

of oxygen into blood is given by:

becomes compromised, however, when tTR

is shortened to such a degree that there is

V9O₂5A/l?d?(PAO₂-PcO₂)

(19)

insufficient time for the attainment of

where A is the alveolar surface area in

diffusion equilibrium, i.e. Pc9O₂,PAO₂. As

contact with perfused pulmonary capillaries;

tTR5Vc/Q9, an increase in Q9 (e.g. high-

l is the diffusion path length between the

intensity exercise) can compromise

alveolar surface fluid lining and the

diffusion equilibrium, resulting in arterial

erythrocyte interior that includes alveolar

hypoxaemia. However, the decrease in tTR

epithelium, interstitial space, capillary

with increases in Q9 is less than expected,

endothelial cells, plasma, erythrocyte cell

because the capillary blood volume (Qc)

membrane and, for a reactive gas species

actually increases with Q9, consequent to

such as oxygen, its chemical combination

distension of already-perfused capillaries

with haemoglobin; and PcO₂ is mean

and recruitment of previously unperfused

pulmonary capillary PO₂. It is conventional

capillaries; this serves to protect against

to combine A, l and d into a single term, the

diffusion disequilibrium.

transfer factor of the lung for oxygen (TLO₂):

A lowered PAO₂, as occurs with ascent to

V9O₂5TLO₂?(PAO₂-PcO₂)

(20)

high altitude, when a subject breathes an

ERS Handbook: Respiratory Medicine

hypoxic inspirate or with hypoventilation,

relatively normal PaCO₂; with more severe

slows the PcO₂ rise time. This is because the

impairment, which leads to hypoxic

initial driving pressure (PAO₂-PvO₂) is

ventilatory stimulation, there will be a more

smaller, as the operating slope of the oxygen

marked arterial hypoxaemia, greater

dissociation curve (b) is steeper, with the

widening of the PA-a,O₂ and a low PaCO₂.

arteriovenous oxygen content difference

Right-to-left shunt A right-to-left shunt (Q9s)

expressing a smaller arteriovenous PO₂

occurs when venous blood bypasses the

difference.

pulmonary capillary circulation, thus

A useful expression relating to the interplay

providing a degree of venous admixture with

of factors that dictate whether or not

blood from exchanging alveolar units. It

diffusion equilibrium will actually be

normally reflects venous drainage from the

attained (i.e. whether Pc9,O₂5PAO₂) is:

larger airways (which enters the pulmonary

veins) and from coronary vessels (which

(PAO₂-PcO₂)5(PAO₂-PvO₂)?e-TLO2/Q9?b

(22)

enters the left ventricles via the Thebesian

veins). This represents only a small

The term TLO₂/Q9?b has been termed the

percentage of Q9 and, therefore, amounts to

‘equilibrium coefficient’ by Piiper et al.

a reduction in PaO₂ of only a few mmHg

(1980) and the ‘diffusive-perfusive

below Pc9,O₂. However, Q9s/Q9 can be

conductance’ ratio by West et al. (1998).

markedly increased in congenital heart

Thus, diffusion equilibrium is less likely to

disease (e.g. atrial or ventricular septal

be attained if TLO₂ is low and/or Q9 and b are

defects, and pulmonary arteriovenous

high. For example, an increased path length

fistulae), leading to significant arterial

(e.g. alveolar proteinosis or pulmonary

hypoxaemia and widening of the PA-a,O₂.

oedema) and/or a reduced surface area for

exchange (e.g. pulmonary embolism or

The Q9s/Q9 relationship derives from the

restrictive lung disease) slow the diffusive

recognition that the rate of oxygen delivery

flux of oxygen because of their effects on

into the systemic arterial circulation can be

TLO₂ With very high levels of Q9 (e.g. very fit

viewed as being made up of a homogeneous

endurance athletes exercising at or close to

‘ideal’ pulmonary capillary component and a

maximum) or very high linear capillary-blood

‘pure’ shunt component. Reverting again to

velocities (e.g. pulmonary embolism, where

the Fick principle, but now for the ‘blood’

there are fewer participating capillaries), the

side, and using the simple equality

reduction in tTR can lead to a widened PA-

Q95Q9c+Q9s:

aO₂ and arterial hypoxaemia. Supplemental

Q9?CaO₂5Q9c?Cc9O₂+Q9s?CvO₂

(23)

oxygen can, through its effects on PAO₂ and,

therefore, driving pressure, speed the

were Cc9O₂ is the end-capillary oxygen

increase of PcO₂ and thus ameliorate the

content and CvO₂ is the mixed-venous

degree of gas-exchange impairment.

oxygen content, which rearranges to yield:

However, although severe degrees of arterial

Q9s/Q95(Cc9O₂-CaO₂)/(Cc9O₂-CvO-₂)

(24)

hypoxaemia can result from diffusion

impairment, carbon dioxide retention is

CaO₂ and CvO₂ can be measured directly

rarely a problem. This is because any

from blood samples, while Cc9O₂ is derived

increase in PaCO₂ that might occur tends to

through the standard oxygen dissociation

be corrected by ventilatory control

curve, assuming Pc9O₂5PAiO₂ (equation 17).

mechanisms, which are considered to be

It should be noted that this equation also

exquisitely sensitive to carbon dioxide (i.e.

assumes that all the shunted blood is of

central and carotid body chemoreflexes); in

mixed-venous composition, which may not

contrast, hypoxic ventilatory stimulation

necessarily be the case for bronchial venous

only becomes appreciable when PaO₂ falls

blood. This estimate of Q9s/Q9 thus provides

below ,60 mmHg. Hence, moderate

an overestimate of the true shunt, as it

diffusion impairment is accompanied by a

incorporates a fraction of the perfusion

decreased PaO₂, a widened PA-aO₂ and a

draining from alveolar units having poorly

ERS Handbook: Respiratory Medicine

functional capillaries (with low V9A/Q9

hypoventilation (i.e. low PO₂ and high PCO₂)

values), i.e. creating a ‘shunt-like’ effect.

and, in the extreme, alveolar shunt (V9A/

Q950) (see previously); gas and blood from

A right-to-left shunt must therefore result in

normal V9A/Q9 regions will have a normal

arterial hypoxaemia, i.e. even a small

PO₂ and PCO₂; and gas and blood from high

contribution from nonarterialised blood will

V9A/Q9 regions will reflect hyperventilation

depress the resulting CaO₂, owing to the

(i.e. high PO₂ and PCO₂) with, in the extreme,

influence of the nonlinear oxygen

alveolar dead space (V9A/Q95‘).

dissociation curve. The severity of the

hypoxaemia will depend both on Q9s/Q9 and

An analogous formulation to that for

CvO₂, being more marked when the former is

estimation of Q9s/Q9 can be applied to the

larger and the latter is lower. A hallmark

estimation of VD/VT (recalling that VD

feature of a pure right-to-left shunt is that

reflects the sum of the anatomical and

the elevation of PaO₂ in response to

alveolar dead spaces). That is, the

administration of 100% oxygen is

assumption is made that the volume of

appreciably less than expected. This is

carbon dioxide cleared in exhalation

because the shunt flow cannot ‘see’ the

originates solely from a homogeneous

elevated PAO₂ in the exchanging alveoli, and

exchanging alveolar compartment (Bohr

also that further increases in PAO₂ will have

technique):

little effect on Cc9O₂ because the blood is

VT?FECO₂5VA?FACO₂

(25)

already essentially fully saturated; it is only

the dissolved component of the oxygen

where FECO₂ is mixed expired carbon dioxide

content that can be increased, and this will

fraction and VA is the volume of exchanging

be relatively small because of the low

alveoli. Substituting VT-VD for VA, converting

solubility of oxygen in plasma.

fractional concentrations to gas tensions,

making the reasonable assumption that

A right-to-left shunt also has the potential to

PACO₂5PaCO₂ (attributable to Enghoff) and

cause carbon dioxide retention but this is

rearranging yields:

rarely observed owing to the normally small

mixed venous-to-arterial carbon dioxide

VD/VT5(PaCO₂-PECO₂)/PaCO₂

(26)

tension (PCO₂) difference (,6 mmHg at rest

Even in the normal lung, there is evidence of

versus ,60 mmHg for oxygen) and also (see

mild V9A/Q9 mismatch. Owing to the

earlier) the mechanisms of ventilatory

influence of gravity, Q9 is distributed

control that normally restore an increased

preferentially to the dependent regions of

PaCO₂ to normal. Again, however, should

the lung (i.e. towards the base in the upright

PaO₂ fall sufficiently to cause hypoxic

posture). A similar, gravitationally induced

stimulation of the carotid chemoreceptors,

effect is also seen for V9A, though it is less

then PaCO₂ will fall; but, without this, PaCO₂

striking. Thus, the alveoli in the dependent

will rise. Thus, a moderate right-to-left shunt

regions of the lung are smaller, as the

leads to a reduced PaO₂ and a widened

hydrostatic pressure in the surrounding

PA-aO₂, but a relatively normal PaCO₂. Severe

interstitium is greater. They are therefore

right-to-left shunts cause a markedly

constrained to operate over the steeper,

reduced PaO₂ and a markedly widened

lower portion of the CL curve, in contrast to

PA-aO₂, with the possibility of a lowered PaCO₂.

the larger apical units. Thus, the smaller

V9A/Q9 maldistribution Although overall V9A

basal units undergo a greater expansion for

may be approximately equal to overall Q9 in

a given increase of PTP during inspiration

the lung, there may nonetheless be regions

and are therefore better ventilated than are

with high, normal and low V9A/Q9 ratios.

the apical units. The apical units thus have a

This has important implications for regional

relatively high V9A/Q9 while the basal units

alveolar gas and pulmonary end-capillary

have a low V9A/Q9. Naturally, the degree of

blood composition, and therefore for overall

V9A/Q9 mismatch is considerably greater in

arterial blood-gas status. That is, gas and

many pulmonary disease states (e.g. COPD,

blood from low V9A/Q9 regions will reflect

diffuse interstitial fibrosis and pulmonary

ERS Handbook: Respiratory Medicine

vascular occlusive disease) and its

V9A/Q9 regions (even if haemoglobin is

topographical location is not predictable.

completely saturated) are unable to

compensate for the low V9A/Q9 regions, as

The overall (or mean) PAO₂ and PACO₂ result

their perfusion is usually less. Consequently,

from an averaging of the respective gas

even though the overall V9A/Q9 may be

concentrations from each individual gas

normal, V9A/Q9 mismatch results in arterial

‘stream’, in proportion to the local V9A.

hypoxaemia, with mean PaO₂ being lower

Likewise, the overall (or mean) PaO₂ and

than the actual mean PAO₂ or its ‘ideal’

PaCO₂ will result from a flow-weighted

representation; i.e. PA-aO₂ is widened.

averaging of the respective gas contents

from each individual blood ‘stream’.

In contrast, the carbon dioxide dissociation

However, it is important to recognise that

curve is essentially linear in the physiological

account has also to be taken of the shape of

range (fig. 5). This therefore allows the

the oxygen and carbon dioxide dissociation

hyperventilatory effects of the high V9A/Q9

curves in order to derive these PaO₂ and

regions to better counterbalance the

PaCO₂ values (fig. 5).

hypoventilatory effects of the low V9A/Q9

regions on the resulting mean PaCO₂

(fig. 5).

Owing to the sigmoid shape of the oxygen

It should be noted, however, that the high

dissociation curve, low V9A/Q9 regions lead

V9A/Q9 regions exert a proportionally greater

both to low PO₂ and low oxygen content in

influence on mean PACO₂ than do the low

pulmonary end-capillary blood; in contrast,

V9A/Q9 regions. Hence, PACO₂,PaCO₂.

while high V9A/Q9 regions lead to a high

Pc9O₂, Cc9O₂ is only slightly increased above

The pattern of arterial blood and alveolar gas

the normal value because the oxygen

tensions in V9A/Q9 mismatch is such that

dissociation curve is relatively flat in this

with mild or moderate mismatch, PaO₂ is

range (fig. 5). Mixing blood from low V9A/Q9

low, PA-aO₂ is widened, with PaCO₂ being

regions with blood from high V9A/Q9 regions

normal or low depending on the degree of

will therefore result in a mean PaO₂ that is

ventilatory stimulation consequent to the

weighted towards low V9A/Q9 blood values

hypoxaemia. In severe V9A/Q9 impairment

(fig. 5). PaO₂ will also depend on the volumes

associated with severe airway obstruction,

of blood from each region contributing to

hypoventilation can ensue owing to the

the mixed arterial blood. Thus, the high

increased work of breathing and, therefore,

High V'A/Q'

Low

●

V'A/Q'

Low

V'A/Q'

Normal

●

points

High

V'A/Q'

PaO

PaCO

Figure 5. Influence of altered V9A/Q9 on mean PaO2 and PaCO2 tensions. a) The sigmoid oxygen

dissociation curve leads to arterial hypoxaemia (arrow) compared with ‘normal’ (6). b) This effect is not

evident for carbon dioxide, because the carbon dioxide dissociation curve is linear. Reproduced from Whipp

(2002) with permission from the publisher.

ERS Handbook: Respiratory Medicine

cause an increased PaCO₂. This, of course,

American Physiological Society,

1964;

reduces Pa,O₂ even more.

pp. 592-607.

Piiper J, et al. Blood gas equilibration in

lungs. In: West JB, ed. Pulmonary Gas

Further reading

Exchange, Vol. II. New York, Academic

Press, 1998: pp. 132-161.

D’Angelo E (1999). Dynamics. Eur Respir

Monogr; 12: 54-67.

Pride NB, et al. Lung mechanics in

Farhi LE. Ventilation-perfusion relation-

disease. In: Macklem PT, et al., eds.

ships. In: Farhi LE, et al., eds. Handbook

Handbook

Physiology.

The

of Physiology. The Respiratory System,

Respiratory System, Mechanics of

Mechanics of Breathing, vol. IV.

Breathing, vol. III, part

2. Bethesda,

Bethesda,

American

Physiological

American Physiological Society,

1986;

Society, 1986; pp. 199-215.

pp. 659-692.

Hughes JMB. Diffusive gas exchange. In:

Riley RL, et al. (1949). ‘‘Ideal’’ alveolar air

Whipp BJ, et al., eds. Pulmonary Physiology

and the analysis of ventilation-perfusion

and Pathophysiology of Exercise. New York,

relationships in the lung. J Appl Physiol; 1:

Dekker, 1991; pp. 143-171.

825-847.

Klas JV, et al.

(1989). Voluntary versus

Rodarte JR, et al. Dynamics of respiration.

reflex regulation of maximal exercise flow:

In: Macklem PT, et al., eds. Handbook of

volume loops. Am Rev Respir Dis; 139:

Physiology. The Respiratory System,

150-156.

Mechanics of Breathing, vol. III, part 1.

Lumb AB. Nunn’s Applied Respiratory

Bethesda,

American

Physiological

Physiology.

7th Edn. London, Elsevier,

Society, 1986; pp. 131-144.

2010.

Weibel ER. Pathway for Oxygen.

Maina JN, et al. (2005). Thin and strong!

Cambridge, Harvard University Press.

The bioengineering dilemma in the struc-

1984.

tural and functional design of the blood-

West JB. Ventilation/Blood Flow and Gas

gas barrier. Physiol Rev; 85: 811-844.

Exchange. Oxford, Blackwell, 1990.

Mead J, et al. Dynamics of breathing. In:

West JB, et al.

(1998). Pulmonary gas

Fenn WO, et al., eds. Handbook of

exchange. Am J Respir Crit Care Med; 157:

Physiology,

Respiration,

vol.

S82-S87.

Washington,

American Physiological

Whipp BJ. The physiology and pathophy-

Society, 1964; pp. 411-427.

siology of gas exchange. In: Bittar EE, ed.

Otis AB. The work of breathing. In: Fenn

Pulmonary Biology in Health and

WO, et al., eds. Handbook of Physio-

Disease. New York, Springer-Verlag,

logy, Respiration, vol.

1. Washington,

2002; pp. 189-217.

ERS Handbook: Respiratory Medicine

Cytology of the lung

Venerino Poletti, Giovanni Poletti, Marco Chilosi and Bruno Murer

The role of cytological techniques for

cytological samples or of preparations

investigation of respiratory disorders has

obtained from bioptic samples (smears or

been recognised since the earliest days of

touch imprints) has also improved the

clinical cytology. Improvement in sampling

diagnostic yield of the investigative

techniques, and in particular, the advent of

methods. A knowledge of ‘basic cytology’

fibreoptic bronchoscopy, transparietal fine-

should be part of the education for

needle aspiration, cytological sampling

becoming a pulmonologist and this

assisted by echoendoscopy, the use of

knowledge should be maintained in daily

immunocytochemical and, more recently,

clinical practice.

molecular biology methods, recent advances

in liquid-based cytology, and the use of cell

Technical notes

block processing methods have increased

the clinical impact of cytological diagnoses.

The routine staining procedures that

Finally, the rapid, on-site analysis of

pulmonologists should be familiar with are

Diff-Quik, May-Grünwald-Giemsa (MGG),

Papanicolaou, haematoxylin-eosin and

Key points

Gram staining, and a staining for acid-fast

bacilli (Ziehl-Neelsen and/or Kinyoun).

BAL is an important source of

Papanicolaou stain is a polychrome stain:

cytological samples.

the nucleus stains deep blue, nuclear details

Fine-needle aspiration has increased

are sharp, the nucleolus stains red, and the

the impact of cytological diagnoses.

cytoplasm stains eosinophilic, cyanophilic

or orange. Keratin stains deep orange. The

Cell blocks are easy to prepare and

slides must be wet-fixed swiftly and rapidly.

useful for immunocytochemistry.

Diff-Quik is a three step procedure requiring

Reactive cytological features in

about 20-30 s to complete. The staining kit

respiratory samples can be

includes fixative solution A (trimethane dye

characteristic but nonspecific.

and methyl alcohol, but 95% ethyl alcohol is

valid), solution I that contains xanthene dye

Cytology can be used to diagnose

and solution II that contains a buffered

respiratory infections.

solution of thiazine dyes. Slides are air dried

Lung carcinoma presents a variety of

and then fixed. Material obtained by fine-

characteristic patterns.

needle aspiration techniques should be used

for smears and for cell-block preparations,

Lymphoproliferative disorders are

cytofluorimetric analysis and genetic studies

Further reading

lungs. In: Hasleton P, et al., eds.

Spencer’s Pathology of the Lung.

Adams J, et al. (2012). The utility of fine-

needle aspiration in the diagnosis of

Cambridge, Cambridge University Press,

primary and metastatic tumors to the

2013; pp. 1375-1407.

lung: a retrospective examination of 1,032

Parham DM, et al.

(1993). Cytologic

cases. Acta Cytol; 56: 590-595.

diagnosis of respiratory syncytial virus

Allen TC, et al. Mesenchymal and mis-

infection in bronchoalveolar lavage speci-

cellaneous neoplasms. In: Hasleton P, et

men from a bone marrow transplant

al., eds. Spencer’s Pathology of the Lung.

recipient. Am J Clin Pathol; 99: 588-592.

Cambridge, Cambridge University Press,

Poletti V, et al. (2007). Bronchoalveolar

2013; pp. 1224-1316.

lavage in malignancy. Semin Respir Crit

Borie R, et al.

(2011). Clonality and

Care Med; 28: 534-545.

phenotyping analysis of alveolar lympho-

Ravaglia C, et al. (2012). Diagnostic role

cytes is suggestive of pulmonary MALT

of rapid on-site cytologic examination

lymphoma. Respir Med; 105: 1231-1237.

(ROSE) of broncho-alveolar lavage in

Chilosi M, et al. (2010). Mixed adenocar-

ALI/ARDS. Pathologica; 104: 65-69.

cinoma of the lung: place in new propo-

Shidham VB, et al. Serous effusions. In:

sals in classification, mandatory for target

Gray W, et al., eds. Diagnostic

therapy. Arch Pathol Lab Med; 134: 55-65.

Cytopathology. Philadelphia, Churchill

Giles TM, et al. Respiratory tract. In: Gray

Livingstone Elsevier, 2010; pp. 115-175.

W, et al., eds. Diagnostic Cytopathology.

Tabatowski K, et al.

(1988). Giant cell

Philadelphia,

Churchill

Livingstone

interstitial pneumonia in a hard metal

Elsevier, 2010; pp. 17-111.

worker. Cytologic, histologic and analytic

Kini SR. Color Atlas of Pulmonary

electron microscopic investigation. Acta

Cytopathology. New York, Springer, 2002.

Cytol; 32: 240-246.

Koss L, et al., eds. Koss’ Diagnostic

Travis WD, et al. Tumours of the Lung,

Cytology.

Philadelphia,

Lippincott

Pleura, Thymus and Heart. Lyon, IARC

Williams & Wilkins, 2006.

Press, 2004.

ERS Handbook: Respiratory Medicine

Immunology and defence

mechanisms

Bruno Balbi, Davide Vallese, Alessandro Pitruzzella, Chiara Vicari and

Antonino Di Stefano

Each day, 10 000-15 000 L of air are inhaled

(Bucchieri et al., 2009). Additional

by the respiratory system, air containing

protection comes from polypeptide

microorganisms and pollutants gases and

mediators of the innate, non-antibody-

particles. It is conceivable, therefore, that

mediated host defence, and professional

adequate and efficient immunological and

phagocytes. Once innate host defense

defence mechanisms exist inside the

systems are activated by the cytokine and

respiratory system to avoid damage to its

chemokine pathways, acquired, antibody-

structure and to limit the number, extent

mediated immune responses and

and severity of upper and lower respiratory

subsequent tissue repair and remodelling

tract infections (Reynolds, 1997).

are orchestrated by immunocompetent cells

and mediators.

The first line of defence against pathogens is

represented by the epithelial barrier of the

Anatomical barriers

airways. The epithelium is composed of

several different cell types, the structural and

In the upper respiratory tract (URT), the

functional features of which are described in

density of microbes is greater than in the

table 1.

lower respiratory tract (LRT). In fact, it is

Between the epithelium and the lamina

usually considered that only a small number

propria there is a thin basal membrane,

of bacteria are present in the LRT of healthy

formed by a lamina propria and a lamina

individuals. This process of cleaning the LRT

reticularis; these two laminae have a

of bacteria is due to mechanical barriers and

different protein compositions, the basal

reflex mechanisms. The nose itself can be

being composed of connective proteins

considered a first-line barrier. The vibrissae

present on the vestibular region of the nasal

cavity are able to trap the largest particles

Key points

contained in inhaled air. Nasal mucosa is a

type of respiratory mucosa able to trap other

N The respiratory system is exposed to a

smaller particles by means of its mucus

variety of microbiological, physical and

layer. Nasal cilia are able to transport the

chemical insults through inhaled air.

mucus toward the oropharynx to be

swallowed. LRT airways represent a difficult

N Innate, intrinsic and adaptive,

physical barrier system to overcome

acquired host immune defences

(Reynolds, 1997). Dichotomous branching

cooperate in lowering the risk of

and angulation of the airways favour the

damage to respiratory structures in an

impact of inhaled particles on the bronchial

integrated host defence system.

mucosa surface. At points of impaction,

In disease states, one or more of

bronchial-associated lymphoid tissue

these complex mechanisms can be

(BALT) is able to interact with inhaled

impaired and/or dysfunctional.

airborne microbes and particles, and to start

clearance by phagocytes and immune

reactions by immunocompetent cells.

ERS Handbook: Respiratory Medicine

Table 1. Main features of bronchial epithelium cells

Cell type

Ultrastructural features

Known roles

Putative roles

Ciliated cells: the

Cuboidal

Transport of mucus

most prevalent cell

Each cell has ,250 cilia,

stream

type

each cilium is ,6 mm long

Decreased in chronic

inflammation

Club cells (Clara

Cuboidal/columnar,

Secretory function

Progenitors of

cells): the second

nonciliated, nonmucus-

Airway clearance

type II

most prevalent cell

secreting cells

Increased in chronic

pneumocytes

type

Granules are present in

inflammation

Surfactant

apical cytoplasm

production

Basal cells:

Small round cells with

Precursors of other

Stem cells

rare in bronchioles,

numerous secretory

cell types

unknown cell

granules

Involved in

origin

carcinogenesis

Neuroendocrine

Cuboidal/columnar,

Part of diffuse

Origin of small

(Kulchitsky) cells:

mucus-secreting cells

neuroendocrine

cell lung cancer

rare in bronchioles

system

Goblet cells: rare in

Cuboidal/columnar mucus

Secretory function

bronchioles

secreting cells

contributing to the

cleaning of

smallest airways

Increased in chronic

inflammation

Lymphocytes: rare

Small, round cells with

Immune surveillance

in bronchioles

scarce cytoplasm

Increased in chronic

Scattered among the other

inflammation

cell types or adjacent to

the luminal surface of

epithelium

Reflex mechanisms

Dyspnoea can also be considered, at least

under certain circumstances, a defence

A number of reflex mechanisms may help

mechanism, as it can result from both

the defence of the respiratory tract

hypersecretion of mucus and/or

(Reynolds, 1997). They are made possible by

bronchospasm. By reducing the airway

the presence of irritant and stretch receptors

calibre, both are able to impair the ability of

on the mucosa of the airways of the URT

inhaled harmful particles to reach the LRT.

and of the largest LRT airways.

Mucociliary clearance and fluid

Sneezing is a complex reflex starting from

homeostasis

the irritant receptors in the nose, usually

stimulated by inhaled particles, followed by

The constant mechanical clearance of mucus

itching, mucus secretion and, ultimately,

from the airways is considered a primary

leading to a forceful and sudden expiration

airway defense mechanism (Knowles et al.,

through the nose, preceded by a deep and

2002). Through ciliary function and mucus

fast inspiration, that is able to eliminate the

secretion with proper salt/water components,

potentially harmful inhaled particles.

the airway epithelial surface is able to act

Cough In the tracheobronchial tree, the

to maintain the mucociliary clearance with

cough reflex plays a similar role in

a mucus ‘escalator’ from the lowest

eliminating foreign inhaled particles.

airways to the top. With a mucus layer

ERS Handbook: Respiratory Medicine

distal to the epithelium containing

components by the airway epithelia: salt-

different types of mucins and a largely

sensitive defensins and a low-salt liquid

prevalent aqueous layer beneath this, the

able to activate defensins.

airway secretions are, under normal

conditions, able to entrap the vast

Innate defence molecules

majority of inhaled foreign particles and

microbes on the mucus layer and to

The epithelial lining fluid in the airways

transport the mucus up to the larger

contains a myriad of peptides and proteins

airways to be swallowed or eliminated by

exerting innate antimicrobial activities, not

coughing. More recent studies have

only against bacteria and viruses but also, in

emphasised the role of a ‘chemical shield’

some cases, against fungi and parasites. As

from inhaled bacteria. This view underlies

a whole, these innate antimicrobial

the importance of the production and

molecules, although with many differences

secretion into the airway lumen of two

in site and the cell types producing them,

Table 2. Key antimicrobial factors in epithelial lining fluid and their activities

Factor

Type

Cell origin

Antimicrobial

Main immunomodulatory

of molecule

activities

Defensins

Peptides

Phagocytic cells

Mitogenic

Lymphocytes

Chemotactic

Airway epithelial

Degranulates MCs

cells

Cathelicidins

Pro-peptides

Neutrophils

Downregulation of

Monocytes

TNF-a

MCs

Chemotactic

Lymphocytes

Airway epithelial

cells

SLPI

Protein

Macrophages

Antiprotease

Neutrophils

Anti-inflammatory

Airway epithelial

cells

SP-A, SP-D

Lipoproteins

Alveolar type II

Opsonic

cells

Modulate leukocyte

Club cells (Clara

functions

cells)

Structural barrier

Lactoferrin

Glycoprotein

Neutrophils

Antioxidant

Airway epithelial

Binds LPS

cells

Inhibits

biofilm formation

Lysozyme

Enzyme

Neutrophils

Unknown

Airway epithelial

cells

Lactoperoxidase

Enzyme

Airway epithelial

Antioxidant?

cells

BC: bactericidal; BS: bacteriostatic; AV: antiviral; AF: antifungal; AP: antiparasitic; MC: mast cell; TNF: tumour

necrosis factor; SLPI: secretory leukocyte peptidase inhibitor; SP: surfactant protein; LPS: lipopolysaccharide.

ERS Handbook: Respiratory Medicine

secretory stimuli, and direct and indirect

macrophage phagocytosis and subsequent

activities (table 2), provide a highly

bacterial clearance by the intracellular killing

evolutionarily conserved, powerful screen

systems. The size of the bacterial inoculum,

against infections in the naïve host. They also

virulence and resistance, and possibly

trigger more specific and targeted immune

deficits of local immunity mechanisms in the

reactions taking place into the airways and in

host, may cause the failure, at least in a first

the alveolar structures. In addition, the same

round, of host defences. This will cause

molecules have a role as immune

recruitment of additional phagocytes, such as

modulators, antioxidants and antiproteases.

neutrophils, at sites of infection, and sustain

Not surprisingly, attempts have been made

an immune and inflammatory reaction.

to use some of these ‘natural antibiotics’ for

Acquired immune reactions with

therapeutic purposes.

immunoglobulin, cytokine and chemokine

production

Professional phagocytes

Lymphoid tissue is present in the respiratory

Microbial pathogens activate pattern

tract in different forms:

recognition receptors (e.g. Toll-like

receptors, NOD-like receptors, scavenger

N tonsils and adenoids in the URT

receptors, etc.) on phagocytes, namely

N lymph nodes in the mediastinum and hila

macrophages and neutrophils, as well as on

N submucosal aggregates in branching

epithelial cells, mast cells, eosinophils and

points of the airways (BALT)

natural killer cells. This is followed by the

N free immunocompetent cells on the

release of several mediators and factors with

airways and alveolar surface

effector functions and inflammatory

cascades, such as the complement system,

BALT is also considered to be part of a

acute phase reactant proteins, oxidative and

lymphoid network common to other types of

mucosa. In this model, immunisation can

nitrosative stress molecules, prostaglandins,

occur at a distant site (e.g. gastrointestinal

interferons, cytokines and chemokines.

mucosa) and, by the recirculation of

Macrophages are the resident respiratory

lymphocytes, protection can be provided in

phagocytes. Although they are present

the respiratory system. Acquired immune

throughout the airways and interstitium,

reactions start also in the lung with the

their major roles are played in the alveolar

interaction between antigens and antigen-

spaces, as alveolar macrophages. In the

presenting cells. In the lung, at least two

normal individual, the vast majority of cells

types of antigen-presenting cell exist:

recovered through bronchoalveolar lavage

macrophages and dendritic cells. Dendritic

(BAL) are alveolar macrophages. These cells

cells are present in the bronchi, representing

initiate and orchestrate the immune

roughly 1% of epithelial cells, in the alveolar

reactions against pathogens and chemicals

septa and in the interstitium. Together with a

inhaled by the host (e.g. mineral particles).

phagocytic function, they share with alveolar

In a hypothetical model of infection by a

macrophages the ability to process microbial

bacterial species, a pathogen that has

proteins into small peptide fragments that

reached the alveolar space, eluding URT and

are then transported on the cell surface

LRT first-line defences, represents a risk for

together with major histocompatibility

the host as its replication and associated

complex (MHC) molecules. The complex

alveolar inflammation may damage

between the MHC and antigenic epitopes is

respiratory structures. This invader

then presented to T-cells. Antigen

microorganism will ultimately be enmeshed

presentation is made through the T-cell

with the epithelial lining fluid and, thus, be

receptor (TCR) on the T-cell surface.

coated with opsonins. These may be non-

immune or immune, i.e. specific

Antigen presentation initiates the production

immunoglobulins originated by previous

of immunoenhancing cytokines and

immunisation of the host against the

chemokines. A part from the interleukins

pathogen. Opsonins facilitate alveolar

(ILs) and other mediators associated with the

ERS Handbook: Respiratory Medicine

Intrinsic and innate host

Adaptive and acquired immune

defences

Secretory IgA and other immune

Anatomic barriers

opsonins

Defence reflexes

Antigen recognition and presentation

Mucociliary clearance

Cellular immunity

Fluid homeostasis

Pathogens

T- and B- cells

Particles

Innate defence molecules

Cytokines/chemokine

Nonimmune opsonins

production and networking

Professional phagocytes

Chemotactic influx of

inflammatory, immunoeffector cells

Figure 1. Integrated host defence systems in the respiratory tract.

T-helper (Th) type 1 or 2 immune reactions,

Conclusions

IL-17 is a pro-inflammatory cytokine mainly

produced by T-cells with an important role in

The complex, integrated host defence

system described and depicted in figure 1

induction of a neutrophil-mediated protective

represents a superb model of how the

immune response against bacteria or fungal

human body is able to interact efficiently

pathogens (Matsuzaki et al., 2007; Di Stefano

with the external environment in order to

et al., 2009). IL-17 seems to be an example of

preserve its structure and function.

the crossroads between different host

defense mechanisms, as it regulates cell-

Conversely, impairment and/or dysfunction of

mediated immunity and induction of

each of the different components of this

antimicrobial peptides, such as defensins.

system represent the pathogenetic basis for

the development of many respiratory

This process of specific immune reaction

disorders. As an example, primary ciliary

also promotes adaptive B-cell proliferation

dyskinesia results in recurrent airway

and specific immunoglobulin production.

infections, CF is associated with dysfunction of

The relative proportions of different

mucociliary clearance and fluid homeostasis,

immunoglobulins in the URT and LRT differ

and in chronic colonisation and/or infection of

one from each other as well as compared

the airways and in inflammatory airway

with the blood. Immunoglobulins represent

disorders, many different mechanisms

,10% of total proteins in airway secretions.

undergo changes, enhancement or

In the URT, IgA represent the vast majority

impairment (Di Stefano et al., 2009; Pignatti et

of this immunoglobulin. Airway IgA is

al., 2009).

predominantly polymeric: secretory IgA

comprises two IgA monomers held together

by a joining chain and by another

Further reading

glycoprotein, the secretory component,

Balamayooran T, et al. (2010). Toll-like

which is produced by serous and epithelial

receptors and NOD-like receptors in

cells. In contrast with the URT, in the LRT,

pulmonary antibacterial

immunity.

as detected by BAL, IgG is predominant,

Innate Immun; 16: 201-210.

representing ,5% of the total protein

Bals R, et al. (2004). Innate immunity in

content in BAL fluid from normal

the lung: how epithelial cells fight against

individuals. IgM is present only in trace

respiratory pathogens. Eur Respir J;

23:

amounts, due to its large size.

327-333.

ERS Handbook: Respiratory Medicine

Bucchieri F, et al.

(2009). Stem cell

Pignatti P, et al.

(2009). Tracheostomy

populations and regenerative potential

and related host-pathogen interaction are

in chronic inflammatory lung diseases.

associated with airway inflammation as

J Tissue Eng Regen Med; 2: 34-39.

characterised by tracheal aspirate analy-

Di Stefano A, et al. (2009). T helper type

sis. Respir Med; 103: 201-208.

17-related

cytokine

expression

Reynolds HY. Integrated host defense against

increased in the bronchial mucosa of

infections. In: Crystal RG, et al., eds. The Lung:

stable chronic obstructive pulmonary

ScientificFoundation.Philadelphia, Lippincott-

disease patients. Clin Exp Immunol; 157:

Raven Publishers, 1997: pp. 2353-2365.

316-324.

Rogan MP, et al. (2006). Antimicrobial

Knowles MR, et al.

(2002). Mucus

proteins and polypeptides in pulmonary

clearance as a primary innate defense

innate defence. Respir Res; 7: 29-40.

mechanism for mammalian airways.

Sallenave JM (2010). Secretory leukocyte

J Clin Invest; 109: 571-577.

protease inhibitor and elafin/trappin-2:

Martin TR, et al. (2005). Innate immunity

versatile mucosal antimicrobials and

in the lungs. Proc Am Thor Soc;

regulators of immunity. Am J Respir Cell

403-411.

Mol Biol; 42: 635-643.

Matsuzaki G, et al. (2007). Interleukin-17

Whitsett JA

(2002). Intrinsic and innate

as an effector molecule of innate and

defenses in the lung: intersection of pathways

acquired immunity against infections.

regulating lung morphogenesis, host defense,

Microbiol Immunol; 51: 1139-1147.

and repair. J Clin Invest; 109: 565-569.

McCormack FX, et al. (2002). The pul-

Yang D, et al. (2001). Participation of

monary collectins, SP-A and SP-D,

mammalian defensins and cathelicidins

orchestrate innate immunity in the lung.

in antimicrobial immunity: receptors and

J Clin Invest; 109: 707-712.

activities of human defensins and cathe-

Oppenheim JJ, et al.

(2003). Roles of

licidin (LL-37). J Leuk Biol; 69: 691-697.

antimicrobial peptides such as defensins

Zanetti M (2005).The role of cathelicidins

in innate and adaptive immunity. Ann

in the innate host defenses of mammals.

Rheum Dis; 26: Suppl. 2, ii17-ii21.

Curr Issues Mol Biol; 7: 179-196.

ERS Handbook: Respiratory Medicine

Cough and sputum

Alyn H. Morice

Cough is a vital protective mechanism

defending the airways from inhalation and

Key points

aspiration. Patients with a defective cough

reflex, such as those with stroke or

N Cough is characterised by irritant

Parkinson’s disease, have an increase in

receptor hypersensitivity.

mortality and morbidity caused by the

N Nonacid reflux into the airways

increased propensity for aspiration.

frequently precipitates cough.

However, in lung disease, cough is often not

helpful. Thus, in the commonest form of

N Clinical history followed by

cough, that due to upper respiratory tract

therapeutic trials is the management

infection, coughing serves no useful

strategy of choice.

purpose from the sufferer’s point of view,

but aids viral transmission. In chronic

cough, the frequency and severity of

gatherings. Apart from general health

coughing bouts may cause serious

measures, such as hand washing and

disruption to the patient’s life. Quality-of-life

avoidance of contact, there is no specific

instruments have indicated that patients

treatment for upper respiratory tract

with chronic cough may have a similar

infection-induced cough. The demonstrable

decrement to that seen with conditions such

effect of the many cough remedies is likely

as cancer and severe COPD. Cough may

to be due to a physicochemical (demulcent)

also have significant comorbidity. 50% of

effect rather than through a specific

the females attending cough clinics are

pharmacological action of any particular

incontinent and cough syncope is thought to

agent.

be responsible for a number of driving

fatalities.

Chronic cough

Acute cough

Chronic cough is one of the commonest

presentations to the respiratory physician. A

Acute cough due to one of the myriad upper

survey in Yorkshire, UK, indicated that 12%

respiratory tract viruses places an enormous

of the normal population complain of a

demand on the healthcare community. It is

chronic cough and 7% of these thought it

the commonest new presentation to primary

interfered with activities of daily living. Many

care, accounting for 50% of consultations.

reports from specialist cough clinics point to

In temperate regions there is a marked

a particular syndrome in patients with

seasonal variation with autumn and winter

chronic cough. The typical patient is middle-

epidemics. Viral transmission requires

aged and female. The cough appears to have

person-to-person contact, either through

no pattern to it but a careful history will

airborne droplet infection or the manual

often reveal many common features of the

passage of secretions. Superimposed on

presenting complaint. It has been traditional

this seasonal pattern are peaks caused by

to divide these patients without

socialisation, e.g. return to school for the

radiographic abnormalities and no obvious

autumn term and Christmas family

other lung disease into a triad of diagnoses,

ERS Handbook: Respiratory Medicine

namely asthmatic cough, post-nasal drip

sensitivity to a wide range of environmental

syndrome (rhinitis) and reflux cough

stimuli. This hypersensitivity can be

(table 1). These subdivisions have recently

objectively demonstrated in the laboratory

been called into question. For example,

using cough challenge. Thus, patients cough

asthmatic cough is unlike classic atopic

with ethanol inhalation, whereas normal

asthma in that it is usually of late onset

subjects do not. There is a wide variation in

without obvious precipitants and often

cough reflex sensitivity in normal subjects,

without evidence of bronchoconstriction. In

with females being more sensitive than

the form known as eosinophilic bronchitis

males. Sensitivity is accentuated in cough

there is even an absence of bronchial

patients. Inhalation of capsaicin, the

hyperreactivity. Similar caveats apply to

pungent extract of peppers, is typically used

post-nasal drip syndrome and reflux cough.

to demonstrate cough reflex responsiveness

Thus, the latter frequently does not conform

(fig. 1). Capsaicin works by stimulating one

to the criteria for peptic gastro-oesophageal

of a family of nociceptors of the transient

reflux disease. Because of the commonality

receptor potential (TRP) group (fig. 2). The

of the clinical history in chronic cough

capsaicin-sensitive ‘hot’ receptor (TRPV1) is

(table 2), it has been suggested that there is

upregulated in patients with cough. This is

a single unifying diagnosis of cough

due to pro-inflammatory mediators

hypersensitivity syndrome, with the other

increasing expression of TRPV1, either in

diagnoses representing different phenotypes

neurones or in other airway tissues. Rather

of the condition. The risk factors for chronic

than directly causing a cough, angiotensin-

cough suggest that nonacid reflux may be an

converting enzyme inhibitors alter cough

important precipitant (table 3).

sensitivity by a TRPV1-dependent

mechanism, thus explaining the continued

Virtually all patients presenting with a

irritation long after drug withdrawal. Another

chronic cough complain of increased

TRP receptor, TRPA1, is highly reactive to a

Table 1. Early reports from cough clinics illustrating the variety of cough diagnosis dependent on criteria used

Mean age

Patients

Diagnosis % total

years

(females) n

Asthma

GOR Rhinitis

syndrome

Irwin et al. (1981)

50.3

(27)

Poe et al. (1982)

109

(68)

Poe et al. (1989)

44.8

139

(84)

Irwin et al. (1990)

102

(59)

Hoffstein et al. (1994)

228

(139)

O’Connell et al. (1994)

(63)

Smyrnios et al. (1995)

(32)

Mello et al. (1996)

53.1

(64)

Marchesani et al. (1998)

(72)

McGarvey et al. (1998)

47.5

(29)

Palombini et al. (1999)

(51)

Brightling et al. (1999)

(0)

The typical patient is a middle-aged female. These diagnoses are now thought to represent phenotypes of the

cough hypersensitivity syndrome. GOR: gastro-oesophageal reflux. Studies can be found in Morice et al.

(2004).

ERS Handbook: Respiratory Medicine

Table 2. Areas of enquiry in chronic cough

Hoarseness or a problem with your voice

Clearing your throat

The feeling of something dripping down the back of your nose or throat

Retching or vomiting when you cough

Cough on first lying down or bending over

Chest tightness or wheeze when coughing

Heartburn, indigestion or stomach acid coming up, or do you take medications for this?

A tickle or a lump in your throat

Cough with eating (during or soon after meals)

Cough with certain foods

Cough when you get out of bed in the morning

Cough brought on by singing or speaking (e.g. on the telephone)

Coughing more when awake than asleep

A strange taste in your mouth

Responses may either lead to further questioning or be scored 0-5 and used as a diagnostic tool to

demonstrate the presence of cough hypersensitivity syndrome. A questionnaire version in various languages

is available at www.issc.info

Table 3. Risk factors for chronic cough

Variable

With cough

Unadjusted OR

p-value

n/N (%)

(95% CI)

Sex

Male

78/1704 (4.6)

1.0

Female

135/2179 (6.2)

1.38

(1.03-1.86)

0.028

Heartburn

148/2990 (4.9)

1.0

Yes

65/889 (7.3)

1.51

(1.10-2.06)

0.009

Regurgitation

158/3314 (4.8)

1.0

Yes

54/568 (9.5)

2.10

(1.49-2.92)

,0.0001

IBS

111/2914 (3.8)

1.0

,0.0001

Yes

98/909 (10.8)

3.05

(2.27-4.09)

BMI category

Normal

74/1547 (4.8)

1.0

Overweight

72/1448 (5.0)

1.04

(0.74-1.47)

0.86

Obese

60/776 (7.7)

1.67

(1.15-2.41)

0.006

Nonacid reflux symptoms in the form of regurgitation are more closely associated with cough than acid reflux.

IBS: irritable bowel syndrome.

ERS Handbook: Respiratory Medicine

wide range of environmental irritants and

such as gabapentin. Finally, the use of central

causes cough in humans. Upregulation of

cough suppression in the form of antitussive

this receptor provides a mechanism for the

agents, such as low-dose morphine, can

exquisite hypersensitivity complained of by

ameliorate cough in a third of patients with

patients to agonists such as acrolein, the

otherwise intractable symptoms.

pro-tussive ingredient in smoke.

Sputum

Management of chronic cough

In subjects with chronic cough, production

All patients presenting with chronic cough

of moderate amounts of sputum does not

should have a chest radiograph. The clinical

alter the diagnostic profile. The separation

history should indicate the most likely

from individuals with excessive sputum

treatment options. The European Respiratory

production is arbitrary, but is generally

Society guidelines recommend therapeutic

regarded as a cup of sputum per day. Above

trials based on clinical judgement. Thus, in

this limit, a diagnosis of bronchiectasis

patients with episodes of wheezing and

becomes increasingly likely. The presence of

evidence of eosinophilic inflammation, a trial

sputum purulence indicates a greater

of asthmatic medication may well be

likelihood but does not seem to predict the

beneficial (fig. 3). Where available, exhaled

degree of anatomical damage to the airway.

nitric oxide fraction may be a useful screening

Indeed, the diagnosis of bronchiectasis,

tool. Bronchoconstriction may not be a major

relying as it does on the dilation and

component of this phenotype of cough

destruction of the airways, will not include

hypersensitivity syndrome and, consequently,

many patients with functional abnormalities

long-acting b-agonists may be less effective

of the bronchi.

than anti-eosinophilic medication such as

leukotriene antagonists. Reflux disease may

In conditions characterised by sputum

be very problematical, as much airway reflux

hypersecretion, there is usually a change in

is nonacidic and, therefore, not amenable to

the composition of the mucus. Several

blockade by proton pump inhibitors. Pro-

mechanisms are responsible for this change.

motility agents, such as metoclopramide and

Thus, in CF, the increase in sodium

domperidone, may be used. Other motility

reabsorption leads to a reduction in the sol

agents, such as erythromycin, azithromycin

phase of the airway surface liquid. Airway

and magnesium, have also been advocated.

inflammation, particularly that caused by

Operative treatment via Nissen

release of enzymes such as myeloperoxidase

fundoplication can be effective in intractable

(which produces the characteristic green

coughing. An alternative strategy is to treat

colour) and neutral endopeptidase, and by

the hypersensitivity component with agents

polymorphs, causes alteration of mucin

(MUC) gene expression through proteinase-

activated receptors. The death of

●

●■

■

inflammatory cells and bacteria lead to a

●

■

●

■

soup of DNA that cross-links with

filamentous actin, producing gelatinous

plugs that increase ventilation/perfusion ratio

●

mismatch with resulting systemic hypoxia.

■

■ Placebo

^● Captopril

The treatment of mucus hypersecretion may

●

be challenging. In the presence of purulent

■

sputum, every effort should be made to

0.5

identify the causative organism. Eradication

Capsaicin µmoL·L-1

with appropriate high-dose antibiotic therapy

may lead to sustained remission. More

Figure 1. Capsaicin cough challenge in normal

frequently, there is rapid relapse, indicating

subjects, the effect of captopril enhancing cough

the need for maintenance antibiotics either

reflex sensitivity.

orally or via the nebulised route.

ERS Handbook: Respiratory Medicine

Hot

Cold

55°C

43°C

33°C

30°C

25°C

17°C

TRPV2

TRPV1

TRPV3

TRPV4

TRPM8

TRPA1

Cannabidiol

Capsaicin

Eugenol

Osmotic

Cold/

Isothiocyanates

THC

Protons

Thymol

menthol

Acreolin

Cinnamaldehyde

etc.

Figure 2. The thermosensitive transient receptor potential (TRP) channels that are important in cough

reflex sensitivity. Typical ‘natural’ agonists are listed below each channel. THC: tetrahydrocannabinol.

The advantage of this latter strategy is that

review found the quality of randomised

side-effects may be minimised by using

studies to be poor and concluded that any

agents with high local potency but poor oral

benefits achieved may be small (Osadnik

bioavailability, such as colomycin or

et al., 2012).

tobramycin. Antioxidant mucolytics are

Haemoptysis

widely prescribed but evidence of efficacy is

limited. The largest study of N-acetylcysteine

Haemoptysis presents in two clinical

over 3 years showed no effect on decline in

scenarios. First, the patient may present

lung function or exacerbation rate. In COPD,

with de novo haemoptysis without pre-

two agents, azithromycin and roflumilast,

existing lung disease. Any mucosal lesion

have been shown to be efficacious in those

may cause haemoptysis of small amounts of

with exacerbations of chronic bronchitis.

blood mixed with sputum. Since this is a

common presentation of lung cancer, chest

Perhaps because of the paucity of specific

radiography is obligatory in patients when

agents for mucus hypersecretion,

presenting with haemoptysis and, in heavy

nonpharmacological therapy in the form of

smokers, CT or bronchoscopy is also

airway clearance techniques is frequently

required. Aspergilloma and TB may similarly

advocated. However, a recent Cochrane

cause blood-stained bronchitis. More

peripheral lung pathology, such as lobar

pneumonia, gives rise to sputum that is

■ Off

■

frequently described as ‘rusty’. Haemoptysis

■

of frank blood is a common sign of

pulmonary embolism or infarction.

Obviously, recurrent haemoptysis initially

■

presents with acute haemoptysis. Typically,

bronchiectasis leads to recurrent, sometimes

■

massive and occasionally fatal haemoptysis.

■

100 300 1000

The bronchial blood supply arises from the

Citric acid nM

aorta and, in contrast to the pulmonary

circulation, is at systemic pressure. In

Figure 3. Cough challenge with citric acid in

bronchiectasis, there is hypertrophy of the

eosinophilic bronchitis and the response to inhaled

bronchial arteries as a consequence of

steroids. Number of coughs off and on budesonide

recurrent infection. When the patient presents

is shown.

with life-threatening haemoptysis,

ERS Handbook: Respiratory Medicine

radiographic percutaneous bronchial artery

Ford AC, et al.

(2006). Cough in the

embolisation is the treatment of choice.

community: a cross sectional survey and

Vasculitis is a common and frequently missed

the relationship to gastrointestinal symp-

cause of recurrent haemoptysis and diffuse

toms. Thorax; 61: 975-979.

alveolar haemorrhage. While the systemic

Millqvist E, et al. (2008). Inhaled ethanol

connective tissue diseases, such as systemic

potentiates the cough response to cap-

lupus erythematosus, may produce small-

saicin in patients with airway sensory

vessel haemoptysis, the commonest cause is

hyperreactivity. Pulm Pharmacol Ther; 21:

794-797.

microscopic polyangiitis. The perinuclear

anti-neutrophil cytoplasmic antibody (MPO

Mitchell JE, et al. (2005). Expression and

characterization of the intracellular vanil-

ANCA) is positive in ,70% of cases. Finally,

loid receptor

(TRPV1) in bronchi from

haemoptysis may be the result of alveolar

patients with chronic cough. Exp Lung

haemorrhage. Disease of the vascular or

Res; 31: 295-306.

alveolar wall, such as Goodpasture’s

Morice AH (2010). The cough hypersen-

syndrome or alveolar haemosiderosis, may

sitivity syndrome: a novel paradigm for

present with recurrent haemoptysis. Clearly,

understanding cough. Lung; 188: 87-90.

disorders of coagulation, both congenital and

Morice AH, et al. (2004). The diagnosis

acquired, and including warfarin therapy or

and management of chronic cough. Eur

thrombocytopenia, will predispose to

Respir J; 24: 481-492.

haemoptysis.

Morice AH, et al. (2007). Opiate therapy

in chronic cough. Am J Respir Crit Care

Med; 175: 312-315.

Further reading

Osadnik CR, et al. (2012). Airway clear-

Birrell MA, et al. (2009). TRPA1 agonists

ance techniques for chronic obstructive

evoke coughing in guinea-pig and human

pulmonary disease. Cochrane Database

volunteers. Am J Respir Crit Care Med;

Syst Rev; 3: CD008328.

180: 1042-1047.

Palombini BC, et al. (1999). A pathogenic

Decramer M, et al. (2005). Effects of N-

triad in chronic cough: asthma, postnasal

acetylcysteine on outcomes in chronic

drip syndrome, and gastroesophageal

obstructive pulmonary disease (Bronchitis

reflux disease. Chest; 116: 279-284.

Randomized on NAC Cost-Utility Study,

Rogers DF (2007). Physiology of airway

BRONCUS): a randomised placebo-con-

mucus secretion and pathophysiology of

trolled trial. Lancet; 365: 1552-1560.

hypersecretion. Respir Care; 52: 1134-1146.

ERS Handbook: Respiratory Medicine

Dyspnoea

Pierantonio Laveneziana and Giorgio Scano

Dyspnoea is the major reason for referral for

importance of the different qualities (cluster

pharmacological treatment and respiratory

descriptors) covered by the term dyspnoea,

rehabilitation programmes in patients with

the involvement of integration of multiple

COPD. Dyspnoea is a subjective experience

sources of neural information about

of breathing difficulty that consists of

breathing and the physiological

qualitatively distinct sensations that vary in

consequences. More specifically, it has been

intensity. This definition underlines the

postulated that dyspnoea arises when there

is a conscious awareness of a mismatch

between what the brain expects and what it

Key points

receives in terms of afferent information

from the lungs, airways and receptors in the

tendons and muscles of the chest wall (fig. 1

Dyspnoea is a subjective experience of

and table 1).

breathing discomfort that consists of

qualitatively distinct sensations that

Evaluation of dyspnoea during physical

vary in intensity.

tasks

The mechanisms of dyspnoea are

Exertional dyspnoea can be easily defined as

complex and multifactorial: there is

‘the perception of respiratory discomfort

no unique central or peripheral source

that occurs for an activity level that does not

of this symptom.

normally lead to breathing difficulty’ (Killian

The sense of heightened inspiratory

et al., 1995). It follows that the intensity of

effort is an integral component of

dyspnoea can be determined by assessing

exertional dyspnoea and is pervasive

the activity level required to produce

across health and disease.

dyspnoea (i.e. dyspnoea at rest is more

severe than dyspnoea only when climbing

The NVD theory of dyspnoea states

stairs). The Medical Research Council

that the symptom arises when there is

(MRC) dyspnoea scale can be used for this

a disparity between the central reflex

purpose (table 2), as well as other scales

drive (efferent discharge) and the

such as the Baseline Dyspnoea Index.

simultaneous afferent feedback from

Dyspnoea can also be evaluated during a

a multitude of peripheral sensory

physical task, such as cardiopulmonary

receptors throughout the respiratory

exercise testing (CPET). For this purpose,

system. The feedback system provides

the 10-point Borg scale can be used

information about the extent and

(table 2). In the Borg scale, the end-points

appropriateness of the mechanical

are anchored such that zero represents ‘no

response to central drive.

breathlessness at all’ and 10 is ‘the most

Despite the diversity of causes, the

severe breathlessness that one had ever

similarity of described experiences of

experienced or could imagine experiencing’.

dyspnoea suggests common

Using the Borg scale, subjects rate the

underlying mechanisms.

magnitude of their perceived breathing

discomfort during exercise. Though

ERS Handbook: Respiratory Medicine

Forebrain sensory

areas

Instantaneous

Motor

feedback

cortex

Stretch receptors

(volume)

Airway

Joint receptors

receptors

(muscle displacement)

(flow)

Spindles

(muscle displacement)

Golgi

(muscle

tension)

Figure 1. Schematic representation of the neurophysiological underpinnings of perceived dyspnoea during

exercise in healthy humans. During a voluntary increase in ventilation, the motor cortex increases the

outgoing motor signal to the respiratory muscles and conveys a copy (central corollary discharge) through

cortical interneurons to the sensory/association cortex, which is informed of the increased motor drive to

increase ventilation. Volitional respiratory effort in healthy subjects is harmoniously matched with the

appropriate increase in flow or volume displacement via concurrent afferent proprioceptive information

transmitted via vagal, glossopharyngeal, spinal and phrenic nerves. This information is conveyed to the

medulla and central cortex, where it is integrated. The result is a harmonious neuromechanical coupling

with avoidance of respiratory discomfort or distress. Reproduced and modified from Scano et al. (2010)

with permission from the publisher.

somewhat less popular, the visual analogue

2) What are the neurophysiological

scale (VAS) is another dyspnoea measuring

underpinnings of the most selected cluster

instrument with proven construct validity

descriptors that define the qualitative

during CPET. Both the VAS and Borg scale

dimension of dyspnoea in patients?

have been shown to provide similar scores

3) Do obstructive and restrictive lung

during CPET, and to be reliable and

diseases share some common underlying

reproducible over time in healthy subjects,

mechanisms?

and in patients with asthma and COPD

undergoing CPET.

Dyspnoea is perceived as a sense of effort

Physiology

During voluntary increase in ventilation, the

motor cortex increases the outgoing motor

The recent American Thoracic Society

signal to respiratory muscles and conveys a

statement has emphasised the

copy (central corollary discharge) through

multidimensional nature of dyspnoea in the

cortical interneurones to the sensory/

sensory-perceptual (intensity and quality),

association cortex, which is informed of the

affective distress and impact domains. To

voluntary effort to increase ventilation. It is

gain more insight into our understanding of

also likely that the sense of the respiratory

dyspnoea, a case can be made for answering

effort arises from the simultaneous

the following questions.

activation of the sensory cortex and muscle

1) What is the role of mechanical factors and

contraction: a variety of muscle receptors

ventilatory constraints in dyspnoea?

provides feedback to the central nervous

ERS Handbook: Respiratory Medicine

Table 1. Putative neurophysiological basis of exertional dyspnoea

Central (corollary discharge)

q motor drive (inspiratory effort): cortical

q reflex drive (chemical, neural): medullary

Peripheral (afferent activity)

Airway/lung receptors (pulmonary stretch receptors,

C-fibres, J-receptors)

Ventilatory muscle receptors (muscle spindles, Golgi

tendon organs, joint receptors, type III and IV mechano-

and metaboreceptors in the diaphragm and chest wall

muscles)

Peripheral chemoreceptors

Locomotor muscles receptors (type III and IV afferents)

The most important receptors (afferences) and efferences to respiratory and locomotor muscles involved in

the putative pathogenesis of exertional dyspnoea in cardiopulmonary disease. Please see the main text for

more details.

system about force and tension, and

ventilatory response. In these

information from these receptors may

circumstances, dyspnoea is perceived as a

conceivably underlie the sense of effort. For

sensation of air hunger, the intensity of

clinical purposes, the perceived magnitude

which depends on a mismatching between

of respiratory effort is expressed by the ratio

the level of chemically stimulated drive and

of the tidal oesophageal pressure (Poes) to

ongoing inhibition from pulmonary

the maximal pressure generation capacity of

mechanosensors signalling the current

the respiratory muscles (PImax). In healthy

level of ventilation. In turn, dyspnoea arises

subjects, volitional respiratory effort is

and may qualitatively change when

matched by lung/chest wall displacement

peripheral afferent feedback is altered and

(i.e. change in tidal volume (VT) as

inspiratory motor output either increases

percentage of vital capacity (VC)) via

or stabilises.

concurrent afferent proprioceptive

information, transmitted via vagal,

Pathophysiology

glossopharyngeal, spinal and phrenic

COPD Two qualitative descriptor clusters of

nerves, that monitors displacement, and is

dyspnoea are commonly selected by

processed and integrated in the sensory

patients with COPD during physical activity.

cortex. The result is a harmonious

neuromechanical coupling with avoidance of

The descriptor cluster that alludes to

respiratory discomfort or distress (fig. 1

increased respiratory work/effort (‘breathing

and table 1).

requires more effort or work’) is commonly

selected by patients with COPD. Increased

Dyspnoea is perceived as a sense of air

sense of work/effort is related to the

hunger

increased motor drive to the respiratory

Under some clinical and experimental

muscles and increased central neural drive

circumstances, the relationship between

(due to chemostimulation) as a

dyspnoea and effort is less apparent. If

consequence of progressive metabolic and

normal subjects suppress their ventilation

ventilation/perfusion disruptions during

to a level below that dictated by chemical

exercise. Therefore, increased perceived

drive (carbon dioxide), dyspnoea increases

work/effort during physical activity, in part,

without corresponding increases in indices

reflects the greater ventilatory demand for a

of respiratory effort. Likewise, in

given task compared with health. In

experimental and clinical conditions where

addition, contractile muscle effort is

peripheral stretch receptors are inhibited,

increased for any given ventilation

the sensory cortex is not informed of the

because of:

ERS Handbook: Respiratory Medicine

Table 2. The MRC dyspnoea scale and the Borg scale

Grade

Description

MRC dyspnoea

scale

Not troubled by breathlessness except with strenuous exercise

Troubled by shortness of breath when hurrying on the level or walking up a

slight hill

Walks slower than people of the same age on the level because of

breathlessness or has to stop for breath when walking at own pace on the level

Stops for breath after walking ,90 m or after a few minutes on the level

Too breathless to leave the house or breathlessness when dressing or

undressing

Borg scale

No breathlessness at all

0.5

Very, very slight (just noticeable)

Very slight

Slight breathlessness

Moderate

Somewhat severe

Severe breathlessness

Very severe breathlessness

Very, very severe (almost maximum)

Maximum

1) the acutely increased intrinsic mechanical

abnormalities (chronic bronchitis and

(elastic/threshold) loading; and

emphysema), via their negative

physiological consequences, i.e. expiratory

2) functional respiratory muscle weakness.

flow limitation and dynamic hyperinflation,

result in dyspnoea. A patient’s physical

These respiratory mechanical/muscular

activity is indeed characterised by a growing

abnormalities are, in part, related to resting

mismatch between increase in central neural

and dynamic hyperinflation during exercise,

output to the respiratory muscles and the

and may lead to either a decrease in PImax or

blunted respiratory mechanical/muscular

a further increase in Poes as percentage of

response (lung/chest wall displacement).

PImax. Because of these effects, greater

This mismatch, which we call

neural drive or electrical activation of the

neuroventilatory dissociation (NVD), has

respiratory muscle is required to generate a

been proposed to be, at least in part, the

given force. Furthermore, because of limbic

neurophysiological basis of the perceived

system activation, the corollary discharge

unsatisfied inspiration. In a clinical setting,

may be sensed as abnormal, thus evoking a

the slope that defines NVD (i.e. effort versus

sensation of distress (fig. 1 and table 1).

displacement) is steeper and shifted upward

The other descriptor cluster alludes to

compared with healthy subjects. The steeper

unsatisfied inspiration. Structural

the slope, the greater the intensity of

ERS Handbook: Respiratory Medicine

dyspnoea (fig. 2). In particular, patients

● NMD

●

▲

Controls

experience intolerable dyspnoea during

●●

exercise because VT expansion is

●

constrained from below (by the effects of

●

dynamic lung hyperinflation or the already

●

critically reduced resting inspiratory

●

capacity), as there is no space to breathe.

●

●●

●

▲

●

●▲

▲

This so-called dyspnoea threshold seems to

●

▲

be at the level at which the inspiratory

15 20

25 30

reserve volume (IRV) critically approaches

VT/VCpv %

0.5 L. Once this critical IRV is achieved,

further expansion in VT is negated, the

Figure 3. A mismatch between inspiratory effort

effort-volume displacement ratio (Poes/

(swing in oesophageal pressure (Poes,sw) as a

PImax divided by VT/VC) increases sharply

percentage of oesophageal pressure during a sniff

and dyspnoea intensity rises steeply to

manoeuvre (Poes,sn)) and lung/chest wall

intolerable levels. The data support the

displacement (VT as a percentage of the predicted

central importance of mechanical restriction

value of the vital capacity (VCpv)) in patients with

in causing dyspnoea in COPD patients.

NMD compared with average data from controls.

The steeper the slope, the greater the perception of

Neuromuscular disorders Patients with

dyspnoea.

neuromuscular disorders (NMD) exhibit

heightened neuromotor output, which is

response to the increased metabolic

sensed as increased respiratory muscle

demands of physical tasks. One of the

effort and, as such, is likely to be the

characteristic features of ILD is a reduction

principal mechanism of dyspnoea in NMD.

in lung compliance and lung volumes. This

Nonetheless, a significant positive

has two major consequences.

relationship between increased dyspnoea

per unit increase in ventilation and dynamic

1. Greater pressure generation is required by

elastance affects the coupling between

the inspiratory muscles for a given VT.

respiratory effort and displacement (fig. 3).

2. The resting TLC and IRV are often

Interstitial lung disease As in COPD,

diminished compared with health.

restrictive dynamic respiratory mechanics

limits the ability of patients with interstitial

Therefore, VT expansion is constrained from

lung disease (ILD) to increase ventilation in

above early in exercise (reflecting the

reduced TLC and IRV), which results in

greater reliance on increasing breathing

Healthy

●

frequency to increase ventilation.

COPD

Differences in dynamic ventilatory

mechanics, including possible expiratory

Elastic and

resistive load

flow limitation in some patients, account

●

for distinct qualitative perception in ILD

patients, namely inspiratory difficulty/

unsatisfied inspiration and rapid shallow

breathing. Because of increases in both

VT/VC %

dynamic elastance and efferent respiratory

drive, inspiratory difficulty/unsatisfied

inspiration may have its neurophysiological

Figure 2. NVD. The slope that defines the

mismatch between increase in neural output

basis in the conscious awareness of a

(inspiratory effort, i.e. Poes/PImax) and lung/chest

dissociation between the increased drive to

wall displacement (VT/VC) is steeper and shifted

breathe (and concurrent increased

upwards in patients with COPD compared with

respiratory effort, i.e. Poes/PImax) and the

healthy subjects.

restricted mechanical response of the

ERS Handbook: Respiratory Medicine

respiratory system (i.e. VT/VC), i.e. the

perception of respiratory discomfort. In

inability to expand VT appropriately in the

contrast, ‘deflators’ exhibit a negative

face of an increased drive to breathe. In

relationship between resting end-expiratory

turn, the possibility has also been put

lung volume (EELV) and perceptual

forward that intensity of exertional

respiratory response during exercise: the

dyspnoea in ILD is more closely linked to

lower the EELV, the greater the Borg score.

mechanical constraints on volume

A low EELV has three important

expansion than to indexes of inspiratory

consequences linked together

effort per se.

during exercise:

Chronic heart failure The key message that

1) Decrease in expiratory reserve volume

has emerged from therapeutic intervention

2) Dynamic airway compression

studies in patients with CHF is that

exertional dyspnoea alleviation is

3) Changes in transmural airway pressure

consistently associated with reduced

resulting in airway dynamic compression

excessive ventilatory demand (secondary to

reduced central neural drive), improved

Thus, an alteration in the central drive

respiratory mechanics and muscle function

to the respiratory muscles in response

and, consequently, enhanced

to afferent activity from upper airway

neuromechanical coupling of the

mechanoreceptors may also contribute to

respiratory system during exercise. Pressure

the unpleasant respiratory sensation in

support is reported to reduce the tidal

obese subjects.

inspiratory pleural pressure-time slope

Effects of interventions on dyspnoea

without affecting submaximal dyspnoea

ratings but allows patients to exercise for

Effective improvement in exertional

additional time without experiencing any

dyspnoea represents one of the most

significant rise in dyspnoea. The available

challenging targets of management in

data suggest that increased ventilatory

patients with cardiopulmonary disease.

demand, abnormal dynamic ventilatory

Traditionally, the approach to improving

mechanics and respiratory muscle

exertional dyspnoea in all of the major

dysfunction are instrumental in causing

cardiopulmonary diseases involves

exertional dyspnoea in patients with severe

interventions that:

cardiac impairment.

1) reduce ventilatory demand (by reducing

Obesity An increase in respiratory neural

the drive to breathe);

drive is deemed to be the reason for the

2) improve ventilatory capacity;

similar increase in dyspnoea in obese and

lean subjects. However, different

3) improve respiratory mechanics (by

underlying mechanisms may affect

reducing the mechanical load);

dyspnoea in obese subjects. Exercise

performance is impaired compared with

4) increase the functional strength of

healthy, normal-weight subjects when

weakened ventilatory muscles;

corrected for the increased lean body mass,

but normal when expressed as a

5) address the affective dimension of

percentage of predicted for ideal body

dyspnoea; and

weight in subjects who hyperinflate their

6) any combination of the above.

lungs to the same extent as those obese

subjects who deflate their lungs, with both

It is of note that interventions should be

volume subgroups reaching similar

selected based on the underlying

dyspnoea scores. In ‘hyperinflators’,

pathophysiological background of the

dynamic hyperinflation, along with a

specific disease under examination and may

decrease in IRV, increases respiratory

differ from one disease to another. However,

muscle loading, respiratory drive and

multiple interventions are generally required

ERS Handbook: Respiratory Medicine

and appear to have additive or synergistic

that they share some common

effects.

underlying mechanisms.

Some of these interventions include the

following.

Further reading

DeLorey DS, et al.

(2005). Mild to

N Bronchodilators

moderate obesity:

implications for

N Oxygen

respiratory mechanics at rest and during

N Heliox

exercise in young men. Int J Obes (Lond);

N Exercise training

29: 1039-1047.

N Biventricular pacing (specific for CHF

Guenette JA, et al. (2012). Does dynamic

patients)

hyperinflation contribute to dyspnoea

N Biofeedback techniques

during exercise in patients with COPD?

N NIV

Eur Respir J; 40: 322-329.

N Lung volume reduction surgery and

Killian KJ, et al. Dyspnoea. In: Roussos C,

related endoscopic techniques

ed. The Thorax, part B. New York, Dekker,

N Various combinations of these

1995; pp. 1709-174.

Lanini B, et al.

(2001). Perception of

All of the above strategies have proven to

dyspnea in patients with neuromuscular

provide beneficial sensory consequences in

disease. Chest; 120: 402-408.

a variety of patients with cardiopulmonary

Laveneziana P, et al.

(2009). Effect of

diseases.

biventricular pacing on ventilatory and

perceptual responses to exercise in

In selected patients, interventions such as

patients with stable chronic heart failure.

opiates (oral and inhaled) reduce

J Appl Physiol; 106: 1574-1583.

respiratory drive and alter affective

Laveneziana P, et al. (2011). Evolution of

components of dyspnoea. Recently, it has

dyspnea during exercise in chronic

been shown that inhaled furosemide may

obstructive pulmonary disease: impact

modulate respiratory sensation by altering

of critical volume constraints. Am J

afferent inputs from vagal receptors within

Respir Crit Care Med; 184: 1367-1373.

the lungs. Psychological counselling,

O’Donnell DE, et al. (1997). Qualitative

cognitive/behavioural modification and

aspects of exertional breathlessness in

anxiolytics can have favourable

chronic airflow limitation: pathophysiolo-

influences on the affective dimension

gic mechanisms. Am J Respir Crit Care

of chronic dyspnoea.

Med; 155: 109-115.

O’Donnell DE, et al. (1998). Qualitative

Conclusions

aspects of exertional dyspnoea in patients

with interstitial lung disease. J Appl

We are still a long way from understanding

Physiol; 84: 2000-2009.

the symptom of dyspnoea. Although

O’Donnell DE, et al. (1999). Ventilatory

mechanical factors are important

assistance improves exercise endurance

contributors to dyspnoea, the precise

in stable congestive heart failure. Am J

mechanisms of dyspnoea remain obscure.

Respir Crit Care Med; 160: 1804-1811.

One approach to the study of this

O’Donnell DE, et al. (2006). Sensory-

symptom is to identify the major

mechanical relationships during high

qualitative dimensions of the symptom in

intensity, constant-work-rate exercise

an attempt to uncover different underlying

in COPD. J Appl Physiol;

101:

neurophysiological mechanisms. The

1025-1035.

remarkable similarity in choices of

Ofir D, et al.

(2007). Ventilatory and

qualitative descriptors (work/effort,

perceptual responses to cycle exercise in

inspiratory difficulty/unsatisfied

obese females. J Appl Physiol; 102: 2217-

inspiration, air hunger and rapid

2226.

breathing) for exertional dyspnoea in

Parshall MB, et al.

(2012). An official

patients with restrictive and obstructive

American Thoracic Society statement:

syndromes raises the intriguing possibility

ERS Handbook: Respiratory Medicine

Chest pain

Matthew Hind

Chest pain is a frequent symptom of illness

via the posterior limb of the internal capsule

and a common reason for seeking medical

to the somatosensory cortex. The diaphragm

attention. Rapid assessment is crucial so

has dual nociceptive sensory innervation

that life-threatening disease, such as cardiac

from both the phrenic nerve and the lower

chest pain, aortic dissection and

six intercostal nerves; therefore,

oesophageal rupture, can be identified and

diaphragmatic irritation can present with

managed appropriately. A basic history often

pain referred to the shoulder or upper

points to the cause and is used in the triage

abdomen. The trachea and large airways

of patients attending emergency rooms.

have afferent fibres that project along the

Questions are typically asked about the

vagus nerve. Respiratory chest pain can

character, location, radiation, severity,

therefore originate from the chest wall,

exacerbating and relieving factors, and

pleura, large airways and mediastinum but

relationship to movement such as breathing

visceral ‘lung’ pain is unusual.

or coughing. Objective assessment using a

questionnaire, such as the McGill Pain score

Pleural pain is often described as sharp,

(Melzack, 1975) can be useful. Occasionally,

stabbing and made worse with movement

it is difficult to tease out differences between

such deep respiration. The pain is often

cardiac, gastrointestinal and respiratory

unilateral, reflecting the site of disease. A

causes of pain.

pleural rub may be heard. Pleuritic pain with

sudden onset prompts a diagnosis of

The pathophysiology of chest pain is

pulmonary emboli, infarction or

complex and not completely understood but

pneumothorax, whereas pleuritic pain

involves peripheral nociceptors, either small

building over a few hours may suggest

Ad myelinated or unmyelinated C afferent

infection, such as pneumonia or pleurisy;

fibres that project via sympathetic and

onset over days suggests empyema,

parasympathetic nerves into the dorsal horn

malignancy or tuberculosis.

of the spinal cord. These neurons synapse

with spinothalamic fibres that ascend, cross

Tracheobronchitis can present with a

the spinal cord and terminate in the

midline burning pain made worse with

contralateral venteroposterior thalamic

respiration. Massive mediastinal

nucleus. Thalamocortical neurons project

lymphadenopathy can cause an indistinct,

heavy central chest pain. Similarly, chest

pain associated with pulmonary

Key points

hypertension can be difficult to distinguish

from cardiac chest pain. Nondescript, heavy

N Chest pain can be a feature of a wide

chest pain is quite common in exacerbations

range of pathology.

of bronchiectasis.

N An accurate history is essential to

Chest wall pain is usually well localised,

direct appropriate investigation of

reproduced with movement and associated

patients presenting with chest pain.

with tenderness. Costochondritis and

Tietze’s syndrome are inflammatory

ERS Handbook: Respiratory Medicine

disorders of thoracic joints that present with

Management of chest pain is clearly

chest wall pain and tenderness. Bornholm

influenced by the underlying disease. It is,

disease (epidemic pleurodynia or devil’s

however, essential to provide adequate

grip), often associated with Coxsackie B

analgesia not only to alleviate suffering but

virus, can present with epidemics of chest

prevent secondary complications such as

wall pain of sudden onset.

pneumonia. The use of a pain ladder,

starting with simple analgesics such as

Neuralgic pain can be sharp and knife-like or

paracetamol and nonsteroidal anti-

dull and heavy, and there may be associated

inflammatory drugs escalating to mild then

sensory symptoms. Pain in a dermatomal

stronger opiates, follows guidance by the

distribution requires examination of

World Health Organisation (WHO) for

overlying skin for the characteristic vesicular

management of cancer pain but is also

rash of herpes zoster.

extremely useful for noncancer pain. Topical

ECG is essential for immediate assessment of

analgesia, such as capsaicin creams or

cardiac chest pain. Further investigation may

infiltration of local anaesthetic, are

include exercise ECG, stress echocardiography

particularly useful following thoracic

or myocardial perfusion scanning.

surgery. The use of adjuvants, to calm fear

Angiography offers the opportunity for

and anxiety, can be considered at each step

therapeutic angioplasty and stent insertion.

of the pain ladder. Tricyclic antidepressants

together with anticonvulsants can be

Chest radiographs are useful to identify

particularly helpful in neuropathic pain.

consolidation, pneumothorax, pleural

Nonpharmacological management, such as

effusion and bony abnormalities such as

radiotherapy for painful bony metastasis,

vertebral or rib fractures. Contrast CT has

can also be extremely useful. It is essential

made identification of pulmonary emboli,

drugs are given ‘by the clock’ rather than ‘on

aortic dissection and oesophageal rupture

demand’. The three-step approach

straightforward, and can identify

advocated by WHO of administering the

abnormalities often missed on plain

correct drug, at the correct dose, at the

radiographs. Nuclear medicine scans have a

correct time is inexpensive and 80-90%

role in both diagnosis and management of

effective.

pulmonary emboli. Bone scintigraphy is

useful in the evaluation of ‘bony’ pain. MRI

Further reading

examination is of particular use in visualising

nerve roots. Direct endoscopic visualisation

Melzack R

(1975). The McGill Pain

of either the upper gastrointestinal tract

Questionnaire: major properties and

(oesophagogastroduodenoscopy) or major

scoring methods. Pain; 1: 277-299.

airways (bronchoscopy) allows epithelial

World Health Organization. WHO’s Pain

inspection and offers the opportunity for

Ladder.

www.who.int/cancer/palliative/

direct microbiological, cytological and

painladder/en/

histological sampling.

ERS Handbook: Respiratory Medicine

Physical examination

Martyn R. Partridge

Physical findings in the context of the

history

Key points

The purpose of clinical assessment is to

N It is essential to bear in mind that

make an accurate diagnosis. Making an

breathlessness can have a variety

accurate diagnosis in cases of respiratory

of causes.

disease can be challenging not only because

N Physical examination should follow

of the diversity of respiratory ill health but

the taking of the medical history and

also because symptoms of respiratory

differential diagnoses, and is an

disease are shared with disorders of other

opportunity to confirm normality or

body systems.

discover abnormality.

Breathlessness (a sensation of difficult,

N Physical examination comprises

laboured or uncomfortable breathing) may

inspection, palpation, auscultation

have a physiological or psychological

and percussion.

explanation but it is extremely important

that every time we are faced with a patient

N The respiratory physician must not

complaining of shortness of breath we

forget that disease of other systems

consider the following.

may also be the cause of the symptoms

and that comorbidity is common.

Is this patient breathless because of:

N heart disease,

the differential diagnostic process and this

N lung disease,

is summarised in table 1.

N pulmonary vascular disease,

N a systemic disorder (anaemia, obesity or

Cough and breathlessness

hyperthyroidism), or

N respiratory muscle weakness?

A practical approach to the assessment of

cough and breathlessness is summarised in

It is vital that we go through this checklist

figure 1.

both with new presentations of the symptom

of breathlessness as well as in those with

Physical examination

established disease, and we need to bear this

In the vast majority of cases, the taking of

list in mind when examining the patient. The

the medical history should lead to the

patient with COPD might this time be

construction of a list of differential

breathless not because of an exacerbation

diagnoses. The examination is then an

but because they have gone into atrial

opportunity either to confirm normality or to

fibrillation, or the patient with known heart

discover abnormalities consistent with one

failure may this time be breathless because of

or other of one’s differential diagnoses. Key

a complicating pneumonia.

features, as with all clinical examination,

Asking specifically about the onset of the

depend upon inspection, palpation,

symptom of breathlessness can be helpful in

auscultation and percussion.

ERS Handbook: Respiratory Medicine

Table 1. Breathlessness: differential diagnosis according to onset

Onset

Differential diagnosis

Within minutes

Pulmonary embolus

Pneumothorax

Cardiac rhythm disturbance

Dissecting aneurysm

Acute asthma

Over hours or

Pneumonia

days

Pleural effusion

LVF (LV dysfunction or valve dysfunction or septal rupture post-MI)

Asthma

Blood loss

Lobar collapse

Respiratory muscle weakness (Guillain-Barré syndrome)

Over weeks

Infiltration (malignancy, sarcoidosis, fibrosing alveolitis, extrinsic allergic

alveolitis, eosinophilic pneumonia)

Respiratory muscle weakness (motor neurone disease)

Main airway obstruction

Anaemia

Valvular dysfunction (SBE)

Over months

Same as for ‘Over weeks’

Obesity

Muscular dystrophy

Asbestos-related conditions

Over years

COPD

Chest wall deformity

Heart valve dysfunction

Obesity

MI: myocardial infarction; LVF: left ventricular failure; LV: left ventricular; SBE: subacute bacterial endocarditis.

Inspection

N A note should be made of the neck/collar

size and also of obvious jaw

On inspection, the key points to observe are

abnormalities and oropharyngeal

as follows.

abnormalities

N General appearance (breathlessness

Remember that inspection of relevance to

or cachexia)

the respiratory system involves more than

N Respiratory rate

inspection of the chest itself; for example,

N Appearances of the hand (finger clubbing

one should note erythema nodosum (fig. 6)

(fig. 2), tremor, tobacco staining or

or gynaecomastia (fig. 7).

flapping tremor suggestive of carbon

Palpation

dioxide retention)

N Does the chest wall move symmetrically?

This involves the following.

N Are there any chest wall deformities

(scoliosis or pectus excavatum) or scars

N Assessment of chest expansion, where we

(figs 3 and 4)?

may be able to elicit reduced expansion

N Are there any abnormal vessels suggestive

symmetrically, suggestive of

of superior vena cava obstruction (fig. 5)?

hyperinflation, or reduced movement on

N Nasal stuffiness or obstruction should

one side, suggesting localised pathology

be noted

on that side.

ERS Handbook: Respiratory Medicine

Figure 4. Chest wall abnormalities may be

congenital or acquired. In a case of congenital

Figure 2. The presence of finger clubbing should

absence of the pectoralis major, as seen here, the

obviously be noted and the patient asked if they are

abnormality should be noted, for it will otherwise

aware of how long it has been present or whether a

potentially lead to confusion in interpretation of

doctor has commented upon it previously.

the chest radiograph.

N Determining the position of the trachea

N do so in a symmetrical manner,

by inserting the index and middle fingers

systematically comparing both sides of

in the suprasternal notch.

the chest at a point equidistant from the

N Examining the cervical and

midline.

supraclavicular lymph nodes for

The percussion note may be hyper-resonant

enlargement.

symmetrically in patients with underlying

N Assessing vocal fremitus by asking the

hyperinflated lungs or asymmetrically in a

patient to loudly and deeply repeat the

large pneumothorax, or may be dull in cases

words ‘ninety-nine’ while you compare

of consolidation or pleural effusion.

both sides of the chest. Voice sounds are

better transmitted through consolidated

Auscultation

lung than normal lung and poorly

Listening to the breath sounds involves the

transmitted through pleural effusions.

following.

Percussion

Checking for the presence of bronchial

Percussion is often poorly undertaken and

breathing, which is the presence of breath

the key features are to:

sounds that are similar to those heard

over the large central airways in a more

N make the movement of your finger a

peripheral location. Bronchial breathing is

stroke from the wrist;

classically heard over a consolidated lung

N strike firmly at right angles upon the

(and in association with dullness to

finger of the other hand, which lies along

percussion) but is also sometimes heard

the intercostal space; and

over the upper aspect of a pleural effusion

and sometimes over a collapsed lung.

N Determining whether there are any

abnormal added sounds, which may be

musical sounds (wheezing) or crackles.

In cases of wheezing, it is important to

determine whether the wheezing is

polyphonic and bilateral, as in asthma or

COPD, or monophonic and localised, as

may be found in cases of lung cancer,

Figure 3. The chest wall should be carefully

bronchial stenosis or inhaled foreign

examined for clues as to underlying lung disease.

bodies.

In this case, an infiltrating lung tumour is invading

N Crackles may be fine and occur in cases

the chest wall.

of interstitial lung disease or acutely in

ERS Handbook: Respiratory Medicine

Figure 7. While gynaecomastia can occur for a

number of reasons, its presence is always

Figure 5. Dilated vessels over the anterior chest

important to note and an important underlying

wall are often the most obvious sign of superior

cause to consider is lung cancer.

vena cava obstruction, with the other feature

being a raised jugular venous pressure that is

interpreting a noise as a pleural rub is

nonpulsatile.

necessary in very thin patients where the

cases of pulmonary oedema, or coarse,

diaphragm of the stethoscope may move

as often heard in patients with

over the ribs.

bronchiectasis.

N Vocal resonance is found under the same

Pleural rubs sound like a squeaky noise,

circumstances as vocal fremitus and, when

are usually localised and clearly vary in

found in conjunction with bronchial

intensity with respiration. Care in

breathing, is highly suggestive of

consolidation. Some physicians find

detection of whispering pectoriloquy a more

definite sign; to elicit this, one asks the

patient to whisper ‘ninety-nine’ and, when it

is present, such as in cases of consolidation,

the whispered sound is heard clearly over

the chest wall when transmitted through

consolidated lung whereas a normally air-

filled lung would muffle the whispered

sound and make it indistinct.

Finally, one should remember that disorders of

other systems may coexist and, while

examining the chest, one should especially look

for evidence of heart and pulmonary vascular

disease, noting signs of peripheral oedema and

elevation of the jugular venous pressure.

Further reading

Gibson GJ, et al. Respiratory Medicine.

Philadelphia, Saunders Elsevier Science

Ltd, 2002.

Partridge MR. Understanding Respi-

Figure 6. Inspection of the respiratory system

ratory Medicine: a Problem-Orientated

involves more than inspection of the chest. In this

Approach. London, Manson Publishing

example, the presence of erythema nodosum is

Ltd, 2006.

likely to explain the pulmonary abnormalities.

ERS Handbook: Respiratory Medicine

Static and dynamic lung

volumes

Riccardo Pellegrino and Andrea Antonelli

Ventilation is constrained by the mechanical

section dedicated to functional residual

properties of the airways, lung and chest

capacity). Except during exercise, when a

wall. The latter two determine the volume at

lack of increase in VT with ventilation is a

which the movement of gas is accomplished

functional marker of ventilatory limitation,

at rest and in daily activities such as

and perhaps in patients undergoing assisted

exercise, phonation, laughing, changes in

ventilation, VT has little clinical usefulness in

body posture, etc. However, when

clinical practice.

cardiopulmonary disease is present, lung

volumes may also be modified as a result of

Total lung capacity (TLC) is the volume of

dynamic mechanisms within the airways

gas contained in the lungs after a deep

and changes in breathing pattern, in

breath. It is determined by the maximum

addition to static changes in lung and chest

force exerted by the inspiratory muscles to

wall properties.

balance lung and chest wall elastic recoils

(figs 1 and 2).

Determinants of lung volumes in health

and disease

In healthy conditions, TLC tends to remain

fairly stable with ageing, presumably

Tidal volume (VT) is the volume of gas

because the natural decrease of the force of

inspired during each breath (fig. 1)

the inspiratory muscles and/or the increase

necessary to preserve gas exchange. In

in chest wall stiffness are balanced by the

healthy subjects, inspiration is switched off

progressive loss of lung elastic recoil. Sports

by neural reflexes, whereas expiration is

like swimming are associated with an

terminated near the relaxation volume as a

increase in TLC as a result of an increase in

result of static or dynamic mechanisms (see

inspiratory muscle force.

Key points

Measurement of lung volumes in clinical

IRV

practice has been proven to be important

to assist in the following:

EVC TLC

N Diagnosis of pulmonary defects,

ERV

FRC

N Evaluation of candidates for lung

volume resection surgery,

N Prognosis of COPD and interstitial

lung diseases,

Time

N Evaluation of the bronchomotor

Figure 1. Lung volume plotted versus time.

response to constrictor and dilator

EVC: slow expiratory vital capacity; IRV and ERV:

agents as well as to physical exercise.

inspiratory and expiratory volume reserves,

respectively.

ERS Handbook: Respiratory Medicine

failure), chest wall stiffness (e.g.

100

TLC

neuromuscular diseases, obesity, ascitis

Lung

and pregnancy) or thoracic space

competition (e.g. pleural effusions

Chest wall

FRC

and pneumothorax).

Measuring TLC is of great importance in

clinical practice, as it allows the identifi-

cation of restrictive pulmonary defects. In

addition, TLC is also useful in the evaluation

100

-100

of an emphysematous patient as a candi-

Ppl cmH₂O

date for lung volume resection surgery, or for

follow-up of interstitial lung diseases.

Figure 2. Quasi-static pressure-volume curves of

the chest wall and the lung (dashed lines) related

Residual volume (RV) is the volume of gas

to pleural pressure (Ppl) generated during

that remains in the lungs after a complete

maximum inspiratory and expiratory static efforts

expiration. In young healthy individuals, RV

(PImax and PEmax, respectively; continuous lines).

is, for the most part, determined by the

Volume is expressed as a percentage of TLC. TLC

balance between the force of the expiratory

is the volume at which PImax equals the inward

muscles and the outward recoil of the chest

elastic recoils of both lung and chest wall. RV is

wall (figs 1 and 2). In the elderly, it increases

the volume at which PEmax overcomes the

outward elastic recoil of the chest wall. FRC is the

as a result of airway closure or reduced lung

volume at which inward lung recoil equals

elastic recoil.

outward chest wall recoil (arrows with opposite

In restrictive diseases, RV decreases in pro-

direction).

portion to the increase in lung elastic or chest

wall recoils and/or loss of lung parenchyma.

In contrast, TLC tends to increase in

emphysema and, sometimes, in chronic

In obstructive pulmonary diseases, RV is

bronchitis and severe asthma. Though the

higher than predicted because of premature

decrease in lung elastic recoil is presumably

airway closure, loss of lung elastic recoil,

the most important mechanism of the

and stiffness of the chest wall. Additional

increase in TLC under these conditions, an

mechanisms may dynamically contribute to

increased force of the inspiratory muscles

the elevation of RV in obstructive lung

and chest wall remodelling may also play a

diseases. For instance, in patients with

role. Surprisingly, for the same level of

acutely induced or chronic airflow

airflow obstruction, TLC tends to increase

obstruction, RV achieved after a forced

during spontaneous long-lasting but not

expiration is always higher than after a slow

acutely induced bronchospasm. This is

expiration. This is mainly because of two

presumably because of the different time

mechanisms. First, during forced expiration

course necessary to produce airflow

in airflow obstruction, expiratory flow

obstruction and hyperinflation. That this

limitation (EFL) occurs soon after initiation

may be so is shown by a study documenting

of the manoeuvre, especially within the

that when a resistive valve was implanted in

airways that are already narrowed. In

the dog trachea, it took time for TLC to

contrast, during a slow expiration, pleural

increase. Thus it is possible that breathing

pressure will not exceed the critical pressure

at high lung volumes for long periods of

necessary to generate maximal flow, thus

time as a result of severe chronic airflow

allowing EFL to occur late in expiration and

obstruction may also contribute to the

at a lower lung volume. Secondly, some

increase in TLC.

airways could close near TLC early in

expiration as a result of disease, thus

TLC decreases in all conditions

preventing the subtending alveolar units

characterised by an increase in lung elastic

from emptying and contributing to the

recoil (e.g. pulmonary fibrosis and cardiac

increase in RV.

ERS Handbook: Respiratory Medicine

Airways

Lung

parenchyma

Pressure

Volume

Constrictor

Dilator

force

Figure 3. Effects of deep breath on maximum expiratory flow and residual volume according to the relative

hysteresis theory of Froeb et al. (1968). a) Pressure-volume loops of lung parenchyma and airways on

inspiration (insp) and expiration (exp). The area inside the loop is called hysteresis. b) Partial and maximal

flow-volume loops (dotted and continuous lines, respectively). Upper panels: both hystereses are similar,

so that the constrictor and dilator forces after the deep breath remain equal compared to before inflation.

As a result, forced flow and residual volume during the maximum forced expiratory manoeuvre are the

same as the partial manoeuvre. Middle panels: airway hysteresis prevails over lung hysteresis, so that the

constrictor force is reduced after the large inflation. Consequently, for a given lung volume, maximum flow

will exceed partial flow and residual volume will decrease more after a maximal manoeuvre than after a

partial manoeuvre. Lower panels: lung parenchyma hysteresis prevails over airway hysteresis, so that the

dilator force will decrease after the deep breath. Under these conditions, forced expiratory flow and residual

volume after a maximal manoeuvre will decrease and increase, respectively, compared to a partial

manoeuvre.

In addition, the effects of volume history of

parenchyma. According to Froeb et al.

the manoeuvre preceding the expiration may

(1968), the effects of volume history on

affect RV. For instance, in healthy subjects

airway size depend on the mechanical

or mild-to-moderate asthmatics exposed to

characteristics of the lung parenchyma and

a bronchoconstrictor agent, a manoeuvre

airways. Both tissues may lose energy or

initiated from TLC will generate greater flow

pressure and deform with stretching, a

and lower RV than a manoeuvre initiated

phenomenon named hysteresis. Since lung

from end-tidal inspiration. The opposite

elastic recoil and transmural pressure are

occurs in chronic airflow obstruction. This

the forces that determine airway size, any

suggests that RV is also modulated through

change relative to one of these will

the changes in airway calibre caused by large

necessarily entail a change in flow and RV.

lung inflations. How the deep inspiration

As shown in figure 3, if airway hysteresis

manoeuvre affects lung and airway

exceeds parenchymal hysteresis, airway

mechanics is still a matter of debate. When

volume will be greater during deflation than

a deep breath is taken, the inflating stimulus

inflation, and RV will be achieved at a lower

is transmitted to the lung as well as the

lung volume. This generally occurs when

airways through the elastic network of lung

constriction is mostly limited to the airways

ERS Handbook: Respiratory Medicine

and little affects lung parenchyma, such as

In obstructive pulmonary diseases, FRC

with induced airway narrowing. In contrast,

tends to increase for a series of reasons. For

when lung parenchyma hysteresis is larger

instance, an increase in breathing frequency

than airway hysteresis, airway volume will be

or in time constant of the respiratory

reduced on expiration compared with

system, as a result of either an increase in

inspiration and RV achieved at a higher

airflow resistance or a decrease in lung

volume. This is what presumably occurs in

compliance, will lead to an expiratory time

chronic airflow obstruction or severe

relatively too short to allow the respiratory

asthma. Finally, when airway and lung

system to empty fully. Presumably, the

parenchyma hystereses change by similar

occurrence of EFL during tidal expiration

extent, airway size will be similar before and

may also contribute to an increase in FRC to

after a deep breath, and so will RV. The

a lung volume where EFL is minimal. Under

effects of volume history may be easily

these circumstances, the dynamic

assessed in vivo by comparing forced

compression of the airways downstream

expiratory manoeuvres initiated from total

from the flow limiting segment may evoke

lung capacity and a volume below it

neural reflexes that prematurely activate the

(fig. 3b), or by changes in airflow resistance

inspiratory muscles to avoid breathing for

soon after taking a deep breath.

too long a time under EFL conditions. On

the one hand the increase in FRC in airflow

Vital capacity (VC) is the difference between

obstruction is beneficial as it allows

TLC and RV. Because RV is dependent on

breathing at a volume where the airways are

volume and flow histories in addition to

larger, thus decreasing the resistive work of

airway, parenchyma and/or chest wall

breathing. On the other hand, however,

components of the diseases, as discussed

breathing at high lung volume is associated

above, VC will depend on the type of

with an increase in the elastic work of

respiratory manoeuvre from which it is taken

and the underlying disease. In general, the

breathing and causes dyspnoea.

largest VC is that obtained during a full

A decrease in FRC occurs in restrictive

inflation from RV (achieved after a slow

respiratory diseases due to an increase in

expiration from end-tidal inspiration) to TLC

lung elastic recoil (e.g. in pulmonary fibrosis,

(inspiratory vital capacity), followed by the

atelectasis, lung resection, alveolar liquid

slow expiratory vital capacity from TLC to RV,

filling and cardiac diseases) or in chest wall

and the VC measured during a forced

elastance (e.g. in chest wall and pleural

expiratory manoeuvre (FVC). A decrease of VC

diseases, respiratory muscle paralysis, and

does not allow differentiation between restric-

obesity). This is important, as reduced FRC

tion and obstruction, as it may be due to a

is associated with hypoxaemia and, in

decrease in TLC or an increase in RV, or both.

obesity, with increased airway

In clinical practice, VC is of central

responsiveness.

importance for the diagnosis of obstructive

Inspiratory capacity (IC) is the volume

pulmonary defects.

difference between TLC and FRC. In

Functional residual capacity (FRC) is the

pulmonary diseases, it tends to decrease as

volume of gas remaining in the lungs at the

a result of an increase in FRC (obstructive

end of a tidal expiration performed in a

conditions) or a decrease in TLC (restrictive

seated or upright position (fig. 1). Its

diseases), or both. In clinical practice,

mechanical determinants are the inward

changes in IC with acute interventions on

elastic recoil of the lung and the opposing

airway calibre, such as bronchoprovocation

outward recoil of the chest wall (fig. 2). In

or reversibility tests, or during exercise,

the supine position, the abdominal content

reflect mirror-like changes in FRC, assuming

is displaced towards the chest cavity, thus

that TLC remains unmodified.

reducing FRC. Also, during speech, singing,

laughing or exercise, FRC tends to decrease

IC has no role in the diagnosis of ventilatory

to favour these activities.

defects.

ERS Handbook: Respiratory Medicine

Expiratory and inspiratory reserve volumes

Conclusions

allow VT to expand when necessary (fig. 1).

Measuring lung volumes is now an

Though of little interest at rest, they play a

integrative part of lung function assessment.

critical role during exercise. For instance, in

In addition to assisting in the diagnosis of

healthy subjects the increase in VT with

the ventilatory defects, it helps explain the

exercise is achieved at the expense of a

presence of respiratory symptoms and

decrease in end-expiratory lung volume

hypoxia in cardiopulmonary diseases, has

(EELV) and an increase in end-inspiratory

clinical prognostic implications in both

lung volume (EILV). In contrast, in airflow

obstructive and restrictive diseases, and

obstruction, the increase in VT is limited by

plays an integral role in the functional

the premature and sustained increase in

evaluation for lung volume reduction

EELV that may eventually contribute to

surgery in emphysema.

causing dyspnoea together with the increase

in EILV near TLC.

Further reading

Measurements of lung volumes in clinical

practice: technical aspects

Agostoni E, et al. Static behaviour of

the respiratory system. In: Macklem PT,

VC, VT, IC, EILV and EELV can be measured

et al., eds. Handbook of Physiology. The

by simple spirometry. In contrast, TLC, RV

Respiratory System. Mechanics of breath-

and FRC need to be measured with special

ing. Section 3, Vol. III, part 1. Bethesda,

techniques described below.

American Physiological Society,

1986;

pp. 113-113.

Gas dilution techniques (nitrogen washout

Brusasco V, et al. (1997). Vital capacities

and helium dilution) are based on the

during acute and chronic bronchocon-

principle of the conservation of mass; that

striction. Dependence of flow and volume

histories. Eur Respir J; 10: 1316-1320.

is, the amount of gas resident in the lungs at

Casanova C, et al. (2005). Inspiratory-to-

the beginning of the test can be calculated

total lung capacity ratio predicts mortality

as the product of concentration and volume

in patients with chronic obstructive pul-

of eliminated nitrogen or diluted helium.

monary disease. Am J Respir Crit Care

Both methods yield measurements of lung

Med; 171: 591-597.

volumes that communicate with open

Ceanton TL, et al. (1987). Effects of swim

airways only. In severely obstructed patients,

training on lung volumes and inspiratory

an underestimation of the true lung volume

muscle conditioning. J Appl Physiol; 62:

may be a result of some regions with long

39-46.

time constants.

Criner GJ, et al.

(2008). A clinician’s

guide to the use of lung volume reduction

Body plethysmography allows rapid and

surgery. Proc Am Thorac Soc; 5: 461-467.

reproducible measurements of absolute lung

Froeb HF, et al. (1968). Relative hyster-

volumes. The test is based on Boyle’s law, in

esis of the dead space and lung in vivo.

that lung volume can be calculated from the

J Appl Physiol; 25: 244-248.

relationship between changes in mouth

King TE Jr, et al.

(2001). Predicting

survival in idiopathic pulmonary fibrosis.

pressure (assumed equal to alveolar

Scoring system and survival model. Am J

pressure) and box pressure (constant volume

Respir Crit Care Med; 164: 1171-1181.

plethysmography) or volume (constant

O’Donnell DE, et al. (2007). Pathophysio-

pressure plethysmography) during gentle

logy of dyspnea in chronic obstructive

panting manoeuvres against a closed shutter.

pulmonary disease. Proc Am Thorac Soc;

As opposed to gas dilution techniques,

4: 145-168.

plethysmography measures the whole

Olive JT, et al. (1972). Maximal expiratory

intrathoracic gas, thus including

flow and total respiratory resistance

nonventilated and/or poorly ventilated lung

during induced bronchoconstriction in

regions. This method may overestimate lung

asthmatic subjects. Am Rev Respir Dis;

volumes in cases of severe airflow obstruction

106: 366-376.

if the panting frequency is .1 Hz.

ERS Handbook: Respiratory Medicine

Pellegrino R, et al.

(1979). Expiratory

Pride NB, et al. Lung mechanics in

flow limitation and regulation of end-

disease. In: Macklem PT, Mead J, eds.

expiratory lung volume during exercise.

Handbook of Physiology. The Respiratory

J Appl Physiol; 74: 2552-2558.

System. Mechanics of breathing. Section

Pellegrino R, et al.

(1996). Lung

3, Vol. III, part

2. Bethesda, American

mechanics during induced broncho-

Physiological Society, 1986; pp. 659-669.

constriction. J Appl Physiol;

81:

964-

Torchio R, et al. (2009). Mechanical effects

975.

of obesity on airway responsiveness in

Pellegrino R, et al. (2005). Interpretative

otherwise healthy humans. J Appl Physiol;

strategies for lung function tests. Official

107: 408-416.

statement of the American Thoracic

Vinegar A, et al. (1979). Dynamic mechan-

Society and the European Respiratory

isms determine functional residual capa-

Society. Eur Respir J;

26:

948-

city in mice, Mus musculus. J Appl Physiol;

968.

46: 867-871.

ERS Handbook: Respiratory Medicine

Respiratory mechanics

Daniel Navajas and Ramon Farré

Pulmonary ventilation is determined by the

In this situation, the inward PL is

resistive and elastic properties of the lungs

counterbalanced by the outward PCW and

and chest wall, and by the driving pressure

the alveolar pressure (Palv) equals

of the respiratory muscles. Both the lungs

atmospheric pressure. Inspiration is

and chest wall are elastic structures. The

produced by activation of inspiratory

lungs have a very small resting volume.

muscles. The outward muscular pressure

Above this volume, the lungs are distended,

(Pmus) expands the chest wall, thereby

exerting an inward elastic recoil pressure

lowering pleural pressure (Ppl). This drop in

(PL) that rises markedly with lung volume

Ppl expands the lung and decreases Palv to

(VL). The chest wall has a much higher

subatmospheric values. The mouth-alveolar

resting volume, exhibiting outward and

pressure gradient drives inspiratory flow.

inward elastic recoil pressure (PCW) below

During quiet breathing in a normal subject,

and above its resting volume, respectively.

expiration is achieved by relaxing the

inspiratory muscles. The net inward elastic

At end-expiratory volume during quiet

recoil of the total respiratory system (Prs),

breathing (functional residual capacity

the sum of PL and PCW, tends to return the

(FRC)) in a healthy subject, the respiratory

system to the overall equilibrium volume,

muscles are relaxed and the lungs and chest

wall reach the combined resting state (fig. 1).

Key points

N Palv is lower and higher than Pao

during inspiration and expiration,

respectively.

N The lungs exert inward elastic recoil

that increases with VL.

N Body plethysmography allows the

measurement of both Raw and VL.

N The FOT allows the measurement of

respiratory resistance during

Palv

spontaneous breathing with

minimum patient collaboration.

N Respiratory mechanics can be

monitored in sedated mechanically

PCW

Pmus

ventilated patients performing post-

inspiratory and post-expiratory pauses.

Figure 1. Mechanical behaviour of the respiratory

system.

ERS Handbook: Respiratory Medicine

increasing Palv to above mouth pressure

mouthpiece. First, the shutter is opened and

(Pmo) and driving expiratory flow. The

the ratio between V9 and the pressure within

activation of the expiratory muscles results

the box (Pbox) is measured during breathing

in a faster expiration.

(V9/Pbox).

Airway resistance

During inspiration, air moves from the box

to the lung. The inspired gas takes on a

The airflow generated by the pressure

higher volume in the lungs than in the box

gradient between the mouth and the alveoli

due to the decrease in pressure (Palv,Pbox),

is determined by airway resistance (Raw),

the increase in temperature (37uC) and the

defined as

addition of water vapour. The calibration

ratio of the plethysmograph (k) is

R_aw~^Pmo{^Palv

experimentally determined by closing the

V⁰

shutter at FRC and recording Pmo and Pbox

where V9 is the gas flow. In healthy adults,

during gentle respiratory efforts against the

Raw measured at FRC is ,2 hPa?s?L^-1.

occlusion. Under zero airflow conditions,

Intrathoracic airway calibre increases as

Palv<Pmo and

lungs expand, resulting in a hyperbolic

Palv

dependence of Raw on lung volume.

Therefore, an approximately linear

Pbox

relationship is obtained by computing

Therefore,

airway conductance (Gaw):

Palv

R_aw~

~^k:Pbox

G_aw~

V⁰

R_aw

Body plethysmography measurements of

Since large lungs have wider airways, the

Raw are usually computed at low respiratory

specific airway resistance (sRaw) computed

flows (,0.5 L) recorded during shallow

panting to minimise the effects of

sR_aw~R_aw:FRC

temperature changes during inspiration and

provides a resistance measurement

normalised for differences in lung size.

Shutter

Similarly, specific airway conductance

(sGaw) is defined as

Pmo

sG_aw~^Gaw

FRC

Body plethysmography

Pbox

Measurement of Raw requires the recording

of airflow and driving pressure. Airflow can

be recorded with a pneumotachograph

connected to the mouth. Pmo is simply

Palv

atmospheric pressure or, alternatively, it can

be readily measured with a pressure

transducer. As the alveolar airspace is not

directly accessible, Palv can be estimated by

means of a whole-body plethysmograph

(fig. 2). This technique involves the subject

sitting inside a closed cabin breathing the

gas from the box. The mouth can be

Figure 2. Measurement of Raw by body

occluded with a shutter coupled to the

plethysmography.

ERS Handbook: Respiratory Medicine

expiration. Alternatively, measurements can

This technique is based on applying a small-

be made during quiet breathing after

amplitude (¡1 hPa) pressure oscillation to

computer correction for changes in the

the patient’s mouth or nose with a

physical conditions of the gas.

loudspeaker or a small pump. Rrs is

computed as the ratio of forced pressure

Whole-body plethysmography is the

oscillation and in-phase flow. The ratio

procedure most commonly used to

between forced pressure and the out-of-

measure Raw. An added advantage of this

phase flow defines the reactance (Xrs) that

technique is that it provides a FRC

provides a combined measurement of the

measurement for the computation of sRaw.

inertial and elastic properties of the

However, the device is bulky and expensive,

respiratory system. Forced oscillation is

and is not suited to measurement in

applied at frequencies (.4 Hz) higher than

supine patients.

the breathing rate to facilitate the separation

of forced oscillation from tidal breathing.

Interrupter technique

The use of multifrequency oscillation

Raw can also be measured outside the box

(usually 4-32 Hz) provides a measurement

with a pneumotachograph-shutter system.

of the frequency dependence of

The subject breathes at rest through the

respiratory mechanics.

pneumotachograph. When airflow reaches

Current FOT devices are portable and easy

a given threshold, the mouth is briefly

to use. The technique does not require

(,0.1 s) occluded with the shutter. During

any special collaboration from the patient

flow interruption, the pressure is

and measurements can be performed

equilibrated within the different lung

supine. Changes in Rrs during the

compartments. Therefore, Raw can be

breathing cycle can be precisely monitored.

computed as the ratio between the flow

Moreover, FOT can be coupled to

just before occlusion and the Pmo

mechanical ventilators. Therefore,

recorded during flow interruption. Raw is

FOT is especially useful for epidemiological

usually computed as the mean of

studies, measurements in infants,

flow interruptions performed in

and monitoring respiratory mechanics

several breathings.

in patients during sleep and

The interrupter technique can be

mechanical ventilation.

implemented in handheld devices and

Lung compliance

requires only minimal patient cooperation.

However, due to progressive equilibration

The elastic behaviour of the lung is

between Pmo and Palv, the computed value

described by the PL-VL relationship. Lung

of Raw depends on the time lag between the

deformability is measured as lung

start of occlusion and Pmo measurement.

compliance (CL), defined as the change

Slow pressure equilibration in patients with

in volume divided by the change

airflow obstruction results in an

in pressure:

underestimation of Raw.

Forced oscillation technique

CL~DVL

In addition to Raw, lung and chest wall

tissues also exhibit resistive load because of

DVL can readily be measured with a

internal frictional resistance to motion.

spirometer connected to the mouth. The

Resistance of the total respiratory system

measurement of DPL requires the

(Rrs) is the sum of Raw and tissue resistance.

simultaneous recording of Ppl and Palv. Ppl

The tissue component of Rrs is generally

is usually estimated from the oesophageal

small in comparison with Raw.

pressure (Poes) recorded with a small

balloon attached to the tip of a catheter

Rrs can be measured during quiet breathing

introduced through the nose into the lower

by the forced oscillation technique (FOT).

oesophagus. Palv is estimated in the mouth

ERS Handbook: Respiratory Medicine

during brief flow interruptions. In practice,

In patients ventilated with a constant flow

the subject performs a full inspiration

waveform, Rrs and Ers can also be measured

followed by a very slow expiration to FRC. A

by performing a post-inspiratory pause. Flow

shutter attached to the spirometer

interruption results in a sharp drop in

performs successive brief (,1 s)

pressure from the peak value at end

occlusions during expiration. The PL-VL

inspiration (Pmax) to P1, followed by a slow

relationship is curvilinear, with CL

decay to a plateau (P2). The sudden

decreasing markedly with volume. CL is

decrease in Pao is associated with the

habitually computed in the range of tidal

resistive load of the airways. Therefore, Raw

volume at rest (between FRC and

is estimated as

FRC+0.5 L). In the normal adult, CL is

,0.2 L?hPa^-1. The elastic behaviour of the

R_aw~^Pmax{^P1

lung can also be characterised by lung

V⁰

elastance (EL), defined as the reciprocal

A higher value of resistance due to the

of CL:

contribution of tissue viscoelasticity and gas

redistribution within the lungs is computed

E_L~

C_L

from the pressure drop to the plateau

(Pmax-P2).

Chest wall compliance (CCW) is computed as

The additional performance of a post-

DV_L

C_CW~

expiratory pause allows Ers to be computed

DP_CW

as the ratio of pressure and volume changes

at the end of the post-inspiratory and post-

In healthy subjects, the value of CCW is

expiratory pauses.

comparable to that of CL. Since the elastic

pressure of the respiratory system is

Respiratory muscle strength

Prs5PL+PCW, the compliance of the respira-

Since direct measurements of muscular

tory system (Crs) is related to CL and CCW as

pressure are not clinically available,

respiratory muscle performance is

Crs ~

C_L z

CCW

commonly assessed by measuring

maximal pressures generated at the mouth

Crs and CCW can only be measured during

during maximal inspiratory and expiratory

complete respiratory muscle relaxation,

efforts against an occluded airway (or

which is extremely difficult to achieve in

occluded except for a small leak).

conscious patients.

Maximum expiratory pressure (PEmax) is

Measurement of respiratory mechanics in

measured at TLC. Maximum inspiratory

mechanical ventilation

pressure measurements (PImax) are taken

at either FRC or residual volume (RV).

Respiratory mechanics can be measured in

Alternatively, inspiratory muscle strength

sedated mechanically ventilated patients by

can be assessed during sniffing with one

recording airflow and pressure at the airway

nostril occluded with a plug. Maximum

opening (Pao). The driving pressure required

pressure (sniff Pdi) is recorded into

to overcome the elastic and resistive loads

the occluded nostril during a rapid,

(Ers and Rrs, respectively) of the respiratory

forceful inspiratory sniff performed

system is

at FRC.

Pao~Rrs :V⁰zErs:V

The clinical testing of maximal respiratory

pressures is quick and simple but

where V is volume. Rrs and Ers can be

measurement is dependent on effort. The

computed by least-squares fitting of this

test is useful for excluding significant

equation to Pao, V9 and V recordings.

respiratory muscle weakness.

ERS Handbook: Respiratory Medicine

Further reading

Hyatt RE, et al. Interpretation of

Pulmonary Function Tests. A Practical

American Thoracic Society, et al. (2002).

Guide. 3rd Edn. Philadelphia, Lippincott

ATS/ERS statement on respiratory muscle

Williams & Wilkins, 2008; pp. 75-78.

testing. Am J Respir Crit Care Med; 166:

Lucangelo U, et al.

(2007). Lung

518-624.

mechanics at the bedside: make it

Beydon N, et al.

(2007). An official

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

American Thoracic Society/European

Oostveen E, et al.

(2003). The forced

Respiratory Society statement: pulmonary

oscillation technique in clinical practice:

function testing in preschool children.

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

methodology, recommendations and future

Farré R, et al.

(2004). Noninvasive

developments. Eur Respir J; 22: 1026-1041.

monitoring of respiratory mechanics dur-

Pride NB. Airflow resistance. In: Hughes

ing sleep. Eur Respir J; 24: 1052-1060.

JMB, et al., eds. Lung Function Tests:

Gibson GJ. Clinical Tests of Respiratory

Physiological Principles and Clinical

Function.

3rd Edn. London, Hodder

Applications. London, W.B. Saunders,

Arnold, 2009; pp. 3-5.

1999; pp. 27-24.

ERS Handbook: Respiratory Medicine

Gas transfer: TLCO and TLNO

J. Mike Hughes

Transfer factor of the lung for carbon

monoxide absorbed, per unit time and per

monoxide

unit carbon monoxide partial pressure. The

pressure gradient is the alveolar-plasma

Apart from spirometry, the transfer factor of

carbon monoxide tension (PCO) difference.

the lung for carbon monoxide (TLCO) is the

Carbon monoxide is chosen for alveolar-

most frequently performed pulmonary

capillary exchange because, after diffusing

function test. It focuses on the integrity of

into capillary blood, carbon monoxide binds

the alveolar (gas exchanging) part of the

to Hb as carboxy-Hb (HbCO), but at an

lung. TLCO can detect abnormalities limited

extremely low partial pressure (PCO). Plasma

to the pulmonary microcirculation, the only

PCO is so low that it is not usually measured,

routine test that can do so. It helps to think

but it may reach significant levels in current

of TLCO as a measure of the anatomy of the

smokers. Carbon monoxide uptake is

alveolar region, whereas blood gas

independent of blood flow, but it is

measurements (PaO₂ and PaCO₂) measure a

dependent on the number of Hb-binding

physiological efficiency, which involves

sites, i.e. on capillary volume, as well as

airways and larger blood vessels, as well as

molecular diffusion across the alveolar-

alveolar structures. For example, TLCO is

capillary membranes. ‘Transfer’ is the better

normal in asthma (alveoli are uninvolved),

term, because chemical reaction as well as

but the PaO₂ may be considerably reduced.

‘diffusion’ is involved.

Definition

Technique

The transfer factor (called DLCO in North

Nearly all clinical laboratories use the single-

America) measures the surface area

breath technique of Ogilvie et al. (1957). The

available for gas exchange. It is closely

TLCO is measured during a 10-s breath-hold at

related to the oxygen diffusing capacity.

maximal inspiration (this volume is the TLC).

TLCO is the quantity of inhaled carbon

Breath-holding at TLC optimises the

distribution of the inhaled marker gases

(helium (or another insoluble gas such as

Key points

methane (CH₄)) and carbon monoxide), and

makes TLCO independent of ventilation

N TLCO measures alveolar function.

distribution. The breathing manoeuvre is

N TLCO is the product of KCO and VA

shown in figure 1. The subject is asked to:

) is the more specific

N KCO (or TL/VA

N exhale slowly to residual volume;

index of alveolar integrity.

N make a signal;

N KCO is low in emphysema and

N inspire rapidly to full inflation;

fibrosis.

N hold their breath.

N KCO is high in extrapulmonary

The breath-hold is assisted by automatic

restriction.

closure of the inspiratory and expiratory

valves for a pre-set time (9-11 s), after which

ERS Handbook: Respiratory Medicine

exhalation occurs rapidly (there is no need

of the TLC). In practice, VA in normal subjects

for a forced expiration) and an alveolar

is 93.5% of TLC ¡ 6.6% (1SD) (Roberts et al.,

sample is taken, from which water vapour

1990). The 10-s breath-hold is insufficient

and carbon dioxide are absorbed before

time for complete gas mixing; in airflow

helium and carbon monoxide

obstruction, the measured VA may be much

concentrations are analysed. The effective

less than 80% of the actual TLC (measured

breath-hold time is calculated according to

by multi-breath gas dilution or

Jones et al. (1961) (fig. 1).

plethysmography).

Calculation of the TLCO

The kCO is the rate of alveolar uptake of

The key point is that the TLCO is the product

carbon monoxide during the breath-hold

of two measurements, the alveolar volume

(the slope in fig. 2). It is a rate constant with

(VA) and the rate of alveolar uptake of carbon

units of s^-1 or min^-1. When normalised to

monoxide, given by the slope (kCO) of

barometric pressure (minus water vapour

alveolar uptake of CO (fig. 2), equivalent to

pressure) (Pb*), kCO/Pb* 5 k^{CO

the transfer coefficient of the lung for carbon

(min^-1?kPa^-1). The final step in the

monoxide (KCO). During the breath-hold at

calculation of TLCO is the multiplication of

maximal inspiration, VA should equal TLC

k^{CO by VA (in mmol: 1 mmol522.4 mL

minus the anatomical dead space (97-98%

standard temperature, pressure and dry).

Single breath

0.3% CO

14% He

18% O₂

FACO

FAHe

Spirometer

CO₂+H₂O

He+CO

absorption

analysis

Dead space

Fast

Sample

Expiration

Effective breath-holding time

Time s

Figure 1. TLCO set-up and breathing protocol. The breath-hold time is set automatically, and is calculated

from 0.336inspired time to the time after 1 L of expiration. FACO: alveolar carbon monoxide fraction;

FAHe: alveolar helium fraction; RV: residual volume.

ERS Handbook: Respiratory Medicine

He_(i)

Inspired concentrations

Exhalation

100

●◆

CO_(i)

sample

He_(i)

VA = (VI - VDanat)

He_(t)

Helium (He)

◆●

●

CO_(o)

Calculated from

Expired

CO_(i)·(He_(t)

/He_(i))

concentrations

◆

Slope=kCO

CO_(t)

Inhalation

Breath-hold times

Figure 2. TLCO: carbon monoxide and helium analysis. Carbon monoxide and helium concentrations

versus breath-hold time to illustrate the origin and calculation of the two components (slope of the

transfer coefficient of the lung for CO (kCO) and alveolar volume (VA)) from which TLCO is derived. CO(i)

and CO(t) are carbon monoxide concentrations inspired (i) and after exhalation (with dead space discard)

at time t after breath-hold (the same for He(i) and He(t)). CO(0) is the calculated alveolar concentration

at breath-hold start before alveolar uptake has begun. VI: inspired volume. VDanat: anatomic dead space.

KCO6VA 5 TLCO (mmol?min^-1?kPa^-1)

150% not the 100% required by an accurate

volume ‘correction’.

The next step is the division of TLCO by VA in

L (body temperature, pressure, saturated at

If VA remains constant, TLCO and KCO will

37uC, not mmol):

change equally (as % predicted). There are

formulae to correct TLCO for anaemia, so the

TLCO/VA5KCO (mmol?min^-1?kPa^-1?L^-1)

Hb level should always be known. Smoking

raises plasma PCO (a ‘back pressure’ effect)

but the units only differ from k^{CO by a

and produces HbCO, displacing HbO₂ (an

constant factor except for small variations

‘anaemia’ effect), so smoking should be

in Pb*, (KCO/k^{CO ,37). Thus, TLCO/VA

prohibited for 12-24 h before testing.

(5KCO) remains, in essence, the rate

Oxygen breathing with an increase in

constant for alveolar carbon monoxide

alveolar oxygen tension (PAO2) reduces TLCO

uptake. This terminology is confusing

and KCO by competitive antagonism

(Hughes et al., 2012) because the

between oxygen and carbon monoxide; it is

impression is given that TLCO/VA (5KCO)

the basis of the Roughton-Forster equation

‘corrects’ the TLCO for variations in VA.

which partitions 1/TLCO (transfer resistance)

Unfortunately, this is not the case, and with

into 1/DM (alveolar-capillary membrane

normal lung structure KCO at 50%, TLC

diffusion resistance) and 1/hVc (transfer

predicted (as % of KCO at predicted TLC) is

resistance of red cells).

ERS Handbook: Respiratory Medicine

Table 1. Physiological influences on the TLCO and the KCO

TLCO

KCO

Anaemia

Cardiac output increase

PAO₂ increase

VA Q (reduced alveolar expansion)

VA Q (reduction in no. of aerated units)

PAO2: alveolar oxygen tension.

When VA is reduced and lung structure (or

to KCO, the rate constant for alveolar uptake

the remaining lung structure) is normal,

of CO.

TLCO and KCO change in opposite directions

The same TLCO (say 60% predicted) can

(table 1) if the cause is:

arise from different combinations of KCO

N reduced alveolar expansion, e.g.

and VA, such as: 1) high KCO and low VA

extrapulmonary restriction, or

(extrapulmonary restriction); 2) low KCO and

N a reduction in aerated alveolar units, e.g.

normal VA (pulmonary vasculopathy); or

pneumonectomy or consolidation or

3) low-ish KCO and low-ish VA (fibrosis)

atelectasis.

(table 2).

Transfer factor of the lung for nitric oxide

Other causes of a reduced VA are: 1) diffuse

alveolar damage (emphysema or fibrosis)

The transfer factor of the lung for nitric oxide

(TLCO and KCO both reduced), and 2) airflow

(TLNO) was introduced into clinical medicine

obstruction (VA low due to poor gas mixing),

by Guenard et al. (1987) and Borland et al.

where TLCO and KCO are variable, being low

(1989). The methodology and calculations are

in emphysema and normal or high in

the same as the TLCO, and both tests can be

asthma.

performed simultaneously in one single-

breath manoeuvre. The rate of alveolar uptake

Implications of KCO6VA5TLCO

of nitric oxide (KNO) is 4-5 times faster than

Transfer coefficient of the lung TL/VA does

KCO, so the breath-hold time may have to be

not correct TLCO for a low VA because TL/VA

reduced to 5-6 s unless a very sensitive nitric

often rises when VA falls. TL/VA is equivalent

oxide analyser is used. The faster uptake of

Table 2. Different combinations of KCO and VA but a similar TLCO

Diagnosis

TLCO

KCO

Comment

% pred

Inspiratory muscle

120

Lack of alveolar expansion

weakness

Pneumonectomy

111

Localised loss of lung units

Diffuse interstitial

Alveolar capillary damage

lung disease

(¡loss of units)

Emphysema

Alveolar capillary damage

(FEV1/FVC ratio reduced)

Idiopathic PH

Microvascular damage

(FEV1/FVC ratio normal)

% pred: % predicted; PH: pulmonary hypertension; FEV₁: forced expiratory volume in 1 s; FVC: forced vital

capacity; Reproduced and modified from Hughes et al. (2012).

ERS Handbook: Respiratory Medicine

nitric oxide is due to a two-fold (versus carbon

Guenard H, et al. (1987). Determination

monoxide) increase in diffusivity through the

of lung capillary blood volume and

alveolar-capillary membranes, and a faster

membrane diffusing capacity by measure-

reaction with red blood cell Hb than carbon

ment of NO and CO transfer. Respir

monoxide. The TLNO/TLCO and KNO/KCO

Physiol; 70: 113-120.

ratios (they are identical since VA is common

Hughes JMB, et al. (2012). Examination

to both measurements) are 4.3-4.9 in normal

of the carbon monoxide diffusing capacity

subjects. The TLNO is less sensitive to

(DL(CO)) in relation to its KCO and VA

physiological changes in the pulmonary

components. Am J Respir Crit Care Med;

circulation than the TLCO; the TLNO is

186: 132-139.

Hughes JMB, et al. (2013). The TLNO/TLCO

independent of changes in haematocrit and

ratio in pulmonary function test inter-

PAO₂. The TLNO/TLCO ratio is reduced in

pretation. Eur Respir J; 41: 453-461.

alveolar under expansion and may be a

Jones RS, et al. (1961). A theoretical and

marker of extrapulmonary restriction; it is

experimental analysis of anomalies in the

expected to be reduced in chronic heart

estimation of pulmonary diffusing cap-

failure. Further research is needed to see

acity by the single breath method. Q J Exp

whether the TLNO/TLCO ratio has a role in

Physiol; 46: 131-143.

pulmonary function testing (Hughes

Ogilvie CM, et al. (1957). A standardized

et al. 2013).

breath holding technique for the clinical

measurement of the diffusing capacity of

the lung for carbon monoxide. J Clin

Further reading

Invest; 36: 1-17.

Borland CD, et al. (1989). A simultaneous

Roberts CM, et al. (1990). Multi-breath

single breath measurement of pulmonary

and helium single breath dilution lung

diffusing capacity with nitric oxide and

volumes as a test of airway obstruction.

carbon monoxide. Eur Respir J; 2: 56-63.

Eur Respir J; 3: 515-520.

ERS Handbook: Respiratory Medicine

Control of ventilation

Brian J. Whipp{ and Susan A. Ward

The ventilatory control system is highly

complex, involving:

Key points

N transmission of primary humoral stimuli

Ventilatory carbon dioxide responsive-

from their sites of generation to the

ness is determined as the slope of the

sensing elements;

linear iso-oxic V9E-PETCO₂ relationship

N integration of chemoreceptor afferent

(DV9E/DPETCO₂), using steady-state,

activity within brainstem ‘respiratory

constant-concentration inspirates or

centres’;

hyperoxic rebreathing. DV9E/DPETCO₂

N generation of respiratory motor-discharge

reflects central and, if PaO₂ is not

patterns;

excessive, also carotid chemoreceptor

N neuromuscular transmission at the

activity. Being appreciably shorter, the

respiratory muscles; and

latter test is preferred, although DV9E/

N generation of appropriate pulmonary

DPETCO₂ reflects only central

pressure gradients to produce the

chemoreflex activity.

required airflow and ventilation.

Ventilatory hypoxic responsiveness is

Consequently, while inhalation of

determined from the curvilinear

hypercapnic or hypoxic gas mixtures, either

isocapnic V9E-PETO₂ response, using

singly or in combination, is widely utilised to

steady-state, constant-concentration

assess the normalcy of ventilatory

inspirates or rebreathing. It reflects

‘chemoreflex’ sensitivity, interpretation of

solely carotid chemoreceptor activity.

responses should be made in the context of

Expressing V9E versus SaO₂ linearises

the entire ‘input-output’ relationship.

the profile, with the slope (DV9E/

Individuals with increased airway resistance

DSaO₂) providing the hypoxic

or impaired respiratory muscle function, for

responsiveness index (however, PaO₂,

example, may have an abnormally low

not SaO₂, is the actual stimulus). This

overall ventilatory carbon dioxide or hypoxic

can also be estimated using the

response despite normal chemoreflex

Dejours hypoxia-withdrawal test:

responsiveness.

abrupt oxygen administration from a

prior hypoxic background acutely

Ventilatory response to inhaled carbon

suppresses carotid-body activity to

dioxide

cause a transient, rapid V9E decline;

The relationship between V9E and arterial (a)

the maximum decrease as a fraction

or alveolar (A; typically end-tidal (ET))

of the total hypoxic V9E providing the

carbon dioxide tension (PCO₂), with the

hypoxic index.

subject sequentially inhaling a series of

progressively greater hypercapnic inspirates

(e.g. 3-6%), each for sufficiently long to

typically linear in healthy, normoxic

establish a steady state, is used to estimate

individuals, with a slope (DV9E/DPETCO₂)

overall ventilatory carbon dioxide responsive-

averaging ,2-3 L?min^-1?mmHg^-1. This slope

ness. The resulting V9E-PETCO₂ relationship is

reflects the carbon dioxide responsiveness of

ERS Handbook: Respiratory Medicine

both the central ‘chemoreceptors’, located

progressively greater carotid-body response

predominantly on the ventral medullary

component; it is crucial, therefore, to

surfaces and also, if PaO₂ is not excessive, the

maintain PaO₂ constant (iso-oxic) during the

peripheral chemoreceptors (predominantly,

test. Above a PaO₂ of ,200 mmHg, the

if not exclusively, the carotid bodies in

carotid-body component is effectively

humans).

inactivated and hence the sufficiently

hyperoxic carbon dioxide response entirely

At PaO₂ levels of ,90 mmHg, the central

reflects that of the ‘central’ component.

component accounts for 70-75% of the

Interpretation depends on the relationships

response, with the peripheral component

between the typically measured PETCO₂ (or,

accounting for the remainder. However, as

less typically, PaCO2) and PCO2 (and

the ‘peripheral’ component of carbon

hydrogen ion concentration [H⁺]) at each set

dioxide responsiveness increases with

of chemoreceptors; these relationships

reductions of PaO₂ below normal, DV9E/

depend on factors such as the local-tissue

DPETCO₂ increases with greater, constant

perfusion, carbon dioxide production,

degrees of hypoxaemia and decreases with

carbon dioxide capacitance, H⁺ buffering

greater, constant degrees of hyperoxia. This

capacity and metabolic rate. The equilibrium

results in a ‘fan’ of hypoxia-dependent

process is rapid at the carotid body

carbon dioxide response slopes reflecting

chemoreceptors, but is considerably delayed

altered response ‘sensitivity’ (also termed

at the sites of central chemoreception.

‘potentiation’), with little or no change in the

It has been has proposed that three or more

extrapolated V9E intercept on the PCO₂ axis

levels of inspired (I) PCO₂ should be used for

(fig. 1). By contrast, sustained metabolic

DV9E/DPETCO₂ characterisation. Each level is

acidaemia or alkalaemia results in a parallel

maintained for ,8-10 min, with the average

shift by the carbon dioxide response

V9E and PETCO₂ over the final 2-3 min

relationship (i.e. no change in carbon

providing the steady-state values.

dioxide ‘sensitivity’) with a reduced or

Consequently, the test is time-consuming,

increased V9E intercept, respectively.

although transiently overshooting PICO

beyond the required level can reduce the

The increasing DV9E/DPETCO₂ with greater

time required to attain the new V9E steady

levels of simultaneous hypoxia reflects a

state.

Steady-state test

This concern is obviated, to a considerable

PO2

mmHg

extent, by the rebreathing method of Read et

~60 ~90 ≥200

al. (1967), which takes a small fraction of the

time to perform while providing effectively

the same DV9E/DPETCO₂ value as the steady-

state method. The subject re-breathes from

a 6-7-L bag initially containing ,7% carbon

dioxide balance oxygen. The high initial

PICO₂ is designed to raise PaCO₂ rapidly to, or

close to, the mixed-venous level, such that

'Read' rebreathing

test

the subsequent rebreathing provides an

effectively linear increase in PaCO₂; the high

inspired oxygen tension (PIO₂) maintains

PaO₂ above levels for which variations in

PETCO

mmHg

carotid chemosensitivity would influence the

response slope.

Figure 1. Steady-state ventilatory responses to

inhaled PCO₂ at constant oxygen tension (PO₂;

The rebreathing relationship is shifted to the

solid lines). The dotted line depicts the response to

right of the steady-state relationship,

progressively increasing PCO₂ (hyperoxic

reflecting both the transit delay between the

rebreathing test).

lungs and sites of chemoreception and the

ERS Handbook: Respiratory Medicine

V9E response kinetics. Consequently, as the

The pattern of the V9E response to a step

test is designed to provide a constant rate of

decrease of PIO₂ is not monotonic, even with

change of PCO₂ at the chemoreceptor sites,

PETCO₂ being maintained as constant by

the rate of change of V9E is compared with

controlling the inspired level (i.e. isocapnic

the rate of change of PETCO₂ (DV9E/DPETCO₂).

hypoxia). There is an initial increase to a

This is currently the more common means

peak, usually well within 5 min, followed by a

of assessing carbon dioxide responsiveness,

slow reduction (termed ‘hypoxic ventilatory

although it is important to recognise that

decline’) to a final steady state (fig. 2a). The

the carbon dioxide responsiveness obtained

initial increase is considered to be the carotid

by this hyperoxic method reflects only

body component and the subsequent decline

central chemoreflex activity.

is thought to result from the hypoxia-

mediated increase in cerebral blood flow.

One must be careful, however, to assume

This reduces the degree of central

that hypoxia does not influence central

chemoreceptor stimulation as a result of

chemoreceptor responsiveness; it does

cerebral carbon dioxide wash-out, although

indirectly by increasing cerebral blood flow.

an involvement of altered neurotransmission

This tends to wash out CO₂ from the region,

has also been proposed. If the hypoxic step is

narrowing the difference between the local

limited to the initial (or primary) response

tissue PCO₂ and PaCO₂.

phase, then the resulting V9E-PaO

relationship over a range of increasingly

Beginning at a value below the spontaneous

hypoxic inspirates is curvilinear, with the V9E

control condition, carbon dioxide

rate of change approaching infinity at a PaO₂

responsiveness is not characterised by the

of ,30 mmHg. Naturally, at higher isocapnic

extrapolated dashed lines in figure 1. Rather,

PCO₂ levels, the curvature constant of the

there is a region of virtual insensitivity to

response is increased as a result of greater

increasing PCO₂, if previously lowered by, for

hypoxic-hypercapnic interaction at the

example, acute hyperventilation or sufficient

carotid bodies. It is recommended that the

hypoxia. The transition from the insensitive

subject be switched to air or even a mildly

to the sensitive region is considered to

hyperoxic mixture between successive

reflect a ventilatory recruitment threshold.

hypoxic steady states to avoid possible

The difference between this threshold and

depression of brainstem respiratory

the lower PETCO₂ at which apnoea ensues is

neurones. If, instead of isocapnia being

thought to be important in conditions such

maintained in this test, PaCO₂ is allowed to

as sleep apnoea. Also, as this threshold is

decrease spontaneously as V9E increases

lower in hypoxia than in hyperoxia, it can be

(poikilocapnia), then both the peak initial V9E

used to further understand the interaction

response and the final level achieved after the

between peripheral and central

hypoxic ventilatory decline are reduced.

chemoreceptor mediation. As a practical

expedient, the difference in PETCO₂ between

A rebreathing test, notionally similar to the

these conditions at resting ventilation can

Read-Leigh test of CO₂ sensitivity, yields

be used as an index of the threshold change;

considerably greater data density in a

Duffin (2011) has suggested PETO₂ values of

significantly shorter period, although the

150 and 50 mmHg for this assessment.

requirement for isocapnia throughout the

test does demand a degree of sophistication

Estimation of ventilatory response to

in avoiding, by means of a carbon dioxide-

hypoxia

absorbing system, the otherwise progressive

The V9E response to hypoxia, if defined

hypercapnia. The resulting curvilinear

under isocapnic conditions, is considered

response to the progressive isocapnic

solely to reflect carotid chemoreceptor

hypoxia is shown in figure 2b for two

activity. Both constant-concentration

subjects differing markedly in hypoxic

inspirate and rebreathing techniques have

sensitivity. There is little, from a

been successfully utilised for the

physiological standpoint, to choose between

characterisation.

an exponential and a hyperbolic

ERS Handbook: Respiratory Medicine

140

●

120

●

Hypoxic ventilatory

●

decline

●●

●

100

●

● ●

●

Primary

●

● ●

hypoxic

●

response

●

●●

●

●●

●

●●

●

●●

●

●●●

●

●●

●

●●●

●

●●

●

●●

●

Control

Isocapnic hypoxic step

-5

30 40 50 60 70 80 90100 110

Time min

PO2 mmHg

140

●

120

●

●●

●

100

●

● ●

●

Air

●

● ●

●

●●

●

●●

●

●●

●

●●●

●

●●

●

●●

● ●●

●

●●

●

● ●●

●

● ●●

●

1 min

100

SO2 %

Figure 2. a) V9E time-course to prolonged isocapnic step-decrease in end-tidal oxygen tension (PO2). b and

c) Ventilatory response to progressive isocapnic hypoxia (in two subjects) as a function, respectively, of end-

tidal PO₂ and oxygen saturation (SO₂). d) Ventilatory time-course to a hyperoxic step-increase in an

exercising hypoxic subject with alveolar proteinosis. PETCO2: end-tidal carbon dioxide tension. b and c)

Reproduced from Rebuck et al. (1981) with permission from the publisher. d) Reproduced from

Wasserman et al. (1989) with permission from the publisher.

characterisation of the response. The

the further central carbon dioxide-H⁺

conflicting issues regarding the most

stimulation.

appropriate index for hypoxic response

In addition to the ease of measuring SaO₂

characterisation appear to be obviated (on

noninvasively by pulse oximetry, and averting

empirical grounds) by the demonstration

any assumption regarding the difference

that the curvilinear V9E-PaO₂ relationship

between PETO₂ and PaO₂, the linearity of the

can be transformed into a linear relationship

V9E response makes this rebreathing method

by substituting SaO₂ for PaO₂ (fig. 2c):

a very practical means of assessing hypoxic

V9E 5 G?SaO₂ + V9E(0)

ventilatory responsiveness. It is important to

recognise, however, that the ventilatory

where V9E(0) is the control V9E and the slope

stimulus is PaO2; SaO₂ is merely a practical

parameter G is the hypoxic responsiveness

expedient, with uncertainties regarding the

quantifier. G has been shown to average

influence of conditions altering haemoglobin

,1.5¡1.0 (average¡SD) L?min^-1?% decrease

affinity for oxygen.

of SaO₂ in normal subjects. At higher

isocapnic levels, G is increased as a result of

The current degree of a subject’s hypoxic

the potentiating effect of carbon dioxide on

ventilatory drive may be estimated by the

carotid chemosensitivity, which sums with

hypoxia-withdrawal test of Dejours (1962).

ERS Handbook: Respiratory Medicine

If a particular level of PaO₂ is established by

laboratory-based tests of more chronic

inhalation of a hypoxic gas mixture, or noting

blood-gas and acid-base regulatory

the spontaneous PaO₂ if the subject is already

challenges are less well standardised.

hypoxaemic (as in figure 2d for an exercising

subject with alveolar proteinosis), then the

Further reading

abrupt administration of 100% oxygen will

acutely suppress carotid-body hypoxic

Cunningham DJC, et al. Integration of

responsiveness and cause V9E to fall

respiratory responses to changes in

transiently and rapidly. The maximum

alveolar partial pressures of CO₂ and O₂

decrease in V9E as a fraction of the total

and in arterial pH. In: Widdicombe JG,

hypoxic V9E provides the hypoxic index. In

et al., eds. Handbook of Physiology,

addition to the assumption (probably justified

Respiration. Vol II, Control of Breathing,

in humans) that the consequently high level

Part

Washington DC, American

of oxygen tension (PO₂) actually silences the

Physiological Society, 1986; pp. 475-528.

Dejours P

(1962). Chemoreflexes in

carotid bodies, the validity of the Dejours test

breathing. Physiol Rev; 42: 335-358.

(1962) depends upon the V9E decrement

Dempsey JA, et al. (2004). The ventilatory

reaching its nadir prior to the subsequently

responsiveness to CO₂ below eupnoea as

increased PaCO₂ (caused by the reduced V9E)

a determinant of ventilatory stability in

influencing central sites of carbon dioxide

sleep. J Physiol; 560: 1-11.

responsiveness. As the nadir of the response

Duffin J (2011). Measuring the respiratory

commonly occurs ,20-25 s after the

chemoreflexes in humans. Respir Physiol

hypoxic-hyperoxic transition, there is some

Neurobiol; 177: 71-79.

uncertainty regarding this latter point.

Edelman NH, et al. Effects of CNS

Although this test is quite easy to perform and

hypoxia on breathing. In: Crystal RG,

provides a useful qualitative estimate of

et al., eds. The Lung: Scientific Founda-

hypoxic responsiveness, it remains to be

tions. 2nd Edn. New York, Raven Press,

precisely standardised and quantified.

1997; pp. 1757-1765.

Read DJC, et al.

(1967). Blood-brain

The peripheral-chemosensory potentiation of

tissue PCO₂ relationships and ventilation

the carbon dioxide response by hypoxia may

during rebreathing. J Appl Physiol;

23:

also be used to provide an index of hypoxic

53-70.

ventilatory responsiveness, as follows:

Rebuck AS, et al. Measurement of venti-

latory responses to hypercapnia and

1) from the linear difference between the

hypoxia. In: Hornbein T, ed. The

hyperoxic and the hypoxic carbon dioxide

Regulation of Breathing. New York,

response, and

Dekker, 1981; pp. 745-772.

Severinghaus JW (1976). Proposed stand-

2) the increase in V9E between the hyperoxic

ard determination of ventilatory responses

(peripheral chemoreceptors silenced) and the

to hypoxia and hypercapnia in man. Chest;

hypoxic (40 mmHg PaO₂) carbon dioxide

70: Suppl. 1, 129-131.

response relationship, measured at a standard

Wasserman K, et al. Respiratory control

target level of 40 mmHg PaCO₂ (DV40).

during exercise. In: Widdicombe JG, ed.

Conclusions

International Review of Physiology,

Respiratory Physiology III. Baltimore,

While these approaches provide indices of

Univ Park Press, 1981; pp. 149-211.

acute ventilatory responsiveness,

ERS Handbook: Respiratory Medicine

Arterial blood gas assessment

Paolo Palange, Alessandro Maria Ferrazza and Josep Roca

The fundamental function of the lung is to

and causes of pulmonary gas exchange

contribute to homeostasis by ensuring that

impairment and acid-base (A-B)

pulmonary oxygen uptake (V9O₂) and carbon

disequilibrium. ABG analysis is one of the

dioxide production (V9CO₂) match the body’s

most useful diagnostic tests, not only in the

bioenergetic requirements. We must look at

critical care setting but also in general

pulmonary function as the first step of the

clinical practice, to assess patients with

oxygen transport chain from the atmosphere

respiratory diseases and those with other

to mitochondria.

disorders with potential impact on

pulmonary gas exchange and A-B

Arterial blood gas (ABG) analysis provides

disturbances (diabetes, heart failure (HF)

direct measurements of oxygen (PaO₂) and

and renal failure). Moreover, ABG analysis is

carbon dioxide tension (PaCO₂), and pH in

mandatory to establish a diagnosis of

arterial blood. In clinical practice, ABG

respiratory failure.

analysis is needed to assess both severity

Modern equipment for performing ABG

assessment uses electrodes to measure

Key points

PaO₂, PaCO₂ and pH. Other variables, such as

bicarbonates (actual HCO_3- and standard

ABG is mandatory for the diagnosis of

HCO_3-), base excess (BE) and

respiratory failure and of A-B

oxyhaemoglobin saturation (SaO₂), are

disorders.

computed using well-defined equations.

Pulmonary gas exchange status is

A simple and practical two-step approach

best evaluated by the integrated

for ABG interpretation in the clinical

reading of PaO₂ and PaCO₂.

setting is illustrated in figure 1. The first

A-B status is best evaluated by the

step aims at the analysis of pulmonary gas

integrated reading of PaCO₂ and pH,

exchange status based primarily on PaO₂

with concomitant measurement of

and PaCO₂, while the second step

serum electrolytes.

addresses the assessment of A-B status

using PaCO₂, pH and, eventually, HCO₃

Mixed A-B disorders are very

(or BE). If serum electrolytes, and in

common in clinical practice.

The correct interpolation of ABG

Step 1

represents a fundamental step for the

diagnosis and treatment of A-B

PaO

disorders.

PaCO

The study of serum chloride is

fundamental to further investigate the

Step 2

causes of metabolic disorders

affecting A-B equilibrium.

Figure 1. ‘Two-step’ approach for ABG

interpretation.

ERS Handbook: Respiratory Medicine

particular chloride, are measured, a further

When PaCO₂ values are close to 40 mmHg,

insight into the differential diagnosis of

PaO₂ is an excellent indicator of the efficacy

metabolic A-B disorders can be obtained

of the lung as an oxygen exchanger, but

(third step).

abnormal PaCO₂ values (hypercapnia or

hypocapnia) may benefit from the integrated

Step 1: evaluation

reading of PaO₂ and PaCO₂ values indicated

in table 1. Such an integrated view can be

Healthy subjects at sea level breathing room

numerically obtained by computing the

air (inspiratory oxygen fraction (FIO₂) 0.21)

alveolar-arterial oxygen tension difference

show PaO₂ values close to 90-95 mmHg.

(PA-aO₂) using the simplified formula

PaO₂ values ,80 mmHg are considered

arterial hypoxaemia and PaO₂ ,60 mmHg

PA-aO₂5((PB-PH₂O)?FIO₂-PaCO₂/R)-PaO₂

indicates hypoxaemic respiratory failure.

Because of the characteristics of the

where PB is barometric pressure, PH₂O is the

oxyhaemoglobin dissociation curve, a PaO₂

partial pressure of water vapour in the

airways and R is the respiratory quotient

of 60 mmHg corresponds to a SaO₂ of

,90% and is located at the upper end of the

(V9CO₂/V9O₂, ,0.80 at rest).

steepest portion of the curve. PaO₂ values

At sea level, the normal expected PA-aO₂

,60 mmHg will have a substantial impact,

value is ,15 mmHg in young subjects and

reducing arterial oxygen content and

,20 mmHg in the elderly. Table 1 shows the

compromising tissue oxygenation. The

contribution of the PA-aO₂ in the

accepted reference interval for PaCO₂ is 35-

identification of the mechanisms of

45 mmHg. By convention, hypercapnic

alteration of ABG.

respiratory failure is established at PaCO₂

.50 mmHg.

To further understand the cause of arterial

hypoxaemia, the effect of supplemental

Abnormal respiratory gases in arterial

oxygen breathing on PaO₂ should be

blood are generally due to impaired

examined, keeping in mind that in the

pulmonary gas exchange. Intrapulmonary

normal lung PA-aO₂ widens when breathing

factors that may cause arterial hypoxemia

additional oxygen. While hypoxaemia due to

are listed in table 1. Pulmonary alveolar

pulmonary V9A/Q9 mismatch and diffusion

ventilation (V9A)/perfusion (Q9) mismatch

defects is usually corrected by increasing

is the most frequent determinant of

inspired oxygen concentrations, this does

hypoxaemia and hypercapnia in the clinical

not correct respiratory failure due to shunt.

scenario. However, the identification of

pulmonary shunt (perfusion of

A simple, but less accurate, way to compute

unventilated pulmonary units, V9A/Q950)

PA-aO₂ is to use the rule of ‘130’. It is

as the main cause of hypoxaemia in a

assumed that in a healthy subject, at sea

patient with severe pneumonia has

level (FIO₂50.21), the sum of PaO₂ and PaCO₂

relevant therapeutic implications. It is of

should be ,130 mmHg. Consequently,

note, however, that alterations of

PA-aO₂<130-(PaO₂+PaCO₂)

extrapulmonary factors such as cardiac

output, FIO₂, V9O₂ and V9E are also

The following examples illustrate the use of

determinants of PaO₂ and PaCO₂.

the rule. A patient with PaO₂ 70 mmHg and

Table 1. PA-aO₂ in the evaluation of the causes of arterial hypoxaemia

Cause

PaO2

PaCO2

PA-aO2

Hypoventilation

V9A/Q9 mismatch

«Qq

Oxygen diffusion limitation

«Q

Shunt

«Qq

ERS Handbook: Respiratory Medicine

PaCO₂ 60 mmHg (PA-aO₂

The metabolic component refers to the

<130-(70+60)50 mmHg) is hypoventilating

impact of nonvolatile molecules generating

a lung that is functionally ‘normal’, with a

acidosis or alkalosis. The variable most

PA-aO₂ within the reference interval.

often used to assess the metabolic

However, a patient with hypoxaemic

component is bicarbonate concentration

respiratory failure and hypocapnia (PaO₂

([HCO_3-]) computed through the

50 mmHg, PaCO₂ 20 mmHg; PA-aO₂

Henderson-Hasselbalch equation:

<130-(50+20)560 mmHg) shows worse

pH56.1+log([HCO_3-]/0.03?PCO₂)

pulmonary oxygen exchange (higher PA-aO₂)

than a patient with respiratory failure and

where PCO₂ is carbon dioxide tension. In the

hypercapnia (PaO₂ 50 mmHg, PaCO₂

past, the role of simple rules associating

50 mmHg; PA-aO₂

changes in PaCO₂ with changes in pH (and

<130-(50+50)530 mmHg). The

HCO_3-) has been emphasised as useful for

computation of PA-aO₂ (and the use of the

the diagnosis of simple and mixed A-B

rule of 130) is not useful clinically when FIO₂

disorders. A graphical illustration of this

increases. Calculating the PaO₂/FIO₂ ratio is

approach in presented in figure 2.

recommended to assess the efficacy of the

lung as an oxygen exchanger in critical care

Table 3 displays some examples of simple

when comparing ABG measurements taken

A-B disorders. The first two rows in table 3

at different values of FIO₂. Lung injury is

indicate simple, uncompensated A-B

defined as PaO₂/FIO₂ ,300 mmHg while

disorders. The first row may correspond to a

acute respiratory distress syndrome (ARDS)

COPD patient with an episode of severe

is associated with a PaO₂/FIO₂ ,200 mmHg

exacerbation showing acute hypercapnia

(table 2). Recently, three mutually exclusive

leading to respiratory acidosis. The second

categories of ARDS severity based on the

degree of hypoxaemia have been proposed:

Table 2. Respiratory failure

N mild (PaO₂/FIO₂ from 200 to

Hypoxaemic respiratory failure

f300 mmHg)

PaO₂ f60 mmHg, PaCO₂ normal or low,

N moderate (PaO₂/FIO₂ from 100 to

at sea-level (FIO2 0.21)

f200 mmHg)

Hypoxaemia due to pulmonary V9A/Q9

N severe (PaO₂/FIO₂ f100 mmHg)

mismatching (PaO2 rises with FIO2)

Step 2: diagnosis of A-B disorders

Chronic respiratory diseases

(only pulmonary fibrosis shows

Arterial pH is highly regulated to be

oxygen diffusion limitation with

maintained between 7.38 and 7.42. In the

V9A/Q9 mismatch)

clinical assessment of A-B equilibrium, two

Hypoxaemia due to intrapulmonary

main determinants of arterial pH must be

shunt (lung units with V9A/Q950) (PaO₂

taken into account, namely

responds to FIO₂) (PaO₂/FIO₂ f200)

N the respiratory component (PaCO₂)

Hypercapnic respiratory failure

N the metabolic component

PaCO₂ o50 mmHg and PaO₂ low,

at sea-level (FIO₂

0.21)

Hypercapnia (high PaCO₂) generates

‘Normal’ lung (PA-aO2 gradient

respiratory acidosis (low pH) whereas

preserved)

hypocapnia (low PaCO₂) is associated to

respiratory alkalosis (high pH). In simple

Reduced V9A due to extrapulmonary

acute respiratory disorders, for each

factors

10-mmHg variation in PaCO₂, the expected

Advanced chronic respiratory disease

change in pH is 0.07 for acidosis and 0.08

or severe exacerbation

for alkalosis, while in simple chronic

Hypoxaemia due to pulmonary V9A/Q9

respiratory disorders, it is 0.03 for both

mismatch

acidosis and alkalosis.

ERS Handbook: Respiratory Medicine

example fits any situation leading to

Step 3: more on A-B disorders

hyperventilation and low PaCO₂ that

To further investigate the causes of

generates respiratory alkalosis (e.g.

interstitial oedema in HF). The third row

metabolic disorders, the measurement of

indicates an example of acidosis due to a

serum electrolytes, and in particular

chloride, is of great help. In fact, while

metabolic disturbance (e.g. exercise-related

respiratory disturbances directly affect pH

increase in blood lactate, ketoacidosis, renal

by modifying PaCO₂, metabolic disturbances

failure, etc.). Finally, the fourth example of

A-B disequilibrium corresponds to a

can be derived from changes in the net

metabolic alkalosis that may be seen in

difference between negative and positive

patients with liquid depletion and low

charges dissolved in the serum (strong ions

and weak acids). An increase in negative

intracellular and serum potassium

charges reduces pH, while a reduction

concentrations (e.g. excessive diuretic

increases pH (fig. 3). The negative charges

therapy).

that strongly influence the A-B equilibrium

Common causes of A-B disorders are

are chloride and the so-called non-

illustrated in tables 4 and 5. It is of note that

measurable anions (see later). Several types

although they may begin as simple disorders

of renal tubular acidosis impair renal

(respiratory or metabolic), these often

chloride excretion, resulting in a net increase

evolve to mixed A-B abnormalities.

in serum chloride concentration and, thus,

100

7.0

7.1

Case 1

Case 2

●

7.2

●

7.3

7.4

Metabolic

7.5

alkalosis

7.6

7.7

7.8

8.0

8.5

100

Torr

5.33

kPa

PaCO

Figure

2. PaCO2-pH nomogram for

the diagnosis of A-B disorders. PaCO2 and

pH values that fall in the

acute or chronic, respiratory or nonrespiratory (or metabolic) ‘bands’ should be considered ‘simple’

disorders (case 1: PaCO2 70 mmHg, pH 7.19; acute respiratory acidosis). Values that fall between the

respiratory and metabolic bands should be considered ‘mixed’ disorders (case 2: PaCO₂ 40 mmHg, pH 7.20;

acute respiratory and metabolic acidosis). N: normal. Reproduced and modified from Goldberg et al.

(1973).

ERS Handbook: Respiratory Medicine

common acids that cause high-AG

Table 3. Examples of simple A-B disorders

metabolic acidosis are lactic acid (lactic

pH PaCO₂

[HCO_3-]

acidosis), keto acids (diabetic or alcoholic

Respiratory acidosis

Q q

acidosis) and inorganic acids (renal failure).

The reduction in AG due to severe reduction

Respiratory alkalosis

q Q

in serum albumin can generate a mild

Metabolic acidosis

Q Q Q

metabolic alkalosis.

Metabolic alkalosis

q q q

Conclusion

In clinical practice, the correct interpretation

in metabolic acidosis. Lower gastrointestinal

of ABG provides unique information on the

losses of sodium, potassium and water

characteristics and severity of lung gas

(diarrhoea) cause an increase in the serum

exchange impairment and on A-B

concentration of chloride, thus resulting in

abnormalities. It represents a fundamental

hyperchloraemic acidosis. However,

step towards an appropriate diagnosis of the

reduction of chloride (e.g. loop diuretics)

patient and the adoption of the treatment

causes metabolic alkalosis. The main

strategy. Figure 3 summarises the

mechanism that may cause metabolic

interpretative ‘integrative’ approach to be

alkalosis is the increase in renal

used in the evaluation of the ABG. As a first

ammoniagenesis that stimulates chloride

step (step 1), the combined reading of PaO₂

excretion as ammonium chloride. Several

and PaCO₂ values, on room air and during

factors can increase renal ammoniagenesis:

supplemental oxygen breathing, should be

primitive hyperaldosteronism, hypovolaemia

used to identify the causes and the severity

(e.g. secondary hyperaldosteronism) and

of arterial hypoxaemia (blue squares and

hypokalaemia. In the clinical setting, the

causes of metabolic alkalosis can be

classified as chloride-responsive or chloride-

resistant based on the response to chloride

Table 5. Metabolic disorders

salt administration (table 5). Negative

Metabolic acidosis

charges other than chloride are usually

Normochloraemic acidosis

calculated by the anion gap (AG) formula:

(or high anion gap acidosis)

AG5[Na⁺]-([Cl^-]+[HCO_3-])

Ketoacidosis

Lactic acidosis

The AG represents the amount of non-

measurable anions (acids), and the normal

Renal failure

value is around 12-14 mEq?L^-1. The most

Toxins

Hyperchloraemic acidosis

(or normal anion gap acidosis)

Table 4. Respiratory disorders

Extra-renal loss of sodium

Respiratory acidosis

Renal tubular acidosis

Central nervous system depression,

Metabolic alkalosis

neuromuscular disorders

Chloride-responsive type

Chest wall abnormalities

Gastric fluid loss

Lung diseases

Volume contraction

Respiratory alkalosis

Chloride-resistant type

Anxiety, central nervous system

disorders

Mineral corticoid disorders

Hormones/drugs (catecholamine,

Milk-alkali and Bartter syndromes

progesterone, hyperthyroidism, salicylate)

Hypoalbuminaemia

ERS Handbook: Respiratory Medicine

V 'A/Q' mismatch

Shunt

V 'A

Diffusion

Acidosis

Alkalosis

PA-aO

Respiratory

O2 challenge

Step 1

PaO

PaCO

Step 2

Metabolic

Acidosis

Alkalosis

Electrolytes

Step 3

AG-

Cl-

AG-

Cl-u

Lactate

AGu

Albumin

Cl-

administration

Ketoacids

Creatinine

Renal or

Hypoalbuminaemia

Extra-renal

Cl- responsive

Cl- resistant

Figure 3. Comprehensive approach to ABG interpretation. AG: anion gap; U: urinary.

blue circles). As a second step (step 2), the

Brackett NC Jr, et al.

(1965). Carbon

combined reading of PaCO₂ and pH is

dioxide titration curve of normal man.

needed for the correct diagnosis of A-B

Effect of increasing degrees of acute

disorders (red squares). Furthermore, the

hypercapnia on acid-base equilibrium.

study of serum electrolytes, particularly

N Engl J Med; 272: 6-12.

serum chloride, may be of great help in the

Hughes JMB. Pulmonary gas exchange.

identification of the causes of metabolic

In: Lung Function Tests: Physical

disorders (red squares) (step 3).

Principles and Clinical Applications.

Hughes JMB, et al., eds. London, W.B.

Saunders, 1999; pp. 75-79.

Further reading

Kassirer JP, et al. (1965). Rapid estima-

ARDS Definition Task Force, et al.

tion of plasma carbon dioxide tension

(2012). Acute respiratory distress syn-

from pH and total carbon dioxide

drome: the Berlin Definition. JAMA; 307:

content. N Engl J Med;

272:

1067-

2526-2533.

1068.

Astrup P (1956). A simple electrometric

Kellum JA (2005).Clinical review: reunifi-

technique for the determination of car-

cation of acid-base physiology. Crit Care;

bon dioxide tension in blood and

9: 500-506.

plasma, total content of carbon dioxide

Kellum JA (2007). Disorders of acid-base

in plasma and bicarbonate content in

balance. Crit Care Med; 35: 2630-2636.

‘separated’ plasma at fixed carbon diox-

Narins RG, et al.

(1980). Simple and

ide tension. Scand J Clin Lab Invest; 8:

mixed acid-base disorders: a practical

33-43.

approach. Medicine; 59: 161-187.

ERS Handbook: Respiratory Medicine

Riley RL, et al. (1949). ‘Ideal’ alveolar air

Severinghaus JW, et al. (1958). Electrodes

and the analysis of ventilation-perfusion

of blood PO₂

and PCO₂ determination.

relationships in the lungs. J Appl Physiol;

J Appl Physiol; 13: 515-520.

1: 825-847.

Stewart PA (1983). Modern quantitative

Riley RL, et al. (1951). Analysis of factors

acid-base chemistry. Can J Physiol

affecting partial pressures of oxygen and

Pharmacol; 61: 1444-1461.

carbon dioxide in gas and blood of lungs:

Wagner PD (2003).The biology of oxygen.

theory. J Appl Physiol; 4: 77-101.

Eur Respir J; 31: 887-890.

Roca J, et al. (1994). Principles and informa-

West JB (1971). Causes of carbon dioxide

tion content of the multiple inert gas

retention in lung disease. N Engl J Med;

elimination technique. Thorax; 49: 815-824.

284: 1232-1236.

ERS Handbook: Respiratory Medicine

Exercise testing

Paolo Palange and Paolo Onorati

The ability to exercise largely depends on the

abnormalities (e.g. reduction in venti-

integrated physiological responses of the

latory capacity, dynamic hyperinflation)

respiratory, cardiovascular and skeletal

N In ILD, exercise tolerance is limited by

muscle systems. In healthy individuals,

ventilatory constraints and pulmonary

exercise tolerance is influenced by age,

gas exchange abnormalities (e.g. arterial

gender and level of fitness. In patients with

oxygen desaturation).

lung diseases, exercise tolerance is typically

N In PVD and CHF, both circulatory (e.g.

reduced and limited by symptoms such as

reduced adaptation in cardiac output)

dyspnoea and leg fatigue.

and pulmonary gas exchange

abnormalities contribute to exercise

Cardiopulmonary exercise testing (CPET),

intolerance.

i.e. the study of ventilatory, cardiovascular

and pulmonary gas exchange variables

Exercise protocols

during symptom-limited incremental

Maximal incremental test The symptom-

exercise, is considered the gold standard for

limited maximal incremental exercise

evaluating the degree and causes of exercise

protocol is recommended as a first step in

intolerance in disease states (table 1).

the evaluation of exercise tolerance. V9E,

Moreover, CPET has been extensively used

heart rate, oxygen uptake (V9O₂), carbon

in patients with COPD, CF, interstitial lung

dioxide production (V9CO₂), and end-tidal

diseases (ILDs), pulmonary vascular

oxygen and carbon dioxide tensions are the

disorders (PVDs) and CHF.

primary variables measured, typically on a

breath-by-breath basis using computerised

N In COPD and CF, exercise tolerance is

systems. Additional required measurements

mainly limited by pulmonary mechanical

include ECG, blood pressure, dyspnoea, leg

discomfort, exercise-related arterial oxygen

desaturation and spirometry with flow-

Key points

volume loop recording. Careful selection of

patients minimises the likelihood of serious

CPET is considered the gold standard

complications during maximal incremental

for:

exercise testing. Myocardial infarction

(within 3-5 days), unstable angina, severe

an objective measure of exercise

arrhythmias, pulmonary embolism,

capacity,

dissecting aneurism and severe aortic

N identifying the mechanisms limiting

stenosis represent absolute

exercise intolerance,

contraindications to CPET. Resting lung

function measurements and ECG are usually

N establishing indices of the patient’s

obtained before CPET. Cycle and treadmill

prognosis,

exercise have been used interchangeably,

N evaluating the effects of therapeutic

although the former is largely used as the

interventions.

work rate for incremental and endurance

tests is easier to quantify. As the exercise

ERS Handbook: Respiratory Medicine

for surgery, including lung transplant; and

Table 1. Some causes of exercise intolerance in lung

evaluation of the effects of therapeutic

diseases

intervention, including pulmonary

Ventilatory limitation to exercise

rehabilitation.

Dynamic hyperinflation

Exercise variables and indexes

Increased work of breathing

Pulmonary gas exchange abnormalities

Maximal V9O₂ The classical criterion for

defining exercise intolerance and classifying

Excessive perception of symptoms

degrees of impairment is the maximal

Impaired cardiovascular response to

oxygen uptake (V9O₂max). With good subject

exercise and reduced oxygen delivery

effort on an incremental test, V9O₂max

Peripheral muscle weakness/dysfunction

reflects a subject’s maximal aerobic

capacity. This index is taken to reflect the

attainment of a limitation in the oxygen

period should last 10-12 min, the work rate

conductance pathway from the lungs to the

increment should be selected carefully. In

mitochondria. Values ,80% predicted are

patients with lung diseases, the usual rate of

considered abnormal while values ,40%

workload increase is 10 W?min^-1, although

predicted indicate severe impairment.

slower or faster rates are possible in the very

sick and in fitter patients, respectively. The

Lactate threshold hL is the highest V9O₂ at

maximal incremental exercise test is also

which the arterial lactate concentration is

used to determine the appropriate work rate

not systematically increased, and is

for an endurance protocol.

estimated using an incremental test. It is

considered an important functional

Constant work rate (CWR) tests, on a cycle

demarcator of exercise intensity. Sub-hL

ergometer or on a treadmill, are used for the

work rates can normally be sustained for

measurement of exercise ‘endurance’

prolonged periods. hL is dependent on age,

tolerance and ventilatory and pulmonary gas

sex, body mass and fitness. Noninvasive

exchange kinetics. CWR exercise results in

estimation of hL requires the demonstration

steady-state responses when work rate is of

of an augmented V9CO₂ in excess of that

moderate intensity (i.e. below the lactate

produced by aerobic metabolism, and its

threshold (hL); conversely, high-intensity CWR

associated ventilatory sequelae.

exercise (i.e. above hL) results in steady states

either being delayed or not attained at all.

Oxygen pulse The oxygen pulse is the

product of the stroke volume and the

Walking tests, such as the 6-min walking

difference between the arterial oxygen

test, have been increasingly used for the

content (CaO₂) and the mixed venous oxygen

assessment of exercise tolerance in chronic

content (CvO₂). Given the Fick equation

lung diseases. The object of this test is to

walk as far as possible in 6 min. The test

V9O₂5cardiac output6(CaO₂-CvO₂)

should be performed indoors along a 30-m

flat, straight corridor; encouragement

the oxygen pulse can be calculated as:

significantly increases the distance walked.

Oxygen pulse5V9O₂/heart rate

Measurements of SpO₂, heart rate and

exertional symptoms are recommended

In patients with ILD, the oxygen pulse at

during this test.

peak exercise is lower and its rate of increase

with increasing work rate is usually reduced

Indications for CPET

because of the reductions in stroke volume

In patients with lung diseases, exercise

and CaO₂. In PVD, the oxygen pulse is

testing is mainly used for functional and

characteristically low at peak exercise and

prognostic purposes. Other indications

may not increase during incremental

include: detection of exercise-induced

exercise, reflecting the abnormal cardiac

bronchocontriction; selection of candidates

output adaptation.

ERS Handbook: Respiratory Medicine

Heart rate reserve (HRR) The peak heart rate

(HRpeak) achieved in a symptom-limited

exercise test decreases with age. The most

commonly used equation to predict HRpeak is

Normal

HRpeak,pred5200-age

HRR is defined as the difference between

COPD

HRpeak,pred and HRpeak. In healthy

individuals, HHR is virtually zero; a high

HRR is usually observed in patients with

COPD, CF and ILD.

Rest

Exercise

V9E-V9CO₂ slope and ventilatory equivalent for

Figure 1. Ventilatory response and limitation to

carbon dioxide It is conventional to express

exercise. Ventilatory limitation to exercise is

the ventilatory response to exercise relative

typically observed in patients with COPD

to V9CO₂. It can be measured as the slope of

compared with normal subjects. In COPD, but

the V9E-V9CO2 relationship (DV9E/DV9CO2)

also in CF and ILD, ventilatory reserve is reduced

over its linear region, i.e. typically extending

at peak exercise. See the main text for further

from ‘unloaded pedalling’ to the respiratory

comments.

compensation point. In normal individuals,

In COPD, CF and ILD, BR is usually reduced

DV9E/DV9CO₂ values of around 23-25 have

or absent at peak CPET exercise (fig. 1).

been reported.

Analysis of flow-volume loops is also

emerging as an important tool to assess the

The adequacy of the ventilatory response

degree of airflow and ventilatory limitation

to exercise is also expressed by the ratio

during exercise in patients with COPD.

V9E/V9CO₂ that represents the litres of

ventilation necessary to clear 1 L of carbon

Dynamic hyperinflation In normal subjects,

dioxide. Up to the respiratory

end-expiratory lung volume (EELV)

compensation point, V9E/V9CO₂ declines

decreases with increasing work rate by as

curvilinearly as work rate increases. It is

much as 0.5-1.0 L below functional residual

common practice to record the value at

capacity. Changes in EELV during exercise

hL (V9E/V9CO₂@hL) or the minimum value.

can be estimated by asking the subject to

These have each been proposed to

perform an inspiratory capacity manoeuvre

provide noninvasive indices of ventilatory

at a selected point in the exercise test. In

inefficiency. In normal individuals,

COPD, particularly in the advanced phases

V9E/V9CO₂@hL values of 25-28 have been

of the disease, EELV increases during

reported. Several factors may increase

exercise (i.e. dynamic hyperinflation) in spite

DV9E/DV9CO₂ and V9E/V9CO₂@hL, such as

of expiratory muscle activity.

hypoxaemia, acidosis, increased levels of

Arterial oxygen desaturation During exercise,

wasted ventilation and pulmonary

SpO₂ is normally maintained in the region of

hypertension.

around 97-98%. However, arterial oxygen

desaturation can be observed in patients

Breathing reserve (BR) provides an index of

with moderate-severe ILD and in patients

the proximity of the ventilation at the limit of

with primary pulmonary hypertension.

tolerance (V9Emax) to the maximal voluntary

ventilation (MVV):

Tolerable limit of exercise and ‘isotime’

measurements Tlim is the tolerable limit of

MVV5resting FEV1640

exercise, expressed as function of time

BR can be defined as V9Emax as a percentage

measured during CWR protocols. In clinical

of MVV:

practice, high-intensity (around 70-80% of

maximal work rate) CWR protocols are used

BR51-V9Emax/MVV

for the evaluation of interventions. In

ERS Handbook: Respiratory Medicine

addition to Tlim, measurement of pertinent

physiological variables (e.g. V9E, inspiratory

capacity and dyspnoea) at a standardised

Normal

time (isotime) are obtained.

PVD CHF, COPD

CPET response patterns

Ventilatory Response In normal individuals

during incremental exercise, V9E increases

linearly relative to work rate or V9O₂. At some

point, V9E begins to increase more steeply in

response to the development of lactic

V'CO

acidosis, to maintain acid-base

homeostasis (normal individual in fig. 1).

Figure 2. DV9E/DV9CO₂ during exercise. Different

The ventilatory response to exercise in

DV9E/DV9CO2 slopes are seen in normal subjects

patients with lung disorders is increased

and in patients with PVD, COPD and CHF.

(COPD patient in fig. 1). Conventionally, the

ratio of V9E at peak exercise to the estimated

and during exercise. Normally, PaO₂ does

MVV represents the assessment of the

not decrease during exercise and PA-aO₂ at

ventilatory limitation or of the prevailing

peak exercise usually remains below

ventilatory constraints. Ventilatory limitation

20-30 Torr. In most patients with ILD and

is commonly judged to occur when V9E/MVV

PVD, pulmonary gas exchange efficiency is

exceeds 85%. In lung diseases, the increase

impaired, as indicated by an abnormally

in V9E/MVV may reflect a reduction in MVV

large PA-aO₂ (.30 Torr) at peak exercise

or an increase in V9E. The ventilatory

accompanied by arterial oxygen

response during exercise is influenced by

desaturation. These changes reflect regional

metabolic rate (V9CO₂), PaCO₂ and the

ventilation-perfusion ratio dispersion and

physiological dead space fraction of the tidal

alterations in pulmonary capillary transit

volume (VD/VT). The relationship between

time resulting from the recruited pulmonary

these variables is described as:

capillary volume becoming inadequate for

V9E5(8636V9CO₂)/(PaCO₂6(1-VD/VT))

the high levels of pulmonary blood flow.

where PaCO₂ is expressed in Torr. In lung

Cardiovascular response CPET has proved

diseases, for a given V9CO₂ and PaCO₂, V9E is

very useful in the detection and

usually increased because of a higher VD/VT.

quantification of cardiovascular

DV9E/DV9CO₂ or V9E/V9CO₂@hL is often used

abnormalities during exercise. The

in the functional assessment of patients with

characteristic findings are a reduced

lung diseases (e.g. COPD, ILD and PVD) and

V9O₂max, reduced hL, steeper heart rate-V9O₂

cardiovascular disorders (e.g. CHF). V9E/

relationship (with a reduced heart rate

V9CO₂ is usually increased, particularly in

reserve at peak exercise) and a shallower

patients with PVD (fig. 2). Another particular

profile (or even flattening) of the oxygen

behaviour of the V9E response during exercise

pulse increase with increasing V9O₂. An

is the cyclic fluctuation of V9E and expired gas

abnormal cardiovascular response to

kinetics, also defined as exertional oscillatory

exercise is observed in PVD and, in

ventilation, which can occur in approximately

particular, in patients with idiopathic

one-third of patients with CHF. While the

pulmonary arterial hypertension.

origin of such a ventilatory abnormality is still

Exercise testing in prognostic evaluation

controversial, its clinical relevance in terms of

a negative prognosis is well established.

Exercise tolerance is well recognised as a

Pulmonary gas exchange The efficiency of

valuable predictor of mortality in healthy

pulmonary gas exchange can be assessed by

subjects. This also appears to be the case in

studying the magnitude of alveolar-arterial

chronic pulmonary diseases. Exercise

oxygen tension difference (PA-aO₂) at rest

testing has become an essential component

ERS Handbook: Respiratory Medicine

Table 2. CPET prognostic indices

COPD

ILD

PVD

CHF

QV9O2max

qV9E/V9CO₂

Arterial oxygen desaturation

Exertional oscillatory ventilation

in the prognostic evaluation of patients with

Further reading

lung diseases (table 2).

ATS Committee on Proficiency Standards

for Clinical Pulmonary Function Labora-

Several studies have confirmed that V9O₂max

tories. (2002). ATS statement: guidelines

is superior to other indexes in the risk

for the six-minute walking test. Am J Respir

stratification of patients with end-stage lung

Crit Care Med; 166: 111-117.

diseases; many centres, however, use field

ERS Task Force on Standardization of Clini-

tests for prognostic purposes.

cal Exercise Testing. (1997). Clinical exer-

Evaluating the effects of therapeutic

cise testing with reference to lung diseases:

indications, standardization and interpreta-

interventions

tion strategies. Eur Respir J; 10: 2662-2689.

High-intensity (75-80% of peak work rate)

Guazzi M, et al. (2012). Exercise oscillatory

endurance CWR protocols performed on a

breathing and NT-proBNP levels in stable

heart failure provide the strongest predic-

cycle ergometer or treadmill to Tlim have

tion of cardiac outcome when combining

been successfully used in COPD patients

biomarkers with cardiopulmonary exercise

for the evaluation of the effects of

testing. J Card Fail; 18: 313-320.

therapeutic interventions (e.g.

Johnson B, et al.

(2003). ATS/ACCP

bronchodilators, oxygen, heliox and

statement on cardiopulmonary exercise

rehabilitation). These types of protocols

testing. IV. Conceptual and physiologic

have a greater power to discriminate

basis of cardiopulmonary exercise testing

therapy-induced changes in COPD

measurements. Am J Respir Crit Care Med;

patients, with a higher fractional

167: 228-238.

improvement in exercise tolerance

O’Donnell DE, et al.

(2001). Dynamic

compared with incremental CPET.

hyperinflation and exercise intolerance in

However, it should be recognised that the

chronic obstructive pulmonary disease.

hyperbolic profile of the relationship

Am J Respir Crit Care Med; 164: 770-777.

between the power output and exercise

Palange P, et al.

(2007). Recommen-

dations on the use of exercise testing in

duration (Tlim) (the ‘power-duration

clinical practice. Eur Respir J; 29: 185-209.

curve’) during CWR tests is responsible for

Ward SA, et al., eds. Clinical Exercise

a considerable proportion of variability in

Testing. Sheffield, European Respiratory

the improvement magnitude of Tlim. That

Society, 2007.

is, Tlim is influenced by the pre-intervention

Wasserman K, et al. Principles of

work rate and exercise duration and their

Exercise Testing and Interpretation, 4th

relative positioning on the power-duration

Edn. Philadelphia, Lippincott Williams &

profile. Without knowledge of these

Wilkins. 2005.

aspects, any change in Tlim to a single CWR

Whipp BJ, et al.

(2009). Quantifying

bout must be cautiously interpreted in

intervention-related improvements in exer-

terms of realistic physiological benefits

cise tolerance. Eur Respir J; 33: 1254-1260.

obtained from the intervention.

ERS Handbook: Respiratory Medicine

Bronchial provocation testing

Kai-Ha˚ kon Carlsen

As early as 1859, Sir Henry Hyde Salter

to bronchoconstrictor stimuli in vivo’ (Sterk,

described ‘bronchial sensibility’ in patients

1996).

with asthma. Later, in 1945, Tiffenau

BHR is assessed by bronchial provocation

suggested that measuring changes in

testing (BPT), which may be performed with

expiratory flow after inhaling acetylcholine or

several different aims in mind: it may be

isoproterenol could be helpful in assessing

done as part of research or in the clinical

patients with airways disease. Ultimately,

setting, and with several different chemical

these observations led to the concept of

substances; it may test specific bronchial

bronchial hyperresponsiveness (BHR),

responsiveness to an allergen (allergen

which is defined as ‘an increase in the ease

BPT), or nonspecific bronchial

and degree of airflow limitations in response

responsiveness by BPT to histamine or

methacholine, as well as several other

different substances (table 1).

Key points

Methods of BPT

Bronchial challenge with

BPT can be divided into direct and indirect

methacholine/histamine is a sensitive

methods (Pauwels et al., 1988).

measure of asthma but lacks

Methacholine and histamine BPT represent

specificity.

direct methods, using a transmitter

(methacholine) or a mediator (histamine)

Indirect measures of bronchial

substance as test agents. Indirect methods

responsiveness (exercise, inhaled

include exercise testing (which may also be

AMP, hypertonic saline and mannitol,

regarded as BPT, but which otherwise is

and EVH) are specific, but not

regarded to come outside the present topic),

sensitive, measures of asthma.

inhaled adenosine monophosphate (AMP),

Indirect measures of bronchial

inhaled mannitol and eucapnic voluntary

responsiveness (exercise, etc.)

hyperpnoea (EVH) tests. The indirect tests

respond rapidly (1-3 weeks) to inhaled

have their effect through causing mediator

steroids.

or transmitter release from inflammatory

cells and nerves.

Direct measures of bronchial

responsiveness (methacholine and

Previously, BPT was performed qualitatively

histamine) respond slowly to inhaled

using a 10-fold increase in concentration of

steroids (.3 months).

the test substance (Aas, 1970), whereas

Direct measures of bronchial

during the last 25 years, a doubling of the

responsiveness (methacholine and

concentration/dose of the test substance

histamine) are presently the most

has been used (Cockcroft et al., 1977a).

exact monitoring tool for asthma.

Taking bronchial provocation with

BHR may predict later active asthma.

methacholine as an example, figure 1 shows

the reduction in FEV1 caused by inhaling

ERS Handbook: Respiratory Medicine

Table 1. Different types of bronchial responsiveness assessed by different types of BPT

Bronchial responsiveness

BPT substance

Specific

Allergen BPT

Nonspecific

Direct

Methacholine

Histamine

Indirect

Exercise test

Exercise test while inhaling dry or cold air

Inhaled AMP

Inhaled mannitol

EVH

doubling doses, with interpolation on the x-

When determining bronchial responsiveness

axis to determine the provocative concen-

by measuring PD20, the cumulated dose

tration of methacholine causing a 20%

inhaled is determined. This is done by

decrease in FEV1 (PC20) (Cockcroft et al.,

inhaling doubling doses of the test

1977a). Later, a simplification of the test was

substance. The most often-used delivery

introduced by inhaling single doubling doses

device is an inspiration-triggered nebuliser

of methacholine, determining the provocative

enabling inhalation by controlled tidal

dose of the test agent causing a 20%

ventilation, such as the Spira nebuliser

decrease in FEV1 (PD20) (Yan et al., 1983).

(Spira Respiratory Care Centre,

Hämeenlinna, Finland) (Nieminen et al.,

The test is performed under standardised

1988) or the Aerosol Provocation System

conditions, with specified nebulisation rates

(Jaeger, Würzburg, Germany). Alternatively,

for the tidal breathing method (PC20),

a handheld DeVilbiss nebuliser has been

inhaling the test agent for 2 min, measuring

used (DeVilbiss Healthcare, Somerset, PA,

FEV1 and then inhaling the doubed

USA) (Cockcroft et al., 1977a). A joint Task

concentration. The test is stopped when

Force of the European Respiratory Society

FEV1 is reduced by o20% and the PC20/

and American Thoracic Society is presently

PD20 determined by interpolating the

revising the recommendations for bronchial

semilogarithmic dose-response curve

challenges, including methacholine and

(fig. 1).

histamine BPT. Recommendations given

here may be superseded by new

recommendations from that Task Force.

110

Determinations of PC20 or PD20 are used

both for BPT with methacholine and

100

histamine, as well as with AMP, and may be

used for allergen BPT. BPT with mannitol

was recently developed and launched

commercially by inhaling cumulative doses

through a powder inhaler. Here, a 15%

reduction in FEV1 (PD15) is used as cut-off

(Brannan et al., 2005).

Saline

0.03

0.06

0.125

0.25

In EVH, the subject inhales dry air with 4.9%

Methacholine mg·mL-1

carbon dioxide for 6 min at a preferred

ventilation rate of 85% of maximum voluntary

Figure 1. Determination of PC20 by interpolation

ventilation (MMV), which is often calculated

on the logarithmic x-axis.

as FEV1630, but a ventilation rate as low as

100

ERS Handbook: Respiratory Medicine

65% of MVV (FEV1622) is acceptable

shown that methacholine BPT is superior to

(Rosenthal et al., 1984). A reduction in FEV1

clinical assessment and lung function

o10% is taken as a positive test. EVH testing

measurements in the follow-up of asthma

has been shown to be particularly sensitive

patients. By monitoring the effect of

for asthmatic athletes, particularly endurance

treatment of asthma with inhaled steroids by

athletes (Stadelmann et al., 2011; Cockcroft

follow-up using methacholine BPT, as

et al., 1977b).

compared with follow-up based upon

clinical symptoms and lung function

Clinical relevance of BPT

measurements, it was shown that follow-up

Previously, allergen BPT was often used

by methacholine BPT improved asthma

qualitatively to diagnose asthma and to

control and had a positive effect upon airway

demonstrate the reaction of the airways to

remodelling as assessed by bronchial

the allergen. This has changed recently out of

biopsies (Sont et al., 1999). Thus, BPT with

fear of worsening the asthma after such BPT.

various substances and performed in a

A long-lasting worsening of nonspecific BHR

standardised measure is probably, at the

after performing an allergen BPT has been

present time, the best tool for monitoring

demonstrated (Cockcroft et al., 1977b). Thus,

asthma patients.

allergen BPT is now mostly a tool in research

projects and not used in clinical practice.

Methacholine BPT (PD20) also has a role

in predicting later active asthma, as

However, different measures of nonspecific

shown by follow-up in a birth cohort study

BHR are often used, both in a research

from 10 to 16 years of age (Riiser

context and a clinical setting. With the

et al., 2012).

diagnosis asthma in mind, direct measures

of BHR are seen as most sensitive for

bronchial asthma, whereas indirect

Further reading

measures are considered to be more specific

Aas K (1970). Bronchial provocation tests

and less sensitive. In asthma patients from

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

an outpatient clinic compared with healthy

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

subjects, histamine bronchial responsive-

efficacy of inhaled dry powder mannitol

ness was found to be more sensitive, but

as a bronchial provocation test for airway

less specific, for discriminating asthmatic

hyperresponsiveness: a phase 3 compari-

from healthy subjects (Crockcroft et al.,

son study with hypertonic (4.5%) saline.

1977a). Compared with exercise testing,

Respir Res; 6: 144.

methacholine BPT was more sensitive, but

Carlsen KH, et al.

(1998). Cold air

markedly less specific, for discriminating

inhalation and exercise-induced broncho-

between asthma and other chronic lung

constriction in relationship to metacho-

diseases. When adding cold air inhalation to

line bronchial responsiveness: different

the exercise, sensitivity comparable to

patterns in asthmatic children and chil-

methacholine was reached, while maintaining

dren with other chronic lung diseases.

the specificity (Carlsen et al., 1998).

Respir Med; 92: 308-315.

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

In addition, other differences are found

reactivity to inhaled histamine: a method

between direct and indirect BPT. Indirect

and clinical survey. Clin Allergy; 7: 235-

bronchial responsiveness is rapidly

243.

influenced by treatment with inhaled

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

steroids, with the first effects appearing after

induced increase in non-allergic bronchial

1 week (Henriksen et al., 1983), whereas

reactivity. Clin Allergy; 7: 503-513.

methacholine BPT needs several months of

Dickinson JW, et al.

(2006). Screening

inhaled steroid treatment to show an effect

elite winter athletes for exercise induced

(Essen-Zandvliet et al., 1992).

asthma: a comparison of three chall-

enge methods. Br J Sports Med;

40:

Results of BPT may be used to monitor the

179-182.

effect of treatment in asthma. It has been

ERS Handbook: Respiratory Medicine

101

Essen-Zandvliet EE, et al. (1992). Effects

Rosenthal RR (1984). Simplified eucapnic

of 22 months of treatment with inhaled

voluntary hyperventilation challenge.

corticosteroids and/or beta-2-agonists

J Allergy Clin Immunol; 73: 676-679.

on lung function, airway responsive-

Salter HH. On Asthma: Its Pathology and

ness, and symptoms in children with

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

asthma. Am Rev Respir Dis; 146: 547-

1859.

554.

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

Henriksen JM, et al.

(1983). Effects of

histopathologic outcome of asthma when

inhaled budesonide alone and in combin-

using airway hyperresponsiveness as an

ation with low-dose terbutaline in chil-

additional guide to long-term treatment.

dren with exercise-induced asthma. Am

Am J Respir Crit Care Med; 159: 1043-1051.

Rev Respir Dis; 128: 993-997.

Stadelmann K, et al. (2011). Respiratory

Nieminen MM, et al.

(1988). Metha-

symptoms and bronchial responsiveness

choline bronchial challenge using a dosi-

in competitive swimmers. Med Sci Sports

meter with controlled tidal breathing.

Exerc; 43: 375-381.

Thorax; 43: 896-900.

Sterk PJ (1996). Bronchial hyperrespon-

Pauwels R, et al.

(1988). Bronchial

siveness: definition and terminology.

hyperresponsiveness is not bronchial

Pediatr Allergy Immunol; 7: Suppl. 9, 7-9.

hyperresponsiveness is not bronchial

Tiffeneau R, et al. (1945). Epreuve de bron-

asthma. Clin Allergy; 18: 317-321.

choconstriction et de bronchodilation par

Riiser A, et al.

(2012). Does bronchial

aérosols. Bull Acad de Med; 129: 165-168.

hyperresponsiveness in childhood predict

Yan K, et al. (1983). Rapid method for

active asthma in adolescence? Am J

measurement of bronchial responsive-

Respir Crit Care Med; 186: 493-500.

ness. Thorax; 38: 760-765.

102

ERS Handbook: Respiratory Medicine

Sputum and exhaled breath

analysis

Patrizia Pignatti, Andrea Zanini, Sabrina Della Patrona, Federico Gumiero,

Francesca Cherubino and Antonio Spanevello

Noninvasive techniques such as induced

sputum and exhaled breath analysis have

Key points

been successfully proven to reveal

inflammatory status and to find indicators

Sputum and exhaled breath analysis

of airway oxidative stress involved in the

are useful noninvasive tools to

pathogenesis of lung diseases. These

appraise airway inflammation,

techniques allow longitudinal sampling of

particularly in a longitudinal sense.

inflammatory biomarkers in the lung of the

Eosinophils are the most significant

same individual, providing a possibility to

sputum biomarkers for the evaluation

monitor the lung damage process and

of airway inflammation.

evaluate treatment strategies in

patients with respiratory diseases,

Many inflammatory mediators can be

including children.

measured in the fluid phase of

sputum but their usefulness remains

Induced sputum

at research level.

Induced sputum is one of the most

Nitric oxide is the most reliable

referenced methods used to determine

exhaled biomarker to assess

airway inflammation in asthma, COPD and

eosinophilic airway inflammation.

chronic cough, both in research and in

Other exhaled biomarkers need

clinical practice. The induced sputum

further validation and a clear

technique is a relatively noninvasive method

demonstration of their utility in the

allowing sampling of low airway secretions

diagnosis and/or follow-up of airway

from patients who are not able to produce

diseases.

sputum spontaneously.

Procedure Sputum induction consists of

inhalation of ultrasonically nebulised saline

solution (isotonic or hypertonic) over

different time periods and subsequent

mediators are affected by mucolytic agents,

expectoration of secretions. The subject is

sputum should be processed with

asked to inhale 200 mg salbutamol before

phosphate buffer alone.

induction, and FEV1 is monitored before and

Safety issues Sputum induction is a simple,

after each inhalation to either prevent or

safe and well-tolerated procedure even in

detect possible bronchoconstriction.

patients with severe lung diseases and

After collection, the sputum sample is

exacerbations. It is recommended that

processed within 2 h according to a

experienced personnel apply standard

standardised method with mucolytic agents

operating procedures taking into

(dithiothreitol) and centrifugation is

consideration the degree of airway

required to separate sputum cells from the

obstruction, use a modified protocol for

fluid phase, which is stored at -80uC for

subjects with severe airway obstruction, and

soluble mediator evaluation. If the soluble

assess lung function and symptoms during

ERS Handbook: Respiratory Medicine

103

the procedure. Sputum induction is

considered to be safe if the fall in FEV1 is

within 5% of baseline after waiting for

15 min. If a FEV1 fall .20% occurs, the

inhalation must be stopped. This adverse

effect can affect 11% of asthmatics and

patients with COPD.

Cell counts in different diseases A sputum

sample from a healthy subject is rich in

macrophages and neutrophils, and poor in

eosinophils, lymphocytes and epithelial

cells. The cut-off for sputum eosinophils

varies from .2 or .3% according to

different authors and European Respiratory

Society (ERS) guidelines.

Asthma is characterised by sputum

eosinophilia, which predicts a favourable

response to corticosteroids. However,

noneosinophilic asthma accounts for

25-55% of steroid-naïve asthmatics and

is associated with a poor response to

corticosteroids.

In up to 40% of subjects with chronic

cough, a sputum eosinophil count .3% is

seen. These subjects with cough, sputum

eosinophilia and no lung function

alterations receive the diagnosis of

eosinophilic bronchitis, and have an

objective response to corticosteroid

treatment.

In COPD, neutrophils are usually increased

and they are associated with reduced FEV1,

suggesting that neutrophilic airway

inflammation is functionally relevant. A cut-

off for sputum neutrophilia should take into

account age, since neutrophils accumulate

in the airways with ageing. Sputum

Figure

1. Three representative sputum samples.

eosinophilia could be present in subjects

a) Sputum from a healthy subject containing

with COPD and usually predicts a response

mostly macrophages. b) Sputum from an

to corticosteroid therapy.

asthmatic subject with eosinophilic inflammation.

c) Sputum from a COPD subject with

In figure 1, three representative examples of

neutrophilic inflammation. Original

induced sputum are shown.

magnification: 4006.

Many inflammatory mediators can be

measured in the fluid phase of sputum.

These mediators are granulocyte proteins,

routine evaluation of airway inflammation.

leakage markers, cytokines and chemokines,

Recently, the application of new techniques,

eicosanoids, and proteases. Unlike sputum

such as RT-PCR, in situ hybridisation,

cells, up to now, no determination of

proteomics, etc., has allowed a wider

sputum soluble mediators has entered

approach to the study of sputum soluble

104

ERS Handbook: Respiratory Medicine

Table 1. Biomarkers in induced sputum

Parameters

Asthma

COPD

Sarcoidosis

Cellular phase

TCC

Eosinophils

Neutrophils

Lymphocytes

CD8⁺

CD4⁺

Fluid phase

ECP

IL-8

MMP-9

MPO

IL-6

IL-17

Albumin

TNF-a

IL-23

Fibrinogen

IL-10

Nonkinase plasminogen activator

IL-17

Plasminogen activator

Leptin

Neurokinin A

MPO

IL-5

HNL

IL-8

IL-13

ECP

Cys-LTs

EPO

8-isoprostane

LTB₄

MMP-9/TIMP ratio

GRO-a

VEGF

MCP-1

GM-CSF

MMP-1

MMP-8

MMP-9

MMP-12

Hyaluronan

q: increased level; TCC: total cell count; ECP: eosinophil cationic protein; MPO: myeloperoxidase;

IL: interleukin; Cys-LT: cysteinyl leukotriene; MMP: matrix metalloproteinase; TIMP: tissue inhibitor of

metalloproteinases; VEGF: vascular endothelial growth factor; TNF: tumour necrosis factor; HNL: human

neutrophil lipocalin; NE: neutrophil elastase; EPO: eosinophil peroxidise; LT: leukotriene; GRO: growth

related oncogene; MCP: monocyte chemotactic protein; GM-CSF: granulocyte-macrophage colony-

stimulating factor.

mediators in order to generate a disease

Examination of samples obtained from

associated pattern of mediators.

patients with different respiratory diseases

associated with distinct airway inflammatory

Table 1 summarises cellular and fluid phase

patterns demonstrated significant

markers of airway inflammation in different

differences in cell counts, confirming the

pulmonary diseases.

validity of the technique. Reference values

and the distribution of cell counts in

Reproducibility and validity Sputum

induced sputum were established in a large

induction is a reproducible, sensitive and

number of samples from healthy subjects.

valid method. A standardised methodology

of sputum induction and processing was

Exhaled breath

issued in 2002 by an ERS Task Force in

order to provide guidance for the

Measuring biomarkers in breath is useful for

reproducibility of the results obtained.

monitoring airway inflammation and

ERS Handbook: Respiratory Medicine

105

oxidative stress. Exhaled breath analysis can

be defined as analysis of exhaled gases and/

or exhaled breath condensate (EBC).

Variable-sized particles or droplets that are

aerosolised from the airway lining fluid,

distilled water that condenses from the gas

phase out of the nearly water-saturated

exhalate, and water-soluble volatiles that are

exhaled and absorbed into the condensing

breath are the main components of EBC.

Figure 2. Two commercially available portable

Breath samples include:

FeNO analysers. a) Niox Mino (Aerocrine AB,

Uppsala, Sweden). b) Quark NObreath (Cosmed,

N end-exhaled air, which represents the

Rome, Italy). Images courtesy of the

alveolar air

manufacturers.

N mixed exhaled air, which represents the

gas mixture coming from the dead space

Exhaled breath can be condensed through

of the bronchial tree and the alveolar gas-

cooling devices, resulting in 1-2 mL EBC

exchange space

over 10 min of tidal breathing. This

Sample collection and analysis Exhaled

procedure is noninvasive, simple and easy

breath analysis is completely noninvasive,

to perform in patients of any age. In-house

and is suitable for longitudinal studies and

and commercially manufactured condensers

for monitoring the response to

are available. For pH evaluation, argon

pharmacological therapy.

deaeration of the EBC sample is needed.

Breath analysis consists of direct (on-line)

The analysis of EBC is usually performed by

and indirect (off-line) reading methods.

immunoassays, mass spectrometry, high-

Breath analysis is immediately available in

performance liquid chromatography

the on-line method. The use of indirect

(HPLC), nuclear magnetic resonance,

methods generally involves collecting and

luminometry, spectrophotometry and pH

trapping the breath sample and

measurement.

subsequently transferring it to an analytical

Biomarkers Several molecules can be

instrument.

detected in the exhaled air of healthy

The exhaled gases analysed include:

subjects and patients with inflammatory

lung diseases (table 2).

N exhaled nitric oxide fraction (FeNO),

which is a marker of airway inflammation

Validity FeNO is the most reliable exhaled

N carbon monoxide, a marker of

marker and is clinically used to assess

inflammation and oxidative stress

eosinophilic airway inflammation. It is also

N ethane, a marker of lipid peroxidation

useful for assessing adherence to inhaled

steroid therapy and the need for further anti-

For gas analysis, chemiluminescent or

inflammatory treatment in asthma, for

electrochemical methods and gas

differential diagnosis of cough, and for

chromatography are the most sensitive

differentiating asthma from COPD. The role

methodologies used.

of FeNO in COPD is less clear. Smoking

Figure 2 shows two commercially available

reduces FeNO levels, causing misleading

portable FeNO analysers.

results.

Furthermore, an increase in breath

Immunoassays for many biomarkers still

temperature can also be evaluated with a

need to be validated by reference analytical

high-accuracy thermometer, which is

techniques. Concentrations of markers are

associated with airway inflammation and

often close to the detection limit of the

remodelling.

assays, making analytical data less reliable.

106

ERS Handbook: Respiratory Medicine

Table 2 Biomarkers in EBC

Biomarker

Clinical significance in asthma

Clinical significance in COPD

F2-isoprostanes

Increased, reflecting the severity

Increased, reflecting the severity of the

of the disease and the degree of

disease and the degree of inflammation

inflammation

Leukotrienes

Elevated in both adults and

children

Prostanoids

Elevated in steroid-naïve and steroid-

treated patients and correlated with the

degree of airway inflammation

Decreased and normalises with

glucocorticoid therapy

Hydrogen peroxide Increased in both adults and

Increased in patients with exacerbations

children

Nitrite/nitrate,

Increased and correlated with

Increased in early stages of

nitrosothiol,

eosinophilic inflammation,

exacerbations

nitrotyrosine

reduced by corticosteroid

therapy

FeNO

Increased and falls after

Increased during exacerbations and falls

treatment with corticosteroids

after inhaled steroids in stable COPD

Dilution of airway lining fluid may influence

The latest achievements in standardisation

the results of biomarker analysis in EBC. A

and validation of exhaled breath analysis

confident dilution marker for EBC has not

have been presented in American Thoracic

been found yet. However, the use of dilution

Society/ERS recommendations.

markers can be avoided by: 1) testing for

multiple biomarkers and calculating ratios

Conclusions

among them; and 2) identifying a substance

that serves as an on-off indicator of an

Noninvasive methods such as induced

abnormality.

sputum and exhaled breath analysis have

been successfully introduced in clinical

Standardisation and validation of exhaled

practice and research to study airway

breath analysis is important, and special

inflammation involved in the pathogenesis

attention should be given to:

of respiratory diseases.

N flow and time dependence

N influence of respiratory patterns

Further reading

N origin of markers in EBC

N possible nasal, saliva and sputum

American Thoracic Society, et al. (2005).

contamination

ATS/ERS recommendations for FENO

procedure. Am J Respir Crit Care Med;

New methodologies (HPLC/mass

171: 912-930.

spectrometry, proteomics, metabolomics,

Barnes PJ, et al.

(2006). Pulmonary

etc.) able to define patterns of exhaled

biomarkers in chronic obstructive pul-

biomarkers specific for distinct airway

monary disease. Am J Respir Crit Care

diseases are under evaluation. Volatile

Med; 174: 6-14.

organic compounds (VOCs) (carbon

Brightling CE (2006).Clinical applications

monoxide, ethane, pentane, etc.), in

of induced sputum. Chest;

129:

1344-

particular, are currently studied for their role

1348.

in airway inflammation and oxidative stress.

ERS Handbook: Respiratory Medicine

107

European Respiratory Society Task Force.

Pizzichini E, et al.

(1996). Indices of

(2002). Standardised methodology of

airway inflammation in induced spu-

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tum: reproducibility and validity of

Respir J; 20: Suppl. 37, 1s-55s.

cell and fluid-phase measurements.

Horváth I, et al. (2005). Exhaled breath

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condensate: methodological recommen-

317.

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Spanevello A, et al.

(1997). Induced

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Hunt J (2007). Exhaled breath conden-

a study of reproducibility. Clin Exp Allergy;

sate: an overview. Immunol Allergy Clin

27: 1138-1144.

North Am; 27: 587-596.

Spanevello A, et al.

(2000). Induced

Montuschi P (2007). Analysis of exhaled

sputum cellularity. Reference values

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teers. Am J Respir Crit Care Med;

62:

ical applications. Ther Adv Respir Dis; 1: 5-23.

1172-1174.

108

ERS Handbook: Respiratory Medicine

Bronchoscopy

Pallav L. Shah

Bronchoscopy is an essential tool for the

pulmonary infiltrates (table 1).

pulmonologist that allows inspection and

sampling of the airways. The procedure is

Therapeutic bronchoscopy was traditionally

usually performed with or without conscious

performed for malignant disease. However,

sedation.

there are now a number of therapeutic

procedures for emphysema and asthma:

Equipment

N Clearance of airway secretions

The flexible bronchoscope has evolved from

N Removal of foreign bodies

a fibreoptic instrument to

N Palliation of endobronchial airway

videobronchoscopes, which are now almost

obstruction by tumour ablation or

universally used in most centres (fig. 1). The

insertion of stents

videobronchoscope consists of a video chip

N Bronchoscopic lung volume reduction for

at the distal end, an instrument channel and

emphysema

optical fibres that illuminate the airways.

N Bronchial thermoplasty for asthma:

The images obtained are then transmitted to

a monitor. The distal end of the

Patient preparation

bronchoscope can be angled through to

180u. This, in combination with manual

Patients should be given a full explanation of

rotation movements, allows the

the procedure accompanied by written

bronchoscope to be manipulated in the

information. Below is a simple pre-

airways.

procedure check list:

Indications

N Patient information - verbal and written

Bronchoscopy provides diagnostic

N Informed consent

information in patients with suspected lung

N Full blood count and clotting - before

cancer or diffuse lung disease, and in

transbronchial lung biopsy

patients with persistent infection or local

N ECG if history of cardiac disease

N Ensure patients do not eat or drink for at

least 4-6 h before the procedure

Key points

N Ensure patients have someone to take

them home following the procedure if

they receive sedation

N Bronchoscopy provides diagnostic

N Patients are advised not to drive or

information in suspected lung cancer

and diffuse lung disease, and in

operate machinery for at least 24 h after

patients with persistent infection or

any sedation

local pulmonary infiltrates.

Patients are monitored by continuous

Bronchoscopy also has therapeutic

oximetry throughout the procedure. Those

uses in tumour treatment, and more

with pre-existing cardiac disease or hypoxia

recently in asthma and emphysema.

that is not fully corrected by oxygen therapy

should undergo continuous ECG monitoring.

ERS Handbook: Respiratory Medicine

109

Table 1. Indications for bronchoscopy

Investigation of symptoms

Haemoptysis

Persistent cough

Recurrent infection

Investigation of suspected neoplasia

Unexplained paralysis of vocal cords or

hemidiaphragm

Stridor

Localised monophonic wheeze

Suspicious sputum cytology

Figure 1. Flexible videobronchoscope (model BF-

Q180; Olympus Europa, Hamburg, Germany).

Unexplained pleural effusions

Mediastinal tissue diagnosis and staging

Procedure

Assess suitability for surgery

Staging of lung cancer

The oropharynx is anaesthetised with 4%

lidocaine spray and the nasal passage with

Assessment of persistent or recurrent

2% lidocaine gel. Venous access should

infection

always be secured before the procedure and

Identification of organisms

oxygen administered via a single nasal

Evaluate airways

cannula. Bronchoscopy can be performed

Assessment of diffuse lung disease

with or without sedation (fig. 2). The choice

of sedative drugs varies with local practice.

Midazolam at a dose of 2-5 mg

administered intravenously is more

commonly used and has the advantage of

the coughing has subsided, the

amnesic properties in addition to its

bronchoscope is advanced through the

sedative effect. Alternative agents are

widest part of the glottis, taking care not to

opiates, such as fentanyl or alfentanil, which

touch the vocal cords. The subglottic area of

also have antitussive properties. A number

the trachea is very sensitive and patients

of institutions are now switching to nurse-

initially feel as though they are choking.

administered sedation and using low-dose

Further 2-mL aliquots of 2% lidocaine are

propofol infusions as a very short-acting

administered in the trachea, carina, and

general anaesthetic.

right and left main bronchi. During

bronchoscopy, the trachea, bronchi and

In the nasal approach, the bronchoscope is

airways down to the subsegmental level are

lubricated with 2% lidocaine gel and passed

carefully inspected for the presence of

through the nares under direct vision. It is

mucosal abnormalities, secretions,

then inserted into the nasopharynx until the

anatomical variants, malacia (degree of

epiglottis is visualised.

collapse of trachea and main bronchi in

expiration) and endobronchial lesions

In the oral approach, the patient is asked to

(fig. 3). Narrowing of the bronchial tree as a

bite gently onto a mouth-guard; the

result of external compression from large

bronchoscope is then inserted through this

lymph nodes or masses is also noted.

mouth-guard into the posterior pharynx, to

the level of the epiglottis.

Bronchoscopic sampling

The movement of the vocal cords is

Bronchoscopy also provides an opportunity

assessed and they are then anaesthetised

to obtain a variety of samples which may aid

using 2-mL aliquots of 2% lidocaine. When

diagnosis.

110

ERS Handbook: Respiratory Medicine

Figure 2. Performance of the bronchoscopy.

Bronchial washings The specimens are

obtained by injection of 20 mL normal saline

into the affected segment of the lung,

followed by aspiration.

Figure 3. Image obtained through the

Bronchial brushings A fine cytology brush

videobronchoscope.

may be used to scrape cells from the surface

of any visible lesion or from segments when

patient is asked to take a deep breath and

the lesion is not visible at bronchoscopy.

the open forceps are advanced further.

The bronchial brush specimen may be

When there is further resistance, the patient

smeared onto a slide and fixed before

is asked to breathe out and a biopsy sample

cytological analysis, or shaken into saline or

is taken during expiration. Samples are

cytofix for cytospin preparations.

obtained from the periphery of the lung.

Bronchial biopsy Any endobronchial

Transbronchial fine-needle aspiration (TBNA)

abnormalities should be biopsied. At least

Mediastinal and hilar lymph nodes can be

four samples should be obtained and placed

sampled by TBNA. The site of aspiration is

in 10% formol saline solution. The

planned on the basis of a cross-sectional CT.

diagnostic yield for polypoid lesions should

The needle is inserted at the desired point

be high (.90%) but is less for submucosal

perpendicular to the airway wall. The needle

lesions.

is moved back and forth after penetration of

the airway wall and suction applied with a

Bronchoalveolar lavage (BAL) is used in the

20-mL syringe. Samples collected can then

assessment of diffuse lung disease. The

be used to prepare slides, or be placed in

bronchoscope is wedged into the segment

cytofix or saline solution for cytological

of interest and 50-60-mL aliquots of warm

analysis. This is useful in the staging and

saline are injected into the segment. The

diagnosis of suspected lung cancer. This

fluid is then slowly aspirated using low-

should be performed prior to any other

pressure suction or direct hand suction. A

aspects of bronchoscopy so as not to carry

total of 150-250 mL is instilled and

over cells from endobronchial lesions into

aspirated.

TBNA specimens and, hence, falsely up-

stage the patient. Needle aspiration of

Transbronchial lung biopsy is used to obtain

submucosal lesions may also improve

parenchymal lung tissue for the evaluation

diagnostic yield. Overall, TBNA is a low-risk

of diffuse lung diseases. It is particularly

procedure with a good yield.

useful when a bronchocentric component is

visible on CT scans. The closed biopsy

Complications

forceps are advanced into a specific

bronchial segment until they meet with

The adverse effects of flexible bronchoscopy

resistance. The forceps are then withdrawn a

may be due to the sedation, the local

short distance and the jaws opened. The

anaesthesia or the procedure. The overall

ERS Handbook: Respiratory Medicine

111

incidence of complications is ,2%.

rapidly expanding and is establishing an

Mortality from the procedure is ,0.02%.

important role in the diagnosis and staging

of lung cancer. Its use for other disease,

Sedative drugs may depress respiration

such as sarcoidosis and TB, is increasing.

and have cardiovascular effects (e.g.

hypotension). Lidocaine may very rarely

A radial or mini-probe system can be used

cause bradycardia, seizures, bronchospasm

for localising peripheral pulmonary masses.

or laryngeal spasm.

These probes are passed through the

instrument channel of a flexible

The procedure may cause bronchospasm,

bronchoscope into the desired segment with

laryngospasm, hypoxaemia or cardiac

a guide sheath. The probe is manipulated in

arrhythmias, particularly in patients with

the airways with or without radiological

pre-existing cardiac disease or hypoxia not

guidance. Once the abnormal area is

corrected by oxygen supplementation.

identified, the sheath is maintained in

Infection can be introduced by the

position, the radial ultrasound probe is

bronchoscope. Therefore, it is essential to

removed, and washings, brushings and

clean and disinfect all instruments before

biopsies obtained via the guide sheath.

use. Haemorrhage and pneumothorax may

follow transbronchial lung biopsy. The risk is

Cryoprobes may also utilised to obtain

5-7%, and this is increased with paroxysmal

better tissue samples either endobronchially

coughing. Hypoxia and precipitation of

or for transbronchial lung biopsy. Patients

respiratory failure are the main

need to be intubated with an endotracheal

complications of BAL, particularly as the

tube or laryngeal mask. The cryoprobe is

procedure is often performed in patients

passed through the instrument channel of

with diffuse lung disease.

the bronchoscope and applied to the tissue

to be biopsied. The freezing effects cause

Advanced diagnostic procedures

the tissue to become adherent and gentle

The airway is illuminated by blue light during

traction is applied to tear off a piece off the

fluorescence bronchoscopy. Normal tissue is

frozen tissue. The probe and bronchoscope

visible as fluorescent green, whereas

need to be removed from the airway, and the

abnormal areas appear brown and red in

piece of tissue thawed and placed in

colour. This absence of autofluorescence

formalin. It is not possible to remove the

occurs in dysplasia, carcinoma in situ and

probe through the instrument channel of the

invasive carcinoma, and may enable the

bronchoscope when there is tissue adherent

earlier detection of endobronchial tumours. It

to the tip, hence the need to intubate the

is currently used as a research tool but may

patient. It is still possible to perform the

also be useful in routine practice. Narrow

procedure under sedation. If transbronchial

band imaging emphasises the blood vessels

lung biopsy is performed with cryoprobes, it

and increased capillary loops in the mucosa,

is essential to use fluoroscopy in order to

which is associated with dysplasia and

minimise the risk of a pneumothorax.

carcinoma in situ. Magnification of images

and presentation at high definition further

Therapeutic procedures

enhances the ability of the operator to detect

The therapeutic role of bronchoscopy is rapidly

subtle abnormalities.

increasing. It is well established in the

Endobronchial ultrasound-guided (EBUS)-

treatment of endobronchial tumour

TBNA is performed with an integrated linear

obstruction. A variety of techniques, such as

array ultrasound bronchoscope. It provides

cryotherapy, electrocautery or laser, can be

excellent ultrasound images of the

utilised by flexible bronchoscopy to rapidly

mediastinum and tissue adjacent to the

debulk tumours that are obstructing the main

airways, and allows ultrasound-guided

airways. Several clinical series have

sampling of mediastinal lymph nodes or

demonstrated that these techniques are very

peribronchial tumour masses. The

effective in palliating symptoms and improving

sensitivity of this technique is high. Its use is

the quality of life of patients with

112

ERS Handbook: Respiratory Medicine

endobronchial tumour occlusion. They also

More recently, a number of innovations have

reduce the risk of post-obstructive pneumonia.

been developed for the bronchoscopic

Where the airway wall structure has been

treatment of patients with severe

extensively damaged or there is extrinsic

emphysema with significant hyperinflation.

compression from the tumour, endobronchial

Endobronchial valves, such as zephyr valves

stents can be used to support the airways.

and intrabronchial valves, can be used for

Metal self-expanding stents can be inserted via

bronchoscopic volume reduction. Other

a flexible bronchoscopy and are available in

developments include airway stents,

both uncovered and covered formats.

biological polymers, endobronchial coils and

thermal vapour. Bronchial thermoplasty, a

Brachytherapy is localised radiotherapy

novel treatment for patients with moderate-

administered to an area of tumour

to-severe asthma, is also delivered

infiltration. A blind-ending catheter is

bronchoscopically. A special catheter is used

inserted through the instrument channel of

to apply radiofrequency energy to the

the bronchoscope into the desired airway.

airways in order to destroy airway smooth

The bronchoscope is then removed while

muscle.

maintaining the catheter in the appropriate

position. The catheter can then

Further reading

subsequently be loaded with a remote

device that is used to insert radiotherapy

Shah PL. Atlas of Bronchoscopy. London,

beads and, hence, deliver local radiotherapy.

Hodder Arnold, 2011.

This technique can also be used to treat

Bronchoscopy International.

endobronchial obstruction. However, there

www.bronchoscopy.org

is a risk of acute localised oedema following

Interventional Bronchoscopy.

the procedure and treatment carries a

www.interventionalbronchoscopy.co.uk

significant risk of severe haemorrhage.

ERS Handbook: Respiratory Medicine

113

Bronchoalveolar lavage

Patricia L. Haslam

What it is and when to use it

Society (ERS) and American Thoracic

Society (ATS), confirm that BAL cytological

Bronchoalveolar lavage (BAL) involves using

or microbiological findings can often

a fibreoptic bronchoscope to wash a

increase diagnostic confidence. However,

subsegment of the lungs with sterile

BAL itself is rarely specifically diagnostic and

physiological saline to sample components

must be interpreted together with clinical,

from the peripheral air spaces in health and

physiological, radiological and other

disease. These include immune and

multidisciplinary investigations.

inflammatory cells, other pathological cells

or features, cytokines, enzymes, lipids or

Prior to 2000, BAL was routinely included in

other secreted products, inhaled

the diagnostic work-up of parenchymal lung

environmental or occupational agents, and

diseases. Currently, for ILDs, specialists

infections. Since the 1960s, BAL has been

consider that HRCT patterns are often

used extensively in research and to assist in

sufficiently diagnostic to avoid the need for

the diagnosis of peripheral lung diseases,

BAL or lung biopsy. An ATS/ERS consensus

notably diffuse interstitial lung diseases

terminology for the idiopathic interstitial

(ILDs), occupational lung diseases, rare

pneumonias published in 2002 has also

lung diseases, thoracic malignancies and

changed the way specialists diagnose and

lower respiratory tract infections (table 1).

manage this subgroup of ILDs. However,

Numerous publications, including

BAL is still indicated whenever the

guidelines from the European Respiratory

preliminary clinical investigations plus

HRCT fail to establish a confident diagnosis,

or where additional information is needed to

Key points

confirm, strengthen or exclude a diagnosis.

How to obtain a sample

N BAL is used to sample immune and

inflammatory cells and many other

This section will only describe the

components from the peripheral air

standardised BAL procedure recommended

spaces of the lungs in health and

in Europe and BAL cytology methodology for

disease.

investigation of adults with diffuse lung

diseases where infection is not suspected.

N BAL is mainly used in research and to

A modified BAL procedure is used for the

assist in the clinical diagnosis of ILDs

specialist diagnosis of lower respiratory

or lower respiratory tract infections.

tract infections, designed to minimise

BAL findings must be interpreted in

contamination with irrelevant

conjunction with results from clinical,

microorganisms and to target sites of

pathological and radiological

maximal involvement.

investigations.

For both research and routine applications,

A standardised procedure must be

a standardised BAL procedure must be

followed.

followed in order to minimise variability due

to the unknown dilution factor during lavage

114

ERS Handbook: Respiratory Medicine

and many other potential sources of

variability. There is still no globally agreed

standard for the general conduct of BAL in

adults for cytological and other purposes,

but the ERS has long promoted BAL

standardisation in a series of European

guidelines. In 1999, the ERS published

consensus guidelines recommending a

standardised BAL procedure to use in

adults based on the most comprehensive

review of sources of variability for

measurement of BAL components yet

undertaken. The aim of using optimal BAL

standardisation to minimise variability is to

improve the reliability of quantitative

measurements of all components.

Minimising variability is an essential

scientific requirement for research.

However, a 2012 ATS clinical practice

guideline on the clinical utility of BAL in

ILD, recommends that ‘the BAL target site

be chosen on the basis of an HRCT

performed before the procedure, rather

than choosing a traditional BAL site.’ This

did not achieve full consensus because of

the disadvantage that it would reduce BAL

standardisation before it is known whether

moving away from a standard BAL site

would change diagnostic interpretation. To

avoid compromising BAL standardisation,

more research is needed into ILDs to

compare lavages from both the standard

BAL site and the site selected on the basis

of HRCT, to conclude whether there is any

clinical advantage to be gained. For now,

the established standardised BAL

procedure should also continue to be

employed in patients with diffuse bilateral

lung diseases. The standard site is also

required to study healthy controls or

patients with apparently ‘normal’ lungs, and

to reduce variability for research. The site

recommendation differs for patients with

localised lung diseases such as some

malignancies or infections, where BAL is

targeted to the site of maximal involvement.

A protocol using the European recommended

standard BAL procedure is as follows.

1) Perform BAL under local anaesthesia

using fibreoptic bronchoscopy as part of

pre-treatment assessment.

ERS Handbook: Respiratory Medicine

117

2) Proceed initially as for routine fibreoptic

except for an increased risk of minor post-

bronchoscopy:

lavage pyrexia, which can be minimised by

keeping total BAL introduction volumes to

N generally semisupine patient positioning;

,300 mL.

N pre-medication with a sedating

compound;

Processing of samples for cytology

N local anaesthesia with lidocaine removing

BAL cells deteriorate rapidly in saline and

any excess prior to lavage.

laboratory processing should commence a

3) For lavage, gently wedge the tip of the

maximum of 1 h after BAL sample collection.

bronchoscope into an appropriate

To delay deterioration, BAL cells should be

subsegmental bronchus. The recommended

transferred into serum-free minimum

standard site is right middle lobe in diffuse

essential medium containing 25 mM HEPES

lung diseases and healthy controls, but the

buffer (MEM-HEPES), which maintains

area of greatest radiographic abnormality in

pH 7.2-7.4 in an open system.

localised lung diseases.

Non-cell adherent containers and pipettes

4) Sequentially introduce then aspirate

must be used for all laboratory procedures.

standard aliquots (4660 mL) of sterile

The processing procedure is as follows.

physiological saline pre-warmed to body

1) Measure the total volume of the BAL

temperature through the application tube of

sample.

the bronchoscope. Do not exceed total

introduction volume of 240 mL.

2) Record any abnormality in the gross

appearance of the fluid, e.g. a milky

5) Aspirate each aliquot, keeping dwell time

appearance suggestive of alveolar

to the minimum, using very low suction

lipoproteinosis or a very bloody appearance

pressure (3.33-13.3 kPa/25-100 mmHg) to

suggestive of acute haemorrhagic

avoid airway collapse.

conditions.

6) Collect the recovered fluid into a

3) Mix sample to ensure even suspension

container to which cells are poorly adherent

then divide into measured aliquots for

(e.g. siliconised glass or a non-cell adherent

different departments if required (e.g.

plastic designed for suspension tissue

o20 mL for BAL cytology and flow

cultures).

cytometry, 10 mL for microbiology and

7) Record the lavage site, total BAL fluid

20 mL for electron microscopy).

introduction volume and number of

aliquots, and the total recovery volume.

4) For BAL cytology, the fluid aliquot should

be mixed and a cell viability test conducted

8) Immediately send the BAL sample to the

(e.g. trypan blue). Then, make a total count

laboratory to enable processing to

of nucleated cells (per mL) using an

commence within 1 h because BAL cells

improved Neubauer counting chamber and

deteriorate rapidly in saline.

white cell counting stain (e.g. Kimura stain).

If the original BAL sample is too dilute for an

9) Also send a patient protocol with age,

accurate cell count, the count should be

sex, provisional diagnosis and other factors

performed after separating the cells by

that influence BAL findings including

centrifugation and resuspending them at a

smoking history (current, ex- or

higher concentration.

nonsmoker), current medications and

associated diseases.

5) Centrifuge the BAL sample at low speed

(3006g at 4^oC for 10 min) to separate the

10) If biopsies are needed, perform these

cells and other insoluble components from

after BAL to avoid contamination of BAL

the supernatant fluid. Aspirate the

with blood or bronchial tissue debris.

supernatant and aliquot it for storage at

BAL is safe and side-effects are low, the

-70^oC. Then, wash the BAL cell pellet in

same as for fibreoptic bronchoscopy alone,

MEM-HEPES and resuspend it in a small

118

ERS Handbook: Respiratory Medicine

volume (1-2 mL) to achieve a more

percentage of the total BAL cells (differential

concentrated suspension. Perform a total

percentage cell count). This proportionate

cell count, and calculate the number of cells

approach is not affected by the unknown

per mL and total in the original BAL fluid.

BAL dilution factor.

6) Adjust the volume of the cell suspension

Differential cell counts are performed and

to a standard 1.5610⁶ cells?mL^-1 to make

other cytological features identified by

cytocentrifuge slide preparations. Use 100-

examining May-Grünwald-Giemsa-stained

mL aliquots (1.5610⁵ cells) per slide (spin at

cytocentrifuge slide preparations by light

906g for 4 min). Prepare at least six slides

microscopy. First, low-power magnification

per patient. After air drying, fix two slides in

(610 and 625 objective lenses) is used to

methanol (not formalin, which impairs

search the entire preparation and semi-

staining of mast cells). Stain with May-

quantitatively grade (on a scale from 0 to 5)

Grünwald-Giemsa for differential cell

any mucus and erythrocytes, and identify

counting. Use other slides for special

any unusual cytological features, such as

stains(e.g. Gomori-Grocott silver stain for

inorganic dust particles or fibres, globules of

fungi and Pneumocystis carinii, and Perl stain

lipoprotein, giant cells, malignant cells or

for haemosiderin-laden macrophages).

microorganisms. Secondly, higher-power

Mucus contamination of BAL samples, if

magnification (640 or 660 objectives) is

very excessive, can cause serious technical

used to count all the immune and

problems in processing. When there is such

inflammatory cells and any other type of

heavy contamination from the upper

nucleated cells employing random-field

airways, BAL results must be interpreted

counting methodology until a total of o400

with caution. Mucus can be removed by

cells have been counted. The count for each

filtering the lavage through cotton gauze or

cell type is then expressed as a percentage of

nylon mesh but this can cause loss of

the total cells counted (differential

adherent cells, dust fibres and other

percentage BAL cell count). For diagnostic

components. An alternative to avoid such

purposes, all nucleated cells, not only

loss is to remove mucus by treating the BAL

inflammatory cells, must be included in the

cell pellet with the mucolytic dithiothreitol.

count to ensure that important information

is not omitted (e.g. malignant cells, giant

Some workers consider that when BAL cells

cells and epithelial cells). The presence of

are in tissue culture medium, processing

.5% bronchial epithelial cells indicates

can be delayed for 24 h to enable long-

excessive contamination from the upper

distance transport to centralised processing

airways and such samples are inadequate as

centres. However, this is not advisable

a reliable indicator of alveolar events.

because granulocytes are short lived and

apoptotic changes start within 9 h.

Abnormal cell appearances must also be

Therefore, it is advisable to transfer BAL

reported, including proportions of foamy

cells into tissue culture medium within 1 h

macrophages, multinucleate macrophages,

and make cytocentrifuge preparations within

giant cells, macrophages containing

1-4 h. Staining of air-dried preparations can

smoking-related particles, macrophages

be delayed for o24 h if necessary. It is

containing refractile or birefringent particles

essential that BAL is conducted by clinical

indicative of inorganic dusts, or

and laboratory personnel who are highly

macrophages heavily laden with

trained in the procedure, applications and

haemosiderin confirmed by Perl staining,

interpretation.

indicating possible pulmonary

Differential cell counting and other

haemosiderosis.

cytological appearances

When neutrophil counts are very high it is

The standard approach to counting BAL

important to check for intracellular bacteria,

cells in cytocentrifuge preparations is to

which can indicate active bacterial

express the count of each type as a

pneumonia.

ERS Handbook: Respiratory Medicine

119

Table 2. Normal ranges for differential BAL cell counts

Cell type

Nonsmokers

Smokers

Macrophages

o80

o90

Lymphocytes

f20

f10

Neutrophils

Eosinophils

f0.5

Mast cells

f0.5

Plasma cells

Ciliated or squamous epithelial cells

Cata are presented as % total cells.

Fungal spores or hyphae may also be seen

and other cytological features in a wide

and their presence should be confirmed

range of lower respiratory diseases is given

using Gomori-Grocott silver stain, which

in table 1.

can also detect P. carinii.

Normal cell counts and the effect of

Further reading

smoking

American Thoracic Society, European

Respiratory Society. (2002). International

BAL cells from healthy nonsmokers are mainly

multidisciplinary consensus classification

macrophages and a few lymphocytes but

of idiopathic interstitial pneumonias.

proportions of other cell types are very low.

Am J Respir Crit Care Med; 165: 277-304.

Smoking causes increases in BAL

The BAL Cooperative Steering Group

macrophages up to four-fold higher (total and

Committee.

(1990).

Bronchoalveolar

per mL) in healthy smokers compared with

lavage constituents in healthy individuals,

nonsmokers; smokers also have slight

idiopathic pulmonary fibrosis, and

increases in neutrophils. Thus, smoking must

selected comparison groups. Am Rev

be taken into account when defining normal

Respir Dis; 141: Suppl. 5, S169-S202.

ranges and interpreting any BAL studies.

Bradley B, et al.

(2008). Interstitial lung

Published normal ranges show considerable

disease guideline: the British Thoracic Society

variability when cell counts are expressed per

in collaboration with the Thoracic Society of

mL or absolute total numbers. However,

Australia and New Zealand and the Irish

results are very similar when expressed as

Thoracic Society. Thorax; 63: Suppl. 5, v1-v58.

differential percentage counts, consistent with

Costabel U (2007). Ask the expert - diffuse

these not being influenced by dilution.

interstitial lung disease. Breathe; 4: 165-172.

Dombret MC, et al. (1998). The role of

The normal ranges that can be employed for

fibreoptic bronchoscopy in the diagnosis

differential BAL cell counts are shown in

of bacterial infections. Eur Respir Monogr;

table 2. Smoking-related inclusions are

9: 153-170.

frequent in macrophages from smokers.

Dhillon DP, et al. (1986). Bronchoalveolar

lavage in patients with interstitial lung

Main applications in the diagnostic work-up

diseases: side effects and factors affecting

of peripheral lung diseases

fluid recovery. Eur J Respir Dis; 68: 342-350.

Haslam PL, et al. (1999). Guidelines for

Although this section describes BAL

measurement of acellular components

procedures, it would be incomplete without

and recommendations for standardiza-

a summary of how BAL is used in routine

tion of bronchoalveolar lavage

(BAL).

clinical investigation to increase confidence

Report of European Respiratory Society

in the diagnosis of many parenchymal lung

(ERS) Task Force. Eur Respir Rev;

diseases. A quick guide showing the main

25-157.

types of increased BAL inflammatory cells

120

ERS Handbook: Respiratory Medicine

Haslam PL, et al. (1999). Report of ERS

Mayer KC, et al.

(2012). An official

Task Force: guidelines for measurement

American Thoracic Society Clinical prac-

of acellular components and standardiza-

tice guideline: The clinical utility of

tion of BAL. Eur Respir J; 14: 245-248.

bronchoalveolar lavage cellular analysis

Haslam PL. Bronchoalveolar lavage. In:

in interstitial lung disease. Am J Respir

Mitchell D, et al., eds. Sarcoidosis. London,

Crit Care Med; 185: 1004-1014.

Hodder Education, 2012; pp. 121-131.

Ohshimo S, et al. (2009). Significance

Klech H, et al. (1989). Technical recommen-

of bronchoalveolar lavage for the diag-

dations and guidelines for bronchoalveolar

nosis of idiopathic pulmonary fibrosis.

lavage

(BAL): report of the European

Am J Respir Crit Care Med; 179: 1043-

Respiratory Society of Pneumology Task

1047.

Group on BAL. Eur Respir J; 2: 561-585.

Raghu G, et al. (2011). An official ATS/

Klech H, et al. (1990). Clinical guidelines

ERS/JRS/ALAT statement: idiopathic pul-

and indications for bronchoalveolar

monary fibrosis: evidence-based guide-

lavage

(BAL): report of the European

lines for diagnosis and management. Am

Respiratory Society of Pneumology Task

J Respir Crit Care Med; 183: 788-824.

Group on BAL. Eur Respir J; 3: 937-974.

Reynolds HY, et al. (1974). Analysis of

Klech H, et al. (1992). Clinical guidelines

proteins and respiratory cells obtained

and indications for bronchoalveolar

from human lungs by bronchial lavage.

lavage

(BAL): report of the European

J Lab Clin Med; 84: 559-573.

Society of Pneumology Task Group on

Woodhead M, et al. (2011). Guidelines for

BAL. Eur Respir Rev; 2: 47-127.

the management of adult lower respira-

Luyt C-E, et al. (2010). Fibreoptic broncho-

tory tract infections

- Summary: Joint

scopic techniques for diagnosing pneu-

Task Force of ERS and ESCMID. Clin

monia. Eur Respir Monogr; 48: 297-306.

Microbial Infect; 17: Suppl. 6, 1-24.

ERS Handbook: Respiratory Medicine

121

Fine-needle biopsy

Stefano Gasparini

Percutaneous (or transthoracic) fine-needle

Contraindications

biopsy (PFNB) is a technique that allows

Absolute contraindications are:

cytohistological diagnosis of thoracic

lesions. While the first reports on the use of

N contralateral pneumonectomy

transthoracic needle biopsy date back to the

N bleeding disorders

end of the 19th century, the modern era of

N an uncooperative patient

PFNB did not begin until the mid-1960s

N uncontrollable cough

when Nordenstrom (1965) introduced the

N suspected arteriovenous malformation or

use of fine needles (diameter ,20 Gauge).

hydatid cyst

Indications

Relative contraindications that may increase

the risk of complications are:

PFNB is indicated when a cytohistological

diagnosis is required of peripheral lung

N respiratory failure

lesions (nodules, mass or infiltrates)

N severe COPD

following a negative bronchoscopy. PFNB is

N pulmonary arterial hypertension

also indicated for expansive lesions of the

N unstable ischaemic heart disease

chest wall and pleura or for diagnosis of

mediastinal masses, especially those

Technique

located in the anterior mediastinum.

Guidance systems Biplane fluoroscopy is the

traditional guidance system for PFNB. Its

Key points

main advantage is the real-time visualisation

of the needle during the whole procedure. In

N PFNB is indicated when a

recent years, CT has become the most

common means of guidance. Although

cytohistological diagnosis of a

performing a CT scan is more time-

peripheral lung lesion is required.

consuming, it has several advantages:

PFNB may also be indicated for

diagnosis of mediastinal mass and

N It helps determine the safest needle trajectory

expansive lesions of the pleura and

avoiding vascular structures, fissures, bullae

chest wall.

and necrotic areas of the tumour;

N It allows an approach to lesions not

N The most common guidance system

visible on fluoroscopy, such as small

for PFNB is CT; biplane fluoroscopy

lesions; and

and ultrasound can also be used.

N It avoids radiation exposure to the

The sensitivity of PFNB for lung

operators.

cancer is 85-95%.

However, there are no studies that

The most frequently reported

demonstrate a better sensitivity of CT

complication is minor pneumothorax

compared with fluoroscopy. Ultrasound can

(25%).

also be used as a guidance system when the

lesion is in contact with the thoracic wall.

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ERS Handbook: Respiratory Medicine

Type of needle Commercially available

incidence of ,25% (range 4-42%). Major

needles are either:

pneumothorax, requiring chest tube

drainage, occurs in ,6% of cases.

1. aspiration needles that yield material

Haemoptysis occurs in 5-10% of cases and

satisfactory for cytological evaluation

is generally mild and self-limiting. Rare

(Chiba, Franseen, Westcott or

complications include air embolism

Nordenstrom); or

(0.07%), haemothorax, empyema, tumour

implantation along the needle tract and

2. histology needles that yield a tissue core

haemopericardium.

(Trucut, Menghini or Silverman).

Needle diameter should be ,20 Gauge and

Further reading

generally 20-22 Gauge needles are utilised.

Gasparini S, et al. (1995). Integration of

The evidence is currently insufficient to

transbronchial

and

percutaneous

support a difference between cytology

approach in the diagnosis of peripheral

needles and core-needle biopsy in

pulmonary

nodules

masses.

identifying lung malignancies. Histology

Experience with 1,027 consecutive cases.

needles have a higher specificity to diagnose

Chest; 108: 131-137.

benign lesions and the use of a core-biopsy

Gould MK, et al. (2007). Evaluation of

needle is recommended when either a

patients with pulmonary nodules: when is

benign lesion or a malignancy other than

it lung cancer? ACCP evidence-based

cancer (i.e. lymphoma) is suspected.

clinical practice guidelines (2nd edition).

Chest; 132: Suppl. 3, 108s-130s.

Results

Nordenstrom B (1965). A new technique

for transthoracic biopsy of lung changes.

The reported sensitivity of PFNB ranges from

Br J Radiol; 38: 550-553.

60% to 97%. In patients with lung cancer, a

Shaham D

(2000). Semi-invasive and

diagnosis by PFNB is generally established in

invasive procedures for the diagnosis and

85-95% of cases. Lower sensitivities are

staging of lung cancer. I. Percutaneous

reported for benign lesions (4-14%). Sensitivity

transthoracic needle biopsy. Radiol Clin

may be affected by the size and location of the

North Am; 38: 525-534.

lesion, number of needle passes, size of the

Wiener RS, et al. (2011). Population-based

needle, availability of immediate cytological

risk for complications after transthoracic

assessment and experience of the operator.

lung biopsy of a pulmonary nodule: an

False-positive results are rare and the specificity

analysis of discharge records. Ann Intern

of the technique is extremely high. However, it

Med; 155: 137-144.

is important to emphasise that a non-

Yao X, et al. (2012). Fine-needle aspira-

diagnostic PFNB does not rule out the

tion biopsy versus core-needle biopsy in

possibility of malignancy. Recent papers report

diagnosing lung cancer: a systematic

the feasibility of PFNB for obtaining lung

review. Curr Oncol; 19: e16-e27.

Zhuang YP, et al.

(2011). Use of CT-

tumour samples suitable for gene mutation

guided fine needle aspiration biopsy in

analysis (i.e. epidermal growth factor receptor).

epidermal growth factor receptor muta-

Complications

tion analysis in patients with advanced

lung cancer. Acta Radiologica; 52: 1083-

The most frequently reported complication

1087.

is minor pneumothorax, with an average

ERS Handbook: Respiratory Medicine

123

Medical thoracoscopy/

pleuroscopy

Robert Loddenkemper

Thoracoscopy was first used more than

the pleural cavity can be visualised (fig. 1)

100 years ago, primarily as a diagnostic

and biopsies can be taken from all areas of

procedure, but soon also as a therapeutic

the pleural cavity including the chest wall,

technique for lysis of pleural adhesions by

diaphragm, mediastinum and lung.

means of thoracocautery (Jacobaeus

operation) to facilitate pneumothorax

Key points

treatment in TB. At the end of the last

century, the addition of the term ‘medical’

MT/P has the advantage compared

was necessary in order to distinguish this

with VATS that it can be performed

procedure from ‘surgical’ thoracoscopy,

under local anaesthesia or conscious

which is much more invasive, using general

sedation, in an endoscopy suite using

anaesthesia, a double-lumen endotracheal

non-disposable rigid (or semi-rigid)

tube and multiple points of entry. Other

instruments. Thus, it is considerably

terms used are ‘pleuroscopy’, ‘thoracoscopy

less expensive.

for chest physicians’ and ‘local anaesthetic

The leading indications for MT/P are

thoracoscopy’. Surgical thoracoscopy is

pleural effusions, both for diagnosis -

better described as video-assisted thoracic

mainly in exudates of unknown

surgery (VATS) which is performed in an

aetiology - or for staging in diffuse

operating room under general anaesthesia

malignant mesothelioma, lung cancer

with selective intubation, whereas medical

and for talc poudrage, the best

thoracoscopy can be performed under local

conservative method today for

anaesthetic or conscious sedation in an

pleurodesis.

endoscopy suite using non-disposable rigid

or semi-rigid (semi-flexible) instruments. It

MT/P can also be used efficiently in

is therefore considerably less invasive, less

the management of early empyema

cumbersome to the patient, and less

and pneumothorax.

expensive.

In the above indications, MT/P can

replace most surgical interventions,

Nevertheless, medical thoracoscopy/

which are more invasive and more

pleuroscopy (MT/P) are invasive techniques

expensive.

that would be used only when other more

simple methods fail. Today, it is considered

MT/P is a safe procedure, even easier

to be one of the main areas of interventional

to learn than flexible bronchoscopy,

pulmonology, and as such should be part of

provided sufficient experience with

specialist pleural disease services. As with

chest-tube placement has been

all technical procedures, there is certainly a

gained.

learning curve before full competence is

MT/P as part of the new field of

achieved. Therefore, appropriate training is

interventional pulmonology should be

mandatory. Actually, the technique is very

included in the training programme of

similar to chest-tube insertion by means of a

chest physicians.

trocar, the difference being that, in addition,

124

ERS Handbook: Respiratory Medicine

Figure 2. The semi-rigid (semi-flexible)

pleuroscope. Reprinted with permission from

Olympus Corporation, Tokyo, Japan. Reproduced

from Loddenkemper et al. (2011).

similar to a flexible bronchovideoscope

(fig. 2).

The other technique uses two entries, one

with a 7-mm trocar for the rigid examination

telescope and the other with a 5-mm trocar

for accessory instruments, including the

biopsy forceps. For this technique,

neuroleptic or general anaesthesia is

preferred.

For cauterisation of adhesions and blebs, or

Figure 1. a) Diagram of a CT scan showing several

in case of bleeding after biopsy,

malignant lesions of the parietal pleura for which

electrocoagulation should be available. For

biopsies can be taken under visual control through

pleurodesis of effusions, 4-6 g of a sterile,

the (rigid) thoracoscope. b) Tuberculous pleural

dry, asbestos-free talc is insufflated through

effusion. After drainage of 800 mL of serous

a rigid or flexible suction catheter with a

effusion, typical sago-like nodules on the reddened

pneumatic atomiser. In pneumothorax

inflamed posterior chest wall, firm adhesions

patients, 2-3 g of talc is sufficient. After

(arrows) between right lower lobe (1) and chest

thoracoscopy, a chest tube is introduced

wall (2). Reproduced and modified from

through which immediate suction is started

Loddenkemper et al. (2010).

carefully.

There are two different techniques of

MT/P is a safe examination if the

diagnostic and therapeutic thoracoscopy, as

contraindications are observed and if certain

performed by the pneumologist. One, very

standard criteria are fulfilled. An obliterated

similar to the technique first described by

pleural space is an absolute

Jacobaeus for diagnostic purposes, uses a

contraindication. Relative contraindications

single entry with a rigid, usually 9-mm,

include bleeding disorders, hypoxaemia and

thoracoscope with a working channel for

an unstable cardiovascular status, and

accessory instruments and an optical biopsy

persistent uncontrollable cough. The most

forceps under local anaesthesia. This single-

serious, but fortunately least frequent,

entry technique has now been modified by

complication is severe haemorrhage due to

the introduction of an autoclavable semi-

blood-vessel injury during the procedure.

flexible pleuroscope, which has the

However, this and pulmonary perforations,

advantage that handling is very simple,

can be avoided by using safe points of entry

ERS Handbook: Respiratory Medicine

125

Needle

Effusion

Medical

Needle

Effusion

Medical

biopsy

(cytology)

thoracoscopy

biopsy

(culture)

thoracoscopy

100

Figure 4. The different biopsy techniques used in

the diagnosis of tuberculous pleural effusions and

their sensitivity expressed in percentages

Figure 3. The different biopsy techniques used in

(cytological and histological results combined).

the diagnosis of malignant pleural effusions and

Prospective intra-patient comparison (n5100).

their sensitivity expressed in percentages

Reproduced from Loddenkemper (1998).

(cytological and histological results combined).

Prospective intra-patient comparison (n5208).

classification due to larger and consequently

Reproduced from Loddenkemper (1998).

more representative biopsies, including for

hormone receptor determination in breast

and a cautious biopsy technique. Reported

cancer, as well as a more precise staging.

mortality rates are very low (,0.001). The

most frequent complication is nonspecific,

An additional advantage is that the

transient fever.

diagnostic procedure can easily be

combined with the therapeutic procedure of

Pleural effusions are by far the leading

talc poudrage which is, at present, the most

indication for MT/P, both for diagnosis,

successful conservative pleurodesis

mainly in exudates of unknown aetiology,

method.

and for staging in diffuse malignant

mesothelioma or lung cancer, and for

In tuberculous pleural effusion, MT/P has a

treatment by talc pleurodesis in malignant

high diagnostic sensitivity of almost 100%

or other recurrent effusions, or in cases of

(fig. 4). It provides a bacteriological

empyema. Spontaneous pneumothorax for

confirmation of the diagnosis of TB much

staging and for local treatment is also an

more often and, thus, the possibility to

excellent indication. Malignant pleural

perform susceptibility tests, which may have

effusions represent the leading diagnostic

a considerable impact on the correct

and therapeutic indication for MT/P. MT/P

treatment and final outcome in patients with

has a much higher diagnostic sensitivity and

drug resistances. In parapneumonic pleural

specificity in malignant pleural effusions

effusion and empyema, MT/P offers the

than closed needle biopsy and pleural fluid

possibility to remove fibrinopurulent

cytology (fig. 3). Biopsies can be taken

membranes and break up loculations, thus

under direct visual control not only of the

creating one single pleural cavity for

costal pleura, but also of the visceral and

successful local treatment.

diaphragmatic pleura.

In other pleural effusions, when the origin

MT/P is helpful in the staging of lung cancer,

remains indeterminate, the main diagnostic

diffuse malignant mesothelioma and

value of MT/P lies in its ability to exclude,

metastatic cancers. In lung cancer patients,

with high probability, malignant or

thoracoscopy can determine whether the

tuberculous disease. In pneumothorax

tumour spread to the pleura is secondary to

patients, MT/P allows talc poudrage for

venous or lymphatic obstruction or is

pleurodesis, which is highly effective in

parapneumonic. As a result, it may be

recurrence prevention.

possible to avoid exploratory thoracotomy or

to determine operability. In diffuse

For those who are familiar with the

malignant mesothelioma, MT/P provides an

technique, other (mainly diagnostic)

earlier diagnosis and a better histological

indications are biopsies from the

126

ERS Handbook: Respiratory Medicine

diaphragm, the lung, e.g. in interstitial lung

Loddenkemper R, et al. Medical

diseases, the mediastinum and the

Thoracoscopy/Pleuroscopy: Manual and

pericardium. In addition, MT/P offers a

Atlas. New York, Thieme, 2011.

remarkable tool for research as a ‘gold

Loddenkemper R, et al. (2011). History

standard’ in the study of pleural effusions.

and clinical use of thoracoscopy/pleuro-

scopy in respiratory medicine. Breathe; 8:

145-155.

Further reading

Loddenkemper R, et al. (2011). Medical

thoracoscopy/pleuroscopy: step by step.

Bridevaux PO, et al. (2011). Short-term

Breathe; 8: 157-167.

safety of thoracoscopic talc pleurodesis

Noppen M (2010). Pleural biopsy and

for recurrent primary spontaneous pneu-

thorascopy. Eur Respir Monogr; 48: 119-

mothorax: a prospective European multi-

centre study. Eur Respir J; 38: 770-773.

132.

Rahman NM, et al. (2010). Local anaes-

Davies HE, et al. (2011). The diminishing

role of surgery in pleural disease. Curr

thetic thoracoscopy: British Thoracic

Society pleural disease guideline

2010.

Opin Pulm Med; 17: 247-254.

Grüning W, et al. Medical thoracoscopy/

Thorax; 65: Suppl. 2, ii54-ii60.

Rodriguez-Panadero F, et al.

(2006).

pleuroscopy. Procedure video; 2011. www.

ers-education.org/pages/default.

Thoracoscopy: general overview and

aspx?id52375&dma5156667.

place in the diagnosis and management

Hooper CE, et al. (2010). Setting up a

of pleural effusion. Eur Respir J; 28: 409-

specialist

pleural

disease service.

422.

Respirology; 15: 1028-1036.

Rodriguez-Panadero F, et al.

(2012).

Janssen JP (2010).Why you do or do not need

Mechanisms of pleurodesis. Respiration;

thoracoscopy. Eur Respir Rev; 19: 213-216.

83: 91-98.

Janssen JP, et al.

(2007). Safety of

Tassi GF, et al. (2006). Advanced techni-

pleurodesis with talc poudrage in malig-

ques in medical thoracoscopy. Eur Respir

nant pleural effusion: a prospective

J; 28: 1051-1059.

cohort study. Lancet; 369: 1535-1539.

Tschopp JM, et al. (2011). Titrated seda-

Kern L, et al.

(2011). Management of

tion with propofol for medical thoraco-

parapneumonic effusions and empyema:

scopy: a feasibility and safety study.

medical thoracoscopy and surgical

Respiration; 82: 451-457.

approach. Respiration; 82: 193-196.

Tschopp JM, et al. (2006). Management

Loddenkemper R (1998). Thoracoscopy:

of spontaneous pneumothorax: state of

state of the art. Eur Respir J; 11: 213-221.

the art. Eur Respir J; 28: 637-650.

Loddenkemper R, et al.

(2004).

Vansteenkiste J, et al.

(1999). Medical

Treatment of parapneumonic pleural

thoracoscopic lung biopsy in interstitial

effusion and empyema: conservative

lung disease: a prospective study of

view. Eur Respir Monogr; 29: 199-207.

biopsy quality. Eur Respir J; 14: 585-590.

ERS Handbook: Respiratory Medicine

127

Thoracentesis

Emilio Canalis and Mari Carmen Gilavert

Thoracentesis (pleural tap; fig. 1) is a

(usually the seventh to eighth intercostal

frequently performed procedure that is used

spaces, although clinical examination may

to remove and analyse pleural fluid. Its goals

reveal different locations of the fluid).

may be diagnostic and/or therapeutic.

Once a comfortable position for operating

Diagnostic thoracentesis should be

on the patient is achieved, the site for the

performed on almost all patients with a

puncture must be selected. This is decided

pleural effusion of unknown origin. Its main

according to the results of the physical

purpose is to differentiate between

examination and the radiological findings,

which will indicate characteristics such as

transudate and exudate. The number of

the size and localisation of the main effusion

diagnoses established by pleural fluid

and whether it is free-organised, free-floating

analysis varies with the population being

or encapsulated. Ultrasound examination is

evaluated. Careful history and physical

valuable to assess fluid presence accurately.

examination, radiological evaluation, and

ancillary blood tests are crucial in

The puncture should be guided by

establishing a pre-test diagnosis.

ultrasound or attempted one intercostal

space further down from where dullness on

The main purpose of therapeutic

percussion starts. At least in pleural

thoracentesis is to relieve dyspnoea and

effusions of smaller size, ultrasound

respiratory insufficiency caused by pleural

guidance is strongly recommended.

effusion.

The thoracentesis set

Patient position

The thoracentesis set is detailed in table 1.

A sitting position is preferred in conscious

patients, as this will help the fluid to settle in

Procedure

the posterior and basal regions of the lung

1. Under sterile conditions, the selected

region of puncture is disinfected with

povidone-iodine or alcohol, and a sterile

Key points

draping, preferably with a centre hole, is

taped to the patient’s back.

N Thoracentesis may be diagnostic or

therapeutic in patients with a pleural

2. Local anaesthesia is injected stepwise, at

effusion.

first with an intradermal injection producing

a small wheal, then infiltrated

N Ultrasound examination is valuable in

subcutaneously and into the intercostal

guiding the procedure.

muscle down to the parietal pleura at the

There are no absolute

upper rim of the lower rib in order to avoid

contraindications, and complications

the intercostal nerve and vessels. During the

are rare, but the possibility should be

injection, alternating aspiration is performed

taken into account.

until the parietal pleura is penetrated and

pleural fluid is aspirated. Then, 20-60 mL of

128

ERS Handbook: Respiratory Medicine

Figure 1. Thoracentesis needle through the intercostal space.

pleural fluid should be aspirated for fluid

5. Chest radiography should be carried out

analysis.

to exclude the development of a

pneumothorax, unless the procedure has

Diagnostic thoracentesis can occasionally

be carried out without local anaesthesia if

the adult patient is calm, the puncture is

anticipated to be easy, the subject is not

Table 1. Thoracentesis set

obese and the operator is experienced.

Povidone-iodine solution or alcohol

3. For therapeutic thoracentesis, a catheter

Sterile drapes, gloves and gauzes

should be used, which is immediately

Abbocath-type needle catheters

connected to a closed three-way stop-cock.

Local anaesthesia

This allows aspiration syringes to be

changed or facilitates connection to a

Syringes

suction device.

Three-way stopcock

Aspiration set (if therapeutic)

4. As soon as the procedure is finished, the

needle or the catheter is removed and

Adhesive strips

pressure is applied to the wound for a few

Instrumentation table

minutes, followed by a sterile dressing.

ERS Handbook: Respiratory Medicine

129

been performed under ultrasound guidance

Re-expansion pulmonary oedema This can be

without any problems.

prevented by removing less than 1-1.5 L of

pleural fluid.

Contraindications

Additional recommendations

Diagnostic thoracentesis has no absolute

contraindications provided that it is done

1. The region from the midclavicular line to

with caution by experienced persons. The

the sternum should be avoided, as here the

following are relative contraindications.

vessels are located in the centre of the

intercostal space

N Altered coagulation. A decision must be

taken as to whether thoracentesis is really

2. Sterile conditions are mandatory during

needed. If so, it may be necessary to

the whole procedure to prevent infection,

reverse anticoagulation or to administer

which may lead to empyema.

fresh frozen plasma or platelets.

3. For diagnostic purposes, 20 mL of

N Mechanical ventilation with positive

pleural fluid is usually sufficient to assess

pressure at the end of expiration. Whenever

the appearance of the fluid and for

possible, mechanical ventilation is

chemical, cytological and bacteriological

suspended briefly. If this is not possible,

analysis. Recent work recommends

thoracentesis must be carried out with

,60 mL for cytology in case of suspected

caution using ultrasound guidance.

malignancy.

N Local skin infections such as cellulitis or

herpes zoster.

N Small effusions (this should be done

Further reading

under ultrasound control).

Abouzgheib W, et al. (2009). A prospective

Complications

study of the volume of pleural fluid

required for accurate diagnosis of malig-

As with any invasive investigation,

nant pleural effusion. Chest; 135: 999-1001.

complications may occur, but these are rare.

Alcaide MJ, et al. Toracocentesis y

Patients have to be informed about possible

drenaje pleural

[Thoracentesis and

complications when asked to give their

pleural drainage]. In: De Mendoza D, et

informed consent. The most important are

al.

Medicina Intensiva Respiratoria

[Intensive

Respiratory

Medicine].

as follows.

Tarragona, Silva ed., 2008.

Pneumothorax is usually only small if

Chest Trauma. In: Advanced Trauma Life

caused by entrance of air into the pleural

Support (ATLS) Course Manual. 7th Edn.

cavity through the needle or the aspiration

Chicago, American College of Surgeons,

system. It can become larger if the lung is

2004; pp. 107-121.

Capizzi SA, et al. (1988). Chest roentgen-

injured by the needle.

ography after outpatient thoracentesis.

Hypotension may be induced by a vasovagal

Mayo Clin Proc; 73: 948-950.

reaction when the parietal pleura is

Dev SP, et al. (2007). Videos in clinical

punctured. It can be avoided by careful local

medicine. N Engl J Med; 357: l5.

Duncan DR, et al.

(2009). Reducing

anaesthesia and prevented by administering

iatrogenic risk in thoracentesis: establish-

atropine (not routinely necessary).

ing best practice via experiential training

Bleeding can be prevented by avoiding the

in a zero-risk environment. Chest;

135:

lower rim of the upper rib and by excluding

1315-1320.

coagulopathies.

Feller-Kopman D, et al.

(2009).

Assessment of pleural pressure in the

Haemopneumothorax is rare when the

evaluation of pleural effusions. Chest; 135:

aforementioned technique is observed and

201-209.

the patient has no bleeding disorder.

130

ERS Handbook: Respiratory Medicine

Interventional pulmonology

Marc Noppen

Interventional pulmonology encompasses

procedures; data pertaining to functional

both diagnostic and therapeutic

assessment and evaluation are relatively

bronchoscopic, thoracoscopic and other

scarce. Certainly, in the ‘pioneer era’ of

techniques that go beyond everyday ‘simple’

interventional pulmonology, patients were

procedures performed by pulmonary

referred in a (very) late stage of disease, with

clinicians. In the context of pulmonary

severe dyspnoea and/or stridor or signs of

function testing and interventional

post-obstructive disease, requiring prompt

pulmonology, the following discussion will

intervention without additional testing. In

be limited to the effects on interventional

stable and nonlife-threatened patients with

bronchoscopy of pulmonary function tests.

or without symptoms, however, additional

testing before proceeding with an

In addition, interventional bronchoscopy will

intervention may be helpful in patient

be limited to all (rigid and flexible)

selection, and post-procedure testing may

bronchoscopic procedures designed to

focus the usefulness and efficacy of an

reopen obstructed central airways (including

intervention. Thus, as more centres

laser, electrocautery, cryotherapy,

successfully perform various interventional

brachytherapy and photodynamic therapy)

bronchoscopic techniques, the need is

or to establish airway patency (airway

increasing for a critical evaluation and

stenting).

selection of patients in order to understand

the physiological effects of these

Over the past few decades, the literature on

interventions and gain an evidence-based,

interventional bronchoscopy has mainly

focused on the ‘technicality’ of the various

algorithmic integration of these techniques

in the overall care of these patients.

Alternatively, abnormalities observed during

Key points

pulmonary function testing may prompt the

clinician to suspect an upper (or central)

N Symptoms of central airway stenosis

airway stenosis (UAS).

occur late, after o50% (on exercise)

In patients suffering from malignant airway

or 80% (at rest) of the tracheal lumen

stenosis, which is not candidate for, or is

is obstructed.

unresponsive to, ‘classical’ oncological

The diagnostic accuracy of

treatments, the main interest of

spirometric indices and visual flow-

interventional pulmonological treatment

volume loop criteria in detecting

should lie in the improvement of quality of

central airway stenosis is relatively

life and the avoidance of death by

poor.

suffocation.

N Interventional bronchoscopic

Pulmonary function tests in UAS

techniques have been shown to

significantly improve objective

Inspection of the maximal inspiratory and

pulmonary function and quality of life.

expiratory flow-volume loop is currently the

most widely used method to detect/suspect

ERS Handbook: Respiratory Medicine

131

the presence of UAS (figs 1-3). However,

significant changes in spirometry appear

relatively late in the course of the stenosing

process. The airway cross-sectional area has

to be reduced by o50% in order to cause

breathing impairment, a clinical observation

that recently has been corroborated by a

fluid dynamic study of tracheal stenosis.

There is also a very poor or even absent

correlation between the severity of the UAS

as determined by the flow loop analysis and

its spirometrically derived indices, and

breathing symptoms or radiological

assessment of UAS. UAS becomes more

Figure 2. CT image of the patient in figure 1.

easily symptomatic during exercise (from a

tracheal diameter f8 mm), whereas at rest

N a typical ‘coffin’ or ‘box’ appearance of

the diameter has to be f5 mm before

the flow-volume curve is suspicious for a

symptoms occur. All of this may explain why

fixed UAS due to severe tracheal

the diagnostic accuracy of the various

obstruction

individual spirometric indices and visual

N an isolated plateau during expiration is

flow-volume loop criteria in detecting UAS

suspicious for an intrathoracic airway

is relatively poor (area under the receiver

stenosis

operating curve ,0.52).

N an isolated plateau of the inspiratory loop

suggests extrathoracic obstruction

Typical flow-volume appearances, however,

may be helpful:

Obstructive lesions at multiple airway sites

and associated abnormalities such as severe

COPD may cause atypical flow-volume loop

characteristics.

UAS may lead to typical flow-volume loop

abnormalities and spirometric derived

indices, but

■

N the diagnostic accuracy in detecting UAS

of these tests is (very) low

▲●

■

●

▲

N symptoms of UAS occur relatively late in

●▲

■

●

▲

the UAS process

N symptoms of UAS occur earlier during

exercise

The most commonly used quantitative

criteria to detect UAS include

Predicted

■

N maximal expiratory flow at 50% FVC

●

Pre

(MEF50%)/maximal inspiratory flow at

▲ Post

50% FVC (MIF50%) ,0.30 for

intrathoracic and .1 for extrathoracic

stenosis

Volume L

N FEV1/MEF .10 mL?L^-1?min^-1

N MIF50% ,100 L?min^-1

Figure 1. A typical flattened ‘coffin’ flow-volume

N FEV1/FEV0.5 .1.5

loop curve in a patient with severe fixed tracheal

obstruction due to an inoperable intrathoracic

The visual criteria are the presence of a

goitre. In: inspiration; Exp: expiration.

plateau, biphasic shape, or oscillations in

132

ERS Handbook: Respiratory Medicine

after stenting in a total of 24 patients.

Improvements were more pronounced in

intra- and extrathoracic tracheal stenosis, as

compared with bronchial stenosis. Noppen

et al. (2004) showed improvements after

tracheal stenting for inoperable benign

thyroid disease (FEV1 +470 mL, FVC

+620 mL and PEF +79 L?min^-1) and after

tracheal laser debulking and/or stenting for

inoperable malignant thyroid disease (FEV1

+540 mL, FVC +730 mL and PEF

+96 L?min^-1) (figs 4 and 5). Oviatt et al.

(2011) showed significant improvements in

6-min walk distance (99.7 m), FEV1

(448 mL) and FVC (416 mL) 30 days after

bronchoscopic treatment for malignant

airway obstruction.

Figure 3. Bronchoscopic image of the patient in

figure 1.

Ernst et al. (2007) showed improvements in

some but not all patients stented for severe

the inspiratory or expiratory curves.

tracheomalacia, in terms of respiratory

However, the absence of a good correlation

symptoms, quality of life, and functional

between the severity of UAS as determined

status assessed by exercise testing and

by flow-volume loop analysis and breathing

FEV1. Overall, these retrospective and

symptoms or radiological assessment of

prospective observational case series, in

UAS points to the need for a method that

selected patients, show significant but not

can detect and document UAS in patients at

homogeneous improvements in a number

risk. Forced oscillation tests at different

of functional parameters. Amjadi et al.

breathing flow rates provide an accurate and

(2008) and Oviatt et al. (2011) also

reproducible measure of UAS, namely flow

documented significant and objective

dependence of resistance, as documented in

improvements in quality of life scores. Data

a comparative prospective cohort analysis of

on physiological effects of

10 normal subjects, 10 COPD patients and

repermeabilisation techniques without

10 patients suffering from tracheal stenosis,

additional stenting are even more scarce:

before and after airway stenting (Verbanck et

objective improvements in pulmonary

al., 2010).

function were seen in 58% of patients after

Impact of interventional bronchoscopy on

cryotherapeutic debulking of central airways,

pulmonary function

In most patients, but not all, pulmonary

function significantly improves after

restoration of central airway patency. Eisner

et al. (1999) demonstrated mean

improvements of 388 mL for FVC, 1288 mL

for peak expiratory flow (PEF) and 550 mL

for FEV1 after stenting in nine patients. Gelb

et al. (1992) showed increases in FVC from

64% to 73% predicted, and in FEV1 from

49% to 72% predicted after stenting in 17

patients. Vergnon et al. (1995) showed mean

improvements in FEV1 (440 mL), PEF

(920 mL?s^-1), MEF25-75% (470 mL?s^-1) and

Figure 4. CT image of the patient in figure 1 after

forced inspiratory volume in 1 s (310 mL)

stenting.

ERS Handbook: Respiratory Medicine

133

only minor improvements in symptoms

and spirometry. Repeat endoscopy in

these patients showed upstream

displacement of choke points (distally

from the inserted stents) and ultrasound

showed destructed cartilage at these

sites. Additional stenting at these sites

then improved symptoms and pulmonary

function to levels comparable with the

other groups. This additional

physiological and imaging information

excluded all therapeutic failures.

Conclusions

When patients with UAS present with

dyspnoea on exertion, and certainly with

Figure 5. Patient in figure 1, 1 year after stent

insertion.

dyspnoea at rest, severe central airway

stenosis is already present. In these

patients, flow-volume loop analysis and

and a trial of 19 patients with major airway

spirometry will most probably show

obstruction due to lung cancer showed

aberrations typical of UAS. However, as a

significant improvements in a variety of

screening tool in a general population,

parameters including FEV1, FVC and ratio of

these aberrations show a poor accuracy in

forced expiratory/forced inspiratory flow rate

predicting UAS. Forced oscillation tests

at 50% of vital capacity, after endobronchial

may prove to be more accurate in

radiotherapy.

detecting and documenting UAS. In

A breakthrough article by Miyazawa et al.

extremely symptomatic, almost suffocating

(2004) shed more light on the underlying

patients, immediate intervention with

physiological phenomena occurring after

repermeabilisation/stenting is warranted.

airway stenting, including the

In nonlife-threatening cases, pre-

heterogeneity of response. A total of 64

intervention pulmonary function testing

patients with extrinsic airway stenoses

may yield useful information on the type,

due to advanced malignancy were

site and extent of the stenosis, whereas

studied; patients were classified by

post-procedure testing may be used to

location of the stenosis (tracheal, carinal,

focus the response and can be used as a

bronchial or multisite). Pulmonary

basis for post-procedure follow-up. In the

function tests and CT were performed

case of a multisite, extensive airway

before and after stenting. Prior to stent

stenosis, its relatively typical flow-volume

insertion, patients underwent

loop pattern may be predictive of

endobronchial ultrasound to evaluate the

therapeutic failure of single-site stenting

airway walls and ultrathin bronchoscopy

and may predict the necessity of additional

to evaluate airway patency distal to the

stenting at upstream choke points.

obstruction. Stents were placed at the

Interventional bronchoscopic procedures

visualised flow-limiting segments (choke

offer immediate (and often longstanding)

points). Distinctive flow-volume loop

palliation of respiratory symptoms,

patterns were found for each of the four

improvements in quality of life (and

types of stenosis. Most patients showed

frequently length of life as well) and

symptomatic improvement after stenting,

objective improvements in pulmonary

and most flow-volume loops returned to

function in the majority of patients. When

normal. All 10 patients with multisite,

used judiciously, they are an invaluable

extensive stenosis, however, showed

tool in the armamentarium of modern

persistent choke points, associated with

pulmonology.

134

ERS Handbook: Respiratory Medicine

Further reading

Miyazawa T, et al. (2004). Stenting at the

flow-limiting segment in tracheobronchial

Amjadi K, et al.

(2008). Impact of

stenosis due to lung cancer. Am J Respir

interventional bronchoscopy on quality

Crit Care Med; 169: 1096-1102.

of life in malignant airway obstruction.

Modrykamien AM, et al.

(2009).

Respiration; 76: 421-442.

Detection of upper airway obstruction

Brouns M, et al. (2007). Tracheal steno-

with spirometry results and the flow-

sis: a flow dynamics study. J Appl Physiol;

volume loop: a comparison of quantita-

102: 1178-1184.

tive and visual inspection criteria. Respir

Eisner MD, et al.

(1999). Pulmonary

Care; 54: 474-479.

function improves after expandable metal

Nishine H, et al. (2012). Assessing the

stent placement for benign airway

site of maximal obstruction in the trachea

obstruction. Chest; 115: 1006-1011.

using lateral pressure measurements

Empay DW (1972). Assessment of upper

during bronchoscopy. Am J Respir Crit

airways obstruction. BMJ; 3: 503-505.

Care Med; 185: 24-33.

Ernst A, et al.

(2004). Central airway

Noppen M, et al. (2004). Interventional

obstruction. Am J Respir Crit Care Med;

bronchoscopy for treatment of tracheal

169: 1278-1297.

obstruction secondary to benign or

Ernst A, et al. (2007). Airway stabilization

malignant thyroid disease. Chest;

125:

with silicone stents for treating adult

723-730.

tracheobronchomalacia: a prospective

Oviatt PL, et al. (2011). Exercise capacity,

observational study. Chest; 132: 609-616.

lung function and quality of life after

Gelb AF, et al. (1992). Physiologic studies

interventional bronchoscopy. J Thorac

of tracheobronchial stents in airway

Oncol; 6: 38-42.

obstruction. Am Rev Respir Dis;

146:

Razi SS, et al.

(2010). Timely airway

1088-1090.

stenting improves survival in patients

Gittoes NJ, et al. (1996). Upper airways

with malignant central airway obstruc-

obstruction in

153

consecutive patients

tion. Ann Thorac Surg; 90: 1088-1093.

presenting with thyroid enlargement.

Rotman HH, et al. (1975). Diagnosis of

BMJ; 312: 484.

upper airway obstruction by pulmonary

Goldman JM, et al. (1993). Physiological

function testing. Chest; 68: 796-799.

effect of endobronchial radiotherapy in

Verbanck S, et al. (2010). Detecting upper

patients with major airway occlusion by

airway obstruction in patients with tra-

carcinoma. Thorax; 48: 110-114.

cheal stenosis. J Appl Physiol; 109: 47-52.

Lund ME, et al. (2007). Airway stenting:

Vergnon JF, et al.

(1995). Efficacy of

applications and practice management

tracheal and bronchial stent placement

considerations. Chest; 131: 579-587.

on respiratory functional tests. Chest; 107:

Melissant CF, et al. (1994). Lung func-

741-746.

tion, CT-scan and X-ray in upper airway

Vincken W, et al. (1985). Flow oscillations

obstruction due to thyroid goitre. Eur

on the flow-volume loop: a nonspecific

Respir J; 7: 1782-1787.

indicator of upper airway dysfunction.

Miller RD, et al.

(1973). Evaluation of

Bull Eur Physiopathol Respir; 21: 559-567.

obstructing lesions of the trachea and

Walsh DA, et al. (1990). Bronchoscopic

larynx by flow-volume loops. Am Rev

cryotherapy for advanced bronchial carci-

Respir Dis; 108: 475-481.

noma. Thorax; 45: 509-513.

ERS Handbook: Respiratory Medicine

135

Chest X-ray and fluoroscopy

Walter De Wever

Chest radiography is the most frequently

Key points

used radiological chest imaging technique

and also one of the most challenging. The

technical aspects of this imaging modality

N Chest radiography is the first step

are studied extensively. New approaches to

in radiological diagnosis of chest

image acquisition and display have been

diseases.

introduced in the past decade. As a general

N Although it is a common technique,

rule, establishing the presence of a lung

achieving high image quality is

disease process on the radiograph should

challenging and depends on getting

constitute the first step in radiological

several factors right.

diagnosis of chest disease. Its lower

N The move from film to digital imaging

sensitivity demands greater accuracy in

offers exciting opportunities to

interpretation. This greater accuracy can be

improve image consistency and

achieved by following a standardised and

data management.

systemic approach to a complete review of a

chest radiograph. Technical factors and the

position of the patient should also be

considered when a chest radiograph is

(PA) radiograph is possible and that lung

reported. Comparing prior films with recent

markings behind the heart are clearly visible.

ones is mandatory for the evaluation of

The exposure should be as short as possible,

pulmonary diseases.

consistent with the production of adequate

contrast. A high kilovoltage technique

Basic radiographic techniques

appropriate to the film speed should be

Diagnostic accuracy in chest disease is

used.

partly related to the quality of the

Projections

radiographic images themselves. Several

variables, such as patient position, patient

PA and lateral projection The most

respiration and film exposure factors, must

satisfactory routine radiographic views for

be taken into account to ensure image

evaluating the chest are the PA and lateral

quality (table 1). Positioning of the patient

projections with the patient standing (fig. 1).

must be such that:

The combination of these two projections

provides very good three-dimensional

N the X-ray beam is properly centred;

information. In patients who are too ill to

N the patient’s body is not rotated; and

stand up, anteroposterior (AP) upright or

N the scapulae are rotated so that they are

supine projections offer alternative but

projected away from the lungs.

considerably less satisfactory views. The AP

Patient respiration must be fully suspended,

projection is of inferior quality because of

preferably at total lung capacity. Film

the shorter focal distance, the greater

exposure factors should be such that faint

magnification of the heart and, often, the

visualisation of the thoracic spine and the

restricted ability of these patients to

intervertebral disks on the posteroanterior

suspend respiration or achieve full

136

ERS Handbook: Respiratory Medicine

this projection, the patient stands erect and

Table 1. Key points to obtaining a good chest radiograph

the X-ray tube is angled 15u cephalad. The

Radiographic appearance

main advantage of this modification is its

Frontal view (PA view)

reproducibility. The lordotic projection can

be used:

Area from the lower cervical spine to

below the costophrenic angles

1) for improving the visibility of the lung

Sternoclavicular joints symmetrical

apices, superior mediastinum and thoracic

about the midline

inlet; and

Shadows of the scapulae away from the

2) for identifying the minor fissure in

lung field

suspected cases of atelectasis of the right

Lateral view

middle lobe.

Soft tissues of the axillae should be

Oblique projection Oblique studies are

included

sometimes useful in locating a pleural or

Respiration

chest wall disease process (e.g. pleural

End of normal inspiration

plaque); however, in most situations, CT is

preferred.

Positioning of the patient

Erect position

Inspiratory-expiratory radiography

Very ill patients: horizontal or semierect

Comparison of radiographs exposed in full

PA position

inspiration and maximal expiration may

Film exposure factors

supply useful information in two specific

situations.

High kilovoltage

Focus: film distance

N The first indication is the evaluation of air

trapping, either focal or general. With air

Must be kept constant for any

trapping, diaphragmatic excursion is

particular department

reduced symmetrically and lung density

150-180 cm

changes little between expiratory and

inspiratory radiographs.

The second indication is when a

inspiration. Based on a review of the

pneumothorax is suspected and when the

literature and the recommendations of the

visceral pleural line is not visible on the

American College of Radiology and the

standard inspiratory radiograph or the

American Thoracic Society,

findings are equivocal. In these

recommendations on the use of chest

situations, a film taken in full expiration

radiographs are summarised in table 2.

may show the line more clearly.

Lateral decubitus projection For the lateral

Bedside radiography

decubitus projection, the patient lies on one

side and the X-ray beam is oriented

Chest radiography, performed at the bedside

horizontally. This technique is particularly

with portable apparatus, is one of the most

helpful for the identification of small pleural

frequently performed radiological

effusions. ,100 mL of fluid may be identified

examinations; however, this technique is

also the examination with the most variation

on well-exposed radiographs in this position.

in image quality. The amount of diagnostic

Radiography in the lateral decubitus position

information provided by chest examinations

is also useful to demonstrate a change in the

performed with portable apparatus is high

position of an air-fluid level in a cavity or a

and many abnormalities are detected. These

freely moving intracavitary loose body (e.g.

examinations are useful 76-94% of the

fungus ball in aspergilloma).

time. However, poor image quality and day-

Lordotic projection The lordotic projection

to-day variations in film density interfere

can be made in the AP or PA projection. For

with the detection of interval changes in

ERS Handbook: Respiratory Medicine

137

Figure 1. a) PA chest radiograph. Normal lungs are visible as black fields (air) (*) with superposition of

multiple white linear structures (vessels and walls of airways). The lung hila consist of bronchi (main stem

(1) and lobar bronchi) and vascular structures (pulmonary arteries (2) and pulmonary veins). A normal

pleura is not visible on a chest radiograph. In the mediastinum, we can visualise the trachea (3) as a

translucent tube on the midline, the aortic arch (4), the pulmonary trunk (5), the left border of the heart

formed by the left ventricle (6) and the right border of the heart formed by right atrium (7). A normal

heart has a normal cardiothoracic index: (a+b)/maximal diameter of the chest (c) must be ,0.5. The

bony components of the chest visible on the frontal view are: the ribs (+), the manubrium sternum (8), the

clavicles (9), the scapulae (10) and the vertebral bodies on the midline. The diaphragm (11) is sharply

delineated and the costophrenic angles (12) must be sharp and free. b) Lateral chest radiograph. The

lateral chest film can be used to localise better the findings on the frontal view. Numbers and symbols are

as for a).

patients with pulmonary diseases. The

whole exposure area. Conversion of X-ray

interpretation of a bedside radiograph

intensity into electrical signals can either be

requires extensive radiological experience to

direct (selenium-based systems) or indirect

avoid misinterpretation of pleural and

(scintillator/photodiode systems).

pulmonary disease. In addition, bedside

Advantages of digital radiography systems

radiography is an irreplaceable tool for

are:

detecting the malposition of tubes and lines

N a high image quality; and

and to identify associated complications.

N the potential for dose reduction.

The need to improve the image quality of

this examination has long been recognised

This technique is now the preferred imaging

but it is a difficult problem to solve.

modality for bedside chest imaging because

Digital chest radiography

of its more consistent image quality. Digital

radiography is rapidly replacing film-based

There have been many remarkable advances

chest units for in-department PA and lateral

in conventional thoracic imaging over the

examinations. The final aim is to realise a

past decade. Perhaps the most remarkable

completely integrated digital radiology

is the rapid conversion from film-based to

department throughout the hospital

digital radiographic systems. Digital

connected to a large digital image archiving

radiography is the common name for

system. This concept, referred to as picture

different technologies that are characterised

archiving and communication systems,

by a direct readout matrix that covers the

represents the logical culmination of the

138

ERS Handbook: Respiratory Medicine

Table 2. Recommendations for the use of chest radiography

Indications

Signs and symptoms related to the respiratory and cardiovascular system

Follow-up of previously diagnosed thoracic disease for evaluation of improvement resolution,

or progression

Staging of intrathoracic and extrathoracic tumours

Pre-operative assessment of patients scheduled for intrathoracic surgery

Pre-operative evaluation of patients who have cardiac or respiratory symptoms or patients who

have a significant potential for thoracic pathology that may lead to increased peri-operative

morbidity or mortality

Monitoring of patients who have life support devices and patients who have undergone

cardiac or thoracic surgery or other interventional procedures

No indications

Routine screening of unselected populations

Routine pre-natal chest radiographs for the detection of unsuspected disease

Routine radiographs solely because of hospital admission

Mandated radiographs for employment

Repeated radiograph examinations after admission to a long-term facility

extensive research that is continuing in this

caused by differences in matching the

area.

projections of the two examinations.

New developments in chest radiography

Rib suppression technique This is a

processing technique that suppress ribs in

With the introduction of digital radiography,

the image. Advantages of this technique

development of new techniques became

over dual energy are:

possible. These techniques are dual energy,

temporal subtraction, rib suppression

N no need for an additional radiation dose

technique and digital tomosynthesis.

or specialised equipment

N noise levels are not increased

Dual energy involves weighted subtraction

of low- and high-energy images, and results

Eliminating ribs has already shown to be

in images representing bone structures or

effective in detection of lung lesions.

soft tissue. This technique can improve the

detection of small, noncalcified pulmonary

Digital tomosynthesis is a method of

nodules and the detection of calcified chest

producing coronal cross section images

lesions. Disadvantages of this technique are

using a digital detector and a chest X-ray

the higher radiation dose compared with

system with a moving X-ray tube. This

standard digital radiography, the reduced

technique can improve the detection of

signal to noise ratio and the need for

pulmonary nodules by producing cross-

additional hardware to perform this

section images without overprojection of the

technique.

ribs or overlying vascular structures.

Temporal subtraction involves subtraction of

Chest fluoroscopy

a current image from a prior image of the

same patient. With this technique, the

Chest fluoroscopy was a popular procedure

detection of pathological changes over time

a generation ago. Patients were examined

becomes easier. Sophisticated algorithms

fluoroscopically in various projections and

are needed to eliminate detection errors

multiple spot radiographs were obtained

ERS Handbook: Respiratory Medicine

139

with barium in the oesophagus.

Further reading

Examinations to evaluate pericardial

effusion also were frequent. Overall

American College of Radiology. ACR

diminution in cardiac pulsation and greater

Standard for the Performance of

pulsation of the posterior cardiac wall in the

Pediatric and Adult Chest Radiography.

lateral projection were thought to be signs of

Reston, American College of Radiology,

effusion. Other indications for fluoroscopy

2001.

included the investigation of foreign bodies

American Thoracic Society (1984). Chest

X-ray screening statements. Am Thorac

determined by air trapping and appropriate

News; 10: 14.

mediastinal shift, and the evaluation of

Eisenhuber E, et al. (2012). Bedside chest

diaphragmatic paralysis. This evaluation of

radiography. Respir Care; 57: 427-443.

diaphragmatic paralysis is still an indication

MacMahon H, et al. (1991). Digital chest

for fluoroscopy today.

radiography. Clin Chest Med; 12: 19-32.

Dose and image quality in chest

Raoof S, et al. (2012). Interpretation of

radiography

plain chest roentgenogram. Chest;

141:

545-558.

The radiation dose to the patient for chest

Rigler LG (1931). Roentgen diagnosis of

radiography is relatively low but because of

small pleural effusions: a new roentgeno-

its frequent use, the collective dose can be

graphic position. JAMA; 96: 104-108.

Schaefer-Prokop C, et al. (2003). Digital

considerable. The effective dose of a PA

radiography of the chest: detector techni-

chest radiograph is about 0.02 mSv, which

ques and performance parameters.

is about 0.5% that of a CT scan of the chest.

J Thorac Imaging; 18: 124-137.

The effective dose related to the lateral chest

Veldkamp WJ, et al. (2009). Dose and

image is approximately two times higher

perceived image quality in chest radio-

compared with the dose of a PA projection.

graphy. Eur J Radiol; 72: 209-217.

Studies indicate that dose reduction in PA

Wandtke JC (1994). Bedside chest radio-

chest images to at least 50% of commonly

graphy. Radiology; 190: 1-10.

applied dose levels does not affect diagnosis

Zinn B, et al. (1956). The lordotic position

in lung fields; however, dose reduction in

in fluoroscopy and roentgenography of

the mediastinum, upper abdomen and

the chest. Am J Roentgenol Radium Ther

retrocardiac areas appears to directly

Nucl Med; 75: 682-700.

deteriorate diagnosis.

140

ERS Handbook: Respiratory Medicine

Lung CT and MRI

Johny A. Verschakelen

CT is the second most important imaging

complete one cross-sectional image, the

modality of the chest and is, together with

patient needed to suspend respiration for a

chest X-ray, one of the two basic imaging

few seconds. After that, the table was moved

techniques used to visualise the lungs.

and the next scan was performed. This was

Although there are indications to perform a

repeated about 25 times in order to image

CT of the chest in patients with a normal

the entire thorax.

chest X-ray, this examination usually

succeeds a chest X-ray on which a lesion is

Spiral scanning (also known as helical or

seen or suspected.

continuous volume scanning) has radically

altered CT scanning protocols (table 1). In

Except for visualisation of the heart and

this technique, there is continuous patient

great vessels, MRI of the chest is less

movement with simultaneous scanning by a

frequently used in daily clinical practice, but

constantly rotating X-ray tube and detector

in selected cases, this imaging technique

system. While the first spiral CT scanners

can sometimes add information to what is

had only one row of detectors, todays

seen on CT.

scanners have multiple rows (multislice,

multirow or multidetector row CT). This

Computed tomography

allows for a fast simultaneous acquisition of

Since its introduction, CT has undergone

multiple images in the scan plane with one

several technical changes and

rotation of the X-ray tube around the patient.

improvements. The first scanners were

In this way, very good blood vessel

‘incremental’ CT scanners: in order to

opacification becomes possible using a

limited amount of contrast (fig. 1). Spiral CT

also offers flexible image reconstruction

Key points

options, such as reconstructing images at

various image thicknesses and two- and

N CT is the second most important

three-dimensional reconstructions.

imaging modality of the chest.

Thin-section or high-resolution CT (HRCT)

CT diagnosis of lung diseases is

is a special type of acquisition technique

based on the study of their

that uses 0.5-1-mm slice thickness and

appearance and distribution patterns

high-frequency reconstruction algorithms to

together with a careful analysis of

produce highly detailed images. It is used

patient data.

when detailed information on the lung

parenchyma is needed. These thin slices can

N CT interpretation of diffuse and

be obtained with the incremental acquisition

interstitial lung diseases requires a

technique in which 1-mm slices are

formal multidisciplinary approach.

produced with an image interval of 10-

MRI is second to CT when it comes to

20 mm. However, with multislice spiral CT,

visualising pulmonary structure and

it has become possible to produce a

pathology.

continuous set of thin slices of the entire

chest. Although the quality of the individual

ERS Handbook: Respiratory Medicine

141

although there are certainly indications for

Table 1. Advantages of spiral CT

doing this examination even when the chest

Sectional imaging without superposition of

X-ray does not show any (obvious)

structures

abnormalities. Table 2 lists the most frequent

Rapid acquisition within one breath hold

indications for a CT of the chest.

Very good blood vessel opacification in

Generally, the diagnosis of lung disease on a

vascular studies using a limited

chest CT is based on three elements:

amount of contrast

No respiratory misregistration between

N Recognition of the appearance pattern of

scans improving nodule detection

the disease i.e. classifying the

Fast and high-quality multiplanar and three-

abnormalities into a category that is

dimensional reconstructions

based on their appearance

Determination of location and

distribution of the abnormalities in the

images may be somewhat reduced when

lung: the distribution pattern

multislice acquisition is used, the overall

N Careful analysis of the patient data that

amount of information obtained is usually

are available at the time the CT scan is

larger. Indeed, instead of a small number of

performed

axial slices with an image gap in between, a

Although in some cases, a diagnosis or a

continuous dataset is obtained that allows

narrow differential diagnosis list can be

the production of additional slices in

proposed purely based on the study of the

different imaging planes. For this reason,

appearance and the distribution pattern of

this technique is currently replacing the

the disease on CT, the abnormalities seen in

incremental technique in most institutions,

the lung should be carefully correlated with

especially when it is the initial CT

observations made on other radiological

examination in a patient with a suspected

examinations and with all the clinical data

lung problem. An important drawback may

that are available at the time of the CT

be the increased radiation dose. However,

examination. Particularly, diffuse and

the lung parenchyma is very suitable for

interstitial lung diseases are often very

reduction of the radiation dose without

difficult to diagnose when the interpretation

important quality loss and first reports on

is only based on the CT presentation. Ideally,

the use of low-dose CT in demonstrating

cooperation should be established between

lung disease are indeed promising.

the clinician who is responsible for the

In addition, new reconstruction algorithms,

patient, the radiologist and, when

such as iterative reconstruction, that allow

pathological information is present or

further dose reduction without important

probably required, the pathologist.

loss in image quality are being developed.

Continuous efforts are made to improve

image quality and the diagnostic

Low-dose CT has been used in several lung

performance of CT imaging of the lung.

cancer screening trials to examine whether

Dual-energy CT scanning is helpful to study

any survival benefit can be found in patients

pulmonary perfusion in patients with

with screen-detected cancers compared with

pulmonary embolism (fig. 1). A further

the unscreened. The initial data from one trial

increase in the number of detector rows is

showed a 20.3% reduction in lung cancer

feasible and may reduce acquisition time

mortality among participants in the CT arm

and, hence, image quality. Automated and

of the study. However, other articles have

semiautomated software packages will help

presented conflicting predictions of survival

to interpret the CT images.

benefit and debate over the clinical utility of

CT screening for lung cancer is ongoing. As

Magnetic resonance imaging

mentioned earlier, a CT of the chest is usually

performed when the chest X-ray is abnormal

Like CT, MRI produces multiplanar cross-

or suspicious for the presence of pathology,

sectional images, but allows for a greater

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ERS Handbook: Respiratory Medicine

Figure 1. Dual-energy multislice spiral CT acquisition technique in a patient with pulmonary embolism. a)

An enhancement defect is seen in a small branch of the right pulmonary artery (arrow). b) The perfusion

scan shows a triangular area of decreased lung perfusion (arrows).

tissue characterisation because it has a better

a pre-selected body plane. Processing of

contrast resolution than CT (fig. 2). It also has

these data then yields a sectional image of

the benefit of not using ionising radiation.

the plane of interest.

In MRI, tissue protons are exposed to a

Today, MRI has an established role in the

strong external magnetic field and realign

imaging of the heart and the great thoracic

along the plane of the magnetic gradient.

vessels. For the chest wall, diaphragm,

From this position they are then deflected

mediastinum and lung, MRI was, for many

momentarily by applying a so-called radio

years, considered a useful ‘problem-solving’

frequency (RF) pulse. As they return to their

technique in specific instances, in addition to

original alignment, the protons emit a faint

CT. These instances included the identification

electromagnetic signal, which is detected by

of tumour invasion in the chest wall and

a receiving RF coil. When, in addition, a

mediastinal structures, the differentiation

suitable gradient along the magnetic field is

between solid and vascular hilar masses, the

installed, signal detection can be confined to

assessment of diaphragmatic abnormalities,

Table 2. Indications for CT of the chest

Abnormal chest X-ray

Further evaluations of a chest wall, pleural, mediastinal or lung abnormality seen on a

chest X-ray

Rule out or confirm a lesion seen on a chest X-ray

Lung cancer staging and follow-up

Assessment of thoracic vascular lesions

Normal chest X-ray

Detection of diffuse lung disease

Detection of pulmonary metastases from a known extrathoracic tumour

Demonstration of pulmonary embolism

Investigation of a patient with haemoptysis

Investigation of patients with clinical evidence of a disease that might be related to the

presence of chest abnormalities (e.g. pulmonary infection in an immunocompromised

patient with fever)

ERS Handbook: Respiratory Medicine

143

disease and patterns with high spatial

resolution, the many research and

development efforts that have been made

during recent years have resulted in new and

valuable applications that are very

promising, and that could once be

implemented in the clinical practice. There

has been much interest in the role of MRI in

the diagnosis of pulmonary embolism as a

radiation-free alternative to CT. Some

studies have shown that direct visualisation

of the thrombus in the pulmonary artery is

possible while others have concentrated on

the study of lung perfusion, looking for

decreased signal areas in the lung

representing underperfused lung tissue on

gadolinium-enhanced MRI. In addition,

imaging of pulmonary ventilation by MRI

has become possible. Hyperpolarised

helium-3 gas has been used successfully to

demonstrate perfusion changes in patients

with asthma, COPD and CF, and

hyperpolarised xenon-129, fluorine and

oxygen-enhanced lung MRI are methods of

gas imaging that have opened the field of

imaging pulmonary ventilation by MRI.

Diffusion-weighted magnetic resonance is

another interesting application. This

technique provides a measurement that

reflects the random Brownian motion of

water protons in biological tissue. This

motion causes magnetic resonant signal

Figure

2. Patient with a left-sided malignant

loss that can be measured with the use of

mesothelioma. Both a) CT and b) MRI show the

diffusion-sensitive sequences and that can

irregular and nodular pleural thickening. There is

be quantified by calculating the apparent

suspicion of invasion in the diaphragm and spleen.

diffusion coefficient. In the chest, it has

c) Diffusion-weighted MRI shows increased signal

been used successfully to differentiate

in the spleen (arrowheads) indicating tumour

between malignant and benign lesions.

invasion in this structure. In addition, increased

signal is shown in the chest wall (arrows),

Currently, most of these techniques remain

suggesting chest wall invasion.

in the experimental domain but it can be

and the study and follow-up of mediastinal

expected that some of them will reach daily

lymphoma during treatment. As mentioned

clinical practice.

earlier, nowadays most centres use

multidetector spiral CT for thoracic imaging,

Further reading

including the areas thought previously to be the

domain of problem-solving MRI.

Aberle DR, et al. (2011). Reduced lung-

cancer mortality with low-dose computed

Although it has become clear now that MRI

tomographic screening. N Engl J Med;

will always be second to CT when it comes

365: 395-409.

to the visualisation of pulmonary structure,

144

ERS Handbook: Respiratory Medicine

Amundsen T, et al. (1997). Pulmonary

Kauczor HU, et al. (1996). Normal and

embolism: detection with MR perfusion

abnormal pulmonary ventilation: visuali-

imaging of lung

- a feasibility study.

zation at hyperpolarized He-3 MR ima-

Radiology; 203: 181-185.

ging. Radiology; 201: 564-568.

Bach PB, et al. (2007). Computed tomo-

Klingenbeck-Regn K, et al.

(1999).

graphy screening and lung cancer out-

Subsecond multi-slice computed tomo-

comes. JAMA; 297: 953-961.

graphy: basics and applications. Eur J

Bergin CJ, et al. (1990). MR evaluation of

Radiol; 31: 110-124.

chest wall involvement in malignant

MacFall JR, et al. (1996). Human lung air

lymphoma. J Comput Assist Tomogr; 14:

spaces: potential for MR imaging with

928-932.

hyperpolarized He-3. Radiology; 200: 553-

Bergin CJ, et al. (1993). Magnetic reso-

558.

nance imaging of lung parenchyma. J

Matoba M, et al. (2007). Lung carcinoma:

Thorac Imaging; 8: 12-17.

diffusion-weighted MR imaging - preli-

Brown LR, et al. (1991). Masses of the

minary evaluation with apparent diffusion

anterior mediastinum: CT and MR ima-

coefficient. Radiology; 243: 570-577.

ging. AJR Am J Roentgenol; 157: 1171-1180.

Mirvis SE, et al. (1988). MR imaging of

Coolen J, et al. (2012). Malignant pleural

traumatic diaphragmatic rupture. J

disease: diagnosis by using diffusion-

Comput Assist Tomogr; 12: 147-149.

weighted and dynamic contrast-enhanced

Muller NL (2002).Computed tomography

MR imaging: initial experience. Radiology;

and magnetic resonance imaging: past,

263: 884-892.

present and future. Eur Respir J; 19: Suppl.

Dawn SK, et al. (2001). Multidetector-row

35, 3s-12s.

spiral computed tomography in the

Muller NL, et al.

(1992). Value of MR

diagnosis of thoracic diseases. Respir

imaging in the evaluation of chronic

Care; 46: 912-921.

infiltrative lung diseases: comparison

de Hoop B, et al. (2009). A comparison

with CT. AJR Am J Roentgenol;

158:

of six software packages for evaluation of

1205-1209.

solid lung nodules using semi-automated

Oudkerk M, et al. (2002). Comparison of

volumetry: what is the minimum increase

contrast-enhanced magnetic resonance

in size to detect growth in repeated CT

angiography and conventional pulmonary

examinations? Eur Radiol; 19: 800-808.

angiography for the diagnosis of pulmon-

Gruden JF (2005). Thoracic CT perfor-

ary embolism: a prospective study.

mance and interpretation in the multi-

Lancet; 359: 1643-1647.

detector era. J Thorac Imaging; 20: 253-

Padhani AR (1998). Spiral CT: thoracic

264.

applications. Eur J Radiol; 28: 2-17.

Gupta A, et al. (1999). Acute pulmonary

Padovani B, et al.

(1993). Chest wall

embolism: diagnosis with MR angiogra-

invasion by bronchogenic carcinoma:

phy. Radiology; 210: 353-359.

evaluation with MR imaging. Radiology;

Heelan RT, et al. (1989). Superior sulcus

187: 33-38.

tumors: CT and MR imaging. Radiology;

Silverman PM, et al.

(2001). Common

170: 637-641.

terminology for single and multislice

Henschke CI, et al. (2006). Survival of

helical CT. AJR Am J Roentgenol;

176:

patients with stage I lung cancer detected

1135-1136.

on CT screening. N Engl J Med; 355: 1763-

Thieme SF, et al. (2008). Dual energy CT

1771.

for the assessment of lung perfusion -

Kalender WA, et al. (1990). Spiral volu-

correlation to scintigraphy. Eur J Radiol;

metric CT with single-breath-hold techni-

68: 369-374.

que, continuous transport, and con-

Webb WR (1985). Magnetic resonance

tinuous scanner rotation. Radiology; 176:

imaging of the mediastinum, hila, and

181-183.

lungs. J Thorac Imaging; 1: 65-73.

ERS Handbook: Respiratory Medicine

145

HRCT of the chest

Johny A. Verschakelen

High-resolution computed tomography

thin slices. In this way, more information is

(HRCT) is a CT acquisition and

obtained than with the incremental

reconstruction technique that produces

acquisition technique. In addition, images in

highly detailed images. It differs from

other imaging planes and special

‘classical’ CT by the fact that thin slices

reconstructions like maximal- and minimal-

(0.5-1 mm) are generated and that high-

intensity projections (MIP and MinIP,

frequency reconstruction algorithms are

respectively) can be made.

used to improve image detail. As thin slices

Because of the important image gap that

are necessary, the technique is also called

existed when only incremental acquisition

thin-slice CT. Before the introduction of

could be used - giving information about a

spiral CT, these thin slices were obtained by

small but well and equally distributed

the ‘incremental’ acquisition technique in

sample of the lung - the HRCT technique

which 1-mm slices were produced with an

was (and still is) predominantly used to

image interval of 10 mm. Today, most

study diffuse and interstitial lung disease

institutions have spiral CT scanners and use

(DILD). It should be emphasised, however,

multislice acquisition to obtain a continuous

that with the multislice spiral CT technique,

dataset of the entire chest that allows

thin and highly detailed images of the lung

generation of a large number of adjacent

can be reconstructed from almost every CT

examination.

Key points

HRCT and DILD

Since its introduction into clinical practice,

N HRCT is the imaging technique that

the use of HRCT has constantly increased.

offers the highest image detail of the

This is related not only to the fact that this

lung parenchyma.

technique provides important

HRCT is predominantly used to study

morphological information on the lung

DILDs but thin-slice CT can be useful

parenchyma (it offers the highest image

in the study of focal lung

detail of the lung) but also because it helps

abnormalities too.

to better understand the clinical and

pathological course of some diseases, which

N HRCT of the lungs is an essential

has even resulted in the formulation CT

element in the multidisciplinary

classifications to categorise disease. HRCT

discussion of patients with DILD.

is also partly responsible for the radical

HRCT does not replace lung biopsy

change in the diagnostic work-up of DILDs

but helps to decide in which cases a

that has occurred the last 10 years. The

lung biopsy will very likely give more

historical gold standard of histologic

(or important additional) information

diagnosis has been replaced by an

than CT and in which cases a biopsy is

integrative approach of clinical, radiological

not needed.

and, when necessary, pathologic data during

multidisciplinary discussions. HRCT and

146

ERS Handbook: Respiratory Medicine

Figure 1. Patient with IPF. CT shows the typical appearance and distribution pattern of IPF. Notice the

traction bronchiectasis in the basal part of the middle lobe (arrow), a sign of pulmonary fibrosis. a) axial

view; b) coronal view.

histology are nowadays often considered as

can be diagnostic when a typical pattern

‘silver’ standards. This does not mean that

is present.

lung biopsy is less important but implicates

N If it is decided that a lung biopsy is

that the multidisciplinary discussion defines

necessary, HRCT can help to determine

in which cases a lung biopsy will very likely

the best location for taking the lung

give more (or important additional)

sample by suggesting the most likely

information than CT and in which cases a

areas of active disease and avoiding the

biopsy is not needed.

areas of (nonspecific) terminal fibrosis.

N The information provided by HRCT and

There are several reasons why HRCT plays

histology is very often complementary.

an important role in this multidisciplinary

While histology provides a microscopic

discussion.

view of a small part of the lung, HRCT

gives a ‘sub-macroscopic’ or sub-

N Some DILDs can have a typical HRCT

millimetre view of the entire lung.

pattern and when this disease presents

Combination of this information can

with such a pattern, HRCT may be very

indeed result in a single diagnosis. It

accurate in the diagnosis, i.e. HRCT may

should be emphasised, however, that in

have a high positive predictive value

some patients with DILD, multiple

(PPV). Idiopathic pulmonary fibrosis

(IPF) is such a disease (fig. 1). The PPV of

HRCT in IPF patients is .90% when a

Table 1. Diseases that can present with a typical HRCT

typical appearance pattern (predominant

pattern

cystic, irregular linear pattern, traction

bronchiectasis and no predominant

IPF

ground-glass opacity) is combined with a

Sarcoidosis

typical distribution pattern (subpleural

Langerhans’ cell histiocytosis

and basal lung). Unfortunately, a typical

HRCT pattern of IPF is only seen in less

Hypersensitivity pneumonitis

than half of cases. In that situation, a part

Lymphangitic spread of cancer

of the multidisciplinary discussion will be

Silicosis and coalminers’ pneumoconiosis

Further reading

body position. These are performed in

American Thoracic Society/European

patients suspected of having early DILD

Respiratory Society. (2002). International

when supine CT shows minimal changes in

Multidisciplinary Consensus Classification

the posterior and basal parts of the lung,

of the Idiopathic Interstitial Pneumonias.

areas that are often first involved in DILD

Am J Respir Crit Care Med; 165: 277-304.

but also often show a gravity-related

Dodd JD, et al.

(2008). Conventional

perfusion increase. Prone CT scans are

high-resolution CT versus contiguous

mostly able to differentiate between these

multidetector CT in the detection of

entities as gravity-related changes will

bronchiolitis obliterans syndrome in lung

disappear in the prone body position.

transplant recipients. J Thorac Imaging;

Administration of intravenous contrast is

23: 235-243.

not necessary.

Flaherty KR, et al.

(2004). Idiopathic

interstitial pneumonia: what is the effect

HRCT in the diagnosis of diffuse lung

of a multidisciplinary approach to diag-

disease

nosis? Am J Respir Crit Care Med; 170:

904-910.

As mentioned earlier, HRCT plays an

Hunninghake GW, et al. (2001). Utility of

important role in the process of making the

a lung biopsy for the diagnosis of

diagnosis of diffuse lung disease.

idiopathic pulmonary fibrosis. Am J

Interpreting a HRCT image of the lungs of

Respir Crit Care Med; 164: 193-196.

a patient suspected of having DILD is a

Kawel N, et al.

(2009). Effect of slab

stepwise process. First, it is important to

thickness on the CT detection of pulmon-

decide whether the lung changes are

ary nodules: use of sliding thin-slab

indeed resulting from a diffuse lung

maximum intensity projection and

disease, i.e. a disease that is diffusely

volume rendering. Am J Roentgenol; 192:

spread over an important part of the lung

1324-1329.

and shows CT changes that are composed

ERS Handbook: Respiratory Medicine

149

Mayo JR (2009). CT evaluation of diffuse

Schmidt SL, et al.

(2009). Diagnosing

infiltrative lung disease: dose considera-

fibrotic lung disease: when is high-

tions and optimal technique. J Thorac

resolution computed tomography suffi-

Imaging; 24: 252-259.

cient to make a diagnosis of idiopathic

Nishino M, et al. (2010). The spectrum of

pulmonary fibrosis? Respirology; 14: 934-

pulmonary sarcoidosis: variations of high-

939.

resolution CT findings and clues for

Screaton NJ, et al.

(2011).

The

specific diagnosis. Eur J Radiol; 73: 66-73.

clinical impact of high resolution com-

Nishino M, et al. (2010). Volumetric expira-

puted tomography in patients with

tory HRCT of the lung: clinical applications.

respiratory disease. Eur Radiol; 21: 225-

Radiol Clin North Am; 48: 177-183.

231.

Quadrelli S, et al.

(2010). Radiological

Sverzellati N, et al. (2010). High-resolu-

versus histopathological diagnosis of

tion computed tomography in the diag-

usual interstitial pneumonia in the clin-

nosis and follow-up of idiopathic

ical practice: does it have any survival

pulmonary fibrosis. Radiol Med;

115:

difference? Respiration; 79: 32-37.

526-538.

Raghu G, et al. (2011). An official ATS/

Wells AU (2003). High-resolution com-

ERS/JRS/ALAT statement: idiopathic pul-

puted tomography in the diagnosis of

monary fibrosis: evidence-based guide-

diffuse lung disease: a clinical perspec-

lines for diagnosis and management. Am

tive. Semin Respir Crit Care Med; 24: 347-

J Respir Crit Care Med; 183: 788-824.

356.

150

ERS Handbook: Respiratory Medicine

Nuclear medicine of the lung

Antonio Palla and Duccio Volterrani

Nuclear medicine may contribute to the

diagnosis of pulmonary embolism and

Key points

inflammatory diseases, and the diagnosis

and staging of lung cancer. Among several

N Nuclear medicine of the lung has a

techniques available, perfusion and

role in the diagnosis of pulmonary

ventilation lung scintigraphy (PLS and VLS,

embolism and inflammatory diseases,

respectively), gallium-67 scintigraphy, and

and in the diagnosis and staging of

positron emission tomography (PET)

lung cancer.

scintigraphy are of interest in clinical

N Perfusion scintigraphy is key in the

practice.

diagnosis and follow-up of pulmonary

Diagnosis of pulmonary embolism

embolism as it is safe, cheap and

noninvasive.

Thanks to its noninvasiveness, safety and

N Gallium-67 scintigraphy is useful in

low cost, PLS still remains the cornerstone

identifying and localising intrathoracic

of the diagnosis and follow-up of pulmonary

inflammation and infection.

embolism.

N FDG-PET and PET/CT are used in

PLS has been proven to be useful for:

diagnosis, treatment targeting and

treatment in lung cancer.

N diagnosis of pulmonary embolism

N detection of recurrences under treatment

or after its discontinuation

N differential diagnosis between

available. Nowadays, VLS is only indicated

thromboembolic and

in some individual patients with pulmonary

nonthromboembolic pulmonary

embolism, since similar results can be

hypertension

obtained by using chest radiography. A few

Two main scintigraphic criteria must be

years ago, a new classification of perfusion

considered for the diagnosis: 1)

defects was published in order to optimise

identification of perfusion defects

its diagnostic usefulness in conjunction with

corresponding to one or more pulmonary

chest radiography; this method has made it

segments, and 2) diversion of pulmonary

possible to obtain a diagnostic accuracy

blood flow from lower and posterior lung

similar to that shown by angio-CT. PLS also

regions. Perfusion defects are typically

plays a leading role in the follow-up of

multiple, wedge-shaped and often bilateral.

patients with pulmonary embolism, as it

PLS has a sensitivity of 100%: it allows

helps to monitor the efficacy of treatment in

exclusion with certainty when the diagnosis

the first few days, it allows prompt detection

is negative. The specificity varies in different

of early and late recurrences and evolution

reported series but, on average, does not

towards pulmonary hypertension, and it may

reach acceptable values; to increase the

differentiate between thromboembolic

specificity, VLS has been introduced, but it

pulmonary hypertension and other types of

is cumbersome, time consuming and poorly

pulmonary hypertension.

ERS Handbook: Respiratory Medicine

151

Figure 1. Solitary pulmonary nodule as it appears on a) chest CT, b) PET/CT and c) FDG-PET.

Diagnosis of inflammatory diseases

be of value in the evaluation of the efficacy

of chemotherapy in lymphomatous diseases

Gallium-67 citrate is the most widely

and may help differentiate post-actinic

employed positive tracer in order to identify

fibrosis from residual tumour foci when a

and localise intrathoracic inflammations and

lung density persists after radiotherapy.

infections. To acquire images, a scintillation

gamma camera with a low-energy collimator

Lung cancer

is required. Gallium scintigraphy may help in

PET is a nuclear medicine technique that

evaluating the activity of granulomatous

produces a three-dimensional image of

disorders and the efficacy of steroid

functional and biochemical processes within

treatment. In patients with sarcoidosis, it

the body. Recently, PET has been combined

shows a high diagnostic sensitivity; in some

with CT (PET/CT) (fig. 1); such fusion

cases, the presence of highly specific signs,

generally improves diagnostic accuracy by

such as ‘panda’ or ‘lambda’ signs, allows

increasing specificity compared with PET

avoidance of invasive diagnostic tests.

alone. The most frequently used tracer is 2-

Moreover, this tracer may differentiate

[18F]-fluoro-2-deoxy-D-glucose (FDG), a

between sarcoidosis and non-Hodgkin’s

glucose analogue, the tissue concentration

lymphoma, and detect multiple

of which is directly related to glucose

extrapulmonary sites of sarcoidosis. In

metabolism. The uptake of FDG may be

addition, gallium scintigraphy is indicated in

evaluated by a semiquantitative

investigating metabolic activity in

measurement, the standardised uptake

pulmonary infections and the efficacy of

value (SUV), i.e. the ratio between the

proper therapy. In the diagnosis of

amount of tracer in a specific area and the

pulmonary TB, gallium scintigraphy may

amount potentially present if the tracer had

indicate the necessity of a bronchoalveolar

been evenly distributed in the body.

lavage and the site where it should be

performed. This occurs mostly in cases of

FDG-PET has proven useful in:

suspected re-infection of areas of

pleuroparenchymal fibrosis, in cases of

N diagnosing and staging lung cancer

suspicion where sputum is repeatedly

N monitoring the efficacy of treatment

negative and in immunocompromised

N defining the biological target volume for

patients. Finally, gallium scintigraphy may

radiation treatment planning

152

ERS Handbook: Respiratory Medicine

An indication of increasing clinical relevance

A recent indication of PET/CT is the

of FDG-PET and PET/CT is the

definition of the biological target volume for

differentiation of benign from malignant

radiation treatment planning. This approach

solitary pulmonary nodules by replacing

has the goal of increasing the dose to the

invasive modalities of investigation. A SUV

tumour and focusing the treatment planning

of 2.5 has been reported as a guideline for

to the biological target, which reveals an

the cut-off between benign (SUV ,2.5) and

elevated glucose metabolism.

malignant (SUV .2.5) lesions. A meta-

analysis from 40 studies showed a

Further reading

sensitivity of 97% but a lower specificity

(78%) due to FDG uptake within

Bryant AS, et al. (2006). The maximum

inflammatory/granulomatous lesions.

standardized uptake values on integrated

However, a high rate of false-negative FDG

FDG-PET/CT is useful in differentiating

results can occur when nodules are ,1 cm

benign from malignant pulmonary

(sensitivity of 69% for nodules of 5-8 mm).

nodules. Ann Thorac Surg; 82: 1016-1020.

Moreover, some histotypes, such as

De Geus-Oei LF, et al. (2007). Predictive

and prognostic value of FDG-PET in

bronchoalveolar carcinomas and well-

nonsmall-cell lung cancer: a systematic

differentiated neuroendocrine tumours,

review. Cancer; 110: 1654-1664.

usually present a low glucose metabolic

Kita T, et al. (2007). Clinical significance

activity and cannot be correctly imaged by

of the serum IL-2R level and Ga-67 scan

FDG-PET.

findings in making a differential diagno-

sis between sarcoidosis and non-

FDG PET is also a standard modality for

Hodgkin’s lymphoma. Ann Nucl Med;

staging nonsmall cell lung cancer. Several

21: 499-503.

studies have demonstrated that PET is more

Liu SF, et al. (2007). Monitoring treatment

accurate than CT in the staging of the

responses in patients with pulmonary TB

mediastinum (N state). Due to its high

using serial lung gallium-67 scintigraphy.

negative predicted value, invasive staging

Am J Roentgenol; 188: 403-408.

procedures (mediastinoscopy) can be

Miniati M, et al. (2008). Perfusion lung

omitted in patients with a negative FDG-PET

scintigraphy for the diagnosis of pulmon-

for mediastinal lymph node involvement.

ary embolism: a reappraisal and review of

However, a positive finding should not

the prospective investigative study of

preclude mediastinoscopy. Moreover, the

pulmonary embolism diagnosis methods.

addition of FDG-PET to the standard work-

Semin Nucl Med; 38: 450-461.

up can prevent unnecessary thoracotomies

Sostman HD, et al. (2008). Sensitivity

and specificity of perfusion scintigraphy

and change the therapeutic approach in a

combined with chest radiography for

significant percentage of patients. PET is

acute pulmonary embolism in PIOPED

useful in disclosing distant metastases (M

II. J Nucl Med; 49: 1741-1748.

state) with a high sensitivity and specificity.

Stein PD, et al.

(2006). Multidetector

However, PET cannot replace CT or MRI for

computed tomography for acute pulmon-

detecting brain metastases. Moreover, the

ary embolism. N Engl J Med; 354: 2317-

measurement of FDG SUV within the

2327.

tumour correlates negatively with patient

Van Tinteren H, et al.

(2002).

prognosis; early changes of FDG SUV during

Effectiveness of positron emission tomo-

radiotherapy and chemotherapy can predict

graphy in the preoperative assessment of

therapy efficacy; and PET is more accurate

patients with suspected non-small-cell

than contrast-enhanced CT for detecting

lung cancer: the PLUS multicentre rando-

residual tumour after radiotherapy and

mised trial. Lancet; 359: 1388-1393.

chemotherapy.

ERS Handbook: Respiratory Medicine

153

Transthoracic ultrasound

Florian von Groote-Bidlingmaier, Coenraad F.N. Koegelenberg and

Chris T. Bolliger^{

General technical aspects and appearance

Key points

of the normal thorax

A low-frequency probe (e.g. 3.5 MHz) is

Transthoracic ultrasound can be

routinely used for screening purposes, while

performed with the most basic

detailed assessment of an abnormal chest

ultrasound equipment and allows for

wall or pleura can be performed with a high-

immediate and mobile assessment of

frequency probe (e.g. 8 MHz).

patients with a wide variety of

respiratory diseases.

Special attention must be paid to patient

positioning. The posterior chest is ideally

The major indications for the use of

scanned in the sitting position whereas the

transthoracic ultrasound are the

anterior and lateral chest are best examined

description of pleural effusions,

in the supine or lateral decubitus position.

pleural thickening, diaphragmatic

dysfunction, and chest wall and

Superficial muscles and fascia planes

pleural tumours.

appear as a series of echogenic layers during

the initial surveillance of a normal chest.

Other applications of transthoracic

Curvilinear structures on transverse scans,

ultrasound include the diagnosis of a

associated with posterior acoustic

pneumothorax, pulmonary

shadowing, represent the ribs.

consolidation, tumours, interstitial

The visceral and parietal pleura normally

syndromes and pulmonary

appear as one highly echogenic line.

embolism.

Movement of the lung with the respiratory

Furthermore, ultrasound is ideal to

cycle in relation to the chest wall on real-

guide thoracentesis, drainage of

time ultrasound is called the ‘lung sliding’

effusions and other thoracic

sign.

interventions, and is particularly

Ultrasound cannot visualise normal aerated

useful in intensive care units where

lung tissue. The large change in acoustic

radiographic equipment is

impedance at the pleura-lung interface,

unavailable.

however, causes horizontal artefacts that are

seen as a series of echogenic parallel lines

Major advantages of the technique

equidistant from one another below the

include its mobility, dynamic

pleura. These bright but formless lines are

properties, lack of radiation and low

known as reverberation artefacts or A-lines

cost.

(fig. 1).

The ultrasonographic appearance of

Chest wall pathology

the normal thorax and the most

common pathologies are reviewed in

Soft-tissue masses, such as abscesses,

this section.

lipomas and a variety of other lesions, can

be detected by ultrasound. These lesions are

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ERS Handbook: Respiratory Medicine

Figure 1. The typical appearance of a normal chest

on ultrasound. A transverse view through the

intercostal space is shown. The chest wall is

visualised as multiple layers of echogenicity

representing muscles and fascia. The visceral and

parietal pleura appear as an echogenic bright line

(two distinct lines sliding during respiration are

visible on real-time ultrasound). Reverberation

artefacts beneath the pleural lines imply an

underlying air-filled lung. P: pleura; L: lung; R:

reverberation artefact.

mostly benign, but variable echogenicity and

nonspecific ultrasound findings make

differentiation between various aetiologies

difficult. Supraclavicular and axillary lymph

nodes are usually accessible, and ultrasound

may even help to distinguish benign from

malignant lymph nodes. Hypoechoic

masses disrupting the normal structure of a

rib may represent bony metastases and can

be seen on ultrasound.

Pleural pathology

Figure 2. a) Example of an anechoic pleural effusion. It

presents as an echo-free space between the visceral and

Transthoracic ultrasound is most commonly

parietal pleura. Compressive atelectasis of the lung

used to investigate pleural effusions, and is

may be seen as a tongue-like structure in a large

more sensitive than decubitus radiographs at

effusion. Note the difference to the effusion in b),

demonstrating minimal or loculated effusions.

which is classified as complex septated. Multiple septa

The ultrasound appearance of a pleural

form many compartments in the same effusion. PE:

effusion depends on its nature and chronicity.

pleural effusion; L: lung; S: septum.

ERS Handbook: Respiratory Medicine

155

Figure 3. A peripheral pulmonary lesion is shown schematically without (top) and with (bottom) pleural

contact. Only the lesion with pleural contact is visible on ultrasound. Reproduced from Diacon et al.

(2005) with permission from the publisher.

Four appearances based on the internal

inside a large effusion may appear as a

echogenicity are recognised:

tongue-like structure within the effusion.

Inflammatory effusions are often associated

N anechoic

with strands of echogenic material and

N complex but nonseptated

septations that show more or less mobility

N complex and septated

with respiration and the cardiac cycle (fig. 2).

N homogenously echogenic

The volume of a pleural effusion can be

Transudates are invariably anechoic,

estimated using the following classification:

nonseptated and free flowing, whereas

complex, septated or echogenic effusions are

usually exudates. Malignant effusions are

N minimal if the echo-free space is confined

frequently anechoic. The atelectatic lung

to the costophrenic angle

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ERS Handbook: Respiratory Medicine

N small if the space is greater than the

costophrenic angle but still within the

range of the area covered with a 3.5-MHz

curvilinear probe

N moderate if the space is greater than a

one-probe range but within a two-probe

range

N large if the space is bigger than a two-

probe range

Both small effusions and pleural thickening

may appear as hypoechoic on ultrasound, so

differentiation might be difficult. An

important sign in favour of an effusion is

mobility on real-time ultrasound.

Metastatic pleural tumours and malignant

Figure 4. A sonographic image showing a solid

mesothelioma can be visualised as polypoid

lung lesion with posterior echo enhancement.

pleural nodules or irregular sheet-like pleural

Note that the tumour is abutting the pleura and is

thickening. They are often associated with

therefore visible on ultrasound. P: pleura; L: lung;

large pleural effusions. Benign pleural

T: tumour.

tumours are rare.

Qureshi et al. (2009) found that pleural

staging of malignant lung tumours. Loss of

thickening .1 cm, pleural nodularity and

movement of a visualised tumour with

diaphragmatic thickening .7 mm were

respiration suggests infiltration beyond the

highly suggestive of malignant disease. In

parietal pleura.

their study, ultrasound correctly identified

Ultrasound can detect pneumonic

73% of malignant effusions.

consolidations provided they have contact

The detection of a pneumothorax by means

with the pleura. Early pneumonic

of ultrasound requires a greater deal of

consolidation may appear very similar to the

expertise than the detection of pleural fluid.

diffusely echogenic tissue-like texture of the

A recent meta-analysis concluded that

liver. Both air and fluid bronchograms are

bedside ultrasonography had a higher

usually seen within the consolidated lung.

sensitivity and similar specificity for the

Noninfective causes of consolidations with

diagnosis of a pneumothorax when

similar appearance on ultrasound include

compared with chest radiography. The

pulmonary infarction, haemorrhage and

absence of normal lung sliding, the loss of

bronchoalveolar carcinoma. Consolidation

comet-tail artefacts and exaggerated

can be differentiated from an interstitial

horizontal reverberation artefacts are

syndrome, for which long, laser-like vertical

reliable signs of the presence of a

hyperechoic lines, called B-lines, are

pneumothorax. Ultrasound is also the ideal

pathognomonic. Interstitial syndromes may

tool to screen for a post-procedural

include pulmonary oedema, interstitial

pneumothorax after transthoracic

pneumonia or diffuse parenchymal lung

procedures and transbronchial biopsy.

disease

Pulmonary pathology

A hypoechoic lesion with a well-defined or

irregular wall abutting the pleura might

A lung tumour abutting the pleura will be

represent a lung abscess. The centre of the

detectable by ultrasound (fig. 3). In most

abscess is most often anechoic but may

cases, these tumours present as a

reveal septations and internal echoes.

hypoechoic mass with posterior acoustic

enhancement (fig. 4). Visceral pleura or

Another indication for the use of

chest wall involvement is important for

transthoracic ultrasound is the assessment

ERS Handbook: Respiratory Medicine

157

of pulmonary and pleural-based cysts, which

or thoracoscopy

- which first?

commonly appear as large, round anechoic

Respirology; 16: 738-746.

lesions.

Koegelenberg CF, et al.

(2012).

Transthoracic ultrasonography for the

Conclusion

respiratory physician. Respiration;

84:

337-350.

The value of ultrasound for chest physicians

Koh DM, et al. (2002). Transthoracic US

is firmly established. Basic thoracic

of the chest: clinical uses and applica-

ultrasonography is an elegant and

tions. Radiographics; 22: e1.

inexpensive investigation that extends the

Kreuter M, et al.

(2011). Diagnostische

physicians’ diagnostic and interventional

Wertigkeit der transthorakalen Sonografie

potential at the bedside in peripheral lung,

vergleichend zur Thoraxubersicht beim

pleural and chest wall disease.

Nachweis eines postinterventionellen

Pneumothorax [Diagnostic value of trans-

thoracic ultrasound compared to chest

Further reading

radiography in the detection of a post-

Diacon AH, et al. (2005). Transthoracic

interventional pneumothorax]. Ultraschall

ultrasound for the pulmonologist. Curr

Med; 32: Suppl. 2, E20-E23.

Opin Pulm Med; 11: 307-312.

Lichtenstein DA, et al. (1995). A bedside

Ding W, et al.

(2011). Diagnosis of

ultrasound sign ruling out pneumothorax

pneumothorax by radiography and ultra-

in the critically ill. Chest; 108: 1345-1348.

sonography: a meta-analysis. Chest; 140:

Mathis G (1997). Thoraxsonography -

859-866.

part I: chest wall and pleura. J Ultrasound

Evans AL, et al.

(2004). Radiology in

Med Biol; 23: 1131-1139.

pleural disease: state of the art.

Mayo PH, et al. (2006). Pleural ultra-

Respirology; 9: 300-312.

sonography. Clin Chest Med; 27: 215-217.

Gorg C, et al.

(1997). Sonography of

Qureshi NR, et al.

(2009). Thoracic

malignant pleural effusion. Eur Radiol; 7:

ultrasound in the diagnosis of malignant

1195-1198.

pleural effusion. Thorax; 64: 139-143.

Herth FJ, et al.

(2004). Diagnosis of

Tsai TH, et al. (2003). Ultrasound in the

pneumothorax by means of transthoracic

diagnosis and management of pleural

ultrasound: a prospective trial. Eur Respir

disease. Curr Opin Pulm Med; 9: 282-

J; 24: Suppl. 48, 491s-492s.

290.

Hirsch JH, et al. (1981). Real-time sono-

Volpicelli G, et al.

(2012). International

graphy of pleural opacities. Am J

evidence-based recommendations for

Roentgenol; 136: 297-301.

point-of-care lung ultrasound. Intensive

Kocijancic I, et al.

(2004). Imaging of

Care Med; 38: 577-591.

pleural fluid in healthy individuals. Clin

Yang PC, et al. (1992). Value of sono-

Radiol; 59: 826-829.

graphy in determining the nature of

Koegelenberg CF, et al. Pleural Ultrasound.

pleural effusion: analysis of

320 cases.

In: Light RW, et al., eds. Textbook of Pleural

Am J Roentgenol; 159: 29-33.

Disease,

2nd Edn. London, Hodder &

Yang PC (1997). Ultrasound-guided trans-

Stoughton, 2008; pp. 271-228.

thoracic biopsy of peripheral lung,

Koegelenberg CF, et al.

(2011). Pleural

pleural, and chest wall lesions. J Thorac

controversy: closed needle pleural biopsy

Imaging; 12: 272-284.

158

ERS Handbook: Respiratory Medicine

Lung injury

Bernd Schönhofer and Christian Karagiannidis

Acute lung injury (ALI) and its most severe

ARDS, independent of positive end-

manifestation, acute respiratory distress

expiratory pressure (PEEP)) and by bilateral

syndrome (ARDS), are defined by

pulmonary infiltrates as radiological criteria.

physiological criteria (i.e. ratio of PaO₂ to

Cardiac failure must be excluded based

inspiratory oxygen fraction (FIO₂)

either on pulmonary artery wedge pressure

f300 mmHg for ALI and f200 mmHg for

(,18 mmHg) or on clinical evaluation of left

ventricular function, if the invasive

measurement is unavailable.

These criteria should be re-evaluated after

Key points

24 h, since their persistence is essential for

ALI and its most severe

the correct diagnosis of ALI/ARDS.

manifestation, ARDS, are defined as

Furthermore, timing may be of influence on

PaO₂/FIO₂ f300 mmHg and

the development of ALI/ARDS.

f200 mmHg, respectively, with

Lung oedema may evaluated by CT or other

bilateral infiltrates as radiological

established methods.

criteria. The ARDS Definition Task

Force proposes a new classification

ALI/ARDS may be caused by various

according to the severity of ARDS, i.e.

aetiologies: direct lung injury, e.g.

mild: PaO₂/FIO₂

.200 mmHg and

pneumonia, aspiration, toxic inhalation,

f300 mmHg; moderate: PaO₂/FIO₂

near drowning or lung contusion; or indirect

.100 mmHg and f200 mmHg; and

lung injury, e.g. sepsis, burn, pancreatitis or

severe: PaO₂/FIO₂

f100 mmHg,

massive blood transfusion. The two

because of its better predictive value

aetiologies may coexist.

for mortality (fig. 1).

The exact incidence of ALI/ARDS is not

Principles of protective ventilator

known; its annual mortality rate has been

settings for patients with ALI/ARDS

estimated to be .30 000 patients per year

are low tidal volume (i.e. VT 6 mL per

in the USA. Despite recent advances in the

kg ideal body weight, plateau pressure

understanding of the pathophysiology of

,30 cmH₂O and peak pressure

ARDS, improvements in supportive care,

,35 cmH₂O).

and multiple therapeutic efforts directed at

Permissive hypercapnia may be

modifying the course of the condition,

helpful to realise protective

mortality rates are persistently 35-40%.

mechanical ventilation.

The pathophysiology of ALI/ARDS is related

Protection of the lungs may also be

to altered pulmonary capillary permeability

provided by the pump-driven veno-

and increased intrapulmonary shunt, which

venous ECMO or pumpless ILA.

is associated with impaired gas exchange.

ARDS has been divided into three stages, in

which an initial inflammatory phase

(exudative) is followed by fibro-proliferation,

ERS Handbook: Respiratory Medicine

159

which can lead to established interstitial and

reduce the amount of nonaerated

intra-alveolar fibrosis, the final phase.

atelectatic lung.

Mechanical ventilation itself can seriously

Principles of protective ventilator settings

damage lung parenchyma (ventilator-

for patients with ALI/ARDS are:

induced lung injury). ALI/ARDS often has

systematic manifestations, triggering

N Tidal volume 6 mL?kg^-1 ideal body weight.

systemic inflammatory response syndrome,

N Plateau pressure ,30 cmH₂O, peak

or in extremis multiple organ dysfunction

pressure ,35 cmH₂O.

syndrome.

N This strategy of protective mechanical

ventilation may be associated with

In general, the spectrum of treatment ALI/

permissive hypercapnia.

ARDS includes supportive care, ventilator

support and pharmacological treatment.

The ‘optimal’ setting of PEEP is not clear,

The first principle of treatment is to identify

since several methods have been proposed

potential underlying causes of ALI/ARDS.

without any clear advantages over each

Furthermore, secondary lung injury, such as

other.

aspiration, barotraumas, nosocomial

Higher PEEP (.15 cmH₂O) might be

infections and oxygen toxicity, has to be

recommended in more severe ARDS

avoided. The main aims of supportive care

patients. Prone position might be

are maintaining oxygen delivery to end

recommended in more severe ARDS

organs by avoiding anaemia and optimising

patients, according to the expertise of the

cardiovascular function and body fluid

clinicians. Estimating the transpulmonary

balance; additionally, catabolism and

pressure by means of oesophageal pressure

nutritional support have to be balanced.

measurement might help to find the ideal

With regard to mechanical ventilation, the

PEEP level. Alternative methods of

main goal is to improve oxygenation without

ventilation include high-frequency

increasing the iatrogenic effects caused by

ventilation and airway pressure release

mechanical ventilation; there are different

ventilation.

methods available. Among the methods

Protection of the lungs may also be provided

related to the ventilatory setting, those

by pump-driven veno-venous extracorporeal

found really effective are to reduce tidal

membrane oxygenation (vv-ECMO), which

volume and pressures and to apply PEEP to

improves both oxygenation and carbon

dioxide removal, and allows a highly

protective low tidal volume ventilation.

Current ALI/

Berlin definition

Recently, the CESAR trial provides the first

ARDS definition

of ARDS

evidence that vv-ECMO is superior to

400

conventional treatment in the most severe

ALI

Mild

forms of ARDS. Moreover, a pumpless

300

extracorporeal lung assist was developed

using arterio-venous bypass, in which a gas

ARDS

Moderate

exchange membrane is integrated

200

(interventional lung assist). Interventional

Severe

lung assist provides effective carbon dioxide

100

elimination and a moderate improvement in

oxygenation, and therefore allows a more

protective mechanical ventilation.

Concerning pharmacological treatments of

Figure 1. Current definition of ALI/ARDS and the

ALI/ARDS, inhaled nitric oxide has not been

Berlin definition of ARDS based on PaO₂/FIO₂

found to be particularly effective and there is

criteria.

no clear convincing data to support the

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ERS Handbook: Respiratory Medicine

widespread use of corticosteroids in both

Dreyfuss D, et al.

(1998). Ventilator-

early and late phases of ALI/ARDS.

induced lung injury. Lessons from experi-

mental studies. Am J Respir Crit Care Med;

Finally, based on experimental models a

157: 294-323.

series of molecular mechanisms offer

Gattinoni L, et al. (2005). The concept of

innovative opportunities for cell or gene

‘baby lung’. Intensive Care Med; 31: 776-784.

therapy. These need to be elaborated in

Marini JJ, et al.

(2004). Ventilatory

human studies, however.

management of acute respiratory distress

syndrome - a consensus of two. Crit Care

Med; 32: 250-255.

Further reading

Matthay MA, et al. (2005). Acute lung

American Thoracic Society et al. (1999).

injury and the acute respiratory distress

International consensus conference in

syndrome: four decades of inquiry into

intensive care medicine: ventilator-asso-

pathogenesis and rational management.

ciated lung injury in ARDS. Am J Respir

Am J Respir Cell Mol Biol; 33: 319-327.

Crit Care Med; 160: 2118-2124.

Peek GJ, et al.

(2009). Efficacy and

The Acute Respiratory Distress Syndrome

economic assessment of conventional

Network. (2000). Ventilation with lower

ventilatory support versus extracorporeal

tidal volumes as compared with tradi-

membrane oxygenation for severe adult

tional tidal volumes for acute lung injury

respiratory failure (CESAR): a multicentre

and the acute respiratory distress

randomised controlled trial. Lancet; 374:

sydrome. N Engl J Med; 342: 1301-1308.

1351-1363.

The ARDS Definition Task Force. (2012).

Talmor D, et al.

(2008). Mechanical

Acute Respiratory Distress Syndrome.

ventilation guided by esophageal pres-

The Berlin Definition. JAMA; 307: 2526-

sure in acute lung injury. N Engl J Med;

2533.

359: 2095-2104.

ERS Handbook: Respiratory Medicine

161

Respiratory failure

Nicolino Ambrosino and Fabio Guarracino

The respiratory system consists of two parts.

blood gases and acid-base status; chronic

The lung performs gas exchange and the

respiratory failure is clinically indolent to

pump ventilates the lung. The pump

unapparent, due to mechanisms of

consists of the chest wall, including the

compensation for respiratory acidosis.

respiratory muscles, and the respiratory

controllers in the central nervous system

Respiratory failure due to lung diseases

(CNS) linked to respiratory muscles through

(e.g. pneumonia, acute lung injury, acute

spinal and peripheral nerves.

respiratory distress syndrome (ARDS),

emphysema or interstitial lung disease)

When respiratory failure ensues, the

leads to hypoxaemia with normocapnia or

respiratory system fails in one or both of its

even hypocapnia (type I respiratory failure).

gas exchange functions, i.e. oxygenation of

Four pathophysiological mechanisms are

mixed venous blood and/or elimination of

responsible for hypoxaemic respiratory

carbon dioxide (fig. 1).

failure:

The diagnosis of respiratory failure is not

clinical but based on arterial gas

N ventilation/perfusion (V9/Q9) ratio

assessment: it is defined by a PaO₂

inequalities;

,60 mmHg and/or PaCO₂ .45 mmHg.

N shunt;

These values are not rigid; they must serve

N diffusion impairment; and

as a general guide in combination with the

N hypoventilation.

patient’s history and clinical evaluation.

Respiratory failure may be acute, chronic or

Hypoxaemia with hypoventilation is

acute on chronic, with clinical presentation

characterised by a normal alveolar-arterial

being quite different between these types.

oxygen difference, whereas disorders due to

any of the other three mechanisms are

Acute respiratory failure (ARF) may be life-

threatening in clinical presentation, arterial

Respiratory failure

Lung failure

Pump failure

Key points

N Respiratory failure is failure of one or

Gas exchange

Ventilatory

both of the respiratory system’s gas

failure

exchange functions.

manifested by

hypoxaemia

hypercapnia

N It is diagnosed by arterial blood gas

assessment.

N The clinical presentations of acute,

Figure 1. Types of respiratory failure. The

chronic and acute-on-chronic

respiratory system can be considered as consisting

respiratory failure can differ greatly.

of two parts: the lung and the pump. Reproduced

and modified from Roussos et al. (2003).

162

ERS Handbook: Respiratory Medicine

characterised by a widening of the alveolar-

of the respiratory muscles, and/or

arterial gradient.

adaptation of central controllers in order to

prevent respiratory muscle injury and avoid

Abnormal desaturation of systemic venous

or postpone fatigue (table 2). Hypercapnic

blood in the face of extensive lung disease is

respiratory failure may occur either acutely,

an important mechanism of hypoxaemia.

insidiously or acutely upon a chronic carbon

dioxide retention. In all of these conditions,

Several non-COPD diseases may lead to

hypoxaemic ARF, which is defined as a PaO₂/

the pathophysiological common mechanism

inspiratory oxygen fraction (FIO₂) ratio

f300 (table 1).

Table 2. Causes of acute hypercapnia

Hypoxaemia is treated with an increase in

Decreased central drive

FIO₂ (the lower the V9/Q9, the less the effect)

Drugs

and by recruiting airspaces with assisted

ventilation. Airspace de-recruitment occurs

CNS diseases

when the transpulmonary pressure falls

Altered neural and neuromuscular

below the airspace collapsing or closing

transmission

pressure, and when the transpulmonary

Spinal cord trauma

pressure applied during inspiration fails to

exceed the airspace opening pressure.

Myelitis

Accordingly, airspace opening can be

Tetanus

facilitated by increasing the transpulmonary

ALS

pressure applied at the end of expiration

(CPAP or positive end-expiratory pressure

Poliomyelitis

(PEEP)) and at the end of inspiration

Guillain-Barré syndrome

(inspiratory positive airway pressure).

Myasthenia gravis

Failure of the pump (e.g. neuromuscular

Organophosphate poisoning

diseases or opiate overdose) results in

Botulism

alveolar hypoventilation and hypercapnia

Muscle abnormalities

with parallel hypoxaemia (type II respiratory

failure).

Muscular dystrophies

Disuse atrophy

In some diseases (e.g. COPD and

Prematurity

cardiogenic pulmonary oedema), both

Chest wall and pleural abnormalities

conditions may coexist, hypoxaemia usually

appearing first.

Acute hyperinflation

Chest wall trauma

Hypercapnic respiratory failure may be the

Lung and airway diseases

result of CNS depression, functional or

mechanical defects of the chest wall, an

Acute asthma

imbalance of energy demands and supplies

AECOPD

Cardiogenic and noncardiogenic oedema

Table 1. The most common causes of hypoxaemic ARF

Pneumonia

Cardiogenic pulmonary oedema

Upper airway obstruction

ARDS and ALI

Bronchiectasis

Alveolar haemorrhage

Other causes

Lobar pneumonia

Sepsis

Atelectasis

Circulatory shock

ALI: acute lung injury.

ALS: amyotrophic lateral sclerosis.

ERS Handbook: Respiratory Medicine

163

Airway infection

Raw and ELdyn

ttot, tI and te

Expiratory flow limitation

Hyperinflation

Work of breathing

PEEPi

O₂ cost of breathing

Effectiveness of

Respiratory muscle

respiratory muscles

fatigue

Control of breathing

Mechanics

Figure 2. Schematic representation of the sequence of responsible mechanisms that lead to acute-on-

chronic respiratory failure in COPD patients. ttot: total respiratory cycle time; tI: inspiratory time; te:

expiratory time; Raw: airway resistance; ELdyn: dynamic elastance of the lung; PEEPi: intrinsic PEEP.

Reproduced and modified from Roussos et al. (2003).

is reduced alveolar ventilation for a given

state, and the subsequent physiological

value of carbon dioxide production.

reserve. Worsening of V9/Q9 mismatching is

probably the leading mechanism in the

Acute exacerbations of COPD (AECOPD) are

occurrence of the hypoxaemia by the

periods of acute worsening that greatly affect

enlargement of physiological dead space and

the health status of patients, with an increase

the rise of wasted ventilation. The increase in

in hospital admission and mortality.

airway resistance and the need for a higher V9E

Estimates of in-patient mortality range from

may result in expiratory flow limitation,

4% to 30% but patients admitted due to ARF

dynamic hyperinflation and related intrinsic

experience a higher rate, in particular elderly

PEEP with subsequent increased inspiratory

patients with comorbidities (up to 50%) and

threshold load and dysfunction of the

those requiring intensive care unit admission

respiratory muscles, which may lead to their

(11-26%).

fatigue. A rapid shallow breathing pattern may

ensue in attempting to maintain adequate

Many causes may potentially be involved in

alveolar volume (VA) when these additional

determining ARF during AECOPD, such as

resistive, elastic and inspiratory threshold

bronchial infections, bronchospasm, left

loads are imposed on weakened respiratory

ventricular failure, pneumonia, pneumo-

muscles. Nevertheless, despite increased

thorax and thromboembolism. Acute-on-

stimulation of the respiratory centres and

chronic respiratory failure due to AECOPD is

large negative intrathoracic pressure swings,

characterised by the worsening of

carbon dioxide retention and acidaemia may

hypoxaemia, and a variable degree of

occur. Dyspnoea, right ventricular failure and

hypercapnia and respiratory acidosis. The

encephalopathy characterise severe AECOPD

capacity of the patient to maintain

complicated by ARF. Arterial pH reflects the

acceptable indices of gas exchange during

acute worsening of VA and, regardless of the

an AECOPD or the development of ARF

chronic PaCO₂ level, it represents the best

depends both on the severity of the

marker of the ARF severity. Figure 2 shows a

precipitating cause and on the degree of

schematic representation of the sequence

physiological dysfunction during the stable

of responsible mechanisms that lead to

164

ERS Handbook: Respiratory Medicine

acute-on-chronic respiratory failure in COPD

Calverley PMA (2003). Respiratory failure

patients.

in chronic obstructive pulmonary disease.

Eur Respir J; 22: Suppl. 47, 26s-30s.

Besides medical treatment of the underlying

Donaldson GC, et al.

(2006). COPD

disease, oxygen supplementation and,

exacerbations - 1: epidemiology. Thorax;

eventually, ventilator assistance are

61: 164-168.

appropriate therapy for acute-on-chronic

Koutsoukou A, et al. Acute and chronic

respiratory failure. The goal of assisted

respiratory failure: pathophysiology and

mechanics. In: Fein AM, et al., eds.

ventilation (either invasive or noninvasive)

Respiratory

Emergencies.

London,

during AECOPD is to unload the respiratory

Hodder Arnold, 2006; pp. 17-30.

muscles and to reduce carbon dioxide by

Patil SP, et al. (2003). In-hospital mortal-

increasing VA, thereby stabilising arterial pH

ity following acute exacerbations of

until the underlying problem can be reversed.

chronic obstructive pulmonary disease.

Arch Intern Med; 163: 1180-1186.

Further reading

Plant PK, et al. (2003). Chronic obstruc-

tive pulmonary disease - 9: management

Ambrosino N, et al.

(1997). Advanced

of ventilatory failure in COPD. Thorax; 58:

chronic obstructive pulmonary disease.

537-542.

Monaldi Arch Chest Dis; 52: 574-578.

Rossi A, et al. (1995). Intrinsic positive

Ambrosino N, et al. (2008). Noninvasive

end-expiratory pressure (PEEPi). Intensive

positive pressure ventilation in the acute

Care Med; 21: 522-536.

care setting: where are we? Eur Respir J;

Roussos C, et al.

(2003). Respiratory

31: 874-886.

failure. Eur Respir J; 22: Suppl. 47, 3s-14s.

ERS Handbook: Respiratory Medicine

165

NIV in acute respiratory

failure

Anita K. Simonds

NIV is a key management tool in patients

these have not been subject to large

with acute hypercapnic respiratory failure,

randomised controlled trials (RCTs). A more

and meta-analyses confirm it markedly

limited role in hypoxaemic respiratory failure

reduces mortality and morbidity in acidotic

is described here. Levels of evidence to

hypercapnic exacerbations of COPD

support NIV use in acute respiratory failure

(Lightowler et al., 2003; Keenan et al., 2003).

are shown in table 1.

NIV may also be used in other causes of

NIV in acute exacerbations of COPD

acute ventilatory failure, such as neuro-

muscular disease and bronchiectasis, but

NIV reduces endotracheal intubation rate,

and decreases intensive care unit (ICU) and

hospital duration of stay in acute acidotic

Key points

exacerbations of COPD; therefore, it should

be available in all respiratory centres that

admit COPD patients with exacerbations. In

NIV is the gold standard therapy in

a RCT (Plant et al., 2000) carried out on a

acute dyspnoeic COPD patents with a

general respiratory ward NIV halved

pH ,7.35 and PaCO₂ .45 mmHg

(6.0 kPa) and has been shown to

mortality from 20% to 10%, compared with

halve mortality in this situation.

standard COPD care. In patients already

intubated, prompt extubation onto NIV

Patients with an acute exacerbation of

reduces the duration of ventilation and ICU

COPD and pH ,7.30 being treated

stay, and increases survival (tables 2 and 3).

with NIV should be managed in a

This is largely due to the fact that

high-dependency or ICU area as they

endotracheal tube-related nosocomial

are at risk of deterioration and

infections are reduced. Patients are also able

requirement for invasive ventilation.

to eat and drink normally and mobilise

In acute hypoxaemic respiratory

quicker. Most studies show improvements

failure, NIV and entrained oxygen

in arterial blood gases over the first hour of

therapy may be tried initially but if

therapy and fall in carbon dioxide tension

improvement in arterial blood gas

and respiratory rate have been shown to

tensions and dyspnoea do not occur

predict the success of therapy. Dyspnoea

rapidly, urgent consideration should

may decrease more rapidly with NIV than

be given to progression to invasive

with conventional therapy (Bott et al., 1993).

ventilation.

Indications NIV should be used in

A combination of NIV and cough

tachypnoeic, dyspnoeic acute COPD

assistance with insufflation-

patients with a pH ,7.35 and PaCO₂

exsufflation may be helpful in

.45 mmHg (6.0 kPa). In severe acidotic

neuromuscular patients with acute

exacerbations (pH ,7.30), the risk of NIV

chest infection and reduced cough

failure and need for intubation is higher but,

efficacy.

providing patients are carefully monitored,

NIV in a high-dependency unit or ICU may

166

ERS Handbook: Respiratory Medicine

fit is important as this helps encourage

Table 1. Levels of evidence for use of NIV in acute

adherence to therapy. Before initiating NIV,

respiratory failure

advance planning should take place to clarify

Strong evidence (level A)

whether progression to endotracheal

Acute exacerbations of COPD

intubation is indicated and in accordance

To facilitate weaning of COPD

with the patient’s wishes and best interests,

in the event of NIV failure. An ERS Task

Acute cardiogenic pulmonary oedema

Force survey (Nava et al., 2007) showed that

(cf. CPAP)

NIV was the ceiling of care in 31% of

Immunocompromised patients

patients with acute exacerbations of COPD

Reasonable evidence (level B)

admitted to high-dependency units. As

Post-operative respiratory failure

pointed out by Demoule et al. (2004),

survival in patients with NIV as a ceiling of

‘Do not intubate’ patients

care is 50-60% for the episode, but one year

Upper airway obstruction, OSA, obesity,

after admission falls to 30%.

hypoventilation

CF, asthma

NIV in other causes of hypercapnic

respiratory failure

Case series/reports

Restrictive disorders

NIV is used in acute hypercapnic

Acute respiratory distress syndrome

exacerbations of CF and bronchiectasis. It

may be helpful when combined with

intensive physiotherapy and other airway

be tried first, as a failed trial of NIV leading

clearance techniques (Demoule et al., 2004)

to endotracheal intubation does not lead to

and, indeed, may allow physiotherapy

higher mortality. Relative contraindications

sessions to be extended when these are

to NIV include mental obtundation due to

carried out in patients simultaneously using

severe hypercapnia, poor cough and bulbar

NIV. In one study (Hodson et al., 1991), NIV

was used to bridge CF patients to

function, upper airway obstruction, multiple

comorbidities, and a very high severity

transplantation.

score.

NIV may also be used to reduce the work of

Practicalities of ventilator settings

breathing and improve arterial blood gas

tensions in patients with respiratory muscle

Bilevel positive pressure devices are most

weakness due to neuromuscular conditions

commonly used together with full face mask

such as Duchenne muscular dystrophy,

to obviate leaks from the mouth. Inspiratory

spinal muscular atrophy, myopathies and

positive airway pressure (IPAP) is set to

motor neurone disease. In these situations,

control PaCO₂ and reduce the work of

if cough peak flow is ,160 L?min^-1,

breathing; expiratory positive airway

augmentation of secretion clearance with

pressure (EPAP) is set to overcome

mechanical insufflation-exsufflation is likely

episodes of upper airway obstruction and

to reduce the risk of intubation.

recruit alveoli. A back-up rate a few breaths

below the patient’s spontaneous breathing

There are no RCTs of NIV in acute

rate is usually chosen. Oxygen therapy

ventilatory failure in patients with obesity

should be entrained into the circuit as

hypoventilation syndrome. However,

proximally as possible to the mask in order

nonrandomised comparisons suggest that

to titrate to the prescribed SaO₂ (e.g. 88-

NIV is more effective than CPAP in patients

92%). ‘Intelligent’ ventilators that add either

with significant hypercapnia and superior to

an assured tidal volume or minute volume

endotracheal intubation in those without

may be helpful in some patients but have

major comorbidity. EPAP should be titrated

not yet been shown to be superior to expert

to control the OSA/hypopnoea component

ventilator set-up. Careful attention to mask

and IPAP to control PaCO₂.

ERS Handbook: Respiratory Medicine

167

Table 2. Meta-analysis of NIV in acute COPD

Outcome

Patients n Relative risk (95% CI)

Number needed to treat (95% CI)

Treatment failure

529

0.51

(0.38-0.67)

(4-7)

Mortality

523

0.41

(0.26-0.64)

(6-13)

Intubation

546

0.42

(0.31-0.59)

(4-7)

Complications

143

0.32

(0.18-0.56)

(2-4)

Reproduced and modified from Lightowler et al. (2003) with permission from the publisher.

NIV in acute hypoxaemic respiratory

introduced, compared with acute lung

failure

injury, where there is no specific therapy.

Acute hypoxaemic respiratory failure (AHRF)

In several RCTs of patients with AHRF of

occurs in a multiplicity of disorders

mixed aetiology, NIV reduced the need for

including pneumonia, acute cardiogenic

intubation, ICU stay and mortality (Wysocki

pulmonary oedema, acute lung injury, acute

et al., 1995; Antonelli et al., 1998). However,

respiratory distress syndrome, and following

results are less clear-cut in pneumonia,

immunosuppression, trauma and noxious

where one study (Confalonieri et al., 1999)

gas inhalation. As the underlying

showed a subgroup of patients with COPD

pathophysiological mechanisms of

and community-acquired pneumonia (CAP)

ventilation-perfusion mismatch, shunt and

experienced less intubation than the

diffusion difficulties differ from

pneumonia group as a whole, and a further

hypoventilation in acute ventilatory failure,

study (Jolliet et al., 2001). suggests that

one can predict that success rates with NIV

those with severe CAP experienced a higher

will be lower. While ventilatory support is

intubation rate and longer ICU stay. In

used to reduce the work of breathing,

highly infectious causes of pneumonia (e.g.

improve PaCO₂ control and recruit alveoli, it

severe acute respiratory syndrome and

also buys time for other definitive therapies

pandemic influenza), special measures are

to take effect. Buying time may be more

required when using NIV. Although NIV is

swiftly effective in, for example, acute

categorised as an aerosol-generating

pulmonary oedema, where diuretic and

procedure by some authorities, recent work

vasodilator therapy may be added, or

(Simonds et al., 2010) suggests it mainly

pneumonia, where antibiotics can be

generates large droplets (.10 mm in

Table 3. Meta-analysis of NIV in acute COPD

Outcome

Patients n

Weighted mean difference (95% CI)

Length of hospital stay days

Trials in ICUs

138

-3.28

(-6.09- -0.67)

Trials in wards

408

-3.20

(-4.51- -1.89)

Total

546

-3.24

(-4.26- -2.06)

Respiratory rate at 1 h

380

-3.08

(-4.26- -1.89)

breaths?min^-1

pH at 1 h

408

0.03

(0.02-0.04)

PaCO₂ at 1 h kPa

408

-0.40

(-0.78- -0.03)

PaO₂ at 1 h kPa

378

0.27

(-0.26-0.79)

Reproduced and modified from Lightowler et al. (2003) with permission from the publisher.

168

ERS Handbook: Respiratory Medicine

diameter). However, special precautions

Confalonieri M, et al.

(1999). Acute

should be taken, including using personal

respiratory failure in patients with severe

protective equipment, a high-efficiency N95

community-acquired pneumonia. A pro-

microbial filter between the mask and

spective randomized evaluation of non-

exhalation valve, low pressures, and close

invasive ventilation. Am J Respir Crit Care

Med; 160: 1585-1591.

attention to mask fit.

Crane SD, et al.

(2004). Randomised

controlled comparison of continuous

In acute cardiogenic pulmonary oedema,

positive airways pressure, bilevel non-

there have been several meta-analyses

invasive ventilation, and standard treat-

(Winck et al., 2006; Masip et al., 2005; Peter

ment in emergency department patients

et al., 2006) and a recent large RCT (Crane

with acute cardiogenic oedema. Emerg

et al., 2004). Results suggest that use of NIV

Med J; 21: 155-161.

and CPAP can reduce breathlessness and

Demoule A, et al. (2006). Increased use

improve arterial blood gas tensions, and in

of noninvasive ventilation in French

the meta-analyses, NIV did reduce

intensive care units. Intensive Care Med;

intubation; however, in the large RCT, which

32: 1747-1755.

contained more patients than were included

Fauroux B, et al.

(2004). Setting of

in the meta-analyses, there was no

noninvasive pressure support in young

difference in mortality at 7 days between

patients with cystic fibrosis. Eur Respir J;

24: 624-630.

oxygen therapy, NIV and CPAP, and no

Hodson ME, et al. (1991). Non-invasive

differences in outcomes when NIV and

mechanical ventilation for cystic fibrosis

CPAP were compared. A consensus is that

patients

- a potential bridge to trans-

medical therapy with nitrates is crucial first-

plantation. Eur Respir J; 4: 524-527.

line treatment, with the addition of CPAP in

Jolliet P, et al. (2001). Non-invasive pressure

those with marked respiratory distress and

support ventilation in severe community-

NIV for those who are hypercapnic due to

acquired pneumonia. Intensive Care Med; 27:

high work of breathing and/or concomitant

812-821.

COPD or neuromuscular disorder.

Keenan SP, et al. (2003). Which patients

with an acute exacerbation of chronic

In all the causes of AHRF discussed here,

obstructive pulmonary disease benefit

NIV with entrained oxygen therapy may be

from noninvasive positive pressure venti-

tried initially but close monitoring is

lation? A systematic review of the litera-

required and, if arterial blood gas tensions

ture. Ann Int Med; 138: 861-870.

Lightowler J, et al. (2003). Non-invasive

and dyspnoea are not relieved within the

positive pressure ventilation to treat

first hour of therapy or the patient’s

respiratory failure resulting from exacer-

condition rapidly deteriorates, progression

bations of chronic obstructive pulmonary

to use of invasive ventilation should be

disease: Cochrane systematic review and

urgently considered.

meta-analysis. BMJ; 326: 185.

Masip J, et al.

(2005). Noninvasive

ventilation in acute cardiogenic pulmon-

Further reading

ary edema: systematic review and meta-

Antonelli M, et al. (1998). A comparison

analysis. JAMA; 294: 3124-3130.

of noninvasive positive-pressure ventila-

Nava S, et al. (2007). End of life decision-

tion and conventional mechanical ventila-

making in respiratory intermediate care units:

tion in patients with acute respiratory

a European survey. Eur Respir J; 30: 156-164.

failure. N Engl J Med; 339: 429-435.

Peter JV, et al.

(2006). Effect of non-

Bott J, et al.

(1993). Randomised con-

invasive positive pressure ventilation

trolled trial of nasal ventilation in acute

(NIPPV) on mortality on patients with

ventilatory failure due to chronic obstruc-

acute cardiogenic pulmonary oedema: a

tive airways disease. Lancet; 341: 1555-1557.

meta-analysis. Lancet; 367: 1155-1163.

ERS Handbook: Respiratory Medicine

169

Plant PK, et al.

(2000). Early use of

other airborne infections. Health Tech

noninvasive ventilation for acute exacer-

Assess; 14: 131-172.

bations of chronic obstructive pulmonary

Winck JC, et al.

(2006). Efficacy and

disease on general respiratory wards: a

safety of non-invasive ventilation in the

multicentre randomised controlled trial.

treatment of acute cardiogenic pulmon-

Lancet; 355: 1931-1935.

ary oedema - a systematic review and

Simonds AK, et al. (2010). Evaluation of

meta-analysis. Crit Care; 10: R69.

droplet dispersion during non-invasive

Wysocki M, et al.

(1995). Noninvasive

ventilation, oxygen therapy, nebuliser

pressure support ventilation in patients

treatment and chest physiotherapy in

with acute respiratory failure. A rando-

clinical practice: implications for the

mized comparison with conventional

management of pandemic influenza and

therapy. Chest; 107: 761-768.

170

ERS Handbook: Respiratory Medicine

Acute oxygen therapy

Anita K. Simonds

Acute oxygen therapy

In emergency situations, oxygen therapy can

be delivered by a high-concentration

Acute oxygen therapy is indicated to

reservoir mask at a flow rate of 15 L?min^-1. In

improve oxygen delivery in situations of

hypercapnic patients, 28% and 24% Venturi

cardiac and respiratory arrest, acute severe

masks can be used. All acute patients

hypotension, low cardiac output states in

require regular or continuous assessment by

the presence of metabolic acidosis and

oximetry to ensure hypoxaemia has been

when SaO₂ is ,90%. In respiratory

corrected and the dose is still appropriate.

conditions, oxygen therapy is prescribed to

Blood gas measurements are indicated if

correct hypoxaemia, rather than to reduce

there is deterioration in SaO₂, features of

breathlessness, and so should always be

carbon dioxide retention, such as

titrated to SaO₂ or blood gas measurements.

drowsiness or flap, metabolic conditions, or

In acutely ill patients, high-concentration

low cardiac output state.

oxygen therapy should be prescribed to

correct SaO₂ to 94-98%. In those with

Long-term oxygen therapy

hypercapnic respiratory failure or at risk of

Chronic hypoxaemia occurs either due to

ventilatory decompensation (e.g. severe

ventilation-perfusion mismatch, alveolar

COPD, neuromuscular disease, obesity

hypoventilation or diffusion problems in

hypoventilation syndrome and chest wall

chronic lung disease; in some conditions

disorders), a target SaO₂ of 88-92% should

(e.g. COPD), all factors may be present.

be the aim. If this cannot be achieved

Long-term oxygen therapy (LTOT) is used to

without progressive acidosis and

correct hypoxaemia diurnally and

hypercapnia, ventilatory support should be

nocturnally in the majority of patients. In

added. Indeed, in acute hypercapnic

COPD, LTOT increases survival, reduces

ventilatory failure, ventilatory support is

usually the treatment of choice.

polycythaemia and, in some patients, may

improve sleep quality and/or neuro-

psychiatric symptoms. In individuals with

Key points

chronic ventilatory failure due, for example,

N Oxygen therapy is prescribed to

Table 1. Assessment for LTOT

correct hypoxaemia and should thus

Consider assessment in

be titrated to SaO₂.

All patients with FEV1 ,30% predicted

N In acutely hypoxaemic patients,

oxygen should be delivered to correct

Patients with cyanosis

SaO₂ to 94-98%.

Patients with polycythaemia

N In those with hypercapnic respiratory

Patients with peripheral oedema

failure or at risk of ventilatory

Patients with raised jugular venous

decompensation, a target of SaO₂ of

pressure

88-92% should be the aim.

Patients with SaO₂ on air f92%

ERS Handbook: Respiratory Medicine

171

Table 2. Criteria for LTOT in steady-state patients

Chronic hypoxaemia (PaO₂ ,7.3 kPa on air)

PaO2 ,8.0 kPa on air in addition to pulmonary hypertension, secondary polycythaemia, right

heart failure or nocturnal desaturation

to chest wall disease, first-line treatment is

short-burst oxygen therapy in COPD but it

assisted ventilation (e.g. NIV).

may be prescribed to palliate symptoms in

end-stage disease. The evidence to support

Patients should be assessed for LTOT in the

the use of short-burst oxygen in advanced

presence of the features shown in table 1.

cancer is minimal but it may be helpful in

some individuals as part of a comprehensive

LTOT is prescribed for .15 h a day, e.g. via

supportive care plan.

concentrator, to correct SaO₂ to o90% in

those patients listed in table 2.

Oxygen delivery systems

Ambulatory oxygen therapy is added to

correct hypoxaemia on exercise. In sedentary

patients using LTOT, ambulatory oxygen is

Oxygen can be delivered by oxygen

usually prescribed at the same flow rate as

cylinder, concentrator or liquid oxygen

in daytime use. In active and mobile LTOT

device. LTOT is more cost effectively

recipients and patients who desaturate on

delivered in the home by a concentrator.

exertion but do not fulfil criteria for LTOT,

The advantages and disadvantages of the

optimum flow rates can be derived from a

different systems are shown in table 3.

standard 6-min or shuttle walk, aiming to

LTOT patients should be regularly

correct SaO₂ to .90%, reduce dyspnoea and

assessed (at least once a year) to check the

increase exercise tolerance. There is no

suitability of flow rates, adherence to

evidence to support the routine use of

therapy and safety.

Table 3. Comparison of oxygen delivery devices

Delivery system

Advantages

Disadvantages

Compressed oxygen cylinder

Easily available

Frequent refills required

No power required

High long-term cost

Economical in the short term

Fire risk

Home concentrator

Permanent source

Power required

No need for refills

Needs servicing and spare

Economical in the long term

parts

Liquid oxygen

Small and portable

Refills required

No need for power

High cost

Not widely available

Portable concentrator

Small and portable

High cost

No need for refills

Limited battery life

Can be powered by car battery

Cannot deliver high flow

Pulsed or demand flow, so

unsuitable for use during sleep

FIO2 during pulsed flow will

vary according to pulse

duration, trigger sensitivity

and oxygen concentration

delivered

172

ERS Handbook: Respiratory Medicine

Entrainment of oxygen therapy into NIV

British Thoracic Society Working Group

and CPAP circuits

on Home Oxygen Services. Clinical

component for home oxygen service

In patients receiving acute or long-term

in England and Wales. London, British

therapy with NIV or CPAP, additional oxygen

Thoracic Society, 2006.

therapy may be required to correct SaO₂.

Medical Research Council Working Party

Oxygen can be entrained into the circuit via

(1981). Long term domiciliary oxygen

a T-piece or through the mask. It is

therapy in chronic hypoxic cor pulmonale

important to note that the more proximal

complicating chronic bronchitis and

the entrainment (e.g. ventilator side of

emphysema. Lancet; 1: 681-685.

exhalation port), the greater the inspiratory

Nocturnal Oxygen Therapy Trial Group

oxygen fraction (FIO₂) achieved. In addition,

(1980). Continuous or nocturnal oxygen

FIO₂ is likely to be lower than that achieved

therapy in hypoxaemic chronic obstruc-

by delivering a similar oxygen flow rate

tive lung disease, a clinical trial. Ann

without NIV/CPAP and difficult to predict

Intern Med; 93: 391-398.

accurately, as increases in inspiratory

Thys F, et al.

(2002). Determinant of

FI,O₂

with oxygen supplementation

positive airway pressure may reduce FIO₂.

during noninvasive two-level positive

pressure ventilation. Eur Respir J;

19:

Further reading

653-657.

O’Driscoll BR, et al.

(2008). British

British Thoracic Society. Emergency

Thoracic Society Guideline for emergency

Oxygen. www.brit-thoracic.org.uk/Clinical

oxygen use in adult patients. Thorax; 63:

Information/EmergencyOxygen/tabid/219/

Suppl. 6, vi1-vi68.

Default.aspx

ERS Handbook: Respiratory Medicine

173

Assessment for anaesthesia/

surgery

Macé M. Schuurmans, Chris T. Bolliger^{ and Annette Boehler

Pre-operative assessment of pulmonary risk

is important in order to identify patients at

Key points

risk for peri-operative morbidity and

mortality, to determine possible pre-

N A careful history and physical

operative interventions that are beneficial

examination is necessary to assess

for outcome and to identify patients where

the risk of post-operative pulmonary

surgery may be prohibitive.

complications

N Pulmonary function testing is not

Pre-operative evaluation for lung resection

routine except in the case of

evaluates to what extent lung tissue can

evaluation for lung resection

be resected without unacceptably

increasing post-operative morbidity and

N A number of strategies are available to

mortality.

reduce the risk of complications

A careful history and physical examination

are the most important tools for

Probable risk factors include:

assessment of risk for post-operative

pulmonary complications. Symptoms

N OSA

suggesting occult underlying lung disease

N general anaesthesia (when compared

(exercise intolerance, unexplained

with spinal or epidural anaesthesia)

dyspnoea and cough) and the following risk

N pulmonary hypertension

factors for increased post-operative

N abnormal chest radiograph

pulmonary complications need to be

N cigarette use within previous 8 weeks

assessed.

N current upper respiratory tract infection

Surgery-specific risk factors include:

It is noteworthy that pulmonary function tests

are not part of routine pre-operative

N upper abdominal procedures

assessment unless patients are being

N aortic, thoracic, and head and neck

evaluated for lung resection (see later).

surgery, including neurosurgery

Pulmonary function tests should also be

N surgery lasting .3 h

performed in patients with unexplained

N emergency procedures

dyspnoea or exercise intolerance, and when

Definite risk factors include:

clinical evaluation cannot determine whether

airflow obstruction has been optimally

N COPD

reduced in patients with previously diagnosed

N CHF

COPD or asthma. Well-controlled asthma

N diminished general health status

(free of wheezing, and peak flows .80% of the

(American Society of Anesthesiologists

predicted value or the patient’s personal best)

(ASA) class o2 (table 1))

has been shown not to carry any added risk.

N malnutrition (serum albumin ,35 mg?L^-1)

Age and blood gases have no definitive role in

N use of pancuronium as a neuromuscular

the risk assessment when confounding issues

blocker

such as comorbidities have been considered.

174

ERS Handbook: Respiratory Medicine

Table 1. ASA classification of pre-operative risk

ASA

Systemic disturbance

PPC % Mortality %

class

Healthy patient with no disease outside of the surgical

1.2

,0.03

process

Mild-to-moderate systemic disease caused by the surgical

5.4

0.2

condition or by other pathological processes, medically well

controlled

Severe disease process that limits activity but is not

11.4

1.2

incapacitating

Severe incapacitating disease process that is constant threat

10.9

to life

Moribund patient not expected to survive 24 h with or

without an operation

Suffix to indicate emergency surgery for any class

Increased Increased

PPC: post-operative pulmonary complications; NA: not applicable. Reproduced and modified from

Koegelenberg et al. (2008) with permission from the publisher.

Patients with high risk (surgery-specific risk

Post-operative interventions:

factor plus one or more definite risk factors)

will benefit from the following strategies to

N deep-breathing exercises or incentive

reduce pulmonary complications.

spirometry

epidural analgesia instead of parenteral

Pre-operative interventions:

opioids, selective use of nasogastric tube

if post-operative nausea or vomiting,

N smoking cessation for 8 weeks

inability to tolerate oral intake, or

N inhaled ipratropium or tiotropium for

symptomatic abdominal distension

patients with clinically significant COPD

Cardiac evaluation:

N inhaled b-agonists for symptomatic

COPD and asthma patients

N history, physical examination and resting

N pre-operative systemic glucocorticoids for

ECG are frequently required for the initial

COPD and asthma patients who are not

estimate of the peri-operative cardiac risk

optimised on inhalative treatment

N the inability to climb two flights of stairs

N delay elective surgery if respiratory

or run a short distance indicates poor

infection present

functional capacity and is associated with

N antibiotics for patients with purulent

an increased incidence of postoperative

sputum or change in sputum character

cardiac events

N inspiratory muscle training

N the definitive assessment of cardiac risk

Intraoperative interventions:

should respect current guidelines for

cardiologists

N choose alternative procedure lasting ,3 h

Pulmonary resection

when possible (video-assisted

thoracoscopic and laparoscopic

Pulmonary resection is a high-risk procedure

procedures have ,1/10th the pulmonary

with a mortality of 2-3% for lobectomy and

complication rates of open procedures)

4-6% for pneumonectomy in experienced

N minimise duration of anaesthesia

centres. Clinical evaluation should focus on

N regional anaesthesia (nerve block) in very

respiratory and cardiovascular pathology. Air

high-risk patients

flow limitation should be optimised before

N avoid pancuronium

further evaluation, and cardiac disease

ERS Handbook: Respiratory Medicine

175

identified and managed either medically or

Cardiac

surgically. Initial pulmonary function

assessment:

FEV1

Both

low risk or

TLCO

>80% pred

evaluation should include at least FEV1, FVC

treated patient

and TLCO. Values .80% predicted for FEV1

Either one <80% pred

and TLCO are associated with an

uncomplicated surgical course for resection

<35% pred or

>75% pred or

Exercise testing

up to a pneumonectomy. All other candidates

<10 mL·kg-1

>20 mL·kg-1

·min-1

V'O

2max

·min-1

should undergo a formal exercise test.

35-75% pred or

Patients with a maximal oxygen uptake

10-20 mL·kg-1·min-1

(V9O₂max) .20 mL?kg^-1?min^-1 (or .75% pred)

tolerate pulmonary resection up to a

Split function

Both

pneumonectomy, and values

ppoFEV1

>30% pred

ppoTLCO

.15 mL?kg^-1?min^-1 are sufficient for lobectomy.

Values ,10 mL?kg^-1?min^-1 are predictive of

At least one <30% pred

major post-operative complications and

<35% pred or

disability. Further evaluation according to a

<10 mL·kg-1

ppoV'O

2max

validated algorithm (fig. 1) necessitates the

·min-1

>35% pred or

estimation of the relative contribution of the

>10 mL·kg-1·min-1

tissue earmarked for resection by means of

the predicted post-operative (ppo) values of

Lobectomy or

Resection up to

Resection

pneumonectomy

FEV1, TLCO and V9O₂max (‘split function’). The

calculated

up to

are usually not

extent

pneumonectomy

ppo values of these parameters are equal to

recommended

consider other

their pre-operative values6(1-fractional

options

contribution of the tissue earmarked for

resection). There are three acceptable ways of

Figure 1. Algorithm for assessment of

estimating the relative functional contribution

cardiopulmonary reserve before lung resection in

or split lung function:

lung cancer patients. Reproduced and modified

anatomical calculation

from Brunelli et al. (2009).

quantitative CT

split perfusion scanning

as most lung resection candidates invariably

have a pre-operative chest CT and modern

Anatomical calculations are by far the

software simplifies the three-dimensional

simplest: the number of patent (or

reconstruction for the calculation of the

functional) segments that are due for

relative volume of lung to be resected.

resection is subtracted from the total

number of segments (19) and this value is

Simple stair climbing as a low-cost alternative

divided by 19 to give a fraction. The ppoFEV1

to assess exercise capacity and operative risk is

is estimated to be equal to the pre-operative

increasingly being used. A number of recent

FEV16((19-patent segments removed)/19).

studies have shown that the ability to climb an

Anatomical calculations have been shown to

elevation .22 m is correlated with a favourable

overestimate the functional loss so that

surgical outcome for lung resection surgery.

patients who are deemed operable by

Patients unable to reach this elevation then

anatomical calculations will generally not

require more sophisticated ergometric

require radiological calculations.

evaluation. Adding a time component to the

Calculated ppo values based on lung

evaluation of the stair climbing test appears to

perfusion scans (with technetium-99m-

quantify the overall exercise performance more

labelled macroaggregates) have been shown

precisely: data from one recent study assessing

to correlate best with actual post-operative

additionally speed of ascent during stair

values. Densitometric calculations on the

climbing showed that patients reaching or

basis of CT are marginally less accurate than

passing the 20-m elevation mark within 80 s all

perfusion scans. The advantage of this

had formal exercise tests permitting resection

method is the availability of the information,

up to the extent of a pneumonectomy.

176

ERS Handbook: Respiratory Medicine

Lung volume reduction surgery for end-

tomography, scintigraphy, and anatomy.

stage emphysema has partly redefined the

Respiration; 69: 482-489.

limits of lung resection. Traditional cut-off

Brunelli A, et al. (2009). ERS/ESTS clinical

limits are too prohibitive for these

guidelines on fitness or radical therapy in

patients, as resection of largely

lung cancer patients (surgery and che-

nonfunctional emphysematous tissue

moradiotherapy). Eur Respir J; 34: 17-41.

leads to improved lung mechanics,

Koegelenberg CFN, et al. Preoperative

improving the overall outcome. The latter

pulmonary evaluation. In: Abert RK et al.,

is also partly true for moderate-to-severe

eds. Clinical Respiratory Medicine.

3rd

COPD patients undergoing surgery for

Edn. Philadelphia, Elsevier, 2008.

Puente-Maestú L, et al. (2011). Early and

lung cancer. Patients with either ppoFEV1

long-term validation of an algorithm

or ppoTLCO ,40% pred, or both

assessing fitness for surgery in patients

parameters between 30% and 40% pred

with postoperative FEV1

and diffusing

can undergo extensive resections such as

capacity of the lung for carbon monoxide

lobectomy or even pneumonec-

, 40%. Chest; 139: 1430-1438.

tomy with reasonable safety (mortality of

Salati M, et al.

(2012). Preoperative

13.5%) if they have a ppoV9O₂max of

assessment of patients for lung cancer

.10 mL?kg^-1?min^-1. Survival following this

surgery. Curr Opin Pulm Med;

18:

strategy appears to be superior than for the

289-294.

nonsurgical strategy.

Task Force for Preoperative Cardiac Risk

Assessment and Perioperative Cardiac

Management in Non-cardiac Surgery,

Further reading

et al. (2009). Guidelines for pre-operative

Bernasconi M, et al.

(2012). Speed of

cardiac risk assessment and perio-

ascent during stair climbing identifies

perative cardiac management in non-

operable lung resection candidates.

cardiac surgery. Eur Heart J; 30: 2769-

Respiration; 84: 117-122.

2812.

Bolliger CT, et al. (2002). Prediction of fun-

von Groote-Bidlingmaier F, et al. (2011).

ctional reserves after lung resection: com-

Functional evaluation before lung resec-

parison between quantitative computed

tion. Clin Chest Med; 32: 773-782.

ERS Handbook: Respiratory Medicine

177

Long-term ventilation

Anita K. Simonds

Definition and prevalence

Pathophysiology

Long-term ventilation (LTV) is a term usually

Chronic ventilatory decompensation occurs

used to describe individuals using either NIV

when the load placed on the respiratory

or tracheostomy-delivered ventilation for

system outstrips its capacity. This occurs in

.3 months on a daily basis in the user’s

restrictive disorders, such as chest wall and

home or a long-term care facility. Lloyd-Owen

neuromuscular disease, and in chronic lung

et al. (2005) showed a prevalence rate of 6.6

diseases, such as COPD, CF and

per 100 000 of the population in Europe

bronchiectasis. Disorders of ventilatory drive

receiving LTV but there were widely varying

are less common but LTV is required in

practices ranging from a prevalence rate of 17

patients with congenital central

per 100 000 in France to ,1 per 100 000 in

hypoventilation syndrome (CCHS) or other

Poland. Rates in Denmark, Germany, Spain,

acquired causes of failure of ventilatory drive,

the UK and Italy were 9.6, 6.5, 4.1 and 3.9 per

such as brain stem cerebrovascular or cervical

spinal cord injury events. The clinical course in

100 000 respectively. Numbers will have

many patients is punctuated by episodes of

grown since 2005, but these data exclude

acute-on-chronic ventilator failure precipitated

OSA patients using CPAP. There was also a

by chest infections (e.g. COPD and CF). In

north-south divide with more

others, there is a clear-cut vicious cycle of

neuromuscular and chest wall patients

decline. For example, in chest wall or

receiving LTV in northern Europe and more

neuromuscular disease, small lung volumes

chronic lung disease patients using LTV in

lead to initially nocturnal hypoventilation and,

southern Europe. As the prevalence of these

ultimately, diurnal ventilatory failure if sleep-

conditions does not vary substantially,

disordered breathing is not addressed.

differences in the pattern of LTV are likely to

be historical rather than evidence based.

Types of LTV

The greatest growth in LTV over the last two

Key points

decades has been in the use of home NIV.

This is virtually all mask ventilation or via

N LTV is defined by the requirement for

oral/nasal interface, as very few patients

daily ventilatory support for .3 months.

receive domiciliary negative pressure

The majority of LTV recipients use

ventilation (e.g. via cuirass or iron lung). The

NIV via pressure pre-set ventilators.

indications for tracheostomy ventilation are

bulbar weakness leading to aspiration, near

N NIV should be started for sympto-

24-h ventilator dependence, upper airway

matic nocturnal hypoventilation or

lesions, difficulties with NIV, neonatal age

daytime hypercapnia in restrictive

range and patient preference.

disorders.

Ventilators

N NIV extends survival in MND/

amyotrophic lateral sclerosis patients.

A survey of LTV in Europe (Lloyd-Owen

et al., 2005) showed nearly all patients

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ERS Handbook: Respiratory Medicine

were using positive pressure ventilators

inner tube can be removed for cleaning,

(mostly in pressure support mode) with

which can be helpful in weaning patients,

,1% using volume ventilators. Dual-mode

but long-term use without the inner tube can

ventilators are obtainable but, perhaps not

be complicated by granuloma formation. In

surprisingly, volume ventilators were most

any patient with a long-term tracheostomy,

commonly used in neuromuscular and chest

correct size and placement, and regular

wall patients, and least frequently used in

inspection and bronchoscopy are

those with lung disease (COPD/

recommended as follow-up.

bronchiectasis). The choice of ventilatory

Chest wall disorders

mode and settings should match the

underlying pathophysiology and be carefully

This group includes patients with scoliosis,

titrated to the patient. Further

old tuberculous lung disease, thoracoplasty

considerations include the age and size of

and chest wall fibrosis. Patients with

the patient, degree of ventilator dependency,

scoliosis at high risk of ventilatory

and need for oxygen therapy. Humidification

decompensation are shown in table 1.

is required for nearly all tracheostomy

patients and is indicated in some patients

Neuromuscular disease

using long-term NIV (e.g. those with

Neuromuscular disorders can be grouped

recurrent or viscid secretions).

into those in which the underlying condition

The ventilator care plan should adapt to the

is relatively static (e.g. previous poliomyelitis

patient, as patients with progressive

and phrenic nerve injury due to brachial

disorders will become more ventilator

neuralgia), those that are slowly progressive

dependent over time and require ventilatory

(e.g. Duchenne muscular dystrophy (DMD)

support during the day, and/or progress

and other myopathies) and those that are

from NIV to tracheostomy ventilation if

rapidly progressive (e.g. motor neurone

bulbar function worsens; and in children,

disease and amyotrophic lateral sclerosis).

total ventilatory requirements will change

Management plans should therefore take

with growth.

into account the natural history of the

condition as well as current ventilator needs.

Tracheostomy

Most neuromuscular patients have normal

The choice of tracheostomy tube or cannula

lungs apart from occasional atelectasis, so

is dictated by:

they are relatively easy to ventilate with low

pressures; back-up rates are usually required

N need for mechanical ventilation

due to profound hypoventilation during

N ability of the patient to defend the lower

REM (rapid eye movement) sleep. Careful

airway (adequate cough and bulbar

consideration of the interface is required as

function)

individuals may not be able to affix a mask

N temporary or permanent placement

easily due to weak muscles of the upper

N neck size and anatomy of the patient

The aim is to protect the airway and

Table 1. Risk factors for ventilatory decompensation in

optimise ventilation while preserving speech

scoliosis

and swallowing function, and minimising

complications related to the tracheostomy

Congenital or early-onset scoliosis

tube such as sputum plugging, tracheal

Thoracic curve .100u

stenosis and pressure necrosis resulting in

Curve involves high thoracic and cervical

haemorrhage. Cuffed tracheostomy tubes

vertebrae

may reduce aspiration risk in adults but cuff

pressure should be monitored so that it

Paralytic aetiology e.g. due to

neuromuscular weakness

does not exceed 25 mmHg. Fenestrated

tubes have a window in the posterior curved

Vital capacity ,50% predicted

region and a removable inner tube. The

Comorbidity e.g. COPD, morbid obesity

fenestration aids voice production and the

ERS Handbook: Respiratory Medicine

179

limb, and mid-facial hypoplasia may occur in

may be able to augment spontaneous vital

children and young patients who start NIV

capacity by glossopharyngeal ‘frog’

before facial skeletal growth is complete.

breathing. Phrenic nerve pacing has a role in

Near-100% 5-year survival has been reported

high spinal cord injury patients and central

in previous polio patients receiving NIV. In

hypoventilation syndromes, but may need to

DMD patients, the use of NIV has extended

be supplemented with other forms of

median survival from 18 to 29 years (Eagle

ventilatory support and can only be effective

et al., 2002; Simonds, 2006) and many

if phrenic nerve integrity is maintained.

young males with DMD are now surviving

Central hypoventilation

into their 30s and 40s.

CCHS affects ,1 in 200 000 and is due to

In severe conditions such as Type 1 spinal

mutations in the PHOX2B gene. More

muscular atrophy, where survival is poor,

severe cases experience life-threatening

NIV may be used with the goal of palliating

episodes of apnoea or hypoventilation in the

symptoms and allowing home discharge,

first months of life, complicated by other

rather than extending life expectancy.

features of autonomic dysregulation such as

Bourke et al. (2006) showed in a

cardiac arrhythmias or Hirschsprung’s

randomised trial of NIV in motor neurone

disease. In early infancy, use of ventilation

disease (MND) (amyotrophic lateral

via tracheostomy is recommended to

sclerosis) that overall survival increased by

optimise oxygenation and cognitive

,7 months. This improvement was

function. Transition to NIV may be possible

predominantly seen in patients with mild-to-

later in childhood. Diaphragm pacing has

moderate bulbar weakness and quality of life

been used in some CCHS children but often

improvements were mainly seen in this

has to be combined with invasive ventilation

group too. However, sleep-related

or NIV. Other genetic syndromes associated

symptoms improved, even in patients with

with hypoventilation include Arnold-Chiari

severe bulbar disease. Although it is often

malformation and inborn errors of

reported that NIV cannot be used in MND

metabolism such as pyruvate

patients with severe bulbar disease, this

dehydrogenase deficiency.

belief is overplayed, and a trial is

The obesity hypoventilation syndrome is a

recommended in all MND patients who

form of acquired hypoventilation and is

wish to try NIV. Tracheostomy ventilation

defined by daytime PaCO₂ .45 mmHg

may be the only solution to aspiration

(6.0 kPa) in the presence of a BMI

pneumonia but in some bulbar patients, the

.30 kg?m^-2. Obesity hypoventilation

combination of NIV, a cough assist device

patients with mild hypercapnia (PaCO₂

and percutaneous gastrostomy (PEG)

,53 mmHg) with or without OSA may be

feeding works as effectively.

successfully managed with CPAP therapy.

Ventilatory support should be initiated in

More marked hypercapnia, acute acidotic

patients once daytime hypercapnia or

ventilatory decompensation or failure to

symptomatic nocturnal hypoventilation is

control sleep-disordered breathing with

identified.

CPAP are indications for nocturnal NIV

(Veale, 2008).

Spinal cord injury

Chronic obstructive pulmonary disease

Individuals with high spinal cord injury or

bulbar lesions with no independent

Although numerous selected series of

ventilatory capacity and an inability to clear

hypercapnic COPD patients have shown

secretions will usually require tracheostomy

physiological advantages of LTV, there is a

ventilation, but a proportion of quadriplegic

dearth of adequately powered randomised

patients with minimal ventilatory reserve

controlled trials. Several are currently in

may be managed by a combination of NIV

progress. Meanwhile, McEvoy et al. (2009)

and cough assist devices. As in other

randomised 144 COPD patients with FEV1

neuromuscular conditions, some patients

,1.5 L or 50% predicted and stable PaCO₂

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ERS Handbook: Respiratory Medicine

Table 2. Discharge planning for home ventilator patients

Stability and motivation of patient

Competency training of patient, family and carers

Arrangements for servicing and emergency back-up of ventilator equipment, including suction

machines, cough assist devices and oxygen concentrator if required

Supply of disposables e.g. masks, suction catheters, ventilator circuits, filters

Liaison with all members of care team (home and hospital)

Follow-up assessments/appointments planned

Written guides to management of common problems e.g. chest infection

Suitable modifications to home environment

Risk management plan e.g. battery packs to cover power failure, smaller size tracheostomy tube if

difficulties with tube replacement, low and high pressure and disconnection alarms

Anticipatory care plan detailing agreed actions in event of chest infection, hospital admission,

and preferences regarding resuscitation status and intensive care unit admission

.45 mmHg to receive NIV plus long-term

et al., 2008). Fauroux et al. (2008) has also

oxygen therapy (LTOT) or LTOT alone. The

shown stabilisation of lung function in

NIV group had an improvement in survival

younger CF patients treated for 1 year with

using an adjusted Cox model but there were

nocturnal NIV. Use during physiotherapy

no gains in quality of life. It may be that

can also prove beneficial. Effects on survival

particular subgroups of COPD patients -

are less clear, other than in the situation

those with less emphysema and a greater

where NIV is used to ‘bridge’ patients to

degree of nocturnal hypoventilation, and

transplantation.

those with recurrent hypercapnic

Case-control studies of patients with

exacerbations or additional OSA - benefit

bronchiectasis show improvements in

most, but this remains to be seen.

oxygenation compared to LTOT alone and, in

Pragmatically, current indications for LTV in

some groups, the frequency of infective

COPD are chronic symptomatic hyper-

exacerbations may be reduced. Both CF and

capnia, poor tolerance of LTOT leading to

idiopathic bronchiectasis patients experience

worsening carbon dioxide retention and

ventilation/perfusion mismatch and diffusion

recurrent admissions for acute-on-chronic

problems, and so are likely to require a

hypercapnic respiratory failure responding

combination of NIV and LTOT, judged by

to acute NIV.

overnight monitoring of SaO₂ and PaCO₂.

There is a debate on the use of a high-

Discharge planning and follow-up

intensity ventilatory approach in COPD

Planning for discharge in patients receiving

patients (high pressure and controlled

tracheostomy ventilation is necessarily more

ventilation). This has been shown to reduce

complex than in those using NIV. The key

hypercapnia and improve exercise ability

components of a successful discharge plan

(Windisch et al., 2005) but may be less easy

are listed in table 2.

to tolerate than lower pressures for some

patients.

Further reading

CF and bronchiectasis

Bourke SC, et al. (2006). Effects of non-

Nocturnal NIV can reduce symptoms,

invasive ventilation on survival and qual-

including breathlessness, and improve

ity of life in patients with amyotrophic

nocturnal oxygenation, sleep quality, peak

lateral sclerosis: a randomised controlled

exercise level and quality of life in chronically

trial. Lancet Neurol; 5: 140-147.

hypercapnic adult patients with CF (Young

ERS Handbook: Respiratory Medicine

181

Eagle M, et al.

(2002). Survival in

Simonds AK (2006). Recent advances in

Duchenne muscular dystrophy: improve-

respiratory care for neuromuscular dis-

ments in life expectancy since 1967 and

ease. Chest; 130: 1879-1786.

the impact of home nocturnal ventilation.

Veale D (2008). Respiratory complications

Neuromusc Disord; 12: 926-969.

of obesity. Breathe; 4: 210-223.

Fauroux B, et al. (2008). Long-term non-

Windisch W, et al. (2005). Outcome of

invasive ventilation in patients with cystic

patients with stable COPD receiving

fibrosis. Respiration; 72: 168-174.

controlled non-invasive positive pressure

Lloyd-Owen SJ, et al. (2005). Patterns of home

ventilation aimed at maximal reduction of

mechanical use in Europe: results from the

PaCO2. Chest; 128: 657-662.

Eurovent survey. Eur Respir J; 25: 1025-1031.

Young AC, et al.

(2008). Randomised

McEvoy RD, et al. (2009). Nocturnal non-

placebo controlled trial of non-invasive

invasive ventilation in stable COPD: a rando-

ventilation for hypercapnia in cystic

mised controlled trial. Thorax; 64: 561-566.

fibrosis. Thorax; 63: 72-77.

182

ERS Handbook: Respiratory Medicine

Microbiology testing and

interpretation

Magareta Ieven

In primary care, microbiological work-up in

treatment, particularly in the more severely

respiratory infections is primarily meant as

ill or hospitalised patients. Diagnostic

an epidemiological investigation in order to

testing should not lead to delays in initiation

guide future empiric antimicrobial policies.

of therapy, however. Even with extensive

Hardly any study has shown that initial

diagnostic testing, a specific aetiology is

microbiological studies in primary care

usually identified in only half of all patients,

affect the outcome of respiratory infections.

generally at least 1-2 days after the clinical

Therefore, recent guidelines confirm that

diagnosis is made. With the advent of

microbiological tests such as Gram stains

recently developed rapid techniques, such as

and cultures are not recommended as

immunochromatographic, urinary antigen

routine tests in the primary care setting.

and particularly nucleic acid amplification

Nevertheless, an aetiological diagnosis, of

(NAA) tests, that produce results within

both bacteria and viruses and mixtures of

30 min or 4-5 h, microbiological information

these in community-acquired pneumonia

is becoming clinically useful (table 1).

(CAP) or lower respiratory tract infections

Conventional culture techniques

(LRTIs), may be helpful in guiding

Blood culture For the diagnosis of

pneumonia, blood cultures have a very high

Key points

specificity but are positive in only about 10-

20% of untreated cases. In some studies, a

For the aetiological diagnosis of LRTIs:

direct correlation has been found between

the severity of pneumonia (based on the

N Gram stain and culture of sputum are

Fine Severity Index) and blood culture

valuable in hospitalised patients, if of

positivity rate. Two sets of blood cultures

good quality, for the microbiological

diagnosis of LRTI caused by

should be performed in all patients with CAP

Streptococcus pneumoniae or

who require hospitalisation; they should be

Haemophilus influenzae,

obtained as early as possible in the disease

and before any antibiotic treatment is

Urinary antigen detection is a very

started. If blood cultures are positive,

helpful and rapid test for the

Streptococcus pneumoniae is identified in

diagnosis of pneumococcal or

,60% and Haemophilus influenzae in

Legionella infections,

2-13%. Despite their low sensitivity, blood

N Serology is rarely helpful in the

cultures in CAP are considered the gold

management of the individual patient

standard for diagnosis of pneumonia

with LRTI,

because the organisms are recovered from a

normally sterile source. Results may be

N Molecular tests for the detection of

available after 24-48 h.

respiratory viruses and atypical

pathogens in specific patient

Sputum Gram stain and culture The most

populations are desirable.

frequently submitted specimen in cases of LRTI

and, more specifically, in pneumonia is sputum.

ERS Handbook: Respiratory Medicine

183

Table 1. Diagnostic approach for the most common specific agents in LRTIs

Pathogen

Specimen

Rapid tests

Conventional

Comments

tests

Streptococcus

Blood

Blood culture

Positive in 4-18% of cases when

pneumoniae

collected within 4 days

Sputum

Gram

Culture

Only purulent samples

stain

acceptable; can be obtained in

35-40% of patients; informative

if .90% Gram positive,

diplococcic most relevant if

Gram stain is informative

BAL, PSB

Gram

Culture

Quantitative cultures

stain

Pleural

Gram

Culture

Very specific; only considered if

exudates,

stain

less invasive methods

TNA

nondiagnostic

Urine

Antigen

Sensitivity 50-80% of

test

bacteraemic cases; lacks

specificity in children; more

evaluation necessary

Haemophilus

Blood

Blood culture

Less frequently positive than for

influenzae

S. pneumoniae

Respiratory

Gram

Culture

specimens

stain

Legionella spp.

Urine

Antigen

Sensitivity 66-95%

test

Respiratory

NAA

Culture

Culture on appropriate media;

specimens

late results

Serum

IgM and IgG

Acute and convalescent

serology

specimens; retrospective

diagnosis

Chlamydophila

Respiratory

NAA

Culture

Culture on appropriate medium;

pneumoniae,

specimens

low sensitivity

Mycoplasma

pneumoniae

Serum

IgM and IgG

Acute and convalescent

serology

specimens;

lack of sensitivity, specificity;

not appropriate for individual

patient management;

retrospective results

Respiratory

Direct

Virus isolation

Requirement for appropriate

viruses

specimens

antigen

infrastructure; isolation less

tests,

sensitive than NAA

NAA

NAA tests are not generally available yet and are not US Food and Drug Administration approved. BAL:

bronchoalveolar lavage; PSB: protected specimen brush; TNA: transthoracic needle aspiration.

184

ERS Handbook: Respiratory Medicine

To be of value for microbial diagnosis and

The value of sputum cultures in establishing

early guidance of therapy, sputum specimens

a bacterial cause of LRTI depends on how the

must be representative of lower respiratory

specimens are collected and processed. The

secretions and must be interpreted according

reported yield of sputum cultures has varied

to strict criteria by an experienced observer.

widely, from ,20% for outpatients to .90%

The most widely used method to assess

for hospitalised patients. The sputum Gram

acceptability in this regard is based on

stain is valuable in guiding the processing

cytological criteria. The specimen should

and interpretation of sputum cultures.

therefore be screened by microscopic

Sputum culture results are most convincing

examination for the relative number of

when the organism(s) isolated in culture are

polymorphonuclear cells and squamous

compatible with the morphology of the

epithelial cells in a lower power (106) field.

organisms present in the Gram stain. In the

Invalid specimens (o10 squamous epithelial

absence of an informative Gram stain, the

cells and f25 polymorphonuclear cells per

predictive value of sputum culture is very low.

field) should not be examined further. It may

Rapid antigen tests

be difficult to obtain good-quality, purulent

sputum. Many LRTI or pneumonia patients,

Urinary antigen tests The S. pneumoniae

particularly older ones, do not produce

urinary antigen test has been shown to have a

sputum. Satisfactory sputum specimens can

sensitivity of 65-100% and a specificity of

be obtained in 32-55% of patients.

.90% in adult CAP; however, weak positive

results should be interpreted with caution.

Large studies on the diagnostic value of

There is a relationship between the degree of

Gram staining in primary care patients are

S. pneumoniae urinary antigen test positivity

lacking but some hospital-based studies

and the pneumonia severity index. Therefore,

show that in good-quality Gram-stained

the test could be reserved for high-risk

sputum, the presence of a single or a

patients for whom conclusive results of a

preponderant morphotype of bacteria

sputum Gram stain are unavailable.

(o90%) may be diagnostic. This is based

on correspondence with the organisms

The urinary antigen test may also be applied

recovered from blood cultures obtained in

to pleural fluid and serum samples with a

parallel, which are the gold standard. The

sensitivity of 50% in bacteraemic patients

study by Anevlavis et al. (2009) is the first

and 40% in nonbacteraemic patients. In a

reporting information concerning operating

retrospective study, a rapid

characteristics and the diagnostic value of

immunochromatographic test (ICT) was

sputum Gram staining in 1390 patients with

performed on pleural fluid samples from 34

bacteraemic CAP. The sensitivity of sputum

patients with pneumonia due to

Gram stain was 82% for pneumococcal

S. pneumoniae, and a number of control

pneumonia and 79% for H. influenzae

patients with effusions of non-

pneumonia, with specificities ranging from

pneumococcal origin or pneumonia of

93% to 96%. Data from this study suggest

unknown aetiology. Data on blood cultures,

that a properly collected and read Gram

pleural fluid cultures and urinary antigen

stain provides a simple, readily available,

tests were recorded. The ICT result was

rapid and inexpensive test result, and can be

positive in 70.6% with pneumococcal

a dependable test for the early aetiological

pneumonia and negative in 93.3% of

diagnosis of bacterial pneumonia. Sputum

patients without pneumococcal pneumonia.

with a mixed flora in the Gram stain has no

The sensitivity of the pleural ICT is higher

diagnostic value. The sputum Gram stain is

than that obtained for blood and pleural

therefore valuable in guiding the processing

fluid cultures, but lower than the detection

and interpretation of sputum cultures.

of pneumococcal antigen in urine samples.

However, in some patients with

The sensitivity and specificity of sputum

pneumococcal pneumonia and a negative

cultures are reduced by contamination with

urinary antigen test result, a positive pleural

flora colonising the upper respiratory tract.

fluid antigen test was detected. The ICT

ERS Handbook: Respiratory Medicine

185

performed on pleural fluid samples

human bocavirus. Antigens of the many

therefore augments the standard diagnostic

common respiratory viruses - influenza

methods of blood and pleural fluid cultures,

virus, respiratory syncytial virus (RSV),

even in the case of prior antibiotic therapy,

adenovirus and parainfluenza viruses - can

and enhances the urinary antigen assay.

be detected by direct immunofluorescence

Vaccination does not result in a positive

(DIF) or by commercially available EIAs. The

urinary antigen test. The immuno-

sensitivities of these tests vary from 50% to

chromatographic urinary antigen test for S.

.90% depending on the virus, the patient

pneumoniae is therefore useful for the

population studied and the sampling method

aetiological diagnosis of severe CAP,

used. For respiratory infections due to

especially for patients without demon-

viruses, the optimal specimen is the

strative results of a sputum Gram stain.

nasopharyngeal aspirate. Alternatively, oro-

or nasopharyngeal swabs can be obtained. A

Urinary antigen detection is currently the

few studies comparing the respective

most helpful rapid test for the diagnosis of a

efficacies of two structurally different swabs

Legionella pneumophila serogroup 1 infection.

have been performed and conclude that

Although .50 Legionella spp. have been

nylon flocked swabs appear to be more

identified, .90% of the isolates associated

efficient than rayon swabs, yielding

with legionnaires’ disease are L. pneumophila

significantly more total respiratory epithelial

and up to 84% of these are L. pneumophila

cells and more infected respiratory epithelial

serogroup 1. Several test formats have been

cells, which is likely to have a greater effect on

developed, the enzyme immunoassay (EIA)

diagnostic sensitivity both for antigen- and

format being more suited to test a larger

for PCR-based tests. For the detection of

number of specimens and taking a few hours

influenza virus infections, the sensitivity of

to complete. The immunochromatographic

immunofluorescence can be increased by

format is better suited for single specimens

inoculation of appropriate cells with clinical

and produces a result within minutes. These

sample followed by immunofluorescence

tests are particularly useful since culture of

after 48 h. Several common respiratory

Legionella spp. is slow and takes 3-4 days.

viruses can be detected simultaneously by

L. pneumophila serogroup 1 urinary antigen

the use of pooled monoclonal antibodies.

detection is frequently the first positive

The sensitivity and positive predictive value

laboratory test in this infection. The

of the DIF test is lower in adults and older

sensitivity of the tests varies between 65%

people than in children. Rapid methods for

and 70% in unconcentrated urine and

the detection of influenza virus are of

increases significantly after concentration of

particular interest because of the availability

the specimen. In L. pneumophila infection,

of antiviral agents that must be given within

there is also a relationship between the

48 h after onset of symptoms.

degree of positivity of the urinary antigen test

and the severity of disease: for patients with

Serology

mild legionnaires’ disease, test sensitivities

Efforts have been made to diagnose

range from only 40% to 50%, whereas for

infections caused by slowly growing or

patients with severe legionnaires’ disease

difficult-to-grow organisms by serology,

who need immediate special medical care,

particularly Mycoplasma pneumoniae,

sensitivities reach 88-100%.

Chlamydophila pneumoniae, Legionella

Antigen tests on pharyngeal specimens A

infections and respiratory viruses. It should

variety of antigen tests have been evaluated on

be remembered that the most reliable

respiratory specimens. During recent years, a

serologic evidence of an ongoing infection is

considerable number of previously unknown

based on a four-fold increase in the titre of

respiratory viral agents have been discovered

IgG (or IgG and IgM) antibodies during the

whose in vitro culture is very slow or even

evolution of the disease episode based on

unrealised: human metapneumovirus, the

two serum samples collected at an interval

novel coronaviruses NL63 and HKU1, and

of 14-21 days or longer, and/or the

186

ERS Handbook: Respiratory Medicine

appearance of IgM antibodies during the

Legionella antibody tests also have a

evolution of the disease. IgM tests are

sensitivity of only 61-64%, depending on

usually less sensitive and specific than four-

the assay applied, and do not substantially

fold changes in antibody titres between

improve the diagnosis of legionellosis. The

paired specimens separated by several

acute antibody test for Legionella in

weeks. Solitary high IgG titres have no

legionnaires’ disease is usually negative or

diagnostic meaning for an acute infection

demonstrates very low titres. As for other

since the moment of the seroconversion is

aetiologies, high titres of IgG and/or IgM

unknown and necessarily took place

(above a certain threshold), present early

sometime before the illness under

during the disease, have been interpreted as

observation started.

diagnostic, but at least one study showed

that this titre had a very low positive

The sensitivity and specificity of serological

predictive value.

tests are related to the antigen used. For

M. pneumoniae and C. pneumoniae, a great

For respiratory viral infections, such as for

number of antigen preparations have been

influenza and RSV, a significant or four-fold

proposed: whole organisms, protein

IgG antibody increase is detected by EIA in

fractions, glycoprotein fractions and

approximately 80-90% of patients at only

recombinant antigens. Several studies

20-30 days after the onset of disease.

illustrate a lack of standardisation of

The serological measurement of specific

antigens of M. pneumoniae.

antibody responses mostly cannot offer an

For a number of respiratory agents, a variety

early diagnosis and, therefore, has limited

of tests are available commercially. Some

application for an aetiological diagnosis

assays lack both sensitivity and specificity,

and the routine management of the

emphasising the need for more validation

individual patient with LRTI. Consequently,

and quality control.

it is an epidemiological, rather than a

diagnostic, tool.

IgM antibodies against M. pneumoniae

NAA tests

require up to 1 week to reach diagnostic

titres, and sometimes much longer. Anti-

The newest approach in the diagnosis of

M. pneumoniae IgM antibodies can be

respiratory tract infections is the detection

detected in 7-25% (depending on the test

of microbial nucleic acids by NAA tests.

applied) of acute sera and IgG antibodies in

Culture procedures for viruses and

41-63% of convalescent sera (depending on

fastidious bacteria, M. pneumoniae,

the timing of the second sample),

C. pneumoniae, L. pneumophila and

illustrating the low incidence of IgM

Bordetella pertussis, which do not normally

antibodies in the acute-phase serum

colonise the human respiratory tract, are too

specimens and importance of the delay

insensitive and too slow to be

between the two serum samples. Since IgM

therapeutically relevant, and these

detection in the acute phase shows a

pathogens therefore should be detected

moderate sensitivity, provided a specific test

using NAA tests, whose sensitivity is almost

is used, further research is needed to better

always superior to that of the traditional

define the role of IgM serology: a

procedures.

combination of IgM antibody detection and

PCR may be the most sensitive approach for

A multitude of reports has appeared on the

early diagnosis of M. pneumoniae infections,

epidemiology of LRTIs but most are

especially in symptomatic children. It is

restricted to a few viruses (influenza,

critically important for current and future

sometimes together with RSV, and rhino-,

investigators to recognise the urgent need

metapneumo- or coronaviruses) and/or to

for the adoption of a more unified and

some population groups, e.g. children,

consistent diagnostic approach. A common

adults or the elderly. Great variations occur

set of recommendations should be

as a function of time, place and the age-

developed.

groups studied as well as in the diagnostic

ERS Handbook: Respiratory Medicine

187

gold standard test used, varying between

transplantation, in the setting of graft versus

viral culture and serology. Although the role

host disease. The origin of the infections is

of some new viruses is becoming clearer in

community-acquired as well as nosocomial.

specific patient populations, more studies

As more epidemiological information on the

are needed to identify the clinical relevance

role of a panel of respiratory viral pathogens

of some others, such as the bocavirus. All

becomes available, it is clear that screening

these studies were performed with

for these viruses in specific patient

traditional NAA tests that require at least

populations, such as transplant patients,

1-2 days, producing a posteriori results that

very young children or the elderly, is

were unavailable to the clinician in time to

desirable, and preventive and therapeutic

have an impact on patient management.

recommendations may take this information

Real-time multiplex NAA tests offer a

into account.

solution. To cover the wide spectrum of

aetiological respiratory agents, a number of

NAA tests are, however, not required for

uni- and/or multiplex reactions are

every purpose. For cohorting RSV-infected

performed simultaneously. Both in-house

paediatric patients, the DIF tests can be as

and commercially available multiplex NAA

sensitive as an RT-PCR with results available

tests for the simultaneous detection of two,

within 60 min (and at lower cost than with

three or up to 22 different respiratory

NAA tests). Very rapid chromatographic

pathogens, including the ‘atypical’

tests are also available for RSV, which can be

M. pneumoniae, C. pneumoniae and

performed in the laboratory outside virology

L. pneumophila, and respiratory viruses, with

laboratory operating hours. These tests lack

a mixture of primers, have been developed.

sensitivity, however, when applied to

respiratory samples of adult patients.

The combined use of single-target assays or

of multiplex assays has increased the

Conclusion

diagnostic yield in respiratory infections by

In recent years, significant progress has

30-50%: combined with traditional

been made in the microbiological diagnosis

bacteriological techniques to diagnose

of respiratory infections. A straightforward

S. pneumoniae infections, .50% - and in

interpretation of a good-quality, Gram-

some studies of CAP up to 70% - of

stained sputum sample has been

aetiological agents can be detected.

established, and has been shown to be

The wider application of multiplex reactions

important for rapid diagnosis of pneumonia

during recent years has resulted in the

and the interpretation of culture results in

detection of numerous simultaneous viral

severely ill patients.

infections with widely varying incidences:

The number of possible aetiological agents,

from 3% to even 23% or 35%, depending on

viruses and fastidious bacteria has been

whether bacterial agents are also included.

extended, and their epidemiology has been

The divergent incidences may result from

clarified. Sensitive and rapid methods for

the variety of diagnostic panels applied.

their detection have been developed and are

Combined viral and viral-bacterial

increasingly validated in clinical settings.

infections are diagnosed but no preferential

combinations have been found. The clinical

Amplification techniques are, at present,

significance of combined infections remains

more expensive than conventional

to be further clarified. Respiratory viruses

approaches. However, improvements in

have also been increasingly recognised as

standardisation and automation for sample

causes of severe LRTIs in immuno-

preparation and technical advances will lead

compromised hosts. Respiratory infections

to increased use of amplification methods

are more common in solid organ recipients,

and cost reductions to rates competitive

particularly in lung transplant recipients.

with conventional methods. Several studies

Infections are especially dangerous prior to

have tended to show cost efficiency of rapid

engraftment and during the 3 months after

diagnosis of acute respiratory infections

188

ERS Handbook: Respiratory Medicine

resulting from reduced antibiotic use and

Ieven M. (2007). Currently used nucleic

complementary laboratory investigations,

acid amplification tests for the detection

but most significantly from shorter

of viruses and atypicals in acute respira-

hospitalisation and reduced isolation

tory infections. J Clin Virol; 40: 259-276.

periods. Serological diagnosis of those

Ieven M. Diagnosis of community acquired

cases that remain undetected by the NAA

pneumonia. In: Torres A, ed. Community

Acquired Pneumonia. Chichester, John

tests is of no clinical use, as it is available

Wiley and Sons Ltd, 2007; pp. 43-61.

only after many days or even weeks.

Loens K, et al. (2009). Optimal sampling

sites and methods for detection of

Further reading

pathogens possibly causing community-

acquired lower respiratory tract infec-

Anevlavis S, et al. (2009). A prospective

tions. J Clin Microbiol; 47: 21-31.

study of the diagnostic utility of sputum

Loens K, et al. (2003). Molecular diag-

Gram stain in pneumonia. J Infect; 59: 83-

nosis of Mycoplasma pneumoniae in

89.

respiratory tract infections. J Clin

Beersma MF, et al. (2005). Evaluation of

Microbiol; 41: 4915-4923.

12 commercial tests and the complement

Loens K, et al. (2010). Acute respiratory

fixation test for Mycoplasma pneumoniae-

infection due to Mycoplasma pneumoniae:

specific immunoglobulin G

(IgG) and

current status of diagnostic methods. Eur

IgM antibodies, with PCR used as the

J Clin Microbiol Infect Dis; 29: 1055-1069.

‘gold standard’. J Clin Microbiol; 43: 2277-

Mahony JB. (2008). Detection of respira-

2285.

tory viruses by molecular methods. Clin

Genne D, et al. (2006). Enhancing the

Microbiol Rev; 21: 716-741.

etiologic diagnosis of community-

Templeton KE, et al. (2005). Improved

acquired pneumonia in adults using the

diagnosis of the etiology of community-

urinary antigen assay (Binax NOW). Int J

acquired pneumonia with real-time poly-

Infect Dis; 10: 124-128.

merase chain reaction. Clin Infect Dis; 41:

Ieven M, et al. (2012). Should serology be

345-351.

abolished in favour of PCR for the

Woodhead M, et al. (2011). Guidelines for

diagnosis of Mycoplasma pneumoniae

the management of adult lower respira-

infections? Curr Pediatr Rev

2012

[In

tory tract infections. Clin Microbiol Infect;

press].

17: Suppl. 6, E1-E59.

ERS Handbook: Respiratory Medicine

189

Upper respiratory tract

infections

Gernot Rohde

Prevalence

mainly due to overcrowding inside

buildings. The mean frequency is two to four

Upper respiratory tract infections (URTIs)

episodes annually for adults. In children it is

usually occur during the cold months,

higher. Antigenic variation of hundreds of

respiratory viruses allows repeated

circulation in the community.

Key points

Spectrum

URTIs are the most common

The upper respiratory tract comprises the

infectious illness in the general

airways above the vocal cords and consists

population, and are the leading cause

of the nose, paranasal sinuses, pharynx and

of missed work and school.

larynx. The most prevalent illness is the

Most URTIs are viral in origin, and

common cold (rhinosinusitis), followed by

typical agents are rhinoviruses,

sinusitis, pharyngitis/tonsillitis and

coronaviruses, adenoviruses,

laryngitis (table 1).

coxsackieviruses, influenza and

The onset of symptoms usually begins

parainfluenza viruses, human

1-3 days after exposure to a microbial

metapneumovirus, and respiratory

pathogen. The duration of the symptoms is

syncytial virus.

typically 7-10 days but may be longer.

URTIs rarely cause permanent

Transmission and predisposition

sequelae or death but can progress to

otitis media, bronchitis, bronchiolitis,

Transmission of pathogens is by aerosol,

pneumonia, sepsis, meningitis,

droplet or direct hand-to-hand contact. The

intracranial abscess and other

pathogens invade the respiratory epithelium

infections.

of the corresponding area. Sinusitis is often

Diagnosis is usually purely clinical;

preceded by a common cold. There are

diagnostic investigations should only

predisposing conditions such as allergic

be performed in special

rhinoconjunctivitis, nasal septum deviation,

circumstances, such as influenza,

immunodeficiency or cocaine abuse.

group A streptococcal pharyngitis,

Smoking or exposure to second-hand smoke

infectious mononucleosis and

and travel are additional risk factors.

pneumonia.

Pathogens

Infection will often be self-limiting,

with no specific treatment necessary;

Most URTIs are viral in origin. More than

the only indications for antibiotic

200 different viruses are known to cause the

treatment are group A streptococcal

common cold. Typical viral agents that

pharyngitis, bacterial sinusitis and

cause URTIs are rhinoviruses, corona-

pertussis.

viruses, adenoviruses, coxsackieviruses,

influenza and parainfluenza viruses, human

190

ERS Handbook: Respiratory Medicine

Table 1. Signs and symptoms

Upper

Symptoms

Signs

respiratory

tract infection

Common cold Nasal congestion,

Low-grade fever, nasal vocal tone, inflamed nasal

mucopurulent nasal

mucosa

discharge, sneezing,

sore throat, halitosis

Sinusitis

Unilateral facial pain,

Swelling, redness, tenderness to palpation or

maxillary toothache,

percussion overlying the affected sinuses,

headache, purulent

abnormal transillumination

nasal discharge

Pharyngitis

Sore throat, odynophagia

Pharyngeal erythema and exudate, palatal

or dysphagia, fever,

petechiae (doughnut lesions), tender anterior

absence of cough,

cervical lymphadenopathy, scarlatiniform rash,

halitosis

pharyngeal or palatal vesicles and ulcers

(herpangina), tonsillar hypertrophy

Laryngitis

Hoarseness,

Low-grade fever, cervical lymphadenopathy,

voicelessness, dry

inspiratory stridor, tachypnoea

cough, odynophagia or

dysphagia, halitosis

metapneumovirus, respiratory syncytial

cellulitis, subperiosteal abscess, orbital

virus and others.

abscess, frontal and maxillary osteomyelitis,

subdural abscess, meningitis and brain

Group A, but also group C and G,

abscess. Epiglottitis, a presentation of

streptococci can cause pharyngitis (10-20%

laryngitis caused by H. influenzae type B

of cases), as well as other bacteria like

(Hib), poses a risk of death due to sudden

Neisseria gonorrhoeae, Corynebacterium

airway obstruction and other complications,

diphtheriae and atypical bacteria (Chlamydia

including septic arthritis, meningitis,

and Mycoplasma). Streptococcus pneumoniae,

empyema and mediastinitis.

Haemophilus influenzae and Moraxella

catarrhalis can be the bacterial cause of

Diagnosis

rhinosinusitis. Bordetella pertussis or

In most cases, the diagnosis is purely

Bordetella parapertussis are the cause of

clinical. History, inspection, palpation,

whooping cough associated with

percussion and auscultation (table 1) are

laryngotracheitis.

sufficient. Additional diagnostic

Complications

investigations should only be performed in

special circumstances. These include

URTIs usually are self-limiting and rarely

suspicion of:

cause permanent sequelae or death.

However, they can progress to otitis media,

N influenza (perform pharyngeal swab for

bronchitis, bronchiolitis, pneumonia, sepsis,

PCR)

meningitis, intracranial abscess and other

N group A streptococcal pharyngitis

infections. Specific complications can occur

(perform pharyngeal swab for rapid

with untreated group A streptococcal

antigen detection test)

pharyngitis resulting in acute rheumatic

N infectious mononucleosis (there are

fever (ARF), acute glomerulonephritis,

usually additional symptoms such as

peritonsillar abscess and toxic shock

hepatosplenomegaly and lymphocytosis;

syndrome. Sinusitis can extend into

perform mononucleosis spot test in

surrounding deep tissue leading to orbital

blood)

ERS Handbook: Respiratory Medicine

191

N Pertussis (perform serology or PCR on

common cold or any mild URTI. The only

respiratory specimens, mostly

indications for antibiotic treatment are:

nasopharyngeal swab)

group A streptococcal pharyngitis (oral

Differential diagnosis

penicillin or macrolide for 10 days)

bacterial sinusitis, usually a sinusitis not

Influenza viruses can cause mild URTIs but

resolving within 7 days (aminopenicillin

also systemic disease. The definition of

with or without a b-lactamase inhibitor,

influenza-like illness is fever .38.5uC) and

second- or third-generation

one of the following:

cephalosporins, macrolides, or

trimethoprim-sulfamethoxazole for

N cough

7-10 days)

N sore throat

N pertussis (macrolides, alternatively

N headache

trimethoprim-sulfamethoxazole or

N muscle ache

doxycycline for 7 days)

Allergic rhinoconjunctivitis is characterised by

Nasal decongestants decrease symptoms in

oedema of the conjunctiva, itching and

rhinitis and sinusitis, and topical nasal

increased lacrimation additional to

steroids improve sinusitis. Confirmed cases

symptoms of rhinitis. It shows seasonal

of influenza can be considered for therapy

variation related to allergen exposure.

with neuraminidase inhibitors according to

Centers for Disease Control and Prevention

Acute thyroiditis can present as sore throat,

guidelines. New treatment options for the

a common symptom in URTIs. Investigation

most prevalent respiratory pathogens,

of thyroid hormones, thyroid-specific

human rhinoviruses, are under

autoantibodies, ultrasound and radioactive

development.

iodine uptake can help with diagnosis.

Prevention

Gastro-oesophageal reflux disease can

clinically present as laryngopharyngitis and/

Direct hand-to-hand contact is an important

or tracheobronchitis. History and

mechanism of pathogen transmission.

oesophagogastroduodenoscopy in more

Hence, frequent hand washing or

severe cases should be performed.

disinfection in healthcare can limit spread of

infection significantly. Influenza vaccination

Granulomatosis with polyangiitis (Wegener’s)

has been shown to be very beneficial and

should be considered in patients with

has to be advocated. In children, the routine

sinusitis not responding to therapy. Classic

administration of Hib vaccination has

antineutrophil cytoplasmic antibodies and

practically eradicated Hib as a cause of

biopsy are key to diagnosis.

URTI; a herd effect can be demonstrated, as

the introduction of the pneumococcal

Asthma should be considered in patients

vaccine in children correlated with

with a nonresolving cough for .3 weeks.

significant reduction in invasive pneumo-

Treatment

coccal disease in adults.

The vast majority of URTIs are viral in origin.

In most cases, the infection will be self-

Further reading

limiting and no specific treatment is

Arroll B, et al.

(2005). Antibiotics for

necessary. Sufficient fluid intake should be

the common cold and acute purulent

advocated. The effect of zinc and vitamin C

rhinitis. Cochrane Database Syst Rev;

is still debated. Echinacea seems to be

CD000247.

effective in prevention and treatment of the

Centers for Disease Control and

common cold. Nonsteroidal anti-

Prevention. Seasonal Influenza

(Flu).

inflammatory drugs relieve fever, headache

www.cdc.gov/flu Date last updated:

and malaise. In general, there is no role for

November 21, 2012.

antibiotic therapy in the management of

192

ERS Handbook: Respiratory Medicine

Choby BA (2009). Diagnosis and treat-

Musher DM (2003). How contagious are

ment of streptococcal pharyngitis. Am

common respiratory tract infections? N

Fam Physician; 79: 383-390.

Engl J Med; 348: 1256-1266.

Rosenfeld RM, et al.

(2007). Clinical

Poole MD, et al. (2005). Treatment of

practice guideline: adult sinusitis.

rhinosinusitis in the outpatient setting.

Otolaryngol Head Neck Surg;

137:

Am J Med; 118: Suppl. 7A, 45S-50S.

365-377.

Rohde G (2007). Therapeutic targets in

Meneghetti A, et al. Upper Respira-

respiratory viral infections. Curr Med

tory Tract Infection. http://emedicine.

Chem; 14: 2776-2782.

medscape.com/article/302460-overview

Shah SA, et al.

(2007). Evaluation of

Date last updated: October

15,

echinacea for the prevention and treat-

2012.

ment of the common cold: a meta-

Mossad SB. Upper Respiratory Tract

analysis. Lancet Infect Dis; 7: 473-480.

Infections.

www.clevelandclinicmeded.

Tiwari T, et al.

(2005). Recommended

com/medicalpubs/diseasemanagement/

antimicrobial agents for the treatment

infectious-disease/upper-respiratory-tract-

and postexposure prophylaxis of pertussis:

infection/ Date last updated: August 1,

2005 CDC Guidelines. MMWR Recomm

2010.

Rep; 54: 1-16.

ERS Handbook: Respiratory Medicine

193

Infective exacerbations of

COPD

Marc Miravitlles

The American Thoracic Society/European

Outcomes of exacerbations: risk factors for

Respiratory Society Task Force has defined

failure

the exacerbation of COPD as: ‘an increase in

respiratory symptoms over baseline that

The failure rate of ambulatory treatment of

usually requires medical intervention’. In

exacerbations of COPD ranges from 12% to

fact, the chronic and progressive course of

26%, and failure may lead to hospital

COPD is often aggravated by short periods

admission. COPD severity is associated with

of increasing symptoms, particularly

a higher rate of severe exacerbation

increasing cough, dyspnoea and production

requiring hospitalisation. The mortality of

of sputum, which can become purulent.

patients admitted to hospital with COPD

Patients with moderate-to-severe COPD

exacerbation is around 10-14% and the

present a mean of between one and two of

mortality of those admitted to an intensive

these episodes or exacerbations per year.

care unit may be as high as 24%.

Patients with more advanced disease may

Hospitalisation has an important impact on

suffer from an increasing number of

COPD patients; it is associated with a higher

exacerbations; however, some patients are

risk of short- and long-term all-cause

more prone to suffer from exacerbations

mortality at any stage of severity of COPD.

irrespective of the severity of airflow

Frequent exacerbations have been

impairment - these are the frequent

demonstrated to have a negative impact on

exacerbators, defined as those suffering

health-related quality of life in patients with

from at least two exacerbations the previous

COPD, and survival is significantly related to

year. It is estimated that ,30% of patients

the frequency and severity of exacerbations.

with moderate-to-severe COPD are frequent

Identification of risk factors for failure of

exacerbators.

ambulatory treatment may allow the

implementation of more aggressive broad-

spectrum treatment and closer follow-up

Key points

(table 1).

Aetiology of exacerbations

N Up to 75% of COPD exacerbations are

of infective aetiology.

A variety of causes may deteriorate the

N Haemophilus influenzae is the most

clinical stability of patients with COPD: cold

frequent pathogen causing

temperature, air pollution, lack of

exacerbations.

compliance with respiratory medication,

worsening of comorbidities and pulmonary

N Relapse rate may be as high as 20%.

embolism, among others. However, up to

N Spectrum of antibacterial activity, risk

three-quarters of exacerbations can be

factors for relapse and bacterial

infectious in origin, with bacteria being

resistance to antibiotics are the

responsible for three-quarters of these

criteria used for the selection of

exacerbations. In addition, co-infection with

antibiotics.

respiratory viruses may be frequent in

patients with severe COPD; this co-infection

194

ERS Handbook: Respiratory Medicine

most frequent microorganisms causing

Table 1. Risk factors for failure after ambulatory

exacerbations are presented in table 2.

treatment of exacerbations of COPD

Coexisting cardiopulmonary disease

The role of bacteria in exacerbations has

Increasing number of visits to the GP for

been a matter of controversy, as the

respiratory problems (.3 per year)

respiratory secretions of some patients with

stable COPD carry significant

Increasing number of previous exacerbations

concentrations of bacteria. Therefore, the

(.3 per year)

isolation of such microorganisms during

Increasing baseline dyspnoea

exacerbations should not always be

Severity of FEV1 impairment (FEV1 ,35%

interpreted as a definite demonstration of

predicted)

their pathogenic role. However, studies

Use of home oxygen

performed with specific invasive techniques

have shown that both the number of

Inadequate antibiotic therapy

patients with pathogenic bacteria in

GP: general practitioner.

respiratory secretions and their

concentrations in bronchial secretions

increase during exacerbations. The change

has been identified in around 25% of

in the colonising strain of bacteria is an

admitted COPD patients with an

important mechanism originating

exacerbation. Interestingly, the symptoms

exacerbations. In this case, the host does

and signs of acute exacerbation in patients

not have protective specific antibodies

with COPD have been replicated

against the new strain of bacteria, and the

experimentally in vivo by infecting subjects

microorganism can thereby proliferate and

with respiratory viruses. This is a

cause the exacerbation.

demonstration of the pathogenic role of

viruses in exacerbations of COPD. Since no

Diagnosis of infective exacerbations

effective treatment exists for viral exacerba-

tions, here we will focus on the management

The combination of symptoms described by

of bacterial exacerbations of COPD. The

Anthonisen et al. (1987), i.e. increased

Table 2. Aetiology of exacerbations of COPD

Infectious exacerbations (,60-80% of all exacerbations)

Frequent (70-85% of infectious exacerbations)

Infrequent (15-30% of infectious

Haemophilus influenzae

exacerbations)

Streptococcus pneumoniae

Moraxella catarrhalis

Pseudomonas aeruginosa

Viruses (influenza/parainfluenza, rhinoviruses,

coronaviruses)

Opportunistic Gram-negative

bacteria

Staphylococcus aureus

Chlamydia pneumoniae

Mycoplasma pneumoniae

Noninfectious exacerbations (20-40% of all exacerbations)

Heart failure

Pulmonary embolism

Nonpulmonary infections

Pneumothorax

ERS Handbook: Respiratory Medicine

195

dyspnoea and increased production or

demonstrated to be very sensitive and

purulence of sputum, have been widely used

specific for the diagnosis of bacterial

to identify exacerbations that require

exacerbation and indicates the need for

treatment with antibiotics. However, new

antibiotic therapy. Therefore, most

studies have demonstrated that the

guidelines also recommend antibiotic

presence of green (purulent) sputum as

therapy in patients with two of the three

opposed to white (mucoid) is one of the

aforementioned criteria if one of them is

best and easiest methods to predict the

increased in purulence of sputum.

bacterial aetiology and the need for

On the other hand, placebo-controlled,

antibiotic therapy.

randomised clinical trials and large

Unfortunately, no signs or symptoms can

observational studies have demonstrated

help the clinician to differentiate bacterial

the efficacy of antibiotics in the treatment of

from viral exacerbations. Both viral and

severe hospitalised exacerbation of COPD.

bacterial agents may co-infect a patient with

Studies are ongoing to determine if patients

COPD, and mixed infection is associated

with clear sputum can be safely treated

with higher inflammation, more severe

without antibiotics in the hospital setting.

symptoms and prolonged recovery time.

The antibiotic of choice may vary from

The degree of airflow impairment in COPD

country to country based on the prevalence

patients indicates the presence of different

of different bacteria and, more importantly,

microorganisms during the course of

the differences in susceptibility of the

exacerbations. Individuals with severe

causative bacteria to antibiotics. As an

pulmonary function impairment, manifested

example, in 2000, the prevalence of

by FEV1 ,50% predicted, are at a six-fold

macrolide-resistant Streptococcus

higher risk of developing acute

pneumoniae in the UK was 12.2% but in

exacerbations caused by Haemophilus

France it was 58.1%, while the production of

influenzae or Pseudomonas aeruginosa than

b-lactamase by H. influenzae was 13.9% in

patients presenting FEV1 .50% pred. Those

the UK and 33.1% in France.

with FEV1 ,30% pred have an even higher

Guidelines recommend the use of so-called

risk for P. aeruginosa. Other risk factors for

first-line antibiotics, such as amoxicillin or

infection with Pseudomonas include the

tetracycline, in low-risk patients in countries

presence of bronchiectasis, the previous

with a low prevalence of antibiotic resist-

isolation of Pseudomonas in a given patient

ance, such as the Netherlands, UK and other

and a recent previous courses of antibiotics.

northern European countries. However, in

However, the clinical presentation of

countries with a high percentage of resistant

exacerbation is not characteristic of any

strains or in patients with risk factors for

particular microorganism and no

treatment failure, the choice of an antibiotic

microbiological diagnostic test is available

must consider amoxicillin-clavulanate, the

for differential diagnosis in primary care. To

respiratory fluoroquinolones (moxifloxacin

date, the best biomarker available for

and levofloxacin) or cephalosporins

bacterial exacerbation of COPD is C-reactive

(cefditoren and cefuroxime). Table 3

protein (CRP), which can be quantified in

describes the antibiotic alternatives

capillary blood as a point-of-care test even in

according to the severity of COPD.

primary care.

Nonantibiotic treatment of exacerbations

Antibiotic treatment of exacerbations

Acute exacerbations of COPD present with

Antibiotics have been shown to be superior

increasing dyspnoea in most cases. Both

to placebo in the treatment of exacerbations

infectious and noninfectious exacerbations

when all of the Anthonisen criteria are

are the result of an ongoing inflammatory

present; i.e. increased dyspnoea, increased

reaction in the bronchial mucosa, making

production and purulence of sputum. The

anti-inflammatory and bronchodilator

purulence of sputum has recently been

therapy mandatory.

196

ERS Handbook: Respiratory Medicine

Table 3. Risk classification and suggested antimicrobial therapy

FEV1 %

Most frequent

Suggested treatment

pred

microorganisms

Mild-to-moderate

.50

Haemophilus influenzae

Amoxicillin

COPD without

Moraxella catarrhalis

Tetracycline

risk factors

Streptococcus pneumoniae

In areas of high incidence of

Chlamydophila

resistance: amoxicillin-clavulanate,

pneumoniae

cefditoren, cefuroxime

Mycoplasma pneumoniae

Mild-to-moderate

.50

Haemophilus influenzae

Amoxicillin-clavulanate

COPD with

Moraxella catarrhalis

Moxifloxacin/levofloxacin

risk factors^#

PRSP

Cefditoren

Cefuroxime

Severe COPD

30-50

Haemophilus influenzae

Amoxicillin-clavulanate

Moraxella catarrhalis

Moxifloxacin/levofloxacin

PRSP

Enteric Gram-negative

bacteria

Very severe COPD

,30

Haemophilus influenzae

Moxifloxacin/levofloxacin

PRSP

Ciprofloxacin if Pseudomonas is

Enteric Gram-negative

suspected

bacteria

Amoxicillin-clavulanate (if allergy to

Pseudomonas aeruginosa

quinolones)^"

PRSP: penicillin-resistant S. pneumoniae.^#: risk factors are explained in table 1;^": in the case of intravenous

therapy, other antibiotics can be used, such as piperacillin-tazobactam, imipenem or cefepime.

A short course of oral corticosteroids has been

Oxygen therapy should be provided in cases

demonstrated to accelerate recovery from

of hypoxaemia. Adequate levels of

exacerbations and reduce the rate of relapse in

oxygenation are PaO₂ .8.0 kPa or

patients with moderate-to-severe COPD.

60 mmHg, or SaO₂ .90%. These levels are

Patients can be treated with 0.5 mg?kg^-1

easy to achieve in uncomplicated

methylprednisolone or equivalent in a single

exacerbations. When oxygen is started,

morning dose for 7-14 days. Treatment for

arterial blood gases should be checked 30-

.14 days has not been demonstrated to be

60 min later to ensure satisfactory

more beneficial and increases the likelihood of

oxygenation without carbon dioxide

adverse side-effects. Inhaled bronchodilators,

retention or acidosis.

particularly short-acting inhaled b₂-agonists,

The clinical and gasometric evolution of the

must be given at increased doses during

patients will guide the decision to step down

exacerbations. The short-acting

the treatment and discharge the patient

bronchodilators may be prescribed with a

from the emergency department or hospital.

chamber of inhalation or by nebulisation. In

Family and home support is crucial in the

the acute phase, repeated doses every 30-

first days after discharge.

60 min can be administered with close

monitoring of clinical signs and arterial gas

In mild and moderate ambulatory

exchange with a pulse oximeter. If a prompt

exacerbations, clinical evaluation is required

response to these drugs does not occur, the

48-72 h after initiation of therapy. In mild

addition of an anticholinergic is

cases, this evaluation can be performed

recommended.

by telephone.

ERS Handbook: Respiratory Medicine

197

Further reading

exacerbations: a pooled analysis. Eur

Respir J; 39: 1354-1360.

Anthonisen NR, et al. (1987). Antibiotic

Niewoehner DE, et al. (1999). Effect of

therapy in exacerbations of chronic obstruc-

systemic glucocorticoids on exacerba-

tive pulmonary disease. Ann Intern Med;

tions of chronic obstructive pulmonary

106: 196-204.

disease. N Engl J Med; 340: 1941-1947.

Daniels JMA, et al. (2010). Procalcitonin

Papi A, et al. (2006). Infections and airway

versus C-reactive protein as predictive

inflammation in chronic obstructive pul-

markers of response to antibiotic therapy

monary disease severe exacerbations. Am J

in acute exacerbations of COPD. Chest;

Respir Crit Care Med; 173: 1114-1121.

138: 1108-1115.

Rothberg MB, et al.

(2010). Antibiotic

García-Aymerich J, et al.

(2011). Lung

therapy and treatment failure in patients

function impairment, COPD hospitalisa-

hospitalized for acute exacerbations of

tions and subsequent mortality. Thorax;

chronic obstructive pulmonary disease.

66: 585-590.

JAMA; 303: 2035-2042.

Hurst JR, et al.

(2010). Susceptibility to

Seemungal T, et al. (2001). Respiratory

exacerbation in chronic obstructive pulmon-

viruses, symptoms, and inflammatory

ary disease. N Engl J Med; 363: 1128-1138.

markers in acute exacerbations and stable

Llor C, et al. (2012). Efficacy of antibiotic

chronic obstructive pulmonary disease.

therapy for acute exacerbations of mild to

Am J Respir Crit Care Med; 164: 1618-1623.

moderate COPD. Am J Respir Crit Care

Med; 186: 716-723.

Sethi S, et al.

(2002). New strains of

bacteria and exacerbations of chronic

Mallia P, et al. (2011). Experimental rhino-

virus infection as a human model of chronic

obstructive pulmonary disease. N Engl J

obstructive pulmonary disease exacerba-

Med; 347: 465-471.

tion. Am J Respir Crit Care Med; 183: 734-742.

Stockley RA, et al. (2000). Relationship of

Miravitlles M, et al. (2008). Antimicrobial

sputum color to nature and outpatient

treatment of exacerbation in chronic

management of acute exacerbations of

obstructive pulmonary disease: 2007 con-

COPD. Chest; 117: 1638-1645.

sensus statement. Arch Bronconeumol; 44:

Woodhead M, et al. (2011). Guidelines for

100-108.

the management of adult lower respira-

Miravitlles M, et al.

(2012). Sputum

tory tract infections. Clin Microbiol Infect;

colour and bacteria in chronic bronchitis

17: Suppl. 6, E1-E59.

198

ERS Handbook: Respiratory Medicine

Pneumonia

Mark Woodhead

Background and definitions

Epidemiology

Pneumonia is a condition caused by

CAP occurs in between one and 10 per 1000

microbial infection within the lung

of the adult population each year. It is more

parenchyma. This infection, together with

common in children aged ,5 years and

the associated host inflammatory response,

becomes progressively more common from

impairs normal alveolar function (i.e. gas

age 40 years onwards, with a peak in the very

exchange), which, together with the

elderly. It is more common in those with

systemic effects of the infection, causes the

comorbidity, such as COPD, bronchiectasis,

clinical features of pneumonia. The gold

and chronic cardiac and renal disease. It

standard for recognition of pneumonia is

occurs throughout the year with a peak

the presence of new lung shadowing on the

during the winter months.

chest radiograph in the setting of a

Nosocomial pneumonia can occur in

compatible clinical illness.

anyone resident in hospital for o48 h. It is

especially common in the intensive care unit

Pneumonia is classified into groups that can

.48 h after endotracheal intubation

be easily recognised and within which the

(ventilator-associated pneumonia (VAP))

causative pathogens, and hence the

with risk being proportional to the duration

management, are different (table 1).

of intubation.

Community-acquired pneumonia (CAP) is

Two types of immune dysfunction

that which occurs in the absence of immune

predispose to pneumonia:

compromise or prior hospital admission

within the previous 30 days.

N humoral immune dysfunction, such as

immunoglobulin deficiencies; and

N cell-mediated immune function in, for

Key points

example, cancer chemotherapy, solid

organ transplantation and bone marrow

Pneumonia is very common and has

transplantation.

significant mortality.

Aspiration pneumonia occurs especially in

N Severity assessment, aided by a

those with swallowing impairment and

severity assessment score, is a key

neurological impairment.

management step.

Most cases of CAP are managed in the

N A variety of different pathogens can

community with a variable, but significant,

cause pneumonia.

proportion requiring hospital admission. Of

Antibiotic management is initially

those admitted, 5-10% may die and of those

empirical, and based on guidelines

reaching the intensive care unit, 30-50%

and knowledge of local microbial

may die. Mortality is generally higher in

patterns and resistance rates.

nosocomial pneumonia and pneumonia in

the immunocompromised.

ERS Handbook: Respiratory Medicine

199

bronchograms. More commonly, shadowing

Table 1. Pneumonia classification

may occupy less than a whole lobe and may

Community-acquired pneumonia (CAP)

also be patchy, multilobar and bilateral.

Hospital-acquired pneumonia (HAP) or

Additional features may include pleural

nosocomial pneumonia

effusion and, less commonly, cavitation and

Ventilator-associated pneumonia (VAP)

pneumothorax. The lower lobes are most

commonly affected.

Pneumonia in the immunocompromised

Aspiration pneumonia

In routine blood tests, peripheral blood white

cell count may be raised, especially in

bacterial infection, but C-reactive protein and

Clinical features

procalcitonin are probably more specific.

Blood urea and creatinine are helpful in

The duration of illness before presentation is

severity assessment and the assessment of

usually short. Classically, there is an abrupt

renal impairment, and liver function tests

onset with fever, shivers and pleuritic chest

may be abnormal. Measures of gas exchange,

pain. A slower onset over a few days may also

such as oxygen saturation and/or arterial

occur. Other common symptoms include

blood gases, also aid assessment of illness

cough, sputum production (which may be

severity and guide management.

purulent or blood stained), breathlessness,

muscle aches, headaches and anorexia.

In routine practice, tests to identify a

Nausea and diarrhoea are less common. In

microbial cause are positive in only about

elderly patients, symptoms of cerebral

15% of cases of CAP and hence seldom

dysfunction, such as confusion, incontinence

influence management. They are probably

or falls, may be the presenting feature.

not indicated unless the patient is severely

ill. In such cases blood culture, sputum

Abnormalities on clinical examination

Gram stain and culture, and urine tests for

include focal signs on chest examination,

pneumococcal and Legionella antigens are

most commonly crackles. Only occasionally

indicated. Blood antibody levels or nose/

do the ‘classical’ features of lung

throat secretion PCR-based tests for

consolidation occur: dullness to percussion,

microbe-specific nucleic acids can be used

bronchial breathing and enhanced vocal

for the detection of viruses and less

resonance. Chest signs may, however, be

common bacteria such as Legionella,

absent, making the diagnosis difficult

Mycoplasma and Coxiella.

outside hospital. In addition, raised

temperature, raised heart and respiratory

In nosocomial pneumonia, and especially in

rates, low blood pressure, and mental

VAP, lower respiratory secretions should be

confusion may be found.

sampled either by tracheal aspirate or from

bronchoscopic specimens. The latter may

Clinical features are generally not helpful in

also be of value in the immunocompromised.

predicting the causative organism. The

Clinical Pulmonary Infection Score (CPIS)

Differential diagnosis

may be useful in nosocomial pneumonia.

The differential diagnosis includes acute

Investigations including radiology

bronchitis, COPD exacerbation, left

ventricular failure, pulmonary embolism, TB,

Investigations are unnecessary outside

exacerbation of pulmonary fibrosis and rare

hospital but, in those admitted, are performed

lung disorders (e.g. pulmonary

to aid precise diagnosis, assess illness

eosinophilia).

severity and identify the microbial cause.

Microbial aetiology and resistance

A chest radiograph is essential to confirm

new lung shadowing in those admitted.

The same 10 pathogens commonly cause

Classically, such shadowing conforms to a

CAP worldwide, with Streptococcus

lobar pattern and is associated with air

pneumoniae being the most common overall

200

ERS Handbook: Respiratory Medicine

and the most important cause of severe

Table 2. The CURB65 and CRB65 scores

illness and death. Mycoplasma pneumoniae

Score 1 for each of

is also a common cause of mild illness,

especially in young adults. Severe illness is

C: mental confusion

most likely to be associated with

U: blood urea .7 mmol?L^-1

S. pneumoniae, Legionella, staphylococcal or

R: respiratory rate o30 breaths?min^-1

Gram-negative bacterial infection. Legionella

B: systolic blood pressure ,90 mmHg or

infection may occur in outbreaks associated

diastolic blood pressure f60 mmHg

with a water aerosol source, such as

showers or decorative fountains.

65: age o65 years

Staphylococcal infection is especially

Mild pneumonia: score of 0-1 (mortality 1.5%);

common following influenza virus infection

moderate pneumonia: score of 2 (9%); severe

and in intravenous drug abusers. Influenza

pneumonia: score of 3-5 (22%).

occurs in seasonal outbreaks during the

winter months and occasional pandemics. It

is the most common viral cause of CAP.

Nosocomial pneumonia is most commonly

caused by Gram-negative enterobacteria or

Bacterial antibiotic resistance varies in

Staphylococcus aureus. Pseudomonas

frequency between countries. Clinically

aeruginosa and multiresistant bacteria (e.g.

significant resistance to penicillins in S.

methicillin-resistant S. aureus (MRSA)) are

pneumoniae is rare but clinically significant

important causes of VAP.

macrolide resistance is more common,

especially in Southern Europe (www.earss.

Humoral immune deficiency is associated

rivm.nl).

with bacterial infection and cell-mediated

Table 3. European Respiratory Society/European Society for Clinical Microbiology and Infectious Diseases antibiotic

guideline options for CAP

Outside hospital

Amoxicillin

Tetracycline

Hospitalised

Nonsevere

Aminopenicillin ¡ macrolide

Aminopenicillin/b-lactamase inhibitor ¡ macrolide

Non-antipseudomonal cephalosporin

Cefotaxime or ceftriaxone ¡ macrolide

Levofloxacin

Moxifloxacin

Penicillin G ¡ macrolide

Severe

No Pseudomonas risk

Non-antipseudomonal cephalosporin III + macrolide

Moxifloxacin or levofloxacin ¡ non-antipseudomonal

cephalosporin III

Pseudomonas risk

Antipseudomonal cephalosporin + ciprofloxacin

Antipseudomonal cephalosporin + macrolide + aminoglycoside^#

Acylureidopenicillin/b-lactamase inhibitor + ciprofloxacin

Acylureidopenicillin/b-lactamase inhibitor + macrolide +

aminoglycoside^#

Carbapenem^" + ciprofloxacin

Carbapenem^" + macrolide + aminoglycoside^#

Evidence does not clearly support one regime as better than another so a choice is provided. Decision will

depend on local circumstances.^#: gentamicin, tobramycin or amikacin;^": meropenem is preferred.

ERS Handbook: Respiratory Medicine

201

immune defects with viral and fungal

causes and that for pneumonia in the

infections such as Pneumocystis jirovecii.

immunocompromised by the type of

immune suppression and likely pathogens.

Anaerobic bacteria may be important in

Duration of therapy is usually 7 days in

aspiration pneumonia.

uncomplicated cases but may need to be

Severity assessment

prolonged in severe illness. Failure to

respond should prompt a re-evaluation of

Severity assessment is the key to deciding

the correct diagnosis and a more detailed

the place of care and should also guide

search for microbial cause, for example by

diagnostic tests and antimicrobial therapy.

bronchoscopy, as long as gas exchange

This should be done through clinical

function will allow.

judgement guided by objective severity

scores. There are many of these, but the

Prevention

best validated for CAP are CURB65 (and its

The main preventable risk for pneumonia is

derivative CRB65) and the pneumonia

tobacco smoking. In those with comorbid

severity index (PSI). The latter is based on

disease and in the elderly, influenza and

a score from 20 variables and is often

pneumococcal vaccination is indicated.

not practical in routine practice. The

Recent evidence suggests that conjugate

former is simpler and based on the

pneumococcal vaccination in children not

number of severity variables

only reduces invasive pneumococcal

present (table 2).

infection in this group but also in adults.

Management

Further reading

Correction of gas exchange and fluid balance

abnormalities, and the provision of

Lim WS, et al. (2000). Severity prediction

appropriate antimicrobial therapy are the

rules in community acquired pneumonia:

cornerstones of management. Outside

a validation study. Thorax; 55: 219-223.

hospital, rest, oral fluids and an oral

Pugin J, et al.

(1991). Diagnosis of

antibiotic may be all that is required. In

ventilator-associated pneumonia by bac-

hospital, oxygen at a concentration to

teriologic analysis of bronchoscopic and

maintain SaO2 (92-95%) should be delivered.

nonbronchoscopic ‘blind’ bronchoalveo-

If this cannot be achieved, CPAP may be

lar lavage fluid. Am Rev Respir Dis; 143:

helpful. If there is an unacceptable rise in

1121-1129.

PaCO₂, then assisted ventilation should be

Torres A, et al. Respiratory Infections.

considered. A place for NIV in pneumonia

London, Hodder Arnold, 2006.

Torres A, et al. (2009). Defining treating

management has yet to be proven.

and preventing hospital acquired pneu-

Initial antibiotic therapy must be empirical

monia: European perspective. Intensive

and directed by illness severity according to

Care Med; 35: 9-29.

national or international guidelines (table 3).

Woodhead M, et al. (2011). Guidelines for

Empirical antibiotics for CAP should always

the management of adult lower respira-

include pneumococcal coverage. Treatment

tory tract infections

- full version. Clin

for nosocomial pneumonia should be

Microbiol Infect; 17: Suppl. 6, E1-E59.

guided by knowledge of local microbial

202

ERS Handbook: Respiratory Medicine

Hospital-acquired

pneumonia

Francesco Blasi

The currently proposed classification of

factors are: age, type of hospital and type of

hospital-acquired pneumonias includes

ward. Patients aged ,35 years are less

hospital-acquired pneumonia (HAP),

prone to developing HAP than elderly

ventilator-associated pneumonia (VAP) and

patients; the incidence of HAP may vary

healthcare-associated pneumonia (HCAP)

between five and 15 episodes per 1000

(table 1).

discharges. In large teaching hospitals, the

incidence is higher than in district hospitals,

However, a statement issued by the

possibly relating to differences in patient

European Respiratory Society/European

complexity. HAP is quite uncommon in

Society of Clinical Microbiology and

paediatric and obstetric wards, and clearly

Infectious Diseases/European Society of

most common in surgical wards and

Intensive Care Medicine calls for a

intensive care units (ICUs), particularly in

redefinition of HCAP, particularly in terms of

ventilated patients, in whom the incidence

risk factors and microbial aetiology.

may be .35 episodes per 1000 patient-days.

Epidemiology

Pathogenesis and risk factors

The incidence of HAP is ,0.5-2.0% among

all hospitalised patients and it is the second

The understanding of the pathogenesis of

most common nosocomial infection, yet the

HAPs is a fundamental step for the

first in terms of mortality (ranging from 30%

comprehension of the risk factors involved.

to .70%). The incidence in different

The main sources of HAP pathogens

hospitals and different wards of the same

include:

hospital varies considerably. The main risk

N healthcare devices

N the environment

Key points

N the transfer of microorganisms between

the patient and staff or other patients

N Incidence of hospital-acquired

N oropharyngeal and gastric colonisation,

pneumonia is ,0.5-2%, with risk

with subsequent aspiration of their

factors including age, type of hospital

contents into the lungs in patients with

and type of ward.

impaired mechanical, cellular and

humoral defences.

N Mortality is high (30-70%).

N Diagnosis can be difficult, and

requires a combined clinical and

Table 1. Definitions of HAP

bacteriological approach.

HAP Pneumonia that occurs o48 h after

N Antimicrobial therapy must be both

admission, which was not

prompt and appropriate, and should

incubating at the time of admission

be modified as culture results become

VAP Pneumonia that arises .48-72 h

available.

after endotracheal intubation

ERS Handbook: Respiratory Medicine

203

Table 2. Main recommendations for the management of modifiable risk factors for HAP and VAP

Host related

Adequate nutrition, enteral feeding via orogastric tubes

Reduction/discontinuation of immunosuppressive treatments

Prevent unplanned extubation (restraints, sedation)

Kinetic beds

Incentive spirometry, deep breathing and pain control

Device/treatment

Minimise use of sedatives and paralytics

Avoid gastric overdistention

Avoid intubation and reintubation Expeditious removal of endotracheal

and nasogastric tubes Semirecumbent positioning

Drain condensate from ventilator circuits

Endotracheal tube cuff pressure (.20 cmH₂O prevents leakage of

bacterial pathogens around the cuff into lower respiratory tract)

Continuous aspiration of subglottic secretions

Use of heat-moisture exchangers (reduces ventilator circuit

colonisation but not VAP incidence)

Environment related

Attention to infection-control procedures, i.e. staff education, hand

washing, patient isolation

Microbiological surveillance programme

Risk factors for the development of HAP can

between some European areas and even

be differentiated into modifiable and non-

within countries, from one hospital to

modifiable conditions (table 2).

another.

Microbiology

Taking into account the time course of

pneumonia development, the expected

Gram-negative pathogens are the main

pathogens in early-onset pneumonia (onset

cause of HAP. Pseudomonas aeruginosa,

in f4 days of hospital admission) include

Acinetobacter baumannii, microorganisms

S. aureus, S. pneumoniae and H. influenzae,

belonging to the family Enterobacteriaceae

as well as nondrug-resistant Gram-negative

(Klebsiella spp., Enterobacter spp., Serratia

enteric bacteria (GNEB), and in late-onset

spp., etc.) and, under certain conditions,

pneumonia (onset .4 days of hospital

microorganisms such as Haemophilus

admission) include methicillin-resistant S.

influenzae are involved in HAP aetiology.

aureus, drug-resistant GNEB, P. aeruginosa

Among Gram-positive pathogens,

and A. baumannii among other potentially

Staphylococcus aureus, Streptococcus spp. are

drug-resistant microorganisms.

the most common agents, accounting for

35-39% of all cases. Nonbacterial pathogens

Diagnostic strategy

such as Aspergillus spp. and viruses

(cytomegalovirus) have been described.

The clinical diagnosis of HAP is often

difficult to establish. The American Thoracic

In general, there are significant geographical

Society/Infectious Diseases Society of

differences in the rates of resistance

America guidelines suggest the use of a

Table 3. Major points for HAP diagnosis

Medical history and physical examination

Chest radiograph (posteroanterior and lateral)

Blood gas analysis

Blood cultures

Thoracentesis if pleural effusion

Endotracheal aspirate, bronchoalveolar lavage or protected brush sample for culture before

antibiotic (negative results do not rule out viral or Legionella infections)

Extrapulmonary site of infection should be investigated

204

ERS Handbook: Respiratory Medicine

Table 4. CPIS^#

Criterion

Tracheal secretions

Absent

No purulent

Abundant and

purulent

Chest radiograph infiltrates

Diffuse/patchy

Localised

Temperature uC

.36.5 and .38.4

,38.5 or .38.9

.39 or ,36

Leukocytes cells?mL^-1

4000 and 11 000

,4000 or .11 000

,4000 or .11 000 +

band forms .50% or

.500

PaO₂/FIO₂

.240 or ARDS

,240, no ARDS

Microbiology^"

Negative

o10³ and f10⁴

Positive (.10⁴)

FIO2: inspiratory oxygen fraction; ARDS: acute respiratory distress syndrome.^#: CPIS is considered positive

with a score o6;^": tracheal aspirate.

combined clinical and bacteriological

or leukopenia and purulent secretions) is

strategy. Table 3 summarises the major

sufficient to start antimicrobial treatment.

points and recommendations of the

guidelines.

Concerning the diagnosis of VAP, the lack of

accuracy of specific clinical signs of

In case of doubt or relevant disagreement

pneumonia led investigators to develop

between the clinical presentation and the

scores to identify respiratory infections. In

radiological findings, it is recommended to

particular, the Clinical Pulmonary Infection

perform CT. The presence of new chest

Score (CPIS) is based on six clinical

radiographic infiltrates plus one of the three

assessments (temperature, blood leukocyte

clinical variables (fever .38uC, leukocytosis

count, volume and purulence of tracheal

Table 5. Antimicrobial treatment of nosocomial pneumonia

Recommended treatment

Recommended dosages

options

Early-onset

Aminopenicillin plus

Amoxicillin-clavulanate 362.2 g

pneumonia without

b-lactamase inhibitor

Ampicillin sulbactam 363 g

any additional risk

or second/third generation

Cefuroxime 361.5 g

factors^#

cephalosporin

Cefotaxime 362 g

or respiratory

Ceftriaxone 162 g

fluoroquinolone

Levofloxacin 16750 mg

Moxifloxacin 16400 mg

Late-onset or risk

Anti-Pseudomonas b-lactams

Piperacillin/tazobactam 364.5 g

factors for

or carbapenems plus

Ceftazidime 362 g

multidrug-resistant

fluoroquinolone

Imipenem 361 g

pathogens

Addition of coverage for

Meropenem 361 g

MRSA if suspected

Ciprofloxacin 36400 mg

Levofloxacin 16750 mg

Vancomycin 261 g

Linezolid 26600 mg

MRSA: methicillin-resistant Staphylococcus aureus.^#: ertapenem has been suggested; however, its use on a

regular basis would lead to a considerable risk of overtreatment.

ERS Handbook: Respiratory Medicine

205

secretions, oxygenation, pulmonary

provided that the patient has a good clinical

radiographic findings, and semiquantitative

response and difficult-to-treat pathogens are

culture of tracheal aspirate), each worth

not involved as an aetiological agent.

between 0 and 2 points (table 4). A CPIS

value o6 is a threshold to accurately

Further reading

identify patients with pneumonia. However,

the value of CPIS still needs to be validated

American Thoracic Society, et al. (2005).

in a large prospective study.

Guidelines for the management of

adults with hospital-acquired, ventilator-

Treatment

associated, and healthcare-associated

Prompt administration of appropriate

pneumonia. Am J Respir Crit Care Med;

antimicrobial treatment is crucial in order to

171: 388-416.

achieve an optimal outcome, and inappropriate

Ramirez P, et al.

(2012). Measures to

antimicrobial treatment is associated with an

prevent nosocomial infections during

excess mortality from pneumonia. Antibiotic

mechanical ventilation. Curr Opin Crit

selection for empirical therapy of HAP should

Care; 18: 86-92.

Torres A, et al. (2009). Defining, treating

be based primarily on the risk of multidrug-

and preventing hospital acquired pneu-

resistant pathogen infection. Table 5 shows the

monia: European perspective. Intensive

proposed empirical treatment approach.

Care Med; 35: 9-29.

Once the results of respiratory tract and

Torres A, et al. (2010). Treatment guide-

blood cultures become available, therapy

lines and outcomes of hospital-acquired

should be focused or narrowed, based on

and ventilator-associated pneumonia.

the identity of specific pathogens and their

Clin Infect Dis;

51: Suppl.

1, S48-

susceptibility to specific antimicrobials. An

S53.

8-day antibiotic course can be appropriate

206

ERS Handbook: Respiratory Medicine

Opportunistic infections in

the immunocompromised

host

Thomas Fuehner, Mark Greer, Jens Gottlieb and Tobias Welte

Pulmonary diseases remain prevalent

commonly alter mononuclear phagocytic

among immunodeficient patients,

activity or the complement system. They

manifesting as infections, malignancy,

have also been implicated in structural

structural abnormalities such as

defects such as PCD and hereditary splenic

bronchiectasis or primary ciliary dyskinesia

deficiency. Cellular defects, typically

(PCD), and inflammatory dysregulation. The

involving either T-lymphocytes or both

causes of immunodeficiency are considered

T- and B-lymphocytes are common causes

either primary (congenital) or acquired.

of opportunistic infections, such as

Pneumocystis jiroveci or cytomegalovirus

Primary immunodeficiency

(CMV) pneumonia. While particularly

prevalent among newborns, isolated defects

Primary immunodeficiency results from

in humoral immunity may be compensated

either humoral or cellular immuno-

over subsequent months by persisting

deficiency, although clinical manifestations

maternal antibodies. Impaired T-cell or

commonly result from a combination of

phagocyte function increases the risk of

both. Disorders of innate immunity

opportunistic infections from particular

opportunistic pathogens including

Pseudomonas, Burkholderia, P. jiroveci,

Key points

Aspergillus and CMV. However, the clinical

course varies widely, with late presentation

N Common causes of acquired

in older adults being a not uncommon

immunodeficiency are

feature in some syndromes, such as

immunosuppressive medication

common variable immunodeficiency

(corticosteroids, cytotoxic

syndrome (CVID), in which patients are

chemotherapy and biologicals),

particularly susceptible to encapsulated

radiation, HIV infection and asplenia.

microorganisms such as Streptococcus

The pathogen type depends on the

pneumoniae or Haemophilus influenzae.

nature of the underlying immune defects.

Nontuberculous mycobacterial infections

N Correct assessment of individual risk

have been described in patients with genetic

factors for pneumonia (community

defects in the interleukin (IL)-12 and

versus hospital acquired and

interferon (IFN)-c pathways, as well as in

immunosuppressed patient) helps to

patients with defective regulation of NF-kB

improve treatment.

(NF-kB essential modifier or NEMO defects).

Diagnostic and treatment algorithms

Acquired immunodeficiency

may help to reduce mortality and the

use of antibiotics.

Acquired immunodeficiencies remain much

N These algorithms are solely defined

more prevalent than primary defects and

for community- and hospital-acquired

result mainly from the use of cytotoxic

pneumonia in major guidelines.

medications in chemotherapy, biological

treatments and steroids, and radiotherapy,

ERS Handbook: Respiratory Medicine

207

HIV infection and transplantation. In each of

difficulties arise in diagnosing invasive

these patient groups, there is an increased

pulmonary aspergillosis. In the absence of a

susceptibility to specific groups of

confirmatory biopsy, diagnostic criteria

pathogens based primarily on the underlying

including specific risk factors, CT criteria

immunological deficit. In comparison to

and corresponding microbiological findings

other treatments, less is known about

(positive galactomannan antigen test,

antibody-based treatments directed towards

culture and PCR) are crucial in assisting with

T- and B-cell function or tumour necrosis

decision-making. Current guidelines

factor (TNF)-a, and these should be further

recommend that all cases of ‘probable’ or

evaluated when assessing individual patient

‘proven’ pulmonary aspergillosis be

risk.

immediately treated (Ascioglu et al., 2002).

Neutropenia Infection in neutropenic

Bone marrow transplantation Patients

patients continues to pose major clinical

undergoing allogenic stem-cell or bone

challenges. Host defences are commonly

marrow transplantation (BMT) are at

impaired either by the underlying disease in

understandably high risk of neutropenia,

primary deficiencies, or specific treatments

and impairment of barrier defences and

or iatrogenic manipulation while

both cell-mediated and humoral immunity.

hospitalised.

The degree of neutropenia reflects both the

nature and duration of exposure to the

Due to a lack of neutrophil granulocytes,

precipitating factor. The resulting deficit

pulmonary infiltrations may be absent or

facilitates even microorganisms with limited

difficult to identify. Current recommendations

pathogenicity in causing serious infections.

from the Infectious Disease Work Group of

Patients undergoing allogenic stem-cell

the German Society of Haematology and

transplantation or BMT are subjected to

Oncology reflect this, recommending urgent

sequential suppression of host defences,

thoracic CT in all patients with neutropenic

predisposing to variation in susceptibility to

fever failing to respond after 3 days of

particular organisms at different phases

empirical antibiotic treatment (Maschmeyer

following transplantation. The greatest

et al., 2009). Pulmonary infiltrates, where

infective risk, particularly of opportunistic

present, require further investigation through

pneumonias due to Staphylococcus aureus,

bronchoalveolar lavage (BAL). Storage and

Pseudomonas aeruginosa,

transport of BAL samples is of critical

Enterobacteriaceae, Aspergillus spp. or even

importance, with 4uC considered the optimal

CMV, occurs within the first few weeks

temperature, and testing should ideally begin

following allogenic stem-cell

within 2-3 h of material recovery

transplantation.

(Maschmeyer et al., 2009). Diagnostic work-

up should include mycobacteria (microscopy,

Solid organ transplantation Due to their

culture and PCR), P. jiroveci

chronic immunocompromised state,

(immunofluorescence and PCR), Legionella

infection represents a lifelong threat to

spp. and galactomannan antigen testing for

patients after solid organ transplantation

Aspergillus (Guo et al., 2010). Viral aetiologies

and remains a leading cause of early and

should also be considered, particularly

late mortality. In addition to their direct

common respiratory pathogens, via

impact, several studies have linked infection

immunofluorescence or PCR. CMV infections,

response processes with an increased

including CMV pneumonia, may be detected

predisposition to allograft rejection,

via CMV antigen in blood, i.e. pp65, or CMV

especially in lung transplantation (LTx)

DNA, which is currently considered the gold

(Fuehner et al., 2012).

standard (Hodinka, 2003).

While classical symptoms such as fever and

The presence of Candida spp. on direct

cough may be masked in solid organ

microscopy or even BAL culture requires

transplant recipients, this problem is of

careful interpretation and is not an

particular concern in LTx patients. In the

automatic indication for treatment. Similar

early post-transplant phase, such infections

208

ERS Handbook: Respiratory Medicine

are most commonly bacterial, followed by

first-line treatment of invasive aspergillosis,

fungi and then viruses (Kotloff et al., 2011).

with echinocandins and parenteral lipid

P. aeruginosa is the predominant pathogen,

formulations of amphotericin B used as

followed closely by S. aureus. Common

second-line therapy. Candida infections

gram-negative organisms causing post-

generally respond well to fluconazole. In

transplant pneumonias include Klebsiella

non-albicans species, however, fluconazole

and H. influenzae.

resistance is becoming increasingly

prevalent (Schaberg et al., 2010).

CMV represents the commonest viral

pathogen, occurring in approximately one-

Due to a combination of lifelong co-

third of patients during the first year (Palmer

trimoxazole prophylaxis and low-dose

et al., 2010). CMV-naïve recipients (R^-)

steroid treatment regimes, P. jiroveci

receiving organs from seropositive donors

pneumonia has become rare among

(D⁺) are at the greatest risk of infection and

adherent patients.

are predisposed to particularly severe

infection. Current guidelines recommend

New immunosuppressive drugs In recent

the use of ganciclovir/valganciclovir

years, .40 monoclonal antibodies have

been licensed for treatment of a wide variety

prophylaxis in D⁺/R^- for o6 months

following transplant (Kotton et al., 2010).

of conditions. Inevitably, subsequent studies

have alluded to an increased risk of severe

Community-acquired respiratory viruses

infections in patients receiving antibody-

consisting mainly of adenovirus and

associated immunosuppression (Keyser,

influenza virus along with certain

2011). Due to wide variations in

Paramyxoviridae - respiratory syncytial virus

immunological interactions, significant

(RSV), parainfluenza virus and human

variability exists both in the pathogen

metapneumovirus (hMPV) - have gained

spectrum and the severity of their effects

recognition as pathogens among LTx

(Curtis et al., 2011). Their modes of action

recipients (Kumar et al., 2010; Gottlieb et al.,

can be broadly classified into those affecting

2009). While treatment options remain

B-cell function such as rituximab (anti-

limited, oral ribavirin may improve

CD20), those specifically binding T-cells

outcomes in paramyxoviral infections but

such as alemtuzumab (anti-CD52),

may not be well tolerated in all patients

co-stimulatory T-cell antibodies such as

(Fuehner et al., 2011).

abatacept, anti-TNF antibodies such as

infliximab, adalimumab and certolizumab,

Fungal infections remain a constant, albeit

and etanercept (anti-soluble TNF receptor)

less common, threat and are usually caused

and tocilizumab (anti-IL-6)

by Aspergillus or Candida species. However,

pulmonary candidiasis is rare (Meersseman

HIV infection Reduced CD4⁺ cell counts,

et al., 2009), particularly among LTx

while not correlating directly, do appear to

recipients, and detection should be based on

indicate an increased risk of opportunistic

culture and histology of bronchial mucosa

respiratory pathogens in HIV-infected

biopsies rather than BAL findings

patients. The common bacterial pathogens

(Strassburg et al., 2010). Conversely, the

are S. pneumoniae and Haemophilus spp.

presence of Candida in blood cultures

(Benito et al., 2012). Intravenous drug use

should, be considered significant, with

and smoking appear to increase the

immediate initiation of treatment. BAL

pneumonia risk in these patients.

analysis may be negative in up to 40% of

Worldwide, Mycobacterium tuberculosis is the

patients with an invasive aspergillosis.

most important co-infection in HIV-infected

Infections tend to be limited to the airways,

patients and significantly influences AIDS-

with a preponderance towards bronchial

related mortality. P. jiroveci is the

anastomoses. Invasive disease at the

commonest nonbacterial pathogen.

anastomoses may result in erosion of the

Nocardia spp., Actinomyces spp.,

pulmonary artery precipitating catastrophic

Rhodococcus and Cryptococcus are rare

pulmonary haemorrhage. Voriconazole is the

opportunistic pulmonary pathogens

ERS Handbook: Respiratory Medicine

209

occasionally diagnosed in European patients

Keyser FD

(2011). Choice of biologic

with poorly treated HIV.

therapy for patients with rheumatoid

arthritis: the infection perspective. Curr

Asplenia Antibody production and

Rheumatol Rev; 7: 77-87.

phagocytosis by splenic macrophages

Kotloff RM, et al.

(2011). Lung trans-

represent a fundamental aspect of defence

plantation. Am J Respir Crit Care Med; 184:

against encapsulated bacteria. Following

159-171.

splenectomy, patients are at higher risk of

Kotton CN, et al.

(2010). International

infection with S. pneumoniae, Haemophilus

consensus guidelines on the manage-

spp. and Neisseria meningitidis. Mortality

ment of cytomegalovirus in solid organ

rates from overwhelming post-splenectomy

transplantation. Transplantation; 89: 779-

infection (OPSI) are reported to be up to 600

795.

Kumar D, et al. (2010). A prospective

times greater than in the general population.

molecular surveillance study evaluating

The overall incidence of septicaemia remains

the clinical impact of community-

low, with an estimated lifetime risk for OPSI

acquired respiratory viruses in lung

of ,5% (Lynch et al., 1996).

transplant recipients. Transplantation;

89: 1028-1033.

Further reading

Lynch AM, et al. (1996). Overwhelming

postsplenectomy infection. Infect Dis Clin

Ascioglu S, et al. (2002). Defining oppor-

North Am; 10: 693-707.

tunistic invasive fungal infections in

Maschmeyer G, et al. (2009). Diagnosis

immunocompromised patients with

and antimicrobial therapy of lung infil-

cancer and hematopoietic stem cell

trates in febrile neutropenic patients:

transplants: an international consensus.

guidelines of the infectious diseases

Clin Infect Dis; 34: 7-14.

working party of the German Society of

Benito N, et al. (2012). Pulmonary infec-

Haematology and Oncology. Eur J Cancer;

tions in HIV-infected patients: an update in

45: 2462-2472.

the 21st century. Eur Respir J; 39: 730-745.

Meersseman W, et al.

(2009).

Curtis JR, et al. (2011). The comparative

Significance of the isolation of Candida

risk of serious infections among rheuma-

species from airway samples in critically

toid arthritis patients starting or switch-

ill

patients: a prospective, autopsy

ing biological agents. Ann Rheum Dis; 70:

study. Intensive Care Med;

35:

1526-

1401-1406.

1531.

Fuehner T, et al.

(2011). Single-centre

Palmer SM, et al.

(2010). Extended

experience with oral ribavirin in lung

valganciclovir prophylaxis to prevent cyto-

transplant recipients with paramyxovirus

megalovirus after lung transplantation: a

infections. Antivir Ther; 16: 733-740.

randomized, controlled trial. Ann Intern

Fuehner T, et al.

(2012). The lung

Med; 152: 761-769.

transplant patient in the ICU. Curr Opin

Schaberg T, et al. (2010). Management

Crit Care; 18: 472-478.

der Influenza A/H1N1

- Pandemie im

Gottlieb J, et al.

(2009). Community-

Krankenhaus: Update Januar 2010. Eine

acquired respiratory viral infections in lung

Stellungnahme

der

Deutschen

transplant recipients: a single season

Gesellschaft fur

Pneumologie und

cohort study. Transplantation; 87: 1530-1537.

Beatmungsmedizin.

[Management of a

Guo YL, et al. (2010). Accuracy of BAL

new influenza A/H1N1

virus pandemic

galactomannan in diagnosing invasive

within the hospital. Statement of the

aspergillosis: a bivariate metaanalysis and

German Society of Pneumology.]

systematic review. Chest; 138: 817-824.

Pneumologie; 64: 124-129.

Hodinka RL. Human cytomegalovirus. In:

Strassburg A, et al.

(2010). Infektions-

Murray BE, ed. Manual of Clinical

diagnostik

der

Pneumologie.

Microbiology.

8th Edn. Washington,

[Diagnosis of infections in pneumology.]

ASM Press, 2003; pp. 1304-1318.

Pneumologie; 64: 474-487.

210

ERS Handbook: Respiratory Medicine

Pneumonia in the

immunocompromised host

Santiago Ewig

In contrast to community- and hospital-

pulmonary infections according to the type

acquired pneumonia, pneumonia in the

of immune failure. Some conditions

immunocompromised host is not defined by

additionally show time- or extent-

the setting of pneumonia acquisition but by

dependent risk profiles.

the immune status of the host. In this

Pulmonary infections in the immuno-

context, immune suppression is best

compromised host usually constitute an

defined as a relevant risk for so-called

emergency. Thus, immediate appropriate

opportunistic pathogens such as fungi,

antimicrobial treatment is mandatory. Since

viruses, mycobacteria and parasites.

the spectrum of potential pathogens is far

The expected pathogen patterns differ

more diverse than in immunocompetent

according to the type of immune

hosts, a systematic approach to the

suppression (table 1). Overall, there are five

management of these patients is required.

main types of immunosuppression:

This approach should include a

comprehensive diagnostic evaluation,

N iatrogenic (through steroidal and

indications for empirical initial antimicrobial

nonsteroidal agents)

treatment and in the absence of definite

N neutropenia (usually through

pathogen identification, and for salvage

antineoplastic chemotherapy)

management in case of treatment failure.

N haematopoietic stem-cell transplantation

The basic diagnostic evaluation should

(HSCT)

include history, physical examination and

N solid-organ transplantation

chest radiography as well as a basic

N HIV infection

microbiological work-up (sputum and

blood cultures). A CT scan of the lung

Each immunosuppressive condition

(multi-slice scan and HRCT) is usually

confers characteristic risk profiles for

indicated in patients in whom a

straightforward diagnosis cannot be made.

It can be particularly valuable in patients at

Key points

risk of fungi (Pneumocystis and Aspergillus).

Bronchoscopy is usually indicated in

N Different types of immuno-

patients with bilateral infiltrates, unusual

suppression confer vulnerability to

clinical and radiographic presentations, or

different respiratory pathogens, which

treatment failure. When performing

may be bacterial, viral, mycobacterial

bronchoscopy, particular care has to be

or fungal.

taken to comply with the methodology of

The approach to treatment should

retrieving uncontaminated samples of the

include comprehensive diagnostic

lower respiratory tract and a

evaluation, indications for empirical

comprehensive evaluation of the samples

antimicrobial treatment and a plan in

retrieved. Bronchoalveolar lavage (BAL) is

case of treatment failure.

the most important sample, and stains

and cultures should be investigated for all

ERS Handbook: Respiratory Medicine

211

Table 1. Types of immunosuppression and typical infectious complications

Type of complication

Main immune disorder

Typical Infections

Iatrogenic (steroids)

Macrophages, T-cells

Bacteria, fungi (Aspergillus

spp.), Mycobacterium

tuberculosis

Iatrogenic (anti-TNF-a)

TNF-a

Mycobacterium tuberculosis

Neutropenia, HSCT

Neutrophils

Short duration (,10 days)

Bacteria

Long duration (.10 days)

Additionally:

fungi (Aspergillus spp.)

Solid-organ transplantation

Early (month 1): neutrophils

Bacteria

Intermediate (months 2-6):

Fungi, viruses, parasites

macrophages, T-cells

Late (months .6): depends on

Variable

extent of immune suppression

HIV infection

CD4⁺ T-cell count .500 cells?mL^-1

No risk

CD4⁺ T-cell count 200-

Bacteria, Mycobacterium

500 cells?mL^-1

tuberculosis

CD4⁺ T-cell count ,200 cells?mL^-1

Additionally:

Pneumocystis jirovecii

CD4⁺ T-cell count ,50 cells?mL^-1

Additionally: Aspergillus

spp., atypical mycobacteria

TNF: tumour necrosis factor.

relevant pathogens. Occasionally,

established by examination of induced

transbronchial biopsies and/or

sputum or BAL. The treatment of choice

transbronchial needle aspiration may

(also for prophylaxis) is trimethoprim-

be rewarding.

sulfamethoxazole. Second-line options

include pentamidine and clindamycin/

Pneumocystis jirovecii pneumonia

primaquine. Adjunctive steroids are

indicated in patients with acute respiratory

P. jirovecii pneumonia in HIV-infected

failure.

patients usually occurs in patients with

,200 CD4⁺ helper T-cells per microlitre. It

P. jirovecii pneumonia in non-HIV patients

presents with at least one of the following

differs in that it presents more frequently as

symptoms: fever, cough and dyspnoea on

an acute-onset pneumonia and tends to be

exertion; oral candidiasis is virtually always

associated with higher mortality.

present. Chest radiography typically

discloses bilateral interstitial infiltrates in a

Cytomegalovirus pneumonia

perihilar distribution but may also be normal

in the early course. In the latter case, HRCT

Cytomegalovirus (CMV) pneumonia is

may reveal ground-glass opacities in a

defined as pulmonary signs and symptoms

patchy or geographical distribution. Atypical

and the detection of CMV in pulmonary

cystic presentations may occur. Blood gas

samples. Nevertheless, patients may shed

analysis shows wide alveolar-arterial

CMV in the absence of CMV pneumonia.

gradients. The typical laboratory finding is

Co-infections with other opportunistic

an elevated lactate dehydrogenase level.

pathogens are frequently encountered. After

Specific diagnosis is required and may be

introduction of CMV prophylaxis, the

212

ERS Handbook: Respiratory Medicine

Table 2. Diagnostic criteria for invasive aspergillosis

Definitive

Histological proof or positive culture from otherwise sterile site

Probable

Host factors + CT/tracheobronchitis + mycological criteria

Possible

Host factors + CT/tracheobronchitis

Host factors: several conditions associated with severe immunosuppression; CT: typical (albeit not specific)

CT signs (e.g. the halo sign); tracheobronchitis: bronchoscopic visualisation of typical pseudomembranes on

the tracheal mucosa (maybe subject to biopsy proof); mycological criteria: e.g. culture positive for Aspergillus,

or positive galactomannan test in serum or BAL fluid. Information from the European Organization for

Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute

of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.

incidence in allogeneic HSCT is 10-30%,

susceptibility is mandatory and treatment

with the highest risk in seropositive

must usually be modified in the presence

recipients, while it is rare in autologous

of resistance. Concurrent treatment of TB

HSCT (,10%). In addition, the onset is

and HIV is challenging due to the many

shifted to .100 days. Clinical presentation

complex interactions of anti-TB drugs and

is unspecific. Radiologically, there is typically

antiretroviral agents. Patients who are

an interstitial pattern with tiny pulmonary

candidates for chronic steroid or anti-TNF-

nodules and patchy areas of consolidation.

a treatment should be evaluated for TB

HRCT is more sensitive. Diagnosis is made

infection and, in the case of positive skin

by demonstration of inclusion bodies within

testing or interferon-c release assay,

epithelial cells of the lower respiratory tract

receive prophylaxis.

(sensitivity 90%, specificity 98%). Culture of

BAL fluid lacks specificity. The value of CMV

Aspergillus pneumonia

pp65 antigen and PCR is controversial. The

Definite diagnosis of Aspergillus

treatment of choice is ganciclovir and

pneumonia in neutropenic patients

valganciclovir, combined with CMV

immunoglobulin. Second-line agents are

requires tissue biopsy and can only rarely

foscarnet and cidofivir. Antiviral prophylaxis

be established. Therefore, probable and

and monitoring are the main preventive

possible diagnosis is based on a set of

strategies.

clinical, microbiological and radiographic

criteria (table 2). HRCT is the method of

Tuberculosis

choice to detect Aspergillus pneumonia

early in its course. Typical, albeit not

Patients with reduced CD4⁺ cell counts,

specific, signs of Aspergillus pneumonia

and those on chronic steroid and anti-

include the ‘halo’ sign, as well as nodular

tumour necrosis factor (TNF)-a treatment

and peripheral patchy densities near to

are at increased risk of TB. Co-infection

vessels. The ‘air crescent’ sign,

with TB and HIV alters the natural history

representing cavitation, is a late marker of

of both diseases. TB in HIV-infected

Aspergillus pneumonia. The galactomannan

patients presents like primary infection

antigen test in serum and BAL has a

(patchy infiltrates, mediastinal lymph node

sensitivity of ,70% and a specificity of

enlargement, pleural effusion and

bacteraemia). Anti-TB treatment of

90%. Bronchoscopy is usually indicated.

pulmonary TB follows the rules of standard

Early initiation of treatment is crucial. The

treatment (i.e. usually a 2-month regimen

treatment of choice for definite Aspergillus

consisting of four first-line drugs

pneumonia is voriconazole or,

(isoniazid, rifampicin, ethambutol and

alternatively, liposomal amphotericin B.

pyrazinamide) followed by a 4-month

Second-line options include caspofungin

regimen consisting of two drugs (isoniazid

and posaconazole. Mortality reaches

and rifampicin)). Testing for drug

50-60%.

ERS Handbook: Respiratory Medicine

213

Further reading

Davis JL, et al. (2008). Respiratory infec-

tion complicating HIV infection. Curr

Agusti C, et al. Pulmonary Infection in the

Opin Infect Dis; 21: 184-190.

Immunocompromised Patient. Strategies

Duncan MD, et al. (2005). Transplant-

for

Management. Oxford, Wiley-

related immunosuppression: a review of

Blackwell, 2009.

immunosuppression and pulmonary infec-

Boersma WG, et al.

(2007). Broncho-

tions. Proc Am Thorac Soc; 2: 449-455.

scopic diagnosis of pulmonary infiltrates

Feller-Kopman D, et al. (2003). The role

in granulocytopenic patients with hema-

of bronchoalveolar lavage in the im-

tologic malignancies: BAL versus PSB and

munocompromised host. Semin Respir

PBAL. Respir Med; 101: 317-325.

Infect; 18: 87-94.

Chan KM, et al.

(2002). Infectious

Rañó A, et al. (2001). Pulmonary infil-

pulmonary complications in lung trans-

trates in non-HIV immunocompromised

plant recipients. Semin Respir Infect; 17:

patients: a diagnostic approach using

291-302.

non-invasive and bronchoscopic pro-

D’Avignon LC, et al. (2008). Pneumocystis

cedures. Thorax; 56: 379-387.

pneumonia. Semin Respir Crit Care Med;

Rosen MJ (2008). Pulmonary complications

29: 132-140.

of HIV infection. Respirology; 13: 181-190.

214

ERS Handbook: Respiratory Medicine

Pleural infection and lung

abscess

Amelia Clive, Clare Hooper and Nick Maskell

Pleural infection

Key points

Pleural infection occurs when micro-

organisms, most commonly bacteria, enter

N Pleural infection is common and

the pleural space. This may be due to direct

serious, with a mortality rate of ,15%.

spread from an underlying pneumonia or

N Blood, in addition to pleural fluid,

may result from blood-borne spread of a

should always be cultured. A higher

systemic bacteraemia. It can be confirmed

microbiological yield is achieved if

when pleural fluid has a positive Gram stain

pleural fluid is sent in both a universal

or culture, is frankly purulent or, in the

container and blood culture bottles.

context of sepsis, has an acidic pH (table 1).

N Initial management is with broad-

Pleural infection is a common and serious

spectrum antibiotics and prompt

medical problem and the incidence is rising

chest drainage.

despite advances in medical management. It

is associated with a mortality rate of 15-20%.

N Lung abscess has a 10% mortality

rate.

Epidemiology

N Pleural infection is most common in

N Invasive procedures are only required

when a lung abscess does not

the elderly and children, but can occur

respond to prolonged empirical

at any age

antibiotics or an underlying neoplasm

N It is twice as common in males

is suspected.

20% of adults with pleural infection have

diabetes mellitus

N Other important risk factors include

aspiration, immunosuppression, poor

Bacteriology Bacteria are ultimately cultured

dentition, pleural procedures, thoracic

from either pleural fluid or blood in 60-70%

surgery and penetrating chest trauma

of cases of pleural infection. The microbiology

Pathophysiology Pleural infection most

of community-acquired pleural infection is

different from that of hospital-acquired

frequently follows community-acquired

pleural infection and CAP, such that these

pneumonia (CAP) with bacterial migration

should be considered three distinct diseases

from the lung parenchyma into a

requiring different empirical antibiotic

parapneumonic effusion. It may also follow

regimes. This is probably due in part to the

hospital-acquired and aspiration

differing environment within the pleural

pneumonia with effusion, traumatic or

cavity, which is more hypoxic and has a lower

iatrogenic pleural penetration. Primary

pH than within the lung itself, making certain

pleural infection is more common than

organisms (e.g. anaerobes) more pathogenic.

previously thought, either as a result of

translocation of bacteria from the

In community-acquired pleural infection,

oropharynx or as a consequence of

Streptococcus spp. (largely from the

bacteraemia from other sites.

Streptococcus anginosus group (previously

ERS Handbook: Respiratory Medicine

215

Table 1. Clinical classification of pleural infection

Simple parapneumonic

Complex parapneumonic

Empyema

effusion

Pleural fluid

Straw coloured or bloody

Straw coloured, bloody

Frank pus

appearance

or turbid

Pleural fluid pH

.7.2

Usually ,7.2

Should not be

measured

Pleural fluid

Negative

May be positive

Gram stain

Pleural fluid

Negative

May be positive

culture

Thoracic

Usually anechoic

May show variable

Often

ultrasound

No pleural thickening

echogenicity,

homogenously

appearance

septations or

echogenic

loculations

Usually evidence of

pleural thickening

Loculations and

septations may be

present

Immediate

Effusion will usually resolve

Intravenous antibiotics

Intravenous

management

with antibiotics for

and chest tube

antibiotics and

pneumonia alone

drainage

chest tube drainage

Chest tube drainage can be

performed if required for

symptomatic relief of

breathlessness

known as the Streptococcus milleri group)

Pleural fluid should always be sent for

and Streptococcus pneumoniae) account for

culture and cytological examination. The pH

50% of positive cultures. Staphylococcus

of nonpurulent pleural fluid should be

spp., anaerobic and Gram-negative

measured, and fluid and blood should also

organisms make up the other half.

be sent for protein and lactate

Anaerobic organisms commonly co-exist

dehydrogenase measurement.

with aerobes, particularly with the S.

In the correct clinical context, features

anginosus group. Atypical pneumonia

suggesting that a parapneumonic effusion is

organisms such as Legionella and

complex and, hence, requires chest tube

Mycoplasma spp. are extremely unusual

drainage include:

causes of pleural infection.

In nosocomial pleural infection,

N a pleural fluid pH of ,7.2 (or pleural fluid

Staphylococcus spp. (including methicillin-

glucose of ,2.2 mmol?L^-1)

resistant Staphylococcus aureus (MRSA)) and

N positive pleural fluid culture or Gram

Gram-negative organisms are responsible

stain

for most positive culture results.

N purulent pleural fluid

loculation or septation on thoracic

Investigations When a patient presents with

ultrasound

sepsis and clinical and chest radiographic

signs of a pleural effusion, a diagnostic

A causative organism is not identified in up

pleural aspiration should always be

to 40% of patients with pleural infection, but

performed to establish the presence of

if one is identified, it can be useful to guide

pleural infection.

antibiotic treatment. Culturing the fluid in

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blood culture bottles as well as a standard

drains or thoracic surgical intervention or if

container has been shown to improve the

other pathology such as pulmonary abscess,

microbiological yield and blood cultures

neoplastic lesions or oesophageal rupture is

may also help to achieve a microbiological

suspected.

diagnosis when there is no growth from

Management The following steps should be

pleural fluid.

implemented immediately:

Radiology Chest radiography often

demonstrates a pleural effusion and

N Broad-spectrum intravenous antibiotics

consolidation. When pleural fluid has

N Chest tube drainage

entered the organising phase there may be a

N Nutritional supplementation (oral or

lentiform pleural opacity (fig. 1).

nasogastric)

N Thromboprophylaxis

Thoracic ultrasound is a useful bedside test

N Vigilant monitoring for evidence of

in suspected pleural infection. It helps to

worsening sepsis indicating need for early

differentiate simple parapneumonic

thoracic surgery

effusions from empyema by the presence of

septations and loculations, and should also

Antibiotic choice is usually governed by local

be used to identify a safe site for fluid

prescribing policies and should include

drainage. It also has a role in monitoring the

antibiotics with broad-spectrum coverage

degree of residual pleural fluid collection

and good penetration to the pleural space.

after a chest tube is placed, which may affect

Suitable combinations include penicillin-

the subsequent management plan.

clavulanic acid in community-acquired

infection and carbapenems with vancomycin

Contrast-enhanced CT demonstrates

in nosocomial infection. When cultures are

brightly enhancing pleural thickening in the

available, antibiotics should be modified

organising phase of pleural infection. CT is

accordingly. As anaerobes can be difficult to

only required when initial drainage of fluid is

culture, their presence should be assumed

incomplete, for the planning of further

and cover continued, unless S. pneumoniae

is isolated as this is not known to co-exist

with anaerobes. Conventionally, o5 days’

intravenous antibiotics is followed by

2-4 weeks of oral treatment depending on

clinical and radiological response.

In a clinically stable patient with a small

empyema, chest tube drainage may be

impractical and, hence, treatment with

prolonged antibiotics and careful follow-up

may suffice. However, in the majority of

cases, drainage of the fluid is advocated.

Small-bore (12-14 f) chest tubes are

generally preferred to large-bore tubes as

they can be placed via a Seldinger technique

and are more comfortable for patients.

There is no evidence that large-bore tubes

achieve superior fluid drainage (although

this is still the subject of some debate).

Regular saline flushes (20 mL 6-hourly) may

help to maintain tube patency and larger-

Figure 1. Chest radiograph of left empyema

volume 0.9% saline irrigation of the pleural

demonstrating a D-shaped, lentiform pleural

space has been adopted by some European

opacity.

centres, with reports of improved primary

ERS Handbook: Respiratory Medicine

217

treatment success rates, although this is not

including the elderly and hospital-acquired

yet supported by published evidence.

disease. Overall, mean mortality rates of

15% have been reported in a recent series,

The viscosity of the pleural fluid and degree

but vary depending on certain risk factors. In

of septation may impair tube drainage.

order to identify at presentation which

Routine use of intrapleural fibrinolytics

patients are at the highest risk of a poor

alone have not been shown to be of benefit.

outcome, a validated clinical risk score is

However, recent data suggests the

being developed, which may help guide early

combination of intrapleural tissue

clinical management in those at highest risk.

plasminogen activator (tPA) and DNase

This has highlighted five particular risk

may result in improved radiological

factors for poor outcome, which include age,

outcomes, and showed trends towards a

urea, albumin, hospital-acquired infection

reduction in need for surgery and duration

and nonpurulence.

of hospital stay. However, it has only been

evaluated in a small number of patients and,

Patients should be followed up for

therefore, its place in routine patient

o3 months to allow the early detection of

management is yet to be fully established.

recurrent sepsis or persistent

Approximately 15-20% of patients will

breathlessness.

ultimately require surgical intervention for

Lung abscess

empyema, but selecting which patients are

best suited to this approach can be

Lung abscesses are caused when an area of

challenging. The most compelling indication

infected lung becomes necrotic, which

is failure of sepsis to improve despite

results in the development of a cavity within

appropriate antibiotics and tube drainage,

the lung itself. In contrast to pleural

but other reasons may include a significant

infection, the incidence and mortality rate of

residual pleural collection despite chest tube

lung abscess have steadily declined since

drainage. This assessment is usually made

the advent of penicillin.

after 3-5 days of medical treatment. While

surgical and anaesthetic complications are

Risk factors include:

more common in the elderly and frail, the

vast majority of deaths as a result of pleural

N male sex (2:1)

infection occur in this group and, hence,

N immunocompromised states

early surgical referral for a limited surgical

N aspiration of any cause

drainage procedure may be beneficial.

N pneumonia (particularly S. aureus and

Some European centres advocate early

Klebsiella pneumoniae).

thoracoscopy for these patients.

N bronchial obstruction (e.g. endobronchial

neoplasm is present in 10-20% cases)

Available approaches include:

N haematogenous spread of infection (e.g.

N video-assisted thoracoscopic surgery

tricuspid valve endocarditis and

(VATS)

Lemierre’s syndrome (whereby acute

N open thoracotomy and decortication

oropharyngeal infection caused by

N rib resection and open drainage (often

Fusobacterium spp., results in jugular vein

performed under local anaesthetic)

thrombophlebitis and metastatic septic

N mini-thoracotomy (usually VATS-

embolisation to the lung))

assisted)

Diagnosis Symptoms may be acute or

N thoracoscopy

insidious in onset and commonly include

Outcome It is not possible to reliably

cough, fever, chest pain, night sweats,

identify, by presenting radiological, pleural

weight loss and purulent or blood-stained

fluid or clinical feature,s which patients will

sputum. There may be no specific

go on to require thoracic surgery for

examination findings or chest auscultation

empyema. However, a variety of risk factors

may mimic pneumonia. Anaemia is

for poor outcome have been identified,

common in patients with a chronic lung

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ERS Handbook: Respiratory Medicine

abscess and inflammatory markers are likely

cases, lung abscesses are caused by more

to be raised.

than one microorganism.

Radiology Plain chest radiography classically

Anaerobes (e.g. Fusobacterium, Prevotella

demonstrates a well circumscribed opacity

and Peptostreptococcus spp.), often

within the lung field, which is often thick

originating from the oropharynx, are present

walled and contains an air-fluid level. Right-

in 30-50% and may be particularly

sided abscesses are twice as common as

important in the context of aspiration.

left. Dependent segments are most

However, aerobic bacteria now appear to be

commonly affected when the abscess is

cultured more commonly than anaerobes

caused by aspiration of gastric contents.

(particularly K. pneumoniae and S. aureus).

CT is usually required to distinguish a

Fungi, Nocardia, mycobacteria, Amoeba,

parenchymal abscess from empyema and

actinomycosis and Echinococcus are more

may assist in the detection of neoplastic

unusual causes of a parenchymal lung

lesions. Abscesses have an irregular wall

abscess, and immunocompromise may

and an indistinct outer margin that makes

contribute to their development.

an acute angle with the chest wall. In

contrast, an empyema is lenticular, well

Most patients are treated effectively with

defined and causes compression of the

broad-spectrum antibiotics in the absence of

underlying lung with vascular crowding

a microbiological diagnosis. Blood cultures

(fig. 2).

should be sent and sputum cultured if

available but, frequently, no organism is

The radiological appearances of a lung

identified.

abscess may be mimicked by other

pathologies, including:

Bronchoscopy should be employed when

there is particular suspicion of an underlying

N neoplastic lesions

endobronchial neoplasm or inhaled foreign

N pulmonary vasculitis

body. Culture of bronchial washings is of

N pulmonary infarction

relatively low accuracy and often fails to

N bullae and cysts

focus antibiotic selection beyond empirical

N rheumatoid nodules

choices, but may help to investigate other

N pneumoconiosis

potential causes of lung cavitation, such as

N mycobacterial infection

malignancy or TB. Endobronchial drainage

of large lung abscesses is not usually

Bacteriology and obtaining cultures The

recommended due to the risk of sudden

microbiology of lung abscesses has changed

discharge of pus into the airway, which may

over recent decades, which is predominantly

result in asphyxiation and respiratory

due to an increase in immunocompromise

compromise.

and immunosuppression. In .50% of

Image-guided percutaneous aspiration

using CT, ultrasound or fluoroscopy obtains

a microbiological diagnosis in 80-90% of

cases and changes antibiotic choice in up to

47%. Due to a relatively high risk of

pneumothorax (,14%) as a complication of

these techniques, it is usually reserved for

cases that do not respond to empirical

broad-spectrum antibiotics.

Management A prolonged course of

antibiotics is the foundation of treatment

and, often, up to 8 weeks of treatment is

Figure 2. CT image of a) right pleural empyema

required depending on clinical and

and b) cavitating pulmonary abscess.

radiological response. b-lactam/b-

ERS Handbook: Respiratory Medicine

219

lactamase inhibitor combinations cover the

threatening complications such as

majority of causative bacteria and are a

intractable haemoptysis, bronchopleural

good empirical choice. Local antibiotic

fistula or empyema. A VATS approach is less

policies differ and should be used to guide

invasive than open surgical resection.

antibiotic choices.

Perioperative mortality rates of up to 16%

Patients with very large abscesses should

have been reported following surgery for

ideally be placed in the lateral decubitus

lung abscess and, hence, an attempt at

position with the abscess side down. This

radiological drainage may be considered

may help to prevent spread of the infection

prior to undertaking a surgical procedure.

to the contralateral lung and respiratory

compromise should the abscess suddenly

Lung abscesses are associated with a 10%

discharge the contents into the airway.

mortality rate.

Chest physiotherapy also plays an important

role in management and postural drainage

The elderly or immunocompromised and

may help to clear secretions from the

those with large abscesses (.6 cm),

abscess itself. Preventative measures to

underlying malignancy, malnitrition or a

avoid further aspiration of gastric contents

delay in diagnosis and treatment have a

are also important.

particularly poor outcome.

Fever and infective symptoms usually settle

within a week of appropriate antibiotics.

Further reading

Failure to improve should raise the

Davies CW, et al. (1999). Predictors of

suspicion of drug-resistant organisms, such

outcome and long-term survival in

as MRSA (particularly in the case of

patients with pleural infection. Am J

hospital-acquired infection), or other

Respir Crit Care Med; 160: 1682-1687.

pathologies, such as TB or malignancy.

Davies CWH, et al. (2010). The British

Sustained resolution of sepsis is the most

Thoracic Society Guidelines for the man-

important marker of successful conservative

agement of pleural infection. Thorax; 58:

management as radiological resolution can

Suppl. 2, ii18-ii28.

take up to 3 months.

Grijalva CG, et al. (2011). Emergence of

parapneumonic empyema in the USA.

When appropriate antibiotic therapy fails,

Thorax; 66: 663-668.

invasive intervention to drain the abscess

Kioumis IP, et al. Lung abscess. http://

itself may become necessary. This is more

bestpractice.bmj.com/best-practice/

common in the elderly or immuno-

monograph/927/highlights/summary.html

compromised and for very large abscesses

Maskell NA, et al. (2006). The bacteri-

(.6 cm) and may be necessary in 11-21% of

ology of pleural infection by genetic and

patients. This can either be performed using

standard methods and its mortality sig-

a percutaneous technique or surgery.

nificance. Am J Respir Crit Care Med; 174:

817-823.

Image-guided percutaneous drainage is

Maskell NA, et al. (2012). Rapid Score -

successful in 84% of cases and can be

the first validated clinical score in pleural

achieved with CT, ultrasound or fluoroscopic

infection to identify those at risk of poor

guidance. Complications such as

outcome at presentation. Am J Respir Crit

bronchopleural fistulae, haemothorax and

Care Med; 185: A5341.

empyema are infrequent. As it is usually

Menzies SM, et al. (2011). Blood culture

performed under local anaesthesia, this

bottle culture of pleural fluid in pleural

approach is preferred in patients with

infection. Thorax; 66: 658-662.

significant comorbidities.

Mwandumba HC, et al. (2000). Pyogenic

lung infections: factors for predicting

The precise indications for surgical

clinical outcome of lung abscess and

intervention are not well established, but it

thoracic empyema. Curr Opin Pulm Med;

may be considered in the context of

6: 234-239.

localised obstructing malignancy or life-

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ERS Handbook: Respiratory Medicine

Influenza, pandemics and

SARS

Wei Shen Lim

Seasonal and pandemic influenza

first isolate/laboratory strain number/year of

isolate/H and N subtypes, for example:

Virology Influenza viruses are RNA

influenza A/Hong Kong/1/68/H3N2 (the

orthomyxoviruses with three main types, A,

cause of the 1968 ‘Hong Kong’ pandemic).

B and C. Viral surface proteins include

haemagglutinin (H) and neuraminidase (N),

The natural reservoir hosts of all influenza A

which are involved in viral attachment and

virus subtypes are water birds. The host

release respectively. There are 16

specificity of the various influenza A virus

haemagglutinin (H1-H16) and nine

subtypes is partially determined by the

neuraminidase types (N1-N9). Influenza

binding affinity of haemagglutinin to sialic

viruses are described in a standardised

acid residues on the host cell.

manner according to their type/location of

A notable feature of influenza A viruses is

their propensity to undergo antigenic

variation. The appearance of a novel

Key Points

antigenic type demonstrating efficient

human-to-human transmission is a pre-

Influenza is mostly a self-limiting viral

requisite for a pandemic. Only influenza A

upper respiratory tract infection that is

viruses have been associated with

managed in the community.

pandemics.

Pneumonia is the most frequent

serious complications of influenza.

Seasonal influenza Influenza is mostly a self-

limiting upper respiratory tract infection that

Neuraminidase inhibitors, such as

is managed in the community. In temperate

oseltamivir and zanamivir, are

climates, outbreaks of infections occur

effective in the prophylaxis and

almost exclusively in winter. Attack rates are

treatment of influenza A infection.

highest in young children and the elderly.

The influenza A (H1N1) 2009

pandemic was of low severity

Influenza is highly transmissible. Human-to-

compared to the other pandemics of

human transmission occurs through large-

the 20th century.

droplet spread and direct contact with

secretions (or fomites). There is also

The SARS outbreak of 2003 resulted in

evidence supporting aerosol transmission

8096 cases, of which 774 died.

although the extent and importance of this

SARS-CoV is the causative agent of

is debated.

SARS. Bats are the natural reservoir

The mean incubation period is 2-4 days with

for coronaviruses.

a range up to 7 days. An abrupt onset of high

The management of SARS is chiefly

fever (up to 41uC) is the main presenting

supportive. Basic infection control

feature. The fever peaks within the first 24 h

measures are the cornerstone of

of illness and usually lasts for 3 days. Cough

containment of any future outbreak.

is the next commonest symptom (85%),

which may be associated with sputum

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ERS Handbook: Respiratory Medicine

production in up to 40% of cases. Malaise

associated with tachypnoea, cyanosis and

(80%), chills (70%), headaches (65%) and

bilateral lung crackles on chest examination.

myalgia (50%) may be prominent. Coryza

The commonest chest radiographic

and sore throat are reported in about half of

abnormality is of diffuse bilateral interstitial

patients. In addition, children may present

infiltrates similar to pulmonary congestion.

with vomiting, diarrhoea and abdominal

Progression to respiratory failure is well

pain but these symptoms are uncommon in

recognised. Mortality rates of 6-40% have

adults. The mean duration of symptoms is

been reported. In severe cases, pathological

4 days.

findings are similar to those seen in acute

respiratory distress syndrome (ARDS).

Complications of influenza Although

influenza is mostly a self-limiting illness

Patients with secondary bacterial pneumonia

even without specific treatment, some

complicating influenza typically experience an

patient groups experience significant

amelioration of the initial symptoms of viral

morbidity and mortality. Persons at risk of

infection. However, 4-10 days later, a

complications from influenza include

recurrence of fever together with

pregnant females, the frail elderly, those

breathlessness and a productive cough

who are immunosuppressed, and those with

ensues. Clinical features at this point are

chronic medical conditions such as heart

indistinguishable from community-acquired

bacterial pneumonia. The commonest

disease, chronic respiratory disease (mostly

pathogens implicated are Streptococcus

asthma and COPD), cancer, diabetes, renal

pneumoniae, Staphylococcus aureus,

disease, rheumatologic disease, dementia

Haemophilus influenzae and Streptococcus spp.

and stroke. Rates of hospitalisation and

death are increased in all these patient

In children, the commonest respiratory

groups. Obesity (BMI .30 kg?m^-2) was also

complication, though not the most serious,

identified as being associated with adverse

is otitis media.

outcomes in patients hospitalised with

influenza in the 2009 pandemic.

In addition to the specific complications

listed in table 1, patients with influenza may

Pneumonia is the most frequent serious

also experience a worsening of a pre-existing

complication of influenza. Two main clinical

medical illness, such as COPD or cardiac

patterns are described: primary viral pneu-

failure.

monia and secondary bacterial pneumonia.

Treatment There are two main classes of

Patients with primary viral pneumonia

drug that are active against influenza. The M2

typically become breathless within the first

ion channel inhibitors, amantadine and

few days of the onset of fever. This may be

rimantadine, are effective against influenza A.

Table 1. Complications of influenza in adults and children

Complication

Incidence

Adults

Children

Otitis media

Common

Very common

Secondary bacterial pneumonia

Common

Uncommon

Primary viral pneumonia

Common

Uncommon

Myositis

Uncommon

Rare

Myocarditis

Rare

Encephalitis/encephalopathy

Rare

Reye’s syndrome

Rare

Febrile convulsions

Common

ERS Handbook: Respiratory Medicine

223

However, their use is hindered by the rapid

inadequate, extracorporeal membrane

emergence of resistance to these drugs

oxygenation (ECMO) should be considered

together with a high incidence of side-

based on experience from the 2009

effects. The neuraminidase inhibitors,

H1N1 pandemic.

oseltamivir and zanamivir, are effective

against influenza A and B. Fortunately,

Management of influenza-associated

exacerbations of underlying comorbid

although resistance to oseltamivir has been

illnesses, such as COPD or heart failure,

reported, this is not widespread in seasonal

should follow the same principles for each

influenza A (H3N2). Oseltamivir is often

specific condition regardless of influenza.

generally preferred over zanamivir because

Antibiotics are usually advised for patients

of ease of administration (oral versus

with influenza-associated pneumonia or

inhaled/intravenous). Newer neuraminidase

patients with severe influenza infection who

inhibitors, such as peramivir and

are at high risk of developing secondary

laninamivir, are also being clinically

bacterial infections. The use of

evaluated. A Cochrane meta-analysis of

corticosteroids in severe influenza cannot be

randomised controlled trials of

routinely advocated based on current data;

neuraminidase inhibitors in the treatment

observational cohort studies conducted

of influenza reported that the efficacy of

during the 2009 H1N1 pandemic have

oral oseltamivir at 75 mg daily was 61% (risk

reported mixed results including

ratio (RR) 0.39, 95% CI 0.18-0.85) and of

increased harm.

inhaled zanamivir at 10 mg daily was 62%

(RR 0.38, 95% CI 0.17-0.85). In clinical

Chemoprophylaxis and vaccination Both

terms, this benefit translates to a

oseltamivir and zanamivir, taken as

shortening of the illness by 0.5-1 day. The

prophylactic agents, reduce the chance of

review found the published evidence

symptomatic, laboratory-confirmed

insufficient to answer the question of

influenza (RR 0.38, 95% CI 0.17-0.85 for

whether neuraminidase inhibitors are

zanamivir 10 mg daily; RR 0.39, 95% CI

effective in reducing the complications of

0.18-0.85 for oseltamivir 75 mg daily).

lower respiratory tract infection, antibiotic

However, the effect of neuraminidase

use or admissions to hospital. Oseltamivir

inhibitors on the prophylaxis of influenza-

use is associated with nausea (OR 1.79,

like illness (ILI), which includes infections

95% CI 1.10-2.93). A meta-analysis of

other than influenza, is uncertain.

observational cohort studies of patients

Oseltamivir has also been demonstrated to

with pandemic influenza A (H1N1) 2009

be 58-84% efficacious as post-exposure

found that antiviral treatment was

prophylaxis.

associated with reduced mortality,

hospitalisation and otitis media. However,

Immunisation is the backbone of influenza

the quality of the evidence was graded as

prevention. The relative protective efficacy in

low or very low, reflecting the underlying

children and young healthy adults is 70% to

risk of bias in these observational cohorts.

.90%. Efficacy is lower (,40%) in the

elderly.

For critically ill patients with severe avian

H5N1 influenza infection and for patients

Oseltamivir resistance In 1977, influenza A

(H1N1) re-emerged and co-circulated with

with severe H1N1 primary viral pneumonitis,

an increased dose of antiviral treatment for

influenza A (H3N2), with the latter

an extended duration (e.g. oseltamivir

remaining the dominant seasonal human

150 mg b.d. for 10 days in adults) has been

influenza virus (fig. 1). During the 2007-

used. This practice is not based on evidence

2008 influenza season, oseltamivir-resistant

from randomised controlled trials.

seasonal influenza A (H1N1) viruses

emerged suddenly and spread globally.

For selected critically ill patients with severe

These viruses carried a histidine-to-tyrosine

influenza-associated ARDS and in whom

mutation at residue 275 of the

conventional ventilation is proving

neuraminidase protein (H275Y). Laboratory

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ERS Handbook: Respiratory Medicine

and limited epidemiological data indicated

globally. In contrast, the subsequent two

that the viral fitness and virulence of these

pandemics were much less severe,

oseltamivir-resistant influenza A (H1N1)

accounting for an estimated 1-2 million

viruses were no different from those of

deaths each.

oseltamivir-susceptible strains.

The 2009 pandemic has been the best

In the USA, the prevalence of oseltamivir

studied pandemic of the 20th century. The

resistance among seasonal influenza A

first cases were identified in Mexico in April

(H1N1) viruses increased from ,1% before

2009 and by June 2009, the World Health

the 2007-2008 influenza season to 12%

Organization had declared a pandemic. The

during the 2007-2008 season and rose to

pandemic influenza A (H1N1) 2009 virus

.99% in the 2008-2009 season. This

was a triple-reassortant virus containing

prompted the USA to issue guidelines at the

genes from human, swine and avian

time recommending the use of zanamivir or

influenza viruses. It caused an infection that

a combination of oseltamivir and

was clinically similar to seasonal influenza

rimantadine when oseltamivir-resistant

although gastrointestinal symptoms

seasonal influenza A (H1N1) virus infection

amongst adults were commoner than in

was suspected.

seasonal influenza. Mainly children and

young adults were affected and most

H275Y mutations in pandemic influenza A

illnesses were self-limiting. In persons

(H1N1) 2009 viruses have also been

.60 years old, pre-existing cross-reactive

identified. Fortunately, such oseltamivir-

antibodies due to previous exposure to

resistant isolates remain infrequent and

antigenically related influenza viruses

sporadic, many occurring in immuno-

provided protection against infection.

suppressed patients who appear to be at risk

Compared to the other 20th century

of resistance developing during oseltamivir

pandemics, overall hospitalisation and

therapy.

mortality rates were low. In the UK, the

Pandemic influenza In the 20th century,

overall estimated case fatality rate was 26

pandemics occurred in 1918 (H1N1), 1957

per 100 000; lowest for children aged 5-

(H2N2), 1968 (H3N2) and 2009 (H1N1)

14 years (11 per 100 000) and highest for

(fig. 1). Each of these pandemics had a

those aged o65 years (980 per 100 000).

different impact and tempo. The 1918

Hospitalisation rates varied across

pandemic was the deadliest, claiming the

countries. Of those hospitalised, 9-31%

lives of an estimated 40-100 million people

required intensive care support,

predominantly because of diffuse viral

pneumonitis or ARDS. The mortality of

2009

Pandemic

intensive care unit-admitted patients was

H1N1¶

14-46%.

H1N1

H3N2

After 2009, some countries experienced a

H2N2

further wave of influenza A (H1N1) 2009

H1N1

infections in the 2010-2011 influenza season.

However, in the following 2011-2012 influenza

1918

1957

1968

1977

2009

season, influenza A (H3N2) predominated in

most countries and overall influenza activity

was much lower compared with previous

Figure 1. Influenza pandemics and subtypes,

years. Based on past events, the threat of a

1918-2009.^#: re-emergence of H1N1, possibly

future pandemic remains but its timing and

from accidental laboratory release - strain closely

severity are not currently predictable.

related to 1950 strain.^": new reassortment of six

gene segments from triple-reassortant North

Severe acute respiratory syndrome

American swine influenza virus lineages and two

gene segments from Eurasian swine influenza virus

Epidemiology The global outbreak of severe

lineages.

acute respiratory syndrome (SARS) in

ERS Handbook: Respiratory Medicine

225

2002-2003 affected 8096 individuals in 29

been described that might explain the shift

countries, 774 of whom died. The three most

in mode of transmission. Nosocomial

severely affected regions were mainland

transmission was particularly high, with

China, Hong Kong and Taiwan with 5327,

attack rates amongst healthcare workers in

1755 and 674, cases respectively.

some centres ranging from 10% to 60%. In

contrast, community transmission rates

The first human case was identified in the

were much lower, with typically ,10% of

city of Foshan in Guangdong Province,

contacts infected.

China on November 16, 2002 and the last

known case of the initial outbreak

The mean incubation period of SARS is

experienced the onset of symptoms on

estimated at 4-6 days with a maximum

June 15, 2003 in Taiwan.

incubation period of 10 days. Overall, SARS

may be considered to be low-to-moderately

A novel coronavirus, the SARS coronavirus

transmissible. A few remarkable super-

(SARS-CoV), was identified as the causative

spreading events (SSEs) were associated

agent of SARS in April 2003. Close human-

with SARS in which single individuals were

animal contact associated with many of the

responsible for infecting many more

early cases in China supported the concept

individuals than the average. In one SSE at

of SARS as a zoonotic infection. While

the Prince of Wales Hospital, Hong Kong, a

market animals such as the palm civet cat

single patient infected 143 people.

Paguma larvata have been identified as the

likely animal sources of the 2003 outbreak,

Clinical features The clinical presenting

bats are now recognised as the natural

features of SARS infection are nonspecific.

reservoir for coronaviruses. Coronaviruses

Fever (93%), chills (61%), malaise (46%),

sharing 87-92% genome nucleotide identity

cough (41%) and rigors (38%) were the

with SARS-CoV have been found in

predominant symptoms recorded in the

horseshoe bats (Rhinolophus sp.).

Hong Kong-wide clinical database of SARS

Accordingly, one hypothesis is that

patients. High-volume, watery, nonbloody

coronaviruses were transmitted from

diarrhoea is present in a sizeable minority of

horseshoe bats to civet cats and then to

patients (,20%) in the early stages of

humans (fig. 2).

disease and increases in frequency (up to

70%) by the second week of illness. It is

Subsequent infections later in the course of

usually self-limiting. Similarly, respiratory

the outbreak were due mainly to human-to-

symptoms of cough, breathlessness and

human transmission. Molecular

sputum production are less frequently

evolutionary changes of SARS-CoV have

(,50%) encountered in the first 4 days of

Horseshoe bat - coronavirus Palm civet cat - coronavirus with

Human SARS-CoV - further

with 87-92% genome

99.8% genome sequence identity to

evolution during course of

sequence identify to human

human SARS-CoV

epidemic

SARS-CoV

? Single-step transmission

Natural reservoir

Pre-epidemic source

Human epidemic

Figure 2. Possible origin of SARS, based on phylogenetic studies.

226

ERS Handbook: Respiratory Medicine

illness, but increase to a peak (70%) by day

Chemical compounds that have reported

9 or 10 of illness. Typically, a dry cough is

activity against SARS-CoV include

the first respiratory symptom. This is

glycyrrhizin, baicalin, reserpine,

followed by breathlessness, which worsens

niclosamide, ribavirin, protease inhibitors

at the start of the second week.

(lopinavir and nelfinavir), interferon (IFN)-a

and IFN-b. A comparative study using IFN

Radiological changes of airspace

alfacon-1 (n522) and another using a

consolidation are usually unilateral and

lopinavir/ritonavir combination (n541)

localised in the first week. The infiltrates are

suggested clinical benefit. However, there

commoner in the lower lobes (70%) and the

are no randomised controlled trials of

periphery (75%). Cavitation,

treatment.

lymphadenopathy and pleural effusions are

not described in association with SARS

Corticosteroids were used during the SARS

infection. The extent of radiological

outbreak as an immunomodulatory agent

abnormality correlates with severity of

with the intention of limiting the damage

illness and prognosis.

that might be caused by the host immune

response. In reported series, there were

Laboratory test abnormalities include

large variations in type, dose, route and

lymphopenia, neutropenia,

duration of corticosteroids used.

thrombocytopenia, and raised levels of

Unsurprisingly, different conclusions

lactate dehydrogenase (LDH), alanine

about the efficacies of corticosteroids

aminotransferase (ALT), creatinine kinase

were drawn.

and activated partial thromboplastin time.

Basic infection control measures are the

Respiratory failure occurs in 20-25% of

cornerstone of containment of any future

patients, mainly adults. Unusually, the

outbreak. As subclinical infection with

incidence of barotrauma (manifesting as a

SARS has not been described and the peak

pneumothorax or pneumomediastinum)

in viral load occurs late (second week),

was observed to be higher in severely ill

effective infection control measures can

patients with SARS than might be expected

often be instituted prior to widespread

despite the use of low-volume, low-pressure

transmission.

mechanical ventilation strategies. The

reason for this is unclear. Patients with

Practice points regarding the clinical

SARS requiring critical care support have a

diagnosis of influenza or SARS

mortality of ,25%. Features associated with

a poor prognosis include advanced age,

The early symptoms in both influenza and

male sex, presence of comorbid illness, high

SARS are nonspecific, comprising primarily

serum LDH and neutrophilia at presenta-

of a fever in association with respiratory

tion, and an initial radiograph with more than

symptoms, such as cough, and systemic

one zone of involvement. Overall, adults

symptoms, such as malaise or chills. A

suffer a more severe disease than children.

clinical diagnosis of influenza or SARS is,

therefore, crucially dependent on

Virology SARS-CoV is detectable by RT-PCR

epidemiological features. In the case of

and by culture from respiratory tract, faecal

influenza, an ILI in the setting of local or

and urine samples. Virus RNA is also

community circulation of influenza viruses

detectable in serum, plasma and

(e.g. during an influenza season or during a

cerebrospinal fluid, indicating multisystem

pandemic) greatly increases the likelihood

infection. Diagnostic yields are better with

that the illness is due to influenza virus

nasopharyngeal aspirates and faeces

infection: the positive predictive value of an

compared with throat swabs. A retrospective

ILI for laboratory-confirmed influenza can

diagnosis of SARS is possible using

range from 20% to 70%. Alternative

serological tests.

pathogens to consider in instances of an ILI

Clinical management The management of

include parainfluenza virus, adenovirus,

SARS is chiefly supportive.

rhinovirus, Mycoplasma pneumoniae and

ERS Handbook: Respiratory Medicine

227

even Streptococcus pneumoniae. Similarly, a

Miller E, et al. (2010). Incidence of 2009

clinical diagnosis of SARS requires the

pandemic influenza A H1N1 infection in

establishment of an epidemiological link

England: a cross-sectional serological

with another patient with SARS, or exposure

study. Lancet; 375: 1100-1008.

to likely animal sources of SARS-CoV.

Monto AS et al. (2008). Seasonal and

pandemic influenza: a 2007 update on

Virological testing is necessary to make a

challenges and solutions. Clin Infect Dis;

definitive diagnosis in both influenza

46: 1024-1031.

and SARS.

Palese P (2004). Influenza: old and new

threats. Nat Med; 10: S82-S87.

Further reading

Peiris JS, et al. (2003). The severe acute

respiratory syndrome. N Engl J Med; 349:

Cleri DJ, et al.

(2010). Severe acute

2431-2341.

respiratory syndrome (SARS). Infect Dis

Van Kerkhove MD, et al. (2011). Risk factors

Clin North Am; 24: 175-202.

for severe outcomes following 2009 influ-

Hsu J, et al. (2012). Antivirals for treat-

enza A (H1N1) infection: a global pooled

ment of influenza: a systematic review

analysis. PLoS Med; 8: e1001053.

and meta-analysis of observational

Writing Committee of the WHO

studies. Ann Intern Med; 156: 512-524.

Consultation on Clinical Aspects of

Jefferson T, et al. (2010). Neuraminidase

Pandemic (H1N1) 2009 Influenza, et al.

inhibitors for preventing and treating

(2010). Clinical Aspects of Pandemic

influenza in healthy adults. Cochrane

2009

Influenza A

(H1N1) Virus

Database Syst Rev; 2: CD001265.

Infection. N Engl J Med; 362: 1708-1719.

Lew TW, et al. (2003). Acute respiratory

Yip CW, et al.

(2009). Phylogenetic

distress syndrome in critically ill patients

perspectives on the epidemiology and

with severe acute respiratory syndrome.

origins of SARS and SARS-like corona-

JAMA; 290: 374-380.

viruses. Infect Genet Evol; 9: 1185-1196.

228

ERS Handbook: Respiratory Medicine

Pulmonary tuberculosis

Giovanni Sotgiu and Giovanni Battista Migliori

The World Health Organization (WHO) has

Aetiology

declared TB a global emergency due to its

TB is an infectious disease caused by

burden in terms of cases and deaths.

aerobic, nonmotile, non-spore-forming

Among the factors contributing to

bacteria belonging to the family

maintenance of the TB pandemic are:

Mycobacteriaceae in the order

N the large number of patients co-infected

Actinomycetales. Among the species

with HIV

belonging to the Mycobacterium tuberculosis

N multidrug resistance to anti-TB drugs (i.e.

complex (Mycobacterium africanum,

strains resistant to at least isoniazid (H)

Mycobacterium bovis, Mycobacterium canettii,

and rifampicin (R))

Mycobacterium caprae, Mycobacterium

N migration from high-incidence countries

microti and Mycobacterium pinnipedii), the

N the social determinants of the disease (in

most frequent and important agent of

particular, poverty, drug abuse and

human disease is M. tuberculosis.

homelessness)

Mycobacteria are 2-4 mm long and 0.2-5 mm

wide, with a bacterial generation time of 18-

TB can affect virtually every organ, most

24 h. They are defined as acid-fast bacilli

importantly the lungs (pulmonary TB).

(AFB) by Ziehl-Neelsen staining, owing to

their cell wall structure, which is crucial to

their survival and characterised by a

significant content of mycolic acid attached

Key points

to the underlying peptidoglycan-bound

polysaccharide arabinogalactan. An

With 8.8 million new cases (0.21 being

outermost structure, characterised by an

MDR-TB) and 1.1 million deaths, TB is

elevated concentration of carbohydrates that

a first-class health priority.

function in cell-cell interactions, completes

N Diagnosis of pulmonary TB is simple,

the mycobacterial envelope. The

being primarily based on bacteriology

peptidoglycan network, located just outside

(sputum smear microscopy and

the cell membrane, confers cell wall rigidity

culture). Recently, a new molecular

and protects a genome with ,4000 genes.

technique (Xpert MTB/RIF) for the

Two groups of genes are crucial in the

rapid diagnosis of TB and rifampicin

physiology of the mycobacteria: one

resistance has been recommended as

encoding b-oxidation related-enzymes for

the standard in Europe.

energetic processes; and the other encoding

PE and PEE families of proteins functioning

N Treatment of pan-susceptible cases of

in virulence and molecular mimicry

pulmonary TB is effective and cheap.

processes. Furthermore, a relevant

Management of pulmonary TB in

pathogenic role is attributed to the genes

MDR-TB/HIV co-infected cases is

encoding glycolipids of the envelope,

particularly complicated.

interplaying with the host innate and

adaptive immune responses as well as with

ERS Handbook: Respiratory Medicine

229

the metabolism of anti-TB drugs, due to

N Toll-like receptors

their chemical characteristics.

N nucleotide-binding oligomerisation

domain-like receptors

Pathogenesis

N C-type lectins

N PE and PEE families of acidic, glycine-rich

Mycobacteria are spread through air

proteins

droplets expelled by infectious pulmonary

N induction of regulatory T-cells (delay of

TB individuals coughing, sneezing or

priming following the interaction with

speaking. Close contacts (those with

antigen-presenting cells and the

prolonged, frequent or intense contact with

production of interleukin-10)

pulmonary TB cases) are at highest risk of

becoming infected. Climate and human

Unfortunately, innate and adaptive immunity

population density may affect the intensity

cannot eradicate mycobacterial strains and a

and duration of human relationships and,

latent TB infection (LTBI) follows in the

consequently, the probability of close

majority of cases; rarely, infection progresses

contact. The majority of mycobacteria,

to active disease, called primary progressive

moved on droplet nuclei sized .5 mm, are

pulmonary TB (common among children

trapped in the upper parts of the airways by

aged f4 years). During the initial phase (2-

the nasal vibrissae and by the mucus

12 weeks), the bacteria continue to multiply

secreted by goblet cells, while the cilia of the

slowly but exponentially (a cell division every

epithelial cells constantly beat them upward

25-35 h) and T-cells are attracted by cytokines

for removal. Environmental factors like

released by macrophages. In the

humidity, temperature and ventilation can

immunocompetent, the next defensive stage

modify the dimension and density of

is formation of granulomata around

droplets containing mycobacteria. Bacteria

mycobacteria, which limits bacterial

in droplet nuclei sized 1-5 mm can bypass

replication and spread to other pulmonary

the mucociliary system and reach the alveoli,

sites, establishing latency of the infection

usually located in subpleural and in mid-

(potential sustained T-cell responses).

lung zones, where they are rapidly engulfed

Granulomata, whose size range from 1 mm to

by macrophages, which are part of the

2 cm, are characterised by different

innate immune system and the most

macrophage populations that secrete pro-

abundant phagocytic cells located in the

and anti-inflammatory cytokines, and by a

alveolar spaces; they are readily active

chemical and physical microenvironment,

without requiring previous antigenic

which induces mycobacterial dormancy

exposure. Macrophages engulfing

genes. CD4⁺ T-cells, primed in the regional

mycobacteria transfer to draining lymph

lymph nodes and migrating to the site of

nodes in order to prime naïve lymphocytes,

infection, produce cytokines that function in

after having enrolled other mononuclear and

CD8⁺ lymphocyte enrolment (e.g. interleukin-

nonmononuclear cells in the alveolar

15), the activation of regulatory T-cells and

spaces. Mycobacteria significantly growing

the inhibition of mycobacterial replication

for the first 3 weeks are controlled by

(IFN-c). Lesions in those with an adequate

phagocytic cells, activated mainly by T-cells

immune system undergo fibrosis and

producing interferon (IFN)-c. Infection

calcification, while in immunocompromised

could be crucially favoured by the slow

subjects, they progress to primary

pulmonary enrolment of T-cells. Numerous

progressive pulmonary TB.

bacterial and host mechanisms are involved

in the uptake of the mycobacteria, such as:

The majority of infected individuals

developing pulmonary TB experience the

N mycobacterial lipoarabinomannans

disease within the first 2 years following

N ligands for macrophage receptors

infection. Dormant bacilli, however, may

N complement proteins C2a and C3b, which

persist for years before being reactivated to

bind to the cell wall and enhance

produce secondary pulmonary TB. Overall, it

recognition of the mycobacteria by

is estimated that the lifetime risk of

effector macrophages

developing TB, given infection, is 5-10% in

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ERS Handbook: Respiratory Medicine

those who are immunocompetent and 5-

It was estimated that 210 000-380 000

10% per year in HIV-positive individuals.

(best estimate 290 000 individuals) cases

Age is an important determinant of the risk

of multidrug-resistant (MDR)-TB emerged

of disease after infection. Among infected

worldwide in 2010, with an estimated

subjects, the incidence is highest in

prevalence of 650 000 cases. WHO

childhood up to the age of 8 years (35-50%

identified 27 high MDR-TB burden

in children close contacts of contagious

countries, with almost half of them (13)

patients), with a second peak during

located in the geographical area of the

adolescence and early adulthood. The risk

Former Soviet Union. Belarus and Moldova

may increase in the elderly, possibly because

described the highest prevalence among

of waning immunity and comorbidities (e.g.

new (26%) and previously treated (65%)

diabetes mellitus, chronic renal failure,

patients. In 2006, a new drug-resistant form

of TB was described and defined as

silicosis, gastrectomy, jejunoileal bypass,

extensively drug-resistant (XDR)-TB,

and solid and liquid neoplasias).

characterised as MDR strains resistant to

Epidemiology

fluoroquinolones and to at least one second-

line injectable drug (amikacin, capreomycin

WHO estimates that 8.8 (range 8.5-

or kanamycin). The percentage of XDR-TB

9.2) million new cases of TB occurred in

among MDR-TB cases was 12.2% in the

2010. India, China, South Africa, Indonesia

WHO European Region. Globally, drug

and Pakistan recorded the highest

susceptibility testing (DST) to diagnose

incidence. Asia (South-East Asia and the

MDR/XDR-TB is performed only in ,2% and

Western Pacific region) accounts for 59% of

6% of new and previously treated TB cases,

global cases and Africa for 26%. TB/HIV co-

respectively; moreover, MDR-TB therapy was

infection was detected in 1.1 (range 1.0-

started in only 16% of the 290 000 MDR-TB

1.2) million individuals, mainly living in the

cases in 2010. Those programmatic

WHO African Region (82%). From 1990 to

shortcomings in the diagnosis and

1997, TB incidence decreased but the

treatment of drug-resistant cases will favour

positive trend was reverted by the HIV/AIDS

the emergence and spread of mycobacterial

epidemic; however, the implementation and

strains.

scale-up of several preventive measures, as

Approximately 1.1 (range 0.9-1.2) million TB

well as the distribution of successful

patients died in 2010; an estimated 350 000

antiretroviral drugs, has favoured a positive

were HIV positive.

declining trend since 2004 at an annual rate

of -1.3%. However, the positive declining

Clinical features

trend of TB prevalence since 1990 has not

been affected by the HIV/AIDS epidemic.

Before the HIV/AIDS epidemic, almost two-

thirds of all TB cases were pulmonary; an

The estimated incidence in the WHO

increase in extra-pulmonary, and pulmonary

European region was 418 000 (range

and extra-pulmonary forms has been

335 000-496 000) in 2010, with four

reported over recent decades.

countries showing an elevated TB

notification rate (i.e. Kazakhstan, Moldova,

Primary pulmonary TB frequently occurs

Georgia and Kyrgyzstan with 123, 115, 107

without clinical signs and symptoms or

and 106 cases per 100 000 inhabitants,

takes a paucisymptomatic course

respectively). The global TB notification rate

resembling mild respiratory tract infection.

has declined since 2006, from 47.4 per

100 000 inhabitants to 43.2 per 100 000

In the majority of cases, the primary

inhabitants in 2010 (8.7% decrease).

infection is contained, largely resolves and a

small calcified nodule (Ghon lesion)

Globally, 12 (range 11-14) million prevalent

persists. Mostly in children and in

cases of TB were estimated to exist in 2010,

individuals with impaired immunity, the

equivalent to a prevalence of 178 cases per

primary infection can progress to pleural

100 000 population.

effusion; only in certain circumstances it

ERS Handbook: Respiratory Medicine

231

may develop further to more acute infection,

programmes are absent. Over recent years,

and induce fever, cough, pain and dyspnoea.

fluorescence microscopy was introduced in

In children aged ,4 years, a systemic

numerous laboratories, adding 10%

disease and/or meningoencephalitis can be

sensitivity to that of conventional light

diagnosed after primary regional

microscopy. An increased sensitivity of 10-

lymphadenitis.

20% can be obtained after centrifugation

and/or sedimentation. WHO has proposed a

Secondary pulmonary or post-primary TB

case definition for sputum smear-negative

results from endogenous reactivation of a

pulmonary TB based on three negative

LTBI and is frequently located in pulmonary

sputum smears, radiographic abnormalities

areas where the oxygen concentration is

consistent with active pulmonary TB and no

higher and favours mycobacterial replication

response to a course of broad-spectrum

(upper lobes).

antibiotics. Although sputum smear-

negative pulmonary TB cases are not

Early clinical signs and symptoms consists

considered to be infectious, their high

of low-grade fever, asthenia, weight loss

number is causing increasing concern in

(inappetence and altered metabolism

high HIV prevalence, low-income settings.

associated with systemic inflammatory

response to mycobacteria) and night

Sputum induction with hypertonic saline is a

sweats. A mucopurulent cough develops in

useful technique for diagnosing pulmonary

the majority of patients: a duration of at

TB in individuals who are either sputum

least 2-3 weeks has to be considered the

smear negative or unable to produce

main clinical symptom, whereas

sputum. Repeated sputum induction

haemoptysis (i.e. coughing up of blood) in

increases the yield of both smear and

the late stages of the disease might be due

culture. It avoids invasive procedures and

to the rupture of a dilated vessel in a cavity

provides a means of diagnosis in resource-

(Rasmussen’s aneurysm) or to an

poor settings. It is worth noting that sputum

aspergilloma in an old cavity. A pleuritic

induction should be carefully conducted in a

process can cause chest pain. Rales and

well-ventilated setting, as it is a cough-

dullness can be detected in only a few

inducing procedure with a high risk of

individuals.

mycobacterial exposure.

Diagnosis

Mycobacterial culture is considered the gold

standard; however, false-positive results do

At .100 years old, sputum smear

occur, primarily as a consequence of

microscopy (Ziehl-Neelsen staining) is still

laboratory contamination. Moreover, several

the most widely used technique for the

weeks are required for the performance of

diagnosis of pulmonary TB. Although highly

culture-based methods, although the use of

specific, the lower limit of detection of

liquid media has decreased pulmonary TB

microscopy is 0.5-1610⁴ organisms per mL

diagnosis time. DST for first- and second-

sputum and only about half of all culture-

line drugs is also useful in order to better

positive cases have sputum smear-positive

define the phenotype of the isolated strain in

results. At least two sputum samples should

culture-confirmed cases.

be sent to the laboratory for a microscopic

examination; at least one of them should be

Molecular techniques (nucleic acid

collected in the early morning. The first

amplification (NAA)) based on gene

specimen is positive in 85.8% of the sputum

amplification have shown an unpredictable

smear positive individuals; the average

sensitivity, particularly in sputum smear-

incremental yield of the second specimen is

positive cases and extra-pulmonary forms,

11.1%. However, sensitivity may be lower

and a low negative predictive value. The

among HIV-infected subjects and in

major limitation, mainly for low-income

children. AFB microscopy is simple to

countries, is their current high cost and the

perform but suboptimal results are

risk of contamination (false-positive

described where adequate quality-assurance

results). Recently, WHO endorsed a new

232

ERS Handbook: Respiratory Medicine

molecular technique (Xpert MTB/RIF;

results are obtained when patients have been

Cepheid, Sunnyvale, CA, USA) for the rapid

infected with M. tuberculosis and when

(,1 h 45 min) diagnosis of TB and

subjects have been sensitised by

rifampicin resistance, which is deemed a

nontuberculous mycobacteria acquired

surrogate marker of MDR-TB. Rapid scale-

environmentally or M. bovis bacille Calmette-

up of this technique has started globally. In

Guérin (BCG) vaccination, because of the

2012, this technique was recommended in

antigenic cross-reactivity of PPD.

the European Union standards for TB care.

Finally, IFN-c release assays (IGRAs) have

Chest radiology (fig. 1) and CT are useful

recently been introduced into clinical

tools that complement bacteriological

practice. They detect adaptive cellular

examinations in the diagnosis of pulmonary

immune reactivity towards M. tuberculosis-

TB. Although over- and under-reading have

specific antigens encoded by genes located

been described, these tools can offer

in the RD-1 genomic region. Their

important information to the clinician. Chest

application in specimens collected from the

radiography is commonly used to screen

infected organ (e.g. bronchoalveolar lavage)

individuals harbouring a significantly higher

or tissue for the clinical diagnosis of TB is

risk of pulmonary TB (e.g. prisoners,

still under evaluation, but seems promising

contacts of infectious cases, etc.).

(specificity .80%). These techniques can

increase the low specificity of TST based on

Among the tools indirectly used to detect

the immune response (release of IFN-c) to

mycobacterial infection, the tuberculin skin

the 6-kDa early secreted antigenic target

test (TST) is widely used, even if several

protein (ESAT-6), the 10-kDa culture filtrate

limitations, including poor specificity,

protein (CFP-10) and TB7.7, which are

difficult administration and the risk of

antigens specific to M. tuberculosis and are

anergy, are reported. It identifies adaptive

not produced by M. bovis BCG or

immunity to mycobacterial antigens,

environmental mycobacteria. Although the

injected intradermally as a protein

diagnostic sensitivity of IGRAs performed

precipitate (purified protein derivative

using blood seems higher than that of TST,

(PPD)) in the volar part of the forearm

it is not sufficient to rule out TB. Their

(Mantoux test). PPD, constituted by

negative predictive value for progression

different molecules, is derived by filtration of

from LTBI to active TB disease is 97.8-

M. tuberculosis cultures.

99.8% within 2 years.

False-negative reactions are common in

Treatment

immunocompromised patients and in those

with overwhelming pulmonary TB. Positive

Individuals with active TB and positive

sputum smear test results are the main

source of TB transmission in the community

owing to their high bacillary load. The most

relevant priority in TB control programmes

is the rapid identification of new cases of

sputum smear-positive pulmonary TB and

their effective treatment. It has been

estimated that case-finding and effective

treatment of sputum smear-positive

individuals could halve the global number of

TB cases within a decade.

Short-course regimens are divided into an

initial or bactericidal phase and a

continuation or sterilising phase.

Figure 1. Improvement of pulmonary TB with a

large cavity in the right upper lobe following

WHO recommends treatment of new cases

adequate treatment.

of pulmonary TB with a standardised

ERS Handbook: Respiratory Medicine

233

regimen of four first-line anti-TB drugs,

Total duration should be o20 months.

including isoniazid, rifampicin,

Management of MDR/XDR-TB cases is more

pyrazinamide (Z) and ethambutol (E) for

complicated from a clinical and public

2 months (intensive phase), followed by

health perspective, being more expensive,

isoniazid and rifampicin for 4 months

more toxic and less efficacious (table 4).

(continuation phase) (tables 1-3).

Treatment of MDR- and XDR-TB cases

Fixed-dose combinations of two (isoniazid

should be managed in highly specialised

and rifampicin), three (isoniazid, rifampicin

reference centres by high skilled healthcare

and pyrazinamide) and four (isoniazid,

workers, identified by national authorities.

rifampicin, pyrazinamide and ethambutol)

Relevant clinical decisions (e.g. when to start

drugs are highly recommended.

and interrupt treatment, how to design the

regimen, how to manage an adverse event,

Individuals with a previous TB diagnosis

etc.) should ideally be taken within a team of

and treatment for .1 month are at higher

experts with complementary competences

risk of being infected with drug-resistant

(a consilium or similar body). Consilia,

strains and, consequently, DST is necessary.

which are presently only available to cover

In settings where rapid molecular-based

internationally funded MDR-TB treatment

DST is available, the results should guide

projects, are considered by WHO to be

the choice of the treatment regimen.

important in ensuring the best possible

management of these difficult-to-treat cases

The standard re-treatment regimen

and to prevent development of super-

containing first-line drugs (2HRZES/1HRZE/

resistance. The European Respiratory

5HRE) is recommended by WHO for

Society (ERS) and WHO are presently

treatment of TB patients returning after

offering this service cost-free via an

default or relapsing from their first

electronic platform through which clinicians

treatment course if country-specific data

will receive expert advice within 1 week

show low or medium levels of MDR in such

(www.tbconsilium.org).

patients.

Scaling-up of culture and DST capacities,

If the setting-specific prevalence of MDR-TB

and the expanded use of high-technology

is high, re-treatment cases should be

assays for rapid determination of resistance

managed as if they harbour MDR-TB strains.

(e.g. GeneXpert) are necessary if better

While rapid molecular-based methods allow

control of MDR- and XDR-TB is to be

a first orientation, DST for all second-line

achieved. The majority of resistant cases can

drugs should be promptly requested to allow

be treated successfully if well-designed

the design of an adequate regimen.

regimens are used and surgical options are

Treatment duration is identical in HIV-

carefully considered. Nevertheless, the

positive and -negative patients.

development of new (more effective and less

Antiretroviral therapy should be started

toxic) drugs to treat patients is urgently

within 2 months of the start of the anti-TB

needed. Adherence to internationally agreed

therapy in order to reduce the risk of death,

standards of care and control practices is

irrespective of CD4⁺ cell counts. However,

imperative.

drug-drug interactions, a relevant pill

However, to reduce the emergence of new

burden and the potential occurrence of

cases of TB, it is strategically crucial to

immune reconstitution inflammatory

identify and treat the infected subjects at

syndrome (IRIS) can hinder an adequate

higher risk of developing TB. National and

management.

international guidelines agree on the

A regimen with at least four effective drugs

screening of HIV-positive patients, children

is recommended for MDR-TB cases. At least

and adults with close contact with an

four second-line drugs should be

infectious case, individuals who are going to

administered, with an injectable for the

be treated with anti-tumour necrosis factor-a

intensive phase of treatment (8 months).

drugs. Isoniazid, administered for

234

ERS Handbook: Respiratory Medicine

Table 1. Anti-TB drugs, dosages and common adverse effects

Anti-TB drug

Recommended daily dosage

Common adverse effects (not

exclusive)

Group 1: first-line oral

agents

Isoniazid

5 mg?kg^-1 OD

Elevated transaminases

Should not exceed 300 mg

Hepatitis

per day

Peripheral neuropathy

Always consider co-

GI intolerance

administration of vitamin B6

CNS toxicity

Rifampicin

10 mg?kg^-1 OD

Elevation of liver enzymes

.50 kg: 600 mg

Hepatitis

,50 kg: 450 mg

Hypersensitivity

Fever

GI disorders: anorexia, nausea,

vomiting, abdominal pain

Discoloration (orange or brown)

of urine, tears and other body

fluids

Thrombopenia

Ethambutol

15-25 mg?kg^-1 OD

Optic neuritis

Maximum 2.0 g per day

Hyperuricaemia

Peripheral neuropathy (rare)

Pyrazinamide

30 mg?kg^-1 OD

Arthralgia

Maximum 2.0 g per day

Hyperuricaemia

Toxic hepatitis

GI discomfort

Group 2: injectables

Streptomycin^#

0.75-1 g OD

Auditory and vestibular nerve

,50 kg: 0.75 g per day

damage (irreversible)

.50 kg: 1 g per day

Renal failure (usually reversible)

Maximum cumulative dose 50 g

Allergies

Nausea

Skin rash

Neuromuscular blockade

Amikacin^"

0.75-1 g OD

Auditory and vestibular nerve

,50 kg: 0.75 g per day

damage (irreversible)

.50 kg: 1 g per day

Renal failure (usually reversible)

Maximum cumulative dose 50 g

Allergies

Nausea

Skin rash

Neuromuscular blockade

Capreomycin^#

0.75-1 g OD

Auditory and vestibular nerve

,50 kg: 0.75 g per day

damage (irreversible)

.50 kg: 1 g per day

Renal failure (usually reversible)

Maximum cumulative dose 50 g

Bartter-like syndrome

Allergies

Neuromuscular blockade

ERS Handbook: Respiratory Medicine

235

Table 1. Continued

Anti-TB drug

Recommended daily dosage

Common adverse effects (not

exclusive)

Kanamycin^"

375-500 mg b.i.d.

Auditory and vestibular nerve

,50 kg: 0.75 g per day

damage (irreversible)

.50 kg: 1 g per day

Renal failure (usually reversible)

Maximum cumulative dose 50 g

Allergies

Nausea

Skin rash

Neuromuscular blockade

Group 3: fluoroquinolones⁺

Levofloxacin

500-1000 mg OD

GI discomfort

CNS disorders

Tendon rupture (rare)

Hypersensitivity

Clostridium difficule colitis

Ciprofloxacin

500-750 mg b.i.d.

GI discomfort

CNS disorders

Tendon rupture (rare)

Hypersensitivity

Clostridium difficule colitis

Moxifloxacin

400 mg OD

GI discomfort

Headache

Dizziness

Hallucinations

Increased transaminases

QT prolongation

Clostridium difficile colitis

Group 4: second-line oral

agents

Rifabutin

150-450 mg OD

Anaemia

Consider monitoring drug levels

GI discomfort

Discoloration (orange or brown)

of urine and other body fluids

Uveitis

Elevated liver enzymes

Ethionamide

0.75-1 g OD

Severe GI intolerance

Nausea

Vomiting

Hepatitis

CNS disorders

Prothionamide

0.75-1 g OD

Severe GI intolerance

Nausea

Vomiting

Hepatitis

CNS disorders

236

ERS Handbook: Respiratory Medicine

Table 1. Continued

Anti-TB drug

Recommended daily dosage

Common adverse effects (not

exclusive)

Cycloserine

250 mg t.i.d.

CNS disorders

Maximum 1000 mg per day

Anxiety

Confusion

Dizziness

Psychosis

Seizures

Headache

Terizidone

250 mg t.i.d.

CNS disorders

Maximum 1000 mg per day

Anxiety

Confusion

Dizziness

Psychosis

Seizures

Headache

PAS

4g t.i.d.

GI intolerance

Nausea

Diarrhoea

Vomiting

Hypersensitivity

Thioacetazone

50 mg t.i.d.

Hypersensitivity

GI intolerance

Vertigo

Hepatitis

Group 5: oral reserve drugs

with uncertain anti-TB

activity

Linezolid

600 mg OD (600 mg b.i.d.

Thrombopenia

recommended for MRSA and

Anaemia

VRE infections)

Neuropathy

Clofazimine

100 mg OD

Ichthiosis

GI discomfort

Nausea

Vomiting

Discoloration of the skin

Amoxicillin-clavulanate

875-125 mg b.i.d. or 500-

GI discomfort

250 mg t.i.d.

Diarrhoea

Rash

Clarithromycin

500 mg b.i.d.

GI discomfort

PAS: para-aminosalicylic acid; OD: once daily; MRSA: methicillin-resistant Staphylococcus aureus; VRE:

vancomycin-resistant Enterococcus; GI: gastrointestinal; CNS: central nervous system.^#: intravenous/

intramuscular administration only;^": intravenous administration only;⁺: also available from intravenous

administration.

6-12 months at a dosage of 5 mg?kg^-1 per day,

probability of hepatic dysfunction,

decreases the probability of developing active

irrespective of efficacy. Other alternative

disease by 60% for a 2-year period. Longer

regimens prescribed are: isoniazid and

duration is correlated with a higher

rifampicin for 3 months, or a weekly

ERS Handbook: Respiratory Medicine

237

Table 2. Recommended treatment regimens for new TB cases

TB treatment regimen

Notes

Intensive phase

Continuation phase

2HRZE

4HR

Standard regimen

2HRZE

4HRE

Level of H resistance among new TB

cases is high and H susceptibility

testing result is not available before the

continuation phase

Ethambutol (E) must be prescribed during the intensive phase in individuals with noncavitary, smear-negative

pulmonary TB, or in HIV-negative patients with extrapulmonary TB. In TB meningitis, it should be replaced by

streptomycin (S). Number preceding regimen indicates the length of treatment in months. H: isoniazid; R:

rifampicin; Z: pyrazinamide.

administration of isoniazid and rifapentine

global epidemiological issues, such as

for 3 months.

MDR-TB and TB/HIV co-infection. It was

aimed to meet the 2015 Millennium

Prevention

Development Goals (i.e. to halve TB

In 1993, the United Nations stated that the

prevalence and mortality compared to the

global fight against TB must be a priority

data recorded in 1990) and showed a more

alongside with the fight against HIV/AIDS

comprehensive approach (for instance,

and malaria. On this basis, in 1996, WHO

involvement of the private sector, and

issued a public health strategy called DOTS

engagement of the community and of all

(directly observed treatment, short course),

healthcare providers). WHO and partners

aimed at diagnosing 70% of sputum smear-

are presently discussing the new post-2015

positive patients and successfully treating

strategy, which will be centred around three

85% of them by 2005. It was composed of

main pillars:

five elements:

intensified and innovative TB care

political commitment to TB control

development and enforcement of bold

bacteriological diagnosis through

health-system and social development

smear microscopy

policies

supervised and standardised short-

promotion and intensification of

course therapy

research and innovation

supply of quality drugs without

A relevant tool for the clinical and public

interruption

health management of TB called the

standardised recording and reporting

International Standards of Tuberculosis

system for treatment outcomes

Care (ISTC) was developed by several

In 1996, a new WHO strategy called STOP-

stakeholders, coordinated by WHO, to give

TB was issued in order to address the new

evidence-based standards. Recently, the ERS

Table 3. Recommended treatment regimens for previously treated patients

Probability of MDR-TB

High (failure)

Medium or low (relapse, default)

Pending DST results: empirical MDR-TB

2HRZES/HRZE/5HRE, modified once DST results

regimen, modified once DST results are

are available.

available

Number preceding regimen indicates the length of treatment in months. H: isoniazid; R: rifampicin; Z:

pyrazinamide; E; ethambutol; S: streptomycin.

238

ERS Handbook: Respiratory Medicine

Table 4. General principles for designing an empiric regimen to treat MDR-TB

Basic principles

Comments

1. Use at least four

Effectiveness is supported by a number of factors (the more of them that

drugs of know

are present, the more likely it is the that drug will be effective).

effectiveness or

Susceptibility at DST

highly likely to be

No previous history of treatment failure with the drug

effective

No known close contacts with resistance to the drug

DRS indicates resistance is rare in similar patients

No common use of the drug in the area

If at least four drugs are not certain to be effective, use five to seven

drugs, depending on the specific drugs and level of uncertainty

2. Do not use drugs

Rifamycins (rifampicin, rifabutin, rifapentine and rifalazil) have high level

for which

of cross-resistance

resistance

Fluoroquinolones: variable cross-resistance; in vitro data show some later

crosses over

generation agents remain susceptible when earlier generation are

resistant (clinical significance of the phenomenon still unknown)

Aminoglycosides and polypeptides: not all are cross-resistant; in general,

only kanamycin and amikacin are fully cross-resistant

3. Eliminate drugs

Known severe allergy or difficult-to-manage intolerance

likely to be unsafe

High risk of severe adverse effects including: renal failure, deafness,

for the patient

hepatitis, depression and/or psychosis

Unknown or questionable drug quality

4. Include drugs

Use any group 1 drugs that are likely to be effective (see principle 1 above)

from groups 1-5

Use an effective injectable aminoglycoside or polypeptide (group 2 drugs)

in a hierarchical

Use a later-generation fluoroquinolone (group 3)

order, based on

Use the remaining group 4 drugs starting from ethionamide (or

potency

prothionamide) to make a regimen consisting of at least four effective

drugs plus pyrazinamide in the intensive phase of treatment

Regimens should include at least pyrazinamide, a fluoroquinolone, a

parenteral agent (kanamycin, amikacin or capreomycin), ethionamide

(or prothionamide), and either cycloserine or PAS if cycloserine cannot

be used

An intensive phase of 8 months’ duration is recommended; a total

treatment duration of 20 months is recommended in patients without

any previous MDR-TB treatment

For regimens with up to four effective drugs, add second-line drugs most

likely to be effective, to give five to seven drugs in total, with at least

four of them highly likely to be effective

The number of drugs will depend on the degree of uncertainty

Use group 5 drugs as needed so that at least four drugs are likely to

be effective

5. Be prepared to

Ensure laboratory services for haematology, biochemistry, serology and

prevent, monitor

audiometry are available

and manage

Establish a clinical and laboratory baseline before starting the regimen

adverse effects for

Initiate treatment gradually for a difficult-to-tolerate drug, splitting daily

each of the drugs

doses of ethionamide/prothionamide, cyclosporin and PAS

selected

Ensure ancillary drugs are available to manage adverse effects

Organise intake supervision for all doses

DRS: drug resistance surveillance; PAS: para-aminosalicylic acid.

ERS Handbook: Respiratory Medicine

239

and the European Centre for Disease

Knechel NA (2009). Tuberculosis: patho-

Prevention and Control adapted the ISTC to

physiology, clinical features, and diagno-

the European Union/European Economic

sis. Crit Care Nurse; 29: 34-43.

Area scenario, focusing on the goal of TB

Mack U, et al.

(2009). LTBI: latent

elimination.

tuberculosis infection or lasting immune

responses to M. tuberculosis? A TBNET

Only one vaccine is currently available for

consensus statement. Eur Respir J;

33:

the primary prevention of TB: it consists of a

956-973.

live attenuated strain of M. bovis BCG, the

Migliori GB, et al.

(2012). European

efficacy of which has been proven in children

Union standards for tuberculosis care.

Eur Respir J; 39: 807-819.

for TB meningitis and miliary TB but not for

Orenstein EW, et al. (2009). Treatment

pulmonary TB in endemic geographical

outcomes among patients with

areas. Safety concerns have been reported,

multidrug-resistant tuberculosis: sys-

particularly in HIV-positive patients.

tematic review and meta-analysis. Lancet

Infect Dis; 9: 153-161.

The goal of the global elimination of TB, i.e.

Torrado E, et al. (2011). Cellular response

an incidence of new sputum smear-positive

to mycobacteria: balancing protection

cases ,1 per 1 million inhabitants, seems

and pathology. Trends Immunol; 32: 66-

difficult to meet, but the epidemiological

72.

scenario could improve with a multi-sector

Raviglione MC, et al. Tuberculosis. In:

approach oriented by the evidence-based

Fauci AS, et al., eds. Harrison’s Principles

WHO strategies.

of Internal Medicine. 17th Edn. New York,

McGraw-Hill Medical Publishing Division

Inc., 2008; pp. 1006-1020.

Further reading

Sester M, et al.

(2011). Interferon-c

Blasi F, et al.

(2013). Supporting TB

release assays for the diagnosis of active

clinicians managing difficult cases: the

tuberculosis: a systematic review and

ERS/WHO Consilium. Eur Respir J; 41:

meta-analysis. Eur Respir J; 37: 100-111.

491-494.

World Health Organization. Multidrug

Falzon D, et al. (2011). WHO guidelines

and extensively drug-resistant TB

(M/

for the programmatic management of

XDR-TB). Global report on surveillance

drug-resistant tuberculosis: 2011 update.

and response. Geneva, WHO, 2010.

Eur Respir J; 38: 516-528.

World Health Organization. Global tuber-

Fitzgerald D, et al. Mycobacterium tubercu-

culosis control

2011. Document WHO/

losis. In: Mandell GL, et al., eds. Principles

HTM/TB/2011.16. Geneva, WHO, 2011.

and Practice of Infectious Diseases. 6th

World Health Organization. Guidelines

Edn. Philadelphia, Churchill Livingstone,

for the programmatic management of

2005; pp. 2852-2886.

drug-resistant tuberculosis. Document

Frieden TR, et al. (2003). Tuberculosis.

WHO/HTM/TB/2008.402. Geneva, WHO,

Lancet; 362: 887-899.

2008.

Getahun H, et al. (2010). HIV infection-

World Health Organization. Treatment of

associated tuberculosis: the epidemi-

tuberculosis guidelines. Fourth Edition.

ology and the response. Clin Infect Dis;

Document

WHO/HTM/TB/2009.420.

50: Suppl. 3, S201-S207.

Geneva, WHO, 2010.

Hopewell PC, et al. (2006). International

Yew WW, et al.

(2011). Treatment of

standards for tuberculosis care. Lancet

tuberculosis: update 2010. Eur Respir J;

Infect Dis; 6: 710-725.

37: 441-462.

240

ERS Handbook: Respiratory Medicine

Extrapulmonary tuberculosis

Aik Bossink

Definition

differentiated registry (PTB, EPTB and

EPTB+PTB), EPT localisations comprise

The World Health Organization(WHO)

nearly 50% of all cases. With the arrival of

defines of extrapulmonary TB (EPTB) as ‘A

new, more sensitive detection methods,

patient with tuberculosis of organs other

EPTB could well be even more common.

than the lungs (e.g. pleura, lymph nodes,

EPTB has always been considered less

abdomen, genitourinary tract, skin, joints

important than PTB because of the low

and bones, meninges). Diagnosis should be

infectious potential and the difficulties

based on one culture-positive specimen, or

involved in the diagnosis EPT.

histological or strong clinical evidence

consistent with active extrapulmonary

In low-income countries, males appear to be

disease, followed by a decision by a clinician

affected by TB more often than females.

to treat with a full course of antituberculosis

However, in high-income countries, this

chemotherapy’.

difference is not so clear. This mechanism is

not clearly understood. No evidence is

A patient diagnosed with both pulmonary

available that EPTB affects one sex more

TB (PTB) and EPTB should be classified as a

often than the other.

case of PTB.

Immunosuppression appears to be an

The definition does not mention eyes or the

important cause of EPTB and this is

ear-nose-throat region. However, these

reflected by a sharp incline in reported cases

tissues are also, rarely, possible

of EPTB with the rise of the incidence of HIV

localisations.

infection. In high-income countries and

General aspects of EPTB

countries with a lower incidence of HIV

infection, biologicals like tumour necrosis

Only a minority of TB cases (,30%) suffer

factor-a inhibitors are relatively important

from EPTB. However, this could be biased

causes of EPTB.

by the definition, because in countries with a

‘The result of tuberculous bacillaemia must

be the insemination in various parts of the

Key points

body of foci most of which remain latent’

(Wilkinson, 1940). Therefore, EPTB can be

N EPTB localisations appear in up to

the result of a primary infection in severely

50% of TB patients.

immunocompromised hosts or can be the

result of reactivation of dormant bacilli in

Obtaining culture confirmation is

previously infected subjects.

essential in the treatment of both PTB

and EPTB.

Sites of EPTB

N Treatment of EPTB does not differ

The two most common localisations of EPT

from PTB in the majority of EPTB

are the cervical lymph nodes and pulmonary

localisations.

pleura. Other sites are, in declining order,

bones and joints, the meninges and central

ERS Handbook: Respiratory Medicine

241

nervous system (CNS), abdominal lymph

samples. However, culture and drug

nodes, the peritoneum and gastrointestinal

susceptibility testing remain the cornerstone

tract, the genitourinary tract, and the

of adequate treatment.

pericardium.

Some promising reports of the use of

It should be noted that gastric aspirate from

interferon-c release assays on materials

children with EPTB often contains

other than blood in the diagnosis of EPTB

mycobacteria. This is, however, not an

(pleural, peritoneal, pericardial and

indication of EPT but should be considered

meningitis TB) have been published.

as local spread of mycobacteria by

However, these tests are no proof of active

swallowing sputum.

infection, they will not provide culture

results or drug susceptibility reports and can

In immunocompromised hosts, the

therefore only be supportive in the search for

presentation of EPTB is often different

mycobacteria. However, it remains most

compared to immunocompetent hosts.

important to obtain materials for culture

Dissemination of the disease is more

and DST.

common and clinicians should be aware of

other localisations. Dissemination is more

An increasing number of case and brief

likely because ill-formed granulomata

reports has been published on the use of

are more common in

18-fluorodeoxyglucose (FDG) positron

immunocompromised hosts.

emission tomography (PET)/CT for the

detection of both PTB and EPTB sites.

The term miliary TB is a radiological finding

Unfortunately, most prospective studies

of chest radiography and should not be used

have been designed to differentiate

in this context.

between malignancies and TB. Nuclear

Diagnosis

medicine is, in general, not an appropriate

tool to differentiate between these.

In countries with all possible diagnostic

However, FDG-PET/CT appears to have a

resources, on average, 70% of all the TB

high sensitivity in the detection of lymph-

cases are culture confirmed. One can

node TB and organ localisations. The

imagine that in EPTB samples are more

performance on visceral TB localisations

difficult to obtain compared with PTB

remains unclear. A recent review (Sathekge

samples. Furthermore, some of the EPTB

et al., 2012) concludes that ‘Available data,

localisations contain few mycobacteria.

reviewed above, suggest that SPECT

Culture or PCR confirmation will thus be

[single-photon emission CT] and PET may

lower in these cases. Using the Dutch TB

prove to be valuable adjuncts for the

registry, PTB is culture confirmed in nearly

differentiation of TB from malignant lung

80% and EPTB in about 60% of cases.

lesions, active from nonactive disease, and

for treatment follow-up, and may thus play

In low-income countries, specific staining is

a major role in the work-up of TB patients’.

often the only available diagnostic tool and,

It can be expected that with the use of

because of its relative simplicity, should

more sensitive methods of detection, the

always be undertaken. A relatively novel

proportion of EPTB localisations

method, the Xpert MTB/RIF assay (Cepheid,

will increase.

Sunnyvale, CA, USA), could well be

promising in low-income countries with few

Treatment

laboratory facilities. This real-time

automated nucleic acid amplification

In general, treatment for EPTB does not

technique runs in a closed system and is

differ from that for PTB. Depending on local

suitable for use outside conventional

or national guidelines, the treatment

laboratory settings. Most experience of the

consists of a full course of at least four anti-

performance on this technique is based on

TB drugs (isoniazid, rifampicin, ethambutol

sputum samples but a review (Lawn et al.,

and pyrazinamide) in the first 2 months,

2012) mentions good performance in EPTB

and then another 4-7 months of isoniazid

242

ERS Handbook: Respiratory Medicine

and rifampicin in culture-confirmed cases

paralysis of the abducens nerve. Classically,

with normal drug susceptibility. In

the patient is not able to look outward with

countries with a high prevalence of drug

one eye and this eye is rotated towards the

resistance for one or more of these drugs, a

nose. Neurological deterioration is

fifth or even sixth drug should be added

classified in three grades based on the

awaiting culture and DST.

performance on the Glasgow Coma Scale.

Apart from antibiotic treatment, it is

Specific localisations

recommended to add steroids (0.5 mg?kg^-1)

Cervical lymph nodes Involvement of the

in stage II and III. Survival is positively

lymph nodes or lymphadenitis is the most

influenced by this regimen but neurological

common localisation of EPTB. Concomitant

outcome is no better in the groups treated

pulmonary infection occurs in 5-10% of

with steroids. Others recommend steroids

cases and, therefore, generalised symptoms

independent of the stage. Antibiotic

are unusual. During medical treatment, the

treatment should be for o9 months.

lymph nodes can rapidly increase in size

However, according to the British Infection

(paradox reaction) and fine-needle

Society guidelines, treatment should be

aspiration of its content may prove

continued for 1 year. WHO recommends

beneficial in preventing fistula. In children,

replacing ethambutol with streptomycin in

lymphadenitis is often caused by

TB meningitis.

nontuberculous mycobacteria and this

TB of the pericardium This condition is

requires a different treatment approach.

sometimes difficult to diagnose because,

Confirmation of the causative organism is

just like pleural effusion, the bacterial load

therefore crucial.

is low. Pericardial effusion and, at a later

Other lymph nodes Other common sites of

stage, constrictive pericarditis can cause

lymph node involvement are axillary,

severe inflow limitation resulting in serious

inguinal and abdominal. Culture results

haemodynamic problems. To reduce the

(Mycobacterium tuberculosis versus

effusion and to prevent thickening of the

nontuberculous mycobacteria) for these

pericardium, adjuvant steroids are

localisations do not differ between children

recommended. No data are available on the

and adults.

amount and duration of steroid treatment.

It seems reasonable to prescribe

TB of the pleura In general, TB pleurisy is

0.5 mg?kg^-1 for the first 2 months and then

one sided and the majority of cases have a

decrease the dose gradually to zero over a

tendency toward spontaneous resolution.

period of 4 months.

Therefore, the diagnosis can be delayed for

a prolonged period until a new effusion

Bone and joint TB Any bone or joint can be

appears. Often, large amounts of pleural

affected but the classical lesion is a

fluid are observed with relatively low

fracture of the vertebrae resulting in a

numbers of mycobacteria. An

kyphotic change of the spine (Pott’s

accompanying hypersensitivity reaction is

disease). In general, the larger bones and

responsible for this phenomenon. Because

joints are more often affected compared

of this low bacterial burden, the

with the smaller ones. Joint involvement

confirmation of TB can often be difficult. TB

presents as a monoarthritis. Diagnosis of

empyema is a rare condition compared with

both bone and joint involvement is

pleurisy, and often requires surgical

generally made by biopsy. Aspiration of

drainage and decortication combined with

synovial fluid seldom yields the diagnosis.

medical treatment.

Medical treatment is the treatment of

TB of the meninges and CNS Meningitis is

choice and should be prolonged to

the most common presentation of

9 months. Surgery is reserved for

involvement of the nervous system. The

complicated cases such as neurological

infection can cause hydrocephalus and,

involvement or instability of

through involvement of the cranial nerves,

the spine.

ERS Handbook: Respiratory Medicine

243

Further reading

meningitis in adolescents and adults. N

Engl J Med; 351: 1741-1751.

European Centre for Disease Prevention

Thwaites G, et al.

(2009). British

and Control, et al. Tuberculosis surveil-

Infection Society guidelines for the diag-

lance in Europe 2008. http://ecdc.europa.

nosis and treatment of tuberculosis of the

eu/en/publications/Publications/

central nervous system in adults and

1003_SUR_tuberculosis_surveillance_

children. J Infect; 59: 167-187.

in_europe_2008.pdf

Wilkinson MC (1940). Pathogenesis of

KNCV. Epidemiologie en surveillance

non-pulmonary tuberculosis. Br Med J; 2:

[Epidemiology and surveillance].

660-661.

www.kncvtbc.nl/nl/

World Health Organization. Global

epidemiologie-en-surveillance

Tuberculosis

Control

2009:

Lawn SD, et al.

(2012). Diagnosis of

Epidemiology, strategy and financing.

extrapulmonary tuberculosis using the

Geneva, WHO, 2009.

Xpert¹

MTB/RIF assay. Expert Rev Anti

World Health Organization. Global tuber-

Infect Ther; 10: 631-635.

culosis report

2012. www.who.int/tb/

Sathekge M, et al. (2012). Nuclear med-

publications/global_report/en/

icine imaging in tuberculosis using com-

World Health Organization. Treatment of

mercially available radiopharmaceuticals.

tuberculosis: guidelines for national pro-

Nucl Med Commun; 33: 581-590.

grammes. www.who.int/tb/features_

Thwaites GE, et al.

(2004). Dexame-

archive/new_treatment_guidelines_

thasone for the treatment of tuberculous

may2010/en/index.html

244

ERS Handbook: Respiratory Medicine

Tuberculosis in the

immunocompromised host

Martina Sester

The incidence of active TB and attendant

Pathomechanisms of impaired TB control

mortality is increased in patients with

in immunocompromised patients

impaired cellular immunity, such as HIV-

The general incidence of TB in

infected patients, solid organ and stem cell

immunocompromised patients may vary

transplant recipients, patients receiving

depending on the geographic location and

tumour necrosis factor (TNF)-a antagonists,

and patients with end-stage renal failure. The

may range from ,1% to 15% in low- and

high-prevalence countries, respectively. The

relative risk for TB varies with the type of

relative risk of developing TB and its

immunodeficiency (table 1) and mortality

underlying pathomechanisms may differ

rates may be as high as 75% (Sester et al.,

widely among the various groups due to

2012). This emphasises the particular

differences in the cause and extent of

importance of the cellular arm of the adaptive

immunodeficiency (table 1). The dramatic

immune response for efficient control of

Mycobacterium tuberculosis (Sester et al.,

reduction in CD4⁺ T-cell numbers in HIV

infected patients, in particular in those with

2010, 2012; Bumbacea et al., 2012; Solovic et

AIDS, not only contributes to a severely

al., 2010). Moreover, the presence of M.

impaired control of TB but also to a high

tuberculosis-specific CD4⁺ T-cell immunity is

percentage of false-negative diagnoses by

used as a surrogate marker for a previous

immune-based tests (Sester et al., 2010).

contact (Mack et al., 2009). Consequently, a

detailed knowledge of the pathomechanisms

Similarly, immunosuppressive drug

treatment after transplantation is

leading to increased incidence of TB in

associated with a decrease in T-cell

immunocompromised patients has also

function and may lead to a progressive

contributed to a better understanding of the

decrease in M. tuberculosis-specific T-cell

principles of decreased test sensitivity in this

immunity over time (Sester et al., 2009).

vulnerable patient group.

This not only facilitates reactivation but

also contributes to a decreased sensitivity

of immune-based testing (Bumbacea et al.,

Key points

2012; Sester et al., 2009; Singh et al., 1998).

The uraemia-associated immunodeficiency

N TB has a higher incidence among

syndrome in patients with end-stage renal

people with impaired cellular

failure has been characterised by a defect in

immunity.

co-stimulatory signals to antigen-specific T-

cells, thereby contributing to an impaired

N Diagnosis is often delayed owing to

efficiency of vaccinations and increased

early lack of symptoms or unusual

risk of infectious complications including

presentation.

TB (Girndt et al., 2001). Finally, an

Screening for LTBI prior to

increased incidence of active TB in patients

immunosuppressive treatments can

receiving TNF-a antagonists is attributed

be a useful preventive measure.

to impaired T-cell function and failure to

maintain the integrity of granulomata

ERS Handbook: Respiratory Medicine

245

Table 1. Pathomechanisms and relative risk for TB in immunocompromised patients relative to persons without

known risk factors (risk51)

Relative risk

Pathomechanism

100-170

Low CD4⁺ T-cell counts

50-100

Low CD4⁺ T-cell counts

20-74

Decreased T-cell function and numbers

10-25

Co-stimulation deficiency, chronic inflammation

in latently infected patients (Solovic

individuals, and should consist of a regimen

et al., 2010).

including isoniazid, rifampicin,

pyrazinamide and ethambutol for 2 months

Clinical presentation of active TB in

(2HRZE), followed by a continuation phase

immunocompromised patients

with isoniazid and rifampicin for 4 months

(4HR). Treatment of active TB may be

Active TB in immunocompromised patients

complicated by interactions between

can pose a number of challenges. Due to the

antibacterial and immunosuppressive or

impaired immune response, patients may

antiretroviral drugs. Evidence in favour of

be clinically oligosymptomatic in the

extending the continuation phase is limited.

beginning of active disease, and its

Longer duration is recommended in patients

diagnosis is often delayed due to atypical

with cavitation on their initial chest

presentations and more frequent

radiograph and/or positive cultures after

extrapulmonary dissemination. Active TB is

2 months of treatment, or in patients with

further aggravated by a significantly higher

involvement of the central nervous system

morbidity due to a more fatal course in the

(Sester et al., 2012).

face of a weakened immune system (Sester

et al., 2012). In addition, treatment is

Preventative approaches in

frequently complicated due to complex drug

immunocompromised patients

interactions and altered pharmacokinetics

(Bumbacea et al., 2012). The treatment of TB

The increased risk of active TB in

is also more difficult to manage in HIV-

immunocompromised patients may result

infected patients, as immune restoration

from an immunosuppression-induced

induced by antiretroviral therapy may be

reactivation of a previously acquired latent

responsible for a paradoxical worsening of

TB infection (LTBI) or new infections. While

TB manifestations, a phenomenon defined

the extent of new infections is difficult to

as immune reconstitution inflammatory

control as it largely depends on the overall

syndrome (IRIS) (Sester et al., 2010).

prevalence of TB, the risk of progression

from LTBI to active disease may be

Diagnosis and treatment of active TB

minimised by the early identification and

treatment of latently infected patients

In active TB suspects, diagnosis should

(Sester et al. 2012). Although risk

follow a clinical algorithm that includes

assessment in immunocompromised

acid-fast bacilli (AFB) staining from two

patients is often hampered by a low

sputum samples, and nucleic acid

sensitivity of commonly used immune-

amplification (NAA) testing. In the case of

based tests, current guidelines recommend

negative results, bronchoalveolar lavage

regular screening for evidence of LTBI and -

(BAL) should be obtained for microscopy,

if possible - treatment prior to conditions of

NAA and culture (Sester et al., 2012; Lange

immunodeficiency, i.e. screening and

et al., 2010).

treatment prior to transplantation or TNF-a

The first-choice treatment of immuno-

antagonist therapy (Sester et al., 2012;

compromised patients with active TB does

Bumbacea et al., 2012; Solovic et al., 2010;

not differ from immunocompetent

Singh et al., 1998). Until recently, LTBI

246

ERS Handbook: Respiratory Medicine

screening was exclusively carried out by the

approaches that should consider clinical

use of tuberculin skin testing (TST), where

findings, the extent of immunodeficiency and

the cut-off of positivity is defined by the

the overall prevalence of TB.

extent of immunodeficiency. At present,

however, novel interferon-c release assays

Further reading

(IGRAs) are more widely applied that are of

higher specificity than TST. In addition,

Barry CE 3rd., et al. (2009). The spectrum

accumulating evidence suggests that IGRAs

of latent tuberculosis: rethinking the

may be of higher sensitivity in immuno-

biology and intervention strategies. Nat

compromised patients (Sester et al., 2012).

Rev Microbiol; 7: 845-855.

Bumbacea D, et al. (2012). The risk of

Preventive chemotherapy should be given to

tuberculosis in transplant candidates and

patients with a positive immune-based test

recipients: a TBNET consensus state-

(TST o5 or 10 mm depending on the type of

ment. Eur Respir J; 40: 990-1013.

immunodeficiency, or IGRA), signs of TB on

Diel R, et al. (2011). Interferon-c release

chest radiograph in patients with no or

assays for the

diagnosis of latent

insufficient previous TB treatment, or recent

Mycobacterium tuberculosis infection: a

close contact with a patient with active TB in

systematic review and meta-analysis. Eur

severely immunocompromised patients.

Respir J; 37: 88-99.

Girndt M, et al. (2001). Molecular aspects

Among immune-based assays, IGRA testing

of T- and B-cell function in uremia. Kidney

is preferred over TST because of operational

Int Suppl; 78: S206-S211.

advantages, including internal positive

Lange C, et al. (2010). Advances in the

controls. When using IGRAs as a predictive

diagnosis of tuberculosis. Respirology; 15:

measure for development of active disease,

220-240.

Mack U, et al. (2009). LTBI: latent tubercu-

a recent meta-analysis suggests that in vitro

losis infection or lasting immune responses

tests are superior for predicting

to M. tuberculosis? A TBNET consensus

development of TB (Diel et al., 2011).

statement. Eur Respir J; 33: 956-973.

Nevertheless, the actual risk of progression

Rangaka MX, et al.

(2012). Predictive

to active disease is still overestimated and

value of interferon-c release assays for

may differ according to the local prevalence

incident active tuberculosis: a systematic

of TB (Rangaka et al., 2012). The

review and meta-analysis. Lancet Infect

considerably low predictive value is due to

Dis; 12: 45-55.

the fact that a positive immune response

Sester M, et al. (2010). Challenges and

towards M. tuberculosis does not necessarily

perspectives for improved management

reflect a true infection with viable bacilli that

of HIV/Mycobacterium tuberculosis co-

bears a higher risk of disease progression

infection. Eur Respir J; 36: 1242-1247.

(Barry et al., 2009). As decisions for

Sester M, et al.

(2012). TB in the

chemoprophylaxis depend, to a great extent,

immunocompromised host. Eur Respir

on the results of immunodiagnostic testing,

Monogr; 58: 230-241.

large studies are needed to determine more

Sester U, et al. (2009). Impaired detec-

precisely the negative and positive predictive

tion of Mycobacterium tuberculosis immu-

values of IGRAs in each specific population

nity in patients using high levels of

of immunocompromised patients and in

immunosuppressive drugs. Eur Respir J;

regions of different TB prevalence.

34: 702-710.

Singh N, et al.

(1998). Mycobacterium

Conclusions

tuberculosis infection in solid-organ trans-

plant recipients: impact and implications for

TB in immunocompromised patients is more

management. Clin Infect Dis; 27: 1266-1277.

frequent than in the general population, and

Solovic I, et al. (2010). The risk of tuber-

morbidity and mortality are high. This high

culosis related to tumour necrosis factor

mortality is primarily due to delayed diagnosis

antagonist therapies: a TBNET consensus

and increased incidence of disseminated

statement. Eur Respir J; 36: 1185-1206.

disease. Risk assessment needs integrative

ERS Handbook: Respiratory Medicine

247

Latent tuberculosis

Jean-Pierre Zellweger

Individuals who are in close contact with a

(up to years), in a state of equilibrium called

patient with a transmissible form of TB,

‘latent TB infection’ (LTBI).

usually smear-positive pulmonary TB, may

LTBI and risk of TB

inhale droplets containing mycobacteria,

which settle in the airways and give rise to a

Individuals with latent TB have no signs or

local inflammatory reaction. The risk of

symptoms of active disease, and only

infection is related to the concentration of

immunological markers of a prior contact

mycobacteria in the air and the duration of

with mycobacteria. It is therefore impossible

contact. Some exposed individuals develop

to know whether individuals with LTBI still

active disease (TB) within a couple of weeks

harbour living mycobacteria. The only gold

or months, others will control the incipient

standard for the infection is the

infection and stay, for a prolonged period

development of the disease, which happens

in a minority of exposed individuals. Why

and how the infected individuals will

develop TB is unknown. Estimates are that

,10% of infected individuals may develop

Key points

TB, half of them within 2 years after

infection, and 90% will never develop the

The risk of LTBI depends on the

disease. Some infected individuals have a

intensity and duration of exposure to

higher risk of later reactivation than others

a source case with untreated

(e.g. immunocompromised individuals,

pulmonary TB.

patients receiving immunosuppressive

Some infected contacts will develop

therapy and small children). As only a

TB at a later time-point. Timely

minority of contacts develop TB, there is a

detection of infected contacts and

possibility that most contacts eradicate the

preventive treatment of those at

mycobacteria but still retain an

highest risk of reactivation is cost-

immunological marker of the infection, even

effective and reduces the pool of

in the absence of living mycobacteria.

future cases of active TB.

Treatment of LTBI

Before prescribing a preventive

As the persons in contact with a case of TB

treatment, active TB should be

have a much higher risk of developing the

excluded by a chest radiograph and, if

disease in the future than the general

abnormal, by a bacteriological

population, particularly if they have a

examination of sputum.

positive tuberculin reaction or a positive

The tests for the detection of latent

interferon-c release assay (IGRA) test, the

infection are the tuberculin skin

detection of LTBI among exposed contacts

test and the IGRAs. The latter has

is important because a preventive treatment

the advantage of a greater

can reduce this risk. In countries or

specificity.

populations with a low incidence of TB, the

search for latent infection among contacts

248

ERS Handbook: Respiratory Medicine

and the prescription of preventive treatment

therefore, avoid in practice the false-

may contribute to the control of the disease

positive skin reactions elicited by prior

by reducing the pool of potential future

BCG vaccination or contact with

cases. The currently recommended

nontuberculous mycobacteria.

preventive treatments are 9 months of

Detection in low-prevalence countries

isoniazid, 4 months of rifampicin, or

3 months of a combination of isoniazid and

In low-prevalence countries, the search for

rifampicin. Recently, the use of rifapentine

infected individuals is usually performed

and isonazid once a week for 3 months has

among persons who recently had contact

also been demonstrated to be very effective.

with a patient with pulmonary TB (contact

investigation), in healthcare workers

As the immunological reaction after the

potentially exposed to untreated cases of TB

contact with mycobacteria needs several days

and in immunocompromised patients with a

or weeks to be complete, the proof of a recent

risk of reactivation that is higher than the

sensitisation is usually not present before

general population if they are infected.

this time (the window period). Therefore, the

Infected contacts considered at risk of

search for latent infection is usually

developing TB in the future are either

performed only 4-8 weeks after the last

followed clinically or offered a preventive

contact. In some cases, where the

treatment. All contacts with immunological

progression from infection to disease may be

signs of infection (positive tuberculin skin

rapid (such as immunocompromised

test or IGRA) should have at least a chest

contacts or children aged ,5 years), a first

radiograph for detecting signs of past or

test with a clinical examination may be

current TB. Before prescribing a preventive

performed as soon as possible after the last

treatment in contacts with an abnormal

contact and repeated several weeks later, if

chest radiograph, the presence of an active

the results are negative. A test performed

TB should be excluded by a bacteriological

immediately after the last contact will usually

examination of sputum. The efficiency of the

indicate a prior sensitisation and may be

preventive treatment largely depends on the

observed among contacts born in a region

rate of treatment completion. Contacts of

with high prevalence of TB and in elderly

patients with multidrug-resistant TB have to

people, independently of recent contacts.

be managed with special care.

Tests for detection of LTBI

Detection in high-prevalence countries

The tests used for the detection of latent

In high-prevalence countries, formal contact

infection are all indirect and rely on the

investigations are usually not performed, as

reaction between sensitised lymphocytes

most of the contacts may already have

and antigens from Mycobacterium

immunological signs of prior infection, but

tuberculosis. The traditional test is the

it is currently recommended to search for

tuberculin skin test measuring the

the presence of secondary cases of TB

cutaneous reaction elicited by the

among the close relatives and to consider

intradermal injection of a mixture of

the protection of small children with a

antigens from M. tuberculosis cultures. New

preventive treatment if one of the parents

tests have recently been developed and

has a form of transmissible TB. The search

introduced to the market, measuring in

for infection in HIV-positive contacts and

vitro the release of cytokines (interferon-c)

prescription of preventive treatment is also

by lymphocytes incubated with two or three

recommended.

specific antigens present in M. tuberculosis

but absent in Mycobacterium bovis bacille

Controversies and open questions

Calmette-Guérin (BCG) and in most

nontuberculous mycobacteria (IGRAs). The

There are still controversies about the

in vitro tests are (at least) equally sensitive

definition of infectiousness (only smear-

as the tuberculin test, but have the

positive cases or all cases with pulmonary

advantage of a greater specificity and,

TB), the extent of the contact investigation

ERS Handbook: Respiratory Medicine

249

(only close and prolonged contacts or all

European Centre for Disease Prevention

contacts) and the indications of preventive

and Control. Management of contacts of

treatment (only infected contact with a high

MDR TB and XDR TB patients.

risk of reactivation or all contacts or

Stockholm, ECDC, 2012.

individuals with a positive tuberculin or

Ferebee SH (1970). Controlled chemo-

IGRA reaction). Prospective studies on the

prophylaxis trials in tuberculosis: a gen-

risk of reactivation among contacts with a

eral review. Adv Tuberc Res; 17: 28-106.

positive immunological reaction will help to

Landry J, et al.

(2008). Preventive che-

clarify these issues.

motherapy. Where has it got us? Where to

go next? Int J Tuberc Lung Dis; 12: 1352-

1364.

Further reading

Mack U, et al.

(2009). LTBI: latent

tuberculosis infection or lasting immune

Abdool Karim SS, et al.

(2009). HIV

responses to M. tuberculosis? A TBNET

infection and tuberculosis in South

consensus statement. Eur Respir J;

33:

Africa: an urgent need to escalate the

956-973.

public health response. Lancet; 374: 921-

Mazurek GH, et al.

(2010). Updated

933.

guidelines for using interferon gamma

Andersen P, et al. (2007). The prognosis

release assays to detect Mycobacterium

of latent tuberculosis: can disease be

tuberculosis infection

- United States

predicted? Trends Mol Med; 13: 175-182.

2010. MMWR Recomm Rep; 59: 1-25.

Cardona PJ (2007). New insights on the

Moran-Mendoza O, et al. (2010). Risk

nature of latent tuberculosis infection and

factors for developing tuberculosis: a 12-

its treatment. Inflamm Allergy Drug

Targets; 6: 27-39.

year follow-up of contacts of tuberculosis

cases. Int J Tuberc Lung Dis; 14: 1112-1119.

Diel R, et al. (2005). Cost-effectiveness of

isoniazid chemoprevention in close con-

National

Tuberculosis

Controllers

Association.

(2005). Guidelines for the

tacts. Eur Respir J; 26: 465-473.

Diel R, et al. (2011). Negative and positive

investigation of contacts of persons with

predictive value of a whole-blood

infections tuberculosis.

Recommen-

interferon-c release assay for developing

dations from the National Tuberculosis

active tuberculosis: an update. Am J

Controllers Association and CDC. MMWR

Respir Crit Care Med; 183: 88-95.

Recomm Rep; 54: 1-47.

Diel R, et al. (2011). Interferon-c release

Shapiro AE, et al.

(2012). Community-

assays for the diagnosis of latent

based targeted case finding for tubercu-

Mycobacterium tuberculosis infection: a

losis and HIV in household contacts of

systematic review and meta-analysis. Eur

patients with tuberculosis in South Africa.

Respir J; 37: 88-99.

Am J Respir Crit Care Med; 185: 1110-1116.

Erkens CG, et al.

(2010). Tuberculosis

Sterling TR, et al. (2011). Three months of

contact investigation in low prevalence

rifapentine and isoniazid for latent tuber-

countries: a European consensus. Eur

culosis infection. N Engl J Med; 365: 2155-

Respir J; 36: 925-949.

2166.

250

ERS Handbook: Respiratory Medicine

Nontuberculous

mycobacterial diseases

Claudio Piersimoni

Nontuberculous mycobacteria (NTM) is the

The epidemiology of NTM disease has been

term indicating those Mycobacterium

difficult to determine because reporting is

species that are different from

not mandatory in most countries and

Mycobacterium tuberculosis complex (MTC)

differentiation between infection/

and Mycobacterium leprae, whose detection

colonisation and disease may be

in clinical samples is almost invariably

problematic. However, recent studies from

associated with disease. The most

North America and Europe have

important features distinguishing NTM

documented a steady increase of

from MTC include a lower pathogenicity and

pulmonary disease over the past decade,

the lack of human-to-human transmission.

reporting prevalence rates (range 1.08-8.6

In addition, in vitro resistance to first-line

cases per 100 000 persons) that may

anti-TB drugs is an important distinctive

exceed those of TB.

issue. The majority of the .140 NTM

Although much remains to be understood

species recognised has been associated with

about the pathogenesis of NTM infections,

disease in man or animals.

the following is now well established.

Epidemiology and pathogenesis

N In HIV-infected patients, disseminated

NTM are widely distributed in both natural

NTM infections occur only after the CD4⁺

and man-made environments; organisms

T-lymphocyte count has dropped below

can be found in soil and water with high

50 cells?mL^-1.

isolation rates. Human disease is suspected

N In HIV-uninfected patients, NTM

to be acquired by environmental exposure

infections may be associated with specific

and pulmonary infection is likely to be via

mutations in interferon-c and interleukin-

the aerosol route.

12 synthesis and response pathways.

The most common clinical manifestation of

Key points

NTM infection is pulmonary disease, but

lymphatic, skin/soft tissue, osteoarticular

Important features distinguishing

and disseminated disease are also

NTM from MTC include lower

important.

pathogenicity and lack of human-to-

Pulmonary disease

human transmission.

N Diagnosis of NTM disease requires

In immunocompetent subjects, NTM lung

both clinical and microbiological

disease presents as one of the following

criteria to be met.

clinical forms.

N Treatment is disappointing and is

Cavitary lung disease This pattern, which

characterised by long duration and

closely resembles pulmonary TB, involves

side-effects, leading to poor

the upper lobes of older males usually

compliance.

affected by a pre-existing destructive or

obstructive lung condition such as

ERS Handbook: Respiratory Medicine

251

pneumoconiosis, chronic bronchitis with

sometimes a combination therapy of

emphysema (frequently associated with

steroids and antibiotics may be required.

long-term, heavy smoking) and

In addition, NTM lung disease may be

bronchiectasis. Thin-walled cavities with

associated with the following conditions.

scarce parenchymal infiltrate and a marked

pleural thickening are characteristic. Signs

HIV infection: although NTM are

and symptoms include chronic cough with

frequently recovered from respiratory

sputum production and weakness. With

specimens of HIV-infected subjects,

advanced disease, dyspnoea, fever, weight

extrapulmonary or disseminated disease

loss and haemoptysis can also occur.

are more likely to occur. The most

Nodular bronchiectasis This pattern (also

relevant exception to this generalisation

known as Lady Windermere syndrome) has

is Mycobacterium kansasii.

been described in slender, elderly females

Immune reconstitution disease: this

with structural chest abnormalities (pectus

clinical syndrome has been described in

excavatum, scoliosis and mitral valve

HIV-infected patients with poor immune

prolapse) but no evidence of pre-existing

function soon after the initiation of

lung disease. Indolent productive cough and

antiretroviral therapy (ART). ART-induced

purulent sputum are the most common

restoration of the immune response may

presenting symptoms, while constitutional

cause subclinical mycobacterial disease

symptoms and haemoptysis are not

to manifest suddenly or be ‘unmasked’.

common unless extensive disease is

Transplantation including both solid-

present. The radiographic findings include

organ and haematopoietic stem cell

small nodular infiltrates and cylindrical

transplants: these infections generally

occur late in the post-transplantation

bronchiectasis, predominately located

period, presenting as cutaneous lesions

within the middle lobe and lingula.

of the extremities, tenosynovitis, arthritis

Hypersensitivity pneumonitis A syndrome

or pulmonary disease. Pleuropulmonary

indistinguishable from hypersensitivity

disease is the predominant manifestation

pneumonitis has been reported in subjects

among lung transplant recipients and

exposed to household water laden with

also represents a significant proportion of

Mycobacterium avium complex (MAC)

NTM infections after heart transplant.

organisms (hot tubs and medicinal baths).

The most common species reported to

Full recovery usually occurs without any

cause pulmonary disease include M.

specific therapy (simply by avoiding further

kansasii, M. avium, Mycobacterium

contact with contaminated solutions) but

abscessus and Mycobacterium xenopi.

Table 1. American Thoracic Society criteria for diagnosis of pulmonary disease caused by NTM

Clinical criteria (both required)

Pulmonary symptoms, cavitary or noncavitary lung disease

Appropriate exclusion of other causes for the disease

Microbiological criteria (only one required)

Positive culture results from at least two separate expectorated sputum samples

Positive culture results from at least one bronchial wash or lavage

A transbronchial or lung biopsy showing granulomata and/or AFB and positive culture for

NTM

Biopsy showing granulomata and/or AFB and one or more sputa or bronchial washing that are

culture-positive for NTM

AFB: acid-fast bacilli.

252

ERS Handbook: Respiratory Medicine

Table 2. Clinical and X-ray features of pulmonary infections caused by the most frequently encountered NTM

Species

Pathogenicity Outcome

X-ray findings

Treatment (months)

MAC

Intermediate Poor/fair

Upper lobe

Clarithromycin, ethambutol,

cavitations

rifampicin (18)

Middle lobe

Clarithromycin, ethambutol,

bronchiectasis

rifampicin (18)

M. kansasii

High

Good

Upper lobe

Rifampicin, isoniazid,

cavitations

ethambutol (18)

M. malmoense

High

Fair

Upper lobe infiltrates Rifampicin, ethambutol (24)

M. xenopi

Low

Poor

Upper lobe

Clarithromycin, rifampicin,

cavitations and

ethambutol, moxifloxacin

nodules

(18)

M. szulgai

High

Good

Upper lobe

Rifampicin, isoniazid,

cavitations

ethambutol, pyrazinamide

(18)

M. simiae

Low

Poor

Upper lobe

Clarithromycin,

cavitations and

moxifloxacin, co-

nodules

trimoxazole (18)

M. abscessus

Intermediate

Poor

Multilobar interstitial

Clarithromycin, amikacin,

and nodular lesions cefoxitin, tigecycline (6-12)

Surgical resection

Reproduced and modified from Piersimoni et al. (2008) with permission from the publisher.

N Treatment with tumour necrosis factor-a

these criteria are derived from experience

antagonists

with MAC, it is reasonable to believe they

N CF

would work with other species provided that

contamination of clinical specimens and

Laboratory diagnosis

medical devices with environmental NTM

(pseudoinfection) has been excluded.

Mycobacterial culture remains the

Today, the combined use of automated

cornerstone of definitive diagnosis.

liquid culture for detection and drug

Therefore, appropriate, high-quality

susceptibility testing (DST) plus the use of

specimens properly collected from all

genetic probe technology for identification

patients with suspected NTM disease have

of mycobacteria is mandatory in all

to be sent to a certified laboratory. Due to

laboratories wishing to perform

the ubiquitous occurrence of NTM in the

mycobacteriology.

environment, the recognition of disease, as

opposed to contamination of specimens or

Treatment

transient colonisation, may be difficult.

Treatment regimens for NTM disease are

While smear-positive samples strongly

still largely undefined and outcome remains

suggest an active disease, a single positive

disappointing despite considerable

culture (especially with small numbers of

upgrading in mycobacteriology and the

organisms) does not suffice to set such a

diagnosis. In this context, the American

availability of some new antimicrobials.

Thoracic Society has recently updated the

Treatment success is impaired by the long

criteria for the diagnosis of pulmonary

duration of regimens, their side-effects and

disease caused by NTM (table 1).

drug interactions, which prevent patients

from full compliance (table 2). In addition,

It is necessary to fulfil all the above elements

although many NTM species may be

to establish a correct diagnosis. Although

susceptible in vitro to one or more anti-TB

ERS Handbook: Respiratory Medicine

253

drug, correlation between DST results and

Fujita G, et al.

(2007). Radiological

clinical outcome is poor.

findings of mycobacterial diseases.

J Infect Chemother; 13: 8-17.

Glassroth J

(2008). Pulmonary disease

Further reading

due to nontuberculous mycobacteria.

Brown-Elliott BA, et al.

(2012). Anti-

Chest; 133: 243-251.

microbial susceptibility testing, drug

Griffith DE, et al. (2007). An official ATS/

resistance mechanisms, and therapy of

IDSA statement: diagnosis, treatment,

infections with nontuberculous mycobac-

and prevention of nontuberculous myco-

teria. Clin Microbiol Rev; 25: 545-582.

bacterial diseases. Am J Respir Crit Care

Clinical

and Laboratory Standard

Med; 175: 367-416.

Institute. Laboratory Detection and

Mangione E, et al.

(2001). Nontuber-

Identification of Mycobacteria. M48-A.

culous mycobacterial disease following

Wayne, CLSI, 2008.

hot tub exposure. Emerg Infect Dis;

Clinical

and Laboratory Standard

1039-1042.

Institute.

Susceptibility Testing of

Piersimoni C, et al.

(2008). Pulmonary

Mycobacteria, Nocardiae, and Other

infections associated with non-tubercu-

Aerobic Actinomycetes. M24-A2. Wayne,

lous mycobacteria in immunocompetent

CLSI, 2011.

patients. Lancet Infect Dis; 8: 323-334.

Doucette K, et al.

(2004). Nontuber-

Tortoli E

(2007). Impact of genotypic

culous mycobacterial infection in hema-

studies on mycobacterial taxonomy: the

topoietic stem cell and solid organ

new mycobacteria of the

1990s. Clin

transplant recipients. Clin Infect Dis; 38:

Microbiol Rev; 16: 319-354.

1428-1439.

Yew WW, et al.

(2011). Update in

Field SK, et al. (2006). Lung disease due

tuberculosis and nontuberculous myco-

to the more common nontuberculous

bacterial diseases 2010. Am J Respir Crit

mycobacteria. Chest; 129: 1653-1672.

Care Med; 184: 180-185.

254

ERS Handbook: Respiratory Medicine

Laboratory diagnosis of

mycobacterial infections

Claudio Piersimoni

Although the prevalence of TB in

elimination. Unfortunately, they are at the

industrialised countries is low, one thing

end of decision tree for the patient’s health

remains certain, TB, including multidrug-

improvement; thus, they are unable to

resistant (MDR) and extensively drug-

prevent delays in diagnosis related to both

resistant (XDR)-TB, is no longer restricted to

the patient and the physician.

developing regions of the globe. In addition,

Seven tests performed in clinical micro-

many species of nontuberculous

biological laboratories are recommended for

mycobacteria (NTM) are now recognised as

TB control and elimination:

a cause of pulmonary disease in man with

increasing frequency.

N microscopy for acid-fast bacilli (AFB)

N nucleic acid amplification (NAA)

The rapid and accurate diagnosis of TB is of

N AFB detection by culture

the utmost importance; it involves the

N identification of cultured mycobacteria

isolation and identification of the

N molecular detection of drug resistance

aetiological agent, Mycobacterium

N DST for first-line drugs

tuberculosis complex (MTC), while design of

N DST for second-line drugs

an appropriate therapeutic regimen relies on

the results of anti-TB drug susceptibility

These tests should not only be available to

testing (DST).

every clinician involved in TB diagnosis and

management but also be available in a

Laboratory services are an essential

timely manner according to well-defined

component of effective TB control and

turnaround times.

Specimen procurement, transport and

Key points

processing

N Think of TB; if you do not, the

Success in detecting and isolating

laboratory cannot help you.

mycobacteria strongly depends on the

following principles.

N Do not use microbiological tests as

screening tests.

Select patients soundly suspected of

having an active disease.

N Remember that the best way to

Submit appropriate specimens,

improve testing sensitivity is to

collected from the body sites most likely

submit high-quality specimens.

to yield mycobacteria. Inappropriate or

Molecular tests cannot replace

redundant specimens must be

conventional culture.

discouraged.

Ensure that adequate volumes of

N If your laboratory does not meet

samples are properly collected, stored

current quality standards (testing and

and delivered to the laboratory.

turnaround times), refer your

specimens to a larger laboratory.

Most clinical specimens contain an

abundance of nonmycobacterial organisms.

ERS Handbook: Respiratory Medicine

255

Unless an attempt is made to get rid of such

positive results should be reported

contaminants, they will easily suppress the

immediately by telephone, fax or other

slow growth of mycobacteria. In addition, it

electronic means, as soon as they are

is also necessary to liquefy respiratory

available.

samples so that mycobacteria can be easily

Molecular detection of MTC

harvested after centrifugation. This key

procedure is referred to as

With the purpose of obtaining faster results

‘decontamination’, and is usually performed

and a more accurate diagnosis of TB than

using a mixture of 1% N-acetyl-L-cysteine

those achievable with microscopy and liquid

and 2% sodium hydroxide. As a rule of

culture, several molecular methods were

thumb, ideal decontamination should be

introduced and have been evaluated

mild enough to kill contaminants without

worldwide.

damaging mycobacteria.

These technologies allow for the

Microscopy

amplification of specific target sequences

The first step in the laboratory diagnosis of

that can be detected through the use of a

TB is microscopic examination of sputum

complementary nucleic acid probe. Both

smears stained by an acid-fast procedure.

RNA and DNA amplification systems have

Microscopy is rapid, easy and inexpensive,

been developed.

providing the physician with a presumptive

diagnosis of TB and a simultaneous

Although many in-house amplification

assessment of the patient’s infectiousness.

methods have been described in published

studies, most amplification tests currently

Since the sensitivity of microscopy is

used in clinical laboratories are supplied

relatively low, requiring 10³-10⁴ bacilli per

commercially. While these assays have

mL of specimen to allow detection, smears

demonstrated an excellent specificity, their

should always be prepared from

sensitivity cannot equal that of culture-

concentrated specimens. Centrifugation is a

based methods, especially for smear-

key step, and must be performed with

negative samples. In a recent meta-analysis,

sufficient g-force in appropriately

pooled sensitivities and specificities of 85%

refrigerated and enclosed biosafe

and 97%, respectively, were reported.

centrifuges.

NAA methods can be applied to

The acid-fast staining procedure depends on

decontaminated respiratory specimens

the ability of mycobacteria to retain dye

within hours, producing a positive result

when treated with acid or acid-alcohol

with as few as 10² bacilli per mL of

solution. Two types of acid-fast stains are

specimen. They should be performed within

commonly used:

48 h of specimen receipt. NAA tests are

applied to smear-positive respiratory

N the carbol fuchsin stain, which includes

samples to provide rapid confirmation that

the Ziehl-Neelsen and Kinyoun methods

the infecting mycobacteria belong to the

N a fluorochrome procedure using

MTC. In addition, it is recommended that

auramine O or auramine-rhodamine

NAA tests are used on the first sputum or

dyes

other respiratory sample of all smear-

The latter provides a 10% more sensitive

negative TB suspects.

performance and also permits a faster

Since the clinical utility of NAA tests is for

screening of smears.

ruling in active TB, it is of utmost

AFB seen on smear may represent either

importance that they are employed on the

MTC or NTM. However, because of the

basis of a sound clinical suspicion. Routine

infectious potential of MTC, sputum smear

implementation of NAA testing without

microscopy should be performed within one

consideration of clinical data lacks cost-

working day of specimen receipt and

effectiveness and may be misleading.

256

ERS Handbook: Respiratory Medicine

Culture

clinical laboratories identify these organisms

only to the level of the complex. This

All clinical specimens suspected of

practice is supported by two rapid

containing mycobacteria should be

identification procedures that, based on

inoculated onto culture media for the

distinctive molecular and antigenic

following reasons.

characteristics of the MTC, have gained

widespread use:

N Culture is the most sensitive method,

being able to detect as few as 10

N nucleic acid hybridisation

mycobacteria per mL of specimen

N immunochromatographic assay

N Growth of the organisms is necessary for

proper species identification

It is recommended that laboratories culture

N DST requires culture of the organism

and identify MTC within 21 days of receiving

N Genotyping of the cultured strain may be

the patient’s specimen (table 1). This goal can

useful to study clusters of TB cases

be obtained only by combining liquid culture

with the above rapid identification methods.

Three different types of culture media are

currently available: egg-based (Löwestein-

Drug susceptibility testing

Jensen), agar-based (Middlebrook 7H10 or

DST should be performed on the initial

7H11 medium) and liquid (Middlebrook 7H9

isolate from all new TB cases. In addition, it

and other 7H9-based commercial broths)

should be repeated if the patient continues

whose selectivity may be greatly improved

to be culture-positive after 2-3 months of

by adding antibiotics. A combination of

treatment or exhibits positive culture after a

liquid and solid culture gives the most rapid

period of negative cultures.

and optimal rates of mycobacterial recovery

from clinical specimens.

The source for DST may be either a smear-

positive specimen (direct method) or, most

Among liquid media, automated culture

often, growth is first isolated in pure culture

systems have been developed that are

from clinical specimens and then inoculated

continuously monitored and also able to

into a drug-containing medium (indirect

perform DST. Since none of the above liquid

method). Growth of mycobacteria in the

systems can distinguish between a pure and

presence of the drug(s) is then compared

mixed mycobacterial culture, parallel culture

with a drug-free control.

on solid media will provide confirmation of a

single colonial morphology. For these

Among different DST methods, the

reasons, liquid culture systems should be

proportion method is the most widely used.

available in all laboratories willing to

It allows determining the proportion of MTC

perform mycobacteriology.

organisms that are resistant to a given drug

at a single (critical) concentration. The

Identification

susceptibility proportion was set at 1%,

The genus Mycobacterium consists of .140

because higher proportions of drug-resistant

different species, all of which appear similar

bacilli were shown to be associated with

on acid-fast staining. More than two-thirds

treatment failure. The critical concentration

of them, both saprophytes and (potential)

of a drug is the level of drug that inhibits the

pathogens, may be recovered from human

growth of most organisms within the

sources.

population of a wild-type strain without

affecting the growth of strains recovered

Causative agents of TB in humans (M.

from clinically resistant patients (table 2).

tuberculosis, Mycobacterium bovis, M. bovis

bacille Calmette-Guérin (BCG),

Several studies have established that drug

Mycobacterium africanum, Mycobacterium

resistance in MTC isolates does not rely upon

caprae, Mycobacterium microti,

a ‘on/off’ mechanism, but, on the contrary,

Mycobacterium pinnipedii and Mycobacterium

different mutations may lead to different

canettii) are referred to as MTC and most

levels of resistance. This means that

ERS Handbook: Respiratory Medicine

257

Table 1. Turnaround times for essential laboratory tests recommended by the American Thoracic Society to provide

effective TB control and elimination

Test

Maximum turnaround time

Microscopy for AFB

f24 h from receipt by laboratory

NAA assay

f48 h from date of specimen collection

Mycobacterial growth detection by culture

f14 days from date of specimen collection

Identification of cultured mycobacteria

f21 days from date of specimen collection

DST

First-line drugs

f30 days from date of specimen collection

Second-line drugs

f4 weeks from date of request

Reproduced and modified from American Thoracic Society et al. (2005) with permission from the publisher.

mutation(s) causing low-level resistance do

renewed efforts were spent to develop new

not necessarily imply clinical resistance.

drugs for the chemotherapy of TB. Several

Unfortunately, these data on different levels

classes of drugs including diarylquinoline

of resistance are not available when single

(bedaquiline), nitroimidazole (PA-824 and

critical concentrations are used. Moreover,

delamanid), and oxazolidine compounds

the resistance level determined in vitro bears

have shown promise for the treatment of

little relationship to the drug concentrations

both fully susceptible as well as drug-

achievable in vivo.

resistant TB. These drugs have unique, new

action mechanisms, and no cross-resistance

Results of first-line drugs assay (isoniazid,

between them and the existing TB drugs has

rifampicin, ethambutol and pyrazinamide)

been reported. To date, no information is

should be reported within 4 weeks from

available on DST for these new drugs.

specimen receipt. Although agar proportion

is currently the reference method, two

Molecular detection of resistance

commercially available automated systems

Although detection of drug resistance in

(BACTEC MGIT 960 (BD, Franklin Lakes,

MTC has traditionally been accomplished by

NUJ, USA) and ESP culture system

culture-based assays, the emergence of

(Thermo Scientific, East Grinstead, UK))

MDR- and XDR-TB demands improved and

have been cleared for susceptibility testing

faster detection methods. In this context,

of first-line drugs. The use of these liquid

several molecular approaches have been

systems has not yet been approved for

developed aimed at detecting gene

susceptibility testing of second-line drugs

mutations known to be associated with

(amikacin, capreomycin, ethionamide,

phenotypic resistance to a particular drug.

kanamycin, moxifloxacin, para-

aminosalicylic acid, rifabutin, streptomycin

As DNA sequencing (the reference method

and linezolid), which still relies on the agar

to look for specific mutations) would be

proportion method.

almost impossible for most diagnostic

laboratories, simpler procedures such as

Compared to other laboratory tests,

the line probe assay (LiPA) have recently

accuracy is much more important than

been introduced. It relies on the reverse

speed in the case of drug susceptibility.

hybridisation of oligonucleotides on plastic

Thus, results should come from a small

strips to which specific probes have been

number of well-equipped, experienced

immobilised. Amplified target sequences

laboratories enrolled in a national and/or

from the strain under evaluation are bound

supranational DST quality control scheme.

to probes and hybridisation is revealed by

During the past 10 years, triggered by the

the development of a coloured line on

increasing prevalence of MDR- and XDR-TB,

the strip.

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ERS Handbook: Respiratory Medicine

Table 2. Critical concentrations available for DST of MTC using commercial liquid media systems cleared for use by

the US Food and Drug Administration and their equivalence in the agar proportion method

Antimicrobial agent

Concentration mg?mL^-1

BACTEC MGIT 960

VersaTREK

7H10 Agar

Isoniazid

0.1

0.2

Isoniazid

0.4

1.0

Rifampicin

1.0

Ethambutol

5.0

Ethambutol

7.5

8.0

10.0

Pyrazinamide

100

300

Streptomycin

1.0

2.0

Streptomycin

4.0

10.0

BACTEC MGIT 960 is manufactured by BD (Franklin Lakes, NJ, USA). VersaTREK is manufactured by Thermo

Scientific (East Grinstead, UK). NA: not available. Reproduced from and modified from Clinical Laboratory

Standards Institute (2011) with permission from the publisher.

There are currently three commercially

showed a high diagnostic accuracy for rapid

available LiPAs for the rapid detection of

diagnosis of both smear-positive and

drug resistance in MTC: the INNO-LiPA Rif

-negative pulmonary TB. For diagnosis of

TB (Innogenetics, Ghent, Belgium) for

rifampicin resistance, false-positive results

detecting resistance to rifampicin; the

were observed in settings characterised by a

GenoType MTBDRPlus (Hain Lifesciences,

low prevalence of resistance. XpertMTB/RIF

Nehren, Germany) for the simultaneous

may have the potential to complement the

detection of resistance to rifampin and

current reference standard of TB

isoniazid; and the newly released GenoType

diagnostics, and increase its overall

MTBDRsl (Hain Lifesciences), which

sensitivity and speed. Further studies are

detects the most frequent mutations

required to determine the optimal level of

associated with resistance to

the healthcare system where this system can

fluoroquinolones, aminoglycosides and

be used cost-effectively.

ethambutol. These tests are validated for

Genotyping of MTC isolates

use in cultured strains as well as in smear-

positive respiratory samples.

Genotyping or DNA fingerprinting of MTC

refers to procedures developed to identify

Real-time PCR technology has also been

isolates that are identical in specific parts of

proposed for the rapid detection of drug

the genome. The most extensively used

resistance in MTC. Different assays have

method in the last two decades has been

been developed, which include the

restriction fragment length polymorphism

XpertMTB/RIF (GeneXpert system; Cepheid,

(RFLP) analysis of the distribution of the

Maurens-Scopont, France), an automated

insertion sequence IS6110. The more

molecular test for simultaneous detection of

recently developed spoligotyping and 24-

MTC and rifampicin resistance. This

locus variable number of tandem repeats

cartridge-based NAA assay employs a hemi-

(VNTR) techniques are similarly based on

nested real-time PCR and requires just a

genetic polymorphism of additional

single manual step with minimal sample

mycobacterial repetitive sequences. The

manipulation. The remaining analysis is

various DNA fingerprinting methods serve

performed by the GeneXpert instrument,

different purposes and have variable

relatively rapidly (,2 h). Clinical validation

characteristics that enable their use in

trials performed in many different settings

specific applications. They currently support

ERS Handbook: Respiratory Medicine

259

routine contact tracing as well as

Clinical

and Laboratory Standard

investigations on person-to-person

Institute. Susceptibility testing of myco-

transmission, early disease outbreak

bacteria, nocardiae, and other aerobic

identification and laboratory cross-

actinomycetes. M24-A2. Wayne, CLSI,

contamination, and permit determination of

2011.

whether new cases of TB are due to re-

Davies PDO, et al. (2008). The diagnosis

infection or re-activation. In addition, the

and misdiagnosis of tuberculosis. Int J

recognition of different genotype families

Tuberc Lung Dis; 12: 1226-1234.

has facilitated studies on the population

Drobniewski FA, et al.

(2006).

Recommended standards for modern

structure of MTC and its dynamic. Due to

tuberculosis laboratory services in

the fact that VNTR typing combines a more

Europe. Eur Respir J; 28: 903-909.

user-friendly technique with a significantly

Drobniewski FA (2003). Modern labora-

shorter turnaround time than RFLP typing, it

tory diagnosis of tuberculosis. Lancet

is now considered the gold standard.

Infect Dis; 3: 141-147.

European Centre for Disease Prevention

Organisation of laboratory services

and Control. Mastering the basics of TB

Any TB laboratory-based diagnostic

control: development of a handbook on

procedure should be performed by

TB diagnostic methods. Stockholm,

appropriately trained staff working to

ECDC, 2011.

Ling DI, et al.

(2008). Commercial

standardised operating procedures in

nucleic-acid amplification tests for diag-

appropriately equipped and safe

nosis of pulmonary tuberculosis in

laboratories, to well-defined national and

respiratory specimens: meta-analysis

international proficiency and quality

and meta-regression. PLoS One;

standards. In this context, mycobacteriology

e1536.

laboratory consolidation at the regional level

Palomino JC (2009). Molecular detection,

is strongly recommended.

identification and drug resistance detec-

tion in Mycobacterium tuberculosis. FEMS

Immunol Med Microbiol; 56: 103-111.

Further reading

Parrish NM, et al.

(2011). Role of the

American Thoracic Society, et al.

(2005).

clinical mycobacteriology laboratory in

Controlling tuberculosis in the United States.

the diagnosis and management of tuber-

Am J Respir Crit Care Med; 172: 1169-1227.

culosis in low-prevalence settings. J Clin

Centers for Disease Control and

Microbiol; 49: 772-776.

Prevention. (2009). Updated guidelines

Tenover FC, et al. (1993). The resurgence

for the use of nucleic acid amplification

of tuberculosis: is your laboratory ready?

tests in the diagnosis of tuberculosis.

J Clin Microbiol; 31: 767-770.

MMWR; 58: 7-10.

Weyer K, et al. (2013). Rapid molecular TB

Clinical and Laboratory Standard Institute.

diagnosis: evidence, policy making and

Laboratory Detection and Identification of

global implementation of Xpert MTB/RIF.

Mycobacteria. M48-A. Wayne, CLSI, 2008.

Eur Respir J; 42: 252-271.

260

ERS Handbook: Respiratory Medicine

Chronic rhinitis

Arnaud Bourdin and Pascal Chanez

Rhinitis is one of the most common human

school or work is often reported by subjects

diseases. Its most important features are

suffering from rhinitis. Rhinitis is often

inflammation and structural changes of the

associated with other IgE-related disease,

nasal mucosa. The causes are hetero-

and the continuum linking upper and lower

geneous and, if allergy and infections are

airways is well represented by the association

dominant, it is often difficult to find a single

of rhinitis and asthma, which frequently

common aetiology in chronic rhinitis. It is

coexist: asthma is present in 20-50% of

important to consider that rhinitis is often

patients with allergic rhinitis. Rhinitis is

associated with sinusitis and lower airway

present in up to 80% of asthma patients.

diseases such as asthma. Rhinitis is a mild

Whether allergic rhinitis precedes, triggers

disease, but it interferes with sleep quality

or precipitates asthma lacks supportive

and daily life.

data. Atopic status plays a potentially

prominent role in this relationship,

Epidemiology

although it is not a prerequisite. The risk

Rhinitis is still increasing in prevalence in

factors for rhinitis need to be better known

most countries. In some studies, 25-30% of

and understood in order for preventive

the population suffers from rhinitis, which is

measures to be implemented.

often linked to IgE sensitisation. It may

increase with age, as demonstrated in both

Definition and clinical aspects of rhinitis

children and adults, and there is growing

Allergic rhinitis is defined as inflammation

evidence that emerging countries are

of the nasal mucosa characterised clinically

affected by an increase in prevalence. Thus,

by nasal discharge, blockage, sneezing and

rhinitis is an important health problem

itch, with two or more symptoms occurring

worldwide. It affects health-related quality of

for .1 h on most days. It can be further

life in both adults and children. It is usually a

classified as intermittent (symptoms

mild disease, but its direct and indirect

occurring on ,4 days out of 7 or for

costs are substantial. Absenteeism from

,4 weeks per year) or persistent

(symptoms occurring on o4 days out of 7

Key points

or for o4 weeks per year). The impact of

chronic rhinitis on sleep, daily activities,

N The prevalence of rhinitis is increasing

work or school is a major determinant of

in most countries.

quality-of-life impairment in patients. The

perception of nasal symptoms is highly

N Asthma is present in 20-50% of

variable, a fact illustrated in patients

allergic rhinitis patients, while up to

suffering from COPD, where a discrepancy

80% of asthma patients have rhinitis.

between nasal inflammation and symptoms

Treatment is anti-inflammatory and

has been demonstrated. From a clinical

directed according to whether rhinitis

point of view, it is thus difficult to rely on

is allergic or nonallergic.

patients’ reports of symptoms as the only

way to assess rhinitis.

ERS Handbook: Respiratory Medicine

261

Diagnosis of allergic rhinitis

(history±skin prick tests or serum-specific IgE)

Allergen avoidance

Intermittent symptoms

Persistent symptoms

Mild

Moderate

Mild

Moderate

severe

Intranasal CS

Not in preferred order

• oral H1 blocker

• intranasal H1 blocker

Review the patient

and/or decongestant

after 2-4 weeks

• intranasal CS

(chromone)

Improved

Failure

In persistent rhinitis,

Step-down

Review diagnosis

review the patient

and continue

Review compliance

after 2-4 weeks

treatment

Query infections

for 1 month

or other causes

If failure: step-up

If improved: continue

Increase

Itch/sneeze

for 1 month

Intranasal CS

Add H1 blocker

dose

Blockage add

Rhinorrhoea

decongestant

Add ipratropium

or oral CS

(short term)

Failure

Surgical referral

Figure 1. Treatment algorithm for allergic rhinitis. CS: corticosteroids. Reproduced and modified from the

ARIA guidelines, with permission from the publisher.

Nonallergic rhinitis is difficult to

rhinitis. Inflammatory cells such as

differentiate clinically from allergic rhinitis.

eosinophils, mast cells, T-cells and

Exacerbations are usually associated with

macrophages infiltrate the epithelium and

infections but several other triggers,

submucosa. Mast cell-derived inflammatory

including drugs, may cause recurrent

mediators are overexpressed, such as

symptoms.

histamine, chemokines and cytokines

including interleukin (IL)-5, RANTES

Pathological and mechanistic aspects

(regulated on activation, normal T-cell

Pseudostratified epithelium and a large,

expressed and secreted), IL-4, IL-13 and

highly developed vasculature cover the nasal

granulocyte-macrophage colony-stimulating

wall. Tight junctions, peptidases and a large

factor. Most of these molecules trigger a

antioxidant apparatus are key features of the

local eosinophilic inflammatory process.

anatomical barrier of the nasal epithelium.

Allergens, microorganisms and pollutants

The mucosal-associated lymphoid tissue is

are potential triggers that can generate acute

developed in the nose. Structural

and chronic inflammatory reactions through

abnormalities including changes of the

the epithelium. The release of various

basement membrane have been reported in

mediators is responsible for most of the

262

ERS Handbook: Respiratory Medicine

clinical symptoms reported by patients.

Rhinitis and Its Impact on Asthma (ARIA)

Nasal hypersecretion, sneezing and itching

guidelines (fig. 1).

are related to the release of vasoactive and

The term rhinitis covers a heterogeneous

pro-inflammatory mediators such as

group of diseases. Allergic rhinitis and its

histamine and sulfidoleukotrienes.

associated diseases have been well defined

Persistent nasal obstruction is linked to the

and treatment is codified. Mucosal

perpetuation of inflammatory reactions

inflammation is the hallmark of rhinitis. Its

mostly related, in allergic rhinitis, to

natural history and its relationship with

eosinophilic infiltration.

sinusitis and lower airway diseases need to

Effects of anti-inflammatory treatment

be clarified. New treatments and

management strategies are required,

Intranasal corticosteroids and intranasal or

especially in the most chronic severe forms.

oral antihistamines have been shown to have

effects on different aspects of inflammation

Further reading

in allergic rhinitis. Additionally, intranasal

anticholinergic therapy provides relief for

Allergic Rhinitis and its Impact on

excessive rhinorrhoea, while leukotriene

Asthma. www.whiar.org

antagonists block the cysteinyl leukotriene

Bousquet PJ, et al. (2007). ARIA (Allergic

receptor. Nasal obstruction improves

Rhinitis and its Impact on Asthma)

significantly more with intranasal

classification of allergic rhinitis severity

corticosteroids compared with most of the

in clinical practice in France. Int Arch

other pharmacological strategies. Specific

Allergy Immunol; 143: 163-169.

Carr WW, et al. (2008). Managing rhini-

immunotherapy using sublingual, oral or

tis: strategies for improved patient out-

subcutaneous routes has been proven

comes. Allergy Asthma Proc; 29: 349-357.

effective and safe in intermittent and

Chanez P, et al.

(1999). Comparison

persistent allergic rhinitis. Allergen avoidance

between nasal and bronchial inflamma-

is not effective in persistent allergic rhinitis.

tion in asthmatic and control subjects.

Several studies have demonstrated that

Am J Respir Crit Care Med; 159: 588-595.

the effective treatment of rhinitis

Lipworth BJ, et al.

(2000). Allergic

decreases the burden of asthma as assessed

inflammation in the unified airway: start

by unscheduled visits to physicians and

with the nose. Thorax; 55: 878-881.

emergency rooms due to acute

Raherison C, et al. (2004). How should

exacerbations.

nasal symptoms be investigated in

asthma? A comparison of radiologic and

Treatment should be directed according to

endoscopic findings. Allergy; 59: 821-826.

the cause: nonallergic rhinitis should be

Togias A (2003). Rhinitis and asthma:

treated by nasal decongestant and

evidence for respiratory system integra-

anticholinergic therapy; allergic rhinitis

tion. J Allergy Clin Immunol; 111: 1171-1183.

should be treated according to the Allergic

ERS Handbook: Respiratory Medicine

263

Asthma

Bianca Beghé, Leonardo M. Fabbri and Paul O’Byrne

Asthma is a chronic inflammatory disease of

asthma rather than its exacerbations -

the airways characterised clinically by

remain largely undetermined.

recurrent respiratory symptoms of dyspnoea,

Asthma is a heterogeneous syndrome that,

wheezing, chest tightness and/or cough,

associated with reversible airflow limitation.

over the years, has been divided into many

different clinical subtypes, e.g. allergic

Other characteristics of asthma are an

asthma, adult-onset asthma that is usually

exaggerated responsiveness of the airways to

nonallergic, occupational asthma, asthma in

various stimuli, and, in most cases, a specific

smokers and asthma in the obese.

type of chronic inflammation of the airways

characterised by an increased number of

Minimum requirements for the diagnosis

CD4⁺ T-helper (Th) type 2 lymphocytes,

of asthma

eosinophils and metachromatic cells in the

airway mucosa, increased thickness of the

The diagnosis of asthma is based on an

reticular layer of the epithelial basement

appropriate clinical history, together with

membrane, and increased volume of airway

the demonstration of variable and/or

smooth muscle (fig. 1).

reversible airflow limitation, using lung

function tests, particularly peak expiratory

Familial predisposition, atopy, and exposure

flow (PEF) or spirometry. Allergy tests are

to allergens and occupational sensitising

also often performed during the initial

agents are important risk factors for asthma,

assessment of a patient with suspected

even though the causes of asthma - the

asthma, to identify possible triggers of

factors responsible for the development of

asthma and to guide their avoidance.

Asthma clusters in families and its genetic

Key points

determinants appear to be linked to those of

other allergic IgE-mediated diseases. Thus, a

Asthma is diagnosed based on clinical

personal or family history of asthma and/or

history and lung function testing.

allergic rhinitis, atopic dermatitis, or eczema

Allergy testing may also have a role.

increases the likelihood of a diagnosis of

N The differential diagnosis is extensive.

asthma.

In particular, COPD may be difficult to

Symptoms and medical history

distinguish from asthma.

Patients with asthma seek medical attention

N The goal of pharmacological asthma

because of respiratory symptoms. A typical

treatment is to achieve and maintain

feature of asthma symptoms is their

control of symptoms and prevention

variability. One or more of the symptoms

of exacerbations.

N Asthma is a chronic, lifelong disease

N wheezing

and must therefore be managed in

N chest tightness

partnership with the patient.

N episodic shortness of breath

N cough

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ERS Handbook: Respiratory Medicine

of treatment, unscheduled requests for

medical assistance and, sometimes,

hospitalisation are also among the

characteristic clinical features of asthma.

Physical activity is an important cause of

symptoms for most asthma patients,

particularly in children, and for some it is the

only cause. Exercise-induced broncho-

constriction usually develops not during

exercise but 5-10 min afterward and resolves

spontaneously within 30-45 min. Prompt

relief of symptoms after the use of an

inhaled b₂-agonist or their prevention by pre-

treatment with an inhaled b₂-agonist before

Figure 1. a, b) Photomicrographs showing

exercise supports a diagnosis of asthma.

bronchial biopsy specimens immunostained with

anti-EG-2 (eosinophil cationic protein) a) from a

Important aspects of personal history are

patient with fixed airflow obstruction and a history

exposure to agents known to worsen asthma

of COPD and b) from a patient with fixed airflow

in the home, such as dusty environments,

obstruction and a history of asthma. The two

forced air heating systems or exposure to

patients had a similar degree of fixed airflow

allergens (e.g. pets, house dust mites or

obstruction. In b), there is prominent eosinophilia

cockroaches) to which the patient is

beneath the destroyed epithelium that is not

sensitised, workplace conditions,

present in a). c, d) Photomicrographs showing

environmental tobacco smoke or even the

bronchial biopsy specimens stained with

general environment (e.g. diesel fumes in

haematoxylin and eosin c) from a patient with

traffic).

fixed airflow obstruction and a history of COPD

and d) from a patient with fixed airflow

Since respiratory symptoms of asthma are

obstruction and a history of asthma. The two

nonspecific, the differential diagnosis is

patients had a similar degree of fixed airflow

quite extensive, and the main goal for the

obstruction. In d), there is a thicker reticular layer

physician is to consider and exclude other

of the epithelial basement membrane compared

possible diagnoses (table 1). This is even

with c). Reproduced and modified from Fabbri et

more important if the response to a trial of

al. (2003) with permission from the publisher.

therapy has been negative.

When respiratory symptoms suggest

are reported by .90% of patients with

asthma, the sine qua non condition for the

asthma. However, the presence of these

objective diagnosis of asthma is the

symptoms is not diagnostic because similar

presence of reversible airflow obstruction. In

symptoms can be present with other

patients who have persistent airway

respiratory or even cardiac diseases, or may

obstruction, reversibility may be

be triggered by different stimuli in

demonstrated as response to treatment (e.g.

nonasthmatics, e.g. by acute viral infections.

200-400 mg albuterol or after a period of

In some asthmatics, wheezing and chest

regular treatment). In subject presenting

tightness are absent, and the only symptom

without persistent airway obstruction,

the patient complains of is chronic cough

reversibility may be demonstrated either by

(cough-variant asthma).

measuring airway responsiveness or PEF

variability.

Symptoms of asthma may be triggered or

worsened by several factors, such as

Physical examination

exercise, exposure to allergens, viral

infections and emotions. Recurrent

In mild asthma, physical examination is

exacerbations of respiratory symptoms,

usually normal under stable conditions, but

worsening of lung function requiring change

becomes characteristically abnormal during

ERS Handbook: Respiratory Medicine

265

Table 1. Differential diagnosis of asthma

Localised pathology

Inhaled foreign body

Endobronchial tumour

Vocal cord dysfunction

Diffuse airway pathology

COPD

Eosinophilic bronchitis

Bronchiectasis

Other pathologies

Gastro-oesophageal reflux

Left ventricular failure

Pulmonary embolism

Pulmonary eosinophilia

asthma attacks. Typical physical signs of

the post-bronchodilator FEV1/FVC ratio to

asthma attacks are wheezing on

,0.7. However, because this parameter

auscultation, cough, expiratory rhonchi

varies with ageing, it should be confirmed by

throughout the chest and signs of acute

post-bronchodilator FEV1/VC values below the

hyperinflation (e.g. poor diaphragmatic

lower limit of normal, particularly in younger

excursion on percussion or the use of

subjects. Measurements of residual volume

accessory muscles of respiration). Some

and TLC may be useful in assessing the

patients, particularly children, may present

degree of hyperinflation and/or enlargement

with a predominant nonproductive cough.

of airspaces. Lung volumes may help in the

In some asthmatics, wheezing, which

differential diagnosis with COPD but are not

usually reflects airflow limitation, may be

necessary for the diagnosis or for assessment

absent or detectable only on forced

of the severity of asthma. In asthma, airflow

expiration, even in the presence of

limitation is usually reversible, either

significant airflow limitation; this may be

spontaneously or after treatment, except for

due to hyperinflation or to very marked

moderate/severe asthma with fixed airway

airflow obstruction. In these patients,

obstruction (see later).

however, the severity of asthma is mostly

Peak expiratory flow An important tool for

indicated by other signs, such as cyanosis,

the diagnosis and subsequent treatment of

drowsiness, difficulty in speaking,

asthma is the PEF meter. If spirometry does

tachycardia, hyperinflated chest, use of

not reveal airflow limitation, then home

accessory muscles and intercostal

monitoring of PEF for 2-4 weeks may help to

recession.

detect an increased variability of airway

Lung function tests

calibre, and assist in making the diagnosis

of asthma. Daily monitoring of PEF (at least

Spirometry Lung function tests play a crucial

in the morning at awakening and in the

role in the diagnosis and follow-up of

evening hours, preferably after broncho-

patients with asthma. Spirometric

dilator inhalation) is also useful to assess

measurements - FEV1 and slow vital

the severity of asthma and its response to

capacity (VC) or FVC - are the standard

treatment, and it can help patients to detect

means for assessing airflow limitation.

early signs of asthma deterioration. Diurnal

Spirometry is recommended at the time of

variability is calculated as

diagnosis and for the assessment of the

severity of asthma. It should be repeated to

Diurnal variability~^PEFmax-PEFmin|¹⁰⁰

monitor the disease and when there is a

PEF_max zPEF_min=2

need for reassessment, such as during

exacerbations.

where PEFmax and PEFmin are maximal and

minimal PEF, respectively. A diurnal

Poorly or nonreversible airflow limitation is

variability of PEF .20% is diagnostic of

usually defined by the absolute reduction of

asthma and the magnitude of the variability

266

ERS Handbook: Respiratory Medicine

is broadly proportional to disease severity.

thereby, confirming or excluding the

PEF monitoring may be of use not only in

diagnosis of current asthma. These

establishing a diagnosis of asthma and

measurements are very sensitive, but poorly

assessing its severity but also in uncovering

specific for a diagnosis of asthma. This

an occupational cause of asthma. When

means that while a negative test can be used

used in this way, PEF should be measured

to exclude a diagnosis of active asthma, a

more frequently than twice daily and special

positive test does not always mean that a

attention should be paid to changes

patient has asthma. While the measurement

occurring in and out of the workplace.

of airway hyperresponsiveness may be

useful to confirm asthma in subjects with

Reversibility to bronchodilators Clinical and/or

normal baseline lung function, it is not

functional reversibility on repeated testing is

useful in the presence of irreversible airflow

required for the diagnosis of asthma. Thus,

limitation and, thus, in the differential

even a single reversibility test (defined as

diagnosis between asthma and COPD.

.12% reversibility and/or .200 mL in FEV1

after bronchodilator) can establish the

Arterial blood gases

diagnosis. However, reversibility is often not

present at the time of examination,

In severe asthma and, more importantly,

particularly in patients on treatment, and

during acute exacerbations of asthma, the

thus the absence of reversibility does not

measurement of arterial blood gases while

exclude the diagnosis. Repeated testing of

the patient is breathing air and/or after

reversibility of both clinical features and

oxygen administration is essential for the

functional abnormalities may be useful in

diagnosis of respiratory failure. This test

obtaining the best level of asthma control

should be performed in all patients with

achievable and/or the best lung function for

clinical signs of acute or chronic respiratory

individual patients achieving and

and/or heart failure, patients with an acute

maintaining lung function at the best

asthma exacerbation and PEF ,50%

possible level is one of the objectives of

predicted, patients who do not respond to

asthma management.

treatment, and those with a SaO₂ f92%.

Airway hyperresponsiveness In patients who

Allergy tests

have symptoms consistent with asthma but

have normal lung function, bronchial

The presence of allergic disorders in a

provocation tests with methacholine,

patient’s family history should be

histamine or exercise are helpful in

investigated in all patients with symptoms

measuring airway hyperresponsiveness and,

of asthma. A history provides important

Table 2. History, symptoms and results of pulmonary function tests in the differential diagnosis between asthma and

COPD

Asthma

COPD

Onset

Mainly in childhood

In mid- to late adult life

Smoking

Often nonsmokers

Almost invariably smokers

Chronic cough and sputum Often absent

Frequent (chronic bronchitis)

Dyspnoea on effort

Variable and reversible to

Constant, poorly reversible and

treatment

progressive

Nocturnal symptoms

Relatively common

Relatively uncommon

Airflow limitation

Increased diurnal variability

Normal diurnal variability

Response to bronchodilator Good

Poor

Airway hyperresponsiveness In most patients, with or

In most patients, with airflow

without airflow limitation

limitation

ERS Handbook: Respiratory Medicine

267

information about the patient’s lifestyle and

management of asthma. The utility of chest

occupation, both of which influence

radiography is to exclude other conditions

exposure to allergens, and the time and

that may imitate or complicate asthma,

factors possibly involved in onset and

particularly acute asthma. Examples include

exacerbations of asthma. Skin tests with all

pneumonia, cardiogenic pulmonary

relevant allergens present in the geographic

oedema, pulmonary thromboembolism,

area in which the patient lives are the

tumours (especially those that result in

primary diagnostic tool in determining

airway obstruction with resulting peripheral

allergic status. Measurement of specific IgE

atelectasis) and pneumothorax.

is not usually more informative than a skin

test and is more expensive. Measurement of

Assessment of airway inflammation While

total IgE in serum has no value as a

airway biopsies and bronchoalveolar lavage

diagnostic test for atopy. The main

may provide useful information in research

limitation of methods to assess allergic

protocols, they are considered too invasive

status is that a positive test does not

for the diagnosis or staging of asthma. In

necessarily mean that the disease is allergic

contrast, noninvasive markers of airway

inflammation have been increasingly used in

in nature or that it is causing asthma, as

some individuals have specific IgE

research protocols, particularly to

antibodies without any symptoms and these

differentiate asthma from COPD and

may not be causally involved. The relevant

measure response to treatment. These

exposure and its relation to symptoms must

noninvasive measurements include induced

be confirmed by patient history.

sputum and exhaled nitric oxide fraction

(FeNO) measurement. Induced sputum is

Additional tests

not helpful in the diagnosis of asthma but

can be very useful in the management of

While the diagnosis and assessment of

severe asthma. In particular, induced

severity of asthma can be fully established

sputum helps identify the persistence of

on the basis of clinical history and lung

airway eosinophilia or airway neutrophilia in

function tests, additional tests are

patients with difficult-to-treat asthma, which

sometimes helpful to better characterise

can be useful in deciding appropriate doses

individual patients.

of inhaled corticosteroids and in reducing

Imaging While chest radiography may be

the risks of severe asthma exacerbations.

useful to exclude diseases that may mimic

FeNO is increased in atopic asthma but less

asthma, it is not required in the

so in nonatopic asthma. Again, it is not

confirmation of the diagnosis and

useful in diagnosis but can be helpful in

Table 3. Ancillary tests in the differential diagnosis between stable asthma and COPD

Ancillary test

Asthma

COPD

Reversibility to bronchodilator and/or

Usually present

Usually absent

glucocorticosteroids

Lung volumes, residual volume, TLC

Usually normal or, if

Usually irreversibly

increased, reversible

increased

Diffusion capacity

Normal

Decreased

Airway hyperresponsiveness

Increased

Usually not measurable due

to airflow limitation

Allergy tests

Often positive

Often negative

Imaging of the chest

Usually normal

Usually abnormal

Sputum

Eosinophilia

Neutrophilia

FeNO

Increased

Usually normal

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ERS Handbook: Respiratory Medicine

monitoring adherence to inhaled

in elderly patients, in whom some features

corticosteroids, as it is effectively reduced by

may overlap, such as smoking and atopy,

inhaled corticosteroids but not by

and when the patient has airflow limitation

bronchodilators.

that is poorly reversible after treatment. In

these cases, symptoms, lung function,

Differentiating between asthma and COPD

airway responsiveness, imaging and even

pathological findings may overlap, and thus

Both asthma and COPD are characterised by

chronic airway inflammation but with very

may not provide solid information to

different characteristics (fig. 1). In most

establish a diagnosis. Because an accurate

patients, the clinical presentation and the

diagnosis is needed to provide better

history provide the strongest diagnostic

treatment, it is important in these cases to

criteria to distinguish asthma from COPD

undertake an individual approach and to

(table 2). Results of pulmonary function

perform additional tests. Reversibility to

tests, particularly spirometric

corticosteroids alone or in combination with

measurements that show a nearly complete

long-acting bronchodilators, measurements

reversibility of airflow limitation, will confirm

of lung volumes and diffusion capacity,

a diagnosis of asthma, and measurements

analysis of sputum and FeNO, and imaging

that show poorly reversible airflow limitation

of the chest may help to demonstrate

may help to confirm the diagnosis of COPD

whether asthma or COPD is the

(table 2). Differential diagnosis between

predominant cause of airflow limitation in

asthma and COPD becomes more difficult

these patients (table 3).

Table 4. Levels of asthma control

Assessment of current clinical control (preferably over 4 weeks)

Characteristic

Controlled (all

Partly controlled

Uncontrolled

of the following)

(any measure

present in any week)

Daytime symptoms

None (twice or

More than twice

Three or more

less per week)

per week

features of partly

controlled asthma

present in any week+,1

Limitation of activities

None

Any

Nocturnal symptoms/

None

Any

awakening

Need for reliever/rescue

None (twice or

More than twice

treatment

less per week)

per week

Lung function

Normal

,80% predicted

(PEF or FEV1)#,"

or 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 and high-dose medications

^#: not reliable for children aged f5years;^": 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 Global Initiative for Asthma

(2012) with permission from the publisher.

ERS Handbook: Respiratory Medicine

269

Comorbidities of asthma

to smoking, which is as common in

asthmatics as in the general population.

The coexistence of chronic rhinitis, nasal

Smoking modifies the airway pathology of

polyposis and sinusitis may contribute to

asthmatics to a COPD-like pattern and

the severity of asthma. There is evidence to

reduces the response to treatment.

show that adequate treatment of these

Comorbidities may become important in

upper airway diseases is beneficial to

severe asthmatics, whereas they play a much

asthma by mechanisms that are not clearly

less important role overall in the clinical

understood. The ‘one airway’ concept has

manifestations of mild-to-moderate asthma.

drawn attention to the importance of

treating the whole respiratory tract when

Management

managing asthma. Gastro-oesophageal

reflux is also occasionally associated with

Considering its chronic nature and life-long

asthma, both in adults and in children, but

duration, asthma can be effectively managed

treatment of reflux usually has little overall

only by developing a partnership between

effect on mild-to-moderate asthma. A

the patient and their doctor or health

frequent and quite important comorbidity of

professional, who may provide the tools for

asthma in adults is COPD, most likely due

guided self-management, and possibly a

Level of control

Treatment action

Controlled

Maintain and find lowest controlling step

Partly controlled

Consider stepping up to gain control

Uncontrolled

Step up until controlled

Exacerbation

Treat as exacerbation

Reduce

Treatment steps

Increase

Step 1

Step 2

Step 3

Step 4

Step 5

Asthma education, environmental control (if step-up treatment is being considered for poor

symptom control, first check inhaler technique and confirm symptoms are due to asthma)

As-needed short-

As-needed short-acting β₂-agonist

acting β₂-agonist

Select one

Add one or more

Add one or both

Low-dose ICS

Medium or

Oral

Low-dose

plus long-acting

high-dose ICS plus

glucocorticosteroid

inhaled ICS¶

β₂-agonist

long-acting

(lowest dose)

β₂-agonist

Controller

options#

Leukotriene

Medium or

Leukotriene

Anti-IgE

modifier+

high-dose ICS

modifier

treatment

Low-dose ICS plus

Sustained-release

leukotriene

theophylline

modifier

Low-dose ICS plus

sustained release

theophylline

Figure 2. Asthma management approach based on control for children aged .5 years, adolescents and

adults. Alternative reliever treatments include inhaled anticholinergics, short-acting oral b₂-agonists, some

long-acting b₂-agonists and theophylline. Regular dosing with short- and long-acting b₂-agonists is not

advised unless accompanied by an inhaled glucocorticosteroid. ICS: inhaled corticosteroids.^#:

recommended treatment (shaded boxes) based on group mean data; individual patient needs, preferences

and circumstances (including costs) should be considered.^": inhaled glucocorticosteroids.⁺: receptor

antagonist or synthesis inhibitors. Reproduced and modified from Global Initiative for Asthma (2012) with

permission from the publisher.

270

ERS Handbook: Respiratory Medicine

written plan including self-monitoring, and

an as-needed basis that act quickly to

periodically review of treatment and level of

reverse bronchoconstriction and relieve

asthma control. Education plays a major

asthma symptoms. Ideally, if patients are

role in this partnership.

adequately controlled, they should rarely

need rescue medications. The use of a

Long-term pharmacological treatment The

combination of an inhaled short-acting

aim of pharmacological treatment of asthma

b₂-agonist and a corticosteroid both as

is to achieve and maintain control of day-to-

controller and reliever is effective in

day symptoms, as well as preventing future

maintaining high levels of asthma control.

severe asthma exacerbations (table 4), while

using the safest treatment algorithm. While

Smoking asthmatics are resistant to anti-

the initial treatment should be started

asthma medications and should be primarily

according to the degree of asthma control at

treated for smoking addiction. Asthmatic

the first visit, subsequently treatment should

smokers may develop features of COPD.

be adjusted according to the level of asthma

control achieved (fig. 2). Usually, regular

Specific immunotherapy in asthma is

treatment is lowered only after a significant

limited as:

period of acceptable asthma control (e.g.

o3 months). This means that monitoring of

1) it requires the identification of a single

asthma is essential to maintain asthma

clinically relevant allergen

control and establish the minimal treatment

2) it can be used safely only in mild

requirements. Step-up and -down of

asthmatics who are usually well controlled

treatment are not standardised, and thus

by environmental interventions or

should be tailored to the individual patient

pharmacotherapy

to achieve and maintain control with the

minimum amount of medication.

3) it may be associated with adverse events

Medications to treat asthma can be

Treatment of exacerbations

classified as controllers or relievers.

Medications are preferably administered by

Shortness of breath, cough, wheezing and/or

inhalation, as this approach is the most

chest tightness may develop or worsen in a

effective way to treat asthma and has the

subject with asthma even when they are

fewest side-effects. Controller medications

under regular treatment. Milder

(inhaled corticosteroids alone or in

exacerbations are usually managed by the

combination with long-acting b₂-agonists)

patients with an increased as-needed use of

are taken daily on a long-term basis to keep

short-acting b₂-agonists alone or in

asthma under clinical control. In asthma,

combination in combination with inhaled

long-acting b₂-agonists should be used only

steroids. More severe exacerbations or

in combination with inhaled corticosteroids

exacerbations that do not respond to the

when the latter are insufficient to achieve

increased use of rescue medications require

control, and should be discontinued only

repetitive administration of rescue

when control is maintained.

medication and systemic, preferably oral,

corticosteroids, with oxygen

Only in patients not controlled by optimal

supplementation in very severe cases

doses of inhaled corticosteroids combined

(fig. 3). Severe exacerbations require medical

with long-acting b₂-agonists should other

attention and, in some instances, hospital

secondary agents may be considered. These

admission.

include anti-leukotrienes, theophylline,

systemic corticosteroids or anti-IgE

Special considerations

monoclonal antibodies in very specific

Special considerations are required for

cases.

patients with specific comorbidities, such as

Reliever medications (predominantly short-

rhino/sinusitis and/or nasal polyps, aspirin-

acting b₂-agonists) are medications used on

induced asthma (particularly if associated

ERS Handbook: Respiratory Medicine

271

Initial assessment

• History, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate, PEF

or FEV1, oxygen saturation, arterial blood gas if patient in extremis)

Initial treatment

• Oxygen to achieve SaO2

≥90% (95% in children)

• Inhaled short-acting β₂-agonist continuously for 1 h

• Systemic glucocorticosteroids if no immediate response, or if patient recently took oral

glucocorticosteroid, or if episode is severe

• Sedation is contraindicated in the treatment of an exacerbation

Reassess after 1 h

Physical examination, PEF, SaO2 and other tests as needed

Criteria for moderate episode:

Criteria for severe episode:

• PEF 60_80% pred/personal best

• History of risk factors for near fatal asthma

• Physical exam: moderate symptoms, accessory

• PEF <60% pred/personal best

muscle use

• Physical exam: severe symptoms at rest,

Treatment:

chest retraction

• Oxygen

• No improvement after initial treatment

• Inhaled β₂-agonist and inhaled anticholinergic every

Treatment:

60 min

• Oxygen

• Oral glucocorticosteroids

• Inhaled β₂-agonist and inhaled

• Continue treatment for 1_3 h, provided there is

anticholinergic

improvement

• Systemic glucocorticosteroids

• Intravenous magnesium

Reassess after 1_2 h

Good response within 1_2 h:

Incomplete response within 1_2 h:

Poor response within 1_2 h:

• Response sustained 60 min

• Risk factors for near fatal asthma

• Risk factors for near fatal

after last treatment

• Physical exam: mild to moderate

asthma

• Physical exam normal:

signs

• Physical exam: symptoms

No distress

• PEF <60%

severe,

• PEF >70%

• SaO2 not improving

drowsiness, confusion

• SaO2 >90%

• PEF <30%

Admit to acute care setting

(95% in children)

• PaCO2 >45 mmHg

• Oxygen

• PaO2 <60 mmHg

• Inhaled β2-agonist ± anticholinergic

• Systemic glucocorticosteroid

Admit to intensive care

• Intravenous magnesium

• Oxygen

• Monitor PEF, SaO2, pulse

• Inhaled β₂-agonist +

anticholinergic

• Intravenous

glucocorticosteroids

• Consider intravenous

β₂-agonist

• Consider intravenous

theophylline

• Possible intubation and

mechanical ventilation

Improved: criteria for discharge home

Reassess at intervals

• PEF >60% pred/personal best

• Sustained on oral/inhaled medication

Poor response (see above):

Home treatment:

• Admit to intensive care

• Continue inhaled β₂-agonist

• Consider, in most cases, oral

Incomplete response in 6_12 h

glucocorticosteroids

(see above)

• Consider adding a combination inhaler

• Consider admission to intensive care

• Patient education: Take medicine correctly

if no improvement within 6_12 h

Review action plan

Close medical follow-up

Improved (see opposite)

Figure 3. Management of asthma exacerbations in the acute care setting. Reproduced and modified from

Global Initiative for Asthma (2012) with permission from the publisher.

272

ERS Handbook: Respiratory Medicine

with episodes of anaphylaxis), occupational

Fabbri LM, et al. (2003). Differences in

asthma and obesity.

airway inflammation in patients with

fixed airflow obstruction due to asthma

In addition, patients with asthma may

or chronic obstructive pulmonary dis-

require specific competent medical

ease. Am J Respir Crit Care Med;

167:

attention in case of smoking addiction,

418-424.

pregnancy, surgery, infections (e.g. influenza

Fattahi F, et al.

(2011). Smoking and

epidemics) and, more importantly, if asthma

nonsmoking asthma: differences in clin-

is severe.

ical outcome and pathogenesis. Expert

Rev Respir Med; 5: 93-105.

Global Initiative for Asthma. Global

Further reading

Strategy for Asthma Management and

Barnes PJ (2012).Severe asthma: advances

Prevention 2012. www.ginasthma.org

in current management and future ther-

Global Initiative for Chronic Obstructive

apy. J Allergy Clin Immunol; 129: 48-59.

Lung Disease. Global Strategy for

Bateman ED, et al. (2011). Overall asthma

Diagnosis, Management, and Prevention

control achieved with budesonide/formo-

of COPD 2012. www.goldcopd.org

terol maintenance and reliever therapy for

Hargreave FE, et al. (2009). The defini-

patients on different treatment steps.

tion and diagnosis of asthma. Clin Exp

Respir Res; 12: 38.

Allergy; 39: 1652-1658.

Boulet LP, et al. (2011). Asthma-related

Holt PG, et al. (2012). Viral infections and

comorbidities. Expert Rev Respir Med; 5:

atopy in asthma pathogenesis: new ratio-

377-393.

nales for asthma prevention and treat-

Boulet LP, et al. (2012). A guide to the

ment. Nat Med; 18: 726-735.

translation of the Global Initiative for

Maestrelli P, et al. (2009). Mechanisms

Asthma (GINA) strategy into improved

of occupational asthma. J Allergy Clin

care. Eur Respir J; 39: 1220-1229.

Immunol; 123: 531-542.

Brozek JL, et al. (2011). Grading quality of

Namazy JA, et al. (2011). Asthma and

evidence and strength of recommenda-

pregnancy. J Allergy Clin Immunol;

128:

tions in clinical practice guidelines part 3

1384-1385.

of 3. The GRADE approach to developing

O’Byrne PM (2011). Therapeutic strate-

recommendations. Allergy; 66: 588-595.

gies to reduce asthma exacerbations.

Camargo CA Jr, et al. (2009). Managing

J Allergy Clin Immunol; 128: 257-263.

asthma exacerbations in the emergency

Parsons JP (2013). An official American

department: summary of the National

Thoraeic Society clinical practice guide-

Asthma Education and Prevention Pro-

line. Exercise-induced bronchoconstric-

gram Expert Panel Report 3 guidelines for

tion. Am Respir Crit Care Med;

187:

the management of asthma exacerbations.

1016-1027.

J Allergy Clin Immunol; 124: Suppl., S5-S14.

Petsky HL, et al.

(2012). A systematic

Chung KF (2012). Inflammatory biomar-

review and meta-analysis: tailoring

kers in severe asthma. Curr Opin Pulm

asthma treatment on eosinophilic mar-

Med; 18: 35-41.

kers

(exhaled nitric oxide or sputum

de Groot EP, et al. (2010). Comorbidities of

eosinophils). Thorax; 67: 199-208.

asthma during childhood: possibly impor-

Sin DD, et al. (2008). Obesity and the

tant, yet poorly studied. Eur Respir J;

lung: 4. Obesity and asthma. Thorax; 63:

36: 671-678.

1018-1023.

ERS Handbook: Respiratory Medicine

273

Vocal cord dysfunction

Adel H. Mansur

Vocal cord dysfunction (VCD) is

constitutes VCD, with some limiting it to an

characterised by paradoxical vocal cord

early description by Christopher et al. (1983)

adduction during inspiration and/or

of a conversion disorder meeting a strict

expiration, leading to symptoms of

definition of inspiratory adduction and

breathlessness and wheeze. It is a poorly

posterior chinking of vocal cords, to those

understood condition that often co-exists

who use an all-encompassing VCD

with asthma and chronic cough, and shares

definition of all cases demonstrating PVCM.

common triggers with them, such as

Epidemiology

psychological factors, gastro-oesophageal

reflux and rhinosinus disease. The

While the true prevalence of VCD in the

management of VCD focuses on

general population is unknown, it is more

establishing the correct diagnosis,

common in females, athletes, army recruits,

identification and treatment of underlying

asthmatics and patients with chronic cough

triggers, and speech therapy. Further

(table 1). Using dynamic CT imaging, 50% of

research is required to define VCD, establish

46 difficult asthmatics demonstrated PVCM,

its natural history and develop evidence-

which was severe in nine patients (Low et

based therapies.

al., 2011).

Terminology

Pathogenesis

Numerous terms have been used to

VCD was seen largely as a conversion

describe VCD. These include hysteric croup,

disorder of psychogenic origin. The larynx is

Munchausen’s stridor, pseudo-asthma,

innervated by a complex neurological

factitious asthma, upper airway dysfunction,

network, and the association between stress

functional upper airway obstruction, irritable

and comorbid psychology and VCD attacks

larynx syndrome, emotional laryngeal

strengthened this view. More recently, it

wheeze, laryngeal hyperresponsiveness and

became apparent that PVCM ‘VCD’ exists

paradoxical vocal cord movement (PVCM).

outside the conversion disorder prototype.

Indeed, there is disagreement over what

Laryngeal closure is a normal physiological

reaction to exposure to irritants (e.g.

aspiration), but this reaction normally only

Key points

lasts for a few seconds. Acute (e.g. toxic

fume inhalation) or recurrent irritation (e.g.

VCD is not well understood, and there

repeated extreme cold air exposure) may

is as yet no consensus definition.

lead to laryngeal hypersensitivity

manifesting as vocal cord adduction and

N Classically, symptoms appear

airflow limitation (Cukier-Blaj et al., 2008).

abruptly, resolve quickly and do not

Laryngeal hypersensitivity may form part of

respond well to asthma medication.

unified allergic airway syndrome with

Long-term treatment is based around

asthma and rhinitis. The association of

speech therapy and psychotherapy.

laryngeal hypersensitivity with altered

autonomic balance status maintained by

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ERS Handbook: Respiratory Medicine

Table 1. VCD prevalence in different patient groups.

Patient group

Prevalence %

Refractory asthma

5-10

Dyspnoea

2.8

Army recruits with stress-induced asthma

Olympic athletes

Childhood acute asthma^#

The reported mean age at VCD diagnosis is 14.5 years in children and 33 years in adults.^#: presenting to

emergency department.

central brain activity have been postulated to

oxygen saturation is often normal. Extreme

underlie development of VCD (Ayers et al.,

forms of VCD can lead to collapse and loss

2002).

of consciousness, usually leading to

resolution of the attack or intubation. If

Clinical presentation

intubated, the airway inflation pressure is

characteristically normal.

VCD presentation varies from cases with

predominant throat symptoms usually

Diagnosis

referred to ENT specialists, to asthma

presenting to the respiratory clinic or angio-

Flow-volume loops may show inspiratory

oedema presenting in an immunology clinic.

loop truncation representing extrathoracic

Often, the diagnosis of VCD is made after

airflow obstruction. The maximum

treatment for asthma has not been

inspiratory/expiratory flow ratio at 50% FVC

successful.

(MIF50%/MEF50%) can be reduced due to

predominant inspiratory flow limitation. An

Patients may report rapid-onset attacks of

abnormally high forced inspiratory flow at

dyspnoea, which may be preceded by

25%/75% FVC ratio (FIF25%/FIF75%) would

intense coughing, the sensation of

indicate an initially normal flow followed by

strangulation or breathing through a straw,

rapid flow decline, reflecting PVCM during

throat or upper chest tightness, dysphonia,

inspiration. However, various studies

or stridor. Classical VCD symptoms are of

reported the insensitivity of spirometry for

abrupt onset, resolve quickly and respond

diagnosing VCD (Ruppel, 2009). Sensitivity

poorly to asthma medication.

of spirometry may be enhanced by

histamine or other forms of airway

Elucidation of triggers of VCD attacks is

challenge.

important for diagnostic and therapeutic

purposes. Commonly associated triggers

Impulse oscillometry (IOS) can discriminate

include exposure to cold air, exercise,

between central and peripheral airway

inhalation of strong smells such as

obstruction, and may be more sensitive than

perfumes or chemical cleaning agents,

spirometry. Airway fluoroscopy and colour

smoke, cough, reflux, viral infections,

Doppler ultrasound imaging of vocal cord

allergens, and emotional stress.

movement are other noninvasive tools that

Psychological morbidity and sexual abuse

have not been standardised against

are experienced in some VCD sufferers. The

laryngoscopy.

physical examination of patients with VCD is

usually unremarkable outside symptomatic

Integrated CT software programs have been

attacks. During symptoms, examination may

used to obtain continuous dynamic axial,

reveal stridor or wheeze originating at

sagittal and coronal multiplanar images of

laryngeal level with clear chest auscultation.

the larynx, measuring airway diameters at

The severity of respiratory distress varies

the level of the vocal cords and the first

from mild to severe with tachypnoea, but

tracheal ring. The ratio of vocal cord

ERS Handbook: Respiratory Medicine

275

diameter to tracheal diameter was used as a

False-negative PVCM can be secondary to

marker of PVCM (Low et al., 2011).

gag reflex or coughing.

Laryngoscopy

The larynx should also be inspected for

signs of laryngopharyngeal reflux (Belafsky

VCD diagnosis is established by

et al., 2002). VCD should be distinguished

laryngoscopic demonstration of PVCM while

from vocal cord immobility due to paralysis,

the patient experiences spontaneous or

amyotrophic lateral sclerosis, cricoarytenoid

induced symptoms. Bicycle ergometry

joint dysfunction and Reinke’s oedema.

combined with fibreoptic videolaryngoscopy

Laryngeal electromyography (EMG) may

has been developed as a diagnostic test for

help in differentiation. Normal laryngoscopy

VCD in patients with exercise-induce

in the absence of symptoms does not

dyspnoea. One study reported that if the

exclude VCD. The presence of atypical

symptom of dyspnoea appeared, the most

features of asthma and/or VCD should

frequent diagnosis was exercise-induced

prompt further investigations, such as CT of

VCD (Tervonen et al., 2009).

head, neck and thorax, and bronchoscopy.

Agreed laryngoscopy standards have not

Investigations directed at causes of VCD

been developed, with some advocating pre-

A careful history is essential to guide

procedure sedation and analgesia, while

investigations. The presence of concomitant

others recommend avoiding these

rhinitis/asthma or allergic airway disease

measures. Following a short period of quiet

needs to be assessed by lung function, skin

breathing, specific manoeuvres such as

allergy testing, blood/sputum eosinophils

repeating low- and high-pitched sounds,

and exhaled nitric oxide. Gastro-oesophageal

forceful inspiration and expiration are

reflux diseases symptoms or laryngeal

conducted to induce an attack (Wood et al.,

refluxive changes on laryngoscopy should

1996). Vocal cord movements are timed

prompt further testing (e.g. oesophageal

against respiratory cycle phases by putting a

manometry and pH studies). Underlying

hand on the patient’s chest. In VCD, the

psychological issues should be assessed.

vocal cords adduct anteriorly, leaving an

open posterior glottic chink (fig. 1). The

Differential diagnosis

adduction occurs during inspiration or

throughout the respiratory cycle.

N Laryngeal oedema (angio-oedema)

N Allergic laryngitis

N Subglottic stenosis

N Laryngomalacia or tracheomalacia

N Vocal cord paralysis

N Systemic disease affecting the larynx/

upper airways (e.g. relapsing chondritis or

granulomatosis with polyangiitis

(Wegener’s))

Treatment

Diagnosis and treatment are best conducted

in a multidisciplinary team setting

comprised of a respiratory physician, speech

therapist, ENT specialist and psychologist.

The diagnosis is explained to the patient,

preferably with the support of imaging or

illustration. The patient’s good

understanding of VCD is prerequisite to

Figure 1. Laryngoscopy demonstrating inspiratory

effective treatment. A management plan

vocal cord adduction and posterior glottic chink.

should be formulated that bears in mind

276

ERS Handbook: Respiratory Medicine

co-existing asthma. Due to VCD under-

exercise-induced VCD attacks (O’Connell

recognition, patients should carry an alert

et al., 2006), enhancing inspiratory

card listing medication and treatment

resistance by a face mask device, CPAP and

strategy.

vocal cord injection of botulinum toxin A

(Botox). Tracheostomy has been used as a

Treatment of acute attacks

last resort in intractable cases.

The treating physician should adopt a

Prognosis

calm, reassuring manner and ask the

patient to focus on expiration with an ‘S’

The long-term outcome of VCD is unknown.

sound that helps in diverting attention. A

VCD prognosis will probably depend on

panting manoeuvre can abort acute

initial disease severity and associated

attacks by inducing vocal cord abduction.

morbidities. One study reported complete

Where hypoxaemia and hypercapnia have

resolution of VCD within a 5-year time

been excluded, sedation with

frame, with symptoms disappearing within

benzodiazepines may help patient

6 months in many who had a good response

relaxation. Heliox gas mixture (e.g. 72%

to speech therapy. However, intractable

helium and 28% oxygen) can alleviate

forms of disease did not seem to improve

symptoms by enhancing upper airway

over a 10-year observation period (Doshi

laminar air flow. Intubation or

et al., 2006).

tracheostomy should be avoided. In

Conclusion

extreme cases presenting with an apparent

life-threatening attack, the clinical decision

VCD is a relatively uncommon condition

will remain with the treating physician. If

that mimics and co-exists with asthma, and

intubation is contemplated, prior

presents episodically, thus making its

inspection and documentation of the

diagnosis challenging and often delayed.

status of the vocal cords is recommended.

Patients can become frequent healthcare

Long-term treatment

users with substantial morbidity as result of

erroneous diagnosis and toxic medication

Speech therapy forms the mainstay of VCD

use. Establishing proper diagnosis and

treatment, with the primary aim of teaching

treatment can be effective and rewarding to

patients to relax the upper airways and

both the patient and healthcare

control the laryngeal area. It is conducted in

professionals.

four to six successive sessions to enable the

patient to practice breathing techniques to

Further reading

abort or treat acute attacks (Wood et al.,

1996). Patients are taught to exhale gently

Ayres JG, et al.

(2002). Vocal cord

and avoid forceful inspiration in a rhythmic

dysfunction and laryngeal hyperrespon-

manner, followed by introduction of

siveness: a function of altered autonomic

expiratory resistance by asking patient to

balance? Thorax; 57: 284-285.

produce sounds such as ‘S’. The role of the

Belafsky PC, et al.

(2002). Validity and

speech therapist extends to making the

reliability of the reflux symptom index

diagnosis, identification and treatment of

(RSI). J Voice; 16: 274-277.

triggers, and relaxation therapy.

Christopher KL, et al. (1983). Vocal-cord

dysfunction presenting as asthma. N Engl

Psychotherapy should form an integral part

J Med; 308: 1566-1570.

of VCD management, given VCD’s link to

Cukier-Blaj S, et al.

(2008). Paradoxical

adverse psychology. Psychotherapy can

vocal fold motion: a sensory-motor

include relaxation therapy, management of

laryngeal disorder. Laryngoscope;

118:

stress and anxiety, and development of

367-370.

coping strategies.

Doshi DR, et al. (2006). Long-term out-

come of vocal cord dysfunction. Ann All

Other, unproven therapies for VCD include

Asthma Imm; 96: 794-799.

inhaled anticholinergic drugs to abort

ERS Handbook: Respiratory Medicine

277

Low K, et al. (2011). Abnormal vocal cord

Sullivan MD, et al. (2001). A treatment for

function in difficult-to-treat asthma. Am J

vocal cord dysfunction in female athletes:

Respir Crit Care Med; 184: 50-56.

an outcome study. Laryngoscope;

111:

Newman KB, et al.

(1995). Clinical

1751-1755.

features of vocal cord dysfunction. Am J

Tervonen H, et al.

(2009). Fiberoptic

Respir Crit Care Med; 152: 1382-1386.

videolaryngoscopy during bicycle ergome-

O’Connell M, et al. (2006). Vocal cord

try: a diagnostic tool for exercise-induced

dysfunction: ready for prime-time? Ann

vocal cord dysfunction. Laryngoscope; 119:

All Asthma Imm; 96: 762-763.

1776-1780.

Ruppel GL (2009). The inspiratory flow-

Wood RP, et al.

(1996). Vocal cord

volume curve: the neglected child of pulmo-

dysfunction. J Allerg Clin Imm; 98: 481-

nary diagnostics. Respir Care; 54: 448-449.

485.

278

ERS Handbook: Respiratory Medicine

Bronchitis

Gernot Rohde

Definition

Aetiology/risk factors

Transient airway inflammation localised to the

Respiratory infections are the main trigger of

respiratory mucosa of the central airways and

acute bronchitis. However, pathogens can

clinically characterised by cough and sputum

only be detected in 55% of cases. Respiratory

production. Fever and dyspnoea can occur.

viruses are the most frequent pathogens.

Rhinovirus, adenovirus, echovirus, influenza

Symptoms

virus, parainfluenza virus, enterovirus,

coronavirus, Coxsackie virus, human

Cough is the cardinal symptom and is

metapneumovirus and respiratory syncytial

observed in 100% of cases. It usually

virus (RSV) represent the usual spectrum.

persists for up to 2 weeks, but in 26% of

Parainfluenza viruses, enteroviruses and

cases it can stay for up to 8 weeks. Other

rhinoviruses mainly infect in the autumn,

symptoms include sputum production

while the influenza viruses, RSV and

(90%), dyspnoea, wheezing (62%), rhonchi,

coronaviruses mainly infect in the winter

chest pain, fever, hoarseness and malaise.

and early spring. Typical bacteria are

Epidemiology

Streptococcus pneumoniae, Haemophilus

influenzae and Moraxella catarrhalis. Atypical

Acute bronchitis is one of the most frequent

bacteria, e.g. Mycoplasma pneumoniae or

human diseases worldwide, with children

Chlamydia pneumoniae, and Bordetella

being most often affected. On average

pertussis also play a role.

children contract bronchitis between two to

six times per year, and adults two to three

Specific risk factors have not been dentified

times per year. The prevalence in the UK is

and it is currently not clear whether cigarette

44 cases per 1000 adults per year. 82% of

smoking increases the risk of acute

episodes occur during the cold months.

bronchitis. There are epidemiological data

showing that the frequency of bronchitis is

increased after school holidays, which

Key points

indicates that crowding facilitates the

dissemination of respiratory infections.

N Respiratory viral infection is the most

common cause of acute bronchitis.

Prognosis

N Acute bronchitis is usually a self-

Acute bronchitis is usually a self-limiting

limiting disease.

disease. However there are only sparse data

on prognosis and rate of complications. In a

N The diagnosis of acute bronchitis is

study investigating 653 previously healthy

purely clinical and in most cases

adults with lower respiratory tract

symptomatic treatment is sufficient.

symptoms, 20% of patients had persistent

Chronic bronchitis is defined clinically

symptoms. In 40% of these patients, there

as productive cough for 3 months in

was reversible airway obstruction. In another

each of two successive years.

study, a third of patients developed asthma

or chronic bronchitis symptoms.

ERS Handbook: Respiratory Medicine

279

Diagnosis

whom other causes of productive chronic

cough have been excluded. Cigarette

Diagnosis is purely clinical. Cough, sputum

smoking is by far the most important and

production and optionally accompanied by

preventable risk factor. Chronic bronchitis is

dyspnoea and/or wheezing, are suggestive.

a major component of chronic obstructive

Tachycardia and tachypnoea are usually

pulmonary disease.

absent, and vital signs are normal.

Complicated cases show fever; however, in

these cases differential diagnosis like

Further reading

pneumonia or systemic influenza should be

American Thoracic Society (1962). Chronic

considered. Clinical signs of pneumonia, e.g.

bronchitis, asthma, pulmonary emphy-

rales, egophony, dullness on percussion,

sema: a statement by the committee on

should be absent. Acute bronchitis should be

diagnostic standards for non-tuberculous

differentiated from asthma, which typically

disease. Am Rev Respir Dis; 85: 762-768.

presents as progressive cough accompanied

Antó JM, et al. (2001). Epidemiology of

by wheezing, tachypnoea, respiratory distress

chronic obstructive pulmonary disease.

and hypoxaemia. It should also be

Eur Respir J; 17: 982-994.

distinguished from bronchiectasis, a distinct

Boldy DA, et al. (1990). Acute bronchitis

phenomenon associated with permanent

in the community: clinical features, infec-

dilatation of bronchi and a chronic cough.

tive factors, changes in pulmonary func-

Laboratory investigations are not necessary.

tion and bronchial reactivity to histamine.

In more severe cases, sputum culture can be

Respir Med; 84: 377-385.

considered to guide antibiotic therapy.

Chesnutt MS, et al. Lung. In: Tierney LM,

ed. Current Medical Diagnosis and

Therapy

Treatment, 41st Edn. New York, Lange

Medical/McGraw-Hill,

2002; pp.

269-

Therapeutic goals are the reduction of

362.

symptoms and the prevention of

Jonsson JS, et al. (1998). Acute bronchitis

complications, with as few side-effects as

and clinical outcome three years later:

possible. Antibiotic therapy cannot be

prospective cohort study. BMJ; 317: 1433.

recommended generally, but in patients with

Macfarlane JW, et al. (2001). Prospective

fever and/or comorbidities, aminopenicillins

study of the incidence, aetiology and

or cephalosporins (second generation) can be

outcome of adult lower respiratory tract

administered. Dextromethorphan has been

illness in the community. Thorax;

56:

shown to reduce cough efficiently. In patients

109-114.

with dyspnoea and/or wheezing, short-acting

Wenzel RP, et al. (2006). Acute bronchi-

bronchodilators can be beneficial.

tis. N Engl J Med; 355: 2125-2130.

Williamson HA Jr

(1987). Pulmonary

Chronic bronchitis

function tests in acute bronchitis: evi-

Chronic bronchitis is defined clinically as

dence for reversible airway obstruction.

chronic productive cough for 3 months in

J Fam Pract; 25: 251-256.

each of two successive years in a patient in

280

ERS Handbook: Respiratory Medicine

Gastro-oesophageal reflux

Lieven Dupont

Gastro-oesophageal reflux (GOR), defined

gastro-oesophageal reflux disease (GORD).

as the retrograde flow of gastric contents

GORD is an increasingly prevalent condition

into the oesophagus, is a normal

that affects .20% of the Western

physiological phenomenon that occurs to

population. Although GORD often causes

some extent in most people. Brief exposure

typical symptoms such as heartburn or

of the oesophagus to gastric contents does

regurgitation, 32% of the patients with reflux

not necessarily result in injury or disease.

disease have extraoesophageal symptoms,

When reflux is prolonged and/or when there

including respiratory and ENT symptoms

is a breakdown of the defence mechanisms

and disorders. The relationship between

that act to protect mucosal integrity,

reflux and respiratory symptoms is

symptoms and/or lesions in the oesophagus

frequently difficult to establish with a high

occur. This is then referred to as

degree of certainty and diagnostic, as well as

therapeutic, management remains largely

empirical. In contrast to oesophageal GORD

Key points

manifestations, efficacy of acid-suppressive

therapy in extraoesophageal GORD

symptoms has not been equally well

GORD is a common disorder caused

established.

by the reflux of gastric contents into

the oesophagus because of impaired

Mechanisms of increased reflux

function of the LOS and may result in

oesophageal and extraoesophageal

The oesophagogastric junction (OGJ) is the

symptoms.

first line of defence against reflux. It

comprises two important components: the

The relationship between reflux and

lower oesophageal sphincter (LOS) and the

respiratory symptoms or disorders is

crural diaphragm that regulate the exchange

frequently difficult to establish with a

of contents between the oesophagus and the

high degree of certainty.

stomach. Transient lower oesophageal

Diagnostic, as well as therapeutic,

sphincter relaxations (TLOSRs), defined as

management remains largely

relaxations of the LOS not triggered by

empirical.

swallowing, account for the majority of reflux

episodes, both in healthy subjects and in

Treatment with PPIs has been shown

GORD patients. Not all TLOSRs are

to improve cough in patients with acid

associated with reflux. In healthy subjects,

GOR-induced cough but the effect of

almost half of the TLOSRs are followed by a

PPIs remains disappointing when

reflux episode, which is significantly higher in

treating GOR in other respiratory

GORD patients, where ,70% of the TLOSRs

diseases.

lead to reflux. A hiatal hernia, which is the

Antireflux surgery is associated with

separation of the LOS from the crural

improved allograft function after lung

diaphragm, further diminishes the capacity of

transplantation.

the OGJ to prevent reflux. GORD patients

have a higher gastro-oesophageal pressure

ERS Handbook: Respiratory Medicine

281

gradient during a TLOSR than healthy

The oesophagus is innervated by sensory-type

subjects. The higher pressure gradient is due

nociceptors that express the TRPV1 channel.

to a higher intra-abdominal pressure and

These afferents of the vagus nerve converge

correlates with BMI. Although a delay in

centrally with capsaicin-sensitive C-fibres and

gastric emptying has been shown in ,30% of

capsaicin-insensitive, acid-sensitive

GORD patients, a clear causal relationship

mechanoreceptors from the respiratory tract.

between rate of gastric emptying and reflux

The convergence of these vagal afferent

parameters remains controversial.

neurons in the brainstem may allow

sensitisation of vagally mediated reflexes from

Pathophysiology

the (distal) oesophagus to be triggered by

chemical or mechanical stimuli. A vagally

There are a number of potential

mediated oesophageal-bronchial reflex has

mechanisms of interaction between the

been postulated to account for the association

oesophagus and the lung that explain the

between acid reflux and cough or asthma.

complex interplay between GOR(D) and

respiratory symptoms and disease:

Oesophageal sensory stimulation can

release tachykinins into the airways and may

N aspiration of gastric contents into the

increase the bronchomotor responsiveness

airways

to airway stimuli, resulting in

N stimulation of a vagally mediated reflex

bronchospasms. It has also been postulated

pathway

that chronic exposure of the oesophageal

N hypersensitivity

mucosa to gastric juices can produce long-

lasting hypersensitivity to a variety of stimuli

Direct microaspiration of (duodeno)gastric

that cause cough symptoms even in the

refluxate into the airway occurs as a

absence of increased oesophageal acid

consequence of failure of the normal

exposure or esophagitis.

protective mechanisms against foreign

material, i.e. reflex contraction of the upper

GOR in asthma and COPD

oesophageal sphincter and closure of the

glottis and vocal cords. Aspiration can be

GORD is a common condition among

demonstrated by the presence of pepsin and

patients with obstructive pulmonary

bile acids in saliva, sputum or bronchoalveolar

diseases. At least one-third of asthmatics

lavage (BAL) fluid. While pepsin and bile acids

present with GORD (prevalence 34-89%)

are clearly increased in patients with CF and

and 50-60% of COPD patients have

idiopathic pulmonary fibrosis (IPF), and after

abnormally high oesophageal acid exposure

lung transplantation, there was no difference

times. Often, COPD or asthmatic patients

between chronic cough, patients with asthma

with GORD do not have typical symptoms of

and healthy controls.

GORD. The relationship between GOR and

the clinical course of asthma and COPD

Aspiration of (duodeno)gastric contents

needs to be better understood but it has

into the lungs can lead to chemical injury,

been shown that that abnormal GOR may

which may be followed by an inflammatory

worsen asthma symptoms and has been

response, characterised by the recruitment

associated with increased risk of asthma

of neutrophils to the airways. It has been

and COPD exacerbations. Oxygen

widely accepted that acid causes damage to

desaturation coincides with episodes of

bronchial epithelial cells, but recent data

increased oesophageal acidity in 40% of

demonstrated that nonacidic gastric

patients with severe COPD and GORD.

contents are also important in the

pathogenesis of reflux-induced airway

Several mechanisms may be involved (vagus

inflammation. Pepsin and bile acids may

nerve mediated mechanisms, chronic

even cause cell damage at normal pH, which

microaspiration and bronchial

may explain why some patients have

hyperreactivity). b₂-agonists and theophylline

refractory symptoms on maximal proton

decrease LOS tone and may consequently

pump inhibitor (PPI) therapy.

promote oesophageal reflux. Airway

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ERS Handbook: Respiratory Medicine

obstruction resulting in increased thoracic

patients with a suspected GORD syndrome

pressure changes, hyperinflation and

who do not respond to an empirical trial of

exaggerated diaphragmatic flattening may

PPI therapy, in elderly patients with asthma

also contribute to the occurrence of GOR.

or COPD, or in patients with severe

refractory asthma.

Multiple trials have examined the treatment

of GORD with histamine antagonists or PPIs

GOR-induced cough

in asthma. A Cochrane systematic review

Studies have determined GOR to be a cause

concluded that acid-suppressive therapy did

of chronic cough in .40% of patients

not result in a consistent benefit in patients

referred for specialist evaluation. GOR-

with asthma. Similarly, there was no effect on

induced cough is currently thought to occur

lung function, airway responsiveness or

predominantly via an oesophageal-

asthma symptom control. Even though nine

bronchial reflex. Studies using combined

out of 12 trials included in the meta-analysis

pH/impedance and cough monitoring have

reported at least one significant outcome,

shown that both acid and nonacid reflux

there was no consistency in these effects. The

Study of Acid Reflux in Asthma (SARA), a

events can be associated with cough. The

large randomised control trial evaluated high-

acidity of the refluxate may thus be

dose PPI (esomeprazole 40 mg b.i.d.) in

unimportant if the oesophageal-bronchial

patients with uncontrolled asthma that did

reflex is already sensitised. Findings of an

not have typical GOR symptoms. PPI therapy

equal number of cough events preceding as

did not improve asthma control, quality of life

well as following reflux also suggest the

or lung function and, although 40% of these

possibility that cough may precipitate

patients had abnormal asymptomatic acid

TLOSRs. Reflux should not be considered as

GOR upon oesophageal pH monitoring,

a single independent cause but rather as a

there was also no improvement with PPIs in

contributing factor as well as a consequence

this subgroup. A recent study in children

of chronic cough.

yielded similar results. However, these

Only a minority of patients with chronic cough

studies did not test for nonacid reflux and did

and GORD have typical digestive symptoms

not evaluate the effect of treating nonacid

and/or clear evidence of oesophagitis. As a

reflux on asthma control. A retrospective

result and in accordance with published

study showed improvement of FEV1 with

guidelines, objective evaluation of GOR is

antireflux surgery in patients with adult-onset

indicated in patients with chronic cough.

asthma, typical reflux symptoms and

Detection of both acid and nonacid reflux

proximal extent of the reflux.

events with simultaneous cough detection

No large-scale studies have evaluated

allows for an objective assessment of the

therapeutic options for GOR in patients with

relationship between the two.

COPD. Uncontrolled data suggest that PPI

Treating GOR with the therapeutic strategies

treatment may decrease the number of

currently available may result in only a

COPD exacerbations. Future randomised

partial symptomatic improvement, as

controlled trials are needed.

chronic cough is often a multifactorial

For patients with asthma or COPD and who

process. The treatment of cough-associated

have typical reflux symptoms, empirical

reflux with acid-suppressive therapy has

prescription of acid suppression therapy is

been evaluated in many uncontrolled and a

appropriate but the effect on respiratory

few controlled trials. A Cochrane review

end-points may be limited. Current evidence

concluded that PPI administration was not

does not support the initiation of empirical

efficacious for cough associated with GORD

acid suppression therapy in asthma patients

symptoms in children. There was

who lack symptoms that suggest the

insufficient evidence to conclude that

presence of GORD. Additional testing by

treating GOR with PPI in adults with cough

means of endoscopy and ambulatory pH/

was beneficial, although a slight

impedance is indicated in asthma or COPD

improvement in cough scores was found in

ERS Handbook: Respiratory Medicine

283

those receiving PPIs. Further randomised,

increased GOR or gastric aspiration do not

parallel-design, placebo-controlled, double-

present oesophageal symptoms like

blind trials are needed. Based on these data,

heartburn or regurgitation. The

an empirical course of PPIs for 8 weeks

characteristics of GOR and the material

could be advocated in all patients with

aspirated depend on the genotype, with bile

possible reflux-induced cough, especially in

acid aspiration being more important in

patients who also have typical reflux

CFTRDF508 homozygotes.

symptoms. Prokinetic drugs have no efficacy

The available evidence suggest a possible

in GORD-related cough and gastric

relationship between GOR, aspiration and

emptying has not been shown to be delayed

the severity of CF lung disease, generation of

in patients with GOR-related cough. In

cough symptoms, airway inflammation, and

patients who failed to respond to empirical

the progression of the lung disease. CF

therapy with PPIs, reflux-induced cough is

patients with increased oesophageal acid

not necessarily excluded, as nonacid reflux

exposure have more cough and a positive

may also be implicated. Fundoplication

association between GOR and cough is

provides an alternative method to treat

associated with poorer lung function. Bile

GORD, which similarly controls acid and

acid levels in sputum correlate with elastase

nonacid reflux. Uncontrolled studies with

levels in sputum and FEV1; raised pepsin

surgical treatment in patients with possible

levels in BAL fluid are associated with higher

reflux-induced cough showed a positive

levels of interleukin (IL)-8 in the BAL fluid.

response in 56-100% of surgically treated

GOR might also be involved in earlier onset

patients. A positive symptom association

of first acquisition of Pseudomonas

between acid or nonacid reflux was a good

aeruginosa and the pathogenesis of CF

predictor of successful surgical outcome. In

exacerbations.

selected patients with refractory acidic or

nonacidic reflux and a documented

Retrospective data suggested that CF

correlation between reflux episodes and

patients on acid suppression therapy had a

cough, antireflux surgery may be indicated

smaller yearly decline of FEV1. However, a

for long-term control.

Cochrane review failed to show any

relationship between reflux treatment and

GOR in advanced lung disease

improvement of pulmonary damage in CF.

Antireflux surgery may be considered as a

GOR is an important comorbidity in patients

more efficacious treatment of GOR in CF

with bronchiectasis. The prevalence of

patients and uncontrolled studies showed

abnormal GOR in CF is estimated to be

an improvement in FEV1 decline and cough

between 35% and 81%, and a somewhat

symptoms and a reduction in CF

smaller increase in GORD prevalence has

exacerbation rate.

also been reported in patients with non-CF

bronchiectasis. Acid GOR is most

GOR may play a role in the pathogenesis

predominant in CF, but weakly acidic GOR

and/or progression of IPF as a recurrent

may also occur. CF patients with increased

inflammatory stimulus. Studies have found

GOR often have a high proximal extent of

a high prevalence of reflux (36-87%) among

the reflux into the oesophagus. Many CF

patients with interstitial lung diseases

patients have oesophageal hypomotility and

(ILDs), especially those with IPF or

low basal LOS pressure. The number of

connective tissue disease (CTD)-associated

TLOSRs is similar to controls but TLOSRs in

ILD. Hypopharyngeal multichannel

CF patients are more often associated with

intraluminal impedance measurement in

reflux, due to an more pronounced

patients with IPF demonstrated frequent

reduction in thoracic pressure during

occurrence of abnormal proximal reflux

inspiration. Patients with CF have a high risk

events despite the absence of typical GOR

of gastric aspiration, as demonstrated by

symptoms and a frequently negative

increased bile acids in saliva, sputum or in

DeMeester score. Aspiration, assessed by

BAL fluid. Half of the CF patients with

means of increased BAL fluid pepsin levels,

284

ERS Handbook: Respiratory Medicine

was associated with an increased odds ratio

Sleep and GOR

for an acute exacerbation in IPF patients.

Sleep-related reflux is common, affecting

Pre-transplant patients with IPF undergoing

between 47% and 79% of GORD patients.

antireflux surgery had reduced

Between 54% and 57% of GORD patients and

supplementary oxygen dependence

25% of the general adult population report

compared with other pre-transplant patients

heartburn during the night. Sleep-related

with IPF. There are anecdotal cases of IPF

reflux is more commonly associated with

disease stability and less radiological

oesophageal mucosal injury, malignant

fibrosis on HRCT following treatment for

transformation and extraoesophageal

reflux. In addition, a recent cohort analysis

manifestations of GORD. Poor quality of

found that the use of medications to

sleep and sleep disturbances have also been

suppress reflux was an independent

recently documented in a significant number

predictor of longer survival time.

of GORD patients with night-time reflux.

GOR and microaspiration have also been

Sleep-related GOR occurs primarily during

implicated as a potential nonalloimmune

arousals or conscious awakenings in the

cause of lung allograft rejection

first few hours of the sleep period and is

(bronchiolitis obliterans syndrome (BOS))

primarily caused by TLOSR. Most conscious

after lung transplantation. Standard

awakenings during sleep that also

oesophageal pH recordings indicated an

demonstrated reflux were not associated

increased oesophageal acid exposure in

with typical GORD-related symptoms.

.70% of lung transplant patients. Luminal

Testing for reflux may thus be helpful in

gastric components such as pepsin and bile

patients without typical GOR symptoms

acids have been demonstrated in the

who have disrupted sleep without an

bronchial material of lung transplant

identifiable cause found despite having

recipients and were more prevalent in the

undergone polysomnography sleep testing.

lungs of patients with BOS. Aspiration of

bile acids was related to weakly acidic reflux

Up to 62% of OSA patients have sleep-

events, especially during the night, and was

related GOR symptoms and CPAP improves

associated with a reduced concentration of

GOR symptoms and reduces oesophageal

pulmonary surfactant collectin proteins,

contact times. Treatment of sleep-related

reduced freedom from BOS and reduced

GOR includes behavioural treatment

survival. Aspiration, even in the absence of

(weight loss, not eating prior to bedtime and

avoiding foods known to worsen GOR) and

an increased number of GOR events, might

PPI therapy given an hour before the last

therefore be a risk factor for the

meal. Fundoplication can be helpful in

development of BOS after lung

selected patients with GOR and OSA.

transplantation. Retrospective studies have

linked prophylactic antireflux surgery to

Management of GORD

improved allograft function and decreased

incidence and/or severity of BOS.

In general practice, most cases of GORD are

diagnosed on the basis of typical symptoms

While it cannot be absolutely proven that

and the response to inhibition of gastric acid

disease stability is related to the control of

secretion. Endoscopy, oesophageal

reflux, the aforementioned study data

manometry or acid instillation in the

suggest that a subset of patients with

oesophagus (Bernstein test) have limited

advanced lung disease may benefit from

sensitivity and specificity for the diagnosis

antireflux therapy. Proximal gastrointestinal

of GORD. 24-h oesophageal pH monitoring

tract motility studies, pH/impedance testing

can provide useful information, in particular

and markers of microaspiration appear to be

through the assessment of the temporal

important in management decisions. Future

association between symptoms and reflux

studies should seek to identify the most

events. The addition of impedance

effective tool to determine the timing and

monitoring to pH monitoring further

efficacy of antireflux treatment.

improves GOR diagnosis as it also detects

ERS Handbook: Respiratory Medicine

285

nonacid reflux events and allows testing

acid-sensitive ion channels, metabotropic

while the patient is taking a PPI. The

glutamate receptor-5 antagonists and

detection of biomarkers of aspiration (e.g.

endoscopic antireflux procedures.

pepsin and bile acid concentrations in

At present, the only alternative is a surgical

saliva, sputum or BAL fluid) has increasingly

fundoplication. Laparoscopic antireflux

been recognised as a tool to identify patients

surgery creates a mechanically competent

at risk of disease worsening due to GORD

cardia, and is more effective in preventing

but, currently, there is no consensus on how

microaspiration and in eliminating proximal

best to detect aspiration.

reflux. However, not all patients are eligible

Medications interfering with acid production,

for surgery, the intervention is not without

especially the PPIs, are the cornerstone of

complications and poor responders to PPI

GORD treatment. Acid-suppressive therapy

therapy are also less certain to experience

is highly effective in the healing and

symptom relief from surgery. The key is thus

maintenance of oesophagitis, but seems to

the identification of patients who, with

be poorly effective when GORD is presumed

certainty, have GOR as an important cause

to underlie extraoesophageal symptoms.

of their pulmonary symptoms.

Symptoms that persist during standard acid

suppressive therapy regimens have also been

Further reading

related to nonacid reflux. There is little

evidence that further intensification of acid

Asano K, et al. (2009). Silent acid reflux

suppression beyond high-dose PPIs twice

and asthma control. N Engl J Med; 360:

daily is of any benefit for these patients.

1551-1553.

Dopaminergic antagonists with prokinetic

Blondeau K, et al. (2008). Gastro-oeso-

activity (metoclopramide and domperidone)

phageal reflux and aspiration of gastric

enhance gastric emptying and

contents in adult patients with cystic

gastroduodenal coordination, but they do not

fibrosis. Gut; 57: 1049-1055.

appear to improve LOS pressure or reduce

Dettmar PW, et al. (2011). Reflux and its

reflux events. Serotonin receptor prokinetic

consequences - the laryngeal, pulmonary

agents (cisapride and tegaserod) might be

and oesophageal manifestations. Aliment

useful in the treatment of GOR but these

Pharmacol Ther; 33: Suppl. 1, 1-71.

Dupont LJ, et al. (2009). Emerging risk

drugs are no longer available due to concerns

over possible adverse cardiovascular side-

factors for bronchiolitis obliterans syn-

drome: gastro-oesophageal reflux and

effects. A number of selective 5-HT₄ agonists/

infections. Eur Respir Monogr;

45:

212-

antagonists (prucalopride and mosapride)

225.

show some promise and are undergoing

Galmiche JP, et al.

(2008). Respiratory

investigation for reflux treatment. Baclofen is

manifestations of

gastro-oesophageal

a c-aminobutyric acid (GABA) receptor

reflux disease. Aliment Pharmacol Ther;

blocking agent that diminishes acid and

27: 449-464.

nonacid reflux through GABA receptor

Meyer KC, et al., eds. Gastroesophageal

inhibition of TLOSRs and is now being

Reflux and the Lung. New York, Springer,

used off label in the treatment of GOR.

2013.

Baclofen may also reduce the exposure to

Pashinsky YY, et al. (2009). Gastroeso-

duodenogastric reflux but its use has been

phageal reflux disease and idiopathic

limited by side-effects. Other GABA agonists

pulmonary fibrosis. Mt Sinai J Med; 76:

(arbaclofen and lesogaberan) are currently

24-29.

under evaluation for their ability to reduce

Sweet MP, et al. (2009). Gastro-oesopha-

TLOSRs and improve reflux and symptoms

geal reflux and aspiration in patients with

that are refractory to PPI therapy. Other

advanced lung disease. Thorax; 64: 167-

pathways that are under investigation include

173.

mucosal protective agents, inhibitors of

286

ERS Handbook: Respiratory Medicine

COPD and emphysema

Eleni G. Tzortzaki and Nikolaos M. Siafakas

Chronic obstructive pulmonary disease

COPD comprises pathological changes in

(COPD) is a major cause of morbidity and

four different compartments of the lungs

mortality worldwide. It affects ,10% of the

(central airways, peripheral airways, lung

general population but its prevalence among

parenchyma and pulmonary vasculature),

smokers may reach as much as 50%; COPD

which are variably present in individuals

is projected to rank as the fifth largest

with the disease. Airflow limitation in

worldwide burden of disease by 2020.

COPD is caused by the presence of an

According to the Global Initiative for

inflammatory cellular infiltrate in the small

Chronic Obstructive Lung Disease (GOLD)

airways, remodelling and thickening of the

2013 report, COPD is a preventable and

airway wall. The destruction of alveoli and

treatable disease characterised by airow

enlargement of airspaces, which are

limitation that is not fully reversible. The

anatomical hallmarks of emphysema,

airow limitation is usually progressive and is

contribute to the loss of elastic recoil and

associated with an enhanced inammatory

the loss of outward traction on the small

response of the lungs to noxious particles or

airways, leading to their collapse on

gases, primarily caused by cigarette

expiration. These result in airflow

smoking. Exacerbations and comorbidities

obstruction, air trapping and hyperinflation.

contribute to the overall severity in

In general, the inflammatory and structural

individual patients. The cardinal symptoms

changes in the airways increase with disease

of COPD - dyspnoea, cough and sputum

severity and persist even after smoking

production - are chronic and progressive.

cessation.

Chronic obstructive bronchitis and/or

emphysema

Key points

COPD is a heterogeneous disease; two main

N COPD is a heterogeneous disease,

phenotypes of the disease are recognized:

with two main phenotypes: chronic

chronic bronchitis and emphysema.

bronchitis and emphysema.

Chronic bronchitis is characterised by cough

A strong genetic component, in

and sputum production for o3 months in

conjunction with environmental

each of two consecutive years. The

insult, probably accounts for the

symptoms may precede the development of

development of COPD.

airflow limitation by many years.

Inflammation and secretions provide the

N Smoking cessation is the single most

obstructive component of the disease. In

effective intervention in COPD

contrast to emphysema, chronic bronchitis

prevention and treatment.

is associated with a relatively undamaged

Bronchodilators are central to

pulmonary capillary bed. Emphysema is

symptomatic treatment, backed up if

present to a variable degree but is usually

necessary by other interventions.

centrilobular rather than panlobular. The

body responds by decreasing ventilation and

ERS Handbook: Respiratory Medicine

287

increasing cardiac output (ventilation/

Table 1. Risk factors for COPD

perfusion (V9/Q9) mismatch), leading to

Genes

hypoxaemia, polycythaemia and increased

carbon dioxide retention, and eventually

Exposure to particles

these patients develop signs of right heart

Tobacco smoke

failure.

Occupational dusts, organic and inorganic

Emphysema The second major COPD

Indoor air pollution (heating and cooking

phenotype is the emphysematous patient.

with biomass fuel)

Emphysema is defined by destruction of

Outdoor air pollution

airways distal to the terminal bronchiole,

Lung growth

and gradual destruction of alveolar septa

and the pulmonary capillary bed, leading to

Oxidative stress

a decreased ability to oxygenate blood. The

Sex

body compensates with lowered cardiac

Age

output and hyperventilation. This V9/Q9

mismatch results in relatively limited blood

Respiratory infections

flow through a quite well oxygenated lung

Socioeconomic status

with normal blood gases and pressures.

Nutrition

Eventually, due to low cardiac output, the

rest of the body suffers from tissue hypoxia,

pulmonary cachexia, muscle wasting and

Secondly, assess disease severity by

weight loss.

spirometry and by the frequency of

exacerbations. Spirometry is required to

Diagnosis and assessment

assess the degree of airflow limitation as it

is the most widely available and

A clinical diagnosis of COPD should be

reproducible lung function test. The

considered in any patient who has

presence of a post-bronchodilator FEV1/FVC

dyspnoea, chronic cough and/or sputum

ratio ,0.70 confirms the presence of airflow

production, a history of exposure to risk

obstruction, and thus of COPD. The

factors for the disease (tobacco smoke,

classification of severity of airflow

occupational dusts and chemicals) and a

obstruction in COPD into four stages it is

family history of COPD (table 1). Overall

presented in table 3. Where possible, values

COPD assessment should include the

should be compared to age-related normal

evaluation of current symptoms, the degree

values (a cut-off based on the lower limit of

of airflow limitation, the risk of

normal (LLN) values for FEV1/FVC) to avoid

exacerbations and comorbidity. Combined

overdiagnosis of COPD in the elderly and

COPD assessment including symptoms,

less frequent diagnosis in adults younger

spirometric classification and risk of

than 45 years.

exacerbation is presented in table 2,

categorising COPD patients in four groups

COPD exacerbations deteriorate health

(A, B, C and D).

status, and enhance lung function decline

and mortality. Thus, the assessment of

First, assess symptoms using either the

exacerbation risk can reflect the risk of poor

modified Medical Research Council

outcome and prognosis. The best predictor

(mMRC) questionnaire or the COPD

of having frequent exacerbations (two or

Assessment Test (CAT). Although the

more exacerbations per year) is a history of

mMRC questionnaire is a validated tool to

previous episodes, especially hospital

assess disability due to dyspnoea and CAT

admissions, as the exacerbation rate varies

has a broader coverage of patients’ health

greatly between patients.

status, the proposed classification cut-offs

are relatively arbitrary. Thus, further real-life

Comorbidities such as cardiovascular

studies are needed to better assess COPD

disease, skeletal muscle dysfunction,

patients.

metabolic syndrome, osteoporosis,

288

ERS Handbook: Respiratory Medicine

Table 2. COPD severity assessment

Group A: low risk,

Group B: low risk, Group C: high risk, Group D: high risk,

fewer symptoms more symptoms fewer symptoms more symptoms

Spirometric

FEV1 o50% pred FEV1 o50% pred FEV1 ,50% pred FEV1 ,50% pred

stage

Symptoms

mMRC grade 0-

mMRC grade o2

mMRC grade 0-1

mMRC grade o2

1 or CAT score

or CAT score

or CAT score ,10

or CAT score o10

,10

o10

Exacerbations

0-1

per year

% pred: % predicted.

depression and lung cancer can occur

(gene-environment interaction) most

frequently in patients with COPD.

probably accounts for the development of the

Comorbidities influence mortality and

disease (table 1). Familial clustering of COPD

hospitalisations independently, and should

has been observed and twin studies have

thus be recognised and treated properly in

supported the concept of a genetic

all COPD patients.

predisposition to COPD. Among the

candidate genes that have been studied in

Risk factors

COPD are genes that regulate the production

of proteases and antiproteases, genes that

Although smoking is the best-studied COPD

modulate the metabolism of toxic substances

risk factor, it is not the only one and there is

in cigarette smoke, genes involved with

consistent evidence from epidemiological

mucociliary clearance, and genes that

studies that nonsmokers may develop

influence inflammatory mediators.

chronic airflow obstruction (table 1). Other

factors, such as indoor air pollution from

Although rare, hereditary a₁-antitrypsin

burning biomass fuels for cooking and

(AAT) deficiency is the best documented

heating, are important causes of COPD in

genetic risk factor for emphysema. The AAT

many developing countries, especially

gene is located on chromosome 14q23.1-3

among females. Nevertheless, not all

and is a serum protein made in the liver that

subjects exposed to noxious agents develop

is capable of inhibiting the activity of serine

COPD. Thus, a strong genetic component in

proteases. Neutrophil elastase is the main

relation with an environmental insult

target of AAT; if not inactivated by AAT,

Table 3. Spirometric classification of airflow obstruction in COPD based on post-bronchodilator FEV1

All stages

FEV1/FVC ,0.70

Stage I: mild

FEV1 o80% pred

Stage II: moderate

FEV1 o50- ,80% pred

Stage III: severe

FEV1 o30- ,50% pred

Stage IV: very severe

FEV1 ,30% pred or ,50% pred plus chronic

respiratory failure^#

% pred: % predicted. ^#: respiratory failure is defined as PaO2 ,60 mmHg with or without PaCO2 .50 mmHg

while breathing air at sea level. Respiratory failure may also lead to effects on the heart such as cor pulmonale

(right heart failure). Clinical signs of cor pulmonale include elevation of the jugular venous pressure and

pitting ankle oedema. Patients may have stage IV COPD even if their FEV1 is .30% pred whenever these

complications are present. At this stage, quality of life is significantly impaired and exacerbations may be life

threatening. Reproduced and modified from GOLD (2013) with permission from the publisher.

ERS Handbook: Respiratory Medicine

289

neutrophil elastase destroys lung connective

controlled by inherited genes. Under

tissue, particularly elastin, and this leads to

normal conditions, cells are equipped with

the development of emphysema. Over 90

a number of repair pathways that remove

different phenotypes of AAT have been

damage and restore DNA. However,

described. The common gene variants are

increased and persistent oxidative stress

M, S and Z. Emphysema associated with

(e.g. due to cigarette smoking) may

AAT deficiency is typically panlobular,

inactivate the human DNA mismatch

characterised by uniform destruction of the

repair system, leading to acquired

pulmonary lobule. Cigarette smoking is the

mutations. Smoking-induced acquired

biggest risk factor for the development of

somatic alterations have been detected in

emphysema and airflow obstruction in AAT

COPD patients.

deficiency, and current smokers have an

Management

accelerated decline in FEV1 compared with

ex-smokers and never-smokers with AAT

The overall approach to managing stable

deficiency. Homozygous Z patients have a

COPD is based on an individualised

very low AAT levels and generally show a

assessment of disease severity and response

rapid decline in FEV1 even without smoking.

to various therapies. Patients who still

However, this homozygous state is rare in

smoke should be encouraged to quit.

the general population (one in 5000 live

Smoking cessation is the single most

births) and, thus, as genetic risk factor, it

effective intervention to reduce the risk of

can explain ,1% of COPD.

developing COPD and stop its progression,

and can have a substantial effect on

Recently, epigenetic mechanisms, such as

subsequent mortality.

acquired somatic mutations, have been

explored in COPD. Somatic mutations are

The goals of therapy are to prevent and

not heritable, although the susceptibility to

control symptoms, reduce the frequency and

acquiring such mutations might be

severity of exacerbations, and improve

Table 4. The recommended therapeutic management per severity group

Group A: low risk, Group B: low risk, Group C: high risk, Group D: high risk,

fewer symptoms more symptoms fewer symptoms more symptoms

First-choice

SABA p.r.n.

LABA

ICS+LABA or

ICS+LABA

treatment

LAMA

and/or

SAMA p.r.n.

LAMA

Second-

LABA

LABA and LAMA LABA and LAMA

ICS+LABA and

choice

LAMA and PDE4i

LAMA

treatment

LAMA

or LABA and

PDE4i

ICS+LABA and

SABA and SAMA

PDE4i

LAMA and LABA

LAMA and PDE4i

Alternative

Theophylline

SABA and/or

Carbocisteine

choice

SAMA

SABA and/or

Theophylline

SAMA

Theophylline

Treatments are presented in alphabetical order not in order of preference. SABA: short-acting b₂-agonist;

SAMA: short-acting muscarinic antagonist; LABA: long-acting b-₂-agonist; LAMA: long-acting muscarinic

antagonist; ICS: inhaled corticosteroid; PDE4i: phosphodiesterase-4 inhibitor. Reproduced and modified from

GOLD (2013) with permission from the publisher.

290

ERS Handbook: Respiratory Medicine

exercise tolerance, thus improving overall

protective role. There has been some recent

the quality of life. A summary of the

evidence regarding the use of statins and

proposed pharmacological management

long-term macrolide treatment in

across COPD groups is presented in table 4.

decreasing COPD exacerbations but these

Bronchodilator medications are central to

are not standard recommendations.

the symptomatic management of COPD.

These drugs improve emptying of the lungs,

Influenza vaccination and pneumococcal poly-

tend to reduce static and dynamic

saccharide vaccine are strongly recommended

hyperinflation, and improve exercise

for all COPD patients, as they decrease

performance. Inhaled therapy is preferred

serious illness and death rates by ,50%.

and bronchodilators are prescribed either on

Pulmonary rehabilitation aims to improve

an as-needed basis or on a regular basis,

exercise capacity, reduce symptoms and

although it is evident that regular treatment

improve overall quality of life. It is a

with long-acting bronchodilators is more

multidisciplinary programme ideally

effective and convenient than treatment with

involving several types of health

short-acting ones. Treatment with a long-

professionals. COPD patients at all stages of

acting inhaled anticholinergic drug reduces

disease appear to benefit from exercise

the rate of COPD exacerbations and

training programmes although benefit

improves the effectiveness of pulmonary

decreases after a rehabilitation programme

rehabilitation. A combination of b₂-agonist

ends. Pulmonary rehabilitation improves

and an anticholinergic produces better and

dyspnoea, improves quality of life scores,

more sustained improvements in FEV1 than

reduces the number of hospitalisations and

either drug alone. The addition of inhaled

glucocorticosteroids is appropriate for

days in the hospital, reduces anxiety and

symptomatic COPD patients in groups C

depression related to COPD and improves

and D and repeated exacerbations according

survival. A comprehensive rehabilitation

to the guidelines (table 4). This treatment

programme includes exercise training,

does not modify the long-term decline of

education and nutrition counselling.

FEV1 but it has been shown to reduce the

Nutritional status is an important factor in

frequency of exacerbations and improve the

determining symptoms, respiratory function

health status of COPD patients. Recent data,

and prognosis in COPD. Both extremes

however, based on a single large study of

(overweight and underweight) are

patients with FEV1 ,60% predicted,

detrimental. A reduction in BMI, seen in

indicate that regular treatment with inhaled

,25% of stage III and IV COPD patients, is

glucocorticosteroids can decrease the rate

an independent risk factor for mortality. The

of decline of lung function. Long-term

present evidence suggests a combination of

treatment with oral glucocorticosteroids

nutritional support and exercise regimes

should be avoided in COPD because side-

should be used to induce anabolic action.

effects such as steroid myopathy may

contribute to muscle weakness, decreased

functionality and respiratory failure in

Further reading

patients with advanced COPD. The regular

Blamoun AI, et al. (2008). Statins may

use of mucolytic and antioxidant agents has

reduce episodes of exacerbations and the

been evaluated in COPD patients without

requirement for intubation in patients

significant overall benefit, although there

with COPD: evidence from a retrospective

has been a study reporting reduced

cohort study. Int J Clin Pract; 62: 1373-

frequency of exacerbations. The regular use

1378.

of antibiotics, other than for treating

Castaldi PJ, et al. (2011). The association

infectious exacerbations of COPD, is not

of genome-wide significant spirometric

recommended. The regular use of

loci with chronic obstructive pulmonary

antitussive medications is also not

disease susceptibility. Am J Respir Cell

recommended as cough, although a

Mol Biol; 45: 1147-1153.

troublesome symptom, has a significant

ERS Handbook: Respiratory Medicine

291

Celli BR, et al. (2004). Standards for the

Hogg JC

(2004). Pathophysiology of

diagnosis and treatment of patients with

airflow limitation in chronic obstructive

COPD: a summary of the ATS/ERS

pulmonary disease. Lancet; 364: 709-721.

position paper. Eur Respir J; 23: 932-946.

Nici L, et al. (2009). Pulmonary rehabili-

Celli BR, et al. (2005). Airway obstruction

tation: what we know and what we need

in never smokers: results from the

to know. J Cardiopulm Rehabil Prev; 29:

Third National Health and Nutrition

141-151.

Examination Survey. Am J Med;

118:

Qiu W, et al. (2011). Genetics of sputum

1364-1372.

gene expression in chronic obstructive

Celli B, et al.

(2008). Effect of pharma-

pulmonary disease. PLoS One; 6: e24395.

cotherapy on rate of decline of lung

Seemungal TAR, et al. (2008). Long term

function in chronic obstructive pulmon-

erythromycin therapy is associated with

ary disease: results from the TORCH

decreased COPD exacerbations. Am J

study. Am J Respir Crit Care Med; 178:

Respir Crit Care Med; 178: 1139-1147.

332-338.

Silverman EK, et al. (1996). Risk factors

Coventry PA

(2009). Does pulmonary

for the development of chronic obstruc-

rehabilitation reduce anxiety and depres-

tive pulmonary disease. Med Clin North

sion in chronic obstructive pulmonary

Am; 80: 501-522.

disease? Curr Opin Pulm Med; 15: 143-

Stoller JK, et al.

(2005). a₁-antitrypsin

149.

deficiency. Lancet; 365: 2225-2236.

DeMeo DL, et al. (2004). a₁-Antitrypsin

Tager IB, et al. (1976). Household aggrega-

deficiency.

2: Genetic aspects of

tion of pulmonary function and chronic

a₁-antitrypsin deficiency: phenotypes and

bronchitis. Am Rev Respir Dis; 114: 485-492.

genetic modifiers of emphysema risk.

Tzortzaki E, et al. (2012). Oxidative DNA

Thorax; 59: 259-264.

damage and somatic mutations: a link to

Global Initiative for Chronic Obstructive

the molecular pathogenesis of chronic

Lung Disease. Global Strategy for the

inflammatory airway diseases. Chest; 141:

Diagnosis, Management and Prevention

1243-1250.

of COPD. www.goldcopd.org/uploads/

Tzortzaki EG, et al. (2009). A hypothesis

users/files/GOLD_Report_2013_Feb20.

for the initiation of COPD. Eur Respir J; 34:

pdf

310-315.

Hersh CP, et al.

(2005). Attempted

Zheng JP, et al. (2008). Effect of carbo-

replication of reported chronic obstruc-

cisteine on acute exacerbation of chronic

tive pulmonary disease candidate gene

obstructive pulmonary disease

(PEACE

associations. Am J Respir Cell Mol Biol; 33:

study): a randomized placebo-controlled

71-78.

study. Lancet; 371: 2013-2018.

292

ERS Handbook: Respiratory Medicine

Exacerbations of COPD

Alexander J. Mackay and Jadwiga A. Wedzicha

Definition

be treated, and thus could remain

unidentified if a strict healthcare utilisation

COPD is a chronic inflammatory airway

definition for exacerbations is used. For this

condition associated with episodes of acute

reason, considerable interest exists in the

deterioration termed exacerbations. An

potential of patient reported outcomes, such

exacerbation of COPD is defined in the 2011

as the Exacerbations of Chronic Pulmonary

revision of the Global Strategy for the

Disease Tool (EXACT) to detect and quantify

Diagnosis, Management and Prevention of

the severity of exacerbations.

COPD as an acute event characterised by a

worsening of the patient’s respiratory

Burden

symptoms that is beyond normal day-to-day

Exacerbations are important events in the

variations and leads to a change in

natural history of COPD; they have been

medication. However, around half of all

shown to drive lung function decline and are

COPD exacerbations identified by symptom

responsible for much of the morbidity and

worsening are not reported, hence may not

mortality associated with this highly

prevalent condition. Unreported

exacerbations are also important events,

Key points

significantly impairing quality of life.

Exacerbations are also among the most

Exacerbations are important events;

common causes of medical admission and

they drive lung function decline and

are costly to health services.

are responsible for much of the

morbidity and mortality associated

Patients hospitalised with exacerbations of

with COPD.

COPD are a particularly vulnerable group.

Every new, severe exacerbation that requires

N The majority of COPD exacerbations

hospitalisation increases the risk of a

are triggered by respiratory viral

subsequent exacerbation, and every new

infections and/or bacterial infections.

severe exacerbation increases the risk of

The ‘frequent exacerbator’ phenotype

death, up to five times after the tenth

is stable over time and exists across

hospitalisation when compared with after the

all GOLD stages.

first COPD hospitalisation. Mortality peaks in

the first week after admission, stabilising

N Frequent exacerbators exhibit faster

after 3 months and long-term prognosis is

decline in lung function, have worse

poor, with all-cause mortality approaching

quality of life, increased risk of

50% at 3 years post discharge. Advanced age

hospitalisation and greater mortality.

and severe lung function impairment, in

Both pharmacological and

addition to diabetes and poor health status,

nonpharmacological therapies exist

are particular risk factors for mortality.

that can help prevent COPD

Inpatient mortality of patients admitted with

exacerbations.

COPD exacerbations in the UK is 7.4%, and

rises to 25% for those patients with

ERS Handbook: Respiratory Medicine

293

hypercapnic respiratory failure treated with

understood but may relate to increasing

NIV. Thus prevention, early diagnosis and

prevalence of respiratory viruses in the low

prompt, effective management is vital to

temperature winter months and/or

improve exacerbation recovery, ameliorate

increased susceptibility to upper respiratory

the effects on quality of life and reduce the

tract viral infections in cold weather.

risk of hospitalisation.

Cardiovascular disease, comorbidities and

Causes

exacerbations

Exacerbations are associated with increased

Comorbid ischaemic heart disease is

systemic and airway inflammation, and may

associated with longer exacerbations

be precipitated by environmental factors.

characterised by increased dyspnoea and

However, the majority of COPD

wheeze. The presence of cardiac

exacerbations are triggered by bacterial and/

complications is increasingly being

or respiratory viral infections (fig. 1).

recognised as a predictor for COPD outcome.

Data from The Health Improvement Network

Infection Bacteria are isolated from sputum

(THIN) database demonstrated a 2.27-fold

in 40-60% of acute exacerbations of COPD,

increased risk of myocardial infarction 1-

and respiratory viruses are identified in 40-

5 days after outpatient exacerbations

60% of exacerbations with rhinovirus being

(defined by the prescription of both steroids

the most prevalent species identified.

and antibiotics). And in hospitalised

Experimental infection models provide

exacerbations, raised troponin, chest pain

direct evidence that the symptomatic and

and serial ECG changes are common, with

physiological changes seen in acute

one in 12 patients meeting the criteria for

exacerbations of COPD can be precipitated

myocardial infarction. Furthermore, elevated

by rhinovirus infection. Furthermore, viral

troponin levels predict 30-day mortality in

and bacterial infections demonstrate a

hospitalised COPD exacerbations, and so

synergistic effect at exacerbation;

these studies challenge the way that

exacerbation symptoms, decline in FEV1,

exacerbations are conventionally treated.

and inflammation all being more severe in

Patients receiving b-blockers appear to have a

the presence of bacteria and viruses. These

reduced risk of COPD exacerbations and a

subjects are discussed further in the section

lower mortality from exacerbations.

on Infective exacerbations of COPD.

Therefore, COPD patients in the future,

especially those with elevated cardiac

Air pollution Extensive data exists to support

biomarkers, may be considered for increased

a role for air pollution in the aetiology of

cardiac treatment at exacerbation.

some COPD exacerbations. The Air

Pollution and Health, a European Approach

Diabetes is also an important influence on

(APHEA) collaboration examined short-term

COPD exacerbations. Comorbid diabetes

effects of air pollution on mortality and

mellitus prolongs the length of stay in

morbidity of COPD in six European cities

hospital and increases the risk of death in

and found that increased levels of

patients hospitalised with acute

environmental pollutants (sulfur dioxide,

exacerbations of COPD.

nitrogen dioxide, ozone and particles) were

associated with elevated relative risks of

Frequent exacerbator phenotype

daily admissions for COPD.

Patients with a history of frequent

Low temperature COPD exacerbations are

exacerbations have a worse quality of life,

more common and may be more severe in

increased risk of hospitalisation and greater

the winter months when there are colder

mortality (fig. 2). Frequent exacerbators also

temperatures; small but significant falls in

exhibit a faster decline in lung function and

lung function occur with a reduction in

may have worse functional status, as

outdoor temperature during the winter in

measured by time outdoors. Thus, it is vital

COPD patients. The mechanisms behind

to identify patients at risk of frequent

these observations are not clearly

exacerbations.

294

ERS Handbook: Respiratory Medicine

Poorer quality of life

Higher mortality

Patients with frequent exacerbations

Greater airway

Faster decline

inflammation

in lung function

Figure 2. Effect of COPD exacerbations in the group with frequent exacerbations. Reproduced from

Wedzicha et al. (2007) with permission from the publisher.

history of prior exacerbations. This

Haemophilus influenzae enhances rhinovirus

phenomenon is seen across all GOLD

serotype 39-induced protein expression of

stages (Global Initiative for Chronic

IL-8 and epithelial-derived neutrophil

Obstructive Lung Disease), including

attractant-7 chemokines, which are

patients with stage II disease, of whom 22%

increased in the sputum and airways of

had frequent exacerbations in the first year

patients with COPD exacerbations.

of the ECLIPSE study (the Evaluation of

H. influenzae also increases the expression

COPD Longitudinally to Identify Predictive

of ICAM-1 and Toll-like receptor-3 and

Surrogate Endpoints). Therefore, suggesting

augments binding of rhinovirus to cultured

patients with frequent exacerbator

cells. Through such mechanisms, patients

phenotypes are prone to exacerbations as a

colonised with bacteria may be more

result of intrinsic susceptibility, and develop

susceptible to the development of virally

exacerbations when exposed to particular

triggered exacerbations.

triggers, like respiratory viruses.

Exacerbation prevention

Susceptibility to exacerbations Respiratory

viruses are more likely to be detected in

Vaccines In retrospective cohort studies of

patients with a history of frequent COPD

community-dwelling elderly patients,

exacerbations, suggesting that frequent

influenza vaccination is associated with a

exacerbators may be more susceptible to

27% reduction in the risk of hospitalisation

respiratory viral infections. Cells from

for pneumonia or influenza and a 48%

patients with COPD manifest increased viral

reduction in the risk of death. A

titre and copy number following rhinovirus

pneumococcal polysaccharide vaccine has

infection compared to controls and

been shown to reduce the incidence of

intercellular adhesion molecule (ICAM)-1,

community-acquired pneumonia in COPD

the rhinovirus major group receptor, is

patients under the age of 65 years and those

upregulated on the bronchial epithelium of

with severe airflow obstruction, although no

patients with COPD.

mortality benefit was demonstrated. As a

result, influenza and pneumococcal

Frequent exacerbators also have elevated

vaccines are recommended in the majority

airway inflammation when stable, as

of patients with COPD.

measured by sputum interleukin (IL)-6 and

IL-8 levels, in addition to a higher incidence

Inhaled corticosteroids and long-acting

of lower-airway bacterial colonisation.

bronchodilators The ISOLDE study (Inhaled

296

ERS Handbook: Respiratory Medicine

Table 1. Strategies to prevent COPD exacerbations

Pharmacological therapies

Nonpharmacological therapies

Vaccines

Pulmonary rehabilitation

Inhaled corticosteroids

Home oxygen therapy

Long-acting bronchodilators (LABA and

Home ventilatory support

LAMA)

Combinations of LABA and inhaled

corticosteroids

Phosphodiesterase-4 inhibitors

Mucolytics

Long-term antibiotics

Steroid in Obstructive Lung Disease in

failure. The POET-COPD trial (Prevention of

Europe) showed a 25% reduction in

Exacerbations with Tiotropium in COPD)

exacerbation frequency with inhaled

showed that in patients with moderate-to-

corticosteroids (ICS). Long-acting

very-severe COPD, tiotropium is more

b-agonists (LABA) also reduce exacerbation

effective than salmeterol in preventing

frequency, and in the TORCH study

exacerbations.

(Towards a Revolution in COPD Health), in

which 6112 patients were followed for over

Newer bronchodilators, such as indacaterol,

3 years, both inhaled fluticasone and

may also play a role in future maintenance

salmeterol reduced exacerbation frequency

regimens to reduce COPD exacerbations. To

when administered separately in

date, indacaterol has shown comparable

comparison to placebo. The combination of

exacerbation reduction rates in comparison

fluticasone and salmeterol reduced

with tiotropium in short clinical trials;

exacerbation frequency further, in addition

however, whilst indacaterol in combination

to improving health status and lung function

with tiotropium has recently been shown to

in comparison to placebo. The combination

provide enhanced bronchodilation

of ICS and LABA also resulted in fewer

compared to tiotropium alone, further

hospital admissions over the study period

research is required to assess if this

and trended towards a mortality benefit,

combination provides synergistic benefits to

although this did not reach statistical

reduce exacerbation frequency.

significance. Reduction in exacerbation

Phosphodiesterase-4 inhibitors Inhibit the

frequency has also been found with other

airway inflammatory processes associated

LABA/ICS combinations, such as formoterol

with COPD. Evidence from a pooled analysis

and budesonide.

of two large placebo-controlled, double-blind

Long-acting antimuscarinics (LAMA) also

multicentre trials revealed a significant

reduce exacerbation frequency. In the

reduction of 17% in the frequency of

UPLIFT trial (Understanding Potential Long-

moderate (glucocorticoid treated) or severe

Term Impacts on Function with

(hospitalisation/death) exacerbations.

Tiotropium), 5993 patients were randomised

However, only patients with an FEV1,50%

to tiotropium or placebo for a 4-year

(GOLD stage III and IV), presence of

duration, with concomitant therapy being

bronchitic symptoms and a history of

allowed. Although the primary end-point of

exacerbations were enrolled. There are no

the trial (reduction in the rate of decline in

comparator studies with ICS. Weight loss

FEV1) was negative, tiotropium was

was also noted in the roflumilast group, with

associated with a reduction in exacerbation

a mean reduction of 2.1 Kg after 1 year, and

risk, related hospitalisations and respiratory

was highest in obese patients. Therefore,

ERS Handbook: Respiratory Medicine

297

following treatment with roflumilast, weight

N Be carefully assessed for risk of

needs to be carefully monitored.

potential cardiovascular and auditory

side effects.

Mucolytics The routine use of these agents

is not recommended as only a few patients

Pulmonary rehabilitation with home oxygen

with viscous sputum appear to derive some

and ventilatory support There is some

small benefit from mucolytics.

evidence from clinical trials that pulmonary

rehabilitation programmes reduce hospital

Long-term antibiotics At present there is

stay. There is evidence from epidemiological

insufficient evidence to recommend routine

studies that home oxygen and ventilator

prophylactic antibiotic therapy in the

support may reduce hospital admission, but

management of stable COPD, but some

controlled trials have not yet addressed

studies have shown promise. Erythromycin

these issues. These subjects are discussed

reduced the frequency of moderate and/or

in detail in the sections on Pulmonary

severe exacerbations (treated with systemic

rehabilitation, Acute oxygen therapy and

steroids, treated with antibiotics, or

Long-term ventilation.

hospitalised) and shortened exacerbation

length when taken twice daily over

A summary of the different therapies used to

12 months by patients with moderate-to-

prevent COPD exacerbations is given in

severe COPD. The macrolide azithromycin

table 1.

has been used as a prophylaxis in patients

with CF and, when added to usual

treatment, azithromycin has also been

Further reading

shown to decrease exacerbation frequency

Albert RK, et al. (2011). Azithromycin for

and improve quality of life in COPD patients.

prevention of exacerbations of COPD.

However the benefits were most significant

N Engl J Med; 365: 689-698.

in the treatment-naïve patients with mild

Anderson HR, et al. (1997). Air pollution

disease (GOLD stage II), and significant

and daily admissions for chronic obstruc-

rates of hearing decrement (as measured by

tive pulmonary disease in

6 European

audiometry) and antibiotic resistance were

cities: results from the APHEA project.

found. In addition, a recent large

Eur Respir J; 10: 1064-1071.

epidemiological study has suggested a small

Calverley PM, et al. (2009). Roflumilast in

increase in cardiovascular deaths in patients

symptomatic chronic obstructive pul-

receiving azithromycin, particularly in those

monary disease: two randomised clinical

with a high baseline risk of cardiovascular

trials. Lancet; 374: 685-694.

disease.

Calverley PM, et al.

(2007). Salmeterol

and fluticasone propionate and survival

Furthermore, intermittent pulsed

in chronic obstructive pulmonary disease.

moxifloxacin, when given to stable patients,

N Engl J Med; 356: 775-789.

has been shown to significantly reduce

Donaldson GC, et al.

(2002).

exacerbation frequency in a per-protocol

Relationship between exacerbation fre-

population, and in a post hoc subgroup of

quency and lung function decline in

patients with bronchitis at baseline.

chronic obstructive pulmonary disease.

However, this reduction did not meet

Thorax; 57: 847-852.

statistical significance in the intention-to-

Donaldson GC, et al. (2009). Increased

treat analysis and further work is required in

risk of myocardial infarction and stroke

following exacerbation of COPD. Chest;

this area.

137: 1091-1097.

Hence, before prescription of long-term

Global Initiative for Chronic Obstructive

antibiotics in COPD, patients should be:

Lung Disease. Global Strategy for the

Diagnosis, Management and Prevention

N Treated with an optimum combination of

of COPD. www.goldcopd.org/guidelines-

inhaled therapy

global-strategy-for-diagnosis-management.

N Show evidence of ongoing frequent

html

exacerbations

298

ERS Handbook: Respiratory Medicine

Hurst JR, et al. (2010). Susceptibility to

ICAM-1 and TLR3 expression. FASEB J;

exacerbation in chronic obstructive pul-

20: 2121-2123.

monary disease. N Engl J Med; 363: 1128-

Schneider D, et al.

(2010). Increased

1138.

cytokine response of rhinovirus-infected

Mahler DA, et al. (2012). Concurrent use

airway epithelial cells in chronic obstruc-

of indacaterol plus tiotropium in patients

tive pulmonary disease. Am J Respir Crit

with COPD provides superior bronchodi-

Care Med; 182: 332-340.

lation compared with tiotropium alone: a

Seemungal TA, et al. (1998). Effect of

randomised, double-blind comparison.

exacerbation on quality of life in patients

Thorax; 67: 781-788.

with chronic obstructive pulmonary dis-

Mallia P, et al.

(2011). Experimental

ease. Am J Respir Crit Care Med; 157: 1418-

rhinovirus infection as a human model

1422.

of chronic obstructive pulmonary disease

Sethi S, et al. (2010). Pulsed moxifloxacin

exacerbation. Am J Respir Crit Care Med;

for the prevention of exacerbations of

183: 734-742.

chronic obstructive pulmonary disease: a

McAllister DA, et al. (2012). Diagnosis of

randomized controlled trial. Respir Res; 11:

myocardial infarction following hospitali-

10.

sation for exacerbation of COPD. Eur

Suissa S, et al. (2012). Long-term natural

Respir J; 39: 1097-1103.

history of chronic obstructive pulmonary

Nichol KL, et al. (2007). Effectiveness of

disease: severe exacerbations and mor-

influenza vaccine in the community-

tality. Thorax; 67: 957-963.

dwelling elderly. N Engl J Med;

357:

Tashkin DP, et al. (2008). A 4-year trial of

1373-1381.

tiotropium in chronic obstructive pul-

Patel AR, et al.

(2012). The impact of

monary disease. N Engl J Med;

359:

ischemic heart disease on symptoms,

1543-1554.

health status, and exacerbations in

Vogelmeier C, et al. (2011). Tiotropium

patients with COPD. Chest; 141: 851-857.

versus salmeterol for the prevention of

Ray WA, et al. (2012). Azithromycin and

exacerbations of COPD. N Engl J Med;

the risk of cardiovascular death. N Engl J

364: 1093-1103.

Med; 362: 1881-1890.

Wedzicha JA, et al. (2007). COPD exacer-

Roberts CM, et al. (2011). Acidosis, non-

bations: defining their cause and preven-

invasive ventilation and mortality in

tion. Lancet; 370: 786-796.

hospitalised

COPD exacerbations.

Wilkinson TM, et al. (2004). Early therapy

Thorax; 66: 43-48.

improves outcomes of exacerbations of

Sajjan US, et al.

(2006). H. influenzae

chronic obstructive pulmonary disease.

potentiates

airway

epithelial

cell

Am J Respir Crit Care Med; 169: 1298-

responses to rhinovirus by increasing

1303.

ERS Handbook: Respiratory Medicine

299

Extrapulmonary effects of

COPD

Yvonne Nussbaumer-Ochsner and Klaus F. Rabe

COPD is an inflammatory disease of the

not primarily from a respiratory disease.

lungs that is characterised by a fixed airflow

Extrapulmonary comorbidities significantly

limitation. Over the past few years, the

complicate the management of, and

understanding of COPD has evolved and it

influence the prognosis of, patients with

is no longer justified to consider COPD as a

COPD. The broad range of clinical

disease restricted to the lungs. COPD has

presentations, ranging from chronic

become a complex and multicomponent

bronchitis to hyperinflation and severe

disorder, with the majority of patients dying

emphysema, also illustrates that the term

from cardiovascular diseases or cancer and

‘COPD’ describes patients with very

different clinical phenotypes.

The main recognised extrapulmonary

Key points

manifestations include cardiovascular

disease and heart failure, musculoskeletal

There is clear evidence that COPD is

wasting, osteoporosis, metabolic syndrome

not simply a disease limited to the

and depression (table 1). While some of

airways but should be considered a

these comorbidities share risk factors with

complex and multicomponent

COPD, such as cigarette smoking, other

syndrome.

frequently observed comorbidities cannot be

FEV1

is not just a lung function

attributed to smoking. There is increasing

parameter for grading COPD severity,

evidence that chronic inflammation is a key

but is also a marker for premature

factor in COPD and is present in many other

death from any cause.

chronic diseases associated with COPD. The

theory that COPD could be considered part

The course of the disease and the

of a ‘chronic systemic inflammatory

prognosis is influenced by

syndrome’ takes these different aspects into

extrapulmonary pathology and

account.

accompanying comorbidities.

Patients with COPD show

Local and systemic inflammation

comorbidities that are not only related

In industrialised countries of the Western

to smoking but also to other lifestyle

world, cigarette smoking accounts for most

factors, including diet and inactivity;

cases of COPD. Smoking triggers a local

chronic systemic inflammation seems

inflammatory response throughout the

to link them together and might

whole tracheobronchial tree. The cellular

explain why they often occur together.

pattern is rather heterogeneous and

Future research is needed to answer

inflammatory cells are found in the proximal

the question of whether the successful

and peripheral small airways, the lung

treatment of comorbidities associated

parenchyma, and the pulmonary vasculature.

with COPD positively influences the

Apart from these local effects, smoking may

course of the disease itself.

significantly contribute to or cause

systemic inflammation. COPD patients

300

ERS Handbook: Respiratory Medicine

tumour necrosis factor-a (TNF-a); acute-

Table 1. Systemic manifestations and comorbidities of

phase proteins, i.e. C-reactive protein (CRP)

COPD

and fibrinogen; and circulating inflammatory

Cardiovascular diseases

cells, such as monocytes, neutrophils and

Ischaemic heart disease

lymphocytes. It is debatable whether this

Hypertension

systemic inflammation is the result of: 1) a

Pulmonary hypertension

‘spill-over’ of local inflammation in the lungs;

Congestive heart failure

2) a systemic inflammatory effect that affects

‘Metabolic’ disorders

multiple organ systems; or 3) is attributable

Osteoporosis

to some comorbid conditions that affect the

Skeletal muscle weakness

lungs (fig. 1).

Cachexia: weight loss and muscle wasting

Diabetes mellitus

Systemic inflammation is actually not only

Metabolic syndrome

present in patients with COPD, but is also a

Other comorbid diseases

common feature in various other chronic

Lung cancer

diseases. Compared to healthy individuals,

Chronic kidney disease

elevated levels of inflammatory markers,

Depression

such as CRP and IL-6, are observed in

OSA(S)

patients with stable coronary artery disease,

Normocytic anaemia

peripheral arterial disease and diabetes.

These findings have to be taken into account

when the causative role of COPD in systemic

suffering from an acute exacerbation

inflammation is investigated, because these

or having severe disease show increased

conditions often occur together. Systemic

markers of: interleukin (IL)-6, IL-8 and

inflammation might be the common

Lung cancer

Peripheral lung

inflammation

'Spill-over'

Acute-phase proteins

Systemic

Skeletal muscle

CRP

inflammation

weakness

Serum amyloid A

IL-6, IL-1β, TNF-α

Cachexia

Surfactant protein D

Ischaemic

Diabetes

Cardiac

Osteo-

Normocytic

heart

metabolic

Depression

failure

porosis

anaemia

disease

syndrome

Figure 1. Systemic effects and comorbidities of COPD. Peripheral lung inflammation may cause a ‘spill-

over’ of cytokines, such as IL-6, IL-1b and TNF-a, into the systemic circulation, which may increase the

acute-phase proteins, such as CRP. Systemic inflammation may then led to skeletal muscle atrophy and

cachexia, and may initiate and worsen comorbid conditions. Systemic inflammation may also accelerate

lung cancer. An alternative model is that systemic inflammation causes several inflammatory diseases,

including COPD. Reproduced from Barnes et al. (2009).

ERS Handbook: Respiratory Medicine

301

pathway leading to these chronic diseases

Another approach would be to target the

and might explain the high prevalence of

underlying systemic disease itself. A few

multiple chronic diseases in the same

observational studies have shown that the

patient.

treatment of extrapulmonary manifestations

(e.g. muscle weakness) and comorbid

Impact on patient care

diseases (e.g. heart disease and peripheral

arterial disease) positively influences

Comorbidities and systemic effects in

morbidity and mortality in COPD patients.

patients with COPD not only have

Even though these studies have clear

prognostic value but also have implications

limitations they so far suggest that statins,

for medical treatment. Medical care should

angiotensin-converting enzyme inhibitors

focus on comorbidities that are easier to

and angiotensin receptor blockers might all

prevent and treat than COPD itself. A

have dual cardiopulmonary properties and,

diagnosis of COPD can easily be performed

thereby, be able to positively influence the

using spirometry, but the severity of the

course of the disease. However, these

disease is clearly dependent on the presence

findings have to be confirmed in prospective

of comorbidities. Therefore, it has been

and carefully controlled trials before any

proposed that any patient aged .40 years

conclusions regarding the management of

with a positive smoking history (.10 pack-

COPD patients can be drawn.

years), symptoms, and a lung function

compatible with COPD should be carefully

Assuming that systemic inflammation is a

evaluated for more general disorders

key factor in COPD and other chronic

associated with the chronic systemic

diseases, pulmonary rehabilitation

inflammatory syndrome (table 2).

addresses important extrapulmonary

components that are not targeted by any

Therapeutical implications

pharmacological treatment, and might be

Pharmacological treatment targeting the

the reason for its overwhelming efficacy.

lungs has only a minor impact on the course

Lifestyle interventions in general and more

of the disease, and the treatment of COPD

specifically pulmonary rehabilitation are

should no longer be centred solely on

essential components of patient care and

controlling symptoms and reducing

should be evaluated in any patient with

exacerbations. Large clinical trials have

COPD GOLD stage II or higher (Global

shown that available drugs for COPD

Initiative for Chronic Obstructive Lung

(bronchodilators and inhaled

Disease). Appropriate education about the

corticosteroids) do not significantly

disease itself, its time course and

influence the long-term decline in FEV1.

treatment options, as well as

psychosocial support, including smoking

cessation and nutritional interventions, are

Table 2. Components of the chronic systemic inflammatory

part of a successful rehabilitation

syndrome

programme.

Aged .40 years

Conclusions

Smoking .10 pack-years

Chronic diseases, including COPD, share

Symptoms and lung function compatible

common aspects, and chronic systemic

with COPD

inflammation seems to be one of the linking

Chronic heart failure

elements. Extrapulmonary effects of COPD

Metabolic syndrome

not only influence the prognosis but also

Increased CRP

have an impact on disease management.

The treatment of patients with COPD must

At least three components are required for

become truly multidisciplinary and has to

diagnosis. Reproduced from Fabbri et al. (2007)

move from an organ-specific to a more

with permission from the publisher.

holistic approach.

302

ERS Handbook: Respiratory Medicine

Further reading

Nijm J, et al. (2005). Circulating levels of

proinflammatory cytokines and neutrophil-

Barnes PJ, et al. (2009). Systemic mani-

platelet aggregates in patients with coronary

festations and comorbidities of COPD.

artery disease. Am J Cardiol; 95: 452-456.

Eur Respir J; 33: 1165-1185.

Nussbaumer-Ochsner Y, et al.

(2011).

Fabbri LM.

(2007). From COPD to

Systemic manifestations of

COPD.

chronic systemic inflammatory syn-

Chest; 139: 165-173.

drome? Lancet; 370: 797-799.

van Gestel YR, et al.

(2008). Effect of

Mancini GB, et al. (2006). Reduction of

statin therapy on mortality in patients

morbidity and mortality by statins,

with peripheral arterial disease and com-

angiotensin-converting enzyme inhibi-

parison of those with versus without

tors, and angiotensin receptor blockers

associated chronic obstructive pulmonary

in patients with chronic obstructive pul-

disease. Am J Cardiol; 102: 192-196.

monary disease. J Am Coll Cardiol; 47:

Wisniacki N, et al. (2005). Insulin resis-

2554-2560.

tance and inflammatory activation in

Mannino DM, et al. (2008). Prevalence

older patients with systolic and diastolic

and outcomes of diabetes, hypertension

heart failure. Heart; 91: 32-37.

and cardiovascular disease in COPD. Eur

Young RP, et al. (2007). Forced expiratory

Respir J; 32: 962-969.

volume in one second: not just a lung

Mortensen EM, et al. (2009). Impact of

function test but a marker of premature

statins and ACE inhibitors on mortality after

death from all causes. Eur Respir J; 30:

COPD exacerbations. Respir Res; 10: 45.

616-622.

ERS Handbook: Respiratory Medicine

303

Pharmacology of asthma and

COPD

Peter J. Barnes

The pharmacology of asthma and COPD

involves understanding the mechanisms

Key points

and clinical use of bronchodilators and anti-

inflammatory or controller therapies.

N Long-acting b₂-agonists are effective

as add-on therapy to inhaled

N Relievers (bronchodilators) give

corticosteroids in asthma and for

immediate reversal of airway

reducing symptoms in COPD, and act

obstruction, largely by relaxing airway

as functional antagonists.

smooth muscle.

N Inhaled corticosteroids are the

N Controllers (preventers) suppress the

mainstay of asthma control and

underlying disease process (anti-

suppress activated inflammatory

inflammatory treatments) and provide

genes, but are largely ineffective in

long-term control of symptoms.

COPD (corticosteroid resistance).

N The most effective therapies are given by

inhalation to reduce side-effects.

N Long-acting muscarinic antagonists

are effective bronchodilators in COPD

b₂-adrenergic agonists

where cholinergic tone is the only

reversible component.

Inhaled b₂-agonists are the bronchodilator

treatment of choice in asthma because they

N Low-dose theophylline may be useful

reverse all known bronchoconstrictor

as an add-on therapy in severe asthma

mechanisms and have minimal side-effects

and COPD and may reduce

when used correctly.

corticosteroid resistance.

Mode of action

N b₂-agonists produce bronchodilatation by

directly stimulating b₂-receptors in airway

smooth muscle, leading to relaxation of

are localised to several types of airway cell

central and peripheral airways.

and b₂-agonists may have additional

b₂-agonists are functional antagonists as

effects.

they reverse bronchoconstriction

N b₂-agonists may also have other

irrespective of the contractile agent. This

beneficial effects, by inhibiting the

is important in asthma as many

release of mediators from mast cells and

bronchoconstrictor mechanisms (neural

of neurotransmitters from airway

and mediators) contribute, whereas in

nerves, as well as reducing

COPD, their major effect is to reverse

plasma exudation from airway blood

cholinergic tone. Activation of

vessels.

b₂-receptors results in the activation of

N However, b₂-agonists have no significant

adenylyl cyclase via the stimulatory

long-term effects on chronic

G-protein (G_s), which increases

inflammation of the airways so in asthma

intracellular cyclic AMP, leading to

patients they need to be used with a

relaxation of myosin fibrils. b₂-receptors

controller therapy.

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ERS Handbook: Respiratory Medicine

Short-acting inhaled b₂-agonists

(SABAs) (e.g.

Safety A large trial in the USA showed that

salbutamol and terbutaline) bronchodilate

salmeterol increased mortality and near-

for 3-4 h (less in severe asthma) and used

death asthma attacks in asthmatic patients,

mainly by inhalation as reliever therapy in

but this was mainly in poor patients who

asthma and COPD. They have a rapid onset

were not using concomitant ICS. This

and are without significant side-effects.

provides a strong argument for prescribing

They also protect against

LABAs only in a combination inhaler. There

bronchoconstrictor stimuli such as exercise,

are no safety concerns about LABA use in

cold air and allergens. SABAs are the

COPD.

bronchodilators of choice in acute severe

Tolerance Loss of bronchodilator action is

asthma and COPD, in which the nebulised

minimal, but there is some loss of the

route of administration is as effective as i.v.

bronchoprotective effect against exercise, for

use. Inhaled delivery is preferable to oral

example. This is incomplete and not

because side-effects are less common and

progressive, and does not appear to be a

it may be more effective (better access to

clinical problem.

surface cells such as mast cells). They

should not be used on a regular basis;

Anticholinergics

increased use indicates a need for more

Atropine is a naturally occurring compound

anti-inflammatory therapy.

that was introduced for the treatment of

Long-acting inhaled b₂-agonists (LABAs) (e.g.

asthma but, because of side-effects

salmeterol and formoterol twice daily, and

(particularly drying of secretions), less

indacaterol once daily) have a prolonged

soluble quaternary compounds (e.g.

bronchodilator and bronchoprotective

ipratropium bromide) were developed.

action. Formoterol has a more rapid onset of

Mode of action Anticholinergics are specific

action but is a fuller agonist than salmeterol,

antagonists of muscarinic receptors and

so tolerance is more likely. Formoterol, but

block cholinergic nerve-induced

not salmeterol, is more effective as a reliever

bronchoconstriction. A small degree of

than SABAs. Inhaled LABAs are added to low

resting bronchomotor tone is present

or moderate doses of inhaled corticosteroids

because of tonic cholinergic nerve

(ICS) and this is more effective than

impulses, which release acetylcholine in the

increasing the dose of ICS but should never

vicinity of airway smooth muscle, and

be used without an ICS in asthma.

cholinergic reflex bronchoconstriction may

Combination inhalers with an ICS and a

be initiated by irritants, cold air and stress.

LABA (fluticasone propionate and

Although anticholinergics protect against

salmeterol, budesonide and formoterol, or

acute challenge by sulfur dioxide and

beclomethasone dipropionate and

emotional factors, they are less effective

formoterol) are an effective and convenient

against allergens, exercise and fog. They

way to control asthma and are also useful in

inhibit reflex cholinergic

COPD. Budesonide/formoterol is very

bronchoconstriction only and have no

effective as a reliever when added to

significant blocking effect on the direct

maintenance treatment with the same drug.

effects of inflammatory mediators, such as

LABAs are effective bronchodilators in COPD

histamine and leukotrienes. In COPD,

and reduce exacerbations. Indacaterol has a

cholinergic tone is the only reversible

duration of action .24 h and is approved as a

element of airway narrowing.

once daily treatment for COPD patients.

Clinical use Ipratropium bromide and

Side-effects Unwanted effects result from

oxitropium bromide are inhaled three or four

stimulation of extrapulmonary b-receptors

times daily, whereas tiotropium bromide is

and include muscle tremor, palpitations,

inhaled once daily. In asthmatics,

restlessness and hypokalaemia. Side-effects

anticholinergic drugs are less effective

are uncommon with inhaled therapy, but

bronchodilators than b₂-agonists and offer

more common with oral or i.v. administration

less protection against bronchial challenges.

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305

Nebulised anticholinergics are effective in

may have anti-inflammatory effects in

acute severe asthma, but less effective than

asthma and COPD, either through PDE4

b₂-agonists, so may be added if responses

inhibition or, more likely, through

to nebulised b₂-agonists are insufficient.

inhibition of phosphoinositide-3-kinase-d.

Recent studies have demonstrated that

This may also explain how theophylline can

tiotropium may be an effective add-on

reverse corticosteroid resistance in asthma

bronchodilator in some patients with severe

and COPD by increasing histone

asthma. Inhaled anticholinergic drugs are

deacetylase (HDAC)2 activity to allow

the bronchodilators of choice in COPD and

corticosteroids to switch off activated

once-daily tiotropium bromide is an effective

inflammatory genes.

bronchodilator for COPD, which also

Clinical use Intravenous aminophylline

reduces exacerbations, mortality and

(a stable mixture or combination of

possibly disease progression in early

theophylline and ethylenediamine that

disease.

confers greater solubility in water) is less

Side-effects Inhaled anticholinergic drugs are

effective than nebulised b₂-agonists in the

well tolerated, and systemic side-effects are

treatment of acute severe asthma, and

uncommon because very little systemic

should therefore be reserved for the few

absorption occurs. Ipratropium bromide,

patients who fail to respond to b₂-agonists.

even in high doses, has no detectable effect

Theophylline is less effective as a

on airway secretions. Nebulised ipratropium

bronchodilator than inhaled b₂-agonists

bromide may precipitate glaucoma in elderly

and is more likely to have side-effects.

patients as a result of a direct effect of the

There is increasing evidence that low doses

nebulised drug on the eye; this is avoided by

(giving plasma concentrations of

use of a mouthpiece rather than a facemask.

5-10 mg?L^-1) may be useful when added

Dry mouth occurs in about 10% of patients

to inhaled corticosteroids, particularly in

on tiotropium bromide but rarely requires

more severe asthma and in COPD,

discontinuation of treatment. Urinary

reducing hyperinflation and improving

retention and glaucoma are rare adverse

dyspnoea.

effects.

Pharmacokinetics Theophylline is reliably

Theophylline

absorbed from the gastrointestinal tract, but

there are many factors affecting plasma

Theophylline remains the most widely used

clearance and, thus, plasma concentration.

asthma therapy worldwide because it is

Clearance may be increased by drugs that

inexpensive, but the greater incidence of

induce hepatic cytochrome P450 (e.g.

side-effects with theophylline and the greater

rifampicin and ethanol), by smoking and in

efficacy of b-agonists and ICS have reduced

children, so higher doses may be needed in

its use. It remains a useful drug in patients

these cases, whereas clearance is reduced by

with severe asthma and COPD.

drugs that inhibit hepatic metabolism (e.g.

cimetidine, erythromycin and ciprofloxacin),

Mode of action Theophylline is a weak,

congestive cardiac failure, liver disease, viral

nonselective phosphodiesterase (PDE)

infections, and in the elderly.

inhibitor, which causes bronchodilatation

by inhibiting PDE3 in airway smooth

Side-effects These are related to plasma

muscle at concentrations .10 mg?L^-1. At

concentration and tend to occur when

these concentrations, it is also an

plasma levels exceed 20 mg?L^-1, although

antagonist of adenosine receptors and

some patients develop them at lower

inhibition of A_2B-receptors on mast cells

plasma concentrations. The severity of side-

could contribute to its beneficial effect in

effects may be reduced by gradually

asthma, but blockage of A₁-receptors may

increasing the dose until therapeutic

lead to serious side-effects, such as cardiac

concentrations are achieved. The most

arrhythmias and seizures. At lower

common side-effects are headache, nausea

concentrations (5-10 mg?L^-1) theophylline

and vomiting, abdominal discomfort

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ERS Handbook: Respiratory Medicine

(probably due to PDE4 inhibition), and the

provides acceptable symptom control.

dangerous side-effects are cardiac

Short courses of oral corticosteroids

arrhythmias and seizures (due to A₁-receptor

(prednisolone, 30-40 mg daily for 1-

antagonism).

2 weeks) are indicated for exacerbations of

asthma; the dose may be tapered over

Corticosteroids

1 week once the exacerbation is resolved.

Corticosteroids are the most effective

ICS are currently recommended as first-line

controller therapy available for asthma, but

therapy in all patients with persistent

are poorly effective in COPD.

asthma and may be started in any patient

who needs to use a SABA inhaler for

Mode of action Corticosteroids enter target

symptom control more than twice a week. In

cells and bind to glucocorticoid receptors in

most patients, ICS are used twice daily, but

the cytoplasm. The corticosteroid-receptor

once daily use may be possible in patients

complex is transported to the nucleus, where

with mild asthma. If a dose of .800 mg daily

it binds to specific sequences on the upstream

via a metered-dose inhaler is administered, a

regulatory element of responsive target genes,

spacer should be used to reduce the risk of

resulting in increased or decreased

oropharyngeal side-effects and of absorption

transcription and, subsequently, increased or

from the gastrointestinal tract. ICS in doses

decreased protein synthesis. Glucocorticoid

of f400 mg daily may be used safely in

receptors may also inhibit transcription

children. Patients with COPD show a poor

factors, such as nuclear factor-kB, which

response to ICS with no effect on disease

activate inflammatory gene expression by a

progression or mortality, but reduce

nongenomic mechanism. Corticosteroids

exacerbations in patients who have severe

inhibit histone acetylation and, thereby,

disease and frequent exacerbations.

inflammatory gene expression by recruiting

HDAC2 to the transcriptional complex. The

Side-effects Corticosteroids inhibit cortisol

mechanism of action of corticosteroids in

secretion by a negative feedback effect on the

asthma is most related to their anti-

pituitary gland. Hypothalamic-pituitary-

inflammatory effects and, particularly,

adrenal axis suppression is dependent on

suppression of transcription of activated

dose and usually occurs when an oral dose of

inflammatory (e.g. cytokine) genes. They also

prednisolone of more than 7.5-10 mg daily is

have inhibitory effects on many inflammatory

used. Significant suppression after short

and structural cells that are activated in

courses of corticosteroid therapy is not

asthma, resulting in reduced airway

usually a problem but prolonged suppression

hyperresponsiveness. By contrast,

may occur after several months or years;

corticosteroids have no anti-inflammatory

corticosteroid doses after prolonged

effects in COPD and reduced benefit in severe

oral therapy must therefore be reduced

asthma, which may be explained by a

slowly. Symptoms of ‘corticosteroid

reduction in HDAC2 activity as a consequence

withdrawal syndrome’ include lassitude,

of oxidative stress.

musculoskeletal pains and occasionally fever.

Clinical use Systemic corticosteroids are

Side-effects of long-term oral corticosteroid

used in acute exacerbations of asthma and

therapy include fluid retention, increased

accelerate their resolution. There is no

appetite, weight gain, osteoporosis, capillary

advantage with high doses of i.v.

fragility, hypertension, peptic ulceration,

corticosteroids (e.g. methylprednisolone,

diabetes, cataracts and psychosis. The

1 g). Prednisolone (40-60 mg orally) has an

incidence tends to increase with age.

effect similar to i.v. hydrocortisone and is

easier to administer. Maintenance oral

Systemic side-effects of ICS have been

corticosteroids are reserved for patients

investigated extensively. Effects such as

whose asthma cannot be controlled by other

cataract formation and osteoporosis are

therapy (Global Initiative for Asthma (GINA)

reported, but often in patients who are also

step 5); the dose is titrated to the lowest that

receiving oral corticosteroids. There has

ERS Handbook: Respiratory Medicine

307

been particular concern about growth

anti-inflammatory effects and may reduce

suppression in children using ICS but, in

eosinophilic inflammation.

most studies, doses of f400 mg have not

Clinical use Antileukotrienes may have a

been associated with impaired growth and

small and variable bronchodilator effect,

there may even be a growth spurt because

indicating that leukotrienes may contribute

asthma is better controlled. In COPD

to baseline bronchoconstriction in asthma.

patients, high doses of ICS have been

Long-term administration reduces asthma

associated with cataracts, diabetes and

symptoms and the need for rescue

pneumonia.

b₂-agonists, and improves lung function.

The fraction of corticosteroid inhaled into

However, their effects are significantly less

the lungs acts locally on the airway mucosa

than with ICS in terms of symptom control,

improvement in lung function and reduction

and may be absorbed from the airway and

in exacerbations. They may be useful in

alveolar surface, thereby reaching the

some patients whose asthma is not

systemic circulation. The fraction of ICS

controlled on ICS as an add-on therapy, but

deposited in the oropharynx is swallowed

are less effective in this respect than a long-

and absorbed from the gut, and then is

acting b₂-agonists or low dose theophylline.

metabolised in the liver before it reaches

They are effective in some but not all

the systemic circulation. Budesonide and

patients with aspirin-sensitive asthma.

fluticasone propionate have a greater first-

Patients appear to differ in their response to

pass metabolism than beclomethasone

antileukotrienes, and it is impossible to

dipropionate and are therefore less likely to

predict which patients will respond best. A

produce systemic effects at high inhaled

major advantage is that they are orally active

doses. The use of a spacer reduces

and may improve compliance with long-

oropharyngeal deposition, thereby

term therapy. However, they are expensive,

reducing systemic absorption of

and a trial of therapy is indicated to

corticosteroid.

determine which patients will benefit most.

Antileukotrienes

Side-effects Antileukotrienes are well

Antileukotrienes (leukotriene receptor

tolerated and there are no class-specific

antagonists) are much less effective than

side-effects. Zafirlukast may produce mild

ICS in the control of asthma.

liver dysfunction, so liver function tests are

important. Several cases of Churg-Strauss

Mode of action Elevated concentrations of

syndrome (systemic vasculitis with

leukotrienes are detectable in

eosinophilia and asthma) have been

bronchoalveolar lavage fluid and sputum of

observed in patients on antileukotrienes, but

asthmatic patients. Cysteinyl-leukotrienes

these may be because a concomitant

(Cys-LTs) are generated from arachidonic

reduction in oral corticosteroids (made

acid by the rate-limiting enzyme

possible by the antileukotriene) allows the

5-lipoxygenase. Cys-LTs are potent

vasculitis to flare up.

constrictors of human airways in vitro and

in vivo, cause airway microvascular leakage

Cromones

in animals, and stimulate airway mucus

Cromones include sodium cromoglycate

secretion. These effects are all mediated

and the structurally related nedocromil

in human airways via Cys-LT₁ receptors.

sodium.

Montelukast and zafirlukast are potent

Cys-LT₁ receptor antagonists that markedly

Although they protect against indirect

inhibit the bronchoconstrictor response to

bronchoconstrictor stimuli such as exercise,

inhaled leukotrienes, reduce allergen-,

allergens and fog, they are poorly effective

exercise- and cold air-induced asthma by

compared with low doses of ICS, as they

about 50-70%, and inhibit aspirin-induced

have a short duration of action. Systematic

responses in aspirin-sensitive asthmatics

reviews have concluded that they provide

almost completely. They may also have weak

little benefit in chronic asthma so they are

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ERS Handbook: Respiratory Medicine

now rarely used. There is no role for

Methotrexate Low-dose methotrexate (15 mg

cromones in the management of COPD.

weekly) has a corticosteroid-sparing effect in

some patients with asthma, but side-effects

Anti-IgE

are relatively common and include nausea

(reduced if methotrexate is given as a weekly

Mode of action Omalizumab is a humanised

injection), blood dyscrasia and hepatic

recombinant monoclonal antibody that

binds to circulating IgE and, thus, blocks it

damage. Careful monitoring (monthly blood

from activating high-affinity IgE receptors on

counts and liver enzymes) is essential.

mast cells and low-affinity IgE receptors on

Gold has long been used in the treatment of

other inflammatory cells, resulting in

chronic arthritis. A controlled trial of an oral

reduced responses to allergens. Over time,

gold preparation (auranofin) demonstrated

the blocking of IgE reduces its synthesis by

some corticosteroid-sparing effect in

B-cells and results in a sustained reduction

chronic asthmatic patients maintained on

in IgE.

oral corticosteroids, but side-effects (skin

Clinical use Omalizumab reduces airway

rashes and nephropathy) are a limiting

inflammation in patients with mild-to-

factor.

moderate asthma and reduces the incidence

Cyclosporin A Low-dose oral cyclosporin A in

of asthma exacerbations, with improved

patients with corticosteroid-dependent

control of asthma in patients maintained on

asthma is reported to improve control of

reduced doses of ICS or oral steroids.

symptoms but, in clinical practice, it is

Omalizumab is most useful in patients with

unimpressive and its use is limited by severe

severe asthma who are not controlled on

side-effects (nephrotoxicity and

maximal doses of inhaled therapy as it

hypertension).

reduces exacerbations and improves asthma

control. Only ,30% of patients show a good

Roflumilast

response and this is not predictable by any

clinical features; therefore, a trial of therapy

Roflumilast is a once daily oral PDE4

over 4 months is indicated. Omalizumab

inhibitor that has anti-inflammatory effects

should be given only to patients with serum

in COPD patients. The dose is limited by

IgE levels of 20-700 IU?mL^-1; above these

side-effects (nausea, vomiting, diarrhoea

levels, it is not possible to give enough

and headaches) so its clinical efficacy is

antibody to neutralise the IgE. The dose of

relatively small. Weight loss may also occur

omalizumab is determined by serum IgE

but this is nonprogressive and reversible.

levels and body weight, and is given either

COPD patients with severe disease (FEV1

once or twice a month. Because of its high

,50% predicted), chronic bronchitis and

cost, only patients at GINA steps 4 and 5

frequent exacerbations, there is a small

with frequent exacerbations are suitable for

improvement in lung function and a

this therapy.

reduction in severe exacerbations. It is

therefore used as an add-on therapy in this

Side-effects Occasionally, local reactions

subpopulation of patients with COPD. It

occur at the injection sites and, very rarely,

should never be co-administered with

anaphylactic reactions have been reported.

theophylline, which also has PDE4 inhibitory

Immunosuppressive/corticosteroid-sparing

effects.

therapy

Further reading

Immunosuppressive therapy has been

considered in asthma when other

Barnes PJ. Pulmonary pharmacology. In:

treatments have been unsuccessful or when

Brunton LL, ed. Goodman & Gilman’s The

a reduction in the dosage of oral

Pharmacological Basis of Therapeutics.

corticosteroids is required; it is therefore

12th Edn. New York, McGraw Hill, 2011;

indicated in very few (,1%) asthmatic

pp. 1031-106.

patients at present.

ERS Handbook: Respiratory Medicine

309

Bronchiectasis

Nick ten Hacken

Bronchiectasis is a disorder characterised by

bronchi, due to a vicious circle of transmural

abnormal bronchial wall thickening and lumi-

infection and inflammation with mediator

nal dilation of the central and medium-sized

release. The prevalence varies between

countries but seems to increase with age and

is more common in females. Frequent

symptoms are chronic cough and production

Key points

of mucopurulent sputum. Less frequent are

haemoptysis, pleuritic pain, recurrent fever,

Diagnosis of bronchiectasis is based

wheeze and dyspnoea. Exacerbations of

on the presence of daily production of

bronchiectasis are characterised by an

mucopurulent phlegm and chest

increase in symptoms, i.e. increase in cough

imaging that demonstrates dilated

and change in purulence and volume of

and thickened airways. HRCT is the

sputum associated with an increase in

gold standard.

malaise. These exacerbations are almost

The diagnosis of bronchiectasis

always associated with infections of

should lead to the investigation and

bronchiectasis. Aetiological agents of

treatment of possible causes and

bronchiectasis include bacteria (Haemophilus

associated conditions.

influenzae, Pseudomonas aeruginosa, Moraxella

catarrhalis, Streptococcus pneumoniae and

Antibiotics form the mainstay of

Staphylococcus aureus), mycobacteria

treatment of bronchiectasis. Acute

(Mycobacterium avium-intracellulare complex,

exacerbations should be treated

Myobacterium kansasii and Myobacterium

promptly with short courses of

fortuitum) and fungi (Aspergillus fumigatus).

antibiotics.

The pattern of microbiology is quite stable;

The efficacy of continuous

however, resistance to antibiotics may

administration of antibiotics,

increase in time. Pseudomonas is associated

mucolytics, anti-inflammatory agents

with more severe disease. Nontuberculous

and bronchodilators is not clear, but

mycobacteria are frequently associated with

may be considered on an individual

Aspergillus.

basis.

Underlying causes of bronchiectasis may be

Bronchopulmonary hygiene physical

acquired or inherited, and include post-

therapy techniques are widely used,

infective causes, mechanical obstruction, an

yet there is not enough evidence to

excessive or deficient immune response,

support or refute them.

inflammatory pneumonitis, abnormal

Surgery may be considered if the area

mucus clearance, and fibrosis. Conditions

of the bronchiectatic lung is localised

associated with bronchiectasis include

and if the patient’s symptoms are

infertility, inflammatory bowel disease,

debilitating or life threatening (e.g.

connective tissue disorders, malignancy,

massive haemoptysis).

diffuse panbronchiolitis, a₁-antitrypsin

deficiency and mercury poisoning. In adults,

ERS Handbook: Respiratory Medicine

311

the aetiology is idiopathic in ,50% and in

children, 25%; however, these figures may

differ in time and between countries due to

the availability of diagnostics and antibiotics

(including vaccinations). Particularly in

patients younger than 40 years of age, CF,

primary ciliary dyskinesia (PCD) and

common variable immunodeficiency should

be considered, and in the presence of

suggestive symptoms, further work-up is

indicated.

Work-up

The work-up of bronchiectasis comprises

Figure 1. HRCT image demonstrating the signet

the following.

ring sign (arrow). Reproduced and modified from

Perera et al. (2011).

N Blood tests: C-reactive protein, white

blood count and differentiation, IgG, IgM,

Management

IgA, total IgE, Aspergillus serology, and

Management of bronchiectasis should aim

a₁-antitrypsin

for:

N Consider specific antibodies at baseline,

and re-assay 21 days after immunisation

N fast resolution and prevention of infective

where screening baseline levels are low

exacerbations,

N Specific tests to identify underlying

N no sputum infections,

causes or contributing conditions

N optimal bronchial clearance,

depending on the clinical setting

N minimal respiratory symptoms,

N Spirometry

N normal lung function,

N Sputum smear and cultures for bacteria,

N high quality of life, and

mycobacteria and fungi

N no treatment-related adverse effects.

N Radiography of chest and sinus; if

necessary, a HRCT scan of the lung

Obviously, the prompt recognition and

treatment of the underlying cause(s) and/or

The chest radiograph is abnormal in most

condition(s) is important for both short- and

patients; however, a normal chest

long-term outcomes. Unfortunately, there

radiograph does not exclude bronchiectasis.

are only limited high-quality studies on the

HRCT is the ‘gold standard’ for

management of non-CF bronchiectasis.

bronchiectasis. Characteristic findings

Several reviews list a large number of

include internal bronchial diameters 1.5

treatment options; however, due to small

times greater than that of the adjacent

study samples, different study populations

pulmonary artery (signet ring sign) (fig. 1),

and outcome variables, and other

lack of bronchial tapering, visualisation of

methodological issues, it is difficult to draw

bronchi within 1 cm of the costal pleura,

definitive conclusions. A recent extensive

visualisation of the bronchi abutting the

guideline of the British Thoracic Society

mediastinal pleura and bronchial wall

(BTS) has assessed the level of evidence for

thickening. The distribution of

each referred paper and the grade of each

bronchiectasis on HRCT scan may give

recommendation (Pasteur et al., 2010).

diagnostic clues to allergic

bronchopulmonary aspergillosis (central/

Acute exacerbations Antibiotic treatment is

perihilar), CF (upper lobes), PCD (middle

the mainstay of acute exacerbations and is

lobe) and idiopathic bronchiectasis (lower

targeted to probable organisms (table 1) or

lobes). Severity of bronchiectasis on HRCT

the results of sputum culture(s). A

images is poorly correlated with clinical

fluoroquinolone is recommended for

indices.

7-10 days in outpatients without a history of

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ERS Handbook: Respiratory Medicine

recurrent exacerbations or sputum cultures.

inflammatory markers. 12-day inhalation of

Hospitalised patients may be treated with

mannitol improved the tenacity and

two intravenous antibiotics with efficacy for

hydration of sputum. Inhaled fluticasone

Pseudomonas (www.uptodate.com).

improved sputum production and sputum

Supportive management may consist of

inflammation, but not its microbiological

inhaled bronchodilators, systemic

profile. Nebulised 0.9% and 7% saline as an

corticosteroids and measures to improve

adjunct to physiotherapy improved sputum

bronchial clearance (physical therapy,

production, sputum viscosity and ease of

hydration and mucolytic agents).

sputum expectoration; 7% saline was

superior to 0.9%. Two systematic reviews

Prevention of exacerbations Prolonged use of

found insufficient evidence to support or

antibiotics (.4 weeks) may be considered in

refute bronchial hygiene physical therapy.

patients who quickly relapse (three or more

times per year according to the BTS

Symptoms and quality of life Haemoptysis is

guideline) or demonstrate progressive lung

treated with bronchial embolisation; however,

function decline. Several treatment

surgical resection is sometimes inevitable.

strategies have been described:

Surgical resection may also be considered if

the area of the bronchiectatic lung is localised

N oral antibiotic two or three times daily

and if the patient’s symptoms are debilitating

N oral macrolide three times weekly

or life threatening. In this case, surgery can

N aerosoled tobramycin, gentamycin,

even be curative if there is an absence of an

colistin, ceftazidime or aztreonam twice

ongoing underlying cause. Although surgery

daily (aerosoled antibiotics in non-CF

is widely used, there have been no RCTs of

bronchiectasis are frequently not licensed

this. Recent studies reported that selected

or stopped because of side-effects)

cases were treated successfully with

N i.v. antibiotics, 2-3-week courses with

lobectomy using video-assisted thoracoscopy.

1-2-month intervals (www.uptodate.com)

Inhaled fluticasone improved dyspnoea,

A Cochrane review concluded that there is a

sputum production, days without cough, b₂-

small benefit in overall clinical response

agonist use and health-related quality of life.

scores but not exacerbation rates. A recent

Inhaled medium-dose budesonide combined

randomised controlled trial (RCT)

with formoterol in a single inhaler was more

demonstrated that 500 mg azithromycin

effective than high-dose budesonide

three times a week for 6 months significantly

(Martinez-Garcia et al., 2012).

improved exacerbation frequency in adult

Lung function RCTs on short- and long-

non-CF bronchiectasis patients with a

acting b₂-agonists, anticholinergic therapy,

history of at least one exacerbation in the

oral methylxanthines, leukotriene

past year (Wong et al., 2012).

antagonists, and oral corticosteroids were

Clearly, the indication for prolonged use of

not included in Cochrane reviews.

antibiotics should be based on a benefit-

Nevertheless, bronchodilator therapy may

risk evaluation, also taking possible adverse

be considered if a patient has proven airway

effects into account.

obstruction. Macrolides may improve

methacholine reactivity, airway obstruction

Sputum and bronchial clearance Inhaled

and carbon monoxide diffusion. However, if

recombinant human DNAse (rhDNase)

macrolides are considered, nontuberculous

administered to stable non-CF

mycobacteria must be excluded first and

bronchiectasis patients has been associated

patients must be warned about ototoxicity.

with increased exacerbation frequency and

greater FEV1 decline, and therefore should

Exercise tolerance Pulmonary rehabilitation

not be given. Oral bromhexine improved

is effective in improving exercise capacity

expectoration, quantity and quality of

and endurance, whereas simultaneous

sputum, and auscultatory findings during

inspiratory muscle training may be

acute infective exacerbations. Macrolides

important in the longevity of these training

improved sputum production and sputum

effects.

ERS Handbook: Respiratory Medicine

313

Further reading

Ouellette H (1999). The signet ring sign.

Radiology; 212: 67-68.

Clinical Evidence Handbook. Bronchi-

Rosen MJ (2006). Chronic cough due

ectasis. http://clinicalevidence.bmj.com/

to bronchiectasis: ACCP evidence-based

ceweb/conditions/rdc/1507/1507.jsp

clinical practice guidelines. Chest;

129:

The Cochrane Collaboration. The Co-

Suppl. 1, 122S-131S.

chrane Library. www.thecochranelibrary.

Pasteur MC, et al. (2010). British Thoracic

com

Society guideline for non-CF bronchiecta-

Ilowite J, et al. (2009). Pharmacological

sis. Thorax; 65: Suppl. 1, i1-i58.

treatment options for bronchiectasis:

Pasteur MC, et al. (2000). An investiga-

focus on antimicrobial and anti-inflam-

tion into causative factors in patients with

matory agents. Drugs; 69: 407-419.

bronchiectasis. Am J Respir Crit Care Med;

Lynch DA, et al. (1999). Correlation of

162: 1277-1284.

CT findings with clinical evaluations in

Perera PL, et al.

(2011). Radiological

261 patients with symptomatic bronch-

features of bronchiectasis. Eur Respir

iectasis. AJR Am J Roentgenol; 173: 53-

Monogr; 52: 44-67.

58.

Ten Hacken NH, et al.

(2011).

Martinez-Garcia MA, et al. (2012). Clinical

Bronchiectasis. Clin Evid; 2011: 1507.

efficacy and safety of budesonide-formo-

Wolters Kluwer Health. UpToDate.

terol in non-cystic fibrosis bronchiectasis.

www.uptodate.com

Chest; 141: 461-468.

Wong C, et al. (2012). Azithromycin for

Nicotra MB, et al. (1995). Clinical, patho-

prevention of exacerbations in non-cystic

physiologic, and microbiologic character-

fibrosis bronchiectasis

(EMBRACE): a

ization of bronchiectasis in an aging

randomised, double-blind, placebo-

cohort. Chest; 108: 955-961.

controlled trial. Lancet; 380: 660-667.

314

ERS Handbook: Respiratory Medicine

Cystic fibrosis

Andrew Bush and Jane C. Davies

The autosomal recessive condition CF is the

Key points

most common inherited disease of white

races; its prevalence varies across Europe.

Adult pulmonologists need to know

Although commonest in white people, it has

about CF; it is common across Europe,

been found in virtually every ethnic group.

patients are surviving into middle age

The gene, on the long arm of chromosome

and beyond, and new diagnoses of CF

7, encodes a multifunctional protein, cystic

are being made even in old age; as

fibrosis transmembrane regulator (CFTR),

diagnosis by newborn screening

which is active at the apical membrane of

becomes more widespread across

epithelial cells. The nomenclature of the

Europe, it is likely that fitter CF patients

individual CF genes has recently been

will be transferred to the adult clinics,

revised (table 1). Different classes of

and survival will improve further.

mutation have been described (fig. 1);

severe mutations (classes I-III) are usually

CF is now a true multisystem disease;

associated with pancreatic-insufficient CF

to the well-known complications of

chronic respiratory infection and

and a worse prognosis, whereas those with

malabsorption have been added

milder mutations (IV-VI) are more usually

conditions such as cirrhosis, insulin

pancreatic sufficient. The combination of a

deficiency and diabetes, osteopenia,

mild and severe gene usually leads to a mild

stress incontinence, and infertility.

pancreatic phenotype; however, there is only

a poor correlation between genotype and

Furthermore, with longevity are

pulmonary phenotype. In many parts of

coming new complications, including

Europe, the most common mutation is

the selection of resistant

Phe508del (previously termed DF508), but

microorganisms and antibiotic

there are marked ethnic differences.

allergy; other organ systems will

probably be affected in the aging CF

CFTR functions as a chloride channel and

population.

regulates other ion channels, such as the

Treatment of CF thus requires a

epithelial sodium channel (ENaC). Most of

dedicated multidisciplinary team,

the morbidity and mortality of CF is due to

comprising physicians, specialist

chronic bronchial infection, but as adults

nurses, physiotherapists, dieticians,

survive longer, multisystem complications

clinical psychologists and

are becoming more important. The airways

pharmacists.

of the newborn with CF are effectively

normal at birth, but from an early age, cycles

The increasing knowledge of the

of infection and inflammation supervene,

molecular pathophysiology of CF is

leading ultimately to severe bronchiectasis

leading the way in the development of

and respiratory failure. The most popular

genotype-specific therapies, which will

hypothesis for the pathophysiology of CF

be a paradigm for other diseases.

lung disease is airway surface liquid

dehydration due to uncontrolled activity of

ERS Handbook: Respiratory Medicine

315

Table 1. Old and new nomenclature of the 32 common

Adult physicians will encounter CF patients

CFTR mutations (ARMS-32 kit)

by two routes:

Old Nomenclature

New nomenclature

Referral from a paediatric clinic of an

DF508

p.Phe508del

already diagnosed patient. Transition to a

DI507

p.lle507del

new and strange adult clinic from the

familiar staff and surroundings of the

V520F

p.Val520Phe

paediatric clinic may be a difficult time,

R117H

p.Arg117His

and needs to be handled with

G542X

p.Gly542X

sensitivity. Increasingly, young adult

handover clinics, staffed by

G551D

p.Gly551Asp

paediatricians and adult physicians, are

R553X

p.Arg553X

being set up.

R560T

p.Arg560Thr

A new diagnosis made in adult life. CF is

usually diagnosed in early childhood,

S549R

p.Ser549Arg

increasingly by newborn screening, but

S549N

p.Ser549Asn

mild atypical cases may be missed.

3659delC

p.Thr1176fs

Around 10-15% of CF patients present

in adult life (table 2). Conversely,

W1282X

p.Trp1282X

always consider the possibility that the

3905insT

p.Leu1258fs

diagnosis of CF made in childhood is

N1303K

p.Asn1303Lys

incorrect and whether a repeat

G85E

p.Gly85Glu

diagnostic work-up should be done. The

diagnosis should be considered even in

A455E

p.Ala455Glu

people born in areas where CF newborn

R334W

p.Arg334Trp

screening is offered. Mild cases may be

1078delT

p.Phe316fs

missed by screening; the screening test

may not have been performed or the

R347H

p.Arg347His

result lost; there may have been a

R347P

p.Arg347Pro

technical issue in the laboratory; and

2183AA.G

p.Lys684fs

finally, the patient may have moved

1717-1G.A

from an area where screening is not

offered.

621+1G.T

Diagnostic testing for CF

3849+10kbC.T

711+1G.T

Once the diagnosis is suspected, it is usually

easily confirmed by a sweat test, which must

1898+1G.A

be performed in an experienced centre.

2789+5G.A

Other diagnostic modalities that are

R1162X

p.Arg1162X

employed include:

3876delA

p.Ser1248fs

3120+1G.A

N Genetic testing: .1,800 variants are

described and many rare ones are usually

394delTT

p.Leu88fs

undetected in the routine clinical

2184delA

p.Lys684fs

laboratory, so a negative genotype cannot

exclude disease. Furthermore, ,50

mutations are definitely accepted as

disease-causing, so the presence of rare

ENaC, possibly triggered by viral infection.

mutations should always be interpreted

Median survival for current newborns is

with caution. There is an ongoing US CF

predicted to be ,50 yrs, longer for males. In

Foundation project which aims to try to

parts of Europe there are now more adult

clarify the significance of these rarer

than paediatric CF patients.

mutations (www.cftr2.org).

316

ERS Handbook: Respiratory Medicine

Figure 1. Classes of CF mutation. Class I: no CFTR synthesis (mutation: premature stop codon; G542X,

now termed p.Gly542X); class II: CFTR processed incorrectly and does not reach apical cell membrane

(Phe508del); class III: CFTR reaches apical membrane, but channel opening time is reduced (G551D, now

termed p.Gly551Asp); class IV: CFTR reaches apical membrane, but channel conductance is abnormal

(R117H, now known as p.Arg117His); class V: reduced CFTR synthesis (3849 + 10kb C.T, nomenclature

unchanged); class VI: CFTR reaches apical cell membrane, but has a shortened half-life due to more rapid

turnover (Q1412X, in which the last 70 amino acids are deleted).

N Nasal transepithelial potential difference

semen analysis for congenital bilateral

measurement: only available in a few

absence of the vas deferens (CBAVD).

centres.

Management of CF

N Ancillary testing: human faecal elastase

(pancreatic insufficiency), high-resolution

CF has now become a true multisystem

computed tomography for occult

disease. Treatment can only be optimally

bronchiectasis, scrotal ultrasound or

conducted with the help of a full

ERS Handbook: Respiratory Medicine

317

Table 2. Late presentation of CF

Recurrent respiratory

Consider especially with ‘suggestive’ microorganisms such as

infections

Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia

complex

Atypical ‘asthma’

Especially if chronic productive cough, and a poor response to

standard asthma therapy

Bronchiectasis

Especially if any extrapulmonary features, a positive family history or

infection with atypical microorganisms (above)

Nasal polyps, severe

Nasal polyps more likely due to aspirin-sensitive asthma, unlike in

sinusitis

children, in whom they are virtually diagnostic of CF

Male infertility

Azoospermia due to CBAVD

Electrolyte disturbance Classically as acute heat exhaustion leading to sodium, chloride and

potassium depletion

Atypical mycobacterial

Always consider the possibility of CF if these organisms are isolated

infection

from sputum

Acute pancreatitis

Typically seen in pancreatic-sufficient CF

CF liver disease

Portal hypertension and variceal haemorrhage; liver cell failure is a late

manifestation

Cascade screening

Diagnosis made in a relative leading to extended family screening

Such patients are usually but not invariably pancreatic sufficient. New diagnoses of CF have been made even

in old age; CF diagnosis should always be considered.

multidisciplinary team (CF physician,

complications are also important. If the

specialist nurse, physiotherapist, dietician,

patient has poor lung function, early

clinical psychologist and pharmacist) and

discussion with the local transplant centre

the help of ancillary specialists with expert

is advisable. Routine respiratory care at

knowledge of CF (ENT surgeon,

every clinic visit should include spirometry

obstetrician, and endocrinologist) (table 3).

and pulse oximetry, and sputum (or cough

CF patients should be seen at least every

swab) culture.

3 months by the core CF team. A large

number of treatment guidelines have been

Recently, the importance of CF

published.

exacerbations has been appreciated. They

have more than mere nuisance value, and

Respiratory tract disease The main issues are

are termed ‘CF lung attacks’ by some. There

the prevention of infection where possible

is no uniformly accepted definition, even

by segregation of patients and the

though time to first exacerbation is a

aggressive use of antibiotics; although the

common end-point in clinical trials. Around

conventional teaching is that airway

25% of patients never return to their pre-

infection occurs with a relatively narrow

exacerbation spirometry values, and

spectrum of microorganisms, recent work

frequent exacerbations are a marker of

based on the use of molecular techniques

accelerated decline in lung function.

suggests much greater numbers of

infecting organisms including anaerobes.

Gastrointestinal disease

(table 4) The main

Molecular techniques are still in the

issues are to ensure optimal nutrition and

research arena and cannot be used to guide

be alert to gastrointestinal causes of weight

clinical decisions. Sputum clearance using

loss that are unrelated to pancreatic

a choice of many chest physiotherapy

insufficiency. Bad nutrition is a very poor

techniques and the identification and

prognostic feature. CF patients have higher

aggressive management of late

than normal energy requirements because of

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ERS Handbook: Respiratory Medicine

Table 4. Management of gastrointestinal manifestations of CF in the adult

Organ

Manifestation

Management

Pancreas

Exocrine insufficiency:

High-fat diet

malabsorption, steatorrhoea

Supplementation with enteric coated

microsphere pancreatic enzymes and

fat-soluble vitamins

Fat absorption may be aided by alkaline

environment (H₂-blockers or proton

pump inhibitors)

Gastrostomy feeds if in nutritional failure

(parenteral nutrition only rarely required)

Acute pancreatitis (pancreatic

As for other causes

sufficient patients)

Oral pancreatin powder (anecdotal

evidence only)

Oesophagus

Gastro-oesophageal reflux

Proton pump inhibitors,

(especially common

prokinetic agents

post-lung transplant)

Surgery if refractory symptoms

Small bowel

DIOS

Oral Gastrografin (Bracco, Princeton,

NJ, USA) or Klean-Prep (Norgine,

Amsterdam, the Netherlands)

Review dose of, and adherence to,

pancreatic enzyme replacement therapy;

perform 3-day faecal fat collection

Consider pro-kinetic agents

Severe acute cases, relieve with

colonoscopy; laparotomy a last resort

Coeliac disease (increased

Gluten-free diet, as for isolated

incidence in CF)

coeliac disease

Crohn’s disease (any part

Management as for isolated

of the bowel)

Crohn’s disease

Seek specialist gastroenterology advice

Colon

Constipation

Laxatives, high-fibre diet

Must not be confused with DIOS

Rectum

Rectal prolapse

Rare in adults, usually related to

uncontrolled fat malabsorption

Liver

Fatty liver (usually asymptomatic)

Liver ultrasound at least every 2 years

Macronodular cirrhosis (variceal

Ursodeoxycholic acid, taurine

bleeding, splenomegaly,

(seek specialist advice)

hypersplenism)

Severe cases may need transplantation

Hepatocellular failure a

late manifestation

DIOS: distal intestinal obstruction syndrome.

subclinical malabsorption and a higher

Other organ system disease (table 5) It is

energy consumption secondary to infection.

important to be aware that new

Increased metabolic rate is thought by some

complications are being described as CF

to be part of the underlying defect. Weight

patients survive longer. A full systems

should be measured and BMI calculated at

review is essential at each clinic visit. Finally,

least 3-monthly.

the psychological aspects of CF, the effects

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ERS Handbook: Respiratory Medicine

Table 5. Treatment of other manifestations of CF in the adult

Organ

Manifestation

Management

Upper airway

Nasal polyps (can cause OSA)

Topical steroids; long courses

of antibiotics

Surgery if medical management fails;

re-operation often needed

Sinusitis

Most patients have asymptomatic

changes on radiography or CT scan

and require no treatment

Topical steroids and antibiotics are

given initially in prolonged courses if

mandated by symptoms

Surgery if medical management fails,

but results often disappointing

Some use sinus drainage tubes and

repeatedly instil antibiotics into the

sinuses

Endocrine

Insulin deficiency, which

Screen regularly with annual glucose

pancreas

causes reduced lung function

tolerance test

and nutrition before overt

Increasingly, continuous glucose

hyperglycaemia

monitoring is used to diagnose this

condition

Frank diabetes; although there

Have a low threshold for starting

may be an element of

insulin, especially in females, who

peripheral insulin resistance,

have a worse prognosis if they

the main root cause is

develop diabetes

diminished insulin secretion

Continue high-fat diet, adjust insulin

doses accordingly

Diabetic ketoacidosis is very rare

Oral hypoglycaemic agents not to be

used outside a randomised

controlled trial

Sweat gland

Electrolyte depletion, often

Sodium and potassium chloride

leading to acute collapse

supplementation

Bones and joints

Osteopenia (CFTR is

Measure bone mineral density at

expressed in bones)

least every 2 years

Pathological fracture

Prevention: weight-bearing exercise,

high dairy intake, vitamin D and K

therapy

Treat with bisphosphonates if severe

CF arthropathy (large or

Nonsteroidal anti-inflammatory

small joint)

agents, prednisolone

Seek specialist rheumatological

advice if more than mild

Male reproductive

CBAVD leading to

Sperm aspiration and in vitro

tract

male infertility

fertilisation

Genetic counselling prior to procedure

Female

Vaginal candidiasis

Topical antifungal agents

reproductive tract

ERS Handbook: Respiratory Medicine

323

Table 5. Continued

Organ

Manifestation

Management

Stress incontinence

Seek gynaecological advice

Pregnancy (not an illness, but

Pre-pregnancy genetic

may be a major therapeutic

counselling advisable

challenge); females with

Continue standard CF medications;

severe CF may be subfertile,

close collaboration with obstetric

but normal conception is

unit; may need regular admissions

usual

to hospital for intravenous

antibiotics.

Especially beware if low lung

function prior to pregnancy and CF

related diabetes on insulin

Late iatrogenic

Antibiotic allergy

Consider desensitisation in hospital

Chronic renal failure

Cause controversial

Variously related to multiple courses of

intravenous aminoglycosides, so use

these agents appropriately sparingly,

and diabetes, so work to ensure

good glycaemic control

Miscellaneous

Vasculitis

Rare, usually responds to steroids, but

seek specialist rheumatological advice

Epithelial cancer

Small but definite increase in risk;

careful clinical surveillance mandatory

of chronic illness, and the burden of disease

approaches include the use of ‘correctors’ to

and its treatment should not be

allow misfolded protein (class II mutations)

underestimated; see the poignant stories

to travel to the apical cell membrane (VX-

and poetry on the Breathing Room website.

809 and VX-661, currently in early-phase

trials) and ‘potentiators’ to improve activity

Future developments

when they reach this site. The most

successful of these has been ivacaftor

A large number of novel therapies are

(Kalydeco, VX-770; Vertex, Cambridge, MA,

currently being trialled in CF. Gene therapy,

USA), which has been shown to improve

using as vectors either liposomes, viruses or

lung function significantly in patients with

nanoparticles, has been the subject of proof-

the commonest class III mutation,

of-concept trials, and a large therapeutic trial

is about to start (www.cfgenetherapy.org.

p.Gly551Asp (G551D). This agent works by

uk). The age of genotype-specific therapy

increasing the probability that CFTR will be

dawned with the use of agents such oral

open and, therefore, may also be useful for

ataluren (PTC₁₂₄) to override premature stop

other classes of mutations where CFTR

codons (class I mutations); the results of a

reaches the apical membrane including

large phase III trial have been reported at the

other rare Class III mutations, or in

US CFF meeting; significance was not

conjunction with correctors for class II

reached with the primary end-point but in a

mutations. Alternative strategies under

planned subgroup analysis, those not

investigation include inhibition of ENaC and

receiving nebulised tobramycin, a

stimulation of alternative chloride channels;

compound which also overrides premature

unfortunately, trials with the P2Y2 receptor

stop codons, did show significant

agonist denufosol, despite showing some

improvements. More work is needed to

early promise, have recently been reported

determine the role of PTC124 in CF. Other

as negative. There is no doubt that we are on

324

ERS Handbook: Respiratory Medicine

the verge of a CF treatment revolution. Most

Dodge JA, et al. (2007). Cystic fibrosis

important, however, is to ensure that the

mortality and survival in the UK: 1947-

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de Boer K, et al.

(2011). Exacerbation

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patients with cystic fibrosis. Thorax; 66:

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153: S4-S14.

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Festini F, et al.

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mannitol in cystic fibrosis: an efficacy and

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tysis in cystic fibrosis. Chest; 128:

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One; 3: e2908.

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Flume PA, et al. (2005). Pneumothorax in

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Brenckmann C, et al.

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Kerem E, et al. (2008). Effectiveness of

phosphonates for osteoporosis in people

with cystic fibrosis. Cochrane Database

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Brinson GM, et al.

(1998). Bronchial

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artery embolization for the treatment of

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tuberculous mycobacterial disease: pro-

sis. Am J Respir Crit Care Med; 157: 1951-

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Bush A. In: European Lung White Book.

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CFTR2. www.cftr2.org

in adult cystic fibrosis patients. J R Soc

Chaun H (2001). Colonic disorders in

Med; 91: 7-9.

adult cystic fibrosis. Can J Gastroenterol;

Leus J, et al. (2000). Detection and follow

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up of exocrine pancreatic insufficiency in

Clancy JP, et al. (2012). Results of a phase

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563-568.

CFTR corrector compound, in subjects

Matsui H, et al.

(1998). Evidence for

with cystic fibrosis homozygous for the

periciliary liquid layer depletion, not

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abnormal ion composition, in the patho-

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McKone EF, et al.

(2003). Effect of

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Onady GM, et al. (2005). Insulin and oral

Tunney MM, et al. (2008). Detection of

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UK Cystic Fibrosis Gene Therapy

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Rowe SM, et al. (2011). Nasal potential

Witt H, et al. (2007). Chronic pancreati-

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tis: challenges and advances in pathogen-

ion channel activity. Methods Mol Biol;

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Wood DM, et al.

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Work-related and occupational

asthma

Eleftherios Zervas and Mina Gaga

Definition

Key points

Work-related asthma (WRA) is the most

common form of occupational lung disease,

The burden of WRA is still very high,

causing significant morbidity and disability.

accounting for one in 10 cases of

WRA accounts for 9-15% of cases of asthma

adult asthma, and causing morbidity,

in adults of working age.

disability and high costs.

WRA may be categorised as:

Prevention is very important. Health

officials, workplace managers and

N occupational asthma (OA), which refers

doctors must be aware of the

to asthma caused specifically by exposure

problem, and strict measures for

to an agent present at the workplace; or

exposures to known sensitisers

N work-aggravated or work-exacerbated

should always be followed, conditions

asthma (WEA), in which pre-existing

at work examined and, when

asthma is exacerbated by conditions in

necessary, amended.

the work environment.

Better education of workers and

Thus, the American College of Chest

managerial staff as well as medical

Physicians consensus document and British

professionals is key to the prevention

Occupational Health Research Foundation

and prompt diagnosis and

guidelines define WRA as including OA (i.e.

management of WRA and OA. When

asthma induced by sensitiser or irritant work

WRA is diagnosed, prompt

exposures) and WEA (i.e. pre-existing or

management is required and consists

concurrent asthma worsened by work

of removing or reducing exposure

factors).

through elimination or substitution of

causative agents and, where this is

OA can occur in workers with or without

not possible, by effective control of

prior asthma and can be subdivided into:

exposure.

1. sensitiser-induced OA, characterised by a

Pharmaceutical treatment of OA

latency period between first exposure to a

follows the general asthma guidelines.

respiratory sensitiser at work and the

development of symptoms

2. irritant-induced OA that occurs typically

within a few hours of a high-concentration

In clinical practice, it is often difficult to

exposure to an irritant gas, fume or

differentiate between ‘true’ OA and

vapour at work

aggravation of pre-existing asthma.

When the causal exposure consists of a

Conversely, aggravation of symptoms

single inhalation incident, the condition is

related to work exposure, even in the

commonly called reactive airway dysfunction

absence of new sensitisation, requires

syndrome.

individual and collective measures in the

ERS Handbook: Respiratory Medicine

327

workplace, similar to OA. A recent

methodology of exposure assessment

consensus definition is that ‘OA is defined

requires standardisation. Atopy increases

as asthma induced by exposure in the

the risk of developing OA in workers

working environment to airborne dusts,

exposed to various sensitisers including

vapours or fumes, with or without pre-

enzymes, bakery allergens, laboratory

existing asthma’ (Francis et al., 2007).

animals, crab, prawn and acid anhydrides.

Physicians involved in adult asthma care

The latent interval between first exposure

need to be aware of the high prevalence of

and the onset of symptoms varies

WRA and the importance of inducing or

depending on the agent, the level of

exacerbating factors at work.

exposure/management and biological

variability of exposure. The latent interval

Sensitising and triggering agents

can extend to many years; however, the risk

More than 250 agents causing OA have been

of OA appears to be highest soon after the

described and are categorised into high

first exposure to laboratory animal allergens,

molecular weight (HMW) and low molecular

isocyanates, platinum salts and enzymes.

weight (LMW) agents, according to whether

See table 1 for a list of agents frequently

their molecular weight is above or below

identified by inhalational challenge.

1 kDa. HMW agents are usually proteins of

Diagnosis

animal and vegetal origin such as flour,

laboratory animal proteins and enzymes.

The clinical presentation and symptoms of

LMW agents include a wide variety of

OA are no different from nonoccupational

chemicals, such as acid anhydrides,

asthma. Patients experience attacks of

platinum salts and reactive dyes.

breathlessness, wheezing, cough, chest

Sensitisation to most HMW and some LMW

tightness and limitations in their daily

factors is through an IgE mechanism and

activities. In any working adult patient

can be tested by skin tests. An

presenting with such symptoms, the

immunological mechanism is suspected for

diagnosis of WRA should be considered. In

LMW agents but has not been

individuals with suspected WRA, the

demonstrated, and an antigen-specific

physician should obtain a history of job

immune response cannot easily be tested in

duties and possible exposures, the use of

most affected workers.

protective devices and the presence of

respiratory disease in co-workers. Table 2

The most frequently reported agents of

shows examples of occupations/industries

occupational asthma are:

with sentinel health events for sensitiser-

N isocyanates

induced OA.

N flour and grain dust

Symptoms may get worse when the patient

N colophony and fluxes

enters the work environment but, very often,

N latex

the patients experience delayed symptoms

N animal and plant proteins

and therefore may get worse after leaving

N aldehydes

work. A clinically useful approach, therefore,

N wood dust

is not asking whether the patients

N metal salts

experience worsening of their symptoms

Epidemiological studies have demonstrated

when at work but rather whether they feel

that the level of exposure is the most

better after a weekend or a holiday away

important determinant of OA. This implies

from work. However, this is difficult to

that preventive measures should be aimed

describe, as most people feel rested and

at reducing workplace exposure. Prevention

happier at the end of a holiday. The

through elimination/reduction of exposure is

diagnosis requires first spirometry, with a

the most effective approach for reducing the

positive bronchodilation test and/or

burden of OA. However, the relationship

histamine, methacholine or exercise testing

between the levels of exposure and the

of airway hyperresponsiveness for the

induction of OA is not always clear and the

confirmation of asthma. Furthermore, the

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ERS Handbook: Respiratory Medicine

Table 1. LMW and HMW agents frequently identified by inhalational challenge

LMW agents

HMW agents

Isocyanates

Flour

HDI

Plants and grain dust

MDI

Seafood/fish

TDI

Latex

Metals

Animal-derived allergens

Plicatic acid (white or red cedar)

Leather

Wood dust

Enzymes

Hairdressing products

Talc

Epoxy resins

Gums

Dyes and fabrics

Chemicals

Perfume

HDI: hexamethylene diisocyanate; MDI: methylene diphenyl diisocyanate; TDI: toluene diisocyanate.

Information from Dufour et al. (2009).

Table 2. Examples of occupations/industries with sentinel health events for sensitiser-induced OA

Industry, process or occupation

Selected agents

Jewellery, alloy and catalyst makers

Platinum

Polyurethane, foam coatings, adhesive production

Isocyanates

and end-use settings (e.g. spray painters, and

foam and foundry workers)

Alloy, catalyst, refinery workers

Chromium, cobalt

Solderers

Soldering flux (colophony)

Plastics industry, dye, insecticide makers, organic

Phthalic anhydride, trimetallic anhydride

chemical manufacture

(used in epoxy resins)

Foam workers, latex makers, biologists, and hospital

Formaldehyde

and laboratory workers

Printing industry

Gum arabic, reactive dyes and acrylates

Metal plating

Nickel sulfate and chromium

Bakers

Flour, amylase and other enzymes

Woodworkers and furniture makers

Red cedar (plicatic acid) and other wood

dusts

Laboratory workers and animal researchers

Animal proteins

Detergent formulators

Detergent enzymes such as protease,

amylase and lipase

Seafood (crab, snow crab and prawn) workers

Crab, prawn and other shellfish proteins

Healthcare workers and nurses

Psyllium, natural rubber latex,

glutaraldehyde, methacrylates,

antibiotics and detergent enzymes

Laxative manufacture and packing

Psyllium

Hairdressers and manicurists

Persulfates and acrylates (artificial nails)

Reproduced from Tarlo et al. (2008), with permission from the publisher.

ERS Handbook: Respiratory Medicine

329

patient should be asked to record symptoms,

to chemical agents, biological agents and

use of medication and peak expiratory flow

carcinogens at work. Medical surveillance

(PEF) measurements when working and off

programmes are very important and may

work. PEF should be measured at least four

include symptom questionnaires,

times a day for a period of a month while

spirometry and skin-prick testing at regular

times on and off work should be noted (the

intervals (e.g. every 6 or 12 months), as well

recommendation is at least 2 weeks on and

as monitoring of exposure levels.

2 weeks off work). The sequential self-

Once OA has developed, recovery is directly

measurements of PEF can be complemented

dependent on the duration and level of

by repeated measurements of PC20 (the

exposure to the causative agent. Depending

provocative concentration of histamine or

on the severity of the case, the condition of

methacholine causing a 20% fall in FEV1).

the patient can substantially improve during

Allergic sensitisation to some inducers, such

the first year after removal from exposure.

as animal proteins, can be examined by skin-

Conversely, asthma may persist even after

prick testing or in vitro assays of specific IgE.

removal from exposure to the causative

When the diagnosis cannot be confirmed by

workplace agent. The likelihood of

serial PEF measurements and skin tests or

improvement or resolution of symptoms or

IgE assays, the ‘gold standard’ for diagnosing

prevention of deterioration is greater in

sensitiser-induced OA is a specific bronchial

workers who have no further exposure to the

provocation test (specific inhalation

causative agent, have relatively normal lung

challenge), which may demonstrate a direct

function at diagnosis, and have a shorter

relationship between exposure to a test agent

duration of symptoms prior to diagnosis

and an asthmatic response. The response

and prior to avoidance of exposure.

may be early or late and may carry a risk to the

patient of a severe reaction. Therefore, these

Trigger avoidance is pivotal in preventing

tests should be performed only when

asthma symptoms and progression of

necessary and only in specialised centres

severity. Nevertheless, pharmacological

under medical supervision.

treatment is also required to control

symptomatic patients. Pharmacological

Management

treatment follows the general asthma

Ideally, causal agents should be eliminated

treatment guidelines, and inhaled steroids

from the workplace, an option that is not

and b-agonists are the cornerstone of

often available. The second-best option is to

management. Treatment follows a stepwise

remove the workers from exposure;

approach based on asthma control and

however, many patients cannot leave their

severity, and the approach is identical to

job. In such cases, the early institution of

that of nonoccupational asthma.

preventive measures, including the

Socioeconomic impact of WRA

replacement of specific reagents where

possible, the strict monitoring of exposure

The economic impact of WRA is due not

levels, and the use of extractor fans and

only to direct healthcare costs but also to

masks, is necessary. The European Union

indirect costs from impaired work

(EU) has allocated a high priority to

productivity and compensation/

safeguarding the health and safety of

rehabilitation costs, as well as to the

workers. Existing EU health and safety

intangible costs from impaired quality of life.

legislation aims to minimise the health risks

Income loss is more likely when avoidance

from dangerous substances in the

of exposure leads to a change of job and this

workplace, placing the emphasis on their

income loss is not offset by compensation.

elimination and substitution in order to

In many European countries, compensation

protect workers. There are four important

does not include rehabilitation or retraining,

directives in this field, containing the basic

perhaps accounting for the relatively high

provisions for health and safety at work, and

proportion (30%) of workers who continue

further defining the risks related to exposure

to be exposed to the causative agent.

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ERS Handbook: Respiratory Medicine

Moreover, when considering the cost of OA

Moscato G, et al.

(2003). Diagnosing

and/or compensation, it is not only lung

occupational asthma: how, how much,

function impairment and optimal asthma

how far? Eur Respir J; 21: 879-885.

treatment that need to be taken into

Mullan RJ, et al.

(1991). Occupational

account, but also psychogenic factors.

sentinel health events: an up-dated list for

These can play an important role in the

physician recognition and public health

quality of life of OA patients, and significant

surveillance. Am J Ind Med; 19: 775-799.

Nemery B (2004). Occupational asthma

prevalence of anxiety and depression has

for the clinician. Breathe; 1: 25-32.

been shown in that population.

Newman Taylor AJ, et al., eds. Guidelines

for the prevention, identification and

management of occupational asthma:

Further reading

evidence review and recommendations.

Ameille J, et al. (1997). Consequences of

London, British Occupational Health

occupational asthma on employment and

Research Foundation, 2004.

financial status: a follow-up study. Eur

Newman Taylor AJ (1980). Occupational

Respir J; 10: 55-58.

asthma. Thorax; 35: 241-245.

Dufour M-H, et al. (2009). Comparative

Tarlo SM, et al. (2008). Diagnosis and

airway response to high- versus low-

management of work-related asthma:

molecular weight agents in occupational

American College of Chest Physicians

asthma. Eur Respir J; 33: 734-739.

Consensus Statement. Chest; 134: Suppl.

Dykewicz MS

(2009). Occupational

3, 1S-41S.

asthma: current concepts in pathogen-

Tarlo SM, et al. (2009). An official ATS

esis, diagnosis, and management.

proceedings: asthma in the workplace:

J Allergy Clin Immunol; 123: 519-528.

the Third Jack Pepys Workshop on

Francis HC, et al. (2007). Defining and

Asthma in the Workplace: answered and

investigating occupational asthma: a

unanswered questions. Proc Am Thorac

consensus approach. Occup Environ

Soc; 6: 339-349.

Med.; 64: 361-365.

Vandenplas O, et al. (2003). Definitions

Larbanois A, et al. (2002). Socioeconomic

and types of work-related asthma: a

outcome of subjects experiencing asthma

nosological approach. Eur Respir J;

21:

symptoms at work. Eur Respir J; 19: 1107-1113.

706-712.

ERS Handbook: Respiratory Medicine

331

Respiratory diseases caused

by acute inhalation of gases,

vapours and dusts

Benoit Nemery

Acute inhalation injury may occur in the

evolution to acute respiratory distress

workplace, at home or in the community

syndrome (ARDS) and multiorgan failure.

(e.g. as a result of fires and explosions,

Following inhalation injury, the lesions may

volcanic eruptions, industrial disasters, and

heal completely, or there may be persisting

accidents involving trains or vehicles

structural or functional sequelae.

transporting chemicals). Inhalation

Inhalation fever

accidents may be of catastrophic

proportions, as occurred with the release of

Inhalation fever is the name given to a group

methylisocyanate (MIC) in Bhopal, India, in

of nonallergic, noninfectious, influenza-like

1984. Mass casualties with inhalation

clinical syndromes caused by the acute

injuries may also result from chemical

inhalation of metal fumes, organic dusts or

warfare, and from conventional warfare or

some plastic fumes.

terrorist actions involving explosions, fires

and building destructions.

Metal fume fever is caused by a single

exposure to high amounts of some metallic

The clinical presentation and severity of

fumes, most notably those emitted when

inhalation injury range from self-limited

heating zinc. Organic dust toxic syndrome

inhalation fever to life-threatening chemical

(ODTS) is caused by the inhalation of large

pneumonitis with lung oedema and

quantities of agricultural and other dusts of

biological origin (bio-aerosols), which are

generally heavily contaminated with toxin-

Key points

producing microorganisms. Polymer fume

fever occurs after exposure to the fumes of

heated fluorine-containing polymers.

N An influenza-like response (inhalation

fever) may follow the inhalation of

The clinical features of the inhalation fevers

high quantities of zinc fumes (metal

are similar to those at the beginning of

fume fever) or organic aerosols

influenza. The actual exposure may or may

(ODTS).

not have been experienced as irritant to the

N After inhalation of poorly water-

eyes and respiratory tract. 4-8 h after

soluble agents, such as nitrogen

exposure, the subject begins to feel unwell

dioxide, phosgene or cadmium fumes,

with fever (up to 40uC), chills, headaches,

pulmonary oedema becomes clinically

malaise, nausea and muscle aches.

manifest only 4-12 h after exposure.

Respiratory symptoms are usually mild and

consist mainly of cough and/or sore throat

N Acute inhalation injury may be

but, occasionally, subjects may have more

followed by various structural lesions

severe responses with dyspnoea.

in the airways but also by asthma.

Such asthma induced by a single

The diagnosis of inhalation fever rests

inhalation injury is called acute

essentially on the recent exposure history

irritant-induced asthma or RADS.

and the clinical condition, and when these

clearly point to inhalation fever,

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ERS Handbook: Respiratory Medicine

no sophisticated investigations are required.

community as a result of transportation

In general, chest auscultation and chest

accidents, the use of chlorine for

radiography are normal, but in more severe

disinfecting swimming pools or the mixing

cases, crackles may be heard and there may

of bleach (sodium hypochlorite) with acids;

be transient infiltrates on the chest

mixing bleach with ammonia leads to the

radiograph. Pulmonary function is often

release of volatile and irritant chloramines

within normal limits; in severe cases, there

(including trichloramine). Hydrogen sulfide,

may be a decrease in diffusing capacity and

which is formed by the putrefaction of

arterial hypoxaemia. Increased peripheral

organic material in sewage drains, manure

blood leukocytosis, with a rise in

pits or the holds of ships, and is also a

neutrophils, is a consistent finding in the

frequent contaminant in the petrochemical

first 24 h after the exposure; other blood

industry, not only causes mucosal irritation

tests should be normal, except for indicators

but also leads to chemical asphyxia by

of an inflammatory response. Broncho-

mechanisms that are somewhat similar to

alveolar lavage studies have shown

those of cyanide.

pronounced and dose-dependent increases

in polymorphonuclear leukocytes on the day

Poorly water-soluble agents, such as

after exposure to zinc fumes or organic dust.

nitrogen dioxide, phosgene, ozone, mercury

vapours and cadmium oxide fumes, are

Inhalation fever must not be confused with

particularly hazardous because they cause

other more serious conditions, including

little sensory irritation and are, therefore,

chemical pneumonitis, which, in its early

hardly noticed; they reach the distal airways,

phases, could be mistaken for inhalation

thus potentially causing noncardiogenic

fever. A differential diagnosis must also be

pulmonary oedema, which develops over the

made with various types of infectious

course of several hours.

pneumonias and with acute extrinsic allergic

alveolitis.

Exposure to organic solvents is rarely a

cause of toxic pneumonitis. However,

Inhalation fever is a self-limited syndrome

exposure to very high concentrations of

and recovery normally takes place after a

solvent vapours in confined spaces (e.g. in

night’s rest. Tolerance exists against re-

chemical tanks) may cause chemical

exposures occurring shortly after a bout of

pneumonitis and pulmonary oedema, often

metal fume fever or ODTS.

in victims who have been unconscious.

Pneumonia and respiratory distress

Acute chemical pneumonitis

syndrome caused by loss of alveolar

Major causes The response to acute

surfactant may also result from the

chemical injury in the respiratory tract is

aspiration of solvents or fuels ingested

rarely compound-specific (table 1). The main

unintentionally (e.g. from siphoning petrol)

agents that may cause acute inhalation

or intentionally (e.g. by fire eaters). Severe

injury are as follows.

acute respiratory illness may also be caused

by spraying solvent-propelled, fluorocarbon-

Water-soluble irritants, such as ammonia,

containing water-proofing agents and

sulfur dioxide, hydrochloric acid,

leather conditioners.

formaldehyde and acetic acid, have good

warning properties and mainly affect the

Some agrochemicals (such as paraquat and

upper respiratory tract, unless massive

organophosphate or carbamate

quantities have been inhaled.

insecticides) may cause toxic pneumonitis

after ingestion or dermal exposure.

Gases of intermediate water solubility, such

as chlorine and hydrogen sulfide, penetrate

The commonest cause of toxic pneumonitis

deeper into the bronchial tree. Accidental

is smoke inhalation caused by domestic,

release of gaseous chlorine is one of the

industrial or other fires. Respiratory

most frequent causes of inhalation injury,

morbidity is often the major complication in

not only in industry but also in the

burn victims. It may be caused by direct

ERS Handbook: Respiratory Medicine

333

mucosal irritation include cough,

Table 1. Possible causes of toxic tracheobronchitis

hoarseness, stridor or wheezing, retrosternal

or pneumonitis

pain, and discharge of bronchial mucus,

Irritant gases

possibly with blood, mucosal tissue and

High water solubility: NH₃, SO₂, HCl

soot. Auscultation of the chest may or may

Moderate water solubility: Cl₂, H₂S

not be abnormal, with wheezing, rhonchi or

crepitations. Mucosal oedema,

Low water solubility: O₃, NO₂, COCl

haemorrhage and ulcerations may be visible

Organic chemicals

in the air passages. Victims of inhalation

Organic acids: acetic acid

accidents with poorly soluble agents may

feel - and look - perfectly well initially but

Aldehydes: formaldehyde, acrolein

then experience progressive dyspnoea,

Isocyanates: MIC, TDI

shallow breathing, cyanosis, frothy pink

Amines: hydrazines, chloramines

sputum and, eventually, ventilatory failure. A

Riot control agents: CS gas

clinical picture of ARDS may then develop

gradually over 4-72 h, even after a period of

Vesicants: mustard gas

clinical improvement.

Organic solvents

Pulmonary function can be used to monitor

Leather treatment sprays

ambulatory subjects who have been

Some agrochemicals: paraquat,

exposed. Arterial blood gases show varying

cholinesterase inhibitors

degrees of hypoxaemia and respiratory

Metallic compounds

acidosis, depending on the severity of the

Mercury vapours

injury. The chest radiograph is usually

normal, if only the conducting airways are

Metallic oxides: CdO, V₂O₅, MnO, Os₃O

involved, but there may be signs of

Halides: ZnCl₂, TiCl₄, SbCl₅, UF₆

peribronchial cuffing. After exposure to deep

Ni(CO)₄

lung irritants, the chest radiograph is

Hydrides: B₂H₅, LiH, AsH₃, SbH₃

unremarkable in the first hours after

presentation but signs of interstitial and

Complex mixtures

alveolar oedema may become visible and,

Fire smoke

with time, patchy infiltrates, areas of

Pyrolysis products from plastics

atelectasis and even ‘white lungs’ may

develop. These changes may be due to

Solvent mixtures

tissue damage and organisation or they may

Spores and toxins from microorganisms

reflect superimposed infectious

The agents listed in the table have been

(broncho)pneumonia.

documented to cause toxic lung injury; however,

other agents with similar properties can also

In some instances, particularly in the later

injure the lungs acutely. TDI: toluene

stages of chemical pneumonitis, there may

diisocyanate.

be pathological (and radiological) features

of organising pneumonia with or without

bronchiolitis obliterans. Following

thermal injury (particularly if hot vapours

resolution of the acute pulmonary oedema,

have been inhaled) but, more generally, the

a relapse in the clinical condition may occur

lesions are caused by chemical injury. The

after 2-6 weeks with dyspnoea, cough, fine

toxic components of smoke include gaseous

crackles, a radiographic picture of miliary

asphyxiants (carbon monoxide and

nodular infiltrates, arterial hypoxaemia and a

hydrogen cyanide) and irritants, and

restrictive or mixed impairment, with low

particulates.

diffusing capacity. This relapse phase has

Clinical presentation Depending on the

been attributed to bronchiolar scarring with

circumstances of the accident, there may be

peribronchiolar and obliterating fibrosis of

thermal or chemical facial burns. Signs of

the bronchioli.

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ERS Handbook: Respiratory Medicine

Management At the scene of the accident,

which may be caused by inhalation of

appropriate medical intervention includes

natural or synthetic mineral oils, and with

removal from exposure, resuscitation and

pulmonary alveolar proteinosis, which may

supportive treatment. In some instances,

be caused by heavy exposure to silica (acute

emergency personnel must also be

silicoproteinosis) and by other agents, such

protected from chemicals that remain

as indium tin oxide.

present on victims or their clothes and

The Ardystil syndrome is an example of

decontamination procedures must be

subacute toxic pneumonitis. This outbreak

available. For some types of exposure,

of severe organising pneumonia occurred in

asymptomatic persons must remain under

1992 in Spain, and involved several workers

observation for 24 h; they should not

from factories where textiles were air-

exercise, nor should they be overfilled with

sprayed with dyes.

intravenous fluids. Oxygen treatment should

be given according to SaO₂.

Another recently described form of subacute

toxic lung injury is popcorn worker’s lung.

The further management of acute inhalation

This severe lung disease, characterised as

injury will be governed by the severity of the

bronchiolitis obliterans, occurred in subjects

patient’s condition, and will involve

occupationally exposed to vapours of butter

intensive care treatment with intubation and

flavouring (containing diacetyl) used for

artificial ventilation, as required. Antibiotics

making microwave popcorn and other

are only to be given if there are signs of

foods.

infection. In victims of smoke injury,

bronchoscopic removal of soot from the

Occupational or environmental aetiologies

airways may be necessary. The

should always be envisaged even in patients

administration of (systemic) corticosteroids

presenting with common forms of

is probably justified to prevent

pulmonary disease, such as asthma,

complications arising from (excessive)

bronchitis, COPD, sarcoidosis or interstitial

inflammation, such as bronchiolitis

lung disease (ILD). To discover such

obliterans, although there are no controlled

aetiologies, a thorough environmental

studies on this issue.

history must be taken in all patients. A high

degree of suspicion should exist when the

Physicians treating victims in the early days

occurrence or presentation of the disease is

after an incident must accurately document

unusual. This includes severe pneumonia in

the clinical condition of and all relevant data

young, previously healthy subjects, COPD in

in these patients. Documentation of the

nonsmokers, or ILD in subjects ,40 years of

damage by bronchoscopy and HRCT may be

age. Clustering of a rare disease in time or

justified. Repeated measurements of

space should also lead to scrutiny.

ventilatory function and arterial blood gases

Concomitant skin disease (especially

must be carried out, and victims of acute

airborne dermatitis) may also point to

inhalation injury should never be discharged

occupational exposures. Referral to a

without a comprehensive assessment of

specialist with expertise in occupational

their pulmonary function.

medicine may also be warranted for:

Subacute toxic pneumonitis

patients who report previous or ongoing

high exposure to mineral or organic dust,

Although the concept of chemical-induced

vapours or gases; patients whose work

lung injury is used only for disorders

involves burning or heating metals, plastics

resulting from a single, acute exposure to a

or solvents, or recycling materials; patients

toxic chemical, the term subacute toxic

using high-speed mechanical tools for

pneumonitis may be used to refer to lung

drilling, polishing or crushing; and patients

injury caused by repeated peaks of toxic

involved in air spraying or aerosolising

exposures or a more prolonged toxic

paints or other agents. Attention should also

exposure over weeks to months. This is the

be given to patients reporting recent

case with exogenous lipoid pneumonitis,

changes in procedures, ingredients or

ERS Handbook: Respiratory Medicine

335

suppliers, and those claiming that fellow

Das R, et al.

(1993). Chlorine gas

workers have similar trouble.

exposure and the lung: a review. Toxicol

Indust Health; 9: 439-455.

Possible sequelae of acute inhalation injury

Douglas WW, et al. Fume-related bronch-

iolitis obliterans. In: Epler GR, ed.

Following acute inhalation injury, there is

Diseases of the bronchioles. New York,

often complete recovery. However, this is

Raven Press, 1994; pp. 187-213.

not always the case. Various persistent

Kreiss K, et al. (2002). Clinical bronchio-

anatomical lesions, such as constrictive

litis obliterans in workers at a microwave-

bronchiolitis, bronchiectases, bronchial

popcorn plant. N Engl J Med; 347: 330-

strictures or polyps, may be identified by

338.

imaging studies or through bronchoscopy.

Langford NJ, et al. (2002). Episodes of

environmental poisoning worldwide.

Moreover, even in the absence of such

Occup Environ Med; 59: 855-860.

structural sequelae or in the absence of

Malo J-L, et al.

(2009). Long-term

significant defects in basal spirometry, a

outcomes of acute irritant-induced

state of permanent nonspecific bronchial

asthma. Am J Respir Crit Care Med; 179:

hyperreactivity may be observed. This

923-938.

condition of adult-onset, nonallergic

Moya C, et al.

(1994). Outbreak of

asthma, known as reactive airways

organising pneumonia in textile printing

dysfunction syndrome (RADS) or acute

sprayers. Lancet; 344: 498-502.

irritant-induced asthma, occurs in a

Nemery B (1996). Late consequences of

accidental exposure to inhaled irritants:

proportion of survivors of inhalation injury.

RADS and the Bhopal disaster. Eur Respir

Observations in fire-fighters and other

J; 9: 1973-1976.

personnel involved in rescue operations

Nemery B (2003). Reactive fallout of

during and following the collapse of the

World Trade Center dust. Am J Respir

World Trade Center on September 11, 2001,

Crit Care Med; 168: 2-3.

suggest that RADS may occur even without

Nemery B. Toxic pneumonitis. In:

the occurrence of clinically serious injury.

Hendrick DJ, et al., eds. Occupational

Disorders of the Lung. Recognition,

Management, and Prevention. London,

Further reading

WB Saunders, 2002; pp. 201-219.

Blanc P, et al. (1993). The lung in metal

Olson KR, et al. (1993). Mixing incompat-

fume fever. Semin Respir Med; 14: 212-225.

ibilities and toxic exposures. Occup Med;

Brusselaers N, et al. (2010). Severe burn

8: 549-560.

injury in Europe: a systematic review of

Shusterman DJ (1993). Polymer fume fever

the incidence, etiology, morbidity, and

and other fluorocarbon pyrolysis-related

mortality. Crit Care; 14: R188.

syndromes. Occup Med; 8: 519-531.

336

ERS Handbook: Respiratory Medicine

Hypersensitivity pneumonitis

Torben Sigsgaard and Anna Rask-Andersen

Hypersensitivity pneumonitis (HP), also

accumulation of activated T-lymphocytes in

known as allergic alveolitis, is an

the lung interstitium.

immunologically mediated inflammatory

Epidemiology

lung disease in the lung parenchyma

induced by the inhalation of a variety of

In a large, general population-based cohort

organic or inorganic antigens and

of HP patients from the UK, the overall

characterised by hypersensitivity to the

incidence rate was approximately 1 per

antigens. The disease is usually named

100 000 population and in Japan the

colourfully after the environment in which it

summer-type HP occurs every year in

occurs (e.g. farmer’s lung and bird fancier’s

approximately 1 per million population.

lung) and has been reported in over 30

Most other studies have focused on the risk

different occupations and environments.

of developing clinical disease amongst

Regardless of the causative agents or its

subsets of the population with high levels of

environmental setting, the pathogenesis and

exposure to particular antigens. For

clinical manifestations of the disease are

example, the incidence of farmer’s lung in

similar. The hallmark of the disease is a

Sweden in the 1980s was 20 per 100 000

massive lymphocytic inflammation with

person-years. However, there has been a

decrease in the incidence of farmer’s lung

due to changes in farming practice (hay

making replaced by silage bags). A recent

Key points

study from North America showed that the

most common causes were bird or hot-tub

N Hypersensitivity pneumonitis (HP) is

exposure.

an immunologically mediated

inflammatory lung disease of the

Risk factors

parenchyma.

The first reported HP was farmer’s lung,

HP is induced by the inhalation of a

caused by inhalation of microorganisms

variety of organic or inorganic

from infested crops. The disease was first

antigens, and is characterised by

described among farmers in the Nordic

hypersensitivity to the antigens.

countries; however, it has since been

described in range of farming operations all

N The main characteristic of HP is

over the world, making farming-like

massive lymphocytic inflammation

operations with decaying organic material

with accumulation of activated

one of the important exposures to look for

T-lymphocytes in the lung interstitium.

when confronted with a case of HP. One of

The only treatment is to avoid

the most common appearances of HP is

exposure to the offending allergen; if

bird fancier’s lung, caused by exposure to

the exposure ceases the symptoms

birds, e.g. pigeons or parakeets. Among

usually subside rapidly, but lung

pigeon breeder’s HP intestinal mucin, a high

function impairment may persist.

molecular weight glycoprotein, has been

identified as a major antigen.

ERS Handbook: Respiratory Medicine

337

Host factors

Environmental assessment

Smoking seems to protect towards HP,

The origin of the disease is an adverse

although the disease has been described in

reaction towards an occupational or

a small number of smokers. The reason

environmental factor, so it is imperative to

behind this protection might be the

search the patient’s environment for this

downregulation of the immune system by

exposure, and to minimise further contact

tobacco-smoke and nicotine.

with the offending agent. In many cases it is

obvious what the reason might be, for

In animal models, virus infection seems to

example with a mouldy hay problem

increase the susceptibility of mice towards

occurring after a wet harvest season. In

the antigens, and a higher number of virus

some instances the causal agent might be

antigens have been found in the bronchial

difficult to find and techniques for the

lavage of HP patients.

assessment of micro-organisms should be

Pathological mechanism

employed in order to assess the exposure to

which the patient is exposed.

Although HP is a well-known disease the

pathogenesis still is only partly understood.

Diagnosis

When Pepys (1978) found precipitating

antibodies to mould antigen in many of the

The diagnosis of HP relies on an array of

cases, it was believed that, for many years,

nonspecific clinical symptoms and signs

the immune complexes were the basis of the

developed in an appropriate setting, with

lung changes. It is now believed that the

demonstration of bilateral patchy infiltrates

disease is driven by the cellular immune

on chest radiographs, and serum

response. Following inhalation of antigen, a

precipitating antibodies against offending

complex formed by soluble antigens and IgG

antigens. Several different diagnostic criteria

antibodies triggers the complement cascade

for HP have been proposed, all have

and alveolar macrophage activations is

significant problems that limit their utility.

induced resulting in an increase of

After studying a total of 661 HP patients

macrophages. These cells secrete cytokines

with a stepwise logistic regression, a panel

and chemokines that attract neutrophils in

of clinical experts identified the six

the alveoli and small airways. The number of

significant predictors of HP.

T-lymphocytes is also increased with a

predominance of the CD8⁺ T-lymphocytes

Diagnostic criteria of extrinsic allergic

subset resulting in a decrease in the CD4⁺/

alveolitis are as follows:

CD8⁺ ratio (in contrast to observations

made in sarcoidosis). Different upregulatory

mechanisms result in a stronger interaction

N Exposure to a known offending antigen

between macrophages and T-cells and a

N Symptoms occurring 4-8 h after

more effective antigen-presenting capacity.

exposure

N Positive precipitating antibodies to the

Symptoms and findings

offending antigen

The predominant symptoms in HP are

N Inspiratory crackles on physical

tiredness, dyspnoea, fever, shivering, flu-like

examination

feeling, cough, muscle and joint aches, and

N Recurrent episodes of symptoms

headache. Radiograph of the thorax shows

N Weight loss

diffuse, fine, nodular shadows, either

general or predominantly in the bases. In the

However, diagnosing HP often pose

early stages the changes can be difficult to

challenges, even to expert clinicians.

detect, but widespread patchy opacities may

Additional investigations (including surgical

also be seen. Lung function is decreased

biopsy) are indicated in patients with

with a typical restrictive pattern and

interstitial diseases in whom the diagnosis

decreased diffusing capacity.

remains unclear after initial assessment.

338

ERS Handbook: Respiratory Medicine

Table 1. HP types with typical causative exposures and antigens

HP type

Exposure

Antigen

Farmer’s lung

Mouldy hay

Saccharopolyspora rectivirgula

Bagassosis

Mouldy bagasse

Thermoactinomyces sacchari

Mushroom worker’s lung

Mushroom spores,

Thermophilic actinomycetes

mushroom compost

Malt worker’s lung

Mouldy barley

Aspergillus clavatus, Faenia rectivirgula

Humidifier/air-conditioner

Contaminated water

Thermophilic actinomycetes

lung

reservoirs

Grain handler’s lung

Mouldy grain

Saccharopolyspora rectivirgula,

Thermoactinomyces vulgaris

Cheese worker’s lung

Cheese mould

Penicillium casei

Paprika splitter’s lung

Paprika dust

Mucor stolonifer

Compost lung

Compost

Aspergillus spp.

Peat moss worker’s lung

Peat moss

Monocillium spp., Penicillium

citreonigrum

Suberosis

Mouldy cork dust

Penicillium frequentans

Maple bark stripper’s lung

Mouldy wood bark

Cryptostroma corticale

Wood pulp worker’s lung

Mouldy wood pulp

Alternaria spp.

Wood trimmer’s disease

Mouldy wood

Rhizopus spp.

trimmings

Japanese summer-type HP

Indoor air

Trichosporon cutaneum

Metal-grinding

Metalworking fluids

Mycobacteria

Hot tub lung

Mist from hot tubs

Mycobacteria

Bird breeder’s lung

Pigeons, parakeets,

Avian or animal proteins

fowl and rodents

Mollusk-shell hypersensitivity

Sea snail shells

Shell dust

Chemical worker’s lung

Manufacture of

Trimellitic anhydride, diisocyanate,

plastics, polyurethane

methylene diisocyanate

foam and rubber

Treatment

The effect of medical treatment on the

outcome of HP has been discussed.

Cortisone has been found to reduce IL-8

The only treatment for allergic diseases is

synthesis. Cortisone treatment seems to

to avoid the exposure to the offending

improve the radiological findings and

allergen. This can be done in many

should be given to severely ill patients to

circumstances, such as when the

ameliorate symptoms, but no apparent

occurrence is sporadic and not part of the

benefit is derived from long-term treatment.

daily work of the patient. However, in some

Cortisone treatment should be given for

cases, for example in farmers, it might be

about 2 months.

difficult to completely avoid the exposure

for a range of different reasons. Under such

Prognosis

circumstances, respiratory protection can

be used to minimise the exposure as much

If the exposure ceases, the symptoms

as possible.

usually subside rapidly, but lung function

ERS Handbook: Respiratory Medicine

339

impairment may persist for a longer period

Further reading

and become permanent with a restrictive

Ando M, et al. (1991). Japanese summer-type

pattern and decreased diffusing capacity.

hypersensitivity pneumonitis. Geographic

Repeated attacks increase the risk of a poor

distribution, home environment, and clinical

prognosis. It is therefore important to treat

characteristics of 621 cases. Am Rev Respir

the patient as soon as possible in order to

Dis; 144: 765-769.

avoid more damage to the lung parenchyma

Arya A, et al. (2006). Farmer’s lung is

in addition to that already present at the

now in decline. Irish Med J; 99: 203-205.

time of diagnosis.

Bourke SJ, et al. (2001). Hypersensitivity

pneumonitis: current concepts. Eur Respir

Differential diagnosis

J Suppl; 32: 81s-92s.

Hanak V, et al.

(2007). Causes and

Infectious lung diseases, both of virological

presenting features in

consecutive

and bacteriological origin, as well as other

patients with hypersensitivity pneumoni-

lung diseases such as sarcoidosis have to be

tis. Mayo Clinic Proc; 82: 812-816.

ruled out. Another differential diagnosis is

Lacasse Y, et al. (2003). Clinical diagnosis

the organic dust toxic syndrome (ODTS)

of hypersensitivity pneumonitis. Am J

also known as ‘inhalation fever’: acute,

Respir Crit Care Med; 168: 952-958.

febrile, noninfectious, flu-like, short-term

Malmberg P, et al. (1988). Incidence of

reactions that can be produced by inhalation

organic dust toxic syndrome and allergic

alveolitis in Swedish farmers. Int Arch

of bio-aerosols and organic dusts.

Allergy Appl Immunol; 87: 47-54.

Symptoms are caused by the release of

Pepys J (1978). Antigens and hypersensi-

inflammatory cytokines from the lungs

tivity pneumonitis. J Allergy Clin Immunol;

caused by an inhalatory overexposure to

61: 201-203.

aerosols. ODTS is quite a common

Solaymani-Dodaran M, et al.

(2007).

condition, but the prognosis is good and

Extrinsic allergic alveolitis: incidence and

most people have recovered totally without

mortality in the general population. QJM;

any sequels after 24 h. No treatment is

100: 233-237.

required if the exposure is terminated.

340

ERS Handbook: Respiratory Medicine

Pneumoconiosis

Allan F. Henderson

Pneumoconiosis is the non-neoplastic

frequently issues of compensation, and the

reaction of the lung to inhaled dust.

pneumologist working in industrial and

Conventionally, asthma, bronchitis and

post-industrial situations should become

emphysema are excluded from the

familiar with the local arrangements as well

definition, but these will be included here,

as the purely medical issues.

where relevant.

Asbestos

Exposure to dusts varies greatly throughout

Asbestos is a collective term for a number of

the world, including Europe. The prevalence

silicaceous minerals. The amphiboles

of pneumoconiosis differs as well, even

crocidolite and amosite are no longer mined

within countries. Another confounding

or used industrially, but the serpentine

factor is that dust-related diseases may

chrysotile is still produced and used

occur many years after exposure. For

extensively in Africa, South America and

example, asbestosis may be seen years after

Asia. It is less harmful, but there is

the closure of shipyards. The practicing

frequently contamination with amphiboles.

pneumologist is recommended to become

Asbestos was used extensively in

familiar with the industrial history of their

construction before its use was curtailed

locale. Most cases of pneumoconiosis are

and it is exceedingly persistent. This leads to

due to occupational exposure. There are

workers involved with renovation,

demolition, etc. being at risk of exposure.

This may be particularly relevant in the

Key Points

causation of mesothelioma in cohorts not

exposed to asbestos at the time of its active

N Pleural plaques indicate exposure to

importation and use.

asbestos, but rarely cause problems.

Pleural plaques

N Asbestos-related diseases (except

mesothelioma) are becoming

Hyaline pleural plaques are discrete areas of

increasingly rare.

thickening on the parietal pleura. They are a

common manifestation of asbestos

N Pleural thickening may result from

exposure. Their development is correlated

unrecognised benign asbestos

with cumulative dose exposure to asbestos,

pleurisy.

but only loosely. They may be absent or

CWP and silicosis are much rarer now

profuse in similarly exposed individuals.

in Europe but remain significant

Their diagnosis is usually an incidental

problems worldwide.

radiographic finding and they are not usually

seen on conventional radiology ,15 years

N CWP and silicosis can both be

from the subject’s first exposure. However,

associated with airways obstruction.

earlier detection, particularly of small,

Silicosis and asbestosis increase the

uncalcified lesions, is possible with CT.

risk of lung cancer.

Plaques become increasingly calcified over

time.

ERS Handbook: Respiratory Medicine

341

They are generally regarded as

laggers and joiners, not with casual

asymptomatic but, rarely, grating pleuritic

contact. As asbestos use has reduced

discomfort is reported. Breathlessness is

dramatically, so the incidence of asbestosis

usually due to other causes, but very

has fallen steeply. Cases are virtually

extensive plaques may exert a cuirass effect.

confined to older males who encountered

Some series report impaired lung function

asbestos decades ago. There is controversy

with plaques, which has been attributed to a

as to whether asbestosis progresses after

number of explanations including

removal from exposure or develops many

subradiographic interstitial fibrosis and

years after exposure. Much of the interest

peripheral small airway disease.

in asbestosis is now medicolegal. The

principal issue faced by pneumologists in

Plaques are not pre-malignant but they are a

practice is whether a case of interstitial

marker of asbestos exposure, which implies

lung disease is idiopathic pulmonary

an increased risk of other asbestos-related

fibrosis (IPF) or asbestosis. Occupational

diseases. This may cause anxiety. In the UK,

exposure to asbestos may suggest

this is compensable in Scotland, but not in

asbestosis but a working knowledge of

the rest of the UK.

industrial processes is needed to assess

Benign asbestos pleurisy and diffuse

the relevance of this. The presence of

pleural thickening

pleural plaques may be supportive but IPF

can occur in such patients. Radiological

Once considered separate entities, these

features may help, as does review of

conditions are part of a spectrum of

progression over time, if such data are

inflammatory response to inhaled asbestos

available.

fibres that have traversed the lung and

lodged in the pleura. Asbestos pleurisy may

The Helsinki criteria were developed in 1997

present as an acute illness with pain, fever

to assist with evaluating such cases. They

and dyspnoea, and may be misdiagnosed as

include pathological features. A lung biopsy

infective. Most, but not all, are characterised

is rarely appropriate as the clinical

by a bloody pleural effusion. Many episodes

management is not affected in most cases.

are asymptomatic. The latency from first

Post mortem analysis may assist in

exposure is highly variable but may be

medicolegal assessment.

,10 years. Some episodes may resolve with

There is a high incidence of lung cancer in

little legacy, while others progress to diffuse

patients with asbestosis - around 30% in

pleural thickening (DPT). Asymptomatic

some series. There is controversy as to

asbestos pleurisy is believed to be the

whether asbestos exposure alone increases

precursor of other cases of DPT. Asbestos

the risk of cancer.

pleurisy is frequently recurrent and bilateral,

leading to bilateral DPT. Unlike plaques,

Coal

DPT commonly causes restricted ventilation

and, hence, dyspnoea. Plaques and DPT can

Unlike asbestos, the mining and use of coal

be difficult to distinguish. Radiologically, the

continues on a colossal scale, with

costophrenic angle is obliterated in DPT;

.7 billion tonnes produced worldwide in

pathologically, DPT involves the visceral

2011. There have been big changes in world

pleura while plaques are confined to the

demographics, with greatly reduced mining

parietal surface.

in the UK and huge production in China.

Many European countries have significant

Asbestosis

coal industries. Dust control measures have

Asbestosis is sometimes erroneously used

been successful in reducing coal-related

as a term to describe all types of asbestos-

disease but new cases still occur. The

related disease, whereas it is properly

number of miners employed in the industry

defined as interstitial fibrosis due to

has reduced, serving to reduce the numbers

asbestos. It occurs with significantly heavy

of exposed individuals, but the potential for

exposure to asbestos, such as in shipyard

problems has increased because of higher

342

ERS Handbook: Respiratory Medicine

dust levels produced by increased

the UK, France and Germany. Many of

mechanisation of production.

these date from exposure many years ago.

However, this situation is not global, with

Coal workers’ pneumoconiosis

large numbers of new cases being

Simple coal workers’ pneumoconiosis

recorded in China, making silicosis the

(CWP) is the accumulation of coal dust,

most prevalent pneumoconiosis

predominantly in centrilobular macules 2-

worldwide.

5 mm in diameter, often more in the upper

Simple silicosis, like simple CWP, causes

zones. Despite the dramatic macroscopic

little physiological disturbance or

appearances observed post mortem, and

symptoms despite marked radiological

equally marked radiographic findings,

changes, which are characterised by nodule

simple CWP itself causes no symptoms or

formation with an upper zone

lung function abnormality. Symptoms such

predominance. With increased silica load

as dyspnoea require investigation for

comes an increased fibrotic response,

alternative diagnoses.

which may become extensive and confluent.

Progressive massive fibrosis (PMF) is

Hilar calcification (‘egg-shell’) is

associated with the presence of larger

characteristic but not universal. Dyspnoea,

(.1 cm) nodules pathologically and

accompanied by a dry cough is the usual

radiologically. PMF occurs with greater dust

symptom.

exposure, and improved control measures

have led to a marked decline in its

The lung function disturbance is variable. A

prevalence. PMF is also associated with

restrictive defect is common with fibrotic

impaired lung function, principally

disease but may be accompanied by

restriction.

obstruction that, in the early stages, may be

the sole abnormality. Previously attributed

Caplan’s syndrome is the finding of large

to smoking, it is now recognised that silica

(0.5-5 cm) nodules in miners with

causes emphysema, which may develop in

rheumatoid arthritis. The nodules are not

the absence of nodular change.

profuse and no effect is seen on lung

function.

Silicosis is associated with an increased risk

of lung cancer. As with asbestos, it is

Chronic bronchitis and emphysema are

currently undetermined as to whether this is

caused by coal dust. Bronchitis is

due to silica per se or whether this is

manifested by cough and sputum.

secondary to silicosis.

Centrilobular emphysema is demonstrated

post mortem in coal miners, especially when

TB is a common complication in silicosis.

simple CWP is present. Airway obstruction

Accelerated deterioration in a patient with

due to this (and compounded by smoking)

silicosis should raise suspicion. In the past,

is the main cause of disability in miners with

diagnosis has often been difficult, but

simple CWP.

interferon-c testing has helped. In South

Africa, HIV infection has been shown to be

Silicosis

synergistic with silicosis in increasing the

Silicon is the second most abundant

incidence of TB.

element on earth. Silica (silicon dioxide) and

silicaceous compounds are ubiquitous, and

Further reading

are encountered in a wide variety of

industrial processes including mining and

American Thoracic Society Committee of

quarrying, masonry and construction, and

the Scientific Assembly on Environmental

foundry work.

and Occupational Health.

(1997).

Adverse effects of crystalline silica expo-

Dust control measures have led to a

sure. Am J Respir Crit Care Med;

155:

marked reduction in silicosis in developed

761-768.

countries, with only a few hundred cases in

ERS Handbook: Respiratory Medicine

343

Cassidy A, et al.

(2007). Occupational

Coutts I, et al. (1987). Mortality in cases

exposure to crystalline silica and risk of

of asbestosis diagnosed by a pneumoco-

lung cancer: a multicenter case-control

niosis panel. Thorax; 42: 111-116.

study in Europe.. Epidemiology; 18: 36-43.

Hillerdal G, et al. (1987). Benign asbes-

Coggan D, et al. (1998). Coal mining and

tos pleural effusion:

exudates in

chronic obstructive pulmonary disease.

patients. Eur J Respir Dis;

71:

Thorax; 53: 398-407.

113-121.

Copley SJ, et al. (2003). Asbestosis and

Marine WM, et al.

(1988). Clinically

idiopathic pulmonary fibrosis: compari-

important respiratory effects of dust

son of thin-section CT features. Radiology;

exposure and smoking in British coal

229: 731-736.

miners. Am Rev Respir Dis;

137:

Corbett EL, et al. (2000). HIV infection

106-112.

and silicosis: the impact of two potent

Tossavainen A (1997). Asbestos, asbes-

risk factors on the incidence of mycobac-

tosis, and cancer: the Helsinki criteria for

terial disease in South African miners.

diagnosis and attribution. Scand J Work

AIDS; 14: 2759-2768.

Environ Health; 23: 311-316.

344

ERS Handbook: Respiratory Medicine

Indoor and outdoor pollution

Giovanni Viegi, Marzia Simoni, Sara Maio, Sonia Cerrai,

Giuseppe Sarno and Sandra Baldacci

Air pollution is a well-established hazard to

they inhale a higher volume of air per body

human health. Air quality is particularly

weight than adults, their lungs are growing,

important for subpopulations that are more

their immune system is incomplete and

susceptible (i.e. children, the elderly,

defence mechanisms are still evolving. Air

subjects with cardiorespiratory diseases or

pollution can affect the cells in the lung by

those who are socioeconomically deprived)

damaging those that are most susceptible

or at higher risk of specific exposures

and, if the damaged cells are important in

(workers exposed to inorganic dust, wood

the development of new functional parts of

dust, fumes, gases and cleaning agents).

the lung, the lung may not achieve its full

Children are particularly vulnerable since

growth and function as a child matures to

adulthood. This can lead to enhanced

susceptibility during adulthood to the effects

of ageing and infections, as well as to

Key points

pollutants. Air pollution has both short-term

adverse effects (peak exposures) and long-

Recent epidemiological studies have

term adverse effects, and these effects can

clearly shown that outdoor and indoor

involve the pulmonary system but also the

air pollution affects respiratory health

cardiovascular system.

worldwide, causing an increase in the

prevalence of cardiovascular and

Air pollution is mostly produced by human

respiratory symptoms/diseases (i.e.

activities. Other pollutants derive from

COPD, asthma, hay fever and lung

natural sources, such as biological allergens

function reduction) and of mortality,

(e.g. house dust mites, pets dander and

both in children and in adults.

moulds) and natural phenomena (e.g.

volcanic activity and forest fires).

Rapid industrialisation and

urbanisation have increased air

Recent research focuses on two broad

pollution and, consequently, the

sources:

number of exposed people.

N motor vehicles and industrial plants

Conservative estimates show that

N biomass fuels

between 1.5 and 2 million deaths per

year could be attributed to indoor air

Traffic-related air pollution is a growing

pollution in developing countries.

concern in both developed and less-

The abatement of the main risk

developed countries, and industrial

factors for respiratory diseases, and

smokestacks continue to be a major source

the support of healthcare providers

of outdoor air pollution from the burning of

and the general community for public

fossil fuels throughout the world. However,

health policies improving outdoor/

the most threatened populations live in

indoor air quality can achieve huge

developing and poor countries, where air

health benefits.

pollution reflects a combination of

traditional and modern factors. Rapid

ERS Handbook: Respiratory Medicine

345

industrialisation, urbanisation and growth in

Exposure-response relationships for

vehicle use increase outdoor air pollution,

outdoor pollutants, especially particulates,

and, at the same time, traditional indoor

have been confirmed by epidemiological

burning of solid fuels, such as coal and

studies in recent decades. Short-term

dung, is still widespread.

exposure, due to acute increase in air

pollution, may cause premature mortality

With this in mind and in view of the 2013

and increase hospital admissions for

European ‘Year of Air’, the European Union

exacerbations of COPD or asthma. Long-

is revising its main air pollution control

term cumulative health effects of chronic

policies, and the European Respiratory

exposure comprise an increase in mortality

Society Environment and Health Committee

and morbidity for cardiovascular and

has developed 10 concise principles for

respiratory diseases, including COPD and

clean air that summarise the scientific state

lung cancer, and impaired development of

of the art and provide guidance.

the lungs in children. In COPD patients,

Outdoor pollution

continued exposure to noxious agents

promotes a more rapid decline in lung

The most important outdoor pollutants

function and increases the risk of repeated

derive from fossil fuel combustion. Primary

exacerbations. Air pollution can harm the

pollutants directly emitted into the

fetus if the mother is exposed to high levels

atmosphere are carbon monoxide, sulfur

during pregnancy (i.e. intrauterine growth

dioxide, nitrogen dioxide and particulates.

retardation) and can increase respiratory

Ozone is a secondary pollutant, mainly

neonatal mortality. Particulates, nitrogen

produced by chemical reaction of nitrogen

dioxide and ozone are the most important

dioxide and hydrocarbons in the presence of

pollutants today. The health effects of

sunlight at warm temperature. Rapid

particulates are more serious for fine

industrialisation and urbanisation in many

(particular matter with an aerodynamic

parts of the world have increased air

diameter ,2.5 mm (PM2.5)) and ultrafine

pollution and, consequently, the number of

(PM0.1) particles, as they penetrate deeper

people exposed to it. In China, for instance,

into the airways of the respiratory tract,

rapid economic development has led to

reaching the alveoli. Vehicular exhausts are

severe environmental degradation,

responsible for small-sized airborne

particularly due to coal combustion (which

particulate air pollution in urban areas.

provides 70-75% of all energy in China) and

Recently, much research has pointed out the

vehicular traffic. Chinese mortality and

negative effects of diesel exhaust exposure;

morbidity associated with outdoor pollution

people are exposed not only to motor vehicle

are very high: .300 000 deaths and

exhausts but also to exhausts from other

20 million cases of respiratory illnesses

diesel engines (e.g. diesel trains and ships)

annually. A more recent study raises the

and from power generators. In June 2012,

estimate of the death toll in China due to air

the International Agency for Research on

pollution to 1.2 million.

Cancer (IARC) classified diesel engine

Today, it is recognised that global warming

exhaust as carcinogenic to humans (Group

will increase the effects of outdoor air

1), based on sufficient evidence that

pollution on health: it will lead to more heat

exposure is associated with an increased

waves, during which air pollution

risk of lung cancer.

concentrations are also elevated, and during

The role of air pollution in the epidemics of

which hot temperatures and air pollutants

allergies is still debated, even if experimental

act in synergy to produce more serious

studies have suggested that the effects of air

health effects than expected from heat or

pollutants on the development and

pollution alone.

worsening of allergies are biologically

The main effects of the more common

plausible. Asthma shows a strong familial

outdoor pollutants are summarised in

association but genetic factors alone are

table 1.

unlikely to account for the rapid rise in its

346

ERS Handbook: Respiratory Medicine

Table 1. Major outdoor/indoor pollutants and related health effects

Pollutant

Major sources

Health effects

Particulate

Outdoor

Lung cancer

matter

Vehicular traffic

Premature death

Woodstoves

Mortality for cardiorespiratory

Organic matter and fossil fuel combustion

diseases

Power stations/industry

Reduced lung function

Windblown dust from roadways,

Lower airways inflammation

agriculture and construction

Upper airways irritation

Bushfires/dust storms

Indoor

Woodstoves

Organic matter and fossil fuel combustion

for heating/cooking

ETS

Nitrogen

Outdoor

Exacerbation of asthma

dioxide

Vehicular traffic

Airway inflammation

Power stations/industry

Bronchial hyperresponsiveness

Indoor

Increased susceptibility to

Unvented gas/kerosene appliances

respiratory infection

Ozone

Outdoor

Lung tissue damage

Sunlight chemical reaction with other

Reduced lung function

pollutants

Reduced exercise capacity

Vehicular traffic

Exacerbation of asthma

Power stations/industry

Upper airway and eye irritation

Consumer products

Carbon

Outdoor

Death/coma at very high levels

monoxide

Organic matter and fossil fuel combustion

Headache, nausea,

Vehicular traffic

breathlessness, confusion/

Woodstoves

reduced mental alertness

Indoor

Low birth weight (fetal exposure)

Organic matter and fossil fuel combustion

for heating/cooking

Woodstoves

Unvented gas/kerosene appliances

ETS

Sulfur

Outdoor

Exacerbation of respiratory

dioxide

Coal/oil-burning power stations

diseases including asthma

Industry/refineries

Respiratory tract irritation

Diesel engines

Metal smelting

VOCs

Indoor

Lung cancer

Building materials and products such as

Asthma, dizziness, respiratory

new furniture, solvents, paint,

and lung diseases

adhesives, insulation

Chronic eye, lung or skin irritation

Cleaning activities and products

Neurological and reproductive

Materials for offices

disorders

prevalence seen in recent decades. The rapid

industrialisation. Thus, genetic and

increase in the burden of atopic diseases

environmental factors may interact to cause

occurred along with rapid urbanisation/

asthma. A growing number of studies shows

ERS Handbook: Respiratory Medicine

347

significant associations of traffic with new-

estimates attribute 1.5-2 million deaths per

onset asthma, or asthma symptoms/

year to indoor air pollution. There is

exacerbations, in children.

consistent evidence that exposure to indoor

pollutants increases the risk of several

Some recent studies confirming the

respiratory/allergic symptoms and diseases

association between urban air pollution and

(table 1). Relevant indoor pollution sources

health status are described here.

are environmental tobacco smoke (ETS), a

common source of indoor particulates,

The Italian EpiAir project, performed in 10

biomass (wood/coal) fuel use, and mould/

cities on ,300 000 subjects aged

damp. Furthermore, within the western

o35 years, highlighted an increase in

countries and in the societies that adopt

mortality from respiratory diseases of

western lifestyles, consumer products (i.e.

2.29% (95% CI 1.03-3.58%) per 10-mg?m^-3

computers, televisions, synthetic building

increase in PM10 (lag 0-3 days); the

materials, etc.) emit large quantities of

increase in mortality was higher during

volatile organic compounds (VOCs) and

summer.

nonorganic compounds.

Data from the Cancer Prevention Study II

cohort of the American Cancer Society

ETS is associated with increased risk of

showed an increase of 4% in mortality for

acute respiratory or irritation symptoms,

respiratory diseases per 10-ppb increase

infectious diseases, chronic respiratory

in ozone concentration.

illnesses, lung function reduction and even

Our team in Pisa, Italy, has reported that

lung cancer. In children, ETS also increases

people living in an urban area are at higher

the risk of sudden infant death syndrome,

risk of having increased bronchial

middle-ear disease, lower respiratory tract

responsiveness (OR 1.41, 95% CI 1.13-1.76)

illnesses, wheeze and cough. ETS exposure

than people living in a rural area. Moreover,

exacerbates pre-existing asthma and

we showed long-term effects of the exposure

increases symptom burden and morbidity.

to traffic air pollution: people residing near a

In nonsmokers, the mortality risk for

major road (within 100 m) showed

respiratory diseases is about double for

significantly higher risks (odds ratios

those living with smokers than for those

ranging from 1.61 to 2.07) of persistent

who do not. Studies performed worldwide

wheezing, dyspnoea, attacks of shortness of

suggest higher risk for ETS exposure in

breath with wheezing, asthma, COPD,

females than in males. Table 2 shows the

airway obstruction and atopy. Another

results of meta-analyses regarding the

Italian study, performed on children (aged

associations of ETS exposure with

10-17 years) living in Palermo, Italy,

respiratory symptoms/diseases.

confirmed the negative impact of heavy

traffic exposure, showing significantly higher

About half of the world’s population burns

risks (odds ratios ranging from 1.39 to 1.84)

biomass for cooking, heating and lighting, in

of asthma, rhinoconjunctivitis and reduced

open fires or with inefficient stoves, and in

lung function.

poorly ventilated rooms, especially in

developing countries. Indoor air pollution

Indoor pollution

from biomass fuels is strongly poverty-

Indoor environments contribute significantly

related and represents an important risk

to human exposure to air pollutants. People

factor for acute respiratory illness morbidity

spend most of their time indoors: up to 90%

and mortality in low-income countries,

in industrialised countries. Furthermore,

especially in children and women. In China,

levels of some pollutants are higher inside

indoor air pollution from solid fuel use is

than outside buildings. Even at low

responsible for ,420 000 premature deaths

concentrations, indoor pollutants may have

annually, more than the nearly 300 000

an important biological impact because of

attributed to urban outdoor air pollution in

long exposure periods (e.g. at home or

the country. A more recent study raises the

school, and in workplaces). Conservative

estimate of the death toll in China due to

348

ERS Handbook: Respiratory Medicine

Table 2. Associations between ETS exposure and respiratory symptoms/disease in never-smokers.

Population

Estimated pooled risk

Lower respiratory

,2 years

OR 1.55 (95% CI 1.42-1.69)

tract infection

2-6 years

OR 1.71 (95% CI 1.33-2.20)

Cough

Males

OR 1.60 (95% CI 1.22-2.10)

Females

OR 1.68 (95% CI 1.17-2.34)

Asthma onset

Children

OR 1.32 (95% CI 1.24-1.41)

Adults

OR 1.97 (95% CI 1.19-3.25)

Lung cancer

Adults

OR 1.21 (95% CI 1.13-1.30)

Females

RR 1.27 (95% CI 1.17-1.37)

North America

RR 1.15 (95% CI 1.03-1.28)

Asia

RR 1.31 (95% CI 1.16-1.48)

Europe

RR 1.31 (95% CI 1.24-1.52)

OR: odds ratio; RR: relative risk.

household air pollution to 1 million, close to

Finally, exposure to VOCs may result in a

the 1.2 million due to outdoor air pollution.

spectrum of illnesses ranging from mild

The evidence that biomass use increases the

(irritations) to very severe effects, including

risk of COPD in females and acute respiratory

cancer. Such exposure increases the risk for

infections in children is very strong (about

respiratory/allergic effects in infants/

three-fold and more than three-fold higher

children, like asthma, wheeze, chronic

risk in those exposed than in the unexposed,

bronchitis, reduced lung function, atopy and

respectively). The IARC has classified the

severity of sensitisation, rhinitis, and

indoor combustion of coal emissions as

pulmonary infections. Many studies indicate

Group 1, a known carcinogen to humans.

that the effects are related to very low levels

There is strong evidence (moderate for

of exposure. VOC exposure also seems a

males) that females exposed to smoke from

significant risk factor for asthma (odds

coal fires in the home have an elevated risk of

ratios ranging from 1.2 to 2.9). Many of the

lung cancer (OR 1.9, 95% CI 1.1-3.5).

effects observed in children have been

shown also in adults.

Based on meta-analyses, building dampness

and mould are associated with

Biological mechanisms

approximately 30-50% increases in

respiratory and asthma-related health

Many recent studies have shown that

outcomes. In children, a population

oxidative stress, induced by air pollutants,

attributable risk for asthma of 6.7% has

plays a central role in the impact of air

been estimated. In adults, a pooled risk of

pollution. The first contact of inhaled

cough by indoor mould/dampness was

ambient pollutants is with the fluid layer that

estimated at an odds ratio of 2.10 (95% CI

covers the respiratory epithelium, and the

1.27-3.47). There is also evidence for an

responses following the exposure are

association of mould exposure with new-

mediated through oxidation reactions

onset asthma and worsening of pre-existing

occurring within this fluid air-lung interface.

asthma (wheezing, cough and shortness of

These reactions can result in oxidative stress

breath) in both children and adults. Allergic

and consequent increased production of

symptoms are commonly related to mould

inflammatory mediators from human airway

exposure (sneezing; nose, mouth or throat

epithelial cells. Oxidative stress is a

irritations; nasal stuffiness or runny nose;

situation in which the oxidant-antioxidant

and red, itchy or watery eyes).

balance is disturbed. This imbalance can

ERS Handbook: Respiratory Medicine

349

occur when the generation of oxidant

improving outdoor air quality through

molecules (free radicals) exceeds the

programmes for abating/reducing pollutant

available antioxidant defences. The

emissions is also important. Moreover,

consequence of this oxidative stress can be

there is evidence that increased antioxidant

systemic or local inflammations thus

intake may protect against the effects of air

involving the cardiopulmonary system.

pollution. The role of the physician is

essential in patient education on the

The three pollutants of most concern that

preventive actions to reduce health effects

can cause oxidative stress include nitric

due to pollution.

oxide, which is a free radical, PM10, and

ozone. The majority of human genetic

Hopefully, these actions will reduce the

association studies of air pollutants have

negative effects of air pollution on the

examined ozone exposure. Ozone is a

respiratory health status and quality of life of

powerful oxidant and reacts with the

the general population, particularly of more

bronchial epithelium lining fluid to generate

susceptible individuals.

free radicals. It depletes levels of protective

antioxidants and increases the production of

Further reading

inflammatory mediators.

Brunekreef B, et al. (2012). Ten principles

The size and the surface of particulates

for clean air. Eur Respir J; 39: 525-528.

determine the potential to elicit oxidative

Cibella F, et al. (2011). Proportional Venn

damage. In general, the smaller the size of

diagram and determinants of allergic

the particulates, the higher the toxicity

respiratory diseases in Italian adolescents.

through mechanisms of oxidative stress and

Pediatr Allergy Immunol; 22: 60-68.

inflammation. Nanoparticles (ultrafine

Faustini A, et al. (2011). The relationship

particles with diameter ,100 nm) are more

between ambient particulate matter and

toxic and inflammogenic than fine particles.

respiratory mortality: a multi-city study in

They generate reactive oxygen species to a

Italy. Eur Respir J; 38: 538-547.

greater extent and exacerbate pre-existing

Hulin M, et al. (2012). Respiratory health

respiratory and cardiovascular disease, also

and indoor air pollutants based on

through a dose-response effect.

quantitative exposure assessments. Eur

Respir J; 40: 1033-1045.

Pulmonary impairment related to pollutant

International Agency for Research on

exposure may be higher in individuals who

Cancer. Diesel engine exhaust carcino-

are genetically at risk for higher

genic. www.iarc.fr/en/media-centre/pr/2012/

susceptibility to oxidative stress. The

pdfs/pr213_E.pdf

formation of reactive oxygen species is an

Künzli N, et al. Air quality and health.

important aspect of the inflammatory

www.ersnet.org/index.php/publications/

process of asthma, and genetic aberrations

reference-books.html

Lim SS, et al. (2012). A comparative risk

associated with antioxidants might explain

assessment of burden of disease and

the reason why some people with asthma

injury attributable to 67 risk factors and

seem at higher risk of exacerbations due to

risk factor clusters in 21 regions, 1990-

air pollution exposure.

2010: a systematic analysis for the Global

Conclusion

Burden of Disease Study 2010. Lancet;

380: 2224-2260.

Outdoor and indoor pollution greatly affect

Maio S, et al. (2009). Urban residence is

respiratory health worldwide, as shown by

associated with bronchial hyper-respon-

many recent epidemiological studies.

siveness in Italian general population

samples. Chest; 135: 434-441.

Patient education about the importance of

McGwin G, et al. (2010). Formaldehyde

good indoor air quality in the home and

exposure and asthma in children: a

workplace is essential. The support of

systematic review. Environ Health

healthcare providers and the general

Perspect; 118: 313-317.

community for public health policy aimed at

350

ERS Handbook: Respiratory Medicine

Nuvolone D, et al. (2011). Geographical

J Environ Sci Health C Environ Carcinog

information system and environmental

Ecotoxicol Rev; 26: 339-362.

epidemiology: a cross-sectional spatial

Viegi G, et al. (2007). Definition, epide-

analysis of the effects of traffic-related

miology and natural history of COPD. Eur

air pollution on population respiratory

Respir J; 30: 993-1013.

health. Environ Health; 10: 12-23.

Viegi G, et al. (2004). Indoor air pollution

Oberg M, et al. Second-hand smoke:

and airway disease. Int J Tuberc Lung Dis;

assessing the environmental burden of

8: 1401-1415.

disease at national and local levels.

World Health Organization. Effects of air

Geneva, World Health Organization, 2010.

pollution on children’s health and devel-

Po JY, et al. (2011). Respiratory disease

opment - a review of the evidence. www.

associated with solid biomass fuel expo-

euro.who.int/__data/assets/pdf_file/0010/

sure in rural women and children: systema-

74728/E86575.pdf

tic review and meta-analysis. Thorax; 66:

World Health Organization. WHO guide-

232-239.

lines for indoor air quality: dampness and

Valavanidis A, et al.

(2008). Airborne

mould. www.euro.who.int/__data/assets/

particulate matter and human health: tox-

pdf_file/0017/43325/E92645.pdf

icological assessment and importance of

Yang W, et al.

(2009). Air pollutants,

size and composition of particles for oxidat-

oxidative stress and human health. Mutat

ive damage and carcinogenic mechanisms.

Res; 674: 45-54.

ERS Handbook: Respiratory Medicine

351

Smoking-related diseases

Yves Martinet and Nathalie Wirth

Tobacco use is by far the single largest

avoidable cause of chronic illness and

Key points

premature death worldwide. Smokers die of

cancer of the lung and other organs as well

N Tobacco use is responsible for more

as of respiratory and cardiovascular

than one in seven of all deaths in the

diseases. In the European Union (EU),

EU.

tobacco use kills o650 000 people (more

,50% of tobacco-related deaths are

than one in seven of all deaths) each year.

due to lung cancer and COPD.

Nearly 50% of these deaths involve diseases

of the respiratory system, mainly lung cancer

N Female smoking is still on the rise in

and COPD. Given the relatively long period

some parts of the EU.

between time of smoking initiation (‘first

N Preventing tobacco use and treating

puff’) and time of onset of smoking-related

tobacco addicts should be given top

lung disease (o10 years), young people who

priority.

start smoking often disregard the future

health risks of tobacco use. Unfortunately,

while male smoking is declining in most

European countries, female smoking rates

poisons, toxic gases, small particles and

are still on the rise in some parts of the EU

carcinogens. The nicotine present in

and in most other countries of the world,

tobacco leaves is highly addictive but has

due to tobacco industry promotion.

little toxicity on the respiratory tract. Thus,

people smoke for the psychoactive effects of

Tobacco smoke

nicotine but die from the high toxicity of the

other components present in smoke. Even if

Almost all tobacco-associated lung cancer

tobacco smoke composition varies slightly

and respiratory diseases result from smoke

(due to tobacco type, substances added

inhalation. In this respect, studies have

during manufacturing and filter type), the

shown that people who only use oral tobacco

health risks and effects of tobacco smoking

during their lifetime (such as Swedish snus,

are quite constant from one cigarette brand

for example) are at no greater risk of

to another. Furthermore, previously labelled

developing these diseases than nonsmokers;

‘low-tar’ and ‘low-nicotine’ cigarettes have

however, the use of oral tobacco is related to

been shown to be as hazardous as ‘regular’

several health problems, such as gum and

ones. Likewise, hand-rolled cigarette, bidi

pancreatic cancer and, possibly,

and water-pipe smoking are at least as

cardiovascular diseases. Given that cigarette

dangerous as cigarette smoking. Finally,

smoking is by far the most common method

while pipe and cigar smoke is more toxic

of tobacco consumption, the following data

than cigarette smoke, cigar and pipe

mainly concern diseases related to active

cigarette smoking.

smokers are seldom deep inhalers.

This explains the lower incidence of

Cigarette smoke is composed of .4000

respiratory disease in these ‘noninhaling’

substances, including nicotine, chemical

smokers. However, these smokers have a

352

ERS Handbook: Respiratory Medicine

high incidence of oral cancer. Nevertheless,

proportion to the first power of smoking

their rate of respiratory disease is still higher

intensity (number of cigarettes smoked per

than in nonsmokers.

day) and, most importantly, to the second

power of smoking duration (total number of

Cannabis smoke

years of smoking). Tobacco smoking results

In respect to effects on the respiratory tract,

in all major histological types of lung cancer.

cannabis smoking is at least as dangerous

Over the years, a shift has been observed

as tobacco smoking. Moreover, since

from squamous cell lung cancer to

cannabis is usually smoked mixed with

adenocarcinoma. Lung cancer risk is similar

tobacco, young people often become

in males and females with comparable

addicted to tobacco for life, even if

smoking histories. With such a highly

occasional users merely seek to experience

specific cause and terrible prognosis, the

the relaxing effects of tetrahydrocannabinol.

best ‘treatment’ of lung cancer is to avoid it

This co-consumption of cannabis and

through tobacco smoking prevention and

tobacco complicates characterisation of the

treatment. Indeed, the relative risk of lung

specific health effects of cannabis smoking.

cancer steadily decreases when smokers

Nevertheless, it has been shown that

give up smoking. For example, in the UK, for

cannabis smoking causes lung cancer

males who stopped smoking at the ages of

and COPD.

30, 40, 50 and 60 years, the risk of lung

cancer by the age of 75 years was 2%, 3%,

Lung cancer

6% and 10%, respectively; whereas for

Lung cancer is the most frequent cause of

males who smoked up to 75 years of age,

death due to tobacco use: 85-90% of the

this cumulative risk reached 16%. In the

225 000 lung cancer deaths occurring each

same way, an increase in overall tobacco

year in the EU are the consequence of

consumption by a population is followed by

tobacco smoking. Lung cancer is one of the

an increase of lung cancer incidence, while a

deadliest cancers, with 5-year survival rates

fall in consumption is followed by a drop in

ranging from 10% to 15%. Lung cancer

lung cancer incidence, as shown for males in

incidence and mortality increase roughly in

France between 1950 and 2006 (fig. 1).

Cigarette smoking

Lung cancer death

Males

Females

Year

Figure 1. Trends in cigarette smoking and death from lung cancer by sex in France, 1950-2006.

Reproduced and modified from Hill et al. (2010) with permission from the publisher.

ERS Handbook: Respiratory Medicine

353

COPD and asthma

poorer quality of life. Finally, active cigarette

smoking is a direct cause of asthma onset,

In 2000, ,30% of the 371 000 deaths from

and causes more severe symptoms and lung

nonmalignant respiratory diseases occurring

function decline.

in the EU were caused by cigarette smoking.

Among these cases, COPD was the most

Respiratory infectious diseases

frequent cause of death. Nearly two-thirds of

Bronchial and lung infectious diseases,

these COPD deaths were caused by tobacco

including TB, acute bronchiolitis,

smoking. The COPD mortality rate is

pneumonia, the common cold and

roughly 20 times higher among heavy

influenza, are more frequent and more

smokers (male or female) than nonsmokers.

severe in smokers.

According to international guidelines for

COPD classification (American Thoracic

Interstitial lung diseases

Society, European Respiratory Society), up

Several interstitial lung diseases, namely

to 60% of current smokers aged .65 years

respiratory bronchiolitis-associated

may suffer from COPD. Measurement of

interstitial lung disease, desquamative

FEV1 and its decline is the best marker of

interstitial pneumonia and pulmonary

airflow limitation in COPD, and the FEV1

Langerhans’ cell histiocytosis, are strongly

value is directly related to COPD morbidity

associated with cigarette smoking.

and mortality. Physiological decline of FEV1

with age is accelerated by tobacco smoking,

Passive smoking

whereas, in contrast, smoking cessation

slows lung function decline in smokers

In addition to its direct harmful effects on

(fig. 2). Cessation also improves COPD

active smokers, exposure to tobacco

patient quality of life and is the only measure

combustion products from smoking is

that definitively improves COPD patient

dangerous to nonsmokers, as

survival. Asthmatic patients who smoke

environmental tobacco smoke is highly

have a higher risk of hospitalisation for their

toxic. In the EU, in 2002, an estimated

disease and experience more severe

79 449 deaths were attributable to passive

symptoms with poor clinical control and

smoking from various diseases caused by

100

Never smoker

Stopped at age 45 years

Regular smoker

Disability

Stopped at age 65 years

Death

Age years

Figure 2. Loss of FEV1 in never-smokers, regular smokers and smokers giving up at ages 45 and 65 years.

Reproduced and modified from Fletcher et al. (1977) with permission from the publisher.

354

ERS Handbook: Respiratory Medicine

100

●

Stopped smoking

●

Cigarette smokers

●

Nonsmokers

●

100

●

▲

Stopped smoking

●

▲

Cigarette smokers

●

Nonsmokers

▲

●

▲

●

100

Age years

Figure 3. Survival of male doctors who stopped smoking at ages a) 25-34 years and b) 45-54 years.

Reproduced and modified from Doll et al. (2004) with permission from the publisher.

second-hand smoking, including lung

Further reading

cancer (13 241 deaths), chronic non-

Arcavi L, et al. (2004). Cigarette smoking

neoplastic respiratory disease (5 275 deaths),

and infection. Arch Intern Med;

164:

ischaemic heart disease (32 342 deaths)

2206-2216.

and stroke (28 591 deaths).

The Aspect Consortium. Tobacco or

Health In The European Union. Past,

Furthermore, COPD, asthma and several

Present And Future. Brussels, Luxem-

infectious diseases are more severe in

bourg, Office for Offical Publications of

nonsmokers exposed to passive smoking.

the European Communities, 2004.

Doll R, et al. (2004). Mortality in relation

Conclusion

to smoking:

50 years’ observations on

Since current treatments of lung cancer and

male British doctors. BMJ;

328:

1519-

COPD are poorly efficient, it is obvious that

1528.

Flanders WD, et al. (2003). Lung cancer

preventing tobacco use through tobacco

mortality in relation to age, duration of

control and treating tobacco addiction are

smoking, and daily cigarette consump-

by far the most efficient means to prevent

tion: results from Cancer Prevention

and ‘cure’ these respiratory diseases. This

Study II. Cancer Res;

63:

6556-

conclusion is also true for most other

6562.

diseases related to cigarette smoking.

Fletcher C, et al.

(1977). The natural

Indeed, the overall impact of smoking

history of chronic airflow obstruction. Br

cessation on survival is significant for all

Med J; 1: 1645-1648.

smokers at any age, as shown in figure 3.

ERS Handbook: Respiratory Medicine

355

Foulds J, et al.

(2007). Snus

- what

Mannino DM, et al. (2006). The natural

should the public-health response be?

history of chronic obstructive pulmo-

Lancet; 369: 1976-1978.

nary disease. Eur Respir J;

27:

Hill C, et al.

(2010). Le point sur

627-643.

l’épidémie de cancer du poumon dû au

Ryu JM, et al.

(2001). Smoking-related

tabagisme [Assessment of the lung can-

interstitial lung diseases: a concise

cer epidemic due to smoking]. BEH; 19-

review. Eur Respir J; 17: 122-132.

20: 210-213.

Smoke Free Partnership. Lifting the

Maio S, et al.

(2012). The European

smokescreen:

reasons for a smoke

Respiratory Society spirometry tent: a

free

Europe. Brussels,

European

unique form of screening for airway

Respiratory

Society

Journals

Ltd,

obstruction. Eur Respir J; 39: 1458-1467.

2006.

356

ERS Handbook: Respiratory Medicine

Treatment of tobacco

dependence

Luke Clancy and Zubair Kabir

Tobacco dependence is a disease that would

smoke-free laws in many countries,

be of little consequence if it were not for the

especially within the European Union.

adverse effects of smoking. Instead it causes

However, second-hand smoke remains the

30-40% of all cancers and is the principal

most significant indoor pollutant, especially

cause of lung cancer. It is the biggest cause

in homes and motorised vehicles.

of preventable respiratory disease, even

Treating tobacco dependence is an

when lung and other respiratory cancers are

important issue for respiratory physicians.

excluded. Smoking is linked causally or as

An interest in the prevention of dependence

an important risk factor for: COPD,

through tobacco control mechanisms

emphysema, asthma, and respiratory

should also be a priority.

infections that include TB. Nevertheless, to

speak of smoking as an occupational or

Prevention

environmental disease is perhaps not

entirely accurate. However, without doubt,

As always, prevention is the primary

smoking prevalence has a strong

intervention to be considered. The

occupational bias. Exposure to second-hand

mechanisms for tobacco control are well

smoke at work is also a significant

established and have been incorporated in

occupational hazard. This situation has

the Framework Convention for Tobacco

been greatly improved by the enactment of

Control (FCTC), which is the first medical

treaty from the World Health Organization

(WHO) that has been ratified by 176

countries and the European Community

Key points

(EC). The WHO has also proposed a

strategy, MPOWER as defined in table 1, for

N Tobacco dependence is a disease and

the implementation and monitoring of these

is an important issue for respiratory

mechanisms. It is clearly stated in the FCTC

physicians.

that price is the most effective tobacco

The prevention of tobacco

control measure but that interventions, such

dependence through tobacco control

as workplace restrictions on smoking and

mechanisms is a priority.

the protection from exposure and product

regulation by various means, are also

N Effective and cost-effective treatments

important. Such tobacco control policies

for tobacco dependence exist in the

were recently modelled to tease out

form of motivational support and

individual effects on current and future

pharmacotherapy.

trends in tobacco consumption rates and

The treatment of tobacco dependence

lung cancer death rates, employing

benefits from knowledge, experience

previously validated simulation models, e.g.

and training, which is not provided in

SimSmoke models. It is also agreed that full

medical schools at the undergraduate

information, concerning the dangers of

level, and should be made a priority.

smoking, need to be made common

knowledge through sustained, mass-media

ERS Handbook: Respiratory Medicine

357

campaigns. The value of health warnings,

One-third of the world’s population smokes.

especially graphical images, is emphasised

If this disease is to be tackled by treating all

and there is a realisation that packaging and

smokers, the implications are daunting;

labelling are important methods of

treatment alone will probably never become

advertising for the tobacco industry. This is

the appropriate response to this epidemic,

especially so in countries where direct

unless much improved and cheaper

advertising, promotion and sponsorship are

treatments can be developed to make this

banned. A step further would be to have

possible in the future. A recent controlled

plain packaging. However the role of

trial demonstrated the efficacy of a low-

treating smoking in the plan, although

priced product, namely, cytosine in smoking

cessation. At present treatment has a

regarded as important, is left unclear. The

defined role. Its importance in tobacco

reasons for this are many and include

control will vary from time to time and from

considerations of availability, cost, efficacy

country to country depending on the stage

and efficiency. This is not surprising, but it

of implementation of other tobacco control

is challenging. Even more challenging is the

policies. Our first responsibility as doctors is

fact that the cost for other evidence-based

probably to know what treatments exist,

interventions in the pursuit of tobacco

then to examine the evidence base for their

control are usually much less than those for

usefulness and consider how they could be

treatment. However, tobacco-dependency

made available to our patients. To achieve

treatment is much more cost-effective than

such standards, training of health

other chronic conditions, such as

professionals in the treatment of tobacco

hypercholesterolaemia or hypertension, in

dependence is crucial.

terms of quality-adjusted life years (QALYs).

Effective treatments are available, are very

Evidence-based treatments

cost-effective and compare favourably with

treatment of other diseases in this regard.

Effective and cost-effective treatments for

Despite this, interest in supplying this

tobacco dependence exist. The two

service seems low among policymakers.

treatment modalities proven to be effective

Smoking was, and to some extent still is, not

consist of motivational support, in the form

accepted as a disease by many people. This

of counselling, and pharmacotherapy.

is, in no small part, due to the tobacco

Present knowledge suggests that a

industry. For generations, it denied that

combination of the two is more effective

smoking was harmful and addictive and

than either alone. The duration of

emphasised the argument for free choice

counselling seems to be important. Within

and the apparent glamour of smoking. It is

limits, longer seems better - for instance,

now becoming widely accepted that

brief intervention by a general practitioner of

some 3 min increases success rates by

smoking is a disease and that it is based on

,2.5% when compared with those who did

addiction. It is very difficult to treat, but the

not receive such advice. Sessions lasting

rewards for treating it successfully are

,10 min and repeated three to four times at

enormous.

intervals, according to present knowledge,

seem to be near the optimal; however, these

considerations need to be further defined

Table 1. Definition for MPOWER

along with their application.

Monitor tobacco use

Protect people from tobacco use

As regards pharmacological therapies, a

number of preparations have been shown to

Offer help to quit tobacco use

have measurable success rates. These

Warn about the damages of tobacco

include nicotine replacement therapy (NRT),

Enforce bans on tobacco advertising,

which approximately the doubles success

promotion and sponsorship

rate. Varenicline and buproprion also have

Raise taxes on tobacco products

established success rates. Varenicline

seems to be more effective than NRT, while

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ERS Handbook: Respiratory Medicine

buproprion success rate is similar to that of

outlines the importance of different stages

NRT. The use of these preparations and

of motivation before finally quitting

their safety profiles need to be studied

smoking.

carefully. They provide the clinician with

In addition, evidence suggests that attempts

pharmacotherapy, which has proven efficacy

to quit are more frequent in subjects with

and should be used knowledgably by

high baseline BMI and low weight concerns.

physicians. Tønnesen et al. (2007) recently

Innovative approaches, such as brief

reviewed the evidence for smoking

isometric exercise and the cognitive

cessation, concluding that with the most

technique of body scanning, may be

optimal drugs and counselling a 1-year

effective for reducing the desire to smoke

abstinence rate of ,25% can be expected for

and withdrawal symptoms in temporarily

smoking cessation. This compares very

abstaining smokers. The importance of

favourably with the treatment of any other

targeting specific groups, such as pregnant

chronic relapsing disease. Caponnetta et al.

women and mentally ill patients, also lack

(2008) recently outlined the predictors of

adequate evidence in support of what works

success and failure in treatment. Factors

and what does not work in treating tobacco

which influence outcomes include: degree of

dependence.

nicotine dependence; age at initiation; how

many cigarettes are smoked per day; social

Conclusion

support; and family circumstances, such as

a nonsmoking partner, sex and

The treatment of tobacco dependence

comorbidities, e.g. alcoholism and

benefits from the knowledge, experience and

depression. They also point out the complex

training of clinicians. This is not provided in

relationship with previous attempts and of

medical schools at the undergraduate level.

course the importance of motivation to quit.

We expect that the structure of training for

The motivational chart in figure 1 clearly

the management of this disease, and

Abstain

Pre-contemplation

Relapse

Quit

Ready to quit

Contemplation

Preparation

Figure 1. The different stages involved in the process of quitting smoking. Information from DiClemente et

al. (1991).

ERS Handbook: Respiratory Medicine

359

particularly its treatment, will improve and

Raw M, et al. (2009). A survey of tobacco

increase in the short term. Knowledge of

dependence treatment guidelines in

general tobacco control principles also need

countries. Addiction; 104: 1243-1250.

to be addressed if we are to succeed in this

Rigotti NA, et al. (2008). Smoking cessa-

important endeavour.

tion interventions for hospitalized smo-

kers: a systematic review. Arch Intern

Further reading

Med; 168: 1950-1960.

Tønnesen P, et al.

(2007). Smoking

Caponnetto P, et al.

(2008). Smoking

cessation in patients with respiratory

cessation: tips for improving success

diseases: a high priority, integral compo-

rates. Breathe; 5: 16-24.

nent of therapy. Eur Respir J; 29: 390-417.

Currie LM, et al.

(2012). The effect of

US Department of Health and Human

tobacco control policies on smoking pre-

Services. The Health Consequences of

valence and smoking-attributable deaths

Involuntary Exposure to Tobacco Smoke:

in Ireland using the IrelandSS simulation

A Report of the Surgeon General. Atlanta,

model. Tob Control [In press DOI: 10.1136/

GA: US Department of Health and

tobaccocontrol-2011-050248].

Human Services, Centers for Disease

Cromwell J, et al. (1997). Cost-effective-

Control and Prevention, Coordinating

ness of the clinical practice recommenda-

Center for Health Promotion, National

tions in the AHCPR guideline for smoking

Center for Chronic Disease Prevention

cessation. JAMA; 278: 1759-1766.

and Health Promotion, Office on

DiClemente CC, et al. (1991). The process

Smoking and Health, 2006.

of smoking cessation: an analysis of

Ussher M, et al.

(2009). Effect of

precontemplation, contemplation, and

isometric exercise and body scanning on

preparation stages of change. J Consult

cigarette cravings and withdrawal symp-

Clin Psychol; 59: 295-304.

toms. Addiction; 104: 1251-1257.

Fagerström KO, et al.

(2008).

West R, et al. (2011). Placebo-controlled

Pharmacological treatments for tobacco

trial of cytosine for smoking cessation.

dependence. Eur Respir Rev; 17: 192-198.

N Engl J Med; 365: 1193-2000.

Goodman P, et al. (2007). Effects of the

World Health Organization. WHO Report

Irish smoking ban on respiratory health of

on the Global Tobacco Epidemic, 2009:

bar workers and air quality in Dublin pubs.

Implementing smoke-free environments.

Am J Respir Crit Care Med; 175: 840-845.

Available from: www.who.int/tobacco/

Kabir Z, et al. (2011). Attitudes, training and

mpower/2009/en/ Date last accessed:

smoking profiles of European Respiratory

July 07, 2012; Date last updated July 7,

Society members. Eur Respir J; 38: 225-227.

2012.

360

ERS Handbook: Respiratory Medicine

High-altitude disease

Yvonne Nussbaumer-Ochsner and Konrad E. Bloch

Physiological response to altitude

altitudes .1600 m, mostly during sleep. It

may cause intermittent dyspnoea and sleep

The low barometric pressure at altitude

disturbances (figs 1 and 2).

results in a reduced inspiratory oxygen

tension and PaO₂. The immediate

Prolonged altitude exposure triggers various

acclimatisation mechanisms including an

physiological response comprises a rise in

increased chemoreceptor sensitivity to

heart rate and pulmonary arterial pressure.

hypoxia and hypercapnia, enhanced

Chemoreceptor-mediated hyperventilation

erythropoesis, and alterations in the

tends to mitigate hypoxaemia but the

endocrine system, metabolism and in fluid

associated hypocapnia, with PaCO₂ close to

balance.

the apnoeic threshold, promotes ventilatory

instability with periods of hyperpnoea

The reduced air density at altitude lowers

alternating with central apnoea/hypopnoea.

airflow resistance. Vital capacity is slightly

This pattern, termed high-altitude periodic

reduced due to respiratory muscle weakness

breathing, is observed in healthy subjects at

and pulmonary congestion. Oxygen uptake

through the lungs is affected by a reduced

alveolar-capillary oxygen gradient and a

Key points

reduced transit time of blood through

pulmonary capillaries due to increased

N A low barometric pressure at altitude

cardiac output. This causes diffusion

results in reduced inspired oxygen

limitation leading to hypoxaemia especially

tension and PaO₂.

during exercise.

N Hypoxaemia triggers adaptive

High-altitude-related disease

physiological repsonses termed

In table 1, different forms of acute and

acclimatisation.

chronic altitude-related illness are

Respiratory acclimatisation includes

summarised. Acute mountain sickness

hyperventilation and periodic

(AMS) is the most common altitude-related

breathing, which typically prevails

illness. It affects 10-40% of lowlanders

during sleep.

rapidly ascending to 3000 m and 40-60%

at 4500 m. A lack of prior acclimatisation,

N AMS, HACE and HAPE may affect

rapid ascent, high sleeping altitude and

travellers after rapid ascent to

individual susceptibility predispose to AMS.

altitude. Chronic mountain sickness

Symptoms start within 6-12 h after arrival at

occurs in long-term residents of high

altitude and include headache, loss of

mountain areas.

appetite, nausea or vomiting, weakness,

Treatment of high-altitude related

fatigue and insomnia. The diagnosis relies on

illness consists of descent,

the constellation of typical symptoms in the

supplemental oxygen and, if

setting of altitude exposure. Different scores

necessary, drugs.

(e.g. the Lake Louise Score) help to establish

the diagnosis and to grade AMS severity.

ERS Handbook: Respiratory Medicine

361

PaCO₂

PaO₂

Arousal

Hypoxia

Hyperventilation

Central apnoea

Hyperpnoea

PaCO₂

PaO₂

Figure 1. Mechanisms of high-altitude periodic breathing.

If additional neurological signs such as

alveolar fluid clearance. HAPE is rare below

ataxia, cognitive deficits and impaired

3500 m but occurs in 2-4% of

vigilance develop, a potentially life-

mountaineers within hours to 4 days after

threatening high-altitude cerebral oedema

arrival at 4500 m. It is promoted by rapid

(HACE) must be considered. Treatments of

ascent, physical exertion and individual

AMS include descent to lower altitude,

susceptibility. Manifestations of HAPE

analgesics for headache and acetazolamide.

include excessive dyspnoea, dry cough,

More severe forms of AMS and HACE require

tachycardia, cyanosis, pulmonary crackles

dexamethasone and oxygen if available.

and low-grade fever. Chest radiography

Inflatable hyperbaric bags simulating descent

shows interstitial or alveolar opacities but a

to 1500-2500 m are also used.

normal-sized heart. Descent, supplemental

oxygen or both are nearly always successful

High-altitude pulmonary oedema (HAPE) is

in HAPE. If oxygen is not available or

a noncardiogenic and noninflammatory

descent not possible, pharmaceuticals

oedema resulting from excessive elevation

become necessary (table 2). Pulmonary

of pulmonary capillary pressure, uneven

vasodilators such as nifedipine or

distribution of blood flow and impaired

phosphodiesterase inhibitors (sildenafil)

Sum

Rib cage

Abdomen

140

Heart rate

beats·min^-1

Oxygen

saturation %

Figure 2. Periodic breathing associated with oscillations in oxygen saturation and heart rate recorded in a

28-year-old female resting after a climb at 6850 m. Reproduced and modified from Bloch et al. (2010)

with permission from the publisher.

362

ERS Handbook: Respiratory Medicine

Table 1. Altitude-related illnesses

Condition

Time of exposure

Main manifestations and diagnostic criteria

AMS

Hours to days

Headache

Loss of appetite

Insomnia

Fatigue

HACE

Hours to days

Severe headache

Ataxia

Confusion

Loss of consciousness

HAPE

Days

Dyspnoea

Cough

Cyanosis

Exercise intolerance

Pulmonary hypertension

HAPH, cardiac chronic

Years

Dyspnoea

mountain sickness

Exercise intolerance

Right heart failure

mPpa .30 mmHg or sPpa .50 mmHg at

altitude of residence

Absence of excessive erythrocytosis^#

CMS, Monge’s disease

Years

Headache

Dizziness

Dyspnoea

Sleep disturbances

Fatigue

Excessive erythrocytosis^#

Pulmonary hypertension^"

Right heart failure^"

Hypoventilation^"

Subacute mountain sickness,

Weeks to months

Dyspnoea

or adult and infantile

Exercise intolerance

forms of CSMS

Pulmonary hypertension

Right heart failure

HAPH: high-altitude pulmonary hypertension; mPpa: mean pulmonary artery pressure; sPpa: systolic

pulmonary artery pressure; CMS: chronic mountain sickness; CSMS: cardiac subacute mountain sickness.

^#: excessive erythrocytosis is defined as haemoglobin concentration o19g?dL^-1 in females and o21 g?dL^-1 in

males;

^": in some patients.

lower pulmonary artery pressure. If descent

pulmonary hypertension. Affected people

is impossible and oxygen unavailable, a

suffer from fatigue, dizziness, headache

hyperbaric bag may be lifesaving.

and confusion. Descent to low altitude

leads to prompt relief. High-altitude

Table 2 summarises prevention and

pulmonary hypertension is another

treatment of altitude related diseases.

condition affecting long-term residents at

Chronic mountain sickness, a condition

altitude .2500 m. It causes dyspnoea,

observed in long-term high-altitude

exercise intolerance and signs of right heart

residents, is characterised by severe

failure with oedema but erythrocytosis is

hypoxaemia, excessive erythrocytosis and

not a feature.

ERS Handbook: Respiratory Medicine

363

Table 2. Prevention and treatment of high-altitude disease

Disease

Prevention

Treatment

AMS

Acclimatisation

Analgesics

Slow ascent

Antiemetics

Acetazolamide 26125-

Acetazolamide 26250 mg?day^-1

250 mg?day^-1 starting 24 h

More severe forms: descent; oxygen 2-6 L?min^-1;

before ascent or

dexamethasone (initially 8 mg i.v., then

dexamethasone 264 mg?day^-1

464 mg?day^-1 p.o.); acetazolamide

starting 24 h before ascent

(26250 mg?day^-1), eventually in combination

with dexamethasone; portable hyperbaric

chamber

HACE

As for AMS

Immediate descent

If not possible: oxygen (2-6 L?min^-1), portable

hyperbaric chamber, dexamethasone (initially

8 mg i.v., then 464 mg?day^-1 p.o.), check for

accompanying HAPE, acetazolamide if

descent delayed

HAPE

Acclimatisation

Immediate descent

Slow accent

If not possible: oxygen 2-6 L?min^-1 until oxygen

Avoid overexertion

saturation .90% or hyperbaric chamber,

Nifedipine 30-60 mg?day^-1

nifedipine 10-20 mg initially, switch to an

(extended-release

extended-release formulation (nifedipine 30/

formulation)

60 mg) depending on blood pressure, treat

accompanying AMS by dexamethasone

Patients with lung disease at altitude

hyperventilation. Asthma patients with

controlled disease are advised to take their

Little is known about the risks of altitude

usual medications when travelling to

exposure in patients with pre-existing lung

altitude, to avoid strenuous exercise in a

disease. Recommendations are largely

cold environment and to treat any

based on anecdotal evidence.

exacerbation appropriately. Patients with

uncontrolled, severe asthma should be

Chronic obstructive pulmonary disease In

cautioned against travelling to altitude.

patients with impaired gas exchange, PaO₂

may drop to low levels at altitude so the use

Obstructive sleep apnoea syndrome Untreated

of supplemental oxygen should be

OSAS patients residing at sea level and

considered. It is reasonable that patients

travelling to moderate altitude (.1600 m)

with severe disease (FEV1 ,50% predicted)

experience an exacerbation of sleep apnoea

with SaO₂ ,95% at low altitude should have

with pronounced hypoxaemia and frequent

an individual assessment before travelling to

central events. Sleep quality is worse at

altitude. Acetazolamide should be used with

altitude and daytime testing shows impaired

caution in patients with severe airflow

vigilance and elevated blood pressure.

obstruction, as the metabolic acidosis

Combined treatment with CPAP and

induced by the drug may further stimulate

ventilation thereby worsening dyspnoea and

acetazolamide is advisable.

promoting respiratory failure.

Pulmonary hypertension In general, patients

Asthma A reduced allergen burden with

with more than mild pre-existing pulmonary

increasing altitude can be expected at

hypertension should be counselled against

.1500 m. Conversely, inhalation of cold air

high-altitude travel because pre-existing

may worsen asthma, especially in combin-

pulmonary hypertension may predispose to

ation with exercise or hypoxia-induced

HAPE. In patients not on medical therapy,

364

ERS Handbook: Respiratory Medicine

prophylaxis with nifedipine and

Latshang TD, et al.

(2012). Effect of

supplemental oxygen should be considered.

acetazolamide and autoCPAP therapy on

breathing disturbances among patients

Conclusions

with obstructive sleep apnea syndrome

who travel to altitude. A randomized

Physiological adaptation allows humans to

controlled trial. JAMA; 308: 2390-2398.

tolerate exposure to even very high altitudes.

Luks AM, et al. (2007). Travel to high

Rapid ascent, inappropriate time for

altitude with pre-existing lung disease.

acclimatisation, strenuous physical exertion

Eur Respir J; 29: 770-792.

and individual susceptibility predispose to

Maggiorini M

(2010). Prevention and

high-altitude-related illnesses, which may be

treatment of

high-altitude pulmonary

prevented with appropriate precautions.

edema. Prog Cardiovasc Dis; 52: 500-506.

Nussbaumer-Ochsner Y, et al.

(2010).

Exacerbation of sleep apnoea by frequent

Further reading

central events in patients with the obstruc-

tive sleep apnoea syndrome at altitude: a

Basnyat B, et al.

(2003). High-altitude

randomised trial. Thorax; 65: 429-435.

illness. Lancet; 361: 1967-1974.

Nussbaumer-Ochsner Y, et al.

(2007).

Bloch KE, et al. (2010). Nocturnal peri-

Lessons from high-altitude physiology.

odic breathing during acclimatization at

Breathe; 4: 123-132.

very high altitude at Mt. Muztagh Ata

Nussbaumer-Ochsner Y, et al. Air travel and

(7546m). Am J Respir Crit Care Med; 182:

altitude. In: Ayres JG, et al., eds. Environmental

562-568.

Medicine. London, Hodder Arnold, 201.

Imray C, et al. (2010). Acute mountain

Nussbaumer-Ochsner Y, et al.

(2012).

sickness: pathophysiology, prevention,

Effect of short-term acclimatization to

and treatment. Prog Cardiovasc Dis; 52:

high altitude on sleep and nocturnal

467-484.

breathing. Sleep; 35: 419-423.

ERS Handbook: Respiratory Medicine

365

Diving-related diseases

Einar Thorsen

There are three main groups at risk of

gas breathed. Airway resistance is

diving-related diseases:

proportional to gas density and maximal

expiratory flow rates are inversely

N Professional divers are engaged in

proportional to the square root of gas

underwater construction and inspection,

density. This means that at a depth of 30 m,

and compressed air workers (caisson

when relative gas density is four times that

workers) work at increased ambient

of air at atmospheric pressure, maximal

pressure in a dry environment, mostly in

expiratory flow rates and maximal voluntary

tunnel construction

ventilation are reduced by 50%. Most

N Military forces, police and fire brigades

experimental data are close to this

have teams of divers for specialised

theoretical relationship, as illustrated in

underwater operations

figure 1.

N Recreational divers make up by far the

largest group of divers

When diving to depths .50 m, the gas

breathed is often a mixture of helium and

The physical environment in which these

oxygen to compensate for the mechanical

divers are operating is different, but

limitations of ventilatory capacity due to gas

common to all groups is exposure to

density. The partial pressure of oxygen in

increased ambient pressure and the

exposure factors associated with pressure.

these gas mixtures is usually 30-50 kPa,

corresponding to an oxygen fraction of 2-5%

Pulmonary limitations at depth

at depths of o100 m.

Gas density increases proportionately with

Physical work under water is demanding. It

ambient pressure when air is used as the

requires evaluation of normal ventilatory

capacity and physical work capacity by

Key points

exercise testing. External resistance and

static load related to breathing apparatus

N Normal lung function and physical

and submersion adds to the increased load

work capacity are required for

imposed by gas density. The gas breathed at

underwater work.

depth has to be dry to prevent icing in the

pressure regulators and evaporative heat

N Normal lung function is required to

loss is high. The gas breathed has the

reduce the risk of pulmonary

temperature of the ambient water and,

barotrauma.

because of increased gas density, convective

N Cumulative diving exposure is

heat loss is increased. Subjects with

associated with a long-term reduction

bronchial hyperreactivity may be at

in lung function of an obstructive

increased risk of bronchoconstriction at

pattern, which at some time in the

depth. There are, however, no definite

diver’s career may preclude further

studies confirming this risk, as subjects with

diving.

asthma traditionally have been excluded

from diving.

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ERS Handbook: Respiratory Medicine

oxygen .40 kPa has well known toxic effects

on the lung, causing acute reductions in

diffusion capacity, vital capacity and

maximal expiratory flow rates. The

decompression stress is related to the

amount of inert gas dissolved in the tissues

during the deepest phase of the dive and the

rate of decompression. Supersaturation

resulting in formation of venous gas bubbles

has been demonstrated when the tension of

inert gas in the tissues exceeds ambient

pressure by ,30 kPa. Venous gas

microemboli have been shown to be

Gas density relative to air

common with the decompression

procedures routinely used in commercial

Figure 1. The theoretical relationship between gas

and military diving operations.

density and FEV1 and some experimental data.

The relative gas density of air at atmospheric

The venous gas microemboli are filtered in

pressure is 1.

the pulmonary circulation and are

associated with inflammatory responses

Pulmonary barotrauma

that add to the toxic effects of hyperoxia.

Venous gas microemboli may be shunted

Intra-alveolar gas volume will expand during

over to the systemic circulation through

decompression. If there is any obstruction

intrapulmonary and intracardiac shunts. A

to the free flow of gas out of the alveoli or a

patent foramen ovale is present in 20-30%

decrease in lung compliance, there will be

of the general population. Local circulatory

an increase in intra-alveolar pressure,

disturbances due to gas bubbles that are

imposing a risk of lung rupture or

either formed in situ or transported by the

pulmonary barotrauma. Any processes in

systemic circulation to other areas like

the lung associated with airway obstruction

joints, skin, brain and spinal cord may cause

or decreased compliance locally or generally

decompression sickness.

are considered to increase the risk. Lung

rupture may cause pneumothorax,

The combination of added static and

pneumopericardium, mediastinal

dynamic respiratory load, immersion and

emphysema and, most seriously, arterial gas

exercise results in a large increase in

embolism, which may be fatal. A

pulmonary arterial pressure. Undue

pneumothorax or pneumopericardium

breathlessness after diving, or even

encountered at depth may be fatal because

swimming only, may be related to

of an increase in the transpulmonary

pulmonary oedema.

pressure difference during decompression

Long-term effects of diving

that obstructs venous return. The lowest

pressure drop associated with diving

The exposure to hyperoxia and the

causing pulmonary barotrauma described in

accumulation of gas microemboli in the lung

the literature was ,20 kPa (200 cmH₂O).

are associated with inflammatory responses.

The volume expansion for a given pressure

Several cross-sectional studies of divers’ lung

reduction is larger close to the surface

function indicate that residual effects of single

(Boyle-Mariotte’s law).

dives accumulate to a long-term effect

Pulmonary effects of a single dive

characterised by an obstructive spirometric

pattern and a reduction in diffusion capacity.

A dive is associated with exposure to

There are only a few longitudinal studies of

hyperoxia and a decompression stress, and

divers’ lung function, but these studies confirm

both are related to ambient pressure and

the findings in the cross-sectional studies by

time. Hyperoxia at partial pressures of

demonstrating a negative relationship between

ERS Handbook: Respiratory Medicine

367

cumulative diving exposure and maximal

Hyperbaric oxygen therapy, most commonly

expiratory flow rates and FEV1.

given for 90 min daily at a pressure of

240 kPa for 20-30 days, may be beneficial

Treatment of diving related disease and

for late side-effects of radiation therapy for

hyperbaric oxygen therapy

cancer, chronic ischaemic ulcers and

chronic osteomyelitis. The oxygen dose is

Arterial gas embolism and decompression

lower than for treatment of decompression

sickness, which are caused by free gas in the

sickness but there may be a cumulative

tissues, should be treated promptly with

oxygen toxicity effect. These patients’ lung

recompression and hyperbaric oxygen. The

function should always be evaluated, as lung

rationale is to reduce bubble radius by

disease may pose a risk for arterial gas

increasing ambient pressure and to facilitate

embolism in these patients. Pulmonary

diffusion of inert gas out of the bubbles by

radiation injury is a contraindication to

increasing oxygen tension. The US Navy

hyperbaric oxygen therapy.

Treatment Tables are the most commonly

used reference. Normobaric oxygen therapy

by tight fitting an oronasal mask should

always be started immediately and be given

Further reading

during transport to a hyperbaric treatment

Brubakk AO, et al., eds. Bennett and

facility. Restoration of fluid balance is

Elliott’s Physiology and Medicine of

important while other supportive therapy is

Diving. Edinburgh, Saunders, Elsevier

questionable.

Science Ltd, 2003.

Lundgren CEG, et al., eds. The Lung at

The oxygen exposure during treatment is

Depth. New York, Marcel Dekker Inc.,

relatively large and oxygen toxicity with an

1999.

acute reduction in vital capacity of 10% is

Tetzlaff K, et al.

(2005). Breathing at

acceptable. This is because neurological

depth: physiologic and clinical aspects of

deficits are the most common manifestations

diving while breathing compressed gas.

of decompression sickness and the reduction

Clin Chest Med; 26: 355-380.

in vital capacity is largely reversible.

368

ERS Handbook: Respiratory Medicine

Radiation-induced lung

disease

Robert P. Coppes and Peter van Luijk

Radiotherapy plays an important role in the

radiation pneumonitis. Acute alveolar and

treatment of tumours located in the thoracic

interstitial inflammation and loss of type I

area. The cure rate for these tumours is,

epithelial cells induce proliferation of type II

however, limited by the low radiation dose

epithelial cells. This leads to a cascade of

that can be tolerated by the lungs. The

induction of inflammatory cytokines (fig. 1),

presently set dose (e.g. mean dose ,20 Gy)

potentially aggravated by chemotherapeutic

already results in pulmonary complications

agents. Subsequently, an influx of

in about one-fifth of patients.

inflammatory cells, such as leukocytes,

lymphocytes, neutrophils and macrophages,

The primary insults after radiation of the lungs

is induced. Though macrophages are a

seem to be vascular remodelling and an early

hallmark, T-lymphocytes and mature

inflammatory response termed radiation

dendritic cells also play an important role in

pneumonitis. These are followed by a late

radiation pneumonitis.

fibroproductive phase (fig. 1). All these

pathologies may lead to compromised lung

Radiation-induced lung disease is a

perfusion, increased vascular resistance,

consequence of:

reduced gas-exchange interphase between the

N loss of endothelial and type I epithelial

air and blood, and suboptimal blood

cells

oxygenation. Symptoms range from dyspnoea

N malfunction of microvasculature

on effort to respiratory failure, oxygen

N inflammatory responses

dependency, right heart failure and death.

lung fibrosis

Almost immediately after irradiation, loss of

Increased vascular permeability with protein

endothelial cells causes vascular oedema

exudation contributes to the development of

and remodelling. This leads to pulmonary

radiation pneumonitis. Depending on the

hypertension and right ventricle

irradiated region and volume, the damaged

hypertrophy. Next to this, several

pulmonary blood vessels (low dose and

inflammatory responses contribute to

large volumes) or inflammatory

parenchymal damage (high dose and low

Key points

volumes) affect lung function to induce

complications.

N Radiotherapy for tumour treatment

Following or even without prior

results in pulmonary complications in

symptomatic pneumonitis, chronic

about 20% of patients.

radiation-induced pulmonary fibrosis may

Radiation-induced lung injury involves

develop depending on the irradiated lung

vascular damage leading to

volume. Radiation fibrosis is caused by

pulmonary hypertension and develops

accumulation of collagen and other

from an early, inflammatory phase to

extracellular matrix fibres in the interstitium

a late fibrotic phase.

under persistent cytokine stimuli in

combination with arteriocapillary sclerosis.

ERS Handbook: Respiratory Medicine

369

Pneumonitis

Fibrosis

Pulmonary artery pressure

Time after irradiation weeks

Figure 1. Radiation-induced lung injury develops in an early vascular damage and inflammation phase,

and a late fibrotic phase.

It should be noted that there are other

Johnston CJ, et al. (2004). Inflammatory

causes of occupational-induced radiation

cell recruitment following thoracic irradia-

lung disease, for example, resulting from

tion. Exp Lung Res; 30: 369-382.

nuclear accidents, and radon and uranium

Marks LB, et al.

(2003). Radiation-

exposure (see Further Reading).

induced lung injury. Semin Radiat Oncol;

13: 333-345.

McBride WH, et al. (2004). A sense of

Further reading

danger from radiation. Radiat Res; 162: 1-19.

Medhora M, et al.

(2012). Radiation

Abu-Qare AW, et al.

(2002). Depleted

damage to the lung: mitigation by

uranium - the growing concern. J Appl

angiotensin-converting enzyme

(ACE)

Toxicol; 22: 149-152.

inhibitors. Respirology; 17: 66-71.

Al-Zoughool M, et al.

(2009). Health

Novakova-Jiresova A, et al.

(2007).

effects of radon: a review of the literature.

Changes in expression of injury after

Int J Radiat Biol; 85: 57-69.

irradiation of increasing volumes in rat

Ghobadi G, et al. (2012). Lung irradiation

lung. Int J Radiat Oncol Biol Phys;

67:

induces pulmonary vascular remodelling

1510-1518.

resembling pulmonary arterial hyperten-

Rodemann HP, et al.

(1995). Cellular

sion. Thorax; 67: 334-341.

basis of radiation-induced fibrosis.

Göransson Nyberg A, et al. (2011). Mass

Radiother Oncol; 35: 83-90.

casualties and health care following the

Rübe CE, et al. (2004). Increased expres-

release of toxic chemicals or radioactive

sion of pro-inflammatory cytokines as a

material - contribution of modern bio-

cause of lung toxicity after combined

technology. Int J Environ Res Public

treatment with gemcitabine and thoracic

Health; 8: 4521-4549.

irradiation. Radiother Oncol; 72: 231-241.

370

ERS Handbook: Respiratory Medicine

HRCT in the diagnosis of

interstitial lung disease

Giovanni Della Casa, Stefania Cerri, Paolo Spagnolo, Pietro Torricelli and

Luca Richeldi

The term interstitial lung disease (ILD)

diagnostic test for ILD; instead, a

refers to a heterogeneous group of .200

multidisciplinary approach, with integration

different entities. Because the clinical

of radiological, pathologic and clinical data,

presentation of most of them is similar

is considered the optimal approach.

(mostly, exertional dyspnoea and dry

Anatomy of the lung interstitium

cough) chest HRCT, a CT technique

optimised for high spatial resolution, plays

Understanding of HRCT patterns of ILD

a key role in the assessment of patients who

requires knowledge of the anatomy of the

are known to have, or are suspected of

normal lung. In the high-contrast

having, diffuse lung disease. The study of

environment of the lung, the resolution of

the HRCT appearance and distribution

HRCT is 0.2-0.3 mm. According to Weibel’s

patterns allows a specific diagnosis to be

concept, the interstitium represents the

made in many cases or, at least, is helpful

supporting framework of the lung and is

in narrowing the differential diagnosis. For

composed of connective tissue fibres that

this reason, HRCT has become the imaging

can be divided into two separate, but

modality of choice in ILD. The importance

connected, compartments:

of HRCT is further underlined by the fact

that there is no single gold-standard

the central (or axial) compartment that

surrounds the bronchovascular

bundles, as they emerge from the

Key points

pulmonary hila and extend peripherally

to the level of respiratory bronchioles

N Interstitial lung diseases are a

the peripheral (or septal) interstitium

heterogeneous group of entities

that includes the interlobular septa and

with similar clinical presentations.

the subpleural interstitium

N A pattern-based approach to HRCT

These two compartments are connected to

can help to discriminate between

each other by a fine network of septal

diseases with similar presentations,

connective tissue fibres (the intralobular

making a specific diagnosis in many

interstitium).

cases or, at least, narrowing the

differential diagnosis.

Interlobular septa can occasionally be visible

on HRCT of the normal lung, especially in

N In controversial cases, surgical

the periphery of the anterior, lateral,

biopsy might be necessary and a

juxtamediastinal regions of the upper and

multidisciplinary approach

middle lobes, and in the periphery of the

(integrating clinical presentation

anterior and diaphragmatic regions of the

and laboratory data, chest imaging,

lower zones.

and lung pathology) is considered

the best approach to formulate a

The smallest anatomical unit of the lung

confident diagnosis.

visible on HRCT is the secondary pulmonary

lobule (Miller’s lobule), which is the

ERS Handbook: Respiratory Medicine

371

smallest area of lung parenchyma

a NSIP may proceed from minimal changes

surrounded by connective tissue septa.

to end-stage lung). Moreover, the same

Secondary pulmonary lobules are irregular

pattern may be present in several

polyhedral structures measuring 1.0-2.5 cm

diseases (e.g. collagen vascular disorders).

in diameter, containing roughly three to five

This is intuitive, as the lung can respond to

acini and 30-50 primary lobules.

injury in a limited and predictable mode, so

Interlobular septa extend perpendicularly

that many different diseases may lead to

from the peripheral interstitium and

similar alterations in pulmonary anatomy,

penetrate the lung to form the boundaries of

resulting in overlapping imaging findings.

each secondary lobule. Secondary lobules

These aspects underscore the need for a

are clearly demarcated in the periphery of

multidisciplinary approach (clinical

the lung where interlobular septa are thicker,

presentation and laboratory data, chest

but are poorly demarcated centrally where

imaging, and lung pathology) to formulate

interlobular septa are thinner and less well

a confident diagnosis. Nowadays, the

defined. Each lobule is supplied at its centre

importance of this approach is widely

by a bronchiole and pulmonary artery.

recognised.

Normal lung structures visible on HRCT are

Lung parenchymal abnormalities can be

bronchi (down to eight generations),

grossly divided into those with increased or

pulmonary arteries, pulmonary veins,

decreased attenuation (table 1). As a general

interlobular septa and the visceral pleura

rule, lung volumes are increased by

(double layer as lobar fissures). Under normal

processes that produce decreased

conditions, structures such as lymphatic

attenuation (e.g. air trapping and

vessels, alveoli/acini, capillary vessels and

emphysema) and decreased by processes

visceral pleura (non-fissural surface) are not

that produce reticulation and

visible on HRCT. The centrilobular artery

honeycombing.

(1 mm in diameter) and the intralobular

Increased attenuation

acinar arteries (0.5 mm in diameter) are

identifiable, whereas normal bronchioles

Reticular pattern has several morphological

supplying a secondary lobule (1 mm in

variations, ranging from generalised

diameter), with a wall thickness of ,0.15 mm,

thickening of the interlobular septa to

are beyond the resolution of HRCT.

honeycomb lung. The thickening of

interlobular and intralobular septa, thus

Approach to HRCT

creating a net-like pattern, can generate this.

In ILD, the identification of basic HRCT

On HRCT, this pattern is most frequently

patterns plays a critical role at the

seen in the periphery extending from and

beginning of the diagnostic assessment. In

perpendicular to the pleura. Septa can be

fact, the pattern and distribution of the

classified as:

HRCT lung appearance may suggest a

specific diagnosis and can help to

N smooth, where all interstitial

discriminate among diseases with similar

compartments are thickened with a

morphology. The same disease may present

smooth profile (e.g. pulmonary

with different HRCT patterns. This may

hydrostatic oedema, lymphangitic

result from its variable pathological

carcinomatosis, pulmonary haemorrhage,

expression (e.g. progressive systemic

pulmonary alveolar proteinosis,

sclerosis with lung involvement may

amyloidosis and a number of rarer

present with a usual interstitial pneumonia

conditions)

(UIP), nonspecific interstitial pneumonia

N irregular (e.g. fibrosis, lymphoma or

(NSIP) or organising pneumonia pattern),

secondary solid tumour)

from its temporal phase (e.g.

N nodular, where the interstitial

hypersensitivity pneumonitis may be

compartments are thickened in

detected in its acute, subacute or chronic

nodular form (‘beaded appearance’)

stage) or from its natural progression (e.g.

(e.g. lymphangitic carcinomatosis,

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ERS Handbook: Respiratory Medicine

sarcoidosis, pneumoconiosis and

secondary tumour)

The end-stage fibrotic lung is characterised

by a coarse reticular pattern reflecting

advanced interstitial fibrosis and

architecture destruction, and is commonly

associated with honeycombing (e.g. UIP,

asbestosis, collagen vascular disease and

radiation-induced fibrosis).

Ground-glass pattern Ground-glass opacities

(GGOs) appear as hazy areas of increased

opacity of the lung that are not dense

enough to hide the underlying bronchial and

vascular structures. It can result from

thickening of alveolar septa, or partial

alveolar filling with fluid, cells or amorphous

material leading to a decrease in the normal

ratio between air on the one hand, and

blood and soft tissues on the other. In

pulmonary fibrosis, GGO can also represent

very fine interstitial fibrosis beyond the

spatial resolution of the scan obtained. A

GGO pattern can be observed in a large

number of ILDs, such as:

N NSIP

N acute interstitial pneumonia (AIP)

N desquamative interstitial pneumonia

(DIP)

N respiratory bronchiolitis-associated

interstitial lung disease (RB-ILD)

N lymphoid interstitial pneumonia (LIP)

N cryptogenic organising pneumonia

(COP)

N acute/subacute hypersensitivity

pneumonitis

N acute exacerbation of ILD

GGO distribution, ancillary findings and

clinical phase (acute versus subacute/

chronic) may narrow the differential

diagnosis or even be suggestive of a specific

entity. GGO may be associated in up to one-

third of the cases with fibrosis (traction

bronchiectasis and honeycombing). In the

absence of any of these signs, GGO may, in

theory, represent a reversible disease

process.

Consolidation pattern A consolidation is an

area of increased attenuation where vessels

are obscured by consolidated (white) lung;

an air bronchogram may or may not be

ERS Handbook: Respiratory Medicine

373

present. This situation typically results from

interlobular septa. Ranging in size from a

filling of the airspaces with fluid (e.g.

few millimetres to a centimetre,

oedema, blood or pus). Consolidation is a

centrilobular nodules are usually ill defined.

common finding; the following conditions

They can be further subcategorised on the

may all manifest with consolidation:

basis of the presence of an associated ‘tree

in bud’ pattern (e.g. centrilobular nodules

N organising pneumonia

with a Y-shaped configuration often caused

N chronic eosinophilic pneumonia

by infection or aspiration). Centrilobular

N lipoid pneumonia

nodules are observed in subacute

N bronchoalveolar carcinoma (BAC)

hypersensitivity pneumonitis, in RB-ILD, and

N lymphoma

less commonly in pneumoconiosis,

pulmonary Langerhans’ cell histiocytosis

Nodular pattern is characterised by the

(LCH), LIP and COP.

presence of multiple airspace or interstitial

nodules, well or poorly defined, varying in

A perilymphatic distribution of nodules is

size (up to 3 cm in diameter), with or

commonly seen in patients with sarcoidosis,

without presence of cavitation. Low-density

lymphangitic carcinomatosis, LIP and

nodules with ill-defined margins (nodular

pneumoconiosis. Perilymphatic nodules are

GG) may be difficult to recognise. They are

subpleural in location but may also be found

commonly seen in patients with diseases

along interlobular septa, interlobar fissures

primarily affecting the small airways and

and bronchovascular bundles, where the

surrounding areas. High-density nodules

lymphatics are most concentrated. Typically,

with well-defined margins have a solid

they show a patchy distribution. However, in

aspect and obscure the edges of vessels or

some patients with perilymphatic nodular

other adjacent structures. They are more

disease, nodules can also be found in the

characteristic of diseases primarily affecting

centrilobular areas, in association with

the interstitium. The nodular pattern may be

nodules more typically distributed in

classified as:

subpleural regions and along the

interlobular septa (sarcoidosis and

N centrilobular

lymphangitic carcinomatosis).

N perilymphatic

N random

Randomly distributed nodules are found

diffusely throughout the lung parenchyma

based on the relationship with the secondary

without a predominant distribution within

pulmonary lobule. The distribution of the

either the secondary pulmonary lobules or

nodules depends on the route of arrival and

the lymphatics. They may also be seen at the

on the modality of spread. Diseases caused

termination of small pulmonary arterial

by inhalation show nodules close to the

vessels (feeding-vessel sign). This

bronchiole in the centre of lobules

distribution is typical of haematogenous

(centrilobular), while diseases that grow

dissemination (e.g. miliary TB,

along the lymphatics are more present in the

haematogenous metastasis and miliary

periphery of the lobules and along the

fungal disease).

fissures (lymphatic). The lesions that spread

haematogenously are visible everywhere

Decreased attenuation

(random), sometimes in connection with

Cystic pattern A cyst appears as a round

blood vessels.

parenchymal lucency or low-attenuating area

Centrilobular nodules can be hazy or sharply

with a well-defined interface with the normal

defined. HRCT features that can help in their

lung. Cysts have variable wall thickness but

discrimination are the distinct central

usually display an epithelial or fibrous, thin

location in the secondary pulmonary lobule,

wall (2 mm). The presence of a definable

the respect to one another, and the fact that

wall and the absence of residual

they appear separated by several millimetres

centrilobular artery differentiate cysts from

from the pleural surfaces, fissures and

centrilobular emphysema. Cysts in the lung

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ERS Handbook: Respiratory Medicine

usually contain air but occasionally contain

Society classification of IIPs, published in

fluid or solid material. The shape of the cysts

2002

(and currently under revision), defines

depends on the mechanism of their

the morphological patterns on which

formation, the relationship with each other

clinical, radiological and pathological

and the concomitance of traction

diagnosis of IIPs is based. IIPs include

phenomena in the surrounding parenchyma.

seven entities:

These ‘holes in the lung’ may be due to

IPF, which is characterised by the

dilation of bronchial structures, abnormal

morphologic pattern of UIP

distension of alveolar spaces, focal

NSIP

destruction of lung parenchyma or

COP

cavitation of solid lesions. The profusion of

the cysts may be variable, from scattered to

RB-ILD

very numerous. The craniocaudal

DIP

distribution of the lesions may help in the

LIP

differential diagnosis of LCH, which usually

AIP

spares the costophrenic angle while

HRCT has gained an important role in the

lymphangioleiomyomatosis (LAM) cysts are

diagnosis and management of patients with

distributed throughout the lung. A cystic

IIP, particularly in distinguishing between

pattern can also be indicative of LIP, DIP

UIP and NSIP, the two largest subsets of IIPs.

and more rare conditions.

The typical UIP pattern on HRCT can be

Honeycombing consists of cystic airspaces

found in 50-70% of the biopsy-proven

with thick, clearly definable walls lined with

cases. When present, it allows a noninvasive

bronchiolar epithelium, predominantly in

diagnosis to be made with high accuracy,

the basal and subpleural areas; the cystic

confidence and interobserver agreement. In

spaces are typically layered along pleural

all of the other IIPs, a confident diagnosis

surfaces, in one or more concentric layers.

requires biopsy.

The cyst walls are generally 3-10 mm thick

and have a uniform size. Honeycombing

Specific diseases

represents areas of destroyed and fibrotic

Idiopathic pulmonary fibrosis The term IPF

lung tissue on histology, where the normal

refers to a distinct type of chronic fibrosing

architecture has been lost. Frequently, they

pneumonia of unknown cause. It is the most

are associated with coarse reticulation,

common of the IIPs, accounting for about

architectural distortion and traction

50-60% of IIP cases. The prognosis is

bronchiectasis; as such, honeycombing is

usually dismal, with a median survival time

usually seen in patients with end-stage

of 2-4 years from diagnosis.

fibrosis. Diseases that may present with

honeycombing include idiopathic pulmonary

On chest HRCT, IPF is characterised by the

fibrosis (IPF), fibrotic NSIP, chronic

UIP pattern, which is predominantly

hypersensitivity pneumonitis, sarcoidosis

subpleural with an apical-basal gradient

(fibrotic stages) and collagen vascular

(fig. 1). Specific findings of UIP pattern

disease. A subpleural bibasilar

include honeycombing, peripheral reticular

honeycombing on HRCT has a high positive

opacities that determine irregular interfaces

predictive value for the histologic diagnosis

between the lung and pleura, intralobular

of UIP.

interstitial thickening with minimal GGO

abnormality, traction bronchiectasis and

HRCT features of the most common ILD

bronchiolectasis. Lower lobe volume loss is

Idiopathic interstitial pneumonias (IIPs) are a

also a common finding. In typical IPF, areas

heterogeneous group of non-neoplastic lung

of increased density (GGO) are absent or of

diseases in which the lung parenchyma is

limited extension. When GGO is present in

damaged by varying patterns of

IPF, it usually evolves to fibrosis. If the areas

inflammation and/or fibrosis. The American

of GGO exceed 30% of lung volume,

Thoracic Society/European Respiratory

alternative diagnostic hypotheses should be

ERS Handbook: Respiratory Medicine

375

Figure 2. NSIP. Axial HRCT image shows basilar

GGOs, reticulation and traction bronchiectasis

consistent with fibrotic NSIP.

80-90%. A UIP pattern can, however,

occasionally have other causes, including

collagen vascular diseases, chronic

hypersensitivity pneumonitis, drugs (e.g.

bleomycin and amiodarone) and asbestosis.

In such cases, a histological confirmation of

the diagnosis is required.

Nonspecific interstitial pneumonia is a

pathological term used to describe

interstitial inflammation and fibrosis with

temporal and spatial uniformity that does

Figure 1. UIP/IPF. a) Axial and b) coronal HRCT

not fulfil the clinical-pathological criteria of

images show stacked, thin-walled cysts in the

UIP, DIP or AIP. NSIP can be observed in a

subpleural portion of the lungs. In definite UIP,

number of conditions, such as collagen

honeycombing is most severe in the basilar and

vascular diseases, inhalation of organic/

peripheral portions of the lungs.

inorganic antigens, hypersensitivity

pneumonitis, drug toxicity or slowly

considered, such as NSIP, DIP, COP,

resolving acute lung injury. When no

hypersensitivity pneumonitis or RB-ILD.

associated process can be found in a patient

Honeycombing can mimic the bullae of

with a histological and radiological pattern

emphysema. The association of

of NSIP, the diagnosis of idiopathic NSIP is

centrilobular and paraseptal emphysema

established. On HRCT, the disease is usually

with lung fibrosis, however, can be observed

distributed bilaterally with basal and

in heavy smokers. Honeycombing pattern is

peripheral predominance (fig. 2). The most

present in 80-90% of patients with UIP and

common feature is diffuse GGO, occurring

is considered the strongest predictor of the

in up to 80% of cases. GGO can be the only

diagnosis of IPF, even if it can be present in

visible abnormality in ,30% of cases, or can

pulmonary fibrosis of other causes. As such,

be associated with peripheral irregular linear

a definite UIP pattern on HRCT, in a patient

or reticular opacities in ,50% of cases.

without clinical evidence of an alternative

Consolidation occurs in 20% of patients.

diagnosis, is sufficient for a confident

Traction bronchiectasis and micronodules

diagnosis of IPF and carries an accuracy of

can also be present. Subpleural sparing, if

376

ERS Handbook: Respiratory Medicine

present, is a highly specific feature of NSIP.

or ‘reversed halo sign’ representing

Honeycombing, a rare finding, which, if

peripheral consolidation with inner GGO. A

present, is usually mild compared with UIP,

perilobular pattern of increased attenuation

is only seen in patients with the fibrotic

has also been described in COP, which can

variant of NSIP. Differentiation between

resemble and be confused with interlobular

fibrotic NSIP and UIP requires surgical lung

septal thickening. The lung volumes are

biopsy. At present, there is no single feature

generally preserved. COP tends to

or combination of HRCT features that have

preferentially involve the subpleural and

high specificity for a histological diagnosis

bronchovascular regions of the lung

of NSIP. In fact, features of UIP and

parenchyma. Bronchial dilation and air

organising pneumonia may overlap with

bronchogram associated with regions of

fibrotic and cellular NSIP, respectively.

consolidation can also be present. The

imaging findings in these cases can often be

Cryptogenic organising pneumonia

mistaken for pneumonic consolidation.

Organising pneumonia is often secondary to

However, the foci of consolidation generally

a known cause such as collagen vascular

involve the lower lung zones and have a

disease, viral pneumonia or drug reactions.

tendency to migrate, especially in the case of

The term COP, which refers to idiopathic

relapses, reported in one-third of cases. Few

organising pneumonia, better defines the

cases progress to irreversible fibrosis,

disease previously known as bronchiolitis

probably representing the overlap between

obliterans with organising pneumonia

organising pneumonia and NSIP.

(BOOP), as the main abnormality is the

Radiological presentation is not

organising pneumonia whereas the

pathognomonic but, in the appropriate

bronchiolar obstruction may be absent in up

clinical setting, it allows one to suspect the

to one-third of the cases. HRCT features of

correct diagnosis. HRCT may also be helpful

COP are represented by multiple areas of

in identifying a suitable site for biopsy.

consolidations, which are commonly

bilateral, patchy and asymmetric, peripheral,

Respiratory bronchiolitis-associated ILD

and migrating (in up to 90% of cases) with

Respiratory bronchiolitis is part of the

or without GGOs (fig. 3). The lower lung

spectrum of smoking-related lung diseases.

zones are more frequently affected. Other

It is a distinct histopathological lesion found

HRCT findings include small centrilobular

in the lungs of virtually all cigarette smokers.

nodules, irregular lines, and the ‘atoll sign’

It usually represents an incidental finding

and, as such, is of little clinical significance.

Much less often, patients who are heavy

smokers develop RB-ILD, a clinical-

pathological entity characterised by

pulmonary symptoms, abnormal pulmonary

function test (PFT) results and imaging

abnormalities, with respiratory bronchiolitis

being the histological lesion on surgical lung

biopsy. It is possible that RB-ILD and DIP

are similar processes but at the opposite

ends of the disease spectrum. The most

common HRCT findings are centrilobular

nodules, patchy GGO and thickening of the

bronchial walls, which predominate in the

upper lobes. The GGO abnormality of RB-

ILD has been shown to represent areas of

macrophage accumulation in the distal

Figure 3. COP. Axial HRCT scan shows multiple

airspaces. Upper lobe emphysema is also

bilateral areas of peripheral consolidation with air

commonly present as a result of smoking.

bronchogram and GGO in the lower lobes.

Air trapping is frequently seen in expiratory

ERS Handbook: Respiratory Medicine

377

scans. A small percentage of patients have a

also concentrated in the peripheral and

reticular pattern in the absence of

basal lung zones, and small (,2 cm) thin-

honeycombing and traction bronchiectasis.

walled cystic spaces, which are indicative of

The differential diagnosis of RB-ILD includes

fibrotic changes. Despite differences in the

acute hypersensitivity pneumonitis, DIP and

CT appearance, imaging findings of RB-ILD

NSIP. An important finding that may help to

and DIP may overlap and be

distinguish RB-ILD from DIP is the presence

indistinguishable from each other. Lung

of centrilobular nodules and unusual

biopsy is required for a definite diagnosis.

presence of cyst formations in RB-ILD.

Lymphoid interstitial pneumonia can be

Desquamative interstitial pneumonia is a rare

idiopathic, exceedingly rare, or secondary to

form of ILD. DIP is strongly associated with

systemic disorders, in particular Sjögren’s

cigarette smoking and is considered to

syndrome, HIV infection and variable

represent the end of a spectrum of RB-ILD.

immunodeficiency syndromes. LIP is more

Though rarely, DIP may also occur in

common in females than in males, and

nonsmokers and has been related to a

patients are usually in their fifth decade of

variety of conditions, including lung

life at presentation. HRCT shows bilateral

infections, exposure to organic dust and

abnormalities that are diffuse or have lower

marijuana smoke inhalation. For the

lung predominance. The dominant HRCT

majority of patients, the onset of symptoms

feature in patients with LIP is GGO

is between 30 and 40 years of age. Males are

attenuation, which is related to the

affected about twice as commonly as

histological evidence of diffuse interstitial

females. With smoking cessation and

inflammation (fig. 5). Another frequent

corticosteroid therapy, the prognosis is

finding is thin-walled perivascular cysts.

good. On HRCT, DIP is characterised by

They are the only finding that may be

diffuse or patchy GGOs, which is caused by

irreversible. In contrast to the subpleural,

diffuse macrophage infiltration of the

lower lung cystic changes in UIP, the cysts of

alveoli, and thickening of alveolar septa with

LIP are usually within the lung parenchyma

peripheral and basal lung predominance

throughout the mid-lung zones and

(fig. 4). Other frequent CT findings include

presumably result from air trapping due to

spatially limited irregular linear opacities,

peribronchiolar cellular infiltration. In

combination with GGO, these cysts are

highly suggestive of LIP. Occasionally,

Figure 4. DIP. Axial HRCT scan of heavy smoker

shows diffuse and patchy GGO, and thickening of

alveolar septa with superimposed small cysts.

Figure 5. LIP. Axial HRCT image of patient with

These findings, suggestive of DIP, were confirmed

Sjögren’s syndrome shows thin-walled bilateral

by surgical lung biopsy.

lung cysts within the lung parenchyma.

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ERS Handbook: Respiratory Medicine

centrilobular nodules and septal thickening

dependent areas of the lung during the

are seen.

acute phase of disease, which attenuate the

potential damage associated with

Acute interstitial pneumonia is acute

mechanical ventilation.

respiratory distress syndrome (ARDS) of

unknown cause. The HRCT features of AIP

Although a considerable overlap of HRCT

include GGO abnormalities, traction

findings exists between AIP and ARDS, the

bronchiectasis and architectural distortion.

presence of symmetric lower lobe

The disease commonly has a symmetric,

abnormalities with honeycombing may be

bilateral distribution with lower lobe

more suggestive of AIP.

predominance. The costophrenic angles are

Other diseases

often spared. In the early phase of AIP,

prevalent patchy GGOs are the dominant CT

Hypersensitivity pneumonitis is an

features and reflect the presence of alveolar

immunologically induced inflammatory

septal oedema and hyaline membranes.

disease involving the lung parenchyma and

Areas of consolidation are also present but

terminal airways secondary to repeated

usually they are less extensive and limited to

inhalation of a variety of organic dusts and

the dependent area of the lung (fig. 6). In the

other agents in a sensitised host. Classically,

early phase, airspace consolidation results

it can be separated into three phases:

from intra-alveolar oedema and

acute

haemorrhage. However, consolidations are

subacute

also present in the fibrotic phase, thus

chronic

resulting from intra-alveolar fibrosis. In the

late phase of AIP, architectural distortion,

depending on the temporality relative to

traction bronchiectasis within areas of GGO

initial exposure. A significant clinical and

consolidation and honeycombing are the

radiological overlap can often occur between

most striking CT features and represent

these phases. Acute hypersensitivity

fibrotic change. They are more severe in the

pneumonitis presents within a few hours of

nondependent areas of the lung. This can be

substantial antigen exposure. HRCT scans,

explained by the ‘protective’ effect of

rarely obtained at this stage, demonstrate

atelectasis and consolidation on the

diffuse or patchy GGO with a geographic

distribution, and mosaic perfusion areas

due to air trapping (better or only

recognised on expiratory scans). Subacute

hypersensitivity pneumonitis occurs in

response to intermittent or low-dose antigen

exposure. HRCT is particularly helpful at this

stage of diseases and is characterised by

varying proportions of GG, poorly defined

centrilobular nodules and areas of

decreased attenuation, due to constrictive

bronchiolitis with expiratory air trapping

(fig. 7). The GGO pattern is general

symmetric and diffuse but can be

asymmetric. In some cases, reticulation and

bronchiectasis may coexist, and may

resemble NSIP. Chronic hypersensitivity

pneumonitis occurs after long-term, low-

Figure 6. AIP. Axial HRCT image from contrast-

dose antigen exposure and usually shows a

enhanced chest CT shows diffuse GGO and

fibrotic pattern resembling UIP or fibrotic

reticulation associated with dorsal bilateral

NSIP. HRCT findings include irregular

consolidations, with relative sparing of the

reticular opacities, small nodules,

anterior segments.

honeycombing and traction bronchiectasis

ERS Handbook: Respiratory Medicine

379

Figure 7. Subacute hypersensitivity pneumonitis.

Figure 8. Sarcoidosis. Axial HRCT image shows

Axial HRCT image shows multiple centrilobular,

multiple coalescent nodules with a perilymphatic

hazily defined nodules in both upper lungs. They

distribution in both upper lobes of a young female

appear separated from the pleural surfaces,

with a diagnosis of sarcoidosis.

fissures and interlobular septa.

N Stage III: pulmonary infiltrates without

as well as areas of air trapping and spared

BHL

lobules, with a heterogeneous appearance,

N Stage IV: lung fibrosis

called the ‘head cheese sign’. The finding of

small centrilobular nodules and the

Intrathoracic lymphadenopathy is present in

predominant mid-lung zones distribution on

up to 85% of patients at some point during

HRCT images, with sparing of the bases,

the course of their disease. Hilar and

help distinguish chronic hypersensitivity

mediastinal lymphadenopathy is better

pneumonitis from IPF and fibrotic NSIP,

defined on HRCT, which can also allow a

which tend to affect more severely the lung

more detailed analysis of the nodal

bases. Open-lung biopsy is required to make

calcifications. Sarcoidosis can mimic a

a definite diagnosis in borderline cases.

number of other diseases. As such, besides

a typical manifestation, there may be several

Sarcoidosis is a systemic disorder of

less common presentations. The disease

unknown cause characterised histologically

preferentially involves the upper lung zones,

by the presence of noncaseating

although in advanced stages, it may display

granulomata in affected organs. Thoracic

a diffuse distribution. The most common

manifestations, the most common cause of

features are multiple nodular opacities with

morbidity and mortality, occur in 90% of the

a typical perilymphatic distribution, which

patients and 20% of them develop chronic

correlate with sites of granulomatous

fibrotic lung diseases. The classic

inflammation on histology (fig. 8). Nodules

presentation consists of enlarged hilar and

are clustered along the bronchovascular

mediastinal lymph nodes, with or without

bundles, interlobular septa, interlobar

parenchymal involvement. Frequently, the

fissures, adjacent to the costal pleural (often

diagnosis is suspected following chest

mimicking pleural plaques) and in the

radiography. The radiographic disease

centrilobular regions. Nodules tend to

staging is as follows:

predominate in perihilar and dorsal regions

with relative sparing of the lung periphery.

N Stage 0: no demonstrable abnormality

Nodules of sarcoidosis typically measure

N Stage I: bilateral hilar lymphadenopathy

1-5 mm but, rarely, multiple ill-defined large

(BHL) alone

nodules (ranging in diameter from 1 to

N Stage II: BHL with lung infiltrates

4 cm) can be observed. In addition, multiple

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ERS Handbook: Respiratory Medicine

coalescent nodules and peripheral ground-

specific problems, such as assessment of

glass halos may be seen on HRCT.

disease activity and potential reversibility,

Occasionally, innumerable small satellite

prediction and evaluation of response to

nodules may be adjacent to the large

therapy, choice of the most suitable site for

nodules, a finding termed the ‘galaxy sign’.

lung biopsy, and follow-up. Pulmonologists

In ,10% of patients, a confluence of

have to know the basic HRCT patterns of

granulomata may cause a compression of

ILD and their distribution because this can

the alveoli and result in poorly defined

help to either make a diagnosis or narrowing

bilateral parenchymal consolidations with

the differential diagnosis.

air bronchogram; both parenchymal

consolidations and large nodules may also

Further reading

cavitate. Furthermore, innumerable small

interstitial granulomas (beyond the

Hansell DM (2010). Thin-section CT of

resolution of CT) may cause patchy GGOs

the lungs: the hinterland of normal.

on HRCT. The parenchymal abnormalities

Radiology; 256: 695-711.

described here are still reversible and often

Jawad H, et al.

(2012). Radiological

resolve spontaneously, but they may evolve

approach to interstitial lung disease: a

toward pulmonary fibrosis (in 20-25% of

guide for the nonradiologist. Clin Chest

cases), which is characterised by linear

Med; 33: 11-26.

opacities (radiating laterally from the

Raghu G, et al. (2011). An official ATS/

hilum), fissure displacement, bronchiectasis

ERS/JRS/ALAT statement: idiopathic pul-

monary fibrosis: evidence-based guide-

and honeycombing limited to the upper lung

lines for diagnosis and management. Am

zones, mainly in the dorsal regions.

J Respir Crit Care Med; 183: 788-824.

Expiratory CT images can show focal air

Travis WD, et al.

(2002). American

trapping at any stage of the disease.

Thoracic Society/European Respiratory

Conclusion

Society international multidisciplinary

consensus classification of the idiopathic

The term ILD refers to a large group of

interstitial pneumonias. Am J Respir Crit

entities characterised by radiological

Care Med; 165: 277-304.

findings that often overlap. Chest HRCT is

Webb WR (2006). Thin-section CT of the

the most important imaging method for the

secondary pulmonary lobule: anatomy

assessment of ILD owing to its sensitivity

and the image - the 2004 Fleischner

and specificity. In addition, it plays an

lecture. Radiology; 239: 322-338.

important role in the management of

ERS Handbook: Respiratory Medicine

381

Sarcoidosis

Ulrich Costabel

Sarcoidosis is a multisystem granulomatous

and Africa. Sarcoidosis in Afro-Americans is

disorder of unknown aetiology, which

more severe, while Caucasians are more

commonly affects young and middle-aged

likely to present with asymptomatic disease.

adults. The disease frequently presents with

Overall mortality is 1-5%.

bilateral hilar lymphadenopathy, pulmonary

The cause of sarcoidosis remains unknown.

infiltration, and ocular and skin lesions. Any

Available evidence strongly supports the

organ of the body may be involved. The

hypothesis that the disease develops when a

prevalence rates of sarcoidosis vary widely,

specific environmental exposure with

from ,1 case to 40 cases per 100,000

antigenic properties occurs in a genetically

population. Sarcoidosis is common in

susceptible individual. Potential aetiological

Scandinavia, Central Europe, the USA and

agents include mycobacteria and

Japan. It is less frequently seen in other

Propionibacterium acnes. Sarcoidosis

Asian countries, Central and South America,

susceptibility or chronicity has been

associated with a number of human

leukocyte antigen alleles. Some genetic

Key points

associations have been found with specific

disease subsets, most notably with

Sarcoidosis is a multisystem

Löfgren’s syndrome. A polymorphism of the

granulomatous disorder of unknown

BTNL2 (butyrophilin-like 2) gene has been

aetiology, which commonly affects

linked with sarcoidosis. The immunological

young and middle-aged adults.

abnormalities are characterised by the

Prevalence of sarcoidosis varies from

accumulation of activated T-cells of the

,1 case to 40 cases per 100 000

T-helper cell type 1 and macrophages at sites

population, and overall mortality is

of ongoing inflammation.

1-5%.

Clinical presentation

Clinical presentation varies widely,

though fever, fatigue and skeletal

The clinical presentation of sarcoidosis

muscle weakness are often noted.

varies widely. 30-50% of patients are

asymptomatic at the time of diagnosis.

The decision to treat should be

Symptoms of sarcoidosis are largely

carefully assessed based on the

nonspecific. Low-grade fever (sometimes

benefit to the patient and disease

up to 40uC), weight loss (usually limited to

severity; treatment should mainly

2-6 kg during the 10-12 weeks before

be considered if symptoms develop

presentation), night sweats and arthralgias

or lung function deteriorates.

can be found in about 20-30% of patients.

The clinical course of sarcoidosis

Sarcoidosis is an important and frequently

can be unpredictable, so regular

overlooked cause of fever of unknown origin.

monitoring of signs of disease

Fatigue and skeletal muscle weakness are

progression is advised.

more common, being present in f70% of

patients when carefully sought. According to

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ERS Handbook: Respiratory Medicine

their initial presentation, sarcoidosis

diagnostic assessment should attempt to

patients can be divided into two distinct

accomplish four goals:

subgroups: acute and chronic. The acute

provide histological confirmation of

form can present as classical Löfgren’s

the disease

syndrome, which is characterised by fever,

assess the extent and severity of organ

bilateral hilar lymphadenopathy, ankle

involvement

arthritis and erythema nodosum. The

assess whether the disease is stable or

chronic form shows an insidious onset, and

is likely to process

organ-related symptoms predominate, such

determine whether therapy will benefit

as cough, dyspnoea, and chest pain.

a patient

Diagnostic approach

Granulomas alone are never diagnostic

The criteria of the American Thoracic

proof of sarcoidosis.

Society, European Respiratory Society and

An important step is the choice of site for a

the World Association of Sarcoidosis and

proper biopsy. Transbronchial lung biopsy is

Other Granulomatous Disorders for the

the recommended procedure in most cases,

diagnosis of sarcoidosis include:

with the diagnostic yield reaching 80%. This

can be combined with biopsy of the

N the presence of a consistent clinical and

bronchial mucosa. Transbronchial needle

radiological picture

aspiration of mediastinal lymph nodes

N histological evidence of noncaseating

guided by endobronchial ultrasound is

granulomas

useful for diagnosing stage I and II

N exclusion of other conditions capable of

sarcoidosis with a sensitivity of 83-93%.

producing a similar histological or clinical

Other easily accessible sites for biopsy are

picture

the skin, lip or superficial lymph nodes. In

patients without biopsy, clinical and/or

The initial diagnostic work-up for patients

radiological features alone may be

with suspected sarcoidosis involves careful

diagnostic in stage I (reliability of 98%) or

baseline assessment of disease distribution

stage II (89%), but are less accurate in stage

and severity by organ, with emphasis on

III (52%) or stage 0 (23%). The classical

vital target organs (table 1). Specifically, the

Löfgren’s syndrome may not require biopsy

proof. Bronchoalveolar lavage and studies of

Table 1. Initial evaluation for sarcoidosis

lymphocyte subpopulations showing an

History (occupational and environmental

increase in the CD4/CD8 ratio may be

exposure, symptoms)

helpful. Elevated serum angiotensin-

converting enzyme and calcium levels may

Physical examination

lend support to the diagnosis.

Chest radiography

The chest radiogram can be used to classify

Pulmonary function tests: vital capacity,

sarcoidosis into four stages (table 2). CT

FEV1, TLCO

scanning provides much greater detail of

Peripheral blood counts

mediastinal and parenchymal abnormalities

Serum chemistries: calcium, liver enzymes,

but is not essential for baseline study. It is

creatinine, ACE

indicated when diagnosis is unclear after

Urine analysis

chest radiography and clinical assessment

or to detect complications of the lung

ECG

disease including bronchiectasis,

Eye investigation

aspergilloma or superimposed infection.

Tuberculin skin test

Pulmonary function tests show only a

Selection of site for biopsy

moderate correlation with the extent of lung

involvement detected on imaging. However,

ACE: angiotensin-converting enzyme.

it is important to have initial baseline data

ERS Handbook: Respiratory Medicine

383

Table 2. Chest radiographic stages

Stage

Findings

Frequency %

Normal

5-10

BHL

BHL and parenchymal infiltrates

III

Parenchymal infiltrates without BHL

Signs of fibrosis

5-10

BHL: bilateral hilar lymphadenopathy.

for evaluating the following clinical course.

pulmonary hypertension and chronic

The most sensitive test is the diffusion

respiratory insufficiency.

capacity. The typical finding is a restriction,

Treatment and follow-up

but up to 30% of patients show an

obstructive impairment that may be

The indication to treat a patient depends on

associated with the involvement of the

many factors, the most important being

bronchial mucosa.

whether or not the patients is symptomatic.

Cardiac involvement is a serious

Except for life- and sight-threatening organ

manifestation of sarcoidosis. Cardiac MRI

involvement, it should be carefully

is the preferred diagnostic test as it is a

considered whether the patient might

noninvasive and nonradioactive method

benefit from treatment. For asymptomatic

for diagnosing cardiac sarcoidosis with a

pulmonary patients, a watch-and-wait

high sensitivity.

approach is appropriate; treatment should

mainly be considered if symptoms develop

Pulmonary hypertension is a troublesome

or lung function deteriorates. The goal of

complication of sarcoidosis, with increased

treatment is to make the patient

morbidity and mortality. The frequency is

asymptomatic and to restore or preserve

5-15% in selected patients and 50-60% in

organ function. For patients with symptoms

patients with dyspnoea out of proportion

from a single organ, topical therapy may be

with the pulmonary function test results.

appropriate for anterior eye or for skin

Such patients, most of them in radiographic

involvement. Otherwise, initial therapy is

stage IV, should undergo echocardiography

still based on systemic corticosteroids. For

as a screening test and right heart

pulmonary sarcoidosis, the initial

catheterisation for confirmation.

prednisone dose is 20-40 mg; higher doses

may be needed for cardiac or neural

Natural history and prognosis

sarcoidosis. The dose is slowly tapered to

The disease course is highly variable.

5-10 mg per day; treatment should be

Spontaneous remissions occur in nearly two

continued for a minimum of 12 months.

thirds of patients. Serious extrapulmonary

Patients with Löfgren’s syndrome usually do

involvement (cardiac, central nervous

not require therapy with corticosteroids.

system or hepatic) occurs in 4-7% of

patients at time of presentation. Incidence

For patients with chronic disease requiring

becomes higher as the disease evolves.

years of therapy, alternatives to

Adverse prognostic factors include lupus

corticosteroids include methotrexate,

pernio, chronic uveitis, age at onset

azathioprine and hydroxychloroquine, all

.40 years, chronic hypercalcaemia,

given usually in combination with low-dose

nephrocalcinosis, African ethnic origin,

corticosteroids. For refractory sarcoidosis

progressive pulmonary sarcoidosis, nasal

patients, new therapeutic approaches have

mucosal involvement, cystic bone lesions,

begun to emerge through the use of

neural sarcoidosis, cardiac sarcoidosis,

immunomodulatory agents. Based on

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ERS Handbook: Respiratory Medicine

current understanding of pathogenic

the high rate of relapses in this context,

mechanisms, these are tumour necrosis

ranging 15-70%.

factor-a-blocking drugs, such as infliximab,

thalidomide and pentoxyfylline. Lung

Further reading

transplantation can be considered for severe

or end-stage pulmonary sarcoidosis.

Baughman RP, et al., eds. Sarcoidosis.

New York, Thieme Medical Publishers,

Because the clinical course of sarcoidosis can

2010.

be unpredictable, regular monitoring for

Costabel U, et al.

(2010). Diagnostic

signs of disease progression is necessary,

modalities in sarcoidosis: BAL, EBUS,

using the least invasive and most sensitive

and PET. Semin Respir Crit Care Med; 31:

tools. For pulmonary sarcoidosis, this is

404-408.

spirometry and diffusion capacity. For stable

Drent M, et al., eds. Sarcoidosis. Eur

stage I disease, follow-up every 6-12 months

Respir Monogr; 32. 2005.

is usually adequate; more frequent

Grutters JC, et al. (2009). Sarcoidosis. Eur

evaluations (every 3-6 months) are advised

Respir Monogr; 46: 126-154.

for stage II, III or IV sarcoidosis. All patients

Hunninghake GW, et al. (1999). ATS/ERS/

should be monitored for a minimum of

WASOG statement on sarcoidosis.

3 years after therapy is discontinued. Follow-

Sarcoidosis Vasc Diffuse Lung Dis;

16:

up needs to be more vigilant after

149-173.

corticosteroid-induced remissions, due to

ERS Handbook: Respiratory Medicine

385

Idiopathic interstitial

pneumonias

Dario Olivieri, Sara Chiesa and Panagiota Tzani

Idiopathic interstitial pneumonias (IIPs)

represent a heterogeneous group of

Key points

disorders with different clinical and

histological features, and different

N IIPs represent a heterogeneous group

prognosis. They can be considered as

of disorders with different clinical and

inflammatory disorders of the interstitium.

histological features and prognoses.

Extrapulmonary involvement does not

N The most recent ATS and ERS

occur. The cause and pathogenetic

classifications of IIPs include seven

mechanisms responsible for IIPs have not

different diseases identified by a

been elucidated. The first stage of the

typical histological pattern: NSIP,

pathological process consists in the

cryptogenic organising pneumonia/

recruitment of inflammatory cells in the

bronchiolitis obliterans organising

interstitium, leading to injury of the

pneumonia, acute interstitial

epithelial and alveolar cells, and the

pneumonia, respiratory bronchiolitis/

subsequent abnormal wound healing

interstitial lung disease, desquamative

response, particularly due to the fibroblasts.

interstitial pneumonia/alveolar

Nowadays, the dysregulation of fibroblasts

macrophage pneumonia and

and an excessive deposition of extracellular

lymphoid interstitial pneumonia.

matrix are considered the cardinal points of

the pathogenesis of the IIPs.

N The terms IPF and NSIP should only

be used for chronic fibrosing

Because of the poor comprehension of the

interstitial pneumonia of unknown

underlying pathogenetic mechanisms, there

cause limited to the lungs. The

is no therapeutic intervention able to affect

prognosis in IPF is worse with a

the cellular and molecular target responsible

histological pattern of UIP.

for the disease and change its course.

The most recent American Thoracic Society

29 cases per 100 000 persons. The disease

(ATS) and European Respiratory Society

typically affects adults, with a peak after the

(ERS) classification of the IIPs includes

sixth decade of life; incidence is higher in

seven different diseases identified by a

males and in smokers (Coultas et al., 1994).

typical histological pattern; each histological

There is a familial variant of idiopathic

pattern has precise clinical and radiological

pulmonary fibrosis (IPF)/usual interstitial

features, and a different prognosis (table 1).

pneumonia (UIP) that accounts for 0.5-3%

Here, we discuss the most important clinical

of cases of IIP; this form is indistinguishable

aspects of the IIPs, particularly therapeutic

from the nonfamilial forms except that

possibilities.

patients tend to be younger.

Epidemiology

Pathogenesis

The incidence of the IIPs has been estimated

at seven to 11 cases per 100 000 persons

The pathogenetic mechanisms of the IIPs

and the prevalence ranges between two and

are not completely clear; there are various

386

ERS Handbook: Respiratory Medicine

penetrance in two-thirds of patients.

Table 1. Classification of IIPs

Familial IPF has been associated with

IPF/UIP

altered a₁-antitrypsin inhibitor alleles on

Desquamative interstitial pneumonia/

chromosome 14. Genetic polymorphism for

alveolar macrophage pneumonia

interleukin (IL)-1 receptor antagonist or

Respiratory bronchiolitis/interstitial lung

TNF-a may be involved.

disease

Physiology

Acute interstitial pneumonia

The physiological aberrations in IIPs are

Cryptogenic organising pneumonia/

typical of a restrictive pattern and include

bronchiolitis obliterans organising

pneumonia

reduced lung volumes (vital capacity and

TLC) and normal or increased expiratory

NSIP

flow rates. TLCO is typically reduced,

Lymphoid interstitial pneumonia

indicating interstitium damage and, thereb,y

gas exchange impairment (Chetta et al.,

2004). A further consequence of this

hypotheses relating to the initial stimulus

alteration is the hypoxaemia, which is

responsible for the pathogenetic process,

accentuated with exercise. Late in the course

such as exposure to toxic substances or viral

of the disease, severe hypoxaemia may also

infections. Independently of the initial

be observed at rest; hypercapnia may be

cause, the inflammatory-fibrotic process of

present as well.

UIP is characterised by an injury of the

alveolar epithelial cells, destruction of the

Clinical features and diagnosis

subepithelial basement membrane and

subsequent abnormal cicatrisation with an

The initial symptoms of IIPs are hidden and

increased fibroblastic response, and

insidious: persistent nonproductive cough

excessive deposition of collagen and

and progressive dyspnoea. In most patients,

extracellular matrix.

physical examination reveals end-inspiratory

rales (velcro type). The course of the disease

The interplay between inflammatory and

may vary depending the variant of IIP; in

mesenchymal cells is regulated by a number

UIP, the prognosis is extremely severe and

of cytokines produced by fibroblasts and

the course of the disease is rapid, even if

epithelial cells; the most important of these

some patients stabilise after an initial period

mediators are transforming growth factor

of decline. Respiratory failure appears in 3-

(TGF)-b, tumour necrosis factor (TNF)-a,

8 years and the mean survival from the onset

platelet-derived growth factor (PDGF),

of the disease is around 3-5 years. During

connective tissue growth factor, integrin-

the late phases of the disease, patients often

mediated intercellular adhesion molecules,

show cor pulmonale. Respiratory failure is

proteases and oxygen radicals. Deficiency of

the main cause of death, followed by

interferon (IFN)-c may contribute to

pulmonary embolism and heart failure.

activation and perpetuation of the

fibroblastic process. Histologically, the

Diagnosis of IIP is the result of an integrated

presence of fibroblastic foci is typical of UIP;

and multidisciplinary process, requiring

the fibroblastic foci are formed by

cooperation of the clinician, the radiologist

mesenchymal cells similar to myofibroblasts.

and the pathologist. International guidelines

state that histology is useful for diagnosis.

Under the influence of TGF-b, the cells

Surgical lung biopsy shows higher diagnostic

increase the production of collagen, vimentin

value than transbronchial biopsy and

and actin, leading to an excessive deposition

bronchoalveolar lavage. However, it is

of extracellular matrix.

invasive with potential risks and, sometimes,

In the rare familial form, the mode of

patients may present clinical and

transmission is not known; it is probably

physiological contraindications to surgery. In

autosomal dominant with variable

some cases, an acute exacerbation of the

ERS Handbook: Respiratory Medicine

387

disease may follow surgery, leading to a

Secondary features include coarse reticular

decline in general condition.

opacities, thickened bronchial walls,

bronchiectasis and bronchiolectasis.

HRCT has become a crucial tool for the

diagnostic process and allows an accurate

Nonspecific interstitial pneumonia (NSIP) is

and objective follow-up of the disease.

characterised by the presence of ground-

HRCT images consistent with IIP represent

glass areas, as a sign of an active

one of the most important ATS/ERS/

inflammatory process. The main aspects to

Japanese Respiratory Society (JRS)/

consider for differential diagnosis of UIP or

Asociación Latinoamericana de Tórax

NSIP are the geographic and temporal

(ALAT) guideline diagnostic criteria. HRCT

histological and radiological heterogeneity,

features are often typical of the disease and,

the high concentration of fibroblastic foci

given the high-quality evidence regarding

and honeycombing in the UIP form.

HRCT specificity for the recognition of a

Cellular analyses of bronchoalveolar lavage

histopathological UIP pattern, surgical lung

(BAL) and transbronchial lung biopsy can be

biopsy is not essential. In the appropriate

useful in the diagnosis of certain forms of

clinical setting, the presence of a UIP

IIPs (Meyer et al., 2012).

pattern on HRCT is sufficient for the

diagnosis of IPF (fig. 1).

Natural history and exacerbations

In particular, in case of UIP, HRCT images

The course of the disease is characterised

show a heterogeneous distribution with a

by a progressive pulmonary function

predilection for the peripheral, especially

decline, leading to worsening of general

subpleural and basilar, regions of the lung.

condition and death (fig. 2). A subset of

The main radiologic feature in UIP is

patients develop an accelerated and usually

honeycombing, i.e. cystic radiolucencies as

fatal course, showing an extremely rapid

an expression of severe and irreversible

decline; this condition is known as acute

fibrotic conversion of the parenchyma.

exacerbation.

The criteria for defining an exacerbation are:

Suspected IPF

N progressive dyspnoea during the last

30 days

Identifiable causes

Yes

N new pulmonary infiltrates in chest

for ILD?

radiographs

Stable

HRCT

Slow

UIP

Possible UIP

progression

Inconsistent with UIP

Acute

worsening

Not UIP

Surgical lung biopsy

UIP

Probable UIP/possible UIP

Nonclassifiable fibrosis

Rapid

MDD

progression

IPF

IPF/not IPF

Not IPF

Time

Figure 1. Diagnostic algorithm for IPF. ILD:

interstitial long disease; MDD: multidisciplinary

Figure 2. Natural history of IPF. Reproduced and

discussion. Reproduced and modified from Raghu

modified from Raghu et al. (2011) with permission

et al. (2011) with permission from the publisher.

from the publisher.

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ERS Handbook: Respiratory Medicine

N worsening of hypoxaemia with a

suppressive agents have been used, usually in

reduction in oxygen tension .10 mmHg;

combination with corticosteroids.

N absence of pulmonary infection

supported by negative BAL

The most recent developments in the field

identify the initial phase of the disease as

N absence of any other cause, such as HF,

alveolar epithelial cell injury and destruction

pulmonary embolism or conditions that

of the subepithelial basement membrane,

may cause acute lung damage

leading to abnormal wound healing with a

Diagnosis of exacerbation may be

vigorous fibroblastic response and excessive

controversial, despite the codification of the

deposition of collagen and extracellular

diagnostic criteria; ground-glass opacities

matrix. This new pathogenetic theory

are not specific for IIP and may be present in

suggests a primary role for fibroblast

infection. Nonintubated patients in the

dysregulation. Thus, the fibroproliferative

acute phase of the disease often cannot

process becomes the therapeutic target, and

undergo BAL because of their unstable

new drugs that arrest the proliferation of

conditions and they are treated with

fibroblasts and the deposition of

antibiotics as a precautionary measure.

extracellular matrix are being testing

Lung biopsy shows diffuse alveolar damage;

(Bouros et al., 2005).

however, the invasiveness of the procedure

The increasing clinical awareness of IPF has

is a limiting factor and only a few well-

resulted in the recent publication of

selected patients undergo surgical lung

guidelines for the accurate diagnosis of IPF

biopsy. It is our duty to mention the

and recommendations for its management.

correlation between surgical lung biopsy or

The recommendations for diagnosis and

lung resection and acute exacerbation,

treatment intervention in the new ATS/ERS/

which is not clear yet, as far as causality is

JRS/ALAT guidelines are evidence-based and

concerned. Risk factors involved in this

eliminate the bias from expert opinions and

accelerated phase may be a high

ongoing practices in the management of IPF.

concentration of oxygen (100%),

hyperexpansion of the lung parenchyma and

Anti-inflammatory drugs Although

the use of mechanical ventilation in the

corticosteroids have been considered the

post-operative phase.

mainstay of IPF treatment for decades, there

are no randomised placebo-controlled trials

Generally, the factors responsible for the

using corticosteroids alone. The ATS/ERS

exacerbations are still unknown; clinical

international consensus statement

presentation in some patients (fever,

concludes that existing therapies are of

influenza-like symptoms and neutrophilia in

unproven benefit.

BAL) may be consistent with a viral

infection; however, the pathogen has not

In the past, high doses of prednisone or

been identified.

prednisolone (1 mg?kg^-1?day^-1, considering

ideal body weight) for 4-6 weeks, with a

Treatment

gradual taper, were used. Given the high risk

IIP treatment is one of the most

of systemic side-effects and the significant

controversial aspects in the field of the

toxicity, especially when used in

diffuse infiltrative lung diseases. Poor

combination with other drugs, the dose has

understanding of the pathogenetic

been re-evaluated and more recent

mechanisms underlies the ineffectiveness

therapeutic regimens recommend low doses

of the current treatment options.

of prednisone or prednisolone

(0.5 mg?kg^-1?day^-1 for 4 weeks followed by

The initial pathogenetic theory considering IIP

0.25 mg?kg^-1?day^-1 for 8 weeks, then

as an inflammatory process makes reasonable

0.125 mg?kg^-1?day^-1). The rate of taper

the use of anti-inflammatory drugs, such as

depends on individual characteristics of

corticosteroids, which are considered first-line

patients. In the case of responders with

drugs. Later, cytotoxic and immuno-

clinical and radiological improvement,

ERS Handbook: Respiratory Medicine

389

prolonged maintenance therapy with low-

no clinical trials that confirm a certain

dose, alternate-day prednisone may be

benefit of combination (corticosteroids plus

established to reduce the chance of

azathioprine) therapy. Given the minor

recrudescent disease. In the case of

toxicity compared with cyclophosphamide,

exacerbation, 2 mg?kg^-1?day^-1 of

azathioprine should be administered in

methylprednisolone for ,14 days should be

patients with symptomatic or progressive

administered, depending on individual

disease for 6 months unless adverse effects

clinical response.

that suggest interruption or modification of

the treatment appear. A more prolonged

Given the lack of any scientific evidence of

treatment is reserved only in patients with a

proven benefit, especially a dose-response

clinical response or complete remission of

effect, corticosteroid treatment should not

the disease.

be used in patients at high risk for adverse

effects, such as elderly patients.

Cyclophosphamide is usually used as a

second-line drug for patients who presented

When the inflammatory component

adverse effects from high-dose corticosteroid

dominates, prompt corticosteroid treatment

therapy. It is an alkylating agent that activates

may lead to a significant improvement and,

the liver microsomal system and inhibits

sometimes, to complete resolution of the

DNA synthesis; it has a marked effect on

disease. Desquamative interstitial

lymphocytes, thus it is used as an

pneumonia/alveolar macrophage

immunosuppressive agent. The route of

pneumonia, acute interstitial pneumonia

administration is usually oral or intravenous

and cryptogenic organising pneumonia/

but it can also be administered by

bronchiolitis obliterans organising

intramuscular injection. Generally,

pneumonia are the IIPs forms with the

cyclophosphamide is used combined with

highest rate of response to steroid therapy.

low-dose corticosteroids. Principal adverse

The new guidelines recommend that

effects are bone marrow suppression,

patients with IPF should not be treated with

haemorrhagic cystitis, nausea and vomiting.

corticosteroid monotherapy.

Scientific evidence confirming the efficacy of

cyclophosphamide in IIP treatment is lacking;

Azathioprine and cyclophosphamide are

no clinical benefit regarding survival and

the most frequently used second-line

progression of the disease has been reported.

drugs, alone or in combination with

corticosteroids. Currently, there is poor

Cyclosporine is a fungal peptide that exerts

information regarding their efficacy. A

potent immunosuppressive effects; it

possible adjunctive synergic effect is

inhibits T-lymphocyte proliferation by

unconfirmed.

inhibiting the release of IL-2. It causes some

important adverse effects, especially renal,

Azathioprine is the most frequently used

hepatic and gastrointestinal effects.

cytotoxic agent and is usually well-tolerated.

Cyclosporine is rarely used for IIP treatment

Its metabolism leads to the production of

and its use is limited for selected patients

mercaptopurine, which is similar to purine,

awaiting lung transplantation. There are no

and inhibits DNA synthesis. Azathioprine is

clinical trials showing that cyclosporine

administered p.o., usually in combination

therapy is of benefit.

with low-dose corticosteroids; the initial

dose is 25-50 mg?day^-1 (2-3 mg?kg^-1?day^-1). If

The new guidelines recommend that patients

adverse effects do not appear, an increase of

with IPF should not be treated with

25 mg every 7-14 days is recommended,

cyclosporine. Moreover, combination therapy

until a maximum dose of 150 mg?day^-1 is

with corticosteroid and immunomodulator

reached. During treatment with

therapy should not be recommended in IPF

azathioprine, haemachrome and liver

patients.

function should be monitored; in fact,

azathioprine causes bone marrow

Novel therapeutic strategies The use of novel

suppression and hepatotoxicity. There are

drugs in IIP treatment is suggested by the

390

ERS Handbook: Respiratory Medicine

new pathophysiological theory that

Azuma et al. (2005) published the results of

recognises the fibroproliferative process

a double-blind, randomised, placebo-

plays a central role.

controlled trial but no statistically significant

difference in desaturation during the 6-min

IFN-c is a novel biological antifibrotic drug

walk test (6MWT) was found; however, a

with a number of inhibitory effects on

positive treatment effect with pirfenidone

fibroblasts. In the literature, there are only

was demonstrated in secondary end points,

few studies relating to the real efficacy of

such as vital capacity and prevention of

IFN-c, either alone or in combination

acute exacerbation of the disease. In fact,

therapy with low-dose corticosteroids.

successive studies showed that pirfenidone

Neither Ziesche et al. (1999) nor Raghu et al.

preserves vital capacity and improves

(2004) reported any statistically significant

progression-free survival time better than

differences in the primary outcome

placebo. The new guidelines recommend

variables, such as disease progression,

that the majority of patients with IPF should

mortality and functional deterioration.

not be treated with pirfenidone but this

However, patients with mild-to-moderate

therapy may be a reasonable choice in a

disease presented better, statistically

minority of patients.

significant survival. Although IFN-c may

represent a useful therapeutic tool in

Experimental models in vitro and in vivo

selected patients, additional data supporting

showed that angiotensin-converting enzyme

its efficacy are needed.

inhibitors and statins possess antifibrotic

properties. However, there is no evidence of

The new guidelines recommend that

survival improvement in treated patients.

patients with IPF should not be treated

with IFN-c.

There is evidence that oxidant agents

production increases in IIP. In particular,

Colchicine inhibits the synthesis of collagen

neutrophils, macrophages and fibroblasts

and suppresses some growth factors that

release oxidant agents, such as reactive

are necessary for fibroblast proliferation. On

oxygen species, hydrogen peroxide and

the basis of these properties, the use of this

superoxide anions. These factors, added to

drug is being tested. Data are limited,

the reduction of antioxidants, facilitate

although there is no evidence that colchicine

fibroblast dysregulation and deposition of

improves the progression of the disease and

extracellular matrix.

survival. The new guidelines recommend

that patients with IPF should not be treated

N-acetylcysteine (NAC) is derived from the

with colchicine.

amino acid cysteine. It is considered a

D-penicillamine is a thiolic compound that

precursor of glutathione (GSH) and

interferes with collagen turnover, inhibiting

stimulates GSH synthesis. GSH has strong

collagen synthesis and deposition by

antioxidant properties, as it removes free

interrupting cross-linking of collagen

oxygen radicals and decreases hydrogen

molecules. There are no clinical controlled

peroxide. The route of administration is oral

trials showing any benefit of D-penicillamine

at a dose of 1800 mg?day^-1 added to

therapy. Given the frequency adverse effects,

conventional therapy with corticosteroids

D-penicillamine does not appear to be a

and azathioprine. A significant difference in

treatment choice in IIPs.

the rate of decline of FVC and TLCO has been

described in patients treated with NAC;

Pirfenidone (5-methyl-1-phenyl-2[1H]-

however, no difference was

pyridone) attenuates pulmonary fibrosis in

observed in mortality.

animal models. It reduces synthesis of

collagen (I and III) and TNF-a, and inhibits

A recent study showed that increased risks

TGF-b-stimulated collagen synthesis.

of death and hospitalisation were observed

Moreover, it decreases synthesis of

in patients with IPF who were treated with a

extracellular matrix and blocks the

combination of prednisone, azathioprine,

mitogenic effect of profibrotic cytokines.

and NAC, as compared with placebo.

ERS Handbook: Respiratory Medicine

391

The new guidelines recommend that the

reduction in the decline in lung function

majority of patients should not be treated

compared with placebo, with fewer acute

with NAC monotherapy or with combination

exacerbations and preserved quality of life

corticosteroid, azathioprine and NAC

(Richeldi et al., 2011).

therapy, but this therapy may be reasonable

The typical fibroproliferative process in IIP

in a minority of patients.

seems to be related to inflammation and

Endothelin 1 (ET-1) is a potent mitogen for

vascular injury. Indeed, endothelium damage

endothelial and smooth muscle cells. ET-1 is

causes exposition of the intimal tissue to the

strongly upregulated in patients with IIP and

circulation and this is strongly pro-thrombotic.

is mainly expressed in epithelial cells. Some

Pulmonary embolism is one of the most

studies have suggested that inhibition of

common causes of death in IIP patients and

ET-1 could have antifibrotic effects.

D-dimer levels often increase in exacerbations

Bosentan is a nonselective ETA and ETB

of the disease (Castro et al., 2001). In a

receptor antagonist which is used in

prospective study, Kubo et al. (2005)

patients with pulmonary hypertension, and

evaluated the role of thrombotic events in the

it could delay the progression of IIPs. The

natural history of the disease and survival

Bosentan Use in Interstitial Lung Disease

improvement in IIP patients receiving oral

(BUILD)-1 trial showed that bosentan was

anticoagulant therapy. Patients treated with

not superior to placebo in the 6MWT, and

warfarin added to corticosteroids had

the effects of bosentan treatment on health-

significantly higher survival after exacerbation

related quality of life and dyspnoea in the all-

when compared to patients treated with

treated population were minimal. Similarly,

corticosteroids alone. D-dimer levels and

in the BUILD-3 trial, no treatment effects

number of exacerbation-free days did not

were observed on health-related quality of

differ between the two groups. The

life or dyspnoea (King et al., 2011). The new

mechanisms underlying better survival in

guidelines recommend that patients with

patients treated with anticoagulant therapy

IPF should not be treated with bosentan.

are unclear. Certainly, extravascular

deposition of fibrin and thrombotic events

TNF-a has been found to be significantly

play a main role in the fibroproliferative

elevated in bleomycin-induced pulmonary

process and acute lung injury.

fibrosis. TNF-a stimulates a series of

cytokines, such as TGF-b and IL-5, and

The new guidelines recommend that the

modifies eosinophil recruitment in the

majority of patients with IPF should not

parenchyma. Antibodies against TNF-a and

be treated with anticoagulants but this

soluble TNF-a receptor antagonists have

therapy may be a reasonable choice in a

been found to reduce the fibrotic process in

minority of patients.

animals. A recent study of etanercept for

The study by Lee et al. (2011) showed an

patients with IPF failed to show a difference

apparent survival benefit associated with

in the primary end-point of change in FVC.

medications to suppress the acidity of the

Nonsignificant trends were observed in

gastric juice, given as gastro-oesophageal

TLCO and 6MWT parameters. The new

reflux (GOR) therapy. This observation is

guidelines recommend that patients with

consistent with an increasing body of

IPF should not be treated with etanercept.

evidence supporting the concept of silent

Tyrosine kinase receptors have been shown

microaspiration as a result of abnormal

to be involved in lung fibrosis. BIBF 1120 is a

GOR in the pathogenesis of IPF. If GOR

potent intracellular inhibitor of tyrosine

therapy improves survival in patients with

kinases; its targets include PDGF receptors

IPF, then other treatment interventions to

a and b, vascular endothelial growth factor

decrease and/or control GOR should include

receptors 1-3, and fibroblast growth factor

aggressive conservative measures with

receptors 1-3. A recent study showed that

altered eating, drinking and sleep habits/

BIBF 1120 at a dose of 150 mg twice daily

behavioural patterns, decrease in abdominal

was associated with a trend toward a

girth, and/or laparoscopic anti-reflux

392

ERS Handbook: Respiratory Medicine

Table 2. International Society for Heart and Lung Transplantation guidelines

For referral

Radiographic or histological evidence of UIP irrespective of vital capacity

Histological evidence of fibrotic NSIP

For listing

Radiographic or histological evidence of UIP and any of the following:

TLCO ,39% pred

.10% reduction in FVC in the last 6 months

Oxygen saturation ,88% during 6MWT

Honeycombing on HRCT (fibrosis score .2)

Histological evidence of NSIP and any of the following:

TLCO , 35% predicted

.10% reduction in FVC or

.15% in TLCO in the last 6 months

surgery. However, further studies are

matrix, resulting in distortion of lung

needed to confirm these data.

parenchyma architecture. Therefore, lung

tissue regeneration, remodelling and repair

Lung transplantation is the only option that

mechanisms could represent new potential

definitely improves survival in IIP patients

therapeutic targets.

and the only option for patients who

respond poorly to medical therapy. IIPs

The discovery that stem cells can contribute

represent the second most frequent disease

to the formation of differentiated cell types,

that requires lung transplantation. It is

especially after injury, justifies the

extremely important to decide when to list a

experimental use of stem cells in tissue

patient for transplantation. Given the legal

regeneration. It is believed that stem cells

complexity of the process, early listing is

play a central role in cell injury and fibrotic

urged. Recently, the International Society for

process; however, their role is still

Heart and Lung Transplantation published

controversial. In particular, the mechanisms

guidelines for establishing the

of cell recruitment to site in case of tissue

characteristics and the criteria for

damage are not completely clear. Therefore,

transplantation and listing (table 2). The

embryo or adult stem cells transplantation

new guidelines recommend that

could be a valid novel therapeutic option in

appropriate patients with IPF should

pulmonary fibrosis. Official data confirming

undergo lung transplantation.

the efficacy and applicability of this

treatment are lacking; furthermore, the

Unfortunately, many patients die while

importance of immunosuppressive therapy

awaiting transplantation because of the poor

before stem cells transplantation is unclear,

availability of donor organs. Post-operative

as the data are poor.

mortality in transplanted patients is high,

because of rejection, infections and other

complications. 2- and 5-year survival rates

Further reading

following single lung transplantation are

American Thoracic Society, European

,70% and ,50%, respectively.

Respiratory Society.

(2002). Interna-

tional multidisciplinary consensus classi-

Stem cell-based therapy Given the recent

fication of the idiopathic interstitial pneu-

advances in IPF pathogenesis, new

monias. Am J Respir Crit Care Med; 165:

therapeutic models are being investigated,

277-304.

focusing on the cellular and molecular

Azuma A, et al.

(2005). Double-blind,

mechanisms underlying the disease. In

placebo-controlled trial of pirfenidone in

particular, alveolar epithelial cell injury

patients with idiopathic pulmonary fibrosis.

arises from an abnormal accumulation of

Am J Respir Crit Care Med; 171: 1040-1047.

fibroblasts and deposition of extracellular

ERS Handbook: Respiratory Medicine

393

Bouros D, et al.

(2005). Current and

practice guideline: The clinical utility of

future therapeutic approaches in idio-

bronchoalveolar lavage cellular analysis

pathic pulmonary fibrosis. Eur Respir J;

in interstitial lung disease. Am J Respir

26: 693-703.

Crit Care Med; 185: 1004-1014.

Castro DJ, et al. (2001). Diagnostic value

Raghu G, et al.

(2004). A placebo-

of D dimer in pulmonary embolism and

controlled trial of interferon c-lb in

pneumonia. Respiration; 68: 371-375.

patients with idiopathic pulmonary

Chetta A, et al. (2004). Pulmonary func-

fibrosis. N Engl J Med; 350: 125-133.

tion testing in interstitial lung diseases.

Raghu G, et al. (2011). An official ATS/

Respiration; 71: 209-213.

ERS/JRS/ALAT statement: Idiopathic pul-

Coultas DB, et al. (1994). The epidemiology

monary fibrosis: evidence-based guide-

of interstitial lung diseases. Am J Respir Crit

lines for diagnosis and management. Am

Care Med; 150: 967-972.

J Respir Crit Care Med; 183: 788-824.

King TE Jr, et al.

(2011). BUILD-3: a

Richeldi L, et al.

(2011). Efficacy of a

randomized, controlled trial of bosentan

tyrosine kinase inhibitor in idiopathic

in idiopathic pulmonary fibrosis. Am J

pulmonary fibrosis. N Engl J Med; 365:

Respir Crit Care Med; 184: 92-99.

1079-1087.

Kubo H, et al.

(2005). Anticoagulant

The Idiopathic Pulmonary Fibrosis

therapy for idiopathic pulmonary fibrosis.

Clinical Research Network.

(2012).

Chest; 128: 1475-1482.

Prednisone, azathioprine, and N-acetyl-

Lee JS, et al.

(2011). Gastroesophageal

cysteine for pulmonary fibrosis. N Engl J

reflux therapy is associated with longer

Med; 366: 1968-1977.

survival in idiopathic pulmonary fibrosis.

Ziesche R, et al.

(1999). A preliminary

Am J Respir Crit Care Med;

184:

study of long-term treatment with inter-

1390-1394.

feron c-1b and low-dose prednisolone in

Meyer KC, et al.

(2012). An Official

patients with idiopathic pulmonary

American Thoracic Society clinical

fibrosis. N Engl J Med; 341: 1264-1269.

394

ERS Handbook: Respiratory Medicine

Eosinophilic diseases

Andrew Menzies-Gow

The exact role of the eosinophil in health has

Eosinophilic bronchitis accounts for 10-30%

yet to be determined. It is believed to play a

of cases of chronic cough referred for

role in combating helminthic parasitic

specialist investigation. Eosinophilic

infections and, in health, eosinophils

bronchitis is defined as a chronic cough in

primarily reside within the gastrointestinal

patients with no symptoms or objective

mucosa. Eosinophilic lung diseases cover a

evidence of airflow obstruction, a histamine/

wide spectrum of pathology ranging from

methacholine PC20 (provocative concentration

airways disease, such as eosinophilic

causing a 20% fall in FEV1) of .16 mg?mL^-1

bronchitis, to parenchymal disease, such as

and .3% sputum eosinophilia.

eosinophilic pneumonia, and systemic

diseases, such as hypereosinophilic

It is unclear why eosinophilic inflammation

syndrome (HES) (table 1).

leads to asthma in some individuals and

eosinophilic bronchitis in others. Studies by

Nonasthmatic eosinophilic bronchitis

Brightling (2006) suggest that the key may

be mast cell localisation. In asthmatics,

Eosinophilic bronchitis is a common and

mast cells infiltrate airways smooth muscle,

treatable form of chronic cough that was first

resulting in airflow obstruction and

identified in 1989. Nonasthmatic

hyperresponsiveness. In eosinophilic

eosinophilic bronchitis is a condition that

bronchitis, mast cells infiltrate the

presents with a corticosteroid-responsive

airway epithelium, leading to bronchitis

chronic cough in nonsmokers. These patients

and cough.

have evidence of eosinophilic airway

inflammation without the variable airflow

Anti-inflammatory therapy with inhaled

obstruction or airway hyperresponsiveness

corticosteroids is the mainstay of the

characteristic of asthma.

treatment of eosinophilic bronchitis. Inhaled

corticosteroids produce a significant

improvement in symptoms as well as fall in

Key points

sputum eosinophilia. There is no evidence

to suggest that any one inhaled

Eosinophilic lung disease covers a

corticosteroid is more effective. Data is also

wide spectrum of pathology from

not available to guide the dose or duration

airways to parenchymal lung disease.

of inhaled corticosteroid therapy. Logically,

antileukotrienes may be of benefit, but this

N Always exclude secondary causes of

hypothesis has not been tested in clinical

eosinophilia before diagnosing acute

trials. In very resistant cases, oral

or chronic eosinophilic pneumonia.

corticosteroids may be required for

Novel therapies are being introduced

symptom control.

for eosinophilia, including tyrosine

kinase inhibitors and monoclonal

Little is known about the natural history of

antibodies against IL-5.

the condition, but it can be transient,

episodic or persistent unless treated.

ERS Handbook: Respiratory Medicine

395

Table 1. The causes and associations of eosinophilic lung disease

Eosinophilic lung disease

Cause/association

Eosinophilic bronchitis

Unknown

HES

Idiopathic

Lymphoproliferative variant with clonal

expansion of T-cells and IL-5 production

Myeloproliferative variant with fusion tyrosine

kinase FIP1L1-PDGFRA

Pulmonary eosinophilic syndromes

Acute eosinophilic pneumonia

Chronic eosinophilic pneumonia

Löffler’s syndrome

Tropical eosinophilia

Allergic bronchopulmonary aspergillosis

Aspergillus proliferation in airway lumen induces

Th2-mediated, IgE-driven bronchial

inflammation

Churg-Strauss syndrome

Eosinophilic vasculitis of small to medium-sized

vessels

Drug-induced pulmonary eosinophilia

Antibiotics

Antifungals

NSAIDS

Antiepileptics

Antipsychotics

Anticoagulants

Allopurinol

Methotrexate

Helminthic infections

Ascaris lumbricoides

Strongyloides

Schistosomiasis

Filariasis

Toxocara canis

Th: T-helper cell; NSAID: nonsteroidal anti-inflammatory drugs.

Acute and chronic eosinophilic pneumonia

hypersensitivity. Acute eosinophilic

pneumonia responds quickly to oral

Acute eosinophilic pneumonia presents as

corticosteroids with no relapse after

an acute febrile illness of ,1 month’s

stopping therapy.

duration and predominately affects cigarette

smokers. The average age at presentation is

Chronic eosinophilic pneumonia typically

30 years with symptoms of dyspnoea, cough,

presents in middle-aged asthmatic females

myalgia and fever. Patients often present

but it can also develop in nonasthmatic

with severe type I respiratory failure

individuals. The symptoms are gradually

requiring ventilation. Unlike other

progressive and include shortness of breath,

pulmonary eosinophilic syndromes, the

cough, fever and weight loss. Clinical

blood eosinophil count is usually normal.

examination demonstrates wheezing and

The chest radiograph demonstrates diffuse

hypoxia. Patients usually have a raised blood

alveolar and interstitial infiltrates. The

eosinophil count along with elevated

diagnosis is confirmed by the presence of a

inflammatory markers. The majority of

bronchoalveolar lavage eosinophilia of

patients have infiltrates visible on chest

.25% in the absence of parasitic, fungal or

radiography and they are peripherally

other infections, and no history of drug

distributed in about two-thirds of cases (fig. 1).

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ERS Handbook: Respiratory Medicine

HES and Churg-Strauss syndrome, which

should be excluded at the time of diagnosis.

Hypereosinophilic syndrome

HES is a heterogeneous group of disorders

characterised by the presence of marked

blood and tissue eosinophilia resulting in a

variety of clinical manifestations. The

following criteria are used to define

idiopathic HES:

N blood eosinophilia .1500 cells per mm³

for o6 months

absence of an underlying cause for the

eosinophilia

end organ damage due to the

eosinophilia

Idiopathic HES can occur at any age but tends

to develop in the 30s or 40s with a male

predominance. Nonspecific systemic

Figure 1. Chest radiograph of a patient presenting

symptoms are common. More specific

with chronic eosinophilic pneumonia demonstrating

symptoms will depend upon which organs are

the characteristic peripheral infiltrates.

affected. The lungs are involved in ,40% of

patients, and present with cough and airflow

limitation. Pulmonary function tests

demonstrate an obstructive pattern in

HRCT is more sensitive at demonstrating

patients with cough. In patients with cardiac

infiltrates and ,50% of patients also have

involvement, concomitant pulmonary fibrosis

mediastinal adenopathy. Patients respond

can occur, leading to a restrictive or mixed

well to oral corticosteroids but tend to

pattern. The chest radiograph can be normal

relapse on discontinuation of therapy. Many

or demonstrate spontaneously clearing

patients require long-term, low-dose oral

airspace shadowing in early disease. At a later

corticosteroids to control the condition; in a

stage, with multi-organ involvement, up to

small minority, alternative, steroid-sparing

one-third of cases will have diffuse,

agents have been used. This condition is

nonsegmental interstitial infiltrates.

frequently misdiagnosed as asthma. Blood

eosinophilia and pulmonary infiltrates

Dulohery et al. (2011) reported the frequency

respond to corticosteroids within 24-48 h,

of pulmonary HES and associated clinical

making it easy to miss this condition if the

and radiologic features. In their case series

relevant investigations are not performed

of 49 patients, 24% had parenchymal lung

prior to starting steroids.

involvement, which most commonly

consisted of patchy ground-glass opacities

Both acute and chronic eosinophilic

and consolidation; one patient exhibited

pneumonia are idiopathic conditions. It is

numerous pulmonary nodules. 27% had

important to exclude secondary causes of

asthma. Most patients with pulmonary

eosinophilia before diagnosing either

involvement of HES improved and no

condition. In clinical practice, this requires a

deaths were observed.

careful travel history asking about residence

in areas of endemic parasitic infection and a

The most important cause of morbidity and

careful drug history including illicit

mortality in idiopathic HES is cardiovascular

substances. The other main causes of a

involvement. Thromboembolic disease and

pulmonary eosinophilic syndrome are

involvement of the nervous system are also

allergic bronchopulmonary aspergillosis,

common presentations.

ERS Handbook: Respiratory Medicine

397

Until recently, oral corticosteroids have been

Further reading

the mainstay of treatment. Better

understanding of eosinophil biology has led

Allen J (2006). Acute eosinophilic pneu-

to the use of more logical targeted therapies.

monia. Semin Respir Crit Care Med; 27:

Distinct HES subtypes are now recognised.

142-147.

The myeloproliferative variant is associated

Brightling CE (2006). Chronic cough due

with the presence of a fusion tyrosine

to nonasthmatic eosinophilic bronchitis:

ACCP evidence based clinical practice

kinase, FIP1L1-PDGFRA (FIP1-like protein

guidelines. Chest; 129: Suppl. 1, 116S-121S.

1-platelet-derived growth factor receptor-a).

Dulohery MM, et al.

(2011). Lung

Historically, these patients had a poor

involvement in hypereosinophilc syn-

prognosis with poor steroid responsiveness.

dromes. Respir Med; 105: 114-121.

The use of the tyrosine kinase inhibitor

Klion AD, et al. (2006). Approaches to the

imatinib in this group of patients has

treatment of hypereosinophilic syndromes:

significantly improved their outcome.

a workshop summary report. J Allergy Clin

Immunol; 117: 1292-1302.

The lymphoproliferative variant is a

Marchand E, et al.

(2006). Idiopathic

consequence of increased production of

chronic eosinophilic pneumonia. Semin

eosinophilopoietic cytokines by clonal

Respir Crit Care Med; 27: 134-141.

populations of phenotypically abnormal,

Rhee CK, et al. (2013). Clinical character-

istics and corticosteroid treatment of

activated T-lymphocytes. Identification of

acute eosinophilic pneumonia. Eur Respir J;

interleukin (IL)-5 as a key mediator of

41: 402-409.

eosinophilopoiesis led to the use in clinical

Rothenberg ME, et al. (2008). Treatment

trials of an anti-IL-5 monoclonal antibody

of patients with the hypereosinophilic

(mepolizumab) for HES. Mepolizumab is an

syndrome with mepolizumab. N Engl J

effective corticosteroid-sparing agent in patients

Med; 358: 1215-1228.

with HES negative for FIP1L1-PDGFRA.

398

ERS Handbook: Respiratory Medicine

Drug-induced respiratory

disease

Philippe Camus and Philippe Bonniaud

Drug-induced respiratory disease (DIRD) is

Key points

a relatively common, generally

unpredictable set of complications of

DIRD is not uncommon, and can

therapy with or exposure to one of .700

involve the larynx, major and lower

distinct drugs (www.pneumotox.com).

airways, lung, pleura, pulmonary

Drugs account for about 3% of all

circulation, neuromuscular system and

interstitial lung disease (ILD) cases and

haemoglobin. Chemotherapy agents,

about 8-10% of acute lung injury (ALI)

amiodarone, ACE inhibitors, NSAIDs

cases are due to drugs, mainly

and b-blockers pose particular risk of

chemotherapy and amiodarone. The

adverse respiratory effects.

biologics (erlotinib, dasatinib, gefitinib,

Some DIRDs cause acute life-

imatinib and nilotinib), monoclonal

threatening respiratory distress,

antibodies (abciximab, adalimumab,

requiring immediate management.

bevacizumab, cetuximab and infliximab)

and etanercept can cause mechanism-

The clinical, imaging and pathological

based or idiosyncratic adverse respiratory

expression of DIRD may closely

reactions. Irradiation, inhaled or injected

resemble that of illnesses of other

substances of abuse, excipients and

causes or that occur idiopathically.

vehicles, herbals, and vaccines can also

Pathology is rarely specific for drug

cause respiratory injury. Iatrogenic non-

aetiology.

drug-induced complications include the

Diagnosing DIRD requires a high

adverse consequences of catheters, and

degree of awareness, up-to-date

medical, imaging and surgical procedures

knowledge and ruling out of other

(these are not covered here). The diagnosis

causes, particularly infection, using

of DIRD is mainly one of exclusion (table 1).

BAL and appropriate tests.

Aetiologies other than drugs must be

carefully excluded, including the pulmonary

Stopping the drug is often followed by

manifestations of the underlying illness

improvement in symptoms, signs and

when present, and opportunistic infections

imaging. Care should be taken to

due to Pneumocystis jiroveci or other fungi,

avoid relapse of the condition for

parasites, viruses or bacteria. Patients

which the drug was given.

exposed to methotrexate, chemotherapy

Corticosteroid therapy is reserved for

agents or immunosuppressive drugs

severe cases and where dechallenge

including prolonged corticosteroid therapy,

does not produce satisfactory

tumour necrosis factor (TNF)-a

improvement; duration varies with

antagonists, rituximab, and those who have

drug and pattern.

received radiation therapy to the chest, or

are stem cell or lung transplant recipients

Generally, rechallenge with the drug is

are particularly exposed to the risk of

discouraged as severe relapse can occur.

developing opportunistic respiratory

infections.

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399

Table 1. Checklist for diagnosing and managing DIRDs

Emergent management should be placed ahead of causality assessment while

managing acute drug-induced emergencies such as anaphylaxis, bronchospasm, asphyxia,

diffuse white-out, bleeding, tamponade, pulmonary hypertension, respiratory muscle

paralysis or methaemoglobinaemia.

Maintain a high degree of awareness. Two main questions arise:

1) Could new and otherwise unexplained signs and symptoms (respiratory and/or

nonrespiratory) be due to a drug or drugs? Check Pneumotox by drug names.

2) Which pattern of involvement may result from the drug the patients is on?

Check Pneumotox by patterns.

Take complete history and list current or past exposure to any medication, abused

substance, or herbal, chemical or physical agent.

Retrieve and review any pre-therapy imaging and pulmonary function, if available.

Review the possibility of respiratory involvement from any underlying disease present

(connective tissue disease including rheumatoid arthritis, malignant conditions, etc.).

Correlate time on each specific drug and timing of exposure (delay between first

exposure and onset of signs and symptoms). This can vary from minutes with

anaphylaxis or bronchospasm, to months or years with ILD.

Attempt to define the pattern of involvement (using clinical features, imaging, HRCT, BAL and

diuresis) in a noninvasive, conservative way. A lung biopsy is rarely indicated as the procedure

carries its own morbidity/mortality and may yield nonspecific findings. A matching table of drugs

and pathology patterns is available on Pneumotox (pattern XV) and in table 2.

Correlate each drug with pattern of involvement in the patient (see Further Reading and

Pneumotox)

Differential: evaluate the possibility of underlying disease or coincidental illness

(including heart failure or an opportunistic infection in the immunodepressed) versus drug-

induced disease

Most in vitro tests have fallen out of favour except the unusual drug-induced ANA,

ANCA and anti-HNE.

Discontinue drug, underlying condition permitting. Cover with a substitute drug

if needed. Expect improvement in hours, weeks or more depending on drug and pattern.

Decide on corticosteroid therapy. Corticosteroid therapy is indicated depending

on severity, extensity of involvement and response to drug discontinuance.

Organise follow-up for resolution of signs, symptoms, pulmonary physiology and imaging.

Consider rechallenge only if drug is vital, or with the purpose of desensitisation or

induction of tolerance, preferably if documented in the literature. Make sure the patient will

never get re-exposed to the culprit drug.

HNE: human neutrophil elastase.

Drugs history is now included in the workup

diagnostic test is used to diagnose it),

of any patient with ILD and the same should

angiotensin-converting enzyme inhibitors

apply to other patterns of drug-induced

(ACEIs), amiodarone (2-4%), methotrexate

respiratory involvement (table 3). Overall,

(0.5-1%), mineral lipids (paraffin) in the

the greatest incidence is with chemotherapy

elderly, mammalian target of rapamycin

agents including bleomycin (up to 50%,

(mTOR) inhibitors, nitrofurantoin, TNF-a

depending on the drug regimen and which

antagonists, tyrosine kinase inhibitors (TKIs),

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Table 2. Main imaging-pathological patterns of DIRDs

Pattern on chest radiograph or CT

Causal drugs

Pathology correlate

Diffuse haze

Drugs that cause interstitial pneumonia

Interstitial inflammation

Ground-glass opacity

(NSIP-like)

Chemotherapy agents

Early/mild pulmonary oedema,

alveolar haemorrhage or DAD

Localised ground-glass opacity

Radiation therapy

Early mild radiation lung injury

(interstitial oedema, cell sloughing,

cell debris)

Diffuse white-out

Drugs that produce acute ILD,

Dense cellular interstitial

pulmonary oedema, eosinophilic

pneumonitis with or without

pneumonia, DAD or DAH^#

eosinophilia

Acute pulmonary oedema

Alveolar haemorrhage

Disseminated ground-glass opacity

Drugs that cause interstitial pneumonia

Cellular interstitial pneumonia

with a mosaic pattern of

DIP

distribution

Bilateral perihilar alveolar opacities

Drugs that cause pulmonary oedema,

Pulmonary oedema

with a batwing pattern of

DAD or DAH

DAD

distribution

DAH

Subpleural areas of consolidation

Drugs that cause pulmonary eosinophilia

Eosinophilic pneumonia

or OP

Opacities with a recognisable

Amiodarone

Phospholipidosis

segmental or lobar pattern of

distribution

Statins

Paraffin

Exogenous lipoid pneumonia

Miliary pattern

BCG therapy

Granulomatous reaction

Methotrexate

Sirolimus

Area of consolidation

Drugs that cause OP or eosinophilic

A mass

pneumonia

Eosinophilic pneumonia

Amiodarone

Phospholipidosis

Amiodaronoma

Paraffin

Paraffinoma

Wandering opacities

Drugs that cause OP or PIE

Eosinophilic pneumonia

Irradiation for breast carcinoma

Multiple nodular opacities

Amiodarone

APT features

Bleomycin

Areas of nodular fibrosis

Pulmonary fibrosis

Chemotherapy agents

Pulmonary fibrosis

Low lung volumes

Amiodarone

NSIP-fibrotic or UIP pattern

Nitrofurantoin

Irradiation

NSIP: nonspecific interstitial pneumonia; DIP: desquamative interstitial pneumonia; OP: organising pneumonia;

BCG: bacille Calmette-Guérin; UIP: usual interstitial pneumonia.^#: see appropriate pattern at www.pneumotox.com

radiation therapy, drugs of abuse including

can be in the form of ILD, noncardiogenic

heroin and cocaine, levamisole, and liquid

pulmonary oedema, ALI/acute respiratory

silicone. As drugs may target any subsystem

distress syndrome (ARDS), alveolar

of the respiratory apparatus, varied clinical

haemorrhage, lung nodules, stridor and

and imaging presentations may ensue. DIRD

asphyxia, catastrophic bronchospasm,

ERS Handbook: Respiratory Medicine

401

Table 3. Patterns and mechanisms of DIRD

Pattern

Pathophysiology

Parenchymal lung disease

Interstitial/alveolar inflammation/filling

Interstitial lung diseases^#

Influx/persistence of inflammatory cells

Interstitial oedema

Endogenous lipoid pneumonia

Disordered phospholipid catabolism^"

(phospholipidosis)

Exogenous lipid pneumonia

Accumulation of nondigestible oil and oil-laden

macrophages in alveolar spaces

Pulmonary fibrosis

Scarring

Diffuse pulmonary calcification

Precipitation of calcium in pulmonary interstitium

Foreign body reaction

Granulomas around drug or excipients

Pulmonary nodules

Circumscribed areas of OP or fibrosis

Pulmonary oedema

Noncardiogenic pulmonary oedema

Increased permeability of alveolar barrier to fluid

Cardiogenic pulmonary oedema

Raised pulmonary venous pressure due to myocardial injury

ALI/ARDS

Increased permeability of alveolar capillary barrier to

fluid and proteins

Transfusion-related ALI

Immune-mediated blood reaction to anti-HLA

antibodies of donor origin. Neutrophil sequestration

Pulmonary haemorrhage

DAH

Synchronous capillary bleeding usually from

disordered coagulation, low platelets or capillaritis

ANCA-associated DAH

ANCA/activated neutrophil-mediated capillaritis and

consequent bleeding

Airway involvement

Bronchospasm/asthma

Subverted prostaglandin/leukotriene handling

Obliterative bronchiolitis

Acceleration of bronchiolitis from the underlying

disease?

Cough

Bradykinin-mediated?

Foreign body bronchiolitis

Airway-centred reaction against drug or vehicle

Large airway involvement or closure

Angio-oedema

Bradykinin-mediated?

Haematoma causing UAO

Localised bleeding causing compression

Pulmonary vasculopathy

Pulmonary thromboembolism

Excessive coagulation

Pulmonary arterial hypertension

Serotonin-based?

Pulmonary vasculitis/capillaritis

Drug-induced ANCAs

Fat/lipid/silicone embolism

Increased capillary permeability

Bypass of foreign fluid through the lung, causing brain injury

Foreign body vasculopathy

Granulomatous reaction around foreign drug-

associated material

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Table 3. Continued

Pattern

Pathophysiology

Cement/mercury embolism

Lodging of acrylate or metallic mercury in the distal

pulmonary circulation

Pleural/pericardial involvement

Pleural effusion

Pleural inflammation

Pleural thickening/fibrosis

Scarring/fibrosis

Pleural effusion and drug lupus

Autoimmune-mediated?

Haemothorax

Drug-induced disordered coagulation

Chylothorax

PDGFR inhibition?

Serositis

Autoimmune-mediated?

Haemopericardium

Drug-induced disordered coagulation

Pleuritic chest pain

Pleural inflammation

Pleuroparenchymal fibroelastosis

Scarring, elastic fibre type

Pleural mass or masses

Scarring around foreign material (talc)

Mediastinal involvement

Lymphadenopathy

Unknown

Mediastinal lipomatosis

Central fat distribution⁺

Fibrosing mediastinitis

Scarring, usually radiation induced

Neuromuscular involvement

Respiratory muscle weakness/

Myoneural presynaptic blockade of acetylcholine

paralysis

release

Ventilatory depression/apnoea

Opiate effect on central ventilatory oscillator

Respiratory muscle/myopathy

Corticosteroid-induced muscle wasting

Statin-induced myopathy

Acquired haemoglobinopathy

Methaemoglobinaemia

Haemoglobin poisoning via iron oxidation

Systemic syndromes

DRESS

T-cells, HHV6 or HHV8

Antiphospholipid antibody

Unknown

syndrome

Drug-induced lupus

Drug-triggered autoimmunity

Anaphylaxis

Some due to drug-induced IgE release

Hypersensitivity reactions

Reaction to foreign (e.g. murine) proteins

Eosinophilic granulomatosis with

Unknown

polyangiitis (Churg-Strauss)

Immune reconstitution syndrome

Exaggerated reaction to microorganisms once immune

cells repopulate tissues

Polymyositis/dermatopolymyositis

Unknown

Sarcoidosis

Unknown

Systemic vasculitis

Drug-induced ANCA-mediated?

ERS Handbook: Respiratory Medicine

403

Table 3. Continued

Pattern

Pathophysiology

Miscellaneous

Vertebral compression fracture

Osteoporosis

Radiation-induced damage

Rib fracture

Osteoporosis

Radiation-induced damage

Chest deformity/platythorax

Pleuropulmonary fibrosis in childhood

Fire-eater’s lung

Aspiration of liquid hydrocarbon

See also www.pneumotox.com UAO: upper airway obstruction; OP: organising pneumonia; HLA: human

leukocyte antigen; PDGFR: platelet-derived growth factor receptor; HHV: human herpesvirus.^#: including

pulmonary infiltration with eosinophilia and OP;^": amiodarone is the typical causal drug;⁺: common with

corticosteroid therapy.

cough, pulmonary hypertension, pleural

Pathophysiology: mechanisms

effusion, cardiac tamponade, haemothorax,

neuromuscular blockade, or haemo-

Mechanisms in DIRD are summarised in

globinopathy.

table 3. With a few drugs (e.g. chemotherapy

agents and amiodarone), reactions may

Life-threatening presentations include

correspond to a dose-related cytopathic

anaphylaxis, acute laryngeal angio-oedema

mechanism. Identification of a threshold

(usually from ACEIs), catastrophic

dosage may then enable risk reduction.

bronchospasm (typically from nonsteroidal

However, most drug reactions are

anti-inflammatory drugs (NSAIDs) or b-

idiosyncratic and unpredictable, occurring in

blockers), acute methotrexate

only a few predisposed individuals, possibly

pneumonitis, minocycline- or tobacco-

with a predilection in those who harbour a

related acute eosinophilic pneumonia,

distinct pharmacokinetic trait. Several drugs

tocolytic- or chemotherapy-induced

in a given family produce a stereotyped

pulmonary oedema, chemotherapy-

pattern of involvement (e.g. b-blockers,

induced ALI or ARDS, anticoagulant-

NSAIDs and bronchospasm, NSAIDs and

induced diffuse alveolar haemorrhage

eosinophilic pneumonia, chemotherapy and

(DAH), large volume-occupying pleural

pulmonary oedema or ALI-ARDS/diffuse

effusions, cardiac tamponade,

alveolar damage (DAD), anticoagulants and

methaemoglobinaemia, neuromuscular

DAH, and ergots and pleural involvement),

paralysis and systemic conditions such as

suggesting a reaction linked to the

DRESS (drug reaction with eosinophilia

pharmacological effect of the drug, even

and systemic symptoms). These

though the pharmacophores differ. Drug

presentations, particularly when they occur

disposition in the lung may be a relevant

in the emergency room or intra- or

factor for toxicity. Amiodarone and its

perioperatively, portend immediate

metabolite concentrate in lung, causing

severity and require prompt evaluation.

toxicity to lung cells. The slow efflux of these

Management is aimed at restoring airway

compounds from the lung may explain both

patency, maintaining oxygenation and

the slow resolution of amiodarone

reversing drug-induced inflammation and

pulmonary toxicity (APT) and relapses of the

oedema using drug withdrawal and

condition even when amiodarone is

corticosteroid therapy. Further

discontinued, at a time when corticosteroid

compounding these issues, drugs can

therapy is being tapered. The pulmonary

cause cardiac injury, which may cause

metabolism of nitrofurantoin,

heart failure and can impact the lung and

cyclophosphamide, mitomycin, bleomycin

pleura (table 3).

and paraquat in designated lung cells

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ERS Handbook: Respiratory Medicine

generates reactive oxygen species, which

For many drugs, there may be a delay of

cause cell stress and death, pulmonary

weeks, months or years before symptom

inflammation, and/or fibrosis. The

presentation. Presenting symptoms include

heterogeneous distribution of activating

a nonproductive cough, dyspnoea,

enzymes in lung may account for the

wheezing, cyanosis, fever, rigors and

selective targeted alveolar or bronchiolar

malaise. Acute bronchospasm, angio-

injury seen with certain drugs. Drug-induced

oedema, cardiovascular collapse, shock,

asthma is largely non-IgE-dependent. Small

stridor, hoarseness, wheezing, haemoptysis

incremental doses of NSAIDs or aspirin can

or acute chest pain are less common

be given to asthmatics who are intolerant to

presentations. Other features include a

these drugs to induce a state of tolerance

cutaneous rash, lymph-node enlargement,

that can be maintained on continued

myositis, livedo reticularis, skin necrosis,

exposure to the medication. Unusual cases

hepatitis or other deep-seated organ

of respiratory injury result from deposition

involvement. Rare patients present with a

of drug excipients in the small airways and

systemic picture reminiscent of the lupus

pulmonary arterioles, causing reactive

erythematosus (lupus-inducing agents),

foreign body obstructive granulomas that

granulomatous polyangiitis

cause obstruction to airflow or pulmonary

(propylthiouracil), eosinophilic

hypertension. Amiodarone, radiation and

granulomatous polyangiitis (leukotriene

chemotherapy agent toxicity is potentiated

receptor antagonists) or

by molecular oxygen. Patients must be

dermatopolymyositis (statins). Severity of

spared unnecessary association of these

DIRD is linked to the acuteness of

factors. Patients on chemotherapy for

presentation, extent and location of the

malignant conditions or who receive

pathological process, and reversibility upon

amiodarone in the long term may exhibit a

drug discontinuance or under the influence

time- or dose-related decrease in TLCO

of therapy. Life-threatening presentations

thought to reflect subclinical toxicity,

include anaphylactic shock, upper airway

without necessarily annunciating the

angioedema and closure, acute ILD,

development of clinical disease. In that

pulmonary infiltration with eosinophilia

setting, risk-to-benefit evaluation of drug

(PIE), organising pneumonia,

discontinuation or maintenance is indicated

noncardiogenic pulmonary oedema or

alveolar haemorrhage, catastrophic

in each patient.

bronchospasm, large pleural effusions,

Clinical presentation

tamponade, methaemoglobinaemia,

apnoea, and respiratory paralysis. Drug

Drugs can cause injury when administered

withdrawal, if followed by abatement of

by the oral, intravenous, intramuscular,

signs and symptoms, supports the drug

inhaled, pleural, dermal, intrathecal,

aetiology. The risk of rechallenge should be

intracoronary or gynaecological route. DIRD

balanced against the merit of securing the

can also develop following delivery in organs

diagnosis, as fatal reactions may ensue.

situated upstream of the lung (e.g.

vertebrae, brain, liver and oesophagus). A

Many clinical situations are inextricably

high index of suspicion is warranted. Drugs

complex, particularly in ILD patients who are

should be a diagnostic consideration in any

exposed to several possible causal drugs,

patient with otherwise unexplained

who have received radiation therapy, or in

symptoms, abnormal pulmonary physiology

whom DIRD cannot be confidently

or new radiographic findings while being

separated from underlying disease-related

treated with a compatible drug or set of

pulmonary involvement or from an

drugs. Some adverse reactions develop

infection. Oncology patients who are

within minutes of exposure, suggesting

receiving chemotherapy, TKIs, mTOR

causality (e.g. b-blocker-induced

inhibitors and/or radiation therapy, or those

bronchospasm, and chemotherapy- or

with rheumatoid arthritis who receive

tocolytic-induced pulmonary oedema).

combination therapy with corticosteroids

ERS Handbook: Respiratory Medicine

405

and/or anti-TNF antibody therapy exemplify

Mediastinal or hilar lymphadenopathy

these difficulties. Careful assessment of

characterises those cases with a drug-

each drug’s causality and meticulous

induced sarcoid-like reaction. Pulmonary

exclusion of an infection are required using

opacities in exogenous lipoid pneumonia

molecular techniques on bronchoalveolar

exhibit low attenuation numbers, and

lavage (BAL) fluid. Notwithstanding that,

pulmonary arteries and their branches are

patients may progress without a firm

discernible within the involved area.

diagnosis despite exclusion of an infection,

Radiation pneumonitis develops

withdrawal of the suspect drug,

preferentially in the area of the radiation

corticosteroids and empiric antibiotic

beam, although current stereotactic body

therapy. Diagnosing drug-induced ILD is

irradiation tends to produce circumscribed

also difficult in patients with autoimmune

whorled foci of radiation pneumonitis.

conditions, or in recipients of solid organ or

Inferring pathology from the pattern seen on

stem cell transplants who receive long-term

imaging should be interpreted with caution.

treatments with cytotoxic agents,

Fatty mediastinal deposits suggest

immunosuppressive drugs, rituximab and

corticosteroid therapy. Embolism of acrylate

corticosteroids.

cement or mercury can be visualized as

branched vascular densities on unenhanced

Imaging

CT. An air-fluid level or pneumothorax can

be a complication of chemotherapy-induced

Imaging is most useful in patients presenting

tumoural cavitation.

with pulmonary opacities. Patterns and

correlates are shown in table 2.

BAL, pathology and other tests

The extent of involvement seen on imaging

BAL is indicated to rule out an infection

roughly correlates with gas exchange. HRCT

(particularly P. jiroveci) via stains, cultures

discloses inter- and intralobular septal

and reverse transcriptase PCR. BAL can also

thickening, disseminated lobular opacities,

indicate which cell type (i.e. lymphocytes,

faint or dense ground-glass shadowing, or

eosinophils or neutrophils) is increased, and

alveolar filling. Pleural effusion denotes

whether atypical cells or phospholipid-laden

severe ILD or pulmonary oedema, or occurs

(foamy) alveolar macrophages are present.

in isolation as a complication of therapy

BAL is useful to diagnose methotrexate

with one or more of ,60 different drugs.

pneumonitis, drug-induced eosinophilic

Amiodarone pulmonary toxicity takes the

pneumonias, APT and chemotherapy lung.

form of asymmetric pulmonary opacities,

BAL cell numbers normalise as patients

areas of condensation that may be electron-

improve. The BAL in exogenous lipoid

dense due to the two iodine atoms per

pneumonia contains stainable mineral lipids

amiodarone molecule, a density with

free in the BAL fluid and within vacuoles in

recognisable segmental distribution or,

alveolar macrophages.

rarely, shaggy lung nodules. Early

‘chemotherapy lung’ corresponding to DAD

Drugs can cause virtually any known pattern

and ALI is in the form of a diffuse haze or

of ILD, including: cellular or fibrotic

ground glass. Late chemotherapy lung

nonspecific interstitial pneumonia;

resembles pulmonary fibrosis. Eosinophilic

eosinophilic pneumonia; ALI or DAD;

pneumonia can manifest with lung

classic or acute fibrinous organising

opacities, having a preferentially subpleural

pneumonia; interstitial granulomas; alveolar

distribution. Acute nitrofurantoin lung is in

haemorrhage; pulmonary capillaritis or

the form of diffuse haze and small pleural

vasculitis; desquamative, giant-cell or

effusions, while the chronic form of the

lymphocytic-interstitial pneumonia; a usual

disease shows scattered

interstitial pneumonia or pulmonary alveolar

peribronchovascular zonal consolidation.

proteinosis pattern; and diffuse pulmonary

Organising pneumonia may present with

calcification. These are not specific to the

characteristic migratory opacities on serial

drug aetiology. Only phospholipidosis and

chest films or diffuse involvement.

exogenous lipoid pneumonia are suggestive

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ERS Handbook: Respiratory Medicine

enough to point to the drug aetiology. While

causal drugs include NSAIDs, antibiotics

examination of a lung biopsy sample helps

(e.g. minocycline), abused drugs and recent

eliminate a condition other than drugs,

uptake of tobacco smoking. Rechallenge is

including an infection, a risk-benefit

contraindicated, as relapse will almost

analysis is not available and mortality is

inevitably occur. Severe systemic

significant, especially in the hypoxaemic or

presentations characterised by a cutaneous

immunodepressed. A conservative approach

rash and deep-seated organ involvement are

is advised, where drug dechallenge is the

termed DRESS or anticonvulsant syndrome.

usual first step.

APT is a distinctive condition that develops

No in vitro test of monocyte cell migration in

insidiously over months or years into

the presence of a drug or metabolite has

treatment with amiodarone in ,3% of

demonstrated utility in DIRD, and these can

patients. High dosages and advanced age

be misleading. Certain phenotypic traits may

increase the risk of developing the

indicate an increased risk of developing DIRD.

condition. APT takes the form of asymmetric

However, these tests are not widely available.

areas of pneumonitis or consolidation that

can be electron-dense on HRCT, as is liver

Monitoring of drug levels in plasma can be

tissue. Pulmonary function is restrictive in

helpful to track aspirin over-dosing, or

nature. Foamy cells in the BAL are

exposure to illicit opiates or levamisole.

suggestive but not diagnostic of APT. Other

Specific reactions

APT presentations include ground-glass

shadowing, lung nodules, pulmonary

Parenchymal lung disease Methotrexate

fibrosis or pleural effusion. Amiodarone

pneumonitis typifies acute fulminant drug-

withdrawal may not be sufficient for APT to

induced ILD, a condition that can be

resolve due to the high affinity and

produced by ,70 other drugs. The condition

persistence of amiodarone in lung tissue.

develops with no forewarning symptoms in

Corticosteroid therapy often is indicated to

patients on long-term methotrexate, typically

speed up recovery. Severe APT can occur

those with rheumatoid arthritis. A

after thoracic surgery, particularly in oxygen-

background of pre-existing ILD is a risk

exposed patients in the form of an ARDS

factor. The disease manifests with cough,

picture. Prognosis is guarded.

fever, dyspnoea and diffuse pulmonary

opacities, sometimes with rapidly

About 150 drugs can cause NCPE

progressive white-out and hypoxaemic

(noncardiogenic pulmonary oedema),

respiratory failure. Lymphocytes dominate in

including the chemotherapeutic agents

the BAL. The main differential is

taxanes and gemcitabine, blood products,

Pneumocystis or another opportunistic

tocolytics, and aspirin. Severity ranges from

infection that needs be ruled out using the

transient pulmonary infiltrates following

BAL. Methotrexate pneumonitis may also

each course with the drug to acute

follow less severe a course with faint

pulmonary oedema or an ARDS picture.

pulmonary opacities on imaging. Rarely,

Chemotherapy lung takes the form of

pulmonary fibrosis develops following an

pulmonary infiltrates during or shortly after

episode of methotrexate lung. Corticosteroid

completion of treatment with the drug.

therapy is indicated in severe cases.

Bleomycin, cyclophosphamide, gemcitabine,

Pulmonary eosinophilia is a common

nitrosoureas and taxanes are classic causal

pattern of reaction to one of .150 drugs.

drugs, with more recent evidence

Other causes of pulmonary infiltrates and

implicating TKIs (cetuximab, erlotinib,

eosinophilia must be ruled out, including

gefitinib and pemetrexed). On pathology,

parasitic infestation. There is bilateral

there is modest interstitial inflammation

shadowing in the context of peripheral and

and oedema, a reactive epithelium, and

BAL eosinophilia. Acute eosinophilic

areas of ALI or DAD. The condition may

pneumonia is a severe form of PIE with

improve upon drug discontinuance and

acute respiratory failure. Characteristic

corticosteroid therapy. In more advanced

ERS Handbook: Respiratory Medicine

407

cases, an ARDS picture develops. Late cases

is reasonably excluded and wherever drug

present irreversible pulmonary fibrosis.

withdrawal is not followed by improvement.

Drug-induced organising pneumonia

Airway involvement Angio-oedema classically

resembles cryptogenic organising

occurs with ACEIs and it is more common in

pneumonia or organising pneumonia of

middle-aged or elderly African-American

other causes. It is in the form of migratory

women. The condition may develop within

opacities, a fixed opacity or mass, or diffuse

hours of the first administration of the drug

shadowing with respiratory failure. Main

or it occurs months or years into an

causal agents include amiodarone,

uneventful treatment, in the form of rapidly

interferons, minocycline, rituximab, statins

progressive breathing difficulty due to upper

and breast radiation therapy. Drug

airway oedema and narrowing. Oedema of

withdrawal is followed by improvement

the lips, tongue, mouth floor, arytenoids and

while failure to recognise the drug aetiology

larynx has been reported, but the thoracic

exposes to the risk of relapses.

trachea is typically spared. Yearly incidence is

Corticosteroid therapy is reserved for severe

,1%, which makes it a significant cumulative

organising pneumonia cases or those with

risk in patients treated with these

equivocal effect of drug dechallenge.

medications over the long term. Some

patients develop the condition after airway

Interferons, anti-TNF agents and a few other

manipulation or the trauma of intubation.

drugs may cause pulmonary infiltrates and

About 40% of the patients are admitted to an

lymphadenopathy, and a granulomatous

intensive care unit (ICU) and mechanical

pattern of reaction mimicking sarcoidosis. A

ventilation is indicated in about 10%.

confirmatory biopsy and interferon-c test for

Emergent identification and maintenance of

TB may be indicated to rule out an infection.

upper airway patency is essential.

Orotracheal intubation is indicated in severe

Drug-induced DAH is best diagnosed by

cases. Short of stabilising the airway,

BAL, which shows bloodier return on

emergent tracheostomy may be required,

sequential aliquots. Anticoagulants,

with significant attending risks. Although

thrombolytic agents, abciximab and other

patients improve upon drug discontinuance,

antiplatelet agents, propylthiouracil, and

close follow-up is necessary as a rebound

cocaine (among 70 other drugs) can cause

phenomenon can occur in the first 24-48 h.

the syndrome. DAH is with or without

Patients should not be re-exposed to any

capillaritis. Rarely, alveolar haemorrhage

ACEI, or grave relapse can occur. Angiotensin

occurs as a manifestation of drug-induced

receptor II blockers should be given

anti-neutrophil cytoplasmic antibody

prudently, as a few patients will cross-react.

(ANCA) vasculitis (mainly propylthiouracil-

or levamisole-induced).

Catastrophic bronchospasm may follow

Pulmonary fibrosis can occur as a

exposure to as little as one tablet of NSAID,

complication of treatments with

aspirin or nonselective b-blockers (among

chemotherapy agents, amiodarone and

120 other drugs). The accident occurs within

irradiation (then conforming to the radiation

minutes, with a predilection for aspirin-

portal). Patients present with dyspnoea,

sensitive individuals, atopics and

diffuse linear or streaky opacities and

asthmatics. About 15% of ICU-admitted

volume loss on imaging. In contrast to

asthma attack cases are triggered by

interstitial pulmonary fibrosis,

exposure to such drugs. Insufflated heroin

honeycombing is unusual. The condition

has recently emerged as a significant cause

may stabilise with or progress despite drug

of severe bronchospasm and urine drug

discontinuance. Response to corticosteroid

screening is indicated. Rechallenge with the

therapy is often limited. A few patients have

culprit drug inevitably leads to relapse with a

received a lung transplant.

risk of hypoxic brain damage and death.

Corticosteroid therapy is indicated in severe

Lone, chronic, annoying cough is a common

drug-induced ILD, preferably if an infection

complication of treatments with ACEI.

408

ERS Handbook: Respiratory Medicine

Figure 1. Radiographic patterns of a-c) drug-induced parenchymal injury, d

and e) bleomycin pulmonary toxicity, f and g) drug-induced eosinophilic

pneumonia, h and i) acute pulmonary oedema, j and k) amiodarone

pulmonary toxicity, and l and m) organising pneumonia.

Incidence depends on which ACEI is used. It

serosanguineous effusion. Lupus-inducing

may be difficult to make sure when exactly

drugs can cause drug lupus, which

the cough started with respect the when the

manifests with pleuritis, pleural or

ACEI was started. When in doubt,

pleuropericardial effusion, and circulating

dechallenge is indicated. The cough remits

and pleural antinuclear antibody (ANA).

with drug discontinuance, except if it was

Anti-TNF agents (infliximab, etanercept and

revealing an underlying lung condition.

adalimumab) and interferons may also

cause lupus. Sometimes, anti-double

Rare cases of penicillamine-induced

stranded DNA antibodies are present as

obliterative bronchiolitis have been reported.

well. Signs, symptoms and ANA resolve

These may reflect acceleration of underlying

upon discontinuation of the drug

small airway disease related to the

background connective tissue disease.

All ergots are notable for the insidious

Obliterative bronchiolitis can complicate

development of bilateral pleural thickening

herbal therapy with the Asian Sauropus shrub

with or without an effusion, causing

leaf, or be a manifestation of graft versus host

dyspnoea, chest pain, audible friction rubs

disease or lung rejection in stem-cell and

and restrictive lung dysfunction. There is

lung transplant recipients, respectively.

definite but slow improvement upon

discontinuance of the drug.

Foreign-body bronchiolitis has been

Pulmonary vasculopathy This condition is

described in a few subjects who intentionally

mostly is in the form of pulmonary

inhaled cosmetic talc.

hypertension analogous to primary

Pleura Nearly 60 drugs can injure the

pulmonary hypertension. Iatrogenic

pleura, including ergolines and dasatinib.

pulmonary hypertension may follow

Involvement is in the form of a free-flowing

treatments with amphetamine-like

exudate with or without eosinophilia, or a

anorectics (fenfluramine and benfluorex) or

ERS Handbook: Respiratory Medicine

409

dasatinib. Pulmonary hypertension in drug

Khasnis AA, et al. (2010). Tumor necrosis

abusers stems from injection of crushed

factor inhibitors and lung disease: a

tablets, or results from stimulant

paradox of efficacy and risk. Semin

(amphetamine) use or abuse.

Arthritis Rheum; 40: 147-163.

Lara AR, et al.

(2010). Diffuse alveolar

Methaemoglobinaemia is a drug-induced

hemorrhage. Chest; 137: 1164-1171.

state of ferric (rather than ferrous) iron

Marchiori E, et al. (2011). Exogenous lipoid

oxidation in haemoglobin. Methaemoglobin

pneumonia. Clinical and radiological man-

is a poor oxygen carrier. Clinical presentation

ifestations. Respir Med; 105: 659-566.

is slate-grey cyanosis, a low SpO₂, and a

Min JH, et al. (2011). Drug-induced inter-

normal measured PaO₂ and calculated SaO₂.

stitial lung disease in tyrosine kinase

Actual measurement of methaemoglobin is

inhibitor therapy for non-small cell lung

indicated in patients exposed to a causative

cancer: a review on current insight. Cancer

drug, mainly benzocaine, dapsone, nitrites

Chemother Pharmacol; 68: 1099-1109.

and nitric oxide.

Newsome BR, et al.

(2011). Diffuse

alveolar hemorrhage. South Med J; 104:

269-274.

Papiris SA, et al.

(2010). Amiodarone:

Further reading

review of pulmonary effects and toxicity.

Barclay JA, et al. (2011). Dapsone-induced

Drug Saf; 33: 539-558.

methemoglobinemia: a primer for clin-

Rubin RL (2005). Drug-induced lupus.

icians. Ann Pharmacother; 45: 1103-1315.

Toxicology; 209: 135-147.

Cacoub P, et al.

(2011). The DRESS

Saito Y, et al. (2012). Current status of

syndrome: a literature review. Am J Med;

DILD in molecular targeted therapies.

124: 588-597.

Int J Clin Oncol; 17: 534-541.

Camus P. The Drug-Induced Respiratory

Sanchez-Borges M, et al.

(2010).

Disease Website. www.pneumotox.com

Angiotensin-converting enzyme inhibitors

Chin KM, et al. (2006). Is methampheta-

and angioedema. Allergy Asthma Immunol

mine use associated with idiopathic

Res; 2: 195-198.

pulmonary arterial hypertension? Chest;

Sarzi-Puttini P, et al.

(2005). Drug-

130: 1657-1663.

induced lupus erythematosus. Autoimmu-

de Jesus Perez V, et al. (2011). Drugs and

nity; 38: 507-518.

toxins-associated pulmonary arterial hyper-

Schreiber J

(2011). Drug-induced lung

tension: lessons learned and challenges

diseases. Dtsch Med Wochenschr;

136:

ahead. Int J Clin Pract Suppl; 169: 8-10.

631-634.

Hadjinicolaou AV, et al.

(2011a). Non-

Schwaiblmair M, et al.

(2012). Drug

infectious pulmonary complications of

induced interstitial lung disease. Open

newer biological agents for rheumatic

Respir Med J; 6: 63-74.

diseases - a systematic literature review.

Slavenburg S, et al. (2010). Pneumonitis

Rheumatology (Oxford); 50: 2297-2305.

as a consequence of

(Peg)-interferon-

Hadjinicolaou AV, et al.

(2011b). Non-

ribavirin combination therapy for hepati-

infectious pulmonary toxicity of rituxi-

tis C: a review of the literature. Dig Dis Sci;

mab: a systematic review. Rheumatology

55: 579-585.

(Oxford); 51: 653-662.

Torrisi JM, et al. (2011). CT findings of

Hamblin MJ, et al. (2011). Rheumatoid

chemotherapy-induced toxicity: what radi-

arthritis-associated interstitial lung dis-

ologists need to know about the clinical

ease: diagnostic dilemma. Pulm Med;

and radiologic manifestations of che-

2011: 872120.

motherapy toxicity. Radiology; 258: 41-56.

410

ERS Handbook: Respiratory Medicine

Pulmonary embolism

Massimo Pistolesi

Despite the recent advances in prevention

General rules for the diagnostic work-up of

and diagnostic imaging, pulmonary

patients clinically suspected of pulmonary

embolism remains a major health problem.

embolism

The incidence of this pathological condition

is as high as one in 1000 cases per year in

N Pre-test clinical probability of pulmonary

embolism should be objectively assessed

the general population. Early diagnosis is

in each patient.

fundamental as early treatment is highly

N D-dimer should be determined if pre-test

effective. However, due to the low specificity

probability of pulmonary embolism is low

of its clinical presentation, this common

or intermediate.

disease is still underdiagnosed and it is

N Diagnostic imaging of the chest should

estimated that in the USA .100 000 people

be used to assess post-test probability of

die each year of pulmonary embolism.

pulmonary embolism in most patients.

Several points are summarised below

Further testing is necessary when the

concerning the diagnostic strategies to be

post-test probability of pulmonary

adopted in patients with clinical suspicion of

embolism is neither sufficiently low nor

pulmonary embolism that have been

sufficiently high to permit therapeutic

highlighted and brought to the attention of

decisions.

the scientific community by recent scientific

N Diagnostic strategies of pulmonary

publications, expert reviews and

embolism can differ significantly in

international guidelines.

different clinical contexts and special

conditions.

Pre-test clinical probability of pulmonary

Key points

embolism

N Although early treatment is highly

A thorough clinical evaluation is the key step

effective, pulmonary embolism is

in raising the suspicion of the disease and

underdiagnosed and, therefore,

setting up appropriate diagnostic strategies.

remains a major health problem.

A recent study has shown that the vast

majority of patients with pulmonary

N Diagnostic strategy should be based

embolism has at least one of four symptoms

on clinical evaluation of the

which, in decreasing order of frequency, are:

probability of pulmonary embolism.

N The NPVs and PPVs of diagnostic

sudden onset dyspnoea

tests for pulmonary embolism are

chest pain

high when the results are concordant

fainting (or syncope)

with the clinical assessment.

haemoptysis

N Additional testing is necessary when

Although the diagnostic yield of individual

the test results are inconsistent with

clinical symptoms, signs and common

clinical probability.

laboratory tests is limited, the combination

of these variables, either by empirical

ERS Handbook: Respiratory Medicine

411

assessment or by a prediction rule, can be

assessed in each patient with suspected

used to stratify patients by risk of pulmonary

pulmonary embolism before any further

embolism (low, intermediate or high). The

objective testing occurs. Future research is

results of two broad prospective studies in

needed to develop standardised models, of

the 1990s (Prospective Investigation of

varying degrees of complexity, which may

Pulmonary Embolism Diagnosis (PIOPED)

find applications in different clinical settings

and Prospective Investigative Study of Acute

to predict the probability of pulmonary

Pulmonary Embolism Diagnosis (PISA-

embolisms.

PED)) indicate that physicians’ estimates of

D-dimer

the clinical likelihood of pulmonary

embolism, even if based on empirical

Plasma D-dimer levels are elevated in the

assessment, do have predictive value.

presence of simultaneous activation of

Three objective scoring systems have been

coagulation and fibrinolysis. Consequently,

tested prospectively and validated in large-

a normal D-dimer level has a high NPV for

scale clinical trials:

pulmonary embolism or deep vein

thrombosis (DVT). However, endogenous

N Wells score

fibrin production may be increased in a wide

N Geneva score

variety of conditions including, cancer,

N Pisa score

inflammation, infection, pregnancy and

chronic illnesses. Elevated plasma D-dimer

The three scoring systems perform

levels have, for this reason, a low positive

reasonably well in objectively assessing the

predictive value (PPV) for pulmonary

clinical probability of pulmonary embolism

embolism and DVT.

in outpatients or emergency room patients.

The Pisa score seems to perform better than

The value of D-dimer measurement in the

other scoring systems in hospitalised

diagnostic work-up of each patient must be

patients. It appears that fully standardised

considered according to the determined

scoring systems, such as the Wells and

clinical probability of pulmonary embolism

Geneva scores, with no implicit evaluation

and the sensitivity of the particular method

of symptoms (e.g. dyspnoea and chest pain)

of D-dimer measurement employed. A

or simple instrumental findings (e.g. ECG

negative D-dimer test result, measured by

and chest radiograph), did not perform

any method, in combination with a low

better than subjective clinical judgment of

probability clinical assessment, excludes

experienced physicians in the PIOPED and

pulmonary embolism with accuracy. An

the PISA-PED studies. Conversely,

intermediate clinical probability also would

interpretation of ECG and chest radiographs

exclude pulmonary emlbolism with

in these patients, as in the Pisa score,

reasonable certainty if D-dimer was

necessitates a certain level of clinical

measured by a high-sensitivity ELISA. It has

experience and is hard to standardise. The

been shown that the 3-month risk of

three scoring systems are reported in table 1.

pulmonary emlbolism or DVT in untreated

patients with a negative D-dimer and a low

Nevertheless, several prospective studies

or intermediate clinical probability is ,1%.

have shown that, whatever scoring method

Conversely, if clinical assessment results in

is used, pre-test clinical probability

a high probability of pulmonary embolism, a

categorises patients into subgroups with

concomitant negative D-dimer test does not

different prevalences of pulmonary

exclude pulmonary embolism.

embolism, and that the positive and

negative predictive value (NPV) of various

The number of patients with suspected

objective tests is strongly conditioned by the

pulmonary embolism in whom D-dimer

independently assessed pre-test clinical

must be measured to exclude one

probability. Accordingly, recent international

pulmonary embolism episode ranges

guidelines recommend that the clinical

between three in the emergency department

probability of the disease should be

and o10 in hospitalised patients. It then

412

ERS Handbook: Respiratory Medicine

Table 1. Clinical probability scoring systems

Wells score

Geneva score

Pisa score

Signs and

3.0

Recent surgery

High

One or more of three

symptoms of

symptoms (sudden

DVT

onset of dyspnoea,

chest pain and

fainting), not

explained, and one or

more of three chest

X-ray findings

(amputation of hilar

artery, focal

oligaemia and

pleural-based

consolidation)

Heart rate

1.5

Previous PE or

Intermediate

One or more of the

.100 beats?min^-1

DVT

above symptoms,

alone or with ECG

findings of acute

right ventricular

overload

Immobilisation

1.5

Older age

Low

None of the above

of surgery

symptoms is present

or an alternative

diagnosis that may

account for their

presence is identified

Previous DVT

1.5

Hypocapnia

or PE

Haemoptysis

1.5

Hypoxaemia

Malignancy

1.5

Tachycardia

PE more likely

3.0

Plate-like

than an

atelectasis

alternative

diagnosis

Hemidiaphragm

elevation

Low

Intermediate

2-6

Intermediate

5-8

High

PE: pulmonary embolism.

appears recommendable to consider

The sensitivity of D-dimer testing for

D-dimer measurement in the diagnostic

pulmonary embolism increases with the

work-up of pulmonary embolism only in

extent of pulmonary embolism. D-dimer

outpatients or in patients in the emergency

concentrations are the highest in patients

department with low or intermediate levels

with pulmonary embolism involving the

of clinical probability.

pulmonary trunk and lobar arteries and with

ERS Handbook: Respiratory Medicine

413

perfusion scan defects involving .50% of

Ventilation (V9) scanning was added to Q9

the pulmonary circulation.

scanning to increase the specificity of

scintigraphy. This diagnostic approach is

Diagnostic imaging of the chest: post-test

based on the flawed expectation that regions

probability of pulmonary embolism

of the lung excluded from perfusion by

emboli maintain normal ventilation, thus

In recent years, the contribution of CT

giving rise to V9/Q9 mismatch. This criterion

angiography (CTA) to the diagnosis of

for diagnosing pulmonary embolism is at

pulmonary embolism has greatly increased

variance with the notion that ventilation is

as a consequence of the extraordinary

shifted away from embolised lung regions.

advancement in CTA technology.

The concept that deadspace ventilation is

Multidetector CTA has become the most

not significantly increased in the course of

widely used technique for the diagnosis or

pulmonary embolism was widely held in

exclusion of pulmonary embolism, and has

respiratory pathophysiology before the V9/Q9

almost replaced lung scanning as a

scanning approach was developed, as

screening test and conventional pulmonary

asserted by Comroe (1966), who foresaw

angiography as the reference standard for

that ‘decrease in wasted ventilation

the diagnosis of acute pulmonary embolism.

[ventilation to unperfused or poorly perfused

CTA, however, does not escape the simple

lung] helps the patient but hinders the

rule that the combined use of the estimated

physician in diagnosis’. This is in keeping

clinical probability and the results of one

with the results of the PIOPED trial, in which

noninvasive test substantially increases the

it was shown that a high-probability V9/Q9

accuracy of confirming or ruling out a

scan (Q9 defects without matching V9

disease, as compared with either

abnormalities) lacks sensitivity in

assessment alone. As shown by the PIOPED

diagnosing pulmonary embolism, as it fails

II trial, the predictive value of CTA is high

to identify 59% of pulmonary embolism

with a concordant clinical assessment, but

patients (sensitivity 41%, specificity 97%).

additional testing is necessary when clinical

The combination of clinical probability and

probability is inconsistent with the imaging

V9/Q9 scan results either confirms or

results. Several recent papers have shown a

excludes pulmonary embolism in ,30% of

positive yield rate of CTA of ,10% in

patients. The diagnostic value of the Q9 scan

patients who are clinically suspected of

(without V9 imaging) was reappraised in the

pulmonary embolism. This may indicate that

PISA-PED study, in which Q9 scans were

the wide availability of CTA has led to an

read either as compatible with pulmonary

overuse of the technique as a screening

embolism when featuring wedge-shaped

procedure for pulmonary embolism in the

(segmental) perfusion defects or not

emergency department. It has been

compatible with pulmonary embolism when

suggested that a substantial number of

featuring defects other than wedge-shaped

CTAs could be avoided by adhering to the

or normal perfusion. When compared with

information derived from clinical evaluation

the original PIOPED protocol, the PISA-PED

and D-dimer testing.

approach has several advantages:

Perfusion (Q9) lung scanning was

1) Q9 scanning either confirms or excludes

introduced 40 years ago as the first chest

the clinical suspicion of pulmonary

imaging method for the diagnosis of

embolism (thus virtually eliminating

pulmonary embolism. A normal Q9 scan

nondiagnostic examinations)

excludes pulmonary embolism (high

sensitivity and high NPV), whatever the pre-

2) the sensitivity of lung scintigraphy is greatly

test clinical probability. However, Q9

increased (86% versus 41%) but with minor

scanning was thought to be poorly specific

reduction of specificity (from 97% to 93%)

(low PPV) for pulmonary embolism because

all common pulmonary diseases (infections,

3) the combination of clinical probability and

neoplasms and COPD) can produce

Q9 scanning results confirms or excludes

decreased blood flow to the affected regions.

pulmonary embolism in ,80% of patients.

414

ERS Handbook: Respiratory Medicine

More recently, the diagnostic performance

contrast agent, possible pregnancy, critical

of Q9 scanning for pulmonary embolism was

illness, requirement of ventilator support or

confirmed by examining 889 scans from the

recent myocardial infarction. In all these

PIOPED II. PIOPED II data were used to test

conditions, Q9 scanning could be the

the hypothesis that reading Q9 scans

preferred alternative approach to the

without V9 scans, and categorising the Q9

diagnosis of pulmonary embolism. This

scan as ‘pulmonary embolism present’,

approach is particularly important for

‘pulmonary embolism absent’ or

reproductive-age female patients in whom

‘nondiagnostic’ can result in clinically useful

the breast irradiation dose from CTA can be

sensitivity and specificity in a high

minimised by using the Q9 scan as the first

proportion of patients. The study has

imaging test. It has been recently shown that

confirmed that Q9 scan and CTA have

contrast medium-induced nephropathy is at

comparable positive and NPVs, with no

least as common as a diagnosis of

nondiagnostic readings for the Q9 scan

pulmonary embolism after CTA.

(table 2). Accordingly, in 2012, the Society of

Under circumstances in which clinical

Nuclear Medicine revised the practice

probability and imaging test (CTA or

guidelines for lung scintigraphy, reporting

scintigraphy) results are discordant and

that ‘The modified PIOPED II and PISAPED

further testing, such as lower limb

criteria using information from chest

compression ultrasonography, is required to

radiograph and perfusion scans have been

either confirm or exclude the diagnosis.

shown to perform equivalently to those

Another practical approach could be to

including ventilation scintigraphy, with fewer

image the pulmonary circulation with CTA if

nondiagnostic studies’.

Q9 scan was the first imaging test used or

Diagnostic strategies in different clinical

vice versa.

contexts and special conditions

Conclusions

Most clinicians and diagnostic radiologists

The choice of a diagnostic strategy for

feel more comfortable with an anatomical

pulmonary embolism depends on the pre-

demonstration of whether a clot is present

test clinical probability of pulmonary

than assessing the probability of pulmonary

embolism, the condition of the patient, the

embolism by looking at V9/Q9 mismatches

availability of the necessary test, the risks of

(PIOPED) or evaluating the shape of a

testing, the risk of an inaccurate positive or

perfusion defect (PISA-PED). Furthermore,

negative diagnosis, and the cost. Clinical

contrary to scintigraphy, in most hospitals,

evaluation makes it possible to classify

CTA is available 24 h a day, 7 days a week.

patients into probability categories

However, CTA cannot be performed in the

corresponding to an increasing prevalence

whole population of patients suspected of

of pulmonary embolism, whether assessed

pulmonary embolism. As shown in the

by implicit clinical judgment or by a

PIOPED II trial, 50% of the recruited patients

validated prediction rule. Structured models

did not undergo CTA because of documented

to assess clinical probability so far

contraindications, such as renal failure,

developed have different performances in

abnormal creatinine levels, allergy to the

patients of the emergency department and

those who are hospitalised. Exclusion of

Table 2. Predictive value of multidetector CTA and Q9

pulmonary embolism by clinical probability

scanning from retrospective evaluation of PIOPED II

assessment and D-dimer spares the cost

data

and radiation of an imaging evaluation. CTA

Imaging test PPV NPV Nondiagnostic

has become the method of choice for

imaging the pulmonary vasculature when

Q9 scan

pulmonary embolism is suspected in

CTA

routine clinical practice. Scintigraphy can be

considered the preferred alternative chest

Data are presented as %.

imaging technique for patients with

ERS Handbook: Respiratory Medicine

415

contraindication to CTA. If scintigraphy is

Parker AJ, et al.

(2012). SNM practice

used, eliminating the V9 scan can reduce

guideline for lung scintigraphy 4.0. J Nucl

cost and radiation load with gain in

Med Technol; 40: 57-65.

diagnostic yield.

PIOPED Investigators. (1990). Value of

the ventilation/perfusion scan in acute

pulmonary embolism: results of the

Further reading

Prospective Investigation of Pulmonary

Comroe JH Jr (1966). The main function

Embolism Diagnosis (PIOPED). JAMA;

of the pulmonary circulation. Circulation;

263: 2753-2759.

33: 146-158.

Pistolesi M (2010). Pulmonary CT angi-

Eisner MD

(2003). Before diagnostic

ography in patients suspected of having

testing for pulmonary embolism: estimat-

pulmonary embolism: case finding or

ing the prior probability of disease. Am J

screening procedure? Radiology;

256:

Med; 114: 232-234.

334-337.

Mamlouk MD, et al. (2010). Pulmonary

Remy-Jardin M, et al.

(2007).

embolism at CT angiography: implica-

Management of suspected acute pulmon-

tions for appropriateness, cost, and

ary embolism in the era of CT angiog-

radiation exposure in

2003

patients.

raphy. A statement from the Fleischner

Radiology; 256: 625-632.

Society. Radiology; 245: 315-329.

Miniati M, et al. (1996). Value of perfu-

Sostman HD, et al. (2008). Sensitivity

sion lung scan in the diagnosis of

and specificity of perfusion scintigraphy

pulmonary embolism: results of the

for acute pulmonary embolism in

Prospective Investigative Study of Acute

PIOPED II. J Nucl Med; 49: 1741-1748.

Pulmonary Embolism Diagnosis (PISA-

Stein PD, et al. (2011). Controversies in

PED). Am J Respir Crit Care Med; 154:

diagnosis of pulmonary embolism. Clin

1387-1393.

Appl Thromb Hemost; 17: 140-149.

Miniati M, et al. (2012). Clinical presenta-

Stein PD, et al.

(2006). Multidetector

tion of acute pulmonary embolism: sur-

computed tomography for acute pulmon-

vey of 800 cases. PLoS One; 7: e30891.

ary embolism. N Engl J Med; 354: 2317-

Mitchell AM, et al.

(2012). Prospective

2327.

study of the incidence of contrast-

Tsai J, et al.

(2012). Correlates of in-

induced nephropathy among patients

hospital deaths among hospitalizations

evaluated for pulmonary embolism by

with pulmonary embolism: findings from

contrast-enhanced computed tomog-

the

2001-2008

National Hospital

raphy. Acad Emerg Med; 19: 618-625.

Discharge Survey. PLoS One; 7: e34048.

416

ERS Handbook: Respiratory Medicine

Pulmonary vasculitis

Georgios Margaritopoulos and Athol U. Wells

The principles of diagnosis and

vasculitides in rheumatoid arthritis), with an

management are broadly similar across the

annual incidence of 3-11 per million, largely

individual pulmonary vasculitides,

affecting adults aged 30-50 years. CSS has

subdivided into primary systemic and

an annual incidence of ,3 per million and

secondary disorders (table 1). The main

mainly affects adults aged 30-50 years. In

challenges for the clinician are:

neither disorder is there a strong sex

predilection.

N to recognise that vasculitis is a possible

diagnosis

Anti-neutrophil cytoplasmic antibodies

N to make the diagnosis in nonclassical

(ANCAs) are often present in systemic

disease

vasculitides involving the small and

N to select a level of treatment appropriate

medium-sized vessels, including CSS, GPA

to disease severity

and microscopic polyangiitis (MPA). ANCAs

are subcategorised as cytoplasmic,

Granulomatosis with polyangiitis (GPA) (the

perinuclear or atypical, and are directed

entity formerly known as Wegener’s

primarily against proteinase-3 in GPA

granulomatosis) and Churg-Strauss

(cytoplasmic) and against myeloperoxidase

syndrome (CSS) are the most frequent

in CSS (perinuclear), although all ANCA

exemplars of life-threatening anti-neutrophil

patterns have been reported in both

cytoplasmic antibody vasculitides (AAVs).

disorders. In vitro and animal data suggest

Epidemiology and pathogenesis

that ANCAs interact with primed

neutrophils, leading to endothelial damage

GPA is the third most prevalent systemic

and further neutrophil recruitment. Both

vasculitis (after giant cell arteritis and

diseases are generally considered to be

triggered by foreign agents, including drugs

and infections, with the most suggestive

Key points

data relating to chronic nasal carriage of

Staphylococcus aureus in GPA.

Haemoptysis is often scant or absent

in diffuse alveolar haemorrhage.

Clinical presentation

N Vasculitis must often be treated

Vasculitis should be suspected in diffuse

empirically, in the absence of full

alveolar haemorrhage. Haemoptysis is often

diagnostic clinical criteria or a

absent or scant. Diffuse alveolar

histological diagnosis.

haemorrhage should be suspected when

unexplained infiltrates on chest imaging are

N Initial treatment should be definitive,

associated with a fall in haemoglobin over a

even when the diagnosis is tentative.

day or two or, in chronic low-grade

Chronic infection and malignancy are

haemorrhage, with an iron-deficiency

the most frequent differential

anaemia. Bronchoalveolar lavage is usually

diagnosis.

diagnostic of haemorrhage. Vasculitis

should also be suspected: 1) in patients

ERS Handbook: Respiratory Medicine

417

Table 1. Classification of pulmonary vasculitis

Vasculitis

Frequency of lung

involvement

Primary^#

Large vessel

Giant-cell arteritis

Rare

Takayasu’s arteritis

Frequent

Medium-sized vessel

Polyarteritis nodosa

Rare

Kawasaki disease

Small vessel^"

Granulomatosis with polyangiitis (Wegener’s)

Frequent

Churg-Strauss syndrome

Frequent

Microscopic polyangiitis

Frequent

Henoch-Schönlein purpura

Essential cryoglobulinaemia

Secondary

Rheumatological

Pulmonary-renal (e.g. Goodpasture’s syndrome)

Relapsing polychronditis

Behçet’s syndrome

Chronic infection

Lymphoma

Drugs

^#: Chapel Hill international consensus nomenclature;^": with variable medium-sized vessel involvement.

presenting with breathlessness on exertion

by eosinophilia in tissue or peripheral blood

and an unexplained isolated or

and, ultimately, systemic vasculitis. Other

disproportionate reduction in TLCO); 2) in

frequent sites of involvement include the

patients with features of an underlying

nervous system (especially mononeuritis

systemic vasculitis, such as GPA, CSS or a

multiplex) in 75%, skin (60%), heart (50%),

pulmonary-renal syndrome (of which

joints and, less frequently, the kidneys and

Goodpasture’s disease is the best-known

gastrointestinal tract. The classical triad at

example). Investigations that tend to be

lung biopsy is necrotising angiitis,

useful in suspected vasculitis are shown in

granulomata and tissue eosinophilia.

table 2.

Pulmonary infiltrates on chest imaging are

more common than pulmonary nodules

Churg-Strauss syndrome

(which very seldom cavitate). Pleural disease

The American College of Rheumatology

is present in 50%. The diagnostic role of

(ACR) definition of CSS requires the

ANCA continues to be debated. ANCAs,

satisfaction of at least four of six criteria

usually perinuclear ANCAs (p-ANCAs), are

(table 3). There is typically a prodrome of

present in up to two-thirds of patients, but

rhinitis with nasal polyps and the eventual

also occur in many other nonvasculitic

development of late-onset asthma, followed

autoimmune and infectious conditions.

418

ERS Handbook: Respiratory Medicine

Table 2. Useful investigations for suspected pulmonary

Table 3. ACR diagnostic criteria for CSS (four out of six

vasculitis

required)

Imaging

Presence of asthma

Chest radiography

Peripheral blood eosinophilia (.10%)

HRCT

Evidence of a neuropathy in a vasculitic

pattern (e.g. mononeuritis multiplex)

Lung function tests

Transient pulmonary infiltrates

Pulmonary function tests

A history of sinus disease

Arterial gases

Evidence of extravascular eosinophilia on

Renal function

biopsy

Urine dipstick testing and microscopy for

proteinuria, haematuria and cellular casts

Estimation of renal function

alveolar haemorrhage, which may be life-

Consider renal biopsy (if evidence of

threatening and tends to occur before

nephritis)

specific pulmonary manifestations of GPA

are apparent. Fever and weight loss are

Immunology

frequent. There is a wide range of

ANCAs

extrapulmonary organ involvement. Lung

Anti-GBM antibodies

involvement is asymptomatic in a third of

cases. The cardinal histological features are

Immune complexes

granulomatous inflammation and

Rheumatoid factor

necrotising vasculitis, affecting small to

ANAs

medium-sized vessels. Chest imaging may

show one or more nodules that can cavitate,

Antiphospholipid antibodies

localised or diffuse infiltrates (which may

Bronchoalveolar lavage

represent alveolar haemorrhage), or

Iron-laden macrophages

evidence of large and small airway disease.

Biopsy

As in CSS, the diagnosis should never be

dependent upon ANCA positivity:

Renal

cytoplasmic ANCAs (c-ANCAs) are not

Skin

present in all cases (especially when GPA is

Lung (surgical)

confined to the lungs), and are also found in

other vasculitides, chronic bacterial

GBM: glomerular basement membrane; ANA: anti-

infections and cryoglobulinaemia.

nuclear antibody.

Among vasculitides, MPA, a necrotising

vasculitis affecting small to medium-sized

Thus, neither the presence nor the absence

vessels, is the main clinical mimic of GPA.

of p-ANCAs is diagnostically definitive and

Although pulmonary involvement is less

is no more than a useful ancillary finding

frequent than in GPA, this disorder also

increasing or decreasing the diagnostic

often presents with diffuse alveolar

likelihood.

haemorrhage, which can have a poor

prognosis. Necrotising glomerulonephritis,

Granulomatosis with polyangiitis

mononeuritis multiplex and skin lesions are

The classic historical GPA triad consisted of

variably present. The cardinal histological

renal, lower respiratory tract and upper

distinction is the absence of granulomas,

respiratory tract involvement. Most often,

which are characteristically present in GPA.

chronic rhinitis, sinusitis or mastoiditis

Diagnosis of vasculitis

progresses to generalised disease over

months to years, with lower respiratory tract

A confident diagnosis requires histological

involvement in 65-85%, including diffuse

confirmation or satisfaction of the requisite

ERS Handbook: Respiratory Medicine

419

number of clinical criteria. However, many

survival 54%). Mortality is largely ascribable

patients with vasculitis have features

to sepsis (as a complication of treatment) or

overlapping between diagnostic entities with

disease progression. Death from

transient or non-fulfilment of diagnostic

progressive disease is most commonly due

criteria. Thus, a versatile diagnostic

to renal failure or lung involvement in GPA,

approach is required. When vasculitis is

and to renal failure, cerebrovascular

suspected but full clinical criteria are not

involvement and gastrointestinal disease in

satisfied, a histological diagnosis should

CSS (with 10% of deaths accounted for by

made, if possible. However, a negative

lung disease).

biopsy does not exclude vasculitis, which

Treatment

may be patchy or give rise to nonspecific

inflammatory change (as in upper airway

Remission induction therapy of AAVs should

biopsies in GPA patients).

be dictated by disease extent and severity

(table 4).

Thus, the diagnosis of a vasculitic syndrome

is sometimes necessarily empirical, with

In limited disease there are limited data

chronic infection and malignancy the most

supporting the use of oral steroids as

frequent differential diagnoses. In such

monotherapy and/or a single cytotoxic agent

cases, initial treatment and monitoring

such as methotrexate, azathioprine and

should be as for the vasculitic syndrome

mycophenolate mofetil.

most closely corresponding to the clinical

presentation in that patient. Initial treatment

In early generalised disease, oral

should be definitive as a clear response

cyclophosphamide and steroids are the

provides important support for the

cornerstones of treatment. Methotrexate

diagnosis, whereas a tentative therapeutic

(0.3 mg?kg^-1?week^-1) is as effective as daily

approach often prolongs diagnostic

oral cyclophosphamide in the induction of

uncertainty.

remission, although relapse is more likely

with cessation of treatment at 12 months.

Prognosis

In generalised active disease, oral

The poor historical outcome of the vasculitic

cyclophosphamide and intravenous

syndromes has been transformed by more

methylprednisolone have generally been

aggressive therapy but also by the increasing

used. However, oral cyclophosphamide

detection of milder disease, including

(2.0 mg?kg^-1?day^-1) and intravenous

patients with limited involvement. In

cyclophosphamide (600 mg?m^-2, at three to

localised pulmonary GPA and CSS alike, the

four weekly intervals, depending on disease

outcome is much better outcome than with

severity) are equally successful in inducing

multiorgan involvement. In CSS, the

remission. Intravenous therapy is associated

prognosis worsens strikingly with two or

with a slightly higher relapse rate but is

more extrapulmonary complications (5-year

much less toxic in the short term and is

Table 4. EUVAS classification clinical features

Limited isolated upper airway disease

Early generalised end-organ involvement that lacks a clear or immediate threat to organ function

Generalised active end-organ involvement with clinically significant impairment of organ

function

Severe immediate threat of organ failure or death

Refractory disease that has failed to respond to conventional therapies

Remission (maintenance): no evidence of ongoing vasculitic activity

EUVAS: European Vasculitis Study Group.

420

ERS Handbook: Respiratory Medicine

much less likely to provoke haemorrhagic

risk of opportunistic Pneumocystis jiroveci

cystitis and subsequent malignancy, based

infection. In GPA, co-trimoxazole therapy

on long-term systemic lupus erythematosus

has been efficacious in localised respiratory

data. Importantly, in multicentre controlled

tract disease and may have an ancillary role

trials, rituximab given weekly for 4 weeks

in maintaining remission.

was found to be as efficacious as oral

cyclophosphamide in inducing remission

(including a patient with alveolar

Further reading

haemorrhage) and has a particular role in

patients with relapsing disease that is poorly

Conron M, et al. (2000). Churg-Strauss

controlled by traditional immuno-

syndrome. Thorax; 55: 870-877.

suppressive therapy.

Falk RJ, et al. (2011). Granulomatosis with

polyangiitis

(Wegener’s): an alternative

In severe disease with diffuse alveolar

name for

Wegener’s granulomatosis.

haemorrhage or renal failure, plasma

Arthritis Rheum; 63: 863-864.

exchange should be considered early

Frankel SK, et al. (2012). The pulmonary

together with high doses of intravenous

vasculitides. Am J Respir Crit Care Med;

methylprednisolone and oral

186: 216-224.

cyclophosphamide. The early use of

Guillevin L, et al.

(1996). Prognostic

rituximab is strongly recommended in this

factors in polyarteritis nodosa and

difficult clinical scenario and if disease is

Churg-Strauss syndrome. A prospective

overtly life-threatening at presentation,

study in 342 patients. Medicine; 75: 17-28.

initial combination therapy using all three

Jayne D, et al. (2003). A randomized trial

agents should be considered, especially

of maintenance therapy for vasculitis

when plasma exchange is not readily

associated with antineutrophil cytoplas-

available.

mic autoantibodies. New Engl J Med; 349:

36-44.

In refractory disease, intravenous

Jennette JC, et al. (1994). Nomenclature

immunoglobulin and anti-thymocyte

of systemic vasculitides. Proposal of an

globulin have been variably efficacious.

International consensus conference.

Arthritis and Rheumatism; 37: 187-192.

Following initial treatment, less intense

Lanham JG, et al.

(1984). Systemic

long-term therapy is almost invariably

vasculitis with asthma and eosinophilia:

required. Standard maintenance treatment

the clinical approach to the Churg-

has consisted of azathioprine

Strauss syndrome. Medicine (Baltimore);

(2.0 mg?kg^-1?day^-1), usually with in

63: 65-81.

combination with low-dose corticosteroid

Lhote F, et al.

(1998). Polyarteritis

therapy. Methotrexate (25 mg per week) is as

nodosa, microscopic polyangiitis and

efficacious as azathioprine. However,

Churg-Strauss syndrome. Semin Respir

relapse is more prevalent with the use of

Crit Care Med; 19: 27-46.

mycophenolate mofetil and this agent

Pagnoux C, et al. (2008). Azathioprine or

should, therefore, be considered only in

methotrexate maintenance for ANCA-

patients intolerant of azathioprine and

associated vasculitis. N Engl J Med; 359:

methotrexate. Maintenance therapy should

2790-2803.

be continued for a o18 months but in many

Specks U. Pulmonary vasculitis. In:

cases, prolonged maintenance therapy is

Schwarz MI, et al., eds. Interstitial Lung

required, sometimes for decade or longer.

Disease. Hamilton, B.C. Dekker,

1998;

pp. 507-534.

Prophylactic co-trimoxazole (trimethoprim

Stone JH, et al. (2010). Rituximab versus

160 mg/sulphamethoxazole 800 mg three

cyclophosphamide for ANCA-associated

times a week) is often used with prolonged

vasculitis. N Engl J Med; 363: 221-232.

intense immunosuppression, to reduce the

ERS Handbook: Respiratory Medicine

421

Pulmonary hypertension

Marc Humbert and Gérald Simonneau

Classification

pressure (Ppw), pulmonary hypertension can

be pre-capillary (Ppw f15 mmHg) or post-

Pulmonary hypertension is defined as an

capillary (Ppw .15 mmHg).

increase in mean pulmonary arterial

pressure (mPpa) o25 mmHg at rest as

Pulmonary hypertension can be classified into

assessed by right heart catheterisation.

five groups according to pathological,

According to values of pulmonary wedge

pathophysiological and therapeutic

characteristics. Despite comparable elevations

of mPpa in the different clinical groups, the

Key points

underlying mechanisms, diagnostic

approaches, and prognostic and therapeutic

Pulmonary hypertension is defined as

implications are completely different.

an increase in mPpa o25 mmHg at

The clinical classification of pulmonary

rest as assessed by right heart

hypertension is shown in table 1. Group 1

catheterisation.

relates to pulmonary arterial hypertension

PAH is a rare condition characterised

(PAH), corresponding to idiopathic,

by chronic pre-capillary pulmonary

heritable and associated PAH. The term

hypertension leading to right heart

familial PAH has been replaced by heritable

failure and death.

PAH because specific gene mutations have

been identified in sporadic cases with no

PAH can be sporadic (idiopathic

family history, mainly because of the low

PAH), heritable, induced by drugs or

penetrance of the causal mutations.

toxins, or associated with other

Heritable forms of PAH include clinically

conditions such as connective tissue

sporadic idiopathic PAH with germline

diseases.

mutations (mainly in the bone

Doppler echocardiography is the

morphogenetic protein receptor II (BMPR2)

investigation of choice for noninvasive

gene as well as the activin receptor-like

screening but measurement of

kinase type-1 (ALK1) or endoglin genes) and

haemodynamic parameters during

clinical familial cases with or without

right heart catheterisation is

identified mutation. Associated PAH

mandatory to confirm pre-capillary

includes conditions that can have a similar

pulmonary hypertension (mPpa

clinical presentation to that seen in

o25 mmHg and Ppw

f15 mmHg).

idiopathic PAH with comparable histological

findings. Associated PAH accounts for

Recent advances in the management

approximately half of the patients followed

of PAH include prostaglandins, ERA

at specialised centres. Pulmonary veno-

and PDE5 I.

occlusive disease (PVOD) and pulmonary

Lung transplantation is an option for

capillary haemangiomatosis remain difficult

severe patients deteriorating despite

disorders to classify since they share some

medical treatment.

characteristics with PAH but also

demonstrate a number of differences.

422

ERS Handbook: Respiratory Medicine

Table 1. Updated clinical classification of pulmonary hypertension (PH)

1 PAH

1.1 Idiopathic PAH

1.2 Heritable

1.2.1 BMPR2

1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia)

1.2.3 Unknown

1.3 Drug and toxin induced

1.4 APAH

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1.4.6 Chronic haemolytic anaemia

1.5 Persistent PH of the newborn

19 PVOD and/or pulmonary capillary haemangiomatosis

2 PH due to left heart disease

2.1 Systolic dysfunction

2.2 Diastolic dysfunction

2.3 Valvular disease

3 PH due to lung diseases and/or hypoxia

3.1 COPD

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental abnormalities

4 CTEPH

5 PH with unclear and/or multifactorial mechanisms

5.1 Haematological disorders: myeloproliferative disorders, splenectomy.

5.2 Systemic disorders, sarcoidosis, pulmonary Langerhans’ cell histiocytosis,

lymphangioleiomyomatosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

APAH: associated PAH. Reproduced from Simonneau et al. (2009) with permission from the publisher.

Given the current evidence, these conditions

complicating left heart diseases (group 2)

have been individualised as a distinct

and pulmonary diseases (group 3).

category but not completely separated from

PAH, and have been designated as clinical

All forms of pulmonary hypertension have

group 19. Chronic thromboembolic

some common pathological features

pulmonary hypertension (CTEPH) is an

regardless of their aetiology:

important subcategory of pulmonary

hypertension, which may be cured by surgical

pulmonary endarterectomy. It was decided to

N medial hypertrophy of muscular and

maintain only a single category of CTEPH

elastic arteries

without attempting to distinguish between

N dilation and intimal atheromas of elastic

proximal and distal forms. The most frequent

pulmonary arteries

causes of pulmonary hypertension are those

N right ventricular hypertrophy

ERS Handbook: Respiratory Medicine

423

In addition to the aforementioned

Diagnosis

pathological changes common to all forms

The diagnostic process starts with the

of pulmonary hypertension, PAH is

identification of the more common clinical

characterised by constrictive and complex

groups of pulmonary hypertension (group 2:

arterial lesions involving to varying degrees

left heart diseases; group 3: pulmonary

the pre- and intra-acinar pulmonary arteries.

diseases), distinguishing group 4 (CTEPH)

The plexiform lesion is a focal proliferation

and, finally, making the diagnosis and

of endothelial channels lined by

recognising the different types of group 1

myofibroblasts, smooth muscle cells and

(PAH) and the rarer conditions of group 5.

connective tissue matrix. The lesion is

located within pre- and intra-acinar

PAH should be considered in the differential

pulmonary arteries, and is associated with

diagnosis of exertional dyspnoea, syncope,

expansion and partial destruction of the

angina and/or progressive limitation of

arterial wall with extension of the plexiform

exercise capacity, particularly in patients

lesion into the perivascular connective

without apparent risk factors, symptoms or

tissue. The plexiform lesion is often located

signs of common cardiovascular and

at an arterial branching point (fig. 1).

respiratory disorders. Special awareness

should be directed towards patients with

Epidemiology and survival

associated conditions and/or risk factors for

PAH is a rare condition with a prevalence

development of PAH, such as family history,

connective tissue diseases, congenital heart

ranging 15-50 per million in western Europe.

diseases, HIV infection, portal hypertension,

In the early 2000s, the prevalence of

haemolytic anaemia, or a history of drug and

idiopathic PAH was about 6 per million in

toxin intake known to induce PAH. In

the French Registry and its incidence was

everyday clinical practice, such awareness

2 per million per year. Median survival of

may be low. More often, pulmonary

idiopathic PAH was 2.8 years in the National

hypertension is found unexpectedly on

Institutes of Health Registry before the

transthoracic echocardiography requested

recent development of PAH-specific

for another indication.

therapies. Despite improvements in recent

years, idiopathic, familial and anorexigen-

If noninvasive assessment is compatible

associated PAH remains progressive, fatal

with pulmonary hypertension, clinical

diseases in the modern management era.

history, symptoms, signs, ECG, chest

Mortality is most closely associated with

radiograph, transthoracic echocardiogram,

male sex, right ventricular haemodynamic

pulmonary function tests (including

function and exercise limitation.

nocturnal oximetry if required) and HRCT of

the chest are requested to identify the

presence of group 2 (left heart diseases) or

group 3 (pulmonary diseases). If these are

not found or if pulmonary hypertension

seems ‘out of proportion’ to their severity,

less common causes of pulmonary

hypertension should be sought. Ventilation/

perfusion lung scanning should be

considered. If the ventilation/perfusion scan

shows multiple segmental perfusion defects,

a diagnosis of group 4 (CTEPH) should be

suspected. The final diagnosis of CTEPH

(and the assessment of suitability for

pulmonary endarterectomy) will require

Figure 1. A typical plexiform lesion in a patient

helical CT of the chest, right heart

with idiopathic PAH. The lesion is located at an

catheterisation and selective pulmonary

arterial branching point.

angiography. HRCT of the chest may also

424

ERS Handbook: Respiratory Medicine

Table 2. Functional assessment of pulmonary hypertension (PH) modified after the NYHA classification

Functional class

Description

Patients with PH but without resulting limitation of physical activity

Ordinary physical activity does not cause undue dyspnoea or fatigue, chest

pain or near syncope

Patients with PH resulting in slight limitation of physical activity

They are comfortable at rest

Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or

near syncope

III

Patients with PH resulting in marked limitation of physical activity

They are comfortable at rest

Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or

near syncope

Patients with PH with inability to carry out any physical activity without

symptoms

These patients manifest signs of right heart failure

Dyspnoea and/or fatigue may even be present at rest

Discomfort is increased by any physical activity

show signs suggestive of group 19 (PVOD).

heart disease) or with group 3 (pulmonary

If the ventilation/perfusion scan is normal or

diseases). In addition, the different

shows only subsegmental ‘patchy’ perfusion

treatments have been evaluated by

defects, a tentative diagnosis of group 1

randomised control trials mainly in

(PAH) or the rarer conditions of group 5 is

idiopathic PAH, heritable PAH, PAH due to

made. Performing a right heart

anorexigen drugs and in PAH associated

catheterisation will be necessary to confirm

with connective tissue diseases or with

the diagnosis and assess haemodynamic

congenital heart diseases (surgically

severity. Additional specific diagnostic tests,

corrected or not). The grades of

including haematology, biochemistry,

recommendation and levels of evidence for

immunology, serology and ultrasonography,

the other PAH subgroups are lower.

will allow the final diagnosis to be refined. 6-

min walk distance is an important marker of

The suggested initial approach, after the

exercise limitation with prognostic value in

diagnosis of PAH, is the adoption of general

PAH. New York Heart Association (NYHA)

measures, the initiation of supportive

functional class is a simple clinical

therapy and referral to an expert centre.

parameter of major prognostic value

Acute vasoreactivity testing with inhaled

(table 2).

nitric oxide or intravenous prostacyclin or

adenosine should be performed in all

Treatment

patients with group 1 (PAH), although

A treatment algorithm for PAH patients is

patients with idiopathic PAH and PAH

shown in figure 2. The grades of

associated with anorexigen use are the most

recommendation and levels of evidence for

likely to exhibit an acute positive response

the PAH treatments are derived from

and to profit from long-term calcium

European guidelines published jointly by the

channel blocker therapy. Vasoreactive

European Respiratory Society and the

patients should be treated with optimally

European Society of Cardiology in 2009. The

tolerated doses of calcium channel blockers;

treatment algorithm does not apply to

adequate response should be confirmed

patients in other clinical groups and, in

after 3-4 months of treatment.

particular, not to patients with pulmonary

Nonresponders to acute vasoreactivity

hypertension associated with group 2 (left

testing who are in NYHA functional class II

ERS Handbook: Respiratory Medicine

425

should be treated with an endothelin

medical therapy or where medical

receptor antagonist (ERA) or a

treatments are unavailable. These

phosphodiesterase-5 inhibitor (PDE5 I).

procedures should be performed only in

Nonresponders to acute vasoreactivity

experienced centres.

testing or acute responders who do not

respond to chronic calcium channel blocker

Further reading

therapy should be considered candidates for

treatment with either an ERA, a PDE5 I or a

D’Alonzo GE, et al. (1991). Survival in

prostanoid. As head-to-head comparisons

patients with primary pulmonary hyper-

between different compounds are not

tension. Ann Int Med; 115: 343-349.

available, no evidence-based first-line

Galiè N, et al. (2009). Guidelines for the

treatment can be proposed. In this case, the

diagnosis and treatment of pulmonary

choice of drug is dependent on a variety of

hypertension. The task force for the

factors, including the approval status, the

diagnosis and treatment of pulmonary

route of administration, the side-effect

hypertension of the European Society of

profile, patients’ preferences and physicians’

Cardiology

(ESC) and the European

experience. Some experts still use first-line

Respiratory Society

(ERS), endorsed by

i.v. epoprostenol in NYHA functional class

the International Society of Heart and

III patients, because of its survival benefits.

Lung Transplantation (ISHLT). Eur Respir

Continuous i.v. epoprostenol may be

J; 34: 1219-1263.

considered as first-line therapy for NYHA

Humbert M, et al. (2006). Pulmonary

arterial hypertension in France: results

functional class IV PAH patients because of

from a national registry. Am J Respir Crit

the survival benefit in this subset.

Care Med; 173: 1023-1030.

In case of inadequate clinical response,

Humbert M, et al. (2010). Survival in

sequential combination therapy should be

patients with idiopathic, familial, and

considered. Combination therapy can either

anorexigen-associated pulmonary arterial

include an ERA plus a PDE5 I, a prostanoid

hypertension in the modern management

plus an ERA, a prostanoid plus a PDE5 I or a

era. Circulation; 122: 156-163.

Rich S, et al. (1987). Primary pulmonary

triple combination therapy. Appropriate

hypertension: a national prospective

protocols for timing and dosing to limit

study. Ann Int Med; 107: 216-223.

possible side-effects of the combination

Simonneau G, et al.

(2009). Updated

have still to be defined.

clinical classification of pulmonary hyper-

Balloon atrioseptostomy and/or lung

tension. J Am Coll Cardiol; 54: Suppl. 1,

transplantation are indicated for PAH with

S43-S54.

inadequate clinical response despite optimal

ERS Handbook: Respiratory Medicine

427

Pleural effusion

Robert Loddenkemper

Pleural effusion is defined as accumulation

Key points

of fluid in the pleural space that exceeds the

physiological amounts of 10-20 mL. Pleural

Pleural effusions may present as

effusion develops either when the formation

primary manifestations of many

of pleural fluid is excessive or when fluid

diseases. However, most often, they

resorption is disturbed. Pleural effusions

are observed as secondary

may represent a primary manifestation of

manifestations or complications of

many diseases, but most often they are

other diseases.

observed as secondary manifestations or

complications of other diseases.

Cardiac failure is the main cause of

pleural effusions. Of noncardiac

Pleural effusion is found in almost 10% of

causes, parapneumonic effusions are

patients who have internal diseases and the

commonest, followed by malignant

main cause in 30-40% of these is cardiac

pleural effusions and pleural effusions

failure. Among the noncardiac effusions,

due to pulmonary embolism.

parapneumonic effusions are the most

Small pleural effusions can be

common at 36%, of which ,75% are of

detected best by ultrasound (or CT).

bacterial and 25% of viral origin. Malignant

pleural effusions follow in 18% of cases, half

Pleural effusion can, in the majority of

of which are caused by lung or breast

cases, be diagnosed by case history,

cancer. Pleural effusion is secondary to

clinical presentation, imaging

pulmonary embolism in 14% of cases, to

techniques and examination of pleural

liver cirrhosis in 5% and to gastrointestinal

fluid.

diseases, mainly pancreatitis, in 2% of

The most important laboratory

cases. Many other possible causes, such as

parameter of pleural fluid is total

collagen vascular diseases like rheumatoid

protein, distinguishing trans- from

arthritis and systemic lupus erythematosus

exudates.

as well as several drugs (www.pneumotox.

com), play an important role in differential

Biopsy procedures such as closed-

diagnosis. Often, pleural effusions are

needle biopsy or medical

observed after abdominal surgery, liver

thoracoscopy/pleuroscopy may be

transplantation or coronary artery bypass

necessary to confirm or exclude

surgery/pericardiectomy.

malignant or tuberculous causes.

Pleural effusion may result from a number of

Treatment depends upon the

pathophysiological mechanisms, all of

underlying disease.

which disturb the physiological balance

Local treatment options include

between the formation and removal of

therapeutic thoracentesis, chest-tube

pleural fluid (normal production estimated

drainage, chemical pleurodesis and,

at 15 mL?day^-1 in a 60-kg person). Most

rarely, surgical interventions.

effusions develop from both an increase in

the entry rate of liquid into the pleural space

428

ERS Handbook: Respiratory Medicine

and a decrease in the maximal exit rate of

The presence of a pleural effusion is

liquid from the pleural space. Transudative

established only by thoracentesis. The site

effusions are caused either by increased

should be selected according to the results

hydrostatic pressure (e.g. in cardiac failure)

of the diagnostic procedures. At least if the

or by reduced plasma oncotic pressure

effusion is small, thoracentesis should be

because of protein deficiency (e.g. liver

performed under ultrasound guidance.

cirrhosis or nephrotic syndrome). The

Thoracentesis is indicated in all cases of

pleura itself remains intact. Rarely,

pleural effusion of unknown origin and in

transudates may arise from the entry of

effusions that do not resolve after

liquids with low protein concentrations (e.g.

appropriate treatment. Additional biopsy

urine, cerebrospinal fluid or iatrogenic

procedures, such as closed-needle biopsy or

intrapleural infusion of fluids). In contrast,

medical thoracoscopy/pleuroscopy, may be

pathological changes in the pleura result in

necessary to confirm or exclude malignant

exudation caused by a diffuse increase of

or tuberculous causes. These are performed

capillary permeability, due to localised

in a stepwise diagnostic approach (fig. 1).

ruptures (e.g. blood vessels, lymphatic

vessels, lung abscess or oesophagus) or to

In many cases, evaluation of the pleural fluid

disturbed absorption (e.g. lymphatic

yields valuable diagnostic information or

blockage).

Diagnostic approach to pleural effusions

Pleural effusion may present at all ages, but

is mainly found in adults. Malignant pleural

Aetiology probable

effusions are observed predominantly in

Aetiology unknown

(e.g. cardiac/renal)

patients aged .60 yrs.

The most common clinical presentations are

1 Thoracentesis

dyspnoea and chest pain, and those of the

Persistence

Improvement

Colour? Protein?

individual underlying diseases. Physical

with therapy

Cells? Others?

examination reveals dullness on percussion,

usually at the base of the thorax, and

decreased breath sounds.

Positive finding of:

Aetiology unknown

• malignant cells

Pleural effusion may be demonstrated by a

• bacteria, fungi, etc.

number of techniques with different

• other specific parameter,

sensitivities. The demonstration by

e.g. amylase (>serum)

percussion requires at least 300-400 mL of

Blind

fluid, whereas at least 200-300 mL is

pleural biopsy

necessary for standard chest radiography.

Smaller amounts can be recognised by

lateral decubitus radiography, which also

Aetiology unknown

demonstrates whether the fluid is moving

freely. Ultrasound is able to demonstrate

Histological finding

small effusions, and the sensitivity is almost

of malignancy or

100% for volumes of o100 mL. CT and MRI

Thoracoscopy

have very similar sensitivities, but require

including biopsy

more advanced technology and are therefore

much more expensive. However, if

Follow-up

pulmonary embolism is suspected, CT

angiography is the preferred test.

Aetiology unknown

In single cases

In the majority of cases, the aetiology is

(<10%)

open surgical

biopsy

based on the case history, clinical

presentation, imaging techniques and

examination of the pleural fluid.

Figure 1. Diagnostic approach to pleural effusions.

ERS Handbook: Respiratory Medicine

429

which a threshold value of 30 g?L^-1

Table 1. Investigative parameters of pleural effusion

differentiates a transudate from an exudate.

Obligatory

However, this value is not exclusive, and

Appearance

additional parameters such as lactate

dehydrogenase (.200 U?L^-1) or cholesterol

Total protein

(.0.55 mmol?L^-1 (60 mg?dL^-1)) may be

Cell differentiation (cytology)

helpful (table 2). The simultaneous

Optional

determination of serum values is important,

Glucose (pH)

because these may strongly influence the

values in the pleura. Low glucose values may

Lactate dehydrogenase

indicate rheumatoid pleuritis, lupus

Cholesterol

pleuritis, empyema, TB or malignant

NT-proBNP

effusion, or oesophageal perforation.

Elevated levels of N-terminal pro-brain

Triglycerides

natriuretic protein (NT-proBNP) (in pleural

Amylase

fluid and/or blood) are characteristic of

Bilirubin

effusions caused by cardiac failure.

Creatinine

Markedly elevated amylase values are

Haematocrit

observed in acute pancreatitis and pancreatic

Immunocytology

pseudocysts, oesophageal perforation and,

occasionally, in malignant effusions.

Tumour markers

Adenosine deaminase

Haemothorax is characterised by purely

Interferon-c release assay

bloody effusions and haematocrit values that

exceed those in peripheral blood by .50%.

Antinuclear factor, rheumatoid factors, etc.

Search for infecting organisms

In chylothorax, increased triglycerides

distinguish chylous from pseudochylous

Tubercle bacilli

effusions. Although nonspecific, adenosine

Gram staining

deaminase and T-cell-based interferon-c

Anaerobic, aerobic bacteria

release assays may allow support the

diagnosis of TB as the cause of lymphocytic

Fungi and parasites

pleural effusions.

even permits a clear diagnosis. The most

Diagnostic testing for the infecting

important criteria are appearance, protein

organisms that cause pleural effusion is

content and cellular components. In the

indicated in parapneumonic effusions/

case of more specific diagnostic questions,

empyemas with aerobic and anaerobic

routine measurement of the glucose content

cultures, and in suspected tuberculous,

is supplemented by determination of further

fungal or parasitic effusions.

laboratory parameters and search for

Therapeutic aims in patients with pleural

infecting organisms (table 1).

effusion are palliation of symptoms (pain

The most important laboratory parameter is

and dyspnoea), treatment of the underlying

the total protein content in the effusion, for

diseases, prevention of pleural fibrosis with

Table 2. Light’s criteria for exudates

Effusion

Effusion/serum

Sensitivity % Accuracy %

concentration

concentration ratio

Total protein

.3 g?dL^-1

.0.5

89.5

95.4

Lactate dehydrogenase

.200 U?L^-1

.0.6

91.4

94.7

430

ERS Handbook: Respiratory Medicine

reduction of pulmonary function, and

Heffner JE (2006).Discriminating between

prevention of recurrences. The therapeutic

transudates and exudates. Clin Chest Med;

approach depends on the availability of

27: 241-252.

options for causal or only symptomatic

Hooper C, et al. (2010). Investigation of a

treatments.

unilateral pleural effusion in adults:

British Thoracic Society pleural disease

Empyema usually requires, besides antibiotic

guideline 2010. Thorax; 65: Suppl. 2, ii4-

treatment, additional pleural drainage.

ii17.

Resolution may be further facilitated by

Koegelenberg CF, et al.

(2008).

instillation of a fibrinolytic agent. In

Parapneumonic pleural effusions and

empyema. Respiration; 75: 241-250.

malignant pleural effusions, therapeutic

Kolditz M, et al. (2006). High diagnostic

thoracentesis or chest-tube drainage

accuracy of NT-proBNP for cardiac origin

combined with chemical pleurodesis, or

of pleural effusions. Eur Respir J; 28: 114-

medical thoracoscopy with talc poudrage are

150.

the preferred options for local treatment. In

Light RW (2002). Diagnostic approach in

those resulting from tumours likely to

a patient with pleural effusion. Eur Respir

respond to chemotherapy or hormonal

Monogr; 22: 131-145.

treatment, systemic treatment should be

Light RW, ed. Pleural Diseases. 5th Edn.

started and may be combined with

Philadelphia, Lippincott Williams &

therapeutic thoracentesis or pleurodesis.

Wilkins, 2007.

Roberts ME, et al. (2010). Management

of malignant pleural effusion. British

Further reading

Thoracic Society pleural disease guide-

Antony VB, et al. (2001). Management of

line

2010. Thorax;

65: Suppl.

malignant pleural effusions. Eur Respir J;

ii32-ii40.

18: 402-419.

Rodriguez-Panadero F, et al.

(2006).

Chegou NN, et al. (2008). Evaluation of

Thoracoscopy: general overview and

adapted whole-blood interferon-c release

place in the diagnosis and management

assays for the diagnosis of pleural

of pleural effusion. Eur Respir J; 28: 409-

tuberculosis. Respiration; 76: 131-138.

422.

Colice GL, et al.

(2000). Medical and

Trajman A, et al. (2008). Novel tests for

surgical treatment of parapneumonic

diagnosing tuberculous pleural effusion:

effusions: an evidence-based guideline.

what works and what does not? Eur Respir

Chest; 118: 1158-1171.

J; 31: 1098-1106.

ERS Handbook: Respiratory Medicine

431

Pneumothorax and

pneumomediastinum

Paul Schneider

Pneumothorax is defined as an accumulation

pneumothorax progresses and develops

of air in the pleural space with secondary lung

with significant haemodynamic and

collapse. This accumulation is of diverse

respiratory instability, hypoxia and shock.

derivation, but visceral pleural rupture with

This clinical presentation is accompanied by

air leakage is the most common cause. An

a tension pneumothorax and demands

original possibly ruptured oesophagus with

emergency treatment.

diminished chest wall integrity can cause free

The pneumothorax can be classified

air in the pleural space, as can, more rarely, a

according to cause or clinical presentation,

gas-forming organism.

or according to spontaneous, traumatic or

iatrogenic aetiology (table 1). The first

In most instances, the pneumothorax

category includes primary and secondary

presents with minor symptoms without any

causes. A primary spontaneous

physiological changes. Rarely, a simple

pneumothorax occurs in individuals with no

known pulmonary disease. A secondary

Key points

pneumothorax occurs in patients with

clinical or radiographic evidence of

The most likely cause of a primary

underlying lung disease. Traumatic

spontaneous pneumothorax is the

pneumothorax occurs as a result of

rupture of small subpleural bulla.

penetrating or blunt trauma with disruption

of the bronchus, the lung or the

Pneumothorax usually present with

oesophagus. A traumatic pneumothorax is

acute chest pain and dyspnoea.

defined as ‘open’ with an associated

Pneumothorax can be complicated by

disruption of the chest wall. Iatrogenic

persistent air leak for .3 days,

pneumothorax includes the diagnostic and

pneumomediastinum and

therapeutic pneumothorax, which are

haemopneumothorax.

relatively common in the hospital

environment but will not be considered in

Recurrence is the most common

this discussion.

indication for surgery in patients with

a primary spontaneous

Primary spontaneous pneumothorax

pneumothorax.

Clinical features The most likely cause of a

Surgery is accomplished by a video-

primary spontaneous pneumothorax is the

assisted thoracoscopy mechanical

rupture of small subpleural bulla (fig. 1),

abrasion, or by parietal apical

occuring at rest or during exercise. It is seen

pleurectomy in association with

most often in young, tall male patients with

resection of the lung.

admitted cigarette or cannabis smoking

habits. Hereditary aspects have been

In secondary pneumothorax, the

described.

mortality rate for surgery may reach

10% and the morbidity is significant.

In the North American population,

incidence varies from 6-7 per 100 000

432

ERS Handbook: Respiratory Medicine

collapse is defined in decreased chest wall

Table 1. Classification of pneumothorax

movement on the affected side. Percussion

Spontaneous

of the chest cavity is hyperresonant and

Primary (healthy individuals)

tympanic, and on auscultation breath

sounds are decreased or absent. A pleural

Secondary (underlying pulmonary disease)

friction rub can sometimes be heard.

COPD

Tachycardia is found in most patients.

Infection

Diagnosis The clinical diagnosis of a

Neoplasm

pneumothorax is best confirmed by erect

Catamenial

posteroanterior and lateral chest

Miscellaneous

radiographs. Expiration posteroanterior

chest radiography may be useful to

Traumatic

demonstrate a small pneumothorax not

Blunt

seen on standard film.

Penetrating

CT imaging is generally not necessary unless

Iatrogenic

abnormalities are noted on the plain chest

Inadvertent

radiograph or further evaluation is required

(e.g. of suspected secondary

Diagnostic

pneumothorax), or if an aberrant chest drain

Therapeutic

emplacement is suspected.

Complications Air leakage may persist for

males to 1-2 per 100 000 females. Bilateral

.48 h after the treatment of a

pneumothoraces occur in ,10% of patients.

pneumothorax. Often the air leak is seen in

Recurrences are observed in 42% of

patients with a secondary pneumothorax,

patients, usually within 2 years. After the

but occasionally patients with a primary

second pneumothorax, the chances of

spontaneous pneumothorax develop this

having a third episode increase to .50%.

complication. In this instance, surgery must

be considered.

The clinical presentation usually relates to

the degree of pulmonary collapse. Although

Pneumomediastinum (fig. 2) is secondary

some patients have an asymptomatic

to the dissection of air along the bronchial

pneumothorax, more often they present with

and pulmonary vessel sheets or as a

acute chest pain and dyspnoea.

complication of a spontaneous

pneumothorax. It is generally of no clinical

Physical findings may be totally absent if the

consequence, but other causes of

collapse is minimal, while substantial

pneumomediastinum, such as injury to

major airways or oesophagus perforation,

may need to be excluded.

Pneumoperitoneum secondary to a

pneumothorax is rare, and it must be

differentiated from a pneumoperitoneum

associated with a perforated abdominal

organ. Interstitial and subcutaneous

emphysema are usually of no consequence.

Haemothorax (fig. 3) is a rare complication

of a pneumothorax and most often results

from the rupture of a small vessel located in

adhesions between the visceral and the

parietal pleura. Often, re-expansion of the

lung with a chest drain helps to tamponade

Figure 1. Bulla on the apex.

the bleeding point. Occasionally, the patient

ERS Handbook: Respiratory Medicine

433

becomes hypotensive and requires

emergency surgery.

Bilateral pneumothorax happens in ,1% of

cases and can be simultaneous or, more

commonly, sequential.

Management The different clinical

situations in spontaneous pneumothorax

require different therapeutic approaches.

The nonoperative approach includes

observation, simple aspiration, and

thoracostomy with ambulatory chest

drainage. Chemical pleurodesis with

tetracycline or talc are options that can be

used to reduce the risk of recurrence.

Surgical intervention entails apical

bullectomy with or without pleurodesis by

pleurectomy or gauze abrasion.

Figure 3. Haemopneumothorax on the right side.

Observation Asymptomatic patients in good

health (,20%) with a small pneumothorax

and no evidence of radiographic progression

Aspiration and small chest tube drainage

may be treated per observation. To ensure

Simple aspiration of air with a 16-gauge

no complications develop, it is

intravenous cannula connected to a three-

recommended that these patients be

way stopcock and a 60-mL syringe is an

observed in hospital for 24-48 h. Before

option.

discharge, patients must be warned of a

potential tension pneumothorax

Small 9-Fr. chest tubes with or without

development. A weekly follow-up with

flutter valves have also been used as an

clinical examination and chest radiograph is

alternative to larger and more conventional

to be carried out until the pneumothorax has

thoracostomy tubes. The success rate is

been completely resolved. The main

high, but problems associated with kinking

inconvenience in this form of therapy is the

and occlusion of the drains have been

duration, which far exceeds what is seen

described. Treatment is still controversial.

with conventional pleural drainage plus the

Simple aspiration is recommended by the

added risk of a tension pneumothorax

British Thoracic Society - but not by the

development. Therefore, observation only is

American College of Chest Physicians - as

inappropriate in most cases.

first-line treatment for the primary

pneumothorax requiring intervention.

Acceptance by medical staff is seemingly

modest.

Conventional tube thoracostomy

Conventional tube thoracostomy remains

the procedure of choice for the management

of moderate-to-large pneumothoraces. The

drain allows for rapid and complete

evacuation of air from the pleural space.

Although underwater-seal drainage is

sufficient for most cases of pneumothorax,

the current author prefers the use of

negative intrapleural pressure to maintain

Figure 2. Pneumomediastinum.

lung re-expansion over a period of 5 days.

434

ERS Handbook: Respiratory Medicine

many patients are operated on as a result of

Table 2. Indications for surgery in primary spontaneous

complication or disease recurrence.

pneumothorax

Indications for surgery in primary

First episode

spontaneous pneumothorax are presented

Prolonged air leak

in table 2.

No re-expansion of the lung

Surgical therapy The principles of surgical

Bilateral pneumothoraces

intervention for spontaneous pneumothorax

Haemopneumothorax

consist of bulla or bleb resection (fig. 4) and

obliteration of the pleural space to prevent

Occupational hazard (flight personnel,

recurrence. Recurrence is the most common

divers)

indication for surgery in patients with a

Absence of medical facilities in isolated area

primary spontaneous pneumothorax.

Tension pneumothorax

Multiple wedge resections may also be

Associated single large bulla

required when the disease is present at

several sites. Segmentectomy and

Individual indication

lobectomy are usually unnecessary and are

Second episode

contraindicated.

Ipsilateral recurrence

Obliteration of the pleural space is thought

Contralateral recurrence after a first

to be necessary to prevent recurrences. It is

pneumothorax

accomplished by mechanical abrasion, or by

parietal apical pleurectomy (fig. 5), which is

performed in association with resection of

Nonsurgical therapy of recurrences Most

the lung during a video-assisted

surgeons are concerned about the routine

thoracoscopy.

use of chemopleurodesis in the treatment of

The operation is carried out under general

spontaneous pneumothorax. Being a benign

anaesthesia with a dual-lumen endotracheal

disease occurring in young people who may

tube. Only two thoracic incisions are made

require surgery in later life (for other disease

for the thoracoscope and dissecting or

development) the important symphysis

stapling instruments.

which follows chemopleurodesis

complicates and multiplies the risk in

association with high morbidity rates,

especially if lung resection or

transplantation is considered. Chemical

pleurodesis should therefore be used only in

selected cases.

Indications for surgery Surgery may be

indicated in the first instance, if the

pneumothorax is complicated by a

persisting air leak over 3 days. Furthermore,

haemothorax development, failure to re-

expand the lung, bilateral involvement and

tension hazard are indications. Patients with

an occupational risk hazard are a classic

indication. Some authors have proposed

that all young patients with a diagnosed

spontaneous pneumothorax should be

spared a drain thoracostomy and proceed

directly to surgical intervention. This

Figure 4. Specimen of an apical bulla resected by

approach is not standard treatment, though

stapler.

ERS Handbook: Respiratory Medicine

435

Figure 6. Thoracoscopic view of bullous

emphysema with pneumothorax.

pneumothorax because of their limited

Figure 5. Specimen of apical parietal pleurectomy.

pulmonary function. Diagnosis is difficult

due to physical findings associated with

Apical parietal pleurectomy can be

COPD (e.g. hyperresonance on percussion

performed easily using this technique with

and diminished breath sounds at

modern endo-scissors and forceps.

auscultation). In most cases, the diagnosis

However, a single-centre randomised study

is made by chest radiographs, which are also

of 787 patients shows that pleurodesis can

difficult to interpret because of the increased

be achieved with talc poudrage even in

radiolucency of the diseased lung. For these

young patients with a lower morbidity, less

difficult cases, CT may be necessary to

surgical time and no significant differences

confirm the diagnosis, localise the

concerning recurrence of pneumothorax.

pneumothorax and facilitate distinction

between a large bulla and a pneumothorax.

Video-assisted surgery is recommended as

the first-line surgical treatment for patients

The emergency treatment of patients with a

with recurrent primary spontaneous

secondary pneumothorax is similar to that

pneumothorax. This recommendation is

described for primary spontaneous pneumo-

based on its favourable early postoperative

thorax, except that observation alone is

course without major complication and the

seldom justified. If the pleural space is

long-term outcome with 3% recurrence, and

adequately drained and the lung maintains a

patient satisfaction.

re-expanded state, the air leak eventually

closes. In some patients, however, a

Secondary pneumothorax

bronchopleural fistula persists for 10-15 days,

Spontaneous pneumothorax can be

and surgical repair must be considered.

secondary to a variety of pulmonary and

nonpulmonary disorders.

When surgery is required, the procedure

must be individualised and based on the

COPD is the most common cause of

extent and disease infiltration, as well as the

secondary pneumothorax (fig. 6 and

air leak location.

table 3). It occurs typically in patients aged

.50 years and is the result of a bulla

Staple resection of the bullae should be

rupture into the pleural space.

carried out, followed by a subtotal parietal

pleurectomy or pleural abrasion.

Most patients with COPD and pneumo-

thorax present with chest pain and acute

The mortality rate for this surgery may reach

sudden respiratory distress. These patients

10% and morbidity is significant in those

show little tolerance to even a small

individuals with a poor overall physical

436

ERS Handbook: Respiratory Medicine

Table 3. Causes of secondary pneumothorax

Airway and pulmonary disease

COPD (bullous or diffuse emphysema)

Asthma

Intersitial lung disease

Pulmonary fibrosis (fig. 7)

Sarcoidosis

Infectious disease

Tuberculous and other mycobacterial

Bacterial

Pneumocystis jiroveci

Parasitic

Figure 7. Severe pulmonary fibrosis with

Mycotic

pneumothorax on the left side.

AIDS

Neoplasic

surgery is the safest approach with excellent

Bronchogenic carcinoma

long-term results.

Metastatic (lymphoma or sarcoma)

Catamenial

Further reading

Endometriosis

Abolnik IZ, et al. (1991). On the inheri-

Miscellaneous

tance of primary spontaneous pneu-

Marfan’s syndrome

mothorax. Am J Med Genet; 40: 155-158.

Aguinagalde B, et al. (2010). Percutaneous

Ehlers-Danlos syndrome

aspiration versus tube drainage for spon-

Histiocytosis X

taneous pneumothorax: systematic review

Scleroderma

and meta-analysis. Eur J Cardiothorac Surg;

37: 1129-1135.

Lymphangiomyomatosis

Baumann MH, et al. (2001). Management

Collagen disease

of spontaneous pneumothorax: an Ame-

rican College of Chest Physicians Delphi

consensus statement. Chest; 119: 590-602.

Ben-Nun A, et al. (2006). Video-assisted

condition. Other options, such as chemical

thoracoscopic surgery for recurrent spon-

pleurodesis, autologous blood injection and

taneous pneumothorax: the long-term

permanent fistula drainage can be

benefit. World J Surg; 30: 285-290.

considered in individual cases.

Beshay M, et al. (2007). Emphysema and

secondary pneumothorax in young adults

Conclusion

smoking cannabis. Eur J Cardiothorac

Surg; 32: 834-838.

Primary spontaneous pneumothorax occurs

Chambers A, et al. (2009). In patients

in young patients with no evidence of

with first-episode primary spontaneous

coexisting lung disease, while secondary

pneumothorax is video-assisted thoraco-

pneumothorax is mostly seen in emphysema

scopic surgery superior to tube thora-

patients. Unless there is a complication,

costomy alone in terms of time to

most surgeons will manage the first episode

resolution of pneumothorax and inci-

by conventional tube drainage. Recurrences

dence of recurrence? Interact Cardiovasc

are treated by bulla or bleb resection with

Thorac Surg; 9: 1003-1008.

apical parietal pleurectomy. Video-assisted

ERS Handbook: Respiratory Medicine

437

Mediastinitis

Pierre-Emmanuel Falcoz, Nicola Santelmo and Gilbert Massard

The majority of acute mediastinal infections

results from oesophageal perforation or

Key points

infection following a trans-sternal cardiac

procedure. Occasionally, acute mediastinitis

N DNM is a particularly virulent and

results from oropharyngeal abscesses with

potentially lethal mediastinal infection.

severe cervical infection spreading along the

N Initial presentation is toxic shock and

fascial planes into the mediastinum. This

respiratory difficulty, sometimes with

particularly virulent form of mediastinal

other signs such as erythema and

infection is described as descending

oedema of the neck and upper chest.

necrotising mediastinitis (DNM).

DNM is an emergency, and should be

DNM is a potentially lethal condition

treated with broad-spectrum

especially if diagnosis or treatment is

intravenous antibiotics as well as early

delayed or inappropriate. Despite the

and aggressive surgical drainage.

introduction of modern antimicrobial

therapy and CT imaging, DNM has

continued to produce high mortality rates

being the second and third most common

(reported between 25% and 40%).

primary infections, respectively.

Criteria for diagnosis of DNM

Route of diffusion

Criteria for diagnosis of DNM have been

Familiarity with the cervical fascial planes is

accurately defined as follows.

essential in understanding the propagation

N Clinical manifestations of a severe

pathways, symptoms and thoracic

infection

complications of cervical infections. The

infection spreads from neck to mediastinum

N Establishment of a relationship between

along three primary routes: via the

an oropharyngeal or cervical infection and

subsequent mediastinitis

retropharyngeal space, the perivascular

space and the pre-tracheal space. The

N Demonstration of radiographic features

characteristic of DNM

retropharyngeal space has been thought to

N Documentation of a necrotising

be the most important route by which a

mediastinal infection at the time of

cervical infectious disease spreads to the

operative debridement or necropsy

mediastinum (70% of cases in the series of

Moncada et al. (1978)). Rapid spread of

Epidemiology

infection is facilitated by tissue necrosis

(loss of anatomical structure), gravity and

Primary sites of infection are periodontal,

negative intrathoracic pressure.

retropharyngeal and peritonsillar abscesses.

According to Wheatley et al. (1990), the

Pathogens involved

most common primary oropharyngeal

infection is odontogenic (25 out of 43

DNM is a polymicrobial process with

cases), with mandibular or molar abscesses

anaerobic organisms being the most

ERS Handbook: Respiratory Medicine

439

predominant. Freeman et al. (2000)

oesophageal thickening and enlarged

reviewed the English literature and found 96

lymph nodes. Brunelli et al. (1996) found

patients with DNM between 1990 and 1999.

cervicothoracic CT imaging to be

All but four (4%) had mixed aerobic and

immediately diagnostic in all patients in

anaerobic infection, with those pathogens

whom it was used.

often acting synergistically; in the four

Treatment

exceptions, the sole pathogen was b-

haemolytic Streptococcus. Chow et al. (1978)

The principles of treatment are:

reported that anaerobes had been recovered

from 94% of patients with DNM; 52% had

N emergency

mixed infections and 88% had polymicrobial

N intravenous broad-spectrum antibiotic

infections.

therapy: probabilistic and secondarily

adapted to the pathogen(s)

Clinical and radiological signs

N early and aggressive surgical drainage:

The anamnesis of mediastinitis is as follows.

extensive debridement, excision of

necrotic tissue, bacteriological sampling,

N Phase I: periodontal or peritonsillar

mediastinal and pleural irrigation, and

abscess treated by simple antibiotherapy

feeding jejunostomy

N Phase II: erythema and oedema of the

neck with or without associated with

The decision on the type of surgical drainage

subcutaneous emphysema

to be employed is a crucial one. Classically,

N Phase III: acute aggravation of the

four approaches have been reported:

infectious syndrome; onset of cough,

transcervical

dyspnoea, sternal pain and painful

standard posterolateral thoracotomy

dysphagia

median sternotomy

Patients with DNM usually present with

transthoracic via subxyphoid or

toxic shock and respiratory difficulty. Other

clamshell incision

presenting signs may include erythema and

oedema of the neck and upper chest. In

A thoracoscopic approach and video-

severe infections, frank necrosis of the skin,

assisted mediastinoscopic drainage can also

fascia and muscle may be present. In the

be found. Although each of these techniques

chest, DNM may produce abscesses and

offers potential advantages and

empyemas, pleural and pericardial

disadvantages, the posterolateral

effusions, intrathoracic haemorrhage, and

thoracotomy incision (sometimes bilateral)

cardiac tamponade, and frequently results in

remains the standard by which other

the death of the patient.

transthoracic approaches should be

measured.

Delay of diagnosis is one of the primary

reasons for high mortality in DNM.

The optimal surgical approach for

Diagnosis of DNM from conventional

mediastinal drainage is theoretically

radiographic studies may be difficult,

dependent on the level of diffusion of

principally because the signs appear late in

necrotising process. Several studies have

the course of the disease. Cervicothoracic

reported that mediastinal drainage is best

CT imaging is currently considered the

accomplished through a transthoracic

diagnostic study of choice for patients in

approach when the necrotising process

whom DNM is suspected. Indeed, CT scan

extends below the level of the fourth thoracic

findings have been proven to confirm the

vertebra posteriorly or the tracheal

diagnosis of DNM with high accuracy in

bifurcation anteriorly. However, because of

these patients who often have a

the rapid spread of this type of infection,

nonspecific constellation of symptoms.

other investigators have advocated

Various CT imaging findings are increased

mandatory transthoracic mediastinal

attenuation of mediastinal fat, air fluid

exploration regardless of the level of

levels, pleural and pericardial effusions,

infection. This latter point was confirmed in

440

ERS Handbook: Respiratory Medicine

a meta-analysis, where a statistically

patient’s condition and extension of the

significant difference (p,0.05) in survival

mediastinitis (posterolateral thoracotomy

was found between patients undergoing

is frequently required). In the post-

transcervical mediastinal drainage (53%)

operative period, progression of the

versus those receiving transthoracic

disease and effectiveness of surgical

mediastinal drainage (81%).

therapy should be monitored by CT.

Further drainage should be carried out if

Close-watch care Recurrent abscesses and

necessary either surgically or by

collections are common after first operative

percutaneous drainage.

drainage (50%) and they should be drained

promptly. Ideally, CT or, failing that,

ultrasound-guided percutaneous drainage of

Further reading

recurrent abscesses and collections may

Brunelli A, et al.

(1996). Descending

decrease the need for recurrent surgical

necrotizing mediastinitis: cervicotomy or

procedures in these critically ill patients.

thoracotomy? J Thorac Cardiovasc Surg;

Surveillance should be continued until no

111: 485-486.

evidence of progressive infection is found on

Chow AW, et al. (1978). Orofacial odonto-

CT imaging and the patient displays no

genic infections. Ann Intern Med; 88: 392-

clinical signs of infection. Hyperbaric oxygen

402.

therapy has not shown any real proof of

Corsten MJ, et al. (1997). Optimal treat-

effectiveness in this particular framework,

ment of descending necrotizing medias-

when looking at evidence-based medicine. It

tinitis. Thorax; 52: 702-708.

should not take the place of or delay surgical

Devaraj A, et al.

(2007). Computed

treatment.

tomography findings in fibrosing medias-

tinitis. Clin Radiol; 62: 781-786.

Mediastinal fibrosis Fibrosing mediastinitis

Estera AS, et al.

(1983). Descending

is an uncommon chronic sequela of prior

necrotizing mediastinitis. Surg Gynecol

infectious mediastinal involvement. A

Obstet; 157: 545-552.

chronic, noninfectious inflammatory

Freeman RK, et al. (2000). Descending

process results in progressive mediastinal

necrotizing mediastinitis: an analysis of

fibrosis. The fibrosis may constrict or

the effects of serial surgical debridement

on patient mortality. J Thorac Cardiovasc

obstruct virtually any of the mediastinal

Surg; 119: 260-267.

organs (in particular, the superior vena cava,

Marty-Ané CH, et al. (1999). Management

oesophagus, and pulmonary vein or artery).

of descending necrotizing mediastinitis:

CT scans demonstrate a localised (or less

an aggressive treatment for an aggressive

frequently diffuse) mass infiltrating the

disease. Ann Thorac Surg; 68: 212-217.

mediastinum and constricting the structure;

Kocher GJ, et al. (2012). Diffuse descend-

extensive calcification is associated with the

ing necrotizing mediastinitis: surgical

fibrotic mass in a vast majority of the cases.

therapy and outcome in a single-centre

This appearance is pathognomonic of the

series. Eur J Cardiothorac Surg; 42: e66-

disorder.

e72.

Moncada R, et al. (1978). Mediastinitis

Conclusions

from odontogenic and deep cervical

infection: anatomic pathways of propaga-

DNM is caused by downward spread of

tion. Chest; 73: 497-500.

neck infections and constitutes a highly

Shimizu K, et al.

(2006). Successful

fatal complication of oropharyngeal

video-assisted mediastinoscopic drain-

lesions. CT imaging should be performed

age of descending necrotizing mediasti-

in all patients with persistent symptoms of

nitis. Ann Thorac Surg; 81: 2279-2281.

septicaemia after being treated for

Wheatley MJ, et al. (1990). Descending

oropharyngeal infections. Prompt surgical

necrotizing mediastinitis: transcervical

drainage of the mediastinum should be

drainage is not enough. Ann Thorac

performed. The optimal mediastinal

Surg; 49: 780-784.

drainage method should be tailored to each

ERS Handbook: Respiratory Medicine

441

Neuromuscular disorders

Andrea Vianello

Various neuromuscular diseases (NMDs)

essential and may reveal an increase in

can progress to the point where they cause

respiratory rate, followed by alternating

pulmonary complications (table 1); a careful

abdominal and rib cage breathing

respiratory follow-up adapted to the variable

(respiratory alternans), the absence of

time course of each disease is therefore

outward excursion of the abdomen during

mandatory. Although the diseases have

inspiration or even paradoxical inward

different causes and clinical courses,

inspiratory movement due to diaphragm

common principles apply to their

weakness (abdominal paradox), accessory

management.

muscle recruitment, and mucous

encumbrance of upper or lower airways.

Evaluation of patients with suspected

Indicators of bulbar muscle involvement

respiratory impairment

include dysarthria, trouble swallowing

liquids, aspiration manifesting as a new-

Clinical evaluation As the first step, a

onset cough, or frank choking.

systematic clinical evaluation is essential to

detect the subtle respiratory symptoms and

Pulmonary function testing Pulmonary

signs related to respiratory muscle failure.

function tests (PFTs) should be performed

Symptoms are frequently nonspecific,

routinely during the evaluation of patients

including fatigue, lethargy or difficulty

with NMD. Because of the inadequacy of

concentrating. Dyspnoea and orthopnoea

inspiratory muscle function, PFTs generally

are often late findings in patients with

reveal the pattern of a restrictive ventilatory

usually severe functional impairment due to

defect, with the following characteristics:

peripheral muscle weakness. Patients with

sleep-disordered breathing (SDB) often

N preserved TLC until a far-advanced stage

seem to have symptoms such as an

of the disease;

unrefreshed feeling upon awakening,

N elevated residual volume;

morning headaches, disappearance of

N reduced vital capacity (VC); and

snoring, daytime tiredness, and irritability as

N preserved functional residual capacity.

a result of repeated arousals and carbon

When VC falls below 55% predicted, the

dioxide retention. Physical evaluation is

onset of insidiously progressive hypercapnia

is likely. A significant difference between

upright and recumbent lung volumes has

Key points

been reported frequently for patients with

NMD; in particular, a fall in VC of o25% has

N NMD have a range of causes, but

been considered a sensitive indicator of

common principles apply to their

diaphragmatic weakness. A specific

treatment.

evaluation of respiratory muscle strength is

Treatment focuses on ventilatory

mandatory as these tests are both sensitive

assistance and assisted coughing

and highly prognostic. A high negative

techniques.

maximal inspiratory pressure (MIP) result

(, -80 cmH₂O) or a high positive maximal

ERS Handbook: Respiratory Medicine

443

Table 1. NMDs affecting respiratory function

Site of lesion

Specific disorders

Anterior horn cell

Amyotrophic lateral sclerosis

Poliomyelitis

Type I SMA, intermediate SMA

Peripheral nerve and/or

Guillain-Barré syndrome

nerve roots

Charcot-Marie-Tooth disease

Neuromuscular junction

Congenital myasthenia

Muscle

Duchenne/Becker muscular dystrophy

Limb-girdle muscular dystrophy (especially types 2C-2F-2I)

Facioscapulohumeral muscular dystrophy

Congenital muscular dystrophy

Congenital myotonic dystrophy

Acid maltase deficiency

Congenital myopathy

Mitochondrial myopathy

Bethlem myopathy

SMA: spinal muscular atrophy.

expiratory pressure result (. +90 cmH₂O)

signs of sleep-wake abnormality or

excludes clinically relevant inspiratory or

nocturnal respiratory failure. It has been

expiratory muscle weakness. Cough peak

suggested that PSG or respiratory

expiratory flow (CPEF) is the single most

polygraphy should be performed in all NMD

important factor in determining whether the

patients as early as possible to take a

ability to eliminate bronchial secretions is

baseline recording. It should be repeated

well preserved. Patients who, either alone or

according to the course of the disease to

with assistance, are able to generate a CPEF

detect abnormalities during sleep and

.270 L?min^-1 can effectively remove

subsequent indication for long-term

bronchial secretions, whereas those with a

ventilatory treatment.

CPEF ,160 L?min^-1 usually require tracheal

Management

suctioning at the onset of respiratory

infections. The frequency of pulmonary

Long-term noninvasive positive pressure

function monitoring depends on the rapidity

ventilation In recent years, the approach to

of progression of the neuromuscular

care in neuromuscular respiratory failure

syndrome and may range from every 1-

has been revised, due to two new critical

2 months to yearly. Once the VC drops

developments:

below 40-50% pred or MIP below 30% pred,

daytime arterial blood gas analysis should

1) technology has advanced and several new

be performed.

types of ventilatory aids have been

introduced, which deliver effective

Sleep study All patients with NMD should

mechanical ventilation, even noninvasively;

be monitored carefully for the presence of

and

SDB. Nocturnal oximetry alone is

inadequate to detect sleep apnoea and

2) the majority of severely disabled

hypoventilation. In addition, criteria

ventilator users have expressed satisfaction

defining significant desaturations remain

with their lives, even though they are usually

controversial. Overnight polysomnography

unable to achieve some of the goals

(PSG) or respiratory polygraphy is advisable

associated with acceptable quality of life in

for patients who develop symptoms and

the ‘normal’ population.

444

ERS Handbook: Respiratory Medicine

N FVC ,50% pred or MIP ,60 cmH₂O

(only for rapidly progressive disease)

Examinations required in the

assessment of respiratory function in

The following complications are considered

patients with NMD are:

to be contraindications for the noninvasive

ventilatory approach.

checklist of symptoms and signs;

VC sitting or standing, and lying;

N Severely impaired swallowing, leading to

maximal inspiratory and expiratory

chronic aspiration and repeated

pressures;

pneumonia

N cough peak expiratory flow;

Ineffective clearing of tracheobronchial

N arterial blood gases, if symptoms

secretions, despite the use of noninvasive

present; and

manual or mechanical expiratory aids

N PSG or respiratory polygraphy, if

The need for round-the-clock (.20 h)

symptoms or nocturnal respiratory

ventilatory support

failure present.

These conditions usually require an invasive

application of mechanical ventilation via

tracheostomy. There is no consensus on the

As a consequence, increasing numbers of

optimal interface to use in delivering NPPV:

NMD patients with advanced respiratory

nasal masks are usually preferable for

impairment are now being successfully

nocturnal ventilation, due to the fact that

treated by long-term noninvasive positive

they are more comfortable and permit better

pressure ventilation (NPPV), usually in the

speech; conversely, oronasal interfaces may

home setting. The noninvasive

be a suitable alternative for subjects who

administration of positive pressure

have excessive air leaking through the

ventilation requires a positive pressure

mouth or nose. Mouthpiece interfaces have

ventilator delivering pressurised gas to the

also been successfully used to deliver NPPV

lungs through an interface via the nose or

for up to 24 h?day^-1. Finally, the choice of

mouth, or both. In recent years,

ventilator and interface in most cases is

manufacturers have developed a new

individualised according to patients’

generation of microprocessor-controlled

preference and physicians’ intuition and

ventilators aimed at combining a minimum

experience, rather than based on

warranted alveolar ventilation with maximal

standardised evidence-based guidelines.

patient comfort. Also, special features have

Administration of NPPV to NMD patients

been incorporated that are designed to

with chronic respiratory failure may be

facilitate the application of noninvasive

expected to allow some individuals with

techniques and are simple, reliable and easy

nonprogressive pathology to live to nearly

for the patient to use.

normal life expectancy, extend survival by

many years in patients with other

Long-term NPPV is required when

conditions, improve physiological lung

spontaneous respiratory muscle effort is

function and quality of life (QoL), and

unable to sustain adequate alveolar

decrease the frequency of exacerbations

ventilation, causing chronic-stable or slowly

requiring acute care facilities. Although

progressive respiratory failure.

ineffective for prolonging survival in patients

Indications for NPPV therapy in chronic

with rapidly progressive conditions and

NMD are symptoms (such as fatigue,

advanced bulbar muscle involvement, such

dyspnoea, morning headache) and one of

as amyotrophic lateral sclerosis/motor

the following physiological criteria.

neurone disease, NPPV may be added with

the aim of improving some aspects of the

N Significant daytime carbon dixoide

QoL, in particular energy, vitality and

retention (PaCO₂ .50 mmHg)

symptoms related to SDB, being considered

N Nocturnal oxygen desaturation (SaO₂ ,88%

as an important part of the total palliative

for at least five consecutive minutes)

care plan for terminally ill cases.

ERS Handbook: Respiratory Medicine

445

Approach to acute respiratory illness The

onset of acute respiratory failure, due to the

combination of inspiratory, expiratory or

bulbar innervated muscle dysfunction

leading to inadequate cough and inability to

handle oropharyngeal secretions, is a crucial

event in the advanced stage of most NMD

and a major cause of death, unless

mechanical ventilation is used. Respiratory

tract infection is the most common

precipitating factor, potentially aggravating

inspiratory muscle weakness and promoting

atelectasis and pneumonia. A list of

Figure 1. Application of mechanical insufflation-

potential precipitating factors is presented

exsufflation combined with manually assisted

in table 2.

coughing during respiratory tract infection.

A noninvasive approach to the management

Mechanical insufflation-exsufflation can be

of respiratory tract infections causing acute

administered by a device consisting of a

respiratory failure, based on the

two-stage axial compressor that provides

combination of expiratory muscle aid and

positive pressure to the airway, then rapidly

NPPV, has been proposed. This treatment

shifts to negative pressure, thereby

strategy may result in a reduced need for

generating a forced expiration. For NMD

nasal suctioning and conventional

patients who still require endotracheal

intubation, and/or tracheostomy. Among

intubation and invasive mechanical

noninvasive expiratory aids, manually

ventilation, preventive application of NPPV

assisted coughing techniques have been

after extubation may provide a clinically

demonstrated to be effective in facilitating

important advantage by averting the need

the elimination of airway secretions.

for re-intubation or tracheostomy, and

Additionally, mechanical insufflation-

shortening their stay in the intensive care

exsufflation has been shown to effectively

unit.

mobilise mucous secretions and has been

proposed as a complement to manually

Conclusion

assisted coughing techniques in the

prevention of pulmonary morbidity (fig. 1).

It is now clear that life can be greatly

prolonged for most individuals with NMD

by the availability of noninvasive aids and

Table 2. Potential causes of acute respiratory failure

that the great majority of severely disabled

in NMD patients

patients submitted to ventilatory assistance

Common

are satisfied with their lives. Clinicians with a

Upper respiratory tract infection/acute

special competence in the management of

bronchitis

such patients have the responsibility of

offering these treatment options,

Pneumonia

encouraging the patients to decide in

Atelectasis

advance whether or not these measures

Cardiac failure

would be acceptable.

Less common

Pneumothorax

Further reading

Pulmonary embolism

Bach JR, et al.

(1997). Prevention of

Sedatives and hypnotics

pulmonary morbidity for patients with

Duchenne muscular dystrophy. Chest;

Tracheal haemorrhage (patients with

112: 1024-1028.

tracheostomy)

446

ERS Handbook: Respiratory Medicine

Bourke SC, et al. (2006). Effects of non-

Mellies U, et al.

(2003). Daytime pre-

invasive ventilation on survival and qual-

dictors of sleep disordered breathing in

ity of life in patients with amyotrophic

children and adolescents with neuromus-

lateral sclerosis: a randomised controlled

cular disorders. Neuromusc Disord;

13:

trial. Lancet Neurol; 5: 140-147.

123-128.

Braun NM, et al.

(1983). Respiratory

Polkey MI, et al.

(1999). Respiratory

muscle and pulmonary function in poly-

aspects of neurological disease. J Neurol

myositis and other proximal myopathies.

Neurosurg Psychiatry; 66: 5-15.

Thorax; 38: 616-623.

Simonds A, et al. (1998). Impact of nasal

Clinical indications for noninvasive posi-

ventilation on survival in hypercapnic

tive pressure ventilation in chronic

Duchenne muscular dystrophy. Thorax;

respiratory failure due to restrictive lung

53: 949-952.

disease, COPD, and nocturnal hypoventi-

Simonds AK (2006). Recent advances in

lation - a consensus conference report.

respiratory care for neuromuscular dis-

Chest; 116: 521-534.

ease. Chest; 130: 1879-1886.

Gomez-Merino E, et al.

(2002).

Vianello A, et al.

(1994). Long-term

Duchenne muscular dystrophy: prolonga-

nasal intermittent

positive pressure

tion of life by noninvasive ventilation and

ventilation in advanced Duchenne’s

mechanically assisted coughing. Am J

muscular dystrophy. Chest;

105:

445-

Phys Med Rehabil; 81: 411-415.

448.

Hill NS (2002). Ventilator management

Vianello A, et al.

(2000). Non-invasive

for neuromuscular disease. Semin Respir

ventilatory approach to treatment of

Crit Care Med; 23: 293-305.

acute respiratory failure in neuromuscu-

Hull J, et al.

(2012). British Thoracic

lar disorders. A comparison with endo-

Society guidelines for respiratory man-

tracheal intubation. Intensive Care Med;

agement of children with neuromuscular

26: 384-390.

weakness. Thorax; 67: i1-i40.

Vianello A, et al.

(2005). Mechanical

Kohler M, et al. (2005). Quality of life,

insufflation-exsufflation improves out-

physical disability, and respiratory impair-

comes for neuromuscular disease

ment in Duchenne muscular dystrophy.

patients with respiratory tract infections.

Am J Respir Crit Care Med; 172: 1032-1036.

Am J Phys Med Rehabil; 84: 83-88.

Lofaso F, et al. (2002). Polysomnography

Vianello A, et al.

(2011). Prevention of

for the management of progressive

extubation failure in high-risk patients

neuromuscular disorders. Eur Respir J;

with neuromuscular disease. J Crit Care;

19: 989-990.

26: 517-524.

ERS Handbook: Respiratory Medicine

447

Chest wall disorders

Pierre-Emmanuel Falcoz, Nicola Santelmo and Gilbert Massard

There is a large and diverse group of

Pathogenesis

congenital abnormalities of the thorax that

Over the years, the theories concerning the

manifest as deformities and/or defects of

pathogenesis of pectoral deformities

the anterior chest wall. Depending on the

evolved from substernal ligament traction to

severity of the case, there may be

overgrowth of the rib cartilage and later to a

cardiopulmonary (tolerance to exercise) or

stress-strain imbalance. The genetic

psychological implications.

aspects of pectus deformities have just

This diverse group includes:

started to emerge and, hopefully, will answer

many questions.

N pectus excavatum or ‘funnel chest’

Pectus excavatum is a recessively inherited

N pectus carinatum or ‘keel chest’

chest wall deformity with an occurrence of

N Poland syndrome

0.3% of all births (9:1 predominance in

N cleft sternum

males). In patients with pectus excavatum,

the normally moderately convex contour of

Among these, pectus excavatum and pectus

the anterior chest wall is replaced by

carinatum are the two most common chest

precordial depression. Depending on the

wall abnormalities.

severity of the anomaly, the sternovertebral

space is narrowed, there is a shift of the

heart into the left hemithorax and

pulmonary expansion is confined.

Key points

The indications for surgery may be

summarised as follows.

The two most common chest wall

abnormalities are pectus excavatum

N Aesthetic (psychological repercussion)

and pectus carinatum.

N Symptom

N Exercise intolerance, decreased

N The two most common surgical

endurance or exercise-induced asthma

procedures for pectus excavatum

N Body images issues (CT scan)

repair are the modified Ravitch

N Pain

technique and the Nuss procedure.

N Abnormal/low FVC, FEV1 or maximum

N Careful pre-operative evaluation on

voluntary ventilation

the basis of clinical and psychological

N Decreased oxygen pulse, oxygen uptake

symptoms is required to select

or V9E

potential candidates for surgical

N Echocardiogram: compression of right

remodelling.

atrium/right ventricle (rare)

N CT Haller index .3.0

N The optimal timing of surgical repair

N Calliper measurement depth .2.5 cm

would be after the main growth has

stopped (late teens or early 20s).

Pectus carinatum In pectus carinatum, the

clinical aspect includes a variety of

448

ERS Handbook: Respiratory Medicine

protrusion deformities of the anterior chest

of the pectoralis muscles, transverse

wall. The most common variety consists of

osteotomy and resection of the deformed

anterior displacement of the sternal

cartilages, is largely identical to that

gladiolus with the appropriate cartilages in

described in pectus excavatum. Operative

tow. In severe forms, there is also a

correction requires double bilateral

narrowing of the transverse diameter of the

chondrotomy parasternally and at points of

chest, which seems to further exaggerate the

transition to the normal ribs, followed by

anomaly.

detorsion of the sternum, retrosternal

mobilisation and correction of the everted

The indications for surgery may be

sternum, as well as of the everted and

summarised as follows.

inverted ribs. After incomplete wedge

osteotomy, the mobilised sternum is finally

N Aesthetic (psychological repercussion)

stabilised by a temporary support bar

N Pain

anterior to the sternum and cartilages (in

N Frequent injury

place for o6 months).

N Body image issues

N Abnormal pulmonary function testing

Controversies

Surgical treatment

Some controversies do need to be

mentioned. First, concerning pectus

Pectus excavatum Although there are a

excavatum, there has never been a

number of different techniques utilised by

randomised controlled trial comparing the

surgeons, most repairs performed today will

results of the two most common surgical

be either the modified Ravitch technique or

procedures. The meta-analysis by Nasr et al.

the Nuss procedure (note that the Wada

(2010) comparing the Nuss procedure and

procedure of sternal turnover is no longer

the Ravitch technique repair suggested no

used).

differences with respect to overall

The Ravitch technique requires the

complications, length of hospital stay or

exposition of the thorax’s anterior region

time to ambulation. Secondly, concerning

(horizontal inframammary fold incision

the optimal timing of surgical repair, it

preferred) with resection of costal cartilages

seems that the best time for repair would be

affected bilaterally, the performance of a

after the main growth has stopped (i.e. after

cross-sternal osteotomy with the placing of a

adolescence in the late teens or early 20s),

temporary stabiliser (support bar anterior to

as opposed to early repair. Although the

the sternum), and the development of a

operation is more traumatic after

muscular flap.

adolescence, the results are far better with

minimal recurrence. Thirdly, the goal of such

The Nuss technique is an alternative and

an approach remains elusive. Not only are

new technique performed by means of

we unable to reach an agreement on such

minimally invasive surgery, and based on

simple issues as how to measure the clinical

the skeleton’s malleability and the

or even the anatomical severity of pectoral

remodelling capacity of the thorax. The

deformities, but we are still engaged in a

technique consists of the implantation of a

seemingly endless debate with the insurance

retrosternal steel bar that modifies the

companies as to whether these often

concavity of the sternum while maintaining

physiologically and psychologically crippling

the contour of the reformed thorax, all by

abnormalities should be even considered a

means of two small incisions on each side of

‘disease’ at all.

the thorax. In terms of chest wall kinematics,

the Nuss procedure increases chest wall

Conclusion

volume by 11% without affecting chest wall

Chest wall abnormalities (pectus excavatum

displacement or rib cage configuration.

and pectus carinatum) are a relatively rare

Pectus carinatum The repair of pectus

problem but are commonly seen in the

carinatum, including exposure, detachment

practice of general thoracic surgery. Careful

ERS Handbook: Respiratory Medicine

449

pre-operative evaluation on the basis of

Haller JA, et al. (1989). Evolving manage-

clinical but also psychological symptoms is

ment of pectus excavatum based on a

required to select potential candidates for

single institutional experience of

664

surgical remodelling. Surgical procedures,

patients. Ann Surg; 209: 578-583.

based on the surgeon’s personal expertise,

Huddelston CB (2004).Pectus excavatum.

are currently relatively well codified and

Semin Thorac Cardiovasc Surg; 16: 225-232.

Nasr A, et al. (2010). Comparison of the

provide satisfactory results with a low rate of

Nuss and the Ravitch procedure for

complications.

pectus excavatum repair: a meta-analysis.

J Pediatr Surg; 45: 880-886.

Further reading

Nuss D, et al. (1998). A ten-year review of

minimally invasive technique for the

Binazzi B, et al.

(2012). Effects of the

correction of pectus excavatum. J Pediatr

Nuss procedure on chest wall kinematics

Surg; 33: 545-552.

in adolescents with pectus excavatum.

Ravitch MM (1949). The operative treat-

Respir Physiol Neurobiol; 183: 122-127.

ment of pectus excavatum. Ann Surg; 129:

Colombani PM

(2009). Preoperative

429-444.

assessment of chest wall deformities.

Robicsek F, et al. (2009a). Surgical repair

Semin Thorac Cardiovasc Surg; 21: 58-63.

of anterior chest wall deformities: the past,

Emil S, et al. (2012). Pectus carinatum

the present, the future. Introduction.

treatment in Canada: current practices.

Semin Thorac Cardiovasc Surg; 21: 43.

J Pediatr Surg; 47: 862-826.

Robiscek F, et al.

(2009b). Surgical

Feng J, et al. (2001). The biomechanical,

repair of pectus excavatum and carina-

morphologic, and histochemical proper-

tum. Semin Thorac Cardiovasc Surg; 21:

ties of the costal cartilages in children

64-75.

with pectus excavatum. J Pediatr Surg; 36:

Saxena AK, et al. (1999). Surgical repair

1770-1776.

of pectus carinatum. Int Surg; 84: 326-

Fonkalsrud EW, et al.

(2004). Less

330.

extensive techniques for repair of pectus

Shamberger SC, et al. Congenital de-

carinatum: the undertreated chest de-

formities. In: Pearson FG, et al., eds.

formity. J Am Coll Surg; 198: 898-905.

Thoracic Surgery. New York, Churchill

Gurnett CA, et al. (2009). Genetic linkage

Livingstone, 1995; pp. 1189-1209.

localizes an adolescent idiopathic scolio-

Shu Q, et al.

(2011). Experience in

sis and pectus excavatum gene to

minimally invasive Nuss operation for

chromosome 18 q. Spine (Phila Pa 1976);

406

children with pectus excavatum.

34: E94-E100.

World J Pediatr; 7: 257-261.

450

ERS Handbook: Respiratory Medicine

Pathology and molecular

biology of lung cancer

Sylvie Lantuéjoul, Lénaïg Mescam-Mancini, Barbara Burroni and

Anne McLeer-Florin

Lung cancer prognosis is poor, with a global

EGFR gene mutations lead to activation of

survival rate, all stages combined, of ,15%,

the Ras/mitogen-activated protein kinase

mainly because most cases are surgically

(MAPK) and phosphatidylinositol-3-kinase

unresectable at the time of diagnosis.

(PI3K)/AKT downstream pathways. These

However, the discovery in 2004 of EGFR

mutations are found in 50% of

(epidermal growth factor receptor)

adenocarcinomas in Asian patients and in

mutations in a subset of adenocarcinomas,

only 15% of Caucasian patients (West et al.,

leading to a specific clinical response to

2012). They mostly arise in nonsmoking

tyrosine kinase inhibitors (TKIs), has raised

women with papillar or lepidic

high hopes towards development of

adenocarcinomas, according to the new

targeted therapies (Travis et al., 2011). Lung

World Health Organization (WHO)

tumours in nonsmokers are the seventh

classification of lung adenocarcinoma

cause of death by cancer worldwide and are

(Travis et al., 2011), that are thyroid

more readily observed in women, especially

transcription factor (TTF)1 positive

in Asia. These tumours are characterised by

(Shigematsu et al., 2006). In 85% of cases,

the presence of a ‘driver’ mutation -

these activating mutations correspond to a

translocation or amplification of an

deletion in exon 19 (39%) or a point

oncogene - leading to constitutive

mutation (L858R) in exon 21 (46%), and

stimulation of cell proliferation and anti-

confer sensitivity to the EGFR TKI gefitinib

apoptotic signalling pathways in the tumour

(marketed as Iressa by AstraZeneca,

cells (fig. 1) (Weinstein et al., 2008).

London, UK) and erlotinib (Tarceva;

Genentech-Roche, San Francisco, CA,

ErbB family

USA), which are US Food and Drug

Administration (FDA)-approved for the

The ErbB family comprises EGFR (also

treatment of mutated metastatic non-small

known as ErbB1 or HER1), ErbB2 (HER2 or

cell lung carcinomas (NSCLCs) (Uramoto et

Neu), ErbB3 (HER3) and ErbB4 (HER4).

al., 2007). Conversely, insertion in exon 20

is correlated with primary resistance to

EGFR TKIs, and the T790M mutation is

associated with secondary resistance

Key points

(Cheng et al., 2012). Antibodies raised

against the exon 19-deleted form (del746-

N Lung cancer prognosis is poor, most

750)

(clone 6B6; Cell Signaling Technology

cases being surgically unresectable at

(Danvers, MA, USA) monoclonal antibody

the time of diagnosis.

(mAb) 2085) and the exon 21-mutated form

Driver mutations, translocations or

(L858R) (clone D38B1; Cell Signaling

amplifications are involved in lung

Technology mAb 3197) are in development

oncogenesis, and have led to a

for diagnosis by immunohistochemistry,

molecular classification of lung

with sensitivities ranging from 40% to 100%

tumours.

and specificities from 88% to 100%

(Kitamura et al., 2010).

ERS Handbook: Respiratory Medicine

451

BRAF mutation (1%)

EGFR mutation (10%)

Others/unknown

(39%)

RET translocation (1%)

ROS translocation (1%)

HER2 mutation (4%)

PIK3CA

mutation (2%)

MET

KRAS mutation

amplification

(25%)

ALK translocation

(10%)

(7%)

DDR2 mutation (4%)

FGFR1 amplification

MET mutation (1%)

(22%)

MET amplification (5%)

BRAF mutation (2%)

Others/unknown

(39%)

PIK3CA amplification

(33%)

Figure 1. Druggable genetic abnormalities (mutation, amplification and rearrangement) in pulmonary

a) adenocarcinomas and b) squamous cell carcinomas in Caucasian patients.

Mutations of HER2 and HER4 are rare

ALK

(2-4%). HER2 mutations (exon 20) arise in

In 2007, ALK (anaplastic lymphoma kinase)

nonsmoking Asian women, and could confer

(chromosome 2p23) and EML4 (echinoderm

sensitivity to trastuzumab and pan-EGFR/

microtubule-associated protein-like 4)

HER2 inhibitors (lapatinib, BIBW29952,

(2p21) gene rearrangement was identified in

neratinib, etc.) (Brabender et al., 2001).

NSCLC (Soda et al., 2007). Other ALK

KRAS and BRAF

partners have been reported, such as TFG

(TRK-fused gene), KIF5B (kinesin family

KRAS mutations are observed in up to 30% of

member 5B) and KLC1 (kinesin light chain 1)

adenocarcinomas. KRAS and EGFR mutations

(Takeuchi et al., 2012; Togashi et al., 2012).

are mutually exclusive (Shigematsu et al.,

These rearrangements are observed in 3-7%

2006), and KRAS mutations are associated

of NCSLCs and are mutually exclusive with

with a resistance to EGFR TKIs.

EGFR and KRAS mutations. Patients with

ALK rearrangement are often young, light

BRAF is a downstream effector of RAS. The

smokers or nonsmokers at an advanced

BRAF V600E mutation is the most frequent

stage with frequent pleural localisations

(50%), before G469A (39%) and D594G

(Soda et al., 2007). ALK-positive tumours

(11%). They are observed in 3% of NSCLCs.

are mostly TTF1-positive adenocarcinomas

Mutations other than V600E are more

with signet-ring cells (Rodig et al., 2009). A

common in smokers; V600E is more

favourable response with the FDA-approved

common in women with micropapillar

small molecule ALK and Met inhibitor

adenocarcinoma of poor prognosis. These

crizotinib (PF-02341066) has been obtained

mutations could confer sensitivity to MEK

in phase I/II clinical trials. FISH

(MAPK kinase) inhibitors (Paik et al., 2011).

(fluorescence in situ hybridisation) remains

452

ERS Handbook: Respiratory Medicine

the gold-standard technique for diagnosis

amplification, mutations, or alternative

but this technique is costly and time-

splicing (Feng et al., 2012). Various scores

consuming, and several authors have

for c-Met overexpression and MET

suggested pre-screening by

amplification have been proposed (fig. 2c

immunohistochemistry (fig. 2a and b) with

and d). MET amplification seems to be

two antibodies (clone 5A4 (Abcam,

correlated with a poor outcome (Cappuzzo

Cambridge, UK) and D5F3 (Cell Signaling

et al., 2009), and c-Met phosphorylation

Technology)) presenting high sensitivities

with the development of brain metastases

and specificities (92-100% and 99-100%,

and primary and acquired resistance to

respectively) (McLeer-Florin et al., 2012).

EGFR TKIs (Benedettini et al., 2010).

ROS1 and RET

PIK3CA

ROS1 (c-Ros oncogene 1, 6q22)

The PIK3CA gene is mutated in 3.6% of

rearrangements have been detected in

squamous cell carcinomas (SCCs) and 2%

0.9-1.7% of NSCLCs (Bergethon et al., 2012;

of adenocarcinomas with an acinar or

Takeuchi et al., 2012) and RET (Ret proto-

papillary histology (Samuels et al., 2005).

oncogene, 10q11.2) rearrangements are

Mutations affect exons 9 and 20, and

observed in 1.2% of adenocarcinomas. Both

amplification of the 3q25-27 genomic

types of rearrangements arise in young light

region containing PIK3CA (3q26) is

smoking or nonsmoking patients with

detected in 10% NSCLC. In SCC, 3q26

adenocarcinomas, and seem to be mutually

amplification is reported in 40% of cases.

exclusive with EGFR mutations or ALK

These mutations or amplifications are not

rearrangements. Crizotinib could target

exclusive with those of EGFR and KRAS.

ROS1 rearranged tumours and vandetanib, a

Various PI3K inhibitors are under

VEGFR (vascular endothelial growth factor

development, some also targeting mTOR

receptor), EGFR and Ret inhibitor, could

(Heist et al., 2012).

inhibit RET-rearranged tumour cell

proliferation (Takeuchi et al., 2012).

FGFR1

MET

Amplification of FGFR1 (fibroblast growth

In lung cancer, the c-Met pathway, including

factor receptor 1, 8p12) has recently been

PI3K/AKT/mammalian target of rapamycin

discovered in 20% of SCCs and 3.4% of

(mTOR), Ras/MEK/MAPK, Src and STAT

adenocarcinomas (Weiss et al., 2010).

(signal transducer and activator of

Inhibition of FGFR1 by a pan-FGFR TKI,

transcription), is activated either via ligand

PD173074, is being evaluated in a phase I

(hepatocyte growth factor (HGF)) or

trial (www.clinicaltrials.gov identifier

receptor overexpression, MET gene

NCT00979134).

Figure 2. Examples of ALK and c-Met changes in NSCLC. a) Immunohistochemical expression of ALK

fusion protein (Abcam clone 5A4). b) ALK gene rearrangement demonstrated by break-apart FISH (Vysis

LSI ALK Dual-Color Break Apart Rearrangement Probe; Abbott Molecular, Des Plaines, IL, USA) showing

typical split signals (red and green) in the same ALK-rearranged tumour as in a). c) Immunohistochemical

expression of c-Met protein (clone SP44; Ventana Medical Systems, Oro Valley, AZ, USA). d) MET gene

amplification demonstrated by SISH (silver in situ hybridisation) (black: MET gene; red: chromosome 7

centromere) (Ventana Medical Systems).

ERS Handbook: Respiratory Medicine

453

Conclusion

Paik PK, et al. (2011). Clinical character-

istics of patients with lung adenocarcino-

Historically, lung cancer classification and

mas harboring BRAF mutations. J Clin

treatment were based on tumour histology.

Oncol; 29: 2046-2051.

Recent discovery of driver mutations in

Rodig SJ, et al. (2009). Unique clinico-

genes encoding tyrosine kinases have led to

pathologic features characterize ALK-

a molecular classification of lung tumours,

rearranged lung adenocarcinoma in the

allowing the emergence of a personalised,

western population. Clin Cancer Res; 15:

targeted therapy, and improved outcomes.

5216-5223.

Samuels Y, et al. (2005). Mutant PIK3CA

promotes cell growth and invasion of

Further reading

human cancer cells. Cancer Cell; 7: 561-

Benedettini E, et al. (2010). Met activation

573.

in non-small cell lung cancer is associated

Shigematsu H, et al.

(2006). Somatic

with de novo resistance to EGFR inhibitors

mutations of epidermal growth factor

and the development of brain metastasis.

receptor signaling pathway in lung can-

Am J Pathol; 177: 415-423.

cers. Int J Cancer; 118: 257-262.

Bergethon K, et al. (2012). ROS1 rearran-

Soda M, et al. (2007). Identification of the

gements define a unique molecular class

transforming EML4-ALK fusion gene in

of lung cancers. J Clin Oncol; 30: 863-870.

non-small-cell lung cancer. Nature; 448:

Brabender J, et al.

(2001). Epidermal

561-566.

growth factor receptor and HER2-neu

Takeuchi K, et al. (2012). RET, ROS1 and

mRNA expression in non-small cell lung

ALK fusions in lung cancer. Nat Med; 18:

cancer is correlated with survival. Clin

378-381.

Cancer Res; 7: 1850-1855.

Togashi Y, et al.

(2012). KLC1-ALK: a

Cappuzzo F, et al. (2009). Increased MET

novel fusion in lung cancer identified

gene copy number negatively affects survi-

using a formalin-fixed paraffin-embedded

val of surgically resected non-small-cell lung

tissue only. PLoS One; 7: e31323.

cancer patients. J Clin Oncol; 27: 1667-1674.

Travis WD, et al.

(2011). International

Cheng L, et al. (2012). Molecular path-

association for the study of lung cancer/

ology of lung cancer: key to personalized

american thoracic society/european

medicine. Mod Pathol; 25: 347-369.

respiratory society international multidis-

Feng Y, et al.

(2012). MET signaling:

ciplinary classification of lung adenocar-

novel targeted inhibition and its clinical

cinoma. J Thorac Oncol; 6: 244-285.

development in lung cancer. J Thorac

Uramoto H, et al. (2007). Which bio-

Oncol; 7: 459-467.

marker predicts benefit from EGFR-TKI

Heist R, et al. (2012). Genetic changes in

treatment for patients with lung cancer?

squamous cell lung cancer: a review. J

Br J Cancer; 96: 857-863.

Thorac Oncol; 7: 924-933.

Weinstein IB, et al.

(2008). Oncogene

Kitamura A, et al.

(2010). Immuno-

addiction. Cancer Res; 68: 3077-3080.

histochemical detection of EGFR mutation

Weiss J, et al. (2010). Frequent and focal

using mutation-specific antibodies in lung

FGFR1 amplification associates with ther-

cancer. Clin Cancer Res; 16: 3349-3355.

apeutically tractable FGFR1 dependency

McLeer-Florin A, et al. (2012). Dual IHC

in squamous cell lung cancer. Sci Transl

and FISH testing for ALK gene rearrange-

Med; 2: 62-93.

ment in lung adenocarcinomas in a

West L, et al. (2012). A novel classifica-

routine practice: a French study. J

tion of lung cancer into molecular sub-

Thorac Oncol; 7: 348-354.

types. PLoS One; 7: e31906.

454

ERS Handbook: Respiratory Medicine

Lung cancer: diagnosis and

staging

Johan Vansteenkiste, Sofie Derijcke and Inge Hantson

Lung cancer is the most common cause of

from smoking cessation: as the period of

cancer-related mortality worldwide for both

abstinence from smoking increases, the risk

males and females, with a global incidence

of lung cancer decreases, although it

of about 1.3 million cases per year. The term

remains elevated compared with never-

lung cancer, or bronchogenic carcinoma,

smokers. However, in recent years, an

refers to malignancies that originate in the

increasing number of never-smoking

airways or pulmonary parenchyma.

patients present with a lung cancer, often

females with adenocarcinoma histology. A

Epidemiology

number of other factors may affect the risk

of developing lung cancer, such as

Lung cancer occurs through a complex

underlying acquired lung diseases (COPD

multistage process that results from the

and pulmonary fibrosis) and environmental

combination of carcinogen exposure and

exposures, often synergistically with

genetic susceptibility (fig. 1).

smoking (asbestos, radon, metals, ionising

radiation including previous radiotherapy,

A number of lifestyle and environmental

fine dust air pollution and polycyclic

factors have been associated with the

aromatic hydrocarbons).

development of lung cancer, of which

cigarette smoking is the most important.

Several molecular genetic abnormalities

Cigarette smoking accounts for

have been described in lung cancer,

approximately 80-90% of all lung cancers.

including chromosomal aberrations (e.g.

Compared with nonsmokers, smokers have

chromosome 3p or 8p deletions),

an ,20-fold increase in lung cancer risk,

overexpression of oncogenes (EGFR, KRAS,

depending on the duration of smoking and

c-MET, BCL2, etc.), deletions and/or

the number of cigarettes smoked per day.

mutations in tumour suppressor genes

Cigarette smokers can benefit at any age

(TP53, RB1 and genes on chromosome 3p)

or altered telomerase activity.

Key points

Clinical manifestations

The majority of patients with lung cancer

N The pulmonologist has a crucial role

have advanced disease at clinical presen-

in obtaining tissue for diagnosis and

tation, which reflects the frequent asympto-

molecular analyses.

matic course of early-stage lung cancer.

Lung cancer staging is a stepwise

Symptoms due to the intrathoracic effects of

process of more general tests for all,

the tumour are cough (central airway or

and more dedicated tests for patients

pleural involvement), haemoptysis, chest

with a prospect of radical treatment.

pain, dyspnoea, hoarseness (laryngeal nerve

Functional assessment is key for

involvement), superior vena cava syndrome

patients with a prospect of radical

(dilated neck veins and facial oedema),

treatment.

Pancoast syndrome (pain, Horner sign and

hand muscle atrophy).

ERS Handbook: Respiratory Medicine

455

Cigarette

Metabolic

Persistence

smoking

activation

Mutations and other

Nicotine

PAH, NNK and

DNA

Lung

changes: RAS, MYC,

addiction

other carcinogens

adducts

cancer

p53, p16, RB, FHIT,

and other critical genes

Metabolic

Repair

Miscoding

detoxification

Excretion

Normal DNA

Apoptosis

Figure 1. The multistep process leading from nicotine addiction to lung cancer. PAH: polyaromatic

hydrocarbons; NHK: nicotine-derived nitrosamine ketone. Reproduced from Hecht (1999) with permission

from the publisher.

In addition, paraneoplastic effects of lung

sampling of tissue by bronchoscopy

cancer are common: hypercalcaemia

(nowadays assisted by endobronchial

(nausea, lethargy and dehydration),

ultrasound), fine-needle aspiration by CT

syndrome of inappropriate antidiuretic

guidance or, sometimes, surgical sampling by

hormone (hyponatraemia), hypertrophic

video-assisted thoracoscopy.

osteoarthropathy (clubbing and periosteal

proliferation of tubular bones),

Historically, very small diagnostic samples

dermatomyositis, haematological

were sufficient to make the pathological

manifestations (anaemia, leukocytosis and

diagnosis of either non-small cell lung

thrombocytosis), hypercoagulability,

cancer (NSCLC) or small cell lung cancer

Cushing’s syndrome and neurological

(SCLC). One of the major recent advances in

syndromes (Lambert-Eaton). It is important

chemotherapy and molecular targeted

to distinguish paraneoplastic effects from

therapy has been the use tissue-based

symptoms due to metastasis, as only the

predictive factors for treatment efficacy (e.g.

latter impede a radical approach.

nonsquamous histology for pemetrexed,

activating EGFR mutation for gefitinib or

As for extrathoracic disease, the most

erlotinib and EML4-ALK translocation

frequent sites of distant metastases are the

mutation for crizotinib). This has largely

liver (pain and constitutional symptoms),

changed the role of the pulmonologist in the

adrenal glands, bones (pain) and brain

diagnostic process and reversed the

(headache, paresis and seizures). General

evolution of diagnosis based on ever smaller

symptoms such as anorexia, weight loss and

samples to one based on ever less invasive

asthenia are often also present.

techniques. In order to respond to the

Diagnosis

increasing demand for larger amounts of

tissue to perform additional

Bronchoscopy is the appropriate test for

immunohistochemistry, fluorescence in situ

centrally located tumours, where a

hybridisation or mutation testing, it now

pathological diagnosis will be obtained in

important to maximise the number of

,90% of cases, by means of forceps biopsy,

biopsies at bronchoscopy, to make cell

bronchial brushing or washing.

blocks of the cytological samples obtained

at endobronchial ultrasound-guide

Peripheral lesions, especially solitary

transbronchial needle aspiration (EBUS-

pulmonary nodules, can be a diagnostic

TBNA) or to use larger core needles when

challenge. Noninvasive techniques are

taking a CT-guided transthoracic biopsy.

positron emission tomography (PET) with¹⁸F-

2-fluoro-2-deoxy-D-glucose (FDG) (enhanced

Staging

uptake of FDG is seen in tumours) or contrast-

enhanced CT. For most lesions, pathological

Staging, the process of determining the

documentation is needed: peripheral

extent of lung cancer, is crucial for the

456

ERS Handbook: Respiratory Medicine

prognosis and choice of treatment. The stage

comorbidity) will usually need additional

is defined by the international TNM (tumour,

tests. They will benefit from FDG-PET or

node, metastasis) classification. The most

fusion FDG-PET-CT, which improve staging

recent version, adopted since 2010, is

of locoregional lymph node and distant

applicable to NSCLC, SCLC and carcinoid

spread (e.g. PET may indicate unexpected

tumours. The combination of T, N, and M

metastases in up to 20% of patients).

descriptors determines the overall disease

In nonmetastatic patients, the exact

stage: stage I (localised tumour and no

definition of locoregional spread will help to

lymph node spread); stage II (spread to hilar

choose the best type of multimodality

nodes); stage III (more advanced tumour

treatment (i.e. how to combine

and/or mediastinal lymph node spread); and

chemotherapy, surgery and radiotherapy).

stage IV (distant metastasis) (table 1).

Detailed invasive locoregional staging often

Staging is a stepwise process. For all

is indicated for that purpose, as the value of

patients, the minimal noninvasive staging

CT to ascertain the nature of mediastinal

will include a detailed medical history

lymph nodes is limited: pooled positive

(smoking habits, occupational history, intra-

predictive value 50% and negative predictive

and extrathoracic and paraneoplastic

value 80%. Addition of PET has improved

symptoms, and performance status), a

these figures to 80% and 90%, respectively.

physical examination (e.g. careful

Based on a recent landmark randomised

auscultation and percussion may suggest

trial, endoscopic staging has taken over the

the presence of atelectasis, pleural effusion

role of mediastinoscopy as initial test in

or large airway obstruction, liver

most patients. Endoscopic lymph node

enlargement may indicate hepatic

staging consists of EBUS-TBNA (for

metastases, etc.), blood testing and a

paratracheal nodes 2R, 2L, 4R and 4L,

contrast-enhanced CT from the adrenal

subcarinal node 7, and hilar nodes 10R, 10L,

gland to the lung apex. According to

11R and 11L) and/or oesophageal ultrasound-

symptoms and locoregional spread, CT or

guided fine-needle aspiration (for left

MRI of the brain, bone scintigraphy, or other

paratracheal nodes 4L and 5, subcarinal

tests may be appropriate.

node 7, paraoesophageal nodes 8 and 9, and

hilar nodes 10R and 10L) (fig. 2). These

Patients with a potential for radical treatment

techniques can reduce the need for baseline

(i.e. no evident metastatic disease or major

surgical staging by 70%. Endoscopic staging

Table 1. Major staging groups, preferred treatment patterns and expected 5-year survival rates for NSCLC

Stage

Treatment

5-year survival %

Early

Surgical resection (adjuvant chemotherapy for large

58-73

tumours)

Radiotherapy if medically inoperable

Surgical resection and adjuvant chemotherapy

36-46

Radiotherapy if medically inoperable

Locally advanced

IIIA

Surgical or nonsurgical combined-modality

treatment

IIIB

Nonsurgical combined-modality treatment

Advanced

Chemotherapy and/or targeted agents

Data from Goldstraw et al. (2007).

ERS Handbook: Respiratory Medicine

457

Supraclavicular zone

1 Low cervical, supraclavicular,

and sternal notch nodes

SUPERIOR MEDIASTINAL NODES

Upper zone

2R Upper paratracheal (right)

2L Upper paratracheal (left)

3a Prevascular

3p Retrotracheal

4R Lower paratracheal (right)

4L Lower paratracheal (left)

AORTIC NODES

AP zone

5 Subaortic

6 Para-aortic (ascending aorta or

phrenic)

INFERIOR MEDIASTINAL NODES

Subcarinal zone

7 Subcarinal

Lower zone

8 Paraoesophageal (below carina)

9 Pulmonary ligament

N1 NODES

Hilar/interlobar zone

10 Hilar

11 Interlobar

Peripheral zone

12 Lobar

13 Segmental

14 Subsegmental

Figure

2. Map of locoregional lymph nodes. Reproduced and modified from Rusch et al. (2007) with

permission from the publisher.

may lead to false-negative results in ,20%

accurate technique for assessment of lymph

of the cases; therefore, a negative test result

node staging after induction treatment.

in a patient suspected of having lymph node

Functional assessment

disease should be completed by an

adequate surgical procedure. Another

All patients need an ECG and basic

important advantage of using endoscopic

pulmonary function tests, such as FEV1 and

techniques upfront is that mediastinoscopic

FVC. In patients scheduled for radical

staging can be reserved as the most

treatment (surgical or nonsurgical

458

ERS Handbook: Respiratory Medicine

combined-modality treatment), a more

Further reading

detailed functional evaluation is needed,

Alberg AJ, et al. (2007). Epidemiology of

especially as many patients have co-existing

lung cancer: ACCP evidence-based clin-

smoking-related cardiopulmonary disease.

ical practice guidelines

(2nd edition).

To determine the volume of lung that can be

Chest; 132: Suppl. 3, 29S-55S.

removed and to identify patients at risk of

Annema JT,

al.

(2010).

post-operative complications, each patient

Mediastinoscopy versus endosonography

should undergo pulmonary function testing:

for mediastinal nodal staging of lung

lung volumes and TLCO. Post-operative

cancer. A randomized trial. JAMA; 304:

respiratory failure rarely occurs if the

2245-2252.

predicted post-resection FEV1 and TLCO are

Brunelli A, et al. (2009). ERS/ESTS clinical

more than 30-40% of the normal values.

guidelines on fitness for radical therapy in

lung cancer patients (surgery and chemo-

Additional cardiopulmonary exercise testing

radiotherapy). Eur Respir J; 34: 17-41.

with ergospirometry is indicated when

Goldstraw P, et al.

(2007). The IASLC

baseline FEV1 or TLCO values are ,80%

Lung Cancer Staging Project: proposals

predicted. In this group, patients who reach

for the revision of the TNM stage

their target heart rate and exercise capacity

groupings in the forthcoming (seventh)

and who have a maximal oxygen uptake

edition of the TNM Classification of

(V9O₂max) .15 mL?kg^-1?min^-1 are less likely to

malignant tumours. J Thorac Oncol; 2:

706-714.

have post-operative complications or

Hecht SS (1999). Tobacco smoke car-

mortality. If the V9O₂max is between 10 and

cinogens and lung cancer. J Natl Cancer

20 mL?kg^-1?min^-1, quantitative pulmonary

Inst; 91: 1194-1210.

perfusion scanning may be used to calculate

Rusch VW, et al. (2007). The IASLC lung

more precisely the estimated post-operative

cancer staging project: proposals for the

values and the proportion of lung that can

revision of the N descriptors in the

be removed. Moreover, patients with a

forthcoming seventh edition of the TNM

baseline oxygen saturation of ,90%, those

classification for lung cancer. J Thorac

who desaturate more than 4% during

Oncol; 2: 603-612.

exercise testing or those with PaCO₂

Toh CK, et al.

(2006). Never-smokers

.45 mmHg have a greater likelihood of

with lung cancer: epidemiologic evidence

post-operative complications.

of a distinct disease entity. J Clin Oncol;

24: 2245-2251.

Apart from pulmonary function evaluation,

Vansteenkiste J, et al. (2010). Early stage

assessment of other comorbid conditions,

NSCLC: challenges in staging and adju-

such as heart disease (echocardiography

vant treatment: evidence-based staging.

and coronary tests), renal insufficiency and

Ann Oncol; 21: Suppl. 7, 189-195.

diabetes, may be warranted.

ERS Handbook: Respiratory Medicine

459

Chemotherapy and molecular

biological therapy

Amanda Tufman and Rudolf M. Huber

Most patients with lung cancer present in

palliation of symptoms and maintenance of

advanced stages of disease and cannot be

quality of life. Systemic treatment with

cured by surgery or radiation therapy. In

chemotherapy and with newer ‘targeted’

metastatic disease, the focus of treatment is

therapies form the basis of treatment in stage

IV, and can significantly improve symptoms,

and improve both progression-free and

overall survival. Whereas chemotherapy

Key points

involves the use of substances with

nonspecific cytotoxic and antiproliferative

Due to the interdisciplinary nature of

properties, molecular biological therapy aims

lung cancer treatment, decision-

at more specific targets that are usually more

making should take place in

active than normal.

structured tumour boards.

Depending on the clinical situation, either a

Performance status is an important

single chemotherapeutic agent or a doublet

parameter in treatment decision-

may be given. If the patient is fit enough for

making.

chemotherapy, a platinum-based doublet is

The side-effects of chemotherapy vary

used. Differences in tumour histology and

between agents and should be taken

molecular biology are increasingly taken into

into account during treatment

account when planning systemic therapy, in

planning.

particular for non-small cell lung cancer

(NSCLC).

Endobronchial techniques are an

important tool in the palliation of lung

In earlier stages of disease, systemic chemo-

cancer patients.

therapy can be curative when combined with

local irradiation (radiochemotherapy) or

First-line treatment of advanced

surgery. Chemotherapy given after surgery is

NSCLC, adjuvant chemotherapy and

known as adjuvant chemotherapy; that

chemotherapy for radiochemotherapy

administered before surgery is neoadjuvant

is mostly a platinum-based doublet.

or induction chemotherapy. Generally,

The individualisation of treatment

chemotherapy is administered

based on histology and molecular

intravenously, although some agents may be

biology, in particular the EGFR

given orally. There are also circumstances in

mutation and EML4-ALK fusion, is of

which chemotherapeutic agents may be

increasing importance in NSCLC.

administered locally (intrathecally or in the

pleural space). Although most modern

SCLC generally responds well to initial

chemotherapeutic agents have milder side-

chemotherapy.

effects than the older agents, side-effects

Prophylactic cranial irradiation has an

remain problematic and include

important role in the treatment of

neutropenia, neuropathy, nephropathy,

SCLC.

fatigue, hair loss, and nausea and vomiting

(table 1).

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ERS Handbook: Respiratory Medicine

Table 1. The major side-effects of chemotherapeutic agents

Nausea and

Cisplatin is highly emetogenic

vomiting

Prophylactic antiemetics should be given to all patients receiving chemotherapy

Delayed nausea and vomiting may occur days after administration

Commonly used antiemetics include dexamethasone, serotonin antagonists

and neurokinin-1 inhibition

Neutropenia

Severe neutropenia refers to peripheral neutrophil counts ,500 cells?mL^-1

Reverse isolation in hospitalised patients with severe neutropenia may reduce

the risk of nosocomial infections

Febrile neutropenia refers to elevated oral or axillary temperature (.38uC for

.1 h or .38.2uC one-time measurement) in the setting of severe neutropenia,

and should be treated with intravenous antibiotics

The prophylactic use of granulocyte colony-stimulating factors can be

considered in those at increased risk of developing febrile neutropenia

Anaemia

Consider transfusion in symptomatic patients or those with very low haemoglobin

The use of erythrocyte-stimulating factors (e.g. erythropoietin) is generally not

recommended; however, it can reduce the number of transfusions and

improves fatigue

Neuropathy

Most commonly caused by the taxanes and vinorelbine

Fatigue

Multifactorial

Malnutrition, anaemia and depression commonly play a role

How to treat a patient is dependent not only

can be used instead of cisplatin in patients

on the diagnosis itself but on the patient’s

with poor prognosis/performance status or

comorbidities and overall medical condition,

contraindications to cisplatin. Another

as well as on the overall prognosis and goal

commonly used but less effective regimen is

of treatment (table 2). Performance status

adriamycin, cyclophosphamide and

scales attempt to standardise the

vincristine. In SCLC, chemotherapy offers a

assessment of a patient’s general state of

clear survival benefit, from 4-6-week

health; the Karnofsky scale and the World

survival in untreated patients with extensive

Health Organization (WHO)/Eastern

disease, to 12-month survival in extensive

Cooperative Oncology Group (ECOG) scale

disease with chemotherapy.

are commonly used (table 3).

Second line The second-line treatment of

In most cases, the overall management of

SCLC has been shown to increase survival

lung cancer involves a combination of

and quality of life compared with best

chemotherapy, radiation, bronchoscopic

supportive care alone. Here, the choice of

intervention and surgery. For this reason,

medications depends on the length of time

interdisciplinary tumour boards are an

since the initial remission. For patients

important forum for discussion and decision-

whose tumours initially respond well to

making in the care of lung cancer patients.

chemotherapy and then go on to recur or

progress .3-6 months later, the

Chemotherapy in small cell lung cancer

medications used in first-line treatment can

be given again. Tumours that progress

First line Small cell lung cancer (SCLC) is

,3 months after the end of first-line therapy

almost always a systemic disease and,

should be treated with different agents: in

in most cases, the initial response to

chemotherapy is quite good.

this setting, topotecan monotherapy is a

common choice and can be given

Cisplatin plus etoposide is a frequently used

intravenously or orally. If the tumour does

first-line combination, although carboplatin

not respond to first-line therapies or

ERS Handbook: Respiratory Medicine

461

Table 2. Considerations for individual chemotherapeutic agents

Cisplatin

Highly emetogenic (appropriate use of anti-emetics is essential)

Nephrotoxic: avoid in patients with reduced GFR

Pre-hydration (o500 mL NaCl 0.9% per 50 mg cisplatin) reduces the risk of

nephrotoxicity

Carboplatin

Consider as alternative to cisplatin in elderly patients or those with

contraindications to cisplatin, dosed at AUC

Vinorelbine

May cause neuropathy or neutropenia

Available in pill form for oral administration

Gemcitabine

30-min infusion time (more toxicity with slower infusion), avoid combination

with radiotherapy due to increased side-effects

Pemetrexed

Short (10-min) infusion time

Effective in patients with nonsquamous cell NSCLC and mesothelioma

The risk of myelosuppression can be significantly reduced by vitamin B₁₂

(1000 IU i.m. every 9 weeks) and folate (0.35-1 mg?day^-1)

Paclitaxel

Premedication to prevent allergic reaction is required (dexamethasone and

antihistamine)

Docetaxel

Premedication to prevent allergic reaction is required (dexamethasone)

GFR: glomerular filtration rate; AUC: area under the curve; i.m.: intramuscular.

progresses quickly after chemotherapy,

SCLC, thoracic radiation may be considered

second-line treatment is usually

in patients who have responded well to

recommended. Inclusion in clinical trials or

chemotherapy.

best supportive care alone are also

Prophylactic cranial irradiation has been

reasonable options.

shown to improve survival in SCLC patients

Multimodal therapy Studies have shown that

who reach good remission after

adjuvant chemotherapy improves survival in

chemotherapy, including those with

SCLC patients with completely resected, very

extensive disease at the time of diagnosis.

limited disease. In patients with limited

Nonsmall cell lung cancer

disease, local radiation is generally

combined with chemotherapy. Concurrent

Chemotherapy is the treatment of choice for

chemoradiation regimens including

most NSCLC patients with metastases or

cisplatin are the most effective. In extensive

malignant pleural effusion, although its

Table 3. The WHO/ECOG scale

WHO/ECOG performance

Description

status

Patient is fully active and unrestricted in daily activities

Patient cannot carry out physically strenuous activities but is able to

care for self and carry out light work

Patient is ambulatory and can care for self but is unable to work

Up and about for .50% of waking hours

Patient is limited in self-care activities and confined to bed or chair

for .50% of waking hours

Completely disabled

Cannot care for self

Totally confined to bed or chair

462

ERS Handbook: Respiratory Medicine

efficacy is limited. In fit patients, first-line

one of the original substances (continuation

treatment should consist of cisplatin (or

maintenance) may be beneficial, perhaps

carboplatin) paired with one of gemcitabine,

especially for patients who did not respond

docetaxel, paclitaxel, pemetrexed or

particularly well to first-line chemotherapy

vinorelbine, administered over four to six

(stable disease patients compared to partial/

cycles. The increase in survival offered by

complete responders).

platinum-based chemotherapy is in the

Targeted therapies The role of targeted

range of several months, although some

therapies in NSCLC is growing rapidly. At

patients experience durable remissions, and

the moment, especially in adenocarcinoma,

there is evidence that chemotherapy

in ,50 % of the tumours, we can detect a

improves patients’ quality of life and

so-called driving mutation. Unlike traditional

performance status. Unfortunately, ,40%

chemotherapeutics, which interfere with cell

of NSCLC tumours do not respond to

division in all rapidly dividing cells, targeted

chemotherapy and only 20% of NSCLC

therapies attempt to inhibit cell activity

patients experience significant regression of

more selectively at the level of growth factor

their tumours. In earlier randomised trials

receptors and intracellular signalling

with platinum-based chemotherapy doublets

cascades.

(cisplatin/paclitaxel, cisplatin/gemcitabine,

cisplatin/docetaxel, vinorelbine/cisplatin or

EGFR is involved in signalling cascades

carboplatin/paclitaxel), there were no

leading to cell division and proliferation. In

significant differences in response rate or

tumour cells, mutations in and

overall survival. More recent studies show

overexpression of the EGFR gene or

that histology plays a role in the response of

downstream components of the EGFR

NSCLC to various chemotherapeutic

pathway increase proliferation, survival and

medications. In particular, nonsquamous

metastasis. Several targeted therapies

histology (adenocarcinomas and large cell

attempt to interfere with this abnormal

NSCLC) is predictive for better activity of

EGFR activity: erlotinib and gefitinib are

pemetrexed.

both TKIs that inactivate the intracellular

portion of EGFR, whereas cetuximab, as an

Patients with poor performance status may

antibody, binds to the extracellular domain

not tolerate platinum-based doublet

of the receptor. EGFR inhibitors do not

chemotherapy but can often be treated with

cause typical chemotherapy side-effects, but

a single chemotherapeutic agent, for

commonly cause clinically significant rash,

instance gemcitabine or paclitaxel, or in

diarrhoea and liver enzyme elevation.

some cases with a carboplatin-based

doublet. First-line treatment with targeted

There is evidence that EGFR mutations in

therapies (see later) is an option for some

exon 19 and 21 (activating mutations)

patients.

predict a good response to EGFR TKIs,

whereas other mutations, such as T790M,

Second/third-line chemotherapy in NSCLC

may cause resistance. Response to EGFR

generally involves monotherapy with a

inhibitors is also associated with certain

chemotherapeutic agent (docetaxel for all

clinical characteristics (female patients,

NSCLC histologies and pemetrexed for

nonsmokers, adenocarcinoma and Asian

nonsquamous histology) or the epidermal

ethnicity). Erlotinib is approved as a second-

growth factor receptor (EGFR) tyrosine

or third-line therapy in NSCLC regardless of

kinase inhibitor (TKI) erlotinib. Participation

EGFR mutation status but should only be

in phase II or III clinical trials with newer

given in the first line if an activating EGFR

targeted agents may offer patients the

mutation is present. Gefitinib is only

option of treatment with medications not yet

approved for use in patients with a

available on the market. There is some

documented activating mutation in EGFR.

recent evidence that early second-line or

First-line treatment with erlotinib has been

maintenance therapy with an alternative

demonstrated to improve progression-free

medication (switch maintenance) or with

survival in European patients harbouring

ERS Handbook: Respiratory Medicine

463

EGFR mutation compared with first-line

use of carboplatin can be considered. There

chemotherapy.

is evidence supporting off-label second-line

treatment with vinorelbine, gemcitabine or,

Usually, a secondary resistance develops

in some cases, pemetrexed.

during treatment with erlotinib or gefitinib,

which is, among others, caused by MET

Palliative treatments

amplification or resistance mutations in

In advanced lung cancer, progressive tumour

EGFR. For this situation, further treatment

growth in the central airways can produce

in clinical trials would be possible.

haemoptysis, cough and airway obstruction

Further treatable growth-activating targets

leading to shortness of breath or pneumonia.

are ALK (anaplastic lymphoma kinase) gene

In these situations, quality of life may

rearrangements, which occur in

primarily be improved through the palliative

approximately 3-5% of NSCLC, especially in

use of endoscopic tumour debulking

adenocarcinoma. EML4 (echinoderm

techniques or prosthetic measures.

microtubule-associated protein-like 4)-ALK

Brachytherapy is also an effective option for

fusion is especially found in patients with

the local treatment of tumour growth in or

NSCLC. Crizotinib is a TKI of MET, c-Ros

around the central airways, and stents may be

and ALK. Phase II data have shown these

used to maintain airway patency in patients

tumours to be highly sensitive to the ALK

with compression due to tumour. The

TKI crizotinib. Crizotinib is approved for the

general supportive/palliative measures are

treatment of EML4-ALK-positive NSCLC in

applied additionally as needed.

the USA and Europe.

Palliative radiation provides symptomatic

Because tumours are dependent on the

relief in patients with brain and bone meta-

growth of new blood vessels, inhibition of

stases. Pleurodesis is an option for patients

angiogenesis is of major therapeutic

with recurrent malignant pleural effusions.

interest. Bevacizumab is a monoclonal

antibody against vascular endothelial growth

Further reading

factor. In stage IIIB and IV NSCLC patients,

there is evidence that the addition of

American College of Chest Physicians.

bevacizumab to platinum-based doublets is

www.chestnet.org.

beneficial. The combination of bevacizumab

American Society of Clinical Oncology.

with carboplatin plus paclitaxel was shown

www.asco.org.

to provide a survival benefit, whereas the

Azzoli CG, et al. (2011). American society

combination of bevacizumab with cisplatin

of clinical oncology clinical practice

plus gemcitabine only showed a benefit in

guideline update on chemotherapy for

progression-free survival.

stage IV non-small-cell lung cancer. J Clin

Oncol; 29: 3825-3831.

Bevacizumab can cause severe

D’Addario G, et al.

(2010). Metastatic

haemoptysis, seen in a randomised phase II

non-small cell lung cancer: ESMO clinical

trial, mostly in patients with squamous cell

practice guidelines for diagnosis, treat-

histology. Thereafter, most studies have

ment and follow-up. Ann Oncol; 21: Suppl.

excluded patients with brain metastases,

5, v116-v119.

previous haemoptysis, cavitary lung lesions

International Association for the Study of

Lung Cancer. www.iaslc.org.

or concurrent anticoagulation.

Keedy VL, et al. (2011). American Society

Malignant mesothelioma

of Clinical Oncology provisional clinical

opinion: epidermal growth factor receptor

If systemic treatment is applied, usually

(EGFR) mutation testing for patients with

cisplatin plus pemetrexed is given. The data

advanced non-small cell lung cancer

in the literature are not adequately

considering first-line EGFR tyrosine-

elaborated; in practice, more than six cycles

kinase inhibitor

(TKI) therapy. J Clin

are often used. In patients with

Oncol; 29: 2121-2127.

contraindications to cisplatin, the off-label

464

ERS Handbook: Respiratory Medicine

Surgical treatment for lung

cancer

Gilbert Massard, Nicola Santelmo and Pierre-Emmanuel Falcoz

Despite the progress made in thoracic

and radiofrequency ablation; these

oncology over the past 30 years, surgical

treatments are not yet scientifically validated

treatment based on anatomical resection

and ignore lymphatic spread (see later). In

with complete mediastinal lymph node

the N2 category, surgery has been

dissection remains the mainstay of cure for

challenged by exclusive radiochemotherapy

nonsmall cell lung cancer (NSCLC).

in a recent multicentre trial by Van

Although combined modality treatments

Meerbeeck et al. (2007), whose conclusions

based on neoadjuvant or adjuvant

are not acceptable: the surgical arm

chemotherapy are credited with a slight

comprised an incomplete resection rate of

advantage in survival, the area under the

nearly 50%. Most patients nowadays are

survival curve proves that the most

subjected to combined treatments, but the

substantial part of cure is owed to surgery.

scientific evidence remains ambiguous and

Contemporary alternatives to surgery for

controversial. It is unclear whether

small tumours are stereotaxic radiotherapy

neoadjuvant therapies are more beneficial to

the N2 population or to those with incipient

disease. Meta-analysis demonstrated a

benefit for patients undergoing adjuvant

Key points

therapy; this is of weak clinical relevance for

The following recommendations are

the individual patient, given that treatment

evidence based.

of 20 patients is needed to save one at

2 years. The result deteriorates in the long

Optimal results are obtained by

term, and long-term complications of

specialised surgeons working in high-

chemotherapy appear in survivors. In

volume units.

summary, to date, the best possible surgery

needs to be performed in operable patients.

N Anatomical resection combined with a

Classic resection by open thoracotomy is

complete lymph node dissection is the

increasingly challenged by VATS (video-

gold standard. Increasingly VATS is

assisted thoracoscopic surgery) in the case

becoming an alternative to open

of small tumours. Generalisation of

surgery in patients with small tumours.

screening programmes with low-dose CT is

Bronchoplastic and angioplastic

expected to increase considerably accrual of

lobectomies are viable alternatives to

small, T1 tumours in the future (National

pneumonectomy, provided that a

Lung Screening Trial Research Team, 2011).

complete resection can be achieved.

Work-up of the patient should include a

Segmentectomies could be applied to

check-up of fitness according to European

high-risk patients with tumours

Respiratory Society/European Society of

,2 cm in diameter; wedge excisions

Thoracic Surgeons (ESTS) guidelines.

may be recommended for very small

bronchoalveolar carcinoma (ground-

The aim of this section is to describe the

glass opacity).

quality requirements of contemporary

oncologic thoracic surgery, based on

466

ERS Handbook: Respiratory Medicine

recommendations issued by a working

For stage II, reported 5-year survival rates

group of the French Society for Thoracic and

vary between 35% and 50%. Besides a

Cardiovascular Surgery.

difference between T1N1 and T2N1, there is

a very dissimilar survival pattern according

How can we define early-stage lung cancer?

to the intra- or extralobar location of the N1

node. Intralobar N1 is credited with 5-year

Although there is no clear definition of early-

survival close to 55%, whereas in extralobar

stage lung cancer, it seems adequate to

N1 it reaches only 35% (table 2).

restrict this label to patients with reasonable

chances of survival. Since lymph node

For stage IIIA-N2, survival rates at 5 years

invasion at the N2 level is a marker of poor

are considerably lower and range from 15%

prognosis, the medical oncologist would

to 25%. However, minimal N2 is a subgroup

certainly restrict the definition to stages N0

with a possible survival rate of 35% at

and N1.

5 years. There is a small subset of completely

resectable IIIA-T4N0 disease (Pancoast

For the surgeon, resectable disease offers an

tumours, main carina involvement) that can

advantage over nonresectable disease.

achieve a survival of close to 50% at 5 years.

Minimal N2, defined as microscopic

metastasis to a single N2 node, is credited

The large majority of patients with stage IIIB

with a survival rate of 30-35% at 5 years,

are inoperable and global survival at 5 years

which is comparable to the worst N1.

is ,5%.

Furthermore, resectable T4N0 disease, such

as selected cases of Pancoast tumours or

Quality requirements: the surgeon and the

main carinal invasion, may achieve a 5-year

institution

survival of .40%.

Thoracic oncologic surgery is a specialised

Any marginal situation needs to be

medical activity. Well-trained thoracic

discussed with a qualified thoracic surgeon,

surgeons working in high-volume units

and any decision not to operate should be

obtain the best results.

validated by a qualified thoracic surgeon in a

Qualification of the individual surgeon A

multidisciplinary discussion.

comparison of the results of lung resections

What are the usual survival figures?

performed by either general or well-trained

thoracic surgeons in a cohort of 1583 cases

The following figures drawn from the classic

of resection for lung cancer performed

surgical literature apply to surgical

between 1991 and 1995 showed that

treatment, regardless of any neoadjuvant or

operative mortality was twice as high when

adjuvant treatment.

resection was performed by general

surgeons. It is remarkable that 75% of

For stage I, the usual figures vary from 55% to

general surgeons performed ,10 resections

75% with a substantial difference between T1

during the observation period.

and T2. Survival is further influenced by the

type of resection (lobectomy versus

Hospital volume and its impact on post-

pneumonectomy) and the comorbidity, which

operative mortality A review of data from the

accounts for half of late deaths (table 1).

Medicare registry between 1994 and 1999

Table 1. Survival following stage I disease: independent factors of prognosis

Yes %

No %

p-value

Relative risk

Pneumonectomy

62.7

0.031

1.55

Angio-invasion

54.5

61.9

0.029

1.85

Atherosclerosis

46.3

64.3

0.017

1.55

Data from Thomas et al. (2002).

ERS Handbook: Respiratory Medicine

467

Table 2. Comparison of 5-year survival for intralobar and extralobar N1

First author

Patients n

5-year survival %

Intralobar N1

Extralobar N1

Yano

Van Velzen

391

Riquet

256

revealed that operative mortality following

Thoracic and Cardiovascular Surgery. A

lobectomy varied from 6.4% in a low-activity

complete cancer operation requires

centre (fewer than nine cases per year) to

anatomic resection of the primary lesion and

4.2% in a high-activity centre (.46 cases per

complete homolateral lymph-node

year); following pneumonectomy, the range

dissection.

extended from 17% to 10.6%, respectively.

Complete anatomic resection Anatomic

We may conclude that a high hospital

resection means either lobectomy or

volume warrants the necessary routine not

pneumonectomy with precise hilar

only of the operating surgeon, but also of

dissection, according to the locoregional

the surrounding team.

extent of the tumour. The rule is to privilege

lobectomy whenever it enables a complete

Hospital volume and its impact on long-term

resection. Standard lobectomy is not

survival It has been confirmed that hospital

possible if the tumour extends across the

volume affects not only early outcome but

fissure, invades the main pulmonary artery

also long-term survival, in a study that

or involves the bronchial tree proximal to the

included 2118 patients operated upon in one

lobar take-off; a double location in

of 76 hospitals over a 10-year period, divided

different lobes is also an indication for

into quintiles according to hospital volume.

pneumonectomy.

Operative mortality ranged from 3% at high-

to 6% at low-volume units; operative

Lobectomy is preferred to pneumonectomy

morbidity ranged 20-44%. The 5-year

because of a substantially lower operative

survival decreased from 44% at high- to 33%

risk. Operative mortality is ,2% following

at low-volume centres.

lobectomy, and ranges from 6% to 10%

This study suggests that appropriate

following pneumonectomy. Mortality after

decision-making is enhanced by routine.

pneumonectomy may be .10% in patients

aged .70 years, or in case of extended

Qualification of thoracic surgeons depends

resection. There is an ongoing debate

on national rules in the different European

whether mortality of pneumonectomy is

countries. In an attempt at harmonisation

increased after induction chemotherapy,

over the European territory, the European

especially on the right side. We have recently

Union of Medical Specialists has created the

demonstrated a similar risk when compared

European Board of Thoracic Surgery

to standard operations and a survival

certification, which may be obtained by an

advantage even if the patient remains stage

examination conducted every year by the

N2. Other disadvantages of

ESTS.

pneumonectomy are decreased quality of

Basic principles of surgical treatment:

life owing to loss of respiratory function and

complete anatomic resection and complete

decreased possibilities of repeated curative

lymph node dissection.

resection should a metachronous primary

cancer occur (,10% of stages I and II).

The basic principles described here are

based on recommendations issued by a

Resection of less than a pulmonary lobe is

working group of the French Society for

not recommended as routine. The Lung

468

ERS Handbook: Respiratory Medicine

Cancer Study Group (Ginsberg et al., 1995)

As such, intraoperative exploration of the

compared lobectomy and segmentectomy

mediastinum is mandatory and can be

(or wedge excision) for T1N0 cancer in a

achieved by two different procedures:

randomised trial. There was a drop in 5-year

survival of 20% for patients subjected to

N random sampling of nodes

N complete node dissection

segmentectomy and a three-fold increase of

local recurrence following segmentectomy

Obviously, only complete dissection appears

or wedge excision. More recent

to be serious and reliable. The arguments

investigations from Japan conclude that

are as follows.

wedge excisions are valuable in small

bronchoalveolar carcinoma; similarly,

In patients with pathological stage I-N0

segmentectomies could be applied to stage

disease, survival increases with the number

I tumours ,2 cm.

of dissected nodes. This demonstrates that

the more lymph nodes are harvested, the

When the tumour is invading surrounding

lower the risk of ignoring an invaded node

anatomical structures, an enlarged en bloc

and the more reliable the staging.

R-0 resection may achieve satisfactory long-

term results; this should be carried out in

In a cross-sectional analysis, we compared

specialised institutions so that an excessive

sampling and dissection in each single case

operative mortality does not erase the

of 248 resections. Sampling identified 52%

survival benefit of resection.

of resections as N2; multilevel N2 was

identified in 42% of events only. Resection

Complete homolateral lymph node dissection

based on sampling alone would have been

The goals of lymph node dissection are:

complete in only 12%.

1. to ascertain staging

The standard lymph node dissection is

defined as an en bloc dissection of all

2. to ensure complete resection of the

lymphatic tissue along its anatomical

disease

borders (tracheobronchial tree, sheets of

Staging is important at the individual level

major vessels and oesophagus). On the

right side, it includes lower oesophageal

to set prognosis and to define the

nodes within the pulmonary ligament,

mostappropriate treatment strategy. At the

subcarinal space and paratracheal space.

collective level, adequate staging facilitates

On the left side, it includes the pulmonary

comparison of different treatment modal-

ligament, subcarinal space, aortopulmonary

ities or results from different institutions.

window, phrenic nodes and subaortic nodes

Leaving unrecognised lymph node

up to the left tracheobronchial angle.

metastases obviously leads to ‘local

Formal lymph node dissection does not

recurrence’. Medical imaging has serious

increase the post-operative complication

pitfalls. CT underestimates N2 stage in one

rate. There is increasing evidence for a

patient out of five and overestimates in

positive effect on survival. An initial

one patient out of two. A negative positron

nonrandomised study compared sampling

emission tomography (PET) scan matches

to dissection in stage II and III, and

with mediastinoscopy, but the latter

concluded that there is a survival advantage

is subject to 10-15% failures; a positive PET

following dissection.

requires histological assessment

because the false-positive rate is .40%.

A randomised study including .500

Furthermore, .30% of patients with

patients demonstrated a survival advantage

N2 disease have no apparent disease at the

of node dissection without relation to a

N1 level (so-called skip metastases).

stage migration effect: it was observed not

Even among patients with T1 disease,

only stage-by-stage but also when

22% have mediastinal lymph node

comparing the two investigated groups as a

involvement.

whole (table 3).

ERS Handbook: Respiratory Medicine

469

A meta-analysis concluded that 4-year

Table 4. Survival following bronchoplastic lobectomy

survival was increased in patients having

First author

Stage I Stage II Stage III

undergone node dissection, with a hazard

ratio of 0.78.

Tedder

Are there alternatives to pneumonectomy?

Mehran

Van Schil

Given the high operative mortality rate of

Massard

pneumonectomy, it is meaningful to look for

alternatives. Bronchoplastic operations

Icard

(sleeve lobectomy) are indicated:

Tronc

1) when the tumour involves the lobar take-

Data are presented as %.

off on the endobronchial side

2) when positive N1 nodes with capsular

disruption are identified at the origin of the

segmentectomy, performed by VATS, are

lobar bronchus

increasingly offered to patients with small

tumours. The common end-points are that,

Angioplastic lobectomies are indicated when

while operative mortality is similar to that

the lobar branches destined for the upper lobe

of open procedures, there is a significant

cannot be divided safely with tumour-free

decrease of complication rate and length of

margins; this situation is much more frequent

hospital stay. Post-operative pain is

on the left side for anatomical reasons.

considerably lower, recovery is faster

The operative risk of bronchoplastic

and the social cost is decreased (Whitson

lobectomy is comparable to standard

et al., 2008; Paul et al., 2010; Yang

lobectomy, with a mortality of f2%. Long-

et al., 2012).

term survival and rate of local recurrence

match with reported data per stage (table 4).

Oncologic concerns may be addressed as

A meta-analysis by Ma et al. (2007) showed

follows. Minimally invasive resection can

that mortality was almost half that after

be recommended for T1 and small T2

pneumonectomy in experienced teams;

tumours, and achieves equivalent long-

1-year survival was improved after

term survival rates when compared with

bronchoplastic resection.

open surgery . Evidence for N1 or N2

disease primarily orientates towards classic

What is the impact of minimally invasive

open surgery, except for very experienced

surgery?

teams. There is no doubt that a precise

anatomical dissection of the hilar

Minimally invasive major resections, such

structures (artery, vein and bronchus) can

as lobectomy and, more recently,

be safely performed. A negative PET lowers

the risk for mediastinal lymph node

Table 3. Lymph node dissection increases survival:

involvement; furthermore, there is a shift

results of a randomised study

towards less invasive histology in the case

of small tumours (adenocarcinoma with

5-year survival

lepidic growth in particular).

268 dissections

264 samplings

Nevertheless, a careful evaluation of the

Stage I

82.2

57.5

mediastinum with mediastinoscopy and/or

Stage II

50.4

34.0

lymph node dissection is still

recommended.

Stage III

27.0

6.2

Global

48.4

36.9

The demand for minimally invasive surgery

will certainly be increased if lung cancer

Date are presented as %. Reproduced from Wu et

screening programmes with low-dose CT are

al. (2002), with permission from the publisher.

generalised.

470

ERS Handbook: Respiratory Medicine

Further reading

cancer. Eur J Cardiothorac Surg; 16: 276-

282.

Allen MS, et al.

(2006). Mortality and

National Lung Screening Trial Research

morbidity of major pulmonary resections

Team. (2011). Reduced lung cancer mor-

in patients with early stage lung cancer:

tality with low-dose computed tomo-

initial results of the randomized prospec-

graphic screening. N Engl J Med;

365:

tive ACOSOG Z0030 trial. Ann Thorac

395-409.

Surg; 81: 1013-1019.

Paul S, et al. (2010). Thoracoscopic lobect-

American College of Chest Physicians

omy is associated with lower morbidity

(2013). Diagnosis and management of lung

than open lobectomy: a propensity-

cancer, 3rd ed: American College of Chest

matched analysis from the STS database.

Physicians evidence-based clinical practice

J Thorac Cardiovasc Surg; 139: 366-378.

guidelines. Chest; 143: Suppl., 1S-e512S.

Riquet M, et al. (1997). Prognostic value

Berghmans T, et al.

(2005). Survival

of T and N in non small cell lung cancer

improvement in respectable non-small

three centimeters or less in diameter. Eur

cell lung cancer with

(neo)adjuvant

J Cardiothorac Surg; 11: 440-444.

chemotherapy: results of a meta-analy-

Thomas P, et al. (2002). Stage I non-small

sis of the literature. Lung Cancer; 49: 13-

cell lung cancer: a pragmatic approach to

23.

prognosis after complete resection. Ann

Brunelli A, et al.

(2009). ERS/ESTS

Thorac Surg; 73: 1065-1070.

guidelines on fitness for radical therapy

Van Meerbeeck JP, et al.

(2007).

in lung cancer patients

(surgery and

Randomized controlled trial of resection

chemo-radiotherapy). Eur Respir J;

34:

versus radiotherapy after induction che-

17-41.

motherapy in stage IIIA-N2 non-small cell

Cerfolio RJ, et al. (2003). The role of FDG-

lung cancer. J Natl Cancer Instit; 99: 442-

PET scan in staging patients with non-

450.

small cell carcinoma. Ann Thorac Surg;

Whitson BA, et al. (2008). Surgery for

76: 861-866.

early-stage non-small cell lung cancer: a

Ginsberg RJ, et al. (1995). Randomized

systematic review of the video-assisted

trial of lobectomy versus limited resec-

thoracoscopic surgery versus thoraco-

tion for T1N0 non-small cell lung cancer.

tomy approaches to lobectomy. Ann

Ann Thorac Surg; 60: 615-623.

Thorac Surg; 86: 2008-2018.

Mansour Z, et al.

(2007). Induction

Wright G, et al. (2006). Surgery for non-

chemotherapy does not increase the

small cell lung cancer : systematic review

operative risk of pneumonectomy! Eur J

and meta-analysis of randomized trials.

Cardiothorac Surg; 31: 181-185.

Thorax; 61: 597-603.

Martinod E, et al. (2002). Management of

Wu YL, et al. (2002). A randomized trial

superior sulcus tumors: experience with

of systematic nodal dissection in respect-

139 cases treated by surgical resection.

able non-small cell lung cancer. Lung

Ann Thorac Surg; 73: 1534-1540.

Cancer; 36: 1-6.

Massard G

(1999). Local control of

Yang C-FJ, et al. (2012). Thoracoscopic

disease and survival following broncho-

segmentectomy for lung cancer. Ann

plastic lobectomy for non-small cell lung

Thorac Surg; 94: 668-681.

ERS Handbook: Respiratory Medicine

471

Radiotherapy for lung cancer

Luigi Moretti and Paul Van Houtte

While surgery remains the treatment of

treatment planning, multileaf collimators,

choice for early-stage disease, radiotherapy

gating techniques, etc.) allow us to

is the commonest treatment modality for

overcome the challenge of delivering an

lung cancer, with .50% of patients

effective radiation dose while protecting vital

receiving radiation at some point in their

organs or structures (lungs, oesophagus,

disease history, either for cure or palliation.

heart, spinal cord, etc.). This is well

In the past, conventional radiotherapy

illustrated by the breakthrough of

yielded poor outcomes for early-stage

stereotactic body radiation therapy (SBRT)

patients or locally advanced disease due to

for early-stage disease leading to impressive

the radiation techniques available. However,

local control and survival (table 1).

today, major technical advances (positron

Furthermore, the management of locally

emission tomography (PET)/CT-based

advanced non-small cell lung cancer

treatment plans, three-dimensional

(NSCLC) has moved to a multimodality

approach including a platinum-based

chemotherapy delivered concurrently with

Key points

high-dose radiotherapy and surgery for

selected cases. Systemic treatments

For early-stage NSCLC patients,

(chemotherapy and targeted agents) are

surgery (lobectomy or an anatomical

taking a more and more important place

segmentectomy with lymph node

either for stage IV disease or in association

dissection) remains the standard

with radiotherapy and surgery for earlier

treatment, while SBRT is indicated for

cases. Today, NSCLC is no longer

medically inoperable patients.

considered a single disease, and

In locally advanced NSCLC, definitive

pathological subtypes or receptor mutations

concurrent chemoradiotherapy is

(epidermal growth factor receptor, etc.)

preferred while surgery is used for

should be identified.

selected cases (with induction or

For small cell lung cancer (SCLC), definitive

adjuvant chemotherapy).

chemoradiotherapy is usually used for

Although still controversial, post-

limited- or extensive-stage SCLC with a good

operative radiotherapy is

response to chemotherapy, although

recommended for patients with

surgical resection for early-stage SCLC

positive surgical margins and/or

(T1-2N0) may be considered.

pathologic N2 disease.

Mechanism of action

The current management of SCLC

At the cellular level, the most important

includes chemoradiotherapy with or

effects of radiation are linked to double-

without induction chemotherapy.

stranded breaks in nuclear DNA, either by

PCI is indicated for all stages of SCLC

direct ionisation or by indirect formation of

after response to primary therapy.

free radicals, formed by water radiolysis, that

subsequently interact with DNA. Radiation

472

ERS Handbook: Respiratory Medicine

Table 1. Overall survival based on stage at presentation and treatment applied

Disease stage

Overall survival

Median survival

Treatment

NSCLC

I-II (early)

53-80% at 5 years

20-60 months

Surgery

68-77% at 5 years

SBRT

III (locally advanced)

9-16% at 5 years

13-17 months

Chemoradiation

15-22% at 3 years

IV (advanced)

30-40% at 1 year

8-10 months

Chemotherapy

SCLC

Limited

20-30% at 5 years

18 months

Chemoradiation

30-40% at 3 years

50% at 1 year

Extensive

0-2% at 3 years

7-10 months

Chemotherapy

27-40% at 1 year

can also affect the processes of the cell cycle

N Definitive treatment for locally advanced

and alter cell growth. When not able to

(stage III) NSCLC and limited-stage SCLC

repair the damage, cell undergo several

with concurrent chemotherapy

types of death, i.e. apoptosis or senescence,

N Prophylactic cranial irradiation in all

and are ultimately cleared by physiological

stages of SCLC after response to primary

normal mechanisms. Similarly, adverse

treatment

effects of radiation are mainly the

N Post-operative radiation after surgical

consequence of radiation damage to

resection with pathologic N2 disease and

surrounding normal tissues, which were not

T4 disease except for separate nodules in

able to repair adequately.

the same lobe, close/positive surgical

margins and gross residual disease

Tumour radiobiology

N Palliation for pain, bleeding, superior

Tumour radiobiology is complex, as

vena cava syndrome, brain metastasis

response depends not only on dose but also

and cord compression

on individual radiosensitivity, timing, total

Techniques of radiotherapy

dose, fraction size and other agents given

concurrently (i.e. chemotherapy). It allows

N External beam radiation with three-

the optimisation of a radiotherapy schedule

dimensional conformal radiation (3D-

and therapeutic ratio for individual patients

CRT), intensity-modulated radiotherapy

in regards to maximising tumour control

or SBRT

probability and minimising normal tissue

N Intraoperative high dose rate brachy-

complication probability.

therapy (used after wedge resection, this

The biological factors that influence the

may improve local control rates)

response of normal and neoplastic tissues

N Endobronchial brachytherapy (for

to fractionated radiotherapy are repair,

palliation of endobronchial disease or to

redistribution, repopulation, reoxygenation

boost treatment after initial course of

and intrinsic radiosensitivity (the ‘five Rs’ of

definitive 3D-CRT for primary cancer with

radiotherapy).

endobronchial component or for small

endobronchial-only tumour)

Radiotherapy indications

Radiotherapy planning

N Definitive treatment for medically

inoperable stage I NSCLC using

NSCLC For definitive radiotherapy, the

hypofractionated SBRT

prescribed dose depends on the target

ERS Handbook: Respiratory Medicine

473

volumes and the presence of organs at risk

restaging), definitive concurrent

in the region that needs to be treated. In

chemoradiation to a dose of 63-66 Gy is

addition, local tumour control is correlated

indicated.

with total dose delivered and the delivery

time, with a potential impact on survival.

Although it remains globally controversial,

post-operative radiation is generally

Traditionally, the mediastinum or elective

recommended after surgical resection when

nodal area were treated with 45-50 Gy in

a pathological report demonstrates N2

conventional fractions (once-daily doses of

disease, extracapsular nodal extension

1.8-2.0 Gy), and the primary or gross

(ECE), T4 disease, positive surgical margins

tumour boosted to a total dose of o60 Gy.

or macroscopic residual disease. When

The tumour dose of 60 Gy was established

post-operative radiation is indicated, the

as the standard of care in the old Radiation

mediastinum is commonly treated with

Therapy Oncology Group (RTOG) 73-01

50 Gy in 25 fractions, with an additional

randomised trial. Nevertheless, there was

boost of 10 Gy on areas of ECE or bulky

still a high rate of local failure and distant

nodal disease. Similarly, regions of gross

relapse. Thus, higher radiation doses have

residual disease should be treated with

been advocated in an attempt to improve

66 Gy if the normal surrounding structures

local control, either by increasing the total

allow it.

dose with conventional daily dose of 2 Gy or

using an accelerated radiation schedule.

SBRT or stereotactic ablative radiation

This was only possible by changing the old

therapy (SABR) is a novel form of high-

concept of elective nodal irradiation to limit

precision, image-guided radiotherapy for

the radiotherapy fields to the primary

stage I NSCLC. This technique requires

tumour and involved nodes (biopsy-proven,

accurate patient positioning, breathing

or based on CT scan and fluorodeoxyglucose

control, four-dimensional target definition

PET imaging). Another important step was

and the use of multiple non-coplanar

the use of induction chemotherapy, which

radiation beams, subsequently allowing

was showed to improve survival by reducing

steep dose gradients and major

distant metastases. A concurrent schedule

hypofractionation (delivering a high dose in

has been established to be superior to the

a few fractions, approximately three to eight

induction approach both in long-term

treatments). Indeed, high biological effective

survival and local control, but with an

doses (.100 Gy) are required to achieve a

increase in acute toxicities. Different

significant improvement in local tumour

regimens are used, usually a platinum-based

control and survival in medically operable or

doublet with a third-generation drug (i.e.

inoperable NSCLC patients. At this moment,

paclitaxel or vinorelbine). The optimal

concurrent chemotherapy should be avoided

sequence must still be defined: concurrent

with dose-escalated radiotherapy or SBRT

versus induction followed by a concurrent

until further clinical data are available.

chemoradiation strategy. The later approach

SCLC The treatment of limited-stage SCLC

may be of interest in the case of bulky

includes chest radiotherapy delivered

disease for the downsizing of tumour and

concurrently with cisplatin and etoposide

the subsequent volume reduction in normal

during the first cycles if possible. The

tissue irradiated. The place of maintenance

optimal radiation dose or schedule (one or

chemotherapy, targeted agents or

two fractions daily) is still not known (trials

pemetrexed for adenocarcinoma is currently

are ongoing). Hyperfractionation, with

not known.

fraction of 1.5 Gy twice daily to a total dose

In the particular case of superior sulcus

of 45 Gy, was shown to be superior to a

tumours, neoadjuvant concurrent

classical 45 Gy in 5 weeks with one fraction a

chemoradiation (45 Gy) followed by surgery

day, but with an increase in acute toxicities.

and adjuvant chemotherapy is the preferred

Currently, chest radiotherapy for SCLC is

approach. If initially unresectable (or after

similar to NSCLC, increasing the total

474

ERS Handbook: Respiratory Medicine

radiation dose (o60 Gy) and avoiding

Radiotherapy side-effects

elective mediastinal irradiation.

Radiotherapy-induced toxicity is related to

Prophylactic cranial irradiation (PCI) should

the volume of normal tissues surrounding

be given for all stages of SCLC after any

the target tumour. The dose-limiting organs

degree of favourable response to primary

for chest radiation are the spinal cord, lung,

treatment. The current standard total dose

oesophagus and heart. Classically, side-

is 25 Gy given in 10 fractions. No benefit

effects are divided into early/acute and late/

was demonstrated from the use of

chronic toxicity. These unwanted effects can

higher doses.

be reduced using dose-volume constraints,

which are modified by multiples factors,

Despite the fact that the rate of brain

such as concurrent chemotherapy or

metastases is similar to that in limited-

surgery. Most of the toxicity data are derived

stage SCLC, the role of PCI in NSCLC

from conventionally fractionated radiation

remains more controversial since it was

and may not apply with SBRT in which large

shown to reduce brain metastases but

doses per fractions are used. Although the

does not improve overall survival in

results are not mature yet, several studies

randomised studies. Nevertheless, the

suggested limited early toxicity after SBRT

development of brain metastases is

for early-stage NSCLC not close to the

common in patients with locally advanced

central structures. Toxicities should be

NSCLC treated with chemoradiation and,

graded using the Common Terminology

therefore, a subgroup of patients

Criteria for Adverse Events system (CTCAE)

(especially younger patients) may still

from the National Cancer Institute (NCI).

benefit from either PCI or an aggressive

cranial treatment after early detection of

Common acute side-effects seen in

brain metastases.

radiotherapy for lung cancer include

oesophagitis, skin irritation (dermatitis),

Palliative radiotherapy

cough, fatigue and nausea/vomiting. Most

For relief of symptoms such as pain,

of these are resolved 2-4 weeks after

haemoptysis, dysphagia and dyspnoea,

radiotherapy. Acute pneumonitis can occur

different dose schedules are being used and

1-6 months after radiation.

proven adequate: 1610 Gy, 1063 Gy,

Delayed complications include radiation

564 Gy, 268.5 Gy (with a 1-week interval),

pneumonitis, pulmonary fibrosis,

13-1563 Gy (daily) and 2062.5 Gy (daily).

pericarditis, pericardial effusion, coronary

artery disease, oesophageal stricture/fistula,

Selection of treatment should be tailored to

Lhermitte’s syndrome, brachial plexopathy,

the needs of patients, usually being centred

rib fracture and second cancers.

on quality of life, and based on age,

performance status, tumour burden and

Radiation pneumonitis typically occurs

specific symptoms.

approximately 6-10 weeks after radiotherapy.

One schedule (10 fractions of 3 Gy) seems to

Most patients have only radiographic

be favoured among radiation oncologists,

changes without any clinical symptoms or

with a good balance between palliation,

functional end-point modifications. Clinical

1-year survival and treatment time

symptoms are cough, dyspnoea, hypoxia and

commitment.

fever. Symptomatic radiation pneumonitis

can be treated with steroids after excluding

For patients with good performance status

an infection. Pulmonary fibrosis usually

and limited distant disease (e.g.

evolves 6 months to several years after

oligometastatic), a definitive dose of

treatment. Several dosimetric parameters

radiation concurrent with chemotherapy

can be used to help predict the risk of

may be preferred to have a sustained

pulmonary toxicity, commonly the V20 (the

symptomatic improvement, and continuing

total lung volume receiving at least 20 Gy)

good performance status.

and the mean lung dose (MLD). Current

ERS Handbook: Respiratory Medicine

475

guidelines recommend a V20 below 30-35%

include pneumonitis, pleural effusion,

and a MLD below 18-20 Gy. Additionally, the

haemoptysis and rib fracture depending on

use of systemic chemotherapy as well as the

initial tumour location. Accordingly, SBRT

sequencing of therapies may have a

for apical lesions carries a risk of brachial

significant impact on the toxicity.

plexus toxicity. Specific dose constraints

are recommended for SBRT, allowing for

Oesophageal toxicity is globally the most

the prediction of the risk of toxicity as well

common acute toxicity during chest/

as the potential to lower this risk before

mediastinal radiotherapy. While oesophagitis

treatment. Clinical data with a longer

can be severe, it is rarely a reason to stop

follow-up are needed to better quantify the

treatment if managed adequately. Dosimetric

risk of late complications associated

factors that influence oesophageal toxicity

with SBRT.

include the length of oesophagus receiving

beyond 40-50 Gy and the mean oesophageal

dose. Again, the use of concurrent

Further reading

chemotherapy with thoracic radiation

Aupérin A, et al. (2010). Meta-analysis of

significantly increases severe esophagitis

concomitant versus sequential radiochemo-

compared to radiation alone.

therapy in locally advanced non-small-cell

Since patients treated for locally advanced

lung cancer. J Clin Oncol; 28: 2181-2190.

Blanchard P, et al. (2010). Prophylactic

lung cancer typically have pre-existing

cranial irradiation in lung cancer. Curr

cardiopulmonary disease, the risk of

Opin Oncol; 22: 94-101.

radiation-induced cardiovascular disease is

Chi A, et al. (2010). Systemic review of the

rather difficult to define, especially among

patterns of failure following stereotactic

the few long-term survivors. After

body radiation therapy in early-stage non-

mediastinal irradiation with at least a

small-cell lung cancer: clinical implica-

portion of the heart receiving a relatively

tions. Radiother Oncol; 94: 1-11.

high dose, the most common complications

Graves PR, et al.

(2010). Radiation

are pericarditis, coronary artery disease and,

pulmonary toxicity: from mechanisms to

less frequently, myocardial infarction. The

management. Semin Radiat Oncol;

20:

new advances in radiotherapy techniques

201-207.

allow the reduction of heart volume

Le Péchoux C

(2011). Role of post-

irradiated and subsequently potentially

operative radiotherapy in resected non-

reduce the risk of cardiac toxicity.

small cell lung cancer: a reassessment

based on new data. Oncologist; 16: 672-

While rare and sometimes spectacular,

681.

Lhermitte’s syndrome (sudden electric-like

MacManus M, et al. (2009). Use of PET

shocks extending down the spine with head

and PET/CT for radiation therapy plan-

flexion) usually resolves spontaneously, and

ning: IAEA expert report

2006-2007.

is not predictive for chronic myelopathy.

Radiother Oncol; 91: 85-94.

Spinal cord radiation injury is a very rare but

Pantarotto JR, et al. Radiotherapy for

serious complication of radiotherapy.

locally advanced lung cancer: stages IIIA

Accordingly, most centres use conservative

and IIIB. In: Pass HI, et al., eds. Principles

spinal cord dose constraints and limit the

and Practice of Lung Cancer. 4th Edn.

maximum dose to 45-50 Gy.

Philadelphia, Lippincott Williams &

Wilkins, 2010; pp. 579-558.

Caution should be used in treating central

Timmerman RD, et al. Stereotactic techni-

lesions with SBRT as they are at increased

ques for lung cancer treatment. In: Pass HI,

risk of toxicity compared to peripheral

et al., eds. Principles and Practice of

lesions. In addition, tumour volume is a

Lung Cancer.

4th Edn. Philadelphia,

significant predictor of severe toxicity,

Lippincott Williams & Wilkins,

2010;

which suggests limiting the use of SBRT for

pp. 589-600.

early-stage NSCLC. Reported complications

476

ERS Handbook: Respiratory Medicine

Metastatic tumours

Elisabeth Quoix

The thorax is a common site of metastasis

be a higher percentage of malignant pleural

from various cancers, which may affect the

effusions secondary to lung cancer (fig. 1).

hilar or mediastinal lymph nodes, bone

Pericardial effusions

(chest wall and vertebrae), lung, pleura,

muscle, or heart and pericardium. These

Of 55 patients admitted in an intensive care

metastases may induce mediastinal

unit with malignant pericardial effusion, 30

compression syndromes (Pancoast,

had a lung carcinoma as primary site, nine a

superior vena cava syndrome, dysphagia,

breast cancer, five haematological

etc.), just like locoregional extension of a

malignancies and 11 other solid tumors

primary lung cancer.

(Dequanter et al., 2008).

Pleural metastases

Pulmonary metastases

They occur commonly in patients with

The lung is a prominent site of metastasis of

haematological or solid tumours. In a series

breast, colon, kidney, uterus, and head and

of 133 patients (Anderson et al., 1974), the

neck tumours. Some otherwise rare tumours

most common primary sites appeared to be

(choriocarcinoma, osteosarcoma, testicular

breast carcinoma (35 patients), lung cancer

tumour, melanoma, Ewing tumour and

(32 patients), lymphomas (20 patients),

thyroid carcinoma) frequently metastasise

Hodgkin’s disease (12 patient), ovary

to the lung. Endothoracic metastases of

carcinoma (nine patients), adenocarcinoma

breast cancer are essentially

of unknown primary tumour (six patients)

and melanoma (four patients). In females

pleuropulmonary (figs 2 and 3). In a review

specifically, 37% of malignant pleural

of 660 cases of breast cancers followed for a

effusions are due to breast cancer, 20% to

period of 5 years between 1975 and 1979, 119

gynaecological cancers and 15% to lung

endothoracic metastases were recorded.

cancer (Kreisman et al., 1983). Probably, with

the increase in the frequency of lung cancer

in females, in the next few years, there will

Key points

N The thorax is a common site of

metastasis from several cancers.

N It is sometimes difficult to distinguish

between primary lung cancer and

metastases from other primaries.

N Prognosis is linked to the underlying

primary.

Figure 1. Neoplastic pericardial effusion in a

patient with lung cancer.

ERS Handbook: Respiratory Medicine

477

Figure 2. a) Multiple micronodules in a female

who developed chronic cough 2 years after a breast

cancer. b) The same patient 6 years later. Multiple

nodules are present, some of them displaying a

pneumonic pattern.

Figure 3. Multiple excavated pumonary

Among them, 79 were pleural or

metastases. a) Posteroanterior chest radiograph.

pleuroparietal, 80 were pulmonary

b) Lateral chest radiograph.

(lymphangitis, n541; multiple nodules,

n534; solitary nodules, n59; endobronchial,

site being the head and neck (although it

n57; tumoural emboli, n52; alveolar

might be difficult to distinguish them from a

metastasis, n51), 46 were hilar or

primary lung cancer) and the next most

mediastinal, and two were myocardial

common being the breast and kidney

metastases (Kreisman et al., 1983).

(Sorensen, 2004; Milleron et al., 1986).

Pulmonary metastases are also frequent in

lung cancer and their prognosis appears to

It may be quite difficult if not impossible to

be of intermediate value if there is no other

distinguish a primary lung cancer from

site involved; they are now classified as M1a

endobronchial metastasis on a CT image.

in the new staging classification (Ou et al.,

Endobronchial metastases from melanoma

2008). Sometimes, pulmonary metastases

often appear black on CT images.

may be excavated (fig. 3) and may induce

Endobronchial metastases of a kidney

pneumothorax. Some may be calcified either

cancer display strong enhancement on

spontaneously (osteosarcoma, bone giant

contrast-enhanced CT images (Park et al.,

cell tumour or papillary carcinoma of the

2004). Whenever bronchofibroscopy is

thyroid) or after treatment (Seo et al., 2001).

performed, there may be quite severe

bleeding from the biopsy attempt; cough

Endobronchial metastasis is an infrequent

with haemoptysis is the most frequent

feature (table 1), the most frequent primary

symptom.

478

ERS Handbook: Respiratory Medicine

Table 1. Endobronchial metastases: frequency by

primary site

Primary tumour

Metastases n (%)

Head and neck

(31)

Breast

(14)

Kidney

(13)

Colon/rectum

(11)

Melanoma

(8)

Sarcoma

(4)

Thyroid

(4)

Bladder

(3)

Figure 4. Left scapula osteolytic metastasis of a

Ovarian

(2)

right upper lobe adenocarcinoma.

Prostate

(2)

autopsy series by Thomas et al. (1979) of

Oesophagus

(1)

females who had died of disseminated

Testis

(1)

breast cancer, metastatic involvement of

Pancreas

(1)

intrathoracic lymph nodes was found in 71%

of cases. Lymph node involvement was

Adrenal gland

(1)

more extensive in the mediastinum

Stomach

(1)

ipsilateral to the primary breast cancer than

Other

(1)

in the contralateral mediastinum.

Data from Seo et al. (2001).

Bone metastases in the chest

The bones of the chest are common sites of

Tumoural emboli may provide similar

secondary lesions of lung, prostate and

clinical and radiological features as

breast cancer, in which bone is the most

thromboemboli; however, peripheral

common metastatic site (Costelloe et al.,

tumoural microemboli are characterised by

2009).

normal imaging but respiratory failure

(Dizon et al., 2008; Chatkin et al., 2007).

Bone metastases affect 8% of patients with

Diagnosis may be obtained by

breast cancer. Bone scanning remains the

transbronchial biopsy or by

videothoracoscopy; on histological

examination, multiple carcinomatous

emboli are visible in distal pulmonary

arteries, veins and lymphatics.

Hilar and mediastinal metastatic lymph

nodes

Metastatic hilar and mediastinal lymph

nodes are mostly linked to an intrathoracic

carcinoma. Among 565 patients, only 37 had

a history of extrathoracic carcinoma in a

surgical series (Riquet et al., 2009). The

primary cancer was most frequently breast,

with others being from the kidney, testis,

prostate, thyroid and other sites. Metastasis

of breast cancer to intrathoracic nodes

Figure 5. Osteolytic metastasis of the second right

seems to occur quite frequently. In an

rib.

ERS Handbook: Respiratory Medicine

479

mainstay for detection of bone metastases.

Conclusions

In a meta-analysis of six studies comparing

The chest is a frequent site of metastasis,

bone scanning and positron emission

especially for lung, breast, kidney,

tomography (PET) without CT in breast

prostate, colon and ovary carcinomas. The

cancer, a pooled lesion-based sensitivity of

prognosis of these metastases is more

88% and specificity of 87% was found for

related to the possibilities of control of the

bone scanning, and a sensitivity of 69% and

underlying neoplasm than to their possible

a specificity of 98% for PET (Shie et al.,

immediate complications (e.g.

2008).

tamponade). However, some of

Bone is a frequent metastatic site in lung

metastases may alter quality of life, such

cancer (fig. 4). In a recent study of 1000

as bone metastases, with a special

patients, 105 (10.5%) had bone metastases

attention to be paid to the spine because

at diagnosis (Song et al., 2009). The

of the risk of cord compression.

sensitivity of PET/CT was 94.3% compared

to 78.1% with bone scanning and the

Further reading

specificity was, respectively, 98.8% and

97.4%. Among the 346 bone metastases

Anderson CB, et al. (1974). The treatment

detected by PET/CT, 55 were in the thoracic

of malignant pleural effusion. Cancer; 33:

spine, 28 in the scapula or clavicles (fig. 4),

916-922.

Chatkin JM, et al.

(2007). Microscopic

12 in the sternum and 56 in the ribs (fig. 5),

pulmonary neoplastic emboli: report of a

i.e. 44% of the foci were in the chest. The

case with respiratory failure but normal

main problem of PET is poor anatomical

imaging. Prim Care Respir; 16: 115-117.

resolution (fig. 6).

Costelloe CM, et al.

(2009). Imaging

bone metastases in breast cancer: tech-

MRI is the best imaging procedure whenever

niques and recommendations for diag-

spinal cord compression is suspected.

nosis. Lancet Oncol; 10: 606-614.

Dequanter D, et al.

(2008). Severe

pericardial effusion in patients with con-

current malignancy: a retrospective ana-

lysis of prognostic factors influencing

survival. Ann Surg Oncol; 15: 3268-3271.

Dizon DS, et al. (2008). The differential

diagnosis of dyspnea in a woman with

metastatic breast cancer-consideration

CT transaxials

beyond pulmonary embolism. Breast J;

14: 90-91.

Kreisman H, et al. (1983). Breast cancer

and thoracic metastases: review of 119

PET coronals Fused coronals

patients. Thorax; 38: 175-179.

Milleron B, et al. (1986). Endobronchial

metastases of cancer. A propos of 29

cases. Rev Pneumol Clin; 42: 231-234.

PET transaxials

Ou SH, et al. (2008). Validation study of

the proposed IASLC staging revisions of

the T4 and M non-small cell lung cancer

descriptors using data from

23583

patients in the California Cancer registry.

J Thorac Oncol; 3: 216-227.

Park CM, et al.

(2004). Endobronchial

metastasis from renal cell carcinoma: CT

Figure 6. Rib metastasis in a patient with a left

findings in four patients. Eur J Radiol; 51:

hilar relapse of a lung adenocarcinoma without

155-159.

CT finding.

480

ERS Handbook: Respiratory Medicine

Riquet M, et al.

(2009). Intrathoracic

Song JW, et al. (2009). Efficacy compar-

lymph node metastases from extrathor-

ison between 18-FDG PET/CT and bone

acic carcinoma: the place of surgery. Ann

scintigraphy in detecting bony metas-

Thorac Surg; 88: 200-205.

tases of non-small cell lung cancer. Lung

Seo JB, et al. (2001). Atypical pulmonary

Cancer; 65: 333-338.

metastases: spectrum of radiologic find-

Sorensen B (2004). Endobronchial meta-

ings. Radiographics; 21: 403-417.

stases from extrapulmonary solid tumors.

Shie P, et al.

(2008). Meta-analysis:

Acta Oncologica; 43: 73-79.

comparison of F-18 fluorodeoxyglucose-

Thomas JM, et al. (1979). The spread of

positron emission tomography and bone

breast cancer: importance of the

scintigraphy in the detection of bone

intrathoracic lymphatic route and its

metastases in patients with breast can-

relevance to treatment. Br J Cancer; 40:

cer. Clin Nucl Med; 33: 97-101.

540-547.

ERS Handbook: Respiratory Medicine

481

Pleural and chest wall

tumours

Arnaud Scherpereel

Pleural and chest wall malignancies are

.80% of male cases but ,40% of females),

quite common diseases in our practice.

the main factor involved in MPM

Malignant pleural effusions (MPEs) and

pathogenesis.

pleural metastases are much more frequent

Pleural metastases and MPEs Pleural tumour

than primary tumours of these tissues

involvement may result from a direct

(mesothelioma, sarcoma, lymphoma, etc.).

invasion from adjacent structures (lung,

Primary chest wall tumours are a

chest wall, etc.), blood dissemination or,

heterogeneous group of rare tumours (,2%

more often, from tumour emboli to the

of all primary tumours; 60% of them are

visceral pleura with secondary seeding to the

malignant) developing in the bones and soft

parietal pleura (lung cancer). Effusion may

tissues of the thoracic cage, but having

be due to the pleural tumour lesions or to a

similar diagnostic and therapeutic issues.

lymphatic blockade at the mediastinal level.

Epidemiology and pathogenesis

MPEs also depend on interactions between

tumour cells and mesothelial cells through

Malignant pleural mesothelioma (MPM), a

growth factors such as vascular endothelial

highly aggressive tumour involving the

growth factor that increase vascular

pleura in 90% of cases, is a rare tumour but

permeability and angiogenesis.

with increasing incidence. MPM may occur

in subjects up to 40 years of age after

A MPE is found in up to 6% of patients with

occupational asbestos exposure (found in

malignancy. In half of these cases, MPE may

reveal the cancer. Neoplasias responsible

for pleural metastases and/or MPE are

Key points

mostly lung cancer (,30% of cases) or

breast cancer (10-15%), but other cancers

include carcinomas (ovary, stomach, etc.) or

N MPEs are much more frequent than

noncarcinoma proliferations such as

primary pleural or chest wall tumours.

lymphoma, sarcoma, melanoma, seminoma

Diagnostic strategy includes pleural

or thymoma.

cytology, but a firm and reliable

diagnosis of cancer is based on

Pleural effusion is the main clinical element

histology, usually best obtained by

but it is not found in all pleural

biopsies during thoracoscopy.

malignancies. Moreover, pleurisy is not

systematically synonymous with MPE in

N Talc pleurodesis by thoracoscopy is

cancer patients because it may be induced

the best local treatment of recurrent

by other mechanisms, such as pneumonia

or massive MPE, but indwelling

and/or atelectasis due to bronchial

pleural catheters represent an

obstruction, transudate induced by severe

interesting alternative.

denutrition or cardiac failure, or even drug-

Figures 1 and 2 summarise a proposal

or radiotherapy-induced effusion. Therefore,

for MPE and MPM management.

the diagnostic strategy may differ depending

on whether the patient has a cancer

482

ERS Handbook: Respiratory Medicine

Clinical and/or radiological diagnosis of

unilateral pleural effusion: MPE?

Small effusion, haemostasis

disturbancies, etc. relative

contraindications for US-guided

procedure by trained physicians

Previous asbestos exposure?

Clinical and/or radiological

suspicion of MPM

Thoracocentesis

for diagnosis and drainage

Proceed to Figure 2

Light’s

Transudate: seek and

Exudate

criteria

treat cause of

transudate

Cytology: tumour cells?

Previous diagnosis of

YES

malignancy (lung, breast, etc.)?

If no argument

for TB,

YES

infection, etc.

Chest CT

Is pleural histology needed for

mandatory if no contralateral mediastinal shift on

diagnostic clarity?

chest X-ray ± bronchoscopy if main bronchus

Otherwise start treatment

stenosis is suspected: trapped lung?

Contraindications

Thoracoscopy

Surgery at risk

Pleural symphysis

CT scan or US-guided

Mini-thoracotomy

transthoracic biopsies

for pleural biopsies

At the same

time if large

Histological proof of

effusion and

pleural metastases

bulky tumour

lesions of the

pleura

Pleurodesis (talc poudrage, etc.)

Treatment of the primary cancer

also is recurrent pleural effusion;

(chemotherapy and/or hormone therapy

alternatives: undwelled pleural catheter

and BSC, etc.)

(in particular if trapped lung and/or frail

patients), talc slurry, undwelled catheter, etc.

Figure 1. Proposed management for MPE. US: ultrasound; BSC: best supportive care.

background or not but should always rely on

common but mostly involves the

cytology or, better still, on histology.

mediastinum. Lung parenchyma and/or

pleural localisations are less frequent and

Lymphoma and chest wall sarcoma Initial

need to be histologically proven because

thoracic involvement of lymphoma is

they modify the staging and prognosis of the

ERS Handbook: Respiratory Medicine

483

Clinical and/or

radiological suspicion of MPM

Note: avoid unnecessary thoracocentesis

to prevent tumour seeding to the chest wall

HRCT of chest

and upper abdomen

(after removal of pleural effusion if applicable)

Thoracoscopy

Contraindications

for diagnosis and staging

Thoracoscopy

Surgery at risk

Pleural symphysis

CT or US-guided

Mini-thoracotomy

transthoracic biopsies

for pleural biopsies

Histological proof of MPM

(immunohistochemistry)

Staging

History of occupational

asbestos exposure?

Discussion of therapeutic options

(with the patient) by a trained

multidisciplinary team

Reparation

Prophylactic

Active treatment?

Always best

radiotherapy of

chemotherapy

supportive care

chest wall tracts

± surgery ± radiotherapy?

(No consensus,

multimodal approach?

according to institutional practice)

Proposal of clinical trials

Figure 2. Proposed management for MPM. US: ultrasound.

tumour. Primary soft-tissue sarcoma of the

(better outcome for breast cancer or

chest wall is a rare disease (,10% of the

lymphoma) and/or presence of favourable

8000 new cases per year of soft-tissue

markers (EGFR mutation or ALK

sarcomas in the USA). The most common

amplification in non-small cell lung cancer,

sarcomas of the chest wall are

etc.). Sarcomas have a variable prognosis,

chondrosarcoma, osteosarcoma, Ewing’s

with a reported 5-year survival from 15% to

sarcoma/primitive neuroectodermal tumour,

90%, depending mostly on the localisation,

malignant fibrous histiocytoma and

grade and differentiation the tumour, and

fibrosarcoma. Primary pleural and

the possibility of achieving an early wide

pulmonary sarcomas are rare.

resection of the sarcoma.

Prognosis

Diagnosis

The prognosis of patients with pleural

Clinical signs Dyspnoea on exertion and dry

metastases or MPM is poor (median

cough are the most common signs of MPE.

survival ,12 months). However, survival

Dyspnoea is usually progressive and more

may vary according to the primary cancer

marked as the effusion becomes larger but it

484

ERS Handbook: Respiratory Medicine

may be also modulated by other factors, i.e.

¹⁸F-fluorodeoxyglucose positron emission

bronchus obstruction, carcinomatous

tomography (PET) usually shows

lymphangitis or associated (pulmonary or

hypermetabolism of pleural mesothelioma,

cardiac) comorbidities. Chest pain suggests

metastatic adenopathy and metastasis, but

chest wall involvement. Other signs may

should not currently be performed for the

include weight loss, anorexia, asthenia,

diagnosis of MPM. Pleural hypermetabolism

haemoptysis (lung cancer), adenopathy,

is also found after talc pleurodesis. PET may

peritoneal effusion, etc. However, MPE or

be helpful for the staging of pleural

MPM may be diagnosed in asymptomatic

malignancies or in the search of primary

patients by routine chest imaging. A

cancer.

diagnosis of MPM should not be based on

unspecific and usually late clinical signs.

Although histological analysis is almost

However, the association of chest pain,

always required for accurate diagnosis,

thoracic ‘shrinkage’, and/or a unilateral

imaging is important for staging of chest

pleural effusion or thoracic mass in

wall sarcomas, and several of these tumours

asbestos-exposed patients may suggest this

have distinctive radiological features,

diagnosis.

allowing the radiologist to narrow the

differential diagnosis.

There are no reliable clinical features for

distinguishing benign from malignant chest

Pathology and diagnostic procedures In

wall tumours. A palpable mass and pain are

patients suspected of having MPE, a

common in both groups of tumours. The

thoracocentesis is the first diagnostic step

final diagnosis is often obtained only after

(American Thoracic Society/European

surgery.

Respiratory Society (ERS) guidelines).

Pleural fluid analysis usually finds an

Imaging Pleural metastases usually exhibit a

exudate according to Light’s criteria but a

moderate-to-large, nonloculated and

transudate due to major hypoproteinaemia

unilateral pleural effusion. MPE may be

with cachexia or to malignant pericardial

associated with an irregular pleural

effusion does not eliminate the diagnosis of

thickening. Typically, this large pleural

MPE. Assessment of the pleural level of

effusion induces a contralateral mediastinal

adenosine deaminase can yield false-

shift. If not, one should suspect an

positive results in some cases of MPM or

obstruction of a main bronchus by lung

lymphoma but may be helpful in countries

cancer or metastasis, a fixed mediastinum

with medium-to-high prevalence of TB. The

caused by the cancer and/or lymph nodes,

diagnostic sensitivity of pleural cytology in

an extensive tumour infiltration of the

MPE may vary depending on the extension

ipsilateral lung mimicking a large effusion,

of the pleural lesions and the primary

or MPM.

cancer, from 62% to 90% in case series.

In MPM patients, chest radiography or,

Thus, in a patient with a history of cancer,

better, CT typically shows an unspecific,

cytology may be enough for the diagnosis of

unilateral (95% of cases) pleural effusion

pleural metastases. A diagnosis of MPM

with or without mediastinal shift. More

should not be based on cytology alone

rarely, pleural thickening or mass, without

because of its poor sensitivity (30%) and

pleurisy, may be observed. Pleural plugs are

specificity (potential confusion with reactive

very common (70% of cases); about 20% of

mesothelial cells or adenocarcinoma cells).

patients exhibit the association of asbestos-

induced pulmonary interstitial fibrosis.

Closed, percutaneous needle (e.g. Abrams)

Definitive diagnosis of MPM is not possible

pleural biopsies are quite easy to perform

by CT but this is recommended for

with local anaesthesia on an outpatient

diagnosis and staging (after removal of

basis. However, due to the potentially scarce

pleural effusion if applicable). MRI is mostly

and irregular distribution of the tumour

useful to assess the tumour extent into the

lesions in the pleural cavity, the positive

diaphragm and chest wall.

yield of blind biopsies is low (30-40%),

ERS Handbook: Respiratory Medicine

485

adding little to a negative cytology, except in

SMRPs showed interesting sensitivity (70-

countries with a high incidence of TB.

80%) and specificity (80-100%) as

diagnostic markers for MPM. However,

CT- or ultrasound-guided biopsies have a

SMRPs do not capture sarcomatoid (and

better diagnostic sensitivity than blind

some mixed) mesothelioma subtypes, and

biopsies in series of MPEs (70-80%

should not be used for MPM screening.

sensitivity), but lower than that of

thoracoscopy. They are not recommended

Staging and pre-therapeutic assessment of

for MPM diagnosis except in patients for

MPM

whom thoracoscopy (or mini-thoracotomy

It is recommended to use the Union

with pleural symphysis) is contraindicated

Internationale Contre le Cancer/

or rejected by the patient. If MPM is not

International Mesothelioma Interest Group

clearly suspected, closed needle biopsies

1995 TNM staging system, even if it is

may first be proposed in young patients with

inaccurate in describing tumour and node

pleural lesions and exudative, cytology-

extent by current imaging procedures. Only

negative pleural effusion from countries with

a patient’s performance status and

a relatively high prevalence of TB.

histological subtype are recognised as

Medical (pleuroscopy) or surgical (video-

prognostic factors for the management of

assisted thoracoscopic surgery)

MPM in routine.

thoracoscopy with multiple pleural biopsies

The 2010 ERS/European Society of Thoracic

is the ‘gold standard’ for obtaining a

Surgeons (ESTS) guidelines on MPM

diagnosis of MPM or pleural metastasis.

management proposed a simple and

Diagnostic accuracy is .90% and

sequential three-step pretreatment

complications occur in ,10% of cases.

assessment (Scherpereel et al., 2010).

MPM or pleural metastasis will usually

appear as nodules or masses of various

Treatment

diameters. Thoracoscopy is also useful for

the staging of MPM and may permit talc

Treatment includes palliative local therapies,

pleurodesis in case of massive and/or

mostly to improve the patient’s symptoms,

recurrent MPE. However, access to

and treatment of the primary cancer

thoracoscopy may be limited in many places

depending of the nature of the malignancy,

worldwide, as significant resources and

and the clinical status and the wishes of the

expertise are required.

patient.

Immunohistochemistry is helpful in the

Treatment of primary cancer MPM

search for the primary cancer for pleural

treatment, summarised by the 2010 ERS/

metastases or to obtain an accurate

ESTS guidelines, relies mostly on best

diagnosis of mesothelioma, referring to the

supportive care (BSC) (oxygen, pain

international classification of pleural

relief, nutrition, etc.) associated with

tumours (World Health Organization,

chemotherapy.

2004). The epithelioid subtype is the most

frequent mesothelioma subtype.

There is limited evidence for the efficacy of

radical surgery for mesothelioma, except

Soluble biomarkers have been searched to

parietal pleurectomy in very early and rare

obtain an early and reliable diagnosis of

stage Ia disease. Debulking surgery (radical

pleural malignancies but none was

pleurectomy or pleurectomy/decortication

considered as valuable in routine practice.

(P/D)) is now preferred to extrapleural

Soluble mesothelin (or soluble mesothelin-

pneumonectomy because of the lower

related peptides (SMRPs)) levels were

morbidity/mortality and better outcome

increased in the serum and pleural fluid of

when combined with chemotherapy or

patients with MPM compared with healthy

radiotherapy. Both surgical procedures

asbestos-exposed subjects or patients with

should be performed only in clinical trials, in

benign pleural lesions or pleural metastasis.

specialised centres and as a part of

486

ERS Handbook: Respiratory Medicine

multimodal treatment. P/D can also be

the most effective agent available for

considered to achieve symptom control,

pleurodesis and may be administered in the

especially in symptomatic patients with

pleural space through a chest drain (‘talc

entrapped lung syndrome who cannot

slurry’) or, better, during thoracoscopy (‘talc

benefit from chemical pleurodesis.

poudrage’). Pleurodesis is most effective

when performed early in the disease process

Palliative radiotherapy aimed at pain relief

before effusions have become loculated and/

may be considered in the case of painful

or the lung has become fixed and is unable

chest wall infiltration or nodules. The value

to expand fully, but it should not be

of prophylactic radiotherapy to prevent

performed before sufficient tissue for

subcutaneous metastasis developing along

diagnosis has been obtained. Criteria for talc

drainage channels or thoracocentesis tracts

pleurodesis are a sufficient World Health

is questionable based on recent studies and

Organization performance status (WHO PS)

does not permit any recommendation.

,2, an estimated survival .3 months, an

established diagnosis of the tumour and no

When a decision is made to treat patients

arguments for either a trapped lung

with chemotherapy, subjects with a good

performance status should be treated with

(suspected if a pneumothorax persists after

first-line chemotherapy combining platinum

thoracocentesis) or an endobronchial

and an antimetabolite (pemetrexed), or

tumour (massive pleural effusion without a

could be included in clinical trials. No drug

contralateral mediastinal shift). This may

has been validated in second-line

justify a bronchoscopy or a pleural

chemotherapy, and patients with a good

manometry before pleurodesis. To decrease

performance status should be proposed to

the risk of pleurodesis failure in MPE, it is

enter into clinical trials. Patients

recommended to use 4 g of talc after

demonstrating prolonged symptomatic and

complete aspiration of pleural effusion. In a

objective response with first-line

phase III multicentric randomised study,

chemotherapy may be treated again with the

success rates in talc poudrage versus slurry

same regimen in the event of relapse. For

in patients with MPE were, respectively, 67%

tumour assessment and follow-up of MPM,

versus 56% (p50.045), and 82% versus 67%

only chest CT is recommended. PET and

in the subgroup of lung or breast cancers

biological markers (SMRP) are promising

(p50.022). Benign usual side-effects of talc

tools but still under investigation. The

(fever and chest pain) were observed with

modified Response Evaluation Criteria In

both methods, but no acute respiratory

Solid Tumors (RECIST) criteria are the

distress syndrome and death.

preferred method of measuring response to

Alternatives to talc pleurodesis are repeated

treatment.

pleural punctures or better indwelling/

Pleural metastases Treatment of metastatic

tunnelled pleural catheters (TPCs). In fact,

cancer relies on chemotherapy and/or

current guidelines consider TPCs an

hormone therapy, and BSC. The choice of

effective and ambulatory procedure for

cytotoxic drugs depends on the nature of the

symptomatic, recurrent MPE. Their use as a

primary cancer. Mediastinal radiotherapy

first-line treatment is feasible; TPCs should

may be combined with chemotherapy for

be preferred for patients with trapped lung

lymphoma.

or those who are not considered good

candidates for chemical pleurodesis

Chest wall sarcomas The treatment of choice

because of short life expectancy, rather than

is an early adequate and wide resection of

a second talc pleurodesis, a

the sarcoma. Adjuvant radio- and/or

pleuroperitoneal shunt with a high risk of

chemotherapy are considered for high-grade

complications, or parietal pleurectomy.

sarcomas.

Spontaneous pleurodesis may be obtained

Local treatment Pleurodesis is useful in

by TPC without mortality or major morbidity

treating a patient’s symptoms and

in nearly half of the cases when pleural

preventing recurrent effusions. Sterile talc is

drainage is performed via the catheter every

ERS Handbook: Respiratory Medicine

487

other day, or even up to 70% in MPE

disease in pleural effusions: a ran-

patients fit for pleurodesis.

domised controlled trial. Lancet;

361:

1326-1330.

Rodriguez-Panadero F. Effusions from

Further reading

malignancy. In: Light RW, et al., eds.

Textbook of Pleural Diseases. 2nd Edn.

Antony VB, et al. (2001). Management of

malignant pleural effusions. Eur Respir J;

London, Hodder Arnold, 2008; pp. 323-

18: 402-419.

333.

Chee A, et al. (2011). The use of tunneled

Sahn SA. Malignant pleural effusions. In:

pleural catheters in the treatment of

Bouros D, ed. Pleural Disease. Vol. 186.

pleural effusions. Curr Opin Pulm Med;

New York, Marcel Dekker, 2004: pp. 411-

17: 237-241.

438.

Foran P, et al. (2011). Imaging of thoracic

Scherpereel A, et al. (2010). Guidelines of

sarcomas of the chest wall, pleura, and

the European Respiratory Society and the

lung. Semin Ultrasound CT MR; 32: 365-376.

European Society of Thoracic Surgeons

Gross JL, et al. (2005). Soft-tissue sarco-

for management of malignant pleural

mas of the chest wall: prognostic factors.

mesothelioma. Eur Respir J; 35: 479-495.

Chest; 127: 902-908.

Travis WD, et al., eds. World Health

Janssen JP, et al.

(2007). Safety of

Organization Classification of Tumors.

pleurodesis with talc poudrage in malig-

Tumors of the Lung, Pleura, Thymus and

nant pleural effusion: a prospective

Heart. Lyon, IARC, 2004.

cohort study. Lancet; 369: 1535-1539.

van der Bij S, et al. (2011). Markers for the

Maskell NA, et al.

(2003). Standard

non-invasive diagnosis of mesothelioma:

pleural biopsy versus CT-guided cutting-

a systematic review. Br J Cancer;

104:

needle biopsy for diagnosis of malignant

1325-1333.

488

ERS Handbook: Respiratory Medicine

Mediastinal tumours

Paul E. Van Schil, Patrick Lauwers and Jeroen M. Hendriks

Variety of compartments and organs

table 1. Metastases may also occur in the

mediastinum.

Although no universal agreement exists, the

mediastinum is commonly divided into a

Variety of symptoms

superior compartment above a straight line

Mediastinal tumours can grow to a large size

from the sternal angle of Louis to the

before symptoms appear. Pressure on

vertebral column, and an inferior part below

surrounding structures may result in

this imaginary line. The latter is composed

hoarseness, dyspnoea, dysphagia and

of an anterior compartment in front of the

superior vena cava syndrome. Various

heart, a middle compartment at the level of

paraneoplastic syndromes have been

the heart, and a posterior part lying behind

described, such as myasthenia gravis and pure

the heart. Each compartment contains

red cell aplasia in case of thymoma (fig. 1).

different organs and structures, varying from

the heart and great vessels to lymphatic

Variety of diagnostic means

tissue and pluripotent cells.

Chest CT, MRI and positron emission

Variety of histological types and tumours

tomography provide exact anatomical

delineation of a tumour and may suggest a

In both young and old patients, a range of

specific entity. To obtain a precise

primary tumours and cysts is encountered in

histological diagnosis, CT-guided puncture,

the mediastinum; these are summarised in

endoscopic or endobronchial ultrasound,

mediastinoscopy, mediastinotomy, and

video-assisted thoracic surgery are used. In

Key points

the case of suspicion of lymphoma, germ

N Mediastinal tumours are

characterised by a wide variation in

Table 1. Primary tumours and cysts encountered in the

mediastinum

clinical presentation, histological

features and treatment options.

Superior

Substernal goitre

mediastinum

Ectopic thyroid

N A multidisciplinary approach is

necessary to determine optimal

Inferior

treatment.

mediastinum

Thymoma

N Surgical treatment should aim at

Thymic cyst

complete resection.

Germ cell tumours

N The mediastinum, which is defined as

Pleuropericardial cysts

the anatomical compartment between

Middle

Lymphoma

both lungs, is a fascinating region due

Bronchogenic cyst

to its surprising complexity and

Posterior

Neurogenic tumours

variety.

Enterogenic cysts

ERS Handbook: Respiratory Medicine

489

approach. In the case of incomplete

resection or transcapsular invasion,

adjuvant radio- or chemotherapy may be

indicated. Inoperable lesions and

lymphomas are treated by a combination of

chemo- and radiotherapy. In selected cases,

induction therapy may be a valid approach

to downstage a locally aggressive tumour.

Salvage surgery may be attempted in

tumours that are no longer responsive to

chemo- or radiotherapy. Long-term survival

depends on histological type and

Figure 1. A large thymoma in the right hemithorax

completeness of resection.

presenting with myasthenia gravis. The tumour

was resected by a bilateral anterior thoracotomy

(clam-shell incision).

Further reading

Date H (2009). Diagnostic strategies for

cell tumour or thymoma, large biopsies are

mediastinal tumors and cysts. Thorac

required. Well-circumscribed tumours in

Surg Clin; 19: 29-35.

young patients should be excised at once so

Hoffman R, et al., eds. Hematology: Basic

as not to breach the surrounding capsule.

Principles and Practice.

5th Edn.

Variety of therapeutic strategies

Philadelphia,

Churchill

Livingstone

Elsevier, 2009.

Operable lesions are treated by surgical

Spaggiari L, et al.

(2012). Multi-

excision. Minimally invasive and even

disciplinary treatment of malignant thy-

robotic techniques can be applied if a

moma. Curr Opin Oncol; 24: 117-122.

complete resection can be obtained by this

490

ERS Handbook: Respiratory Medicine

Obstructive sleep apnoea/

hypopnoea syndrome

Wilfried De Backer

Obstructive sleep apnoea/hypopnoea

All patients should have more than five

syndrome (OSAHS) is characterised by

obstructed breathing events per hour during

recurrent episodes of partial or complete

sleep. An obstructive apnoea or hypopnoea

upper airway collapse during sleep. The

can be defined as an event that lasts for

collapse is highlighted by a reduction in, or

o10 s and is characterised by an absence or

complete cessation of, airflow despite

a decrease from baseline in the amplitude of

ongoing inspiratory efforts. Due to the lack

a valid measure of breathing during sleep

of adequate alveolar ventilation that results

that either reaches .50% with an oxygen

from the upper airway narrowing, oxygen

desaturation of 3% or an arousal

saturation may drop and carbon dioxide

(alternatively a 30% reduction with 4%

tension may occasionally increase. The

desaturation). These definitions are

events are mostly terminated by arousals.

recommended by the American Academy of

Clinical consequences are excessive daytime

Sleep Medicine (AASM). The AASM Task

sleepiness related to the sleep disruption.

Force also states that there are common

Minimal diagnostic criteria have been

pathogenic mechanisms for obstructive

defined for OSAHS. Patients should have

apnoea syndrome, central apnoea

excessive daytime sleepiness that cannot be

syndrome, sleep hypoventilation syndrome

better explained by other factors, or

and Cheyne-Stokes breathing. It was more

experience two or more of the following

preferable to discuss each of these

symptoms, again that are not better

separately, although they could be placed

explained by other factors:

under the common denominator of ‘sleep-

disordered breathing syndrome’. The

N choking or gasping during sleep

definition of OSAHS using two components,

N recurrent awakenings from sleep

daytime symptoms and breathing pattern

N unrefreshing sleep

disturbances during sleep, may suggest that

N daytime fatigue

there is a tight correlation between the two.

N impaired concentration

However, unfortunately, this is not the case.

The breathing pattern abnormalities, mostly

described by an AHI, only weakly correlate

with quantified measures of sleepiness,

Key points

such as the Epworth Sleepiness Scale (ESS).

This probably means that interindividual

OSAHS is characterised by recurrent

sensitivity, with some individuals coping

episodes of partial or complete upper

better with sleep fragmentation than others,

airway collapse during sleep.

does compromise the relationship between

the AHI and daytime sleepiness scores. In

N Minimal diagnostic criteria exist for

addition, epidemiological studies show a

OSAHS.

broad range of sleepiness in the general

Overnight polysomnography is the

population. Obviously, epidemiological

gold standard for OSAHS diagnosis.

studies investigating the prevalence of

OSAHS are all biased by the lack of a

ERS Handbook: Respiratory Medicine

491

uniform definition. The prevalence of an AHI

pressure and the tissue pressure at the

of .5 events?h^-1 in a general population

collapsible site. The airway remains patent,

(without taking into account symptoms of

regardless of the excessive pressure applied,

sleepiness) has previously been estimated

as long as the critical pressure of positive

to be 24% in a male population. When

end-expiratory pressure (Pcrit) remains low

symptoms of sleepiness were also taken into

relative to the pressure upstream to the

account, the prevalence decreased to 4% in

collapsible segment (Pu). Closure of the

males and 2% in females.

upper airway occurs when Pu falls below the

surrounding tissue pressure (Pcrit). In the

Assessment of OSAHS

model of the Starling resistor, maximal flow

(V9max) becomes a function of the pressure

The most widely used gold standard for

gradient and the resistance in the segment

diagnosis is overnight polysomnography

upstream to the collapsible segment (Ru):

including nasal and/or oral airflow,

thoracoabdominal movement, snoring,

V9max5(Pu-Pcrit)/Ru

(1)

electroencephalography, electro-

oculography, electromyography and oxygen

The collapse of the upper airway then finally

saturation. Cardiorespiratory monitoring

occurs during expiration when, due to the

alone can be considered as highly sensitive

absence of dilator muscle, Pcrit exceeds the

(78-100%) and specific (67-100%).

upstream pressures. Prolonged expiratory

time, as occurs during central apnoeas,

Sleepiness is often evaluated using the ESS,

therefore predisposes to collapse, but other

which assesses the global level of sleepiness

factors may contribute and can be

and is independent of short-term variations

considered as risk factors (table 1).

in sleepiness. The ESS discriminates

between normal and pathological

Central and obstructive events are closely

sleepiness.

linked. Sometimes a central event with an

already partially collapsed upper airway can

Pathophysiology

transit towards an obstructive event with

Structural narrowing of the upper airway at

ongoing occlusion of the upper airway

one specific location is unlikely to be a

despite the resumption of effort. Often,

major cause. Studies have shown that the

however, with resumption of effort at the

upper airway collapse is not restricted to one

end of the central apnoea, the obstruction of

place but is rather a dynamic phenomenon,

the upper airway disappears, presumably

starting at a certain level and spreading

due to reactivation of the upper airway

caudally. Upper airway obstruction involves

dilator muscles. However, the mechanisms

more than one specific site of the upper

remain unclear and more research is needed

airway in the majority of sleep apnoea

to understand why central apnoeas are

patients. The upper airway can collapse

sometimes followed by obstructive apnoeas

when insufficient load compensation is

and, in some cases, followed by reopening

generated when an imbalance between the

of the airways. In any case, since central

activation of the upper airway dilator

apnoeas can trigger classical obstructive

muscles and the diaphragm occurs. When

apnoeas, the mechanisms leading to

this occurs, the airway will collapse during

unstable breathing (and thus central

inspiration or at least narrow with the

apnoeas) are also important in the genesis

development of flow limitation. However,

of obstructive apnoeas.

there is increasing evidence that the collapse

Consequences

of the upper airway occurs during expiration.

Furthermore, it has been convincingly

Cardiovascular Obstructed airways may

shown that the upper airway behaves like a

generate negative intrathoracic pressure that

Starling resistor, making the collapse

increases left ventricular transmural pressure

independent of the suction force brought

and left ventricular afterload. The negative

about by the diaphragm but dependent on

pressure also draws more blood into the

the balance between the upper airway

thorax and increases right ventricular

492

ERS Handbook: Respiratory Medicine

preload. Intermittent hypoxia related to OSA

TABLE 1. Risk factors for OSA: factors promoting upper

will also impair cardiac contractility and

airway collapse

diastolic relaxation (fig. 1).

Abnormal anatomy of the upper airway

Skeletal factors

OSA patients also have attenuated

endothelium-dependent vasodilation and

Maxillary and/or mandibular hypoplasia

decreased circulating markers of nitric

or retroposition

oxide. These effects, together with increased

Hyoid position (inferior displacement)

sympathetic vasoconstrictor activity and

Soft tissue factors

inflammation, will predispose to

hypertension and atherosclerosis. In

Increased volume of soft tissues

addition, platelet activation and

Adenotonsillar hypertrophy

aggregability are increased and predispose

Macroglossia

to thrombotic disease. Epidemiological

studies indicate that OSA can initiate or

Thickened lateral pharyngeal walls

promote cardiovascular disease, such as

Increased fat deposition

hypertension, coronary heart disease,

Pharyngeal inflammation and/or

heart failure, cardiac arrhythmias

oedema

(bradyarrhythmias, atrial fibrillation and

Increased vascular volume

ventricular ectopy) and cerebrovascular

disease.

Increased muscle volume

Pharyngeal muscle factors

Metabolic OSA is associated with several

components of the metabolic syndrome,

Insufficient reflex activation of upper

mainly insulin resistance and abnormal lipid

airway dilator muscles

metabolism. Sleep restriction causes insulin

Impaired strength and endurance of

resistance by inducing a pro-inflammatory

pharyngeal dilators

state (increased release of interleukin (IL)-6

Pharyngeal compliance

and tumour necrosis factor (TNF)-a).

Increased upper airway collapsibility

Epidemiological studies have shown that

sleep-related hypoxaemia is associated with

Sensory function

glucose intolerance independent of age, sex,

Impaired pharyngeal dilator reflexes

BMI and waist circumference. Metabolic

Impaired mechanoreceptor sensitivity

syndrome can be triggered by both

intermittent hypoxia and sleep

Lung volume dependence of upper airway

fragmentation/deprivation. The mechanisms

cross-sectional area

are shown in figure 2.

Increased below functional residual capacity

Ventilatory control system factors

Metabolic syndrome can be due to the

release of free fatty acids, angiotensin II and

Unstable ventilatory control

adipokines by adipose tissue, which may

Increased ventilatory responses and loop gains

damage the pancreas, leading to insufficient

Sex factors

insulin release and apparent insulin

resistance.

Male influences

Centripetal pattern of obesity

Mean and nadir SaO₂ during sleep is an

independent predictor of metabolic syndrome

Absence of progesterone

in overweight children and adolescents.

Presence of testosterone

CPAP treatment

Weight

Therapy with nasal CPAP nCPAP is perceived

Obesity causing peripharyngeal fat accumulation

by most physicians as a very effective

Reproduced from Verbraecken et al. (2009) with

treatment for sleep apnoea and has been

permission from the publisher.

shown to be effective in controlled studies.

ERS Handbook: Respiratory Medicine

493

OSA

PNA

Arousal

Intrathoracic pressure

PO2 PCO2

SNA

Myocardial

Oxidative stress

Catechols

O₂ delivery

Inflammation

Endothelial dysfunction

Hypertension

Atherosclerosis

LV wall tension

Myocardial ischaemia

Cardiac O₂ demand

LV hypertrophy and failure

Cardiac arrhythmias

Cerebrovascular disease

Figure 1. Cardiovascular consequences of OSA. PNA: parasympathetic nerve activity; PO₂: oxygen tension;

PCO₂: carbon dioxide tension; SNA: sympathetic nerve activity; HR: heart rate; BP: blood pressure; LV: left

ventricle. Reproduced and modified from Bradley et al. (2009) with permission from the publisher.

nCPAP results in better sleep quality with a

more clinically effective than was shown in

lower arousal index, and less stage 1 and

previous controlled studies.

more stage 3 and 4 sleep in a placebo-

nCPAP and control of breathing As

controlled (using placebo capsules) study.

mentioned previously, some clinical

In addition, in milder forms of sleep apnoea,

observations initially indicated that unstable

nCPAP improved self-reported symptoms of

breathing is part of OSAS, while more recent

OSA, including snoring, restless sleep,

systematic analysis confirmed the increased

daytime sleepiness and irritability.

loop gain and instability in the breathing

Neuropsychological tests also improved

pattern in OSA patients. It can be

after nCPAP compared with ineffective

questioned, therefore, whether nCPAP can

nCPAP. Blood pressure can also be reduced

influence control of breathing in

with nCPAP when compared with an oral

(obstructive) sleep apnoea patients. One

placebo, especially in patients using nCPAP

could demonstrate that prolonged treatment

for o3.5 h?night^-1 and in those with .20

with nCPAP significantly decreases the slope

desaturations of 4% per hour.

of the hypercapnic ventilatory response

curve when measured during wakefulness,

nCPAP and the upper airway Occlusion of

together with an increase in PaO₂ and a

the upper airway can be prevented when

decrease in the arterial-alveolar oxygen

either the resistance of the upper airway

tension difference. It is clear that all of these

upstream, Ru or Pcrit can be lowered.

changes may contribute to lowering of the

Regardless of the severity of the changes in

gain in the system and promote a more

Pcrit and Pu, nCPAP can effectively increase

stable breathing pattern. Changes in lung

(or restore) flow, largely through its effect on

volume, although mostly small, can also be

Pu (equation 1). Appropriate titration of the

observed during nCPAP therapy.

CPAP restores flow. nCPAP can increase Pu

much more than local interventions, such as

nCPAP has also been demonstrated to be

uvulopalatopharyngoplasty. Therefore, it

effective in central sleep apnoea (CSA).

also explains why overall nCPAP is much

nCPAP can increase carbon dioxide tension

494

ERS Handbook: Respiratory Medicine

OSA

Intermittent

Sleep

hypoxia

fragmentation/

Type 2

sleep deprivation

diabetes

Oxidative

Neurohumoral

Obesity

stress

changes

Metabolic

Insulin

syndrome

resistance

Inflammation

Hypertension

Dyslipidaemia

Figure 2. Mechanisms linking OSA and the metabolic syndrome. Reproduced and modified from Tasali

et al. (2008) with permission from the publisher.

above the apnoeic threshold and, therefore,

cardiac output by reducing left ventricular

eliminate central apnoeas. However,

preload. In contrast, the failing heart is

central apnoeas are often also

relatively insensitive to changes in preload

characterised by (near) occlusion of the

but very sensitive to reductions in afterload.

upper airway; as highlighted earlier, nCPAP

CPAP-induced reductions in left ventricular

can also presumably be effective in

transmural pressure (and afterload) can

preventing this collapse and its associated

augment cardiac output.

local reflexes.

nCPAP may also attenuate sympathetic

nCPAP and the heart nCPAP can effectively

nervous activity and increase cardiac vagal

be used to treat acute cardiogenic

modulation of the heart with favourable

pulmonary oedema with shifting volume

effects on blood pressure regulation.

from intra- to extrathoracic compartments.

In a large prospective study, severe

nCPAP may relieve CSA in chronic heart

untreated OSA patients had more fatal and

failure patients by increasing the PaCO₂

nonfatal cardiovascular events; this

above the apnoeic threshold. nCPAP may

difference disappeared with nCPAP

reduce ventilation by redistributing excess

treatment.

lung water to extrathoracic compartments,

nCPAP and metabolic/systemic effects of OSA

thereby reducing stimulation of pulmonary

nCPAP may improve metabolic syndrome,

vagal irritant receptors. nCPAP may also

although it is not always certain that nCPAP

unload the inspiratory muscles by increasing

has an independent effect. nCPAP also

lung compliance, again due to extrathoracic

lowers TNF-a, IL-6 and C-reactive protein

redistribution of lung water.

levels.

nCPAP may significantly reduce left

Non-CPAP treatment

ventricular afterload by lowering the

transmural pressure in patients with

Mandibular advancement devices (MADs)

compromised cardiac function and, thus,

are the most common oral appliances used

overcome the burden of OSA on the

for the treatment of OSA and/or snoring.

cardiovascular system, as shown in figure 1.

They have either a one-piece (monobloc) or

In the normal heart, where cardiac output is

two-piece (duobloc) configuration.

largely preload dependent, CPAP decreases

Customised devices have a better retention,

ERS Handbook: Respiratory Medicine

495

tolerance and efficacy. MADs are effective if

that site. Sleep endoscopy has been most

they increase the volume of the upper

widely used to identify the site of collapse,

airway, which may enlarge at some sites and

although pressure catheters with multiple

also narrow at other sites. Therefore, the

sensors have also been used to identify the

overall efficacy is sometimes suboptimal;

site of collapse; in addition, functional

65% of patients achieve a 50% reduction in

imaging of the upper airway maybe a

AHI. In addition, snoring, excessive daytime

promising tool.

sleepiness, neuropsychological function and

Bariatric surgery

cardiovascular risk may decrease. It is

important to try to predict the outcome.

Several techniques have been used to

Imaging and modelling studies can be of

perform bariatric surgery including gastric

help for this purpose. Overall, these oral

banding, use of a gastric balloon, gastric

appliances are recommended for patients

sleeve resection and gastric bypass. Bariatric

with mild-to-moderate OSA and for those

surgery is used in morbidly obese patients

with more severe disease when they do not

with a BMI o40 kg?m^-2. Almost half of

tolerate CPAP. Side-effects, such as pain in

patients improve after these interventions

the teeth and jaws, are mostly mild. Short-

but, therefore, a substantial number of

term compliance seems to be very high

patients has still to continue with nCPAP.

while long-term compliance (after .2 years)

is ,50%.

Drug treatment

Surgical treatment Several techniques have

Several drugs have been tried, such as

been performed, all with the aim of

protriptyline (a tricyclic antidepressant),

enlarging the volume of the upper airway

paroxetine (a serotonin reuptake inhibitor)

and reducing the closing pressure.

and mirtazapine (a serotonin receptor

Uvulopalatopharyngoplasty reduces upper

agonist). None of these has given

airway obstruction by shortening the uvula,

convincing results. Acetazolamide, although

trimming the soft plate, and suturing back

quite efficient in the treatment of central

the anterior and posterior pharyngeal pillars.

apnoeas, has also no effect on obstructive

Tonsillectomy is performed at the same time

apnoeas.

if the tonsils are found to be enlarged.

Maxillomandibular advancement osteotomy

Further reading

advances the maxilla and mandible to

enlarge the retrolingual and retropalatal

Bradley TD, et al.

(2009). Obstructive

spaces. This technique is not yet often used

sleep apnoea and its cardiovascular

but additional studies are needed to

consequences. Lancet; 373: 82-93.

establish its place, presumably in the more

Chan AS, et al.

(2008). Non-positive

severe OSA patients who do not tolerate

airway pressure modalities: mandibular

nCPAP and where an adequate therapy is

advancement devices/positional therapy.

needed to improve daytime sleepiness and

Proc Am Thorac Soc; 5: 179-184.

De Backer WJ, et al.

(2008). Novel

prevent cardiovascular and metabolic

imaging techniques using computer

consequences. Adenotonsillectomy is the

methods for the evaluation of the upper

first-line treatment in children. Electrical

airway in patients with sleep-disordered

stimulation of the genioglossus with an

breathing: a comprehensive review. Sleep

implanted pacemaker has recently been

Med Rev; 12: 437-447.

tested and found to be efficient in selected

Jennum P, et al. (2009). Epidemiology of

patients, although more clinical studies are

sleep apnoea/hypopnoea syndrome and

needed in order to learn which patients will

sleep-disordered breathing. Eur Respir J;

benefit most. Overall, the results of upper

33: 907-914.

airway surgery are poor when patients are

Levy P, et al.

(2009). Sleep, sleep-

unselected. Therefore, one must try to

disordered breathing and metabolic con-

identify the site of the upper airway collapse

sequences. Eur Respir J; 34: 243-260.

and correct the anatomical abnormalities at

496

ERS Handbook: Respiratory Medicine

Marin JM, et al.

(2005). Long-term

Tasali E, et al. (2008). Obstructive sleep

cardiovascular outcomes in men with

apnea and metabolic syndrome: altera-

obstructive sleep apnoea-hypopnoea with

tions in glucose metabolism and inflam-

or without treatment with continuous

mation. Proc Am Thorac Soc;

positive airway pressure: an observational

207-217.

study. Lancet; 365: 1046-1053.

Verbraecken JA, et al.

(2009). Upper

Marklund M, et al.

(2012). Non-CPAP

airway mechanics. Respiration;

78:

121-

therapies in obstructive sleep apnoea:

133.

mandibular advancement device therapy.

Verhulst SL, et al.

(2007). Sleep-disor-

Eur Respir J; 39: 1241-1247.

dered breathing and the metabolic

McArdle N, et al.

(2001). Effect of

syndrome in overweight and obese

continuous positive airway pressure on

children and adolescents. J Pediatr; 150:

sleep architecture in the sleep apnea-

608-612.

hypopnea syndrome: a randomized con-

Won CH, et al. (2008). Surgical treatment

trolled trial. Am J Respir Crit Care Med;

of obstructive sleep apnea: upper airway

164: 1459-1463.

and maxillomandibular surgery. Proc Am

Randerath WJ, et al. (2011). Non-CPAP

Thorac Soc; 5: 193-199.

therapies in obstructive sleep apnoea. Eur

Young TM, et al. (1993). The occurrence

Respir J; 37: 1000-1028.

of sleep-disordered breathing among

Sleep-related breathing disorders in

middle-aged adults. N Engl J Med; 328:

adults: recommendations for syndrome

1230-1235.

definition and measurement techniques

Younes M, et al. (2007). Mechanisms of

in clinical research. The Report of an

breathing instability in patients with

American Academy of Sleep Medicine

obstructive sleep apnea. J Appl Physiol;

Task Force. Sleep; 22: 667-689.

103: 1929-1941.

ERS Handbook: Respiratory Medicine

497

Central sleep apnoea

Konrad E. Bloch and Thomas Brack

Central sleep apnoea/hypopnoea refers to

to be significantly less common than OSA,

the cessation or reduction of ventilation

as ,5% of patients referred to a sleep

lasting for o10 s (in adults) due to a

laboratory revealed predominant CSA. In

transient loss of neural output to the

contrast, a relatively high prevalence of CSA

respiratory muscles. Many patients with

is observed in association with various

central sleep apnoea (CSA) have mild

conditions including CHF, pulmonary

hypocapnia or normocapnia but

hypertension, ischaemic stroke,

hypercapnia is less common, although

neuromuscular disease, obesity

hypoventilation may also accompany CSA. A

hypoventilation syndrome and narcotic use,

periodic pattern of waxing and waning of

or during initiation of CPAP therapy in

ventilation with periods of hyperventilation

certain patients with OSA. In healthy

alternating with central apnoea/hypopnoea

subjects, CSA may occur during hypoxia at

is termed Cheyne-Stokes respiration (CSR).

altitude. Idiopathic CSA, by definition, is not

associated with any comorbid condition.

Prevalence, aetiology and pathophysiology

Pathophysiological mechanisms underlying

The prevalence of CSA in the general

CSA include:

population is not known. However, it seems

N respiratory control instability, due to an

increased chemical drive, so that the

prevailing PaCO₂ approaches the apnoea

Key points

threshold

N a prolonged circulation time

N CSA signifies the loss or reduction in

N altered respiratory mechanics

ventilation due to a transient loss of

neural output to the respiratory muscles.

Subsequently, different forms of CSA will be

discussed.

N A high prevalence of CSA is observed

in association with conditions such as

CSR/CSA syndrome in CHF patients

CHF, pulmonary hypertension,

cerebral stroke, neuromuscular

Left-heart failure that increases pulmonary

disease, obesity hypoventilation

venous pressure is regarded as a source of

syndrome and opioid use.

CSR, as pulmonary congestion stimulates

stretch receptors that sensitise the

N Risk factors for CSA/CSR are age

peripheral chemoreceptors to carbon

.60 years, male sex, severe heart

dioxide through vagal afferents. The

failure, hypocapnia and atrial

increased ventilatory sensitivity to carbon

fibrillation.

dioxide drives the PaCO₂ closer to the apnoea

N Treatment includes oxygen,

threshold, thereby promoting the

acetazolamide and positive pressure

susceptibility to central apnoea. Moreover,

ventilation, in particular adaptive

hypoxia that follows apnoea/hypopnea

servoventilation.

enhances post-apnoeic hyperventilation. If

chemical control prevails over cortical

498

ERS Handbook: Respiratory Medicine

influences on the respiratory controller, as

with .50% central events and a LVEF

typically occurs during sleep, patients

,40%. Obviously, the AHI threshold used

develop an oscillatory breathing pattern that

to define the presence of CSR has a major

causes sympathetic overstimulation in

impact on prevalence estimates (fig. 1).

patients who are already sympathetically

In some patients, CSR/CSA and OSA may

stimulated through their heart failure.

coexist and alternate over the course of a

Among patients with moderate to severe

night. Symptoms attributable to CSR/CSA

heart failure (left ventricular ejection fraction

are not well defined and may include

(LVEF) f55%) the prevalence of sleep apnoea

paroxysmal nocturnal dyspnoea, poor sleep

(both obstructive and central) is very high

quality, excessive daytime sleepiness,

irrespective of the clinical suspicion (fig. 1).

fatigue and poor exercise tolerance.

Criteria for CSR/CSA have not been

CSR/CSA in heart failure patients is

uniformly accepted. According to the

associated with poor prognosis. Several

American Academy of Sleep Medicine, CSR

studies have found an increased mortality in

should be scored if at least three successive

patients with CSR/CSA even after controlling

cycles of cyclic crescendo-decrescendo

for the severity of heart failure, age, sex and

changes in breathing amplitude are present

other potential confounders. Mortality was

for at least 10 consecutive minutes or when

particularly high in patients presenting with

a central AHI .5 events?h^-1 arises. In the

daytime CSR during physical activity (fig. 2).

Canadian Continuous Positive Airway

Sleep-related breathing disturbances should

Pressure for Patients with Central Sleep

be suspected in all patients with heart failure

Apnea and Heart Failure (CANPAP) trial, a

who suffer from nocturnal dyspnoea,

large multicentre study that evaluated the

unrefreshing sleep or daytime sleepiness.

effectiveness of CPAP therapy in patients

Particular risk factors for CSA/CSR include:

with heart failure and CSA, inclusion criteria

required o15 apnoeas/hypopnoeas per hour

N severe heart failure

N older age (o60 years)

100

N male sex

CSR/CSA

CHF, LVEF <45-55%

OSA

N hypocapnia

N atrial fibrillation

Stroke

N CSR observed during the day

The diagnosis should be evaluated by

polysomnography or a cardiorespiratory sleep

Males

study, as pulse oximetry cannot make the

>65

important distinction between CSA and OSA.

years

Optimised medical therapy of heart failure is

the first step in the treatment of CSR/CSA.

Cardiac resynchronisation by biventricular

pacing and heart transplantation may also

>15

>10

alleviate CSR/CSA. If medical therapy alone

AHI events·h-1

is ineffective, NIV may also be required.

Nocturnal CPAP has been shown to improve

Figure 1. The prevalence of OSA and CSR/CSA in

nocturnal CSR/CSA, oxygen saturation,

patients with CHF is very high (47-82%),

LVEF, sympathetic nervous system activity

depending on the severity of heart failure and on

the cut-off level of the AHI. Sleep apnoea is also

and 6-min walking distance. These effects

common in patients with stroke or pulmonary

are thought to be mediated by the increase

hypertension (PH). For comparison, data from a

in intrathoracic pressure induced by CPAP,

community sample of males aged .65 years are

which reduces both afterload and preload by

also shown. Reproduced and modified from Brack

decreasing transmural ventricular pressure

et al. (2012) with permission from the publisher.

and venous return so that cardiac function

ERS Handbook: Respiratory Medicine

499

Sum

Rib cage

Abdomen

V'E

SpO

Heart rate

Standing

Supine

58 min

Sum

Rib cage

Abdomen

132 s

144 s

Figure 2. CSR in a patient with CHF. Inductive plethysmographic signals from rib cage and abdominal

sensors showing regular waxing and waning of ventilation with central hypopnoeas and corresponding

oscillations of oxygen saturation. The upper panel represents a 58-min daytime recording, the lower panels

show enlarged portions obtained while standing (left) and in the supine position (right). Reproduced and

modified from Brack et al. (2007) with permission from the publisher.

improves in patients with increased filling

breathing (fig. 3). It is a promising treatment

pressures. Additionally, CPAP stabilises CSR

option for CSR/CSA as it has been shown to

by raising the end-expiratory lung volume.

improve nocturnal breathing pattern,

Despite its positive effects on several

daytime vigilance and quality of life after

outcomes described above, CPAP did not

treatment for several weeks. Studies in

prolong survival without heart

larger patient cohorts over longer time

transplantation during a 2-year follow-up in

periods are needed to confirm these effects

a large trial (CANPAP). Yet, a post hoc

and to evaluate a potentially improved

analysis suggested a survival benefit in a

survival. Acetazolamide and theophylline

subgroup of patients in whom CPAP

both have reduced CSR/CSA in some studies

sufficiently suppressed CSR/CSA. Adaptive

but these drugs are currently not generally

servoventilation is a mode of bilevel positive

recommended because of limited data on

airway pressure ventilation that

their effectiveness and potential adverse

continuously adjusts pressure support

effects. Supplemental nocturnal oxygen has

according to the breathing pattern of the

provided inconsistent results with some

patient in order to stabilise periodic

studies showing a reduction in CSR/CSA,

500

ERS Handbook: Respiratory Medicine

along with improvements in physical

acetazolamide, theophylline, CPAP and

performance or quality of life while others

adaptive servo-ventilation.

failed to reproduce these benefits. Further

CSA in various conditions

studies are required to better define the role

of these adjuncts for the treatment of heart

CSA and ataxic breathing have been

failure in patients with CSR/CSA.

observed in patients on chronic opioid

Complex sleep apnoea syndrome

medication and can be successfully treated

with adaptive servoventilation, although the

In some patients diagnosed with OSA, a

relevance of the breathing disturbances

CSR/CSA breathing pattern may emerge

requires further study. Patients with stroke

during initial CPAP therapy. The clinical

and neuromuscular disease, such as post-

relevance of this phenomenon, referred to as

polio syndrome, motor neuron disease or

complex sleep apnoea, is still a matter of

multiple system atrophy, or with idiopathic

debate, as studies suggest that CSA

central hypoventilation may exhibit CSA with

disappears in the majority of OSA patients

or without associated OSA and/or

during prolonged CPAP therapy. However,

hypoventilation. Depending on the

persistent residual CSA may disturb sleep

prevailing breathing disturbance, bilevel

quality, prevent complete symptomatic

positive pressure ventilation, CPAP or

improvement and may lead to CPAP

adaptive servoventilation may improve

intolerance in OSA patients. In this setting,

breathing and alleviate symptoms.

adaptive servoventilation has been

successfully used to normalise the breathing

High-altitude periodic breathing

pattern and improve sleep quality.

In healthy subjects, hypobaric hypoxia at

Idiopathic CSA syndrome

altitudes of .1600 m may induce periodic

breathing with central apnoea/hypopnoea.

Idiopathic CSA syndrome (fig. 4) is, by

Breathing instability is related to an

definition, not associated with any

underlying disease. CSA causes sleep

fragmentation, which may be perceived as

Nasal flow

unrefreshing sleep and result in daytime

sleepiness. Idiopathic CSA is thought to be

Sum

much less common than OSA, although no

systematic epidemiological studies have

Rib cage

been performed. Treatment options include

Abdomen

Instanteous

lung volume

Microphone

(0-2 L)

Heart rate

Mask pressure

CPAP 5 cmH₂O

PS 3-10 cmH₂O

SpO2

100

SpO

(50-100%)

Figure 3. Recordings of instantaneous lung volume

Figure 4. Idiopathic CSA in a 56-year-old male

by respiratory inductive plethysmography and

suffering from unrefreshing sleep. The 5-min

mask pressure during adaptive servoventilation in

recording shows repetitive central apnoeas of

a patient with severe heart failure. In this mode of

variable duration (20-90 s) associated with severe

pressure support ventilation, the inspiratory

oxygen desaturation (minimal value of 66%). The

pressure support is increased during hypopnoeic or

absence of excursions in the inductive

apnoeic phases of CSR whereas pressure support is

plethysmographic rib cage and abdominal signals

reduced to a minimal level during hyperpnoeic

during cessation of airflow indicates that apnoeas are

phases. PS: pressure support.

due to intermittent loss of respiratory muscle activity.

ERS Handbook: Respiratory Medicine

501

enhanced chemosensitivity (high controller

Further reading

gain) causing a tendency for a ventilatory

Aurora N, et al. (2012). The treatment of

overshoot and hyperventilation with a

central sleep apnoea syndromes in

reduced carbon dioxide reserve, i.e. the

adults: practice parameters with an

eupnoeic carbon dioxide tension

evidence-based literature review and

approaches the apnoeic threshold, which

meta-analyses. Sleep; 35: 17-40.

promotes apnoea during minor ventilatory

Brack T, et al. (2007). Daytime Cheyne-

alterations. Symptoms may include

Stokes respiration in ambulatory patients

paroxysmal dyspnoea and poor sleep

with severe congestive heart failure is

quality. In some subjects, high-altitude

associated with increased mortality.

periodic breathing is associated with acute

Chest; 132: 1463-1471.

mountain sickness, a syndrome

Brack T, et al.

(2012). Cheyne-Stokes

characterised by headaches, insomnia, poor

respiration in patients with heart failure:

appetite, fatigue and, in more severe forms,

prevalence, causes, consequences and

ataxia and altered consciousness. The

treatments. Respiration; 83: 165-176.

diagnosis of high-altitude periodic breathing

Bradley DT, et al.

(2005). Continuous

is based on clinical observations in the

positive airway pressure for central sleep

appropriate context combined with pulse

apnea and heart failure. N Engl J Med; 353:

oximetry or more sophisticated sleep

2025-2033.

studies. Treatment is often not required but

Dai Y, et al. (2008). Central sleep apnea

can be performed by altitude descent or the

and Cheyne-Stokes respiration. Proc Am

administration of supplemental oxygen or

Thorac Soc; 5: 226-236.

acetazolamide, which is also effective

Eckert DJ, et al.

(2007). Central sleep

apnea. Chest; 131: 595-607.

against acute mountain sickness.

Javaheri S, et al. (2009). The prevalence

Conclusions

and natural history of complex sleep

apnea. J Clin Sleep Med; 5: 205-211.

In conclusion, CSA/CSR is less common

Schmidt-Nowara W. Patient information:

than OSA. However, in certain conditions,

Sleep apnea in adults (Beyond the Basics).

including CHF, neuromuscular disorders,

www.uptodate.com/contents/sleep-apnea-

opioid use and high altitude, the prevalence

in-adults-beyond-the-basics?.

of CSA is high. Treatment for CSA is not as

Walker JM, et al. (2007). Chronic opioid

well established as that for OSA, and it may

use is a risk factor for the development of

include oxygen, acetazolamide and positive

central sleep apnea and ataxic breathing.

pressure ventilation, in particular adaptive

J Clin Sleep Med; 3: 455-461.

servoventilation.

502

ERS Handbook: Respiratory Medicine

Hypoventilation syndromes

Jean-François Muir

Sleep-related hypoventilation syndromes,

Sleep-induced hypoventilation is

together with central and obstructive sleep

characterised by elevated levels of PaCO₂

apnoea syndromes, are a part of so-called

of .45 mmHg while asleep or

sleep-related breathing disorders (table 1).

disproportionately increased relative to

levels during wakefulness.

Pathophysiology

Nocturnal hypoventilation can be attributed

Key points

to respiratory pump failure in relation with

decreased ventilatory drive (won’t breathe),

Sleep-induced hypoventilation is

which may be due to respiratory

characterised by increased PaCO

dysfunction secondary to polio sequelae,

levels of .45 mmHg.

central hypoventilation, amyotrophic lateral

Nocturnal hypoventilation is

sclerosis, Arnold-Chiari malformation, or

associated with decreased ventilatory

the following: respiratory centres

drive, respiratory iatrogenic

depression (hypnotics); alteration of

depression, alteration of respiratory

respiratory nerve conduction (Guillain-

nerve conductance, muscular disease,

Barré syndrome), transmission to the

chest wall deformities or severe

respiratory muscles (myasthenia) or

obesity.

worsening mechanics (can’t breathe) with

respiratory muscle alteration (muscular

OHS is the association of obesity and

dystrophy), chest wall deformities or severe

sleep-disordered breathing with

obesity. In the latter situations, lungs are

daytime hypersomnolence and

normal, and associated hypoxaemia is due

hypercapnia in the absence of other

to the displacement of oxygen in the alveoli

respiratory diseases.

from increasing carbon dioxide levels, as

OHS is nowadays the most common

predicted by the alveolar air equation. If the

sleep-related hypoventilation

lungs are abnormal (COPD, tuberculous

syndrome.

sequelae, CF or diffuse bronchiectasis),

Nocturnal polygraphy evaluation is

hypercapnia is mainly due to worsening

needed in order to diagnose OHS.

mechanics and ventilation-perfusion

inequalities.

In OHS, NIV is used as the first-line

treatment with supplementary

During the night, ventilatory response to

oxygen when PaCO₂

o50 mmHg; if

hypoxaemia and hypercapnia is largely

PaCO₂

,50 mmHg, nasal CPAP

reduced during rapid eye movement (REM)

(nCPAP) plus oxygen may be

sleep with dysrhythmic breathing and less

discussed as a first-line treatment

reduced during non-REM sleep. The result is

after a night trial of nCPAP plus

a reduction of alveolar ventilation by altering

oxygen.

V9E and/or dead space volume/tidal volume

(fig. 1).

ERS Handbook: Respiratory Medicine

503

Table 1. Sleep-related breathing disorders

Presence of an extra-/intraspulmonary restrictive disorder

OHS

Neuromuscular diseases

Duchenne muscular dystrophy, Steinert myotony, polio sequelae, amyotrophic lateral

sclerosis, high spinal injuries with tetraplegia and respiratory paralysis (less frequent: acid

maltase deficiency and spinal muscular atrophy)

Chest wall diseases

Kyphoscoliosis and/or tuberculosis sequelae

Other conditions

Respiratory centers depressant drugs

Neurologic conditions

Arnold-Chiari malformations, brainstem tumors, space occupying lesions, vascular

malformations, central nervous system infection, stroke and neurosurgical procedure

which may be associated with central hypoventilation

Congenital central hypoventilation

Presence of an obstructive disorder

COPD, diffuse bronchiectasis and CF are the most frequent conditions

Respiratory mechanics change during sleep

induces skeletal muscle hypotonia sparing

and thereby worsen gas exchange,

the diaphragm and not the accessory

particularly in neuromuscular diseases and

respiratory muscles, with deleterious effects

obstructive airways diseases. REM sleep

in conditions for which these muscles are

Sustained oxygen desaturation

SaO2

Bucconasal

thermistor

Predominant reduction of thoracic contribution to ventilation occurring during phasic REM sleep

Thoracic

movements

Abdominal

movements

Sustained reduction in flow

Nasal

pressure

Reduction of respiratory effort during phasic REM sleep reflecting reduced respiratory drive

Pulse

transit time

Eye

movement

REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM REM

Figure 1. REM hypoventilation in a patient with OHS. Reproduced from Chouri Pontarollo et al. (2007).

504

ERS Handbook: Respiratory Medicine

necessary to maintain normal ventilation.

airway obstruction and, possibly, the

REM sleep also alters upper airways patency

influence of leptin.

and reduces chronic respiratory failure.

Without adequate treatment, patients with

Clinical features

OHS develop cor pulmonale, recurrent

episodes of hypercapnic respiratory failure

Hypoventilation per se generates a clinical

and loss of survival. OHS is one of the many

syndrome associated with, in typical cases,

aetiologies of chronic respiratory failure and

dyspnoea during activities of daily living in

has become a growing indication to initiate

the absence of paralysis, poor sleep

acute and/or long-term mechanical NIV.

quality, excessive daytime fatigue and

Mechanisms of action include resting of the

sleepiness, nocturnal or early morning

respiratory muscles, an increase in thoracic

headache, cyanosis and evidence of right

compliance and resetting of the respiratory

heart failure.

centres. In OHS, nocturnal mechanical NIV

Diagnosis

has been shown to be clinically effective

because of a rapid and sustained

The presence of such symptoms highlights

improvement of daytime arterial blood gas

the need to perform a physical examination,

levels and a net reduction of daytime

pulmonary function tests, a chest

sleepiness.

radiograph as well as measurement of

arterial blood gases in the awake and asleep

In order to establish a diagnosis of OHS,

patient, i.e. SaO2 and transcutaneous carbon

polysomnographic evaluation is needed and

dioxide tension. The results of this initial

the ventilatory treatment needs to be adapted.

investigation are concluded by full night

The sleep respiratory pattern can present as

ventilatory polygraphy (respiratory signals

obstructive apnoeas and hypopnoeas (90%

only) or polysomnography (respiratory and

of cases), obstructive hypoventilation due to

neurological signals; electroencephalography

increased upper airway resistance and/or

(EEG), electrooculography (EOG),

central hypoventilation (10% of cases)

electromyography (EMG)). Chronic daytime

(fig. 2). Data from a large cohort of OHS

hypercapnia is associated with and preceded

patients who had been treated with

by sleep-related hypoventilation.

mechanical NIV showed a very significant

decrease in the number of hospital stays for

Aetiology

cardiac and/or respiratory illness for the

3 years following the initiation of mechanical

Presence of an extra-/intrapulmonary restrictive

NIV, compared with the year prior to the start

disorder If obesity is present the most

of treatment. A dramatic improvement in

frequent diagnosis is obesity hypoventilation

arterial blood gases was observed and a good

syndrome. Previously called the ‘Pickwickian

compliance suggests that this treatment is

syndrome’, obesity hypoventilation

cost-effective and improves morbidity and

syndrome (OHS) is defined as the

mortality in such patients. Recent studies

association of obesity (BMI .30 kg?m^-2)

discussed the necessity to begin with

and sleep-disordered breathing with daytime

mechanical NIV as first-line treatment versus

hypersomnolence and hypercapnia (PaCO₂

nasal CPAP (nCPAP) with supplemental

.45 mmHg) in the absence of any other

oxygen; in patients with low levels of hyper-

respiratory disease. The prevalence of

capnia, a trial of night CPAP is useful to detect

OHS is 36% in patients with a BMI of

patients without severe nocturnal hypoxemia

35-40 kg?m^-2 and 48% if BMI is o50 kg?m^-2.

who could be proposed to nCPAP plus oxygen

The pathogenesis of OHS involves

as a first line treatment. In patients who

abnormal pulmonary mechanics with an

demonstrate a severe nocturnal hypercapnia,

excessive work of breathing and altered

mechanical NIV is chosen; expiratory positive

hypoxic and hypercapnic ventilatory

airway pressure (EPAP) is titrated to

responses, linked, in part, to chronic

control hypopnoeas and apnoeas and

hypoxaemia and poor sleep quality, upper

inspiratory positive airway pressure (IPAP)

ERS Handbook: Respiratory Medicine

505

is added to control PaCO₂. If pressure pre-set

muscular dystrophy; Steinert myotony; polio

NIV fails, target-volume ventilation or, in

sequelae; amyotrophic lateral sclerosis; and

some cases, nasal volume pre-set ventilation

high spinal injuries with tetraplegia and

may be used. In patients with OHS and

respiratory paralysis (less frequent are acid

predominant OSA, once hypercapnia has

maltase deficiency and spinal muscular

improved using mechanical NIV (which may

atrophy), and chest wall diseases with

take several weeks or months), mechanical

kyphoscoliosis and/or TB sequelae.

NIV may be changed to nCPAP (fig. 3).

Mechanical NIV has also largely improved the

These diseases represent the best indication

immediate vital prognosis of OHS and acute

for the application of acute and chronic

respiratory failure.

mechanical ventilation (mainly with NIV)

and, in some severe situations or after

Medical management is mainly orientated

failure of NIV, with invasive mechanical

towards weight loss. A reduction of 5-10%

ventilation and tracheostomy.

of body weight can result in a significant

decrease in PaCO₂. Unfortunately, weight

Other conditions of sleep-related

loss by diet alone is difficult to achieve and

hypoventilation There are less frequent

sustain; thus, bariatric surgery may be

conditions including neurological

proposed in the youngest patients. After

conditions such as Arnold-Chiari

significant weight-reduction surgery,

malformations, brainstem tumours, space

patients with OHS experience long-term

occupying lesions, vascular malformations,

improvement of arterial blood gases and

central nervous system infection, stroke, or

dyspnoea, which may lead, after night

neurosurgical procedure which may be

ventilator polygraphy monitoring showing

associated with central hypoventilation.

disappearance of sleep-disordered

Congenital central hypoventilation

breathing, to discontinuation of the

syndrome is a rare disorder of ventilatory

ventilator treatment.

control that typically presents in newborns

If obesity is absent or not predominant, the

and mainly results from a polyalanine repeat

most frequent conditions are:

expansion mutation in the PHOX2B gene. It

neuromuscular diseases with Duchenne

results in the failure of automatic central

EEG

Apnoeas

Hypopnoeas

Micro-arousals

Central hypopnoeas

Oesophageal pressure

SaO

Figure 2. A ventilator polygraphy from a patient with severe OHS (J.L. Pepin, personal communication,

with permission).

506

ERS Handbook: Respiratory Medicine

Obesity and CRF

(OHS)

Nocturnal ventilatory

polygraphy

Hypoventilation pattern

Hypoventilation and

OSAS predominant

OSAS pattern

pattern

Bilevel NIV + O₂

PaCO

2 ?

≥50 mmHg

<50 mmHg

Bilevel NIV+O₂

nCPAP+O

Continue

Reconsider after 3 months

use of nCPAP±O₂ if the patient

has clinically improved with

PaCO

2 <45 mmHg

Figure 3. A ventilator management algorithm in a patient with severe OHS presenting with chronic

respiratory failure (CRF). F: failure; S: success.^#: an alternative is assisted control ventilation.

control of breathing in infants who do not

respiratory centres depressors (morphine,

breathe spontaneously or who breathe

antitussive drugs, hypnotic and sedatives

shallowly and erratically. Sufferers are

compounds) which are often used by elderly

generally treated by mechanical ventilation

people.

with tracheostomy and, in less severe

Presence of an obstructive disorder

situations, by mechanical NIV.

Electrostimulation of the phrenic nerves

COPD, diffuse bronchiectasis and CF are

and/or the diaphragm is currently being

the most frequent conditions. During sleep

tested as a new therapeutic option.

there is a worsening of awake hypoxaemia

Some rare conditions of proven sleep-

and hypercapnia, especially during REM

related hypoventilation for which all the

sleep. Mechanical NIV is generally

previous aetiologies have been ruled out are

proposed after failure of long-term oxygen

considered as idiopathic; it is always

therapy in hypercapnic COPD when

important to review the medications of such

frequent episodes of acute respiratory

patient in order to detect intake of

decompensation occur and/or when

ERS Handbook: Respiratory Medicine

507

baseline PaCO₂ progressively worsens.

obesity-hypoventilation syndrome. Respir

COPD patients with obesity must be

Med; 98: 961-967.

investigated for possible overlap syndrome,

Guo YF, et al. (2007). Respiratory pat-

which is associated with obstructive sleep

terns during sleep in OHS patients

apnoea and COPD and is frequently a good

treated with nocturnal pressure support.

Chest; 131: 1090-1099.

responder to mechanical NIV.

Kessler, R, et al.

(2001). The obesity-

hypoventilation syndrome revisited: a

Further reading

prospective study of

consecutive

cases. Chest; 120: 369-376.

Bannerjee D, et al.

(2007). Obesity

Mokhlesi B (2007). Positive airway pres-

hypoventilation syndrome: hypoxemia

sure titration in obesity hypoventilation

during CPAP. Chest; 131: 1678-1684.

syndrome. CPAP or bi-level AP? Chest;

Casey KR, et al.

(2007). Sleep related

131: 1624-1626.

hypoventilation/hypoxemic syndromes.

Mokhlesi B (2010). Obesity hypoventila-

Chest; 131: 1936-1948.

tion syndrome. A state of the art review.

Chouri-Pontarollo N, et al.

(2007).

Respir Care; 55: 1347-1365.

Impaired objective daytime vigilance

Muir JF, et al. Management of chronic

in obesity-hypoventilation syndrome:

respiratory failure and obesity. In:

impact of noninvasive ventilation. Chest;

Ambrosino N, eds. Ventilatory Support

131: 148-155.

for Chronic Respiratory Failure. Vol.

Cuvelier A, et al. (2007). Obesity hypo-

New York, Informa Healthcare,

2008;

ventilation syndrome. New insights in the

pp. 433-444.

Pickwick papers. Chest; 131: 7-8.

Piper AJ, et al. (2011). Obesity hypoventi-

de Lucas-Ramos P, et al. (2004). Benefits

lation syndrome: mechanism and man-

at 1 year of nocturnal intermittent positive

agement. Am J Respir Crit Care Med; 183:

pressure ventilation in patients with

292-298.

508

ERS Handbook: Respiratory Medicine

Pulmonary diseases in

primary immunodeficiency

syndromes

Federica Pulvirenti, Cinzia Milito, Maria Anna Digiulio and Isabella Quinti

Almost all patients with primary antibody

Pneumonia is a common acute infection in

deficiencies suffer from upper and lower

primary antibody deficiency (PAD). Studies

respiratory tract bacterial infections. Severe

of PAD patients have revealed that at least

and recurrent infections with capsulated

two-thirds of patients have one or more

bacteria, asthma, and bronchiectasis

episodes of pneumonia prior to diagnosis.

represent the most important morbidity

Patients are prone to pneumonia-associated

and mortality factors. The pathogens

complications that require hospitalisation.

commonly isolated from the sputum are

Respiratory infections lead over time to

Haemophilus influenzae, Streptococcus

permanent lung damage.

pneumoniae and Streptococcus pyogenes,

Chronic lung disease (CLD) represents the

with Pseudomonas aeruginosa and

principal morbidity factor. As already

Moraxella catarrhalis occurring less

demonstrated in patients with CF, dyspnoea

frequently (table 1).

and sputum production are conditioning

factors of increased morbidity. Accumulated

mucus in the airways is the prominent

feature of bronchiectasis, leading to airway

Key points

obstruction, bacterial colonisation and

recurrent infections.

PIDs include multiple genetic defects

that belong to the group of rare

The events that define the pathogenesis of an

diseases. The World Health

infection depend on a large range of variables,

Organization recognises .70

including the specific infecting organism, its

diseases classified as PID.

virulence and the overall immunological state

of the host. IgG antibodies are only one player

The risk and type of infections change

in the complex network of cells and mediators

according to the main defect of the

required to protect the respiratory tract

immune system: they are classified as

against various insults, including infections.

antibody deficiencies, combined

In support of this, data indicate the role of a

immunodeficiencies, phagocytic

very low IgA level as a major independent risk

disorders and innate immunity

factor for all the main primary

disorders.

immunodeficiency (PID)-associated clinical

In pulmonology, a PID diagnosis

conditions (pneumonia, CLD, and acute and

should be considered in patients

chronic sinusitis), underlining the well-known

presenting with: 1) severe and

role of IgA in immune defence against a

recurrent respiratory infections;

variety of potentially pathogenic organisms

2) granulomatous diseases; and 3)

when they are encountered in the respiratory

life-threatening invasive pulmonary

and intestinal tracts. The generation of

infections. In some cases, there are

secretory IgA has a basic impact on the

unique features of lung abnormalities

epithelial barrier, a function lacking in the

in specific defects.

majority of PID patients. Moreover, low

IgA levels reflect a severely impaired

ERS Handbook: Respiratory Medicine

509

Table 1. Microorganisms in PID

Antibody deficiencies Combined immunodeficiencies Phagocytic defects

Viruses

Enteroviruses

CMV

Respiratory syncytial virus

EBV

Parainfluenza virus type 3

Bacteria

Streptococcus pneumoniae

As for antibody deficiencies,

Staphylococcus

Haemophilus influenzae

plus:

aureus

Moraxella catarrhalis

Salmonella typhi

Pneumoniae

Pseudomonas aeruginosa

Listeria monocytogenes

aeruginosa

Staphylococcus aureus

Nocardia asteroides

Neisseria meningitidis

Salmonella typhi

Mycoplasma

pneumoniae

Campylobacter

Mycobacteria

Nontuberculous, including

Nontubercolous,

BCG

Fungi

Candida

Aspergillus

Pneumocystis jirovecii

CMV: cytomegalovirus; EBV: Epstein-Barr virus; BCG: bacille Calmette-Guérin. Reproduced and modified

from Notarangelo (2010) with permission from the publisher.

isotype-switching process. Thus, the loss of

Noninfectious associated respiratory

function of memory B-cells seems to represent

diseases might also occur in PID

the major cause of PID-associated clinical

patients and should be taken into

conditions, as demonstrated in common

consideration in the differential

variable immunodeficiency (CVID) patients

diagnosis: nonspecific interstitial

with bronchiectasis: patients with decreased

pneumonia, granulomatous lymphocytic

frequencies of memory B-cells have low levels

interstitial pneumonia, cryptogenic

of IgG/IgM, and high rates of autoimmune

organising pneumonia and lymphocyte

disease and bronchiectasis. Thus, assessment

interstitial pneumonia.

of memory B-cells could be considered a

Medical imaging, especially HRCT, plays a

prognostic factor in CVID patients.

crucial role in the initial detection and

characterisation of changes, and in

In patients with cellular and combined

monitoring the response to therapy. The

immunodeficiencies and in patients with

spectrum of abnormalities seen in thoracic

PID who have undergone a haematopoietic

imaging includes noninfectious airway

stem cell transplant, respiratory viral

disorders, infections, CLD, chronic

infections are major causes of morbidity and

inflammatory conditions, and benign and

mortality. Any virus may be detected and all

malignant neoplasm. Bronchial wall

worsen the clinical outcome. Herpes

thickening and bronchiectasis are the most

viruses, paramyxoviruses and adenoviruses

common pulmonary changes observed in

are common significant pathogens in these

patients with primary humoral

patients. Aggressive antiviral treatments

immunodeficiencies: their presence is

may reduce viral replication and lung

indicative of a poor prognosis and is

damage. Fungal infections can result in

suggestive of the evolution of the disease

significant morbidity and potentially fatal

process to an irreversible stage (e.g. lung

outcomes if misdiagnosed or not correctly

fibrosis). Small airway involvement leads to

treated.

ventilation abnormalities and chronic

510

ERS Handbook: Respiratory Medicine

obstructive disease, which are found in 33-

disturbance, an obstructive pattern or

43% of patients with PAD and are almost

pattern mix.

always irreversible. In addition, air trapping,

Treatment

emphysema, bullae, ground-glass nodules

and parenchymal abnormalities are

In PID where the defect is an inability to

common.

produce an effective antibody response to

pathogens, IgG can be replaced. However,

Granulomatous-lymphocytic interstitial lung

despite IgG replacement, the percentage of

disease (GLILD) is a ‘sarcoid-like’

patients with CLD and bronchiectasis

inflammatory process with nodular

increases over time (.50% in adults and

lymphocytic infiltrates, bronchus-associated

30-40% in children). The overall probability

lymphoid tissue (BALT) hyperplasia and

of developing CLD reaches ,80% after

peribronchiolar lymphocytic infiltrates,

17 years of follow-up. In fact, substitutive

perivascular granuloma, and lymphocytic

therapy with IgG reduces the risk of acute

interstitial pneumonia. It is present in as

respiratory infections, particularly of

many as 8% of patients with PAD. The

pneumonia, but has a low efficacy in the

presence of sarcoid-like granulomatosis is

reduction of chronic lung complications,

indicative of a dismal prognosis, with

infective exacerbations and asthma

terminal respiratory insufficiency developing

promoted by vicious circle infection-

in ,24% of cases. By HRCT, interstitial

inflammation (protease release from

nonspecific pneumonia findings include

polymorphonucleates, epithelial damage,

ground-glass opacities (in one-third of

epithelial cuboidalisation, mucus

cases, these are the only abnormalities),

accumulation predisposing to recurrent

lobe volume loss, a reticular pattern,

infections and chronic inflammatory

traction bronchiectasis, and areas of fibrosis

phenomena favouring remodelling).

predominantly at the basal level with a

subpleural, peribronchovascular

Treatment strategies for progressive GLILD

distribution.

in CVID include corticosteroids,

methotrexate, azathioprine, leflunomide or

Lung alterations in patient with PID might

mofetil mycophenolate. Biological therapies

be evaluated also by MRI, a radiation-free

have been used in single patients or in small

alternative to CT. Lung function tests are

trials. Aside from immunoglobulin

also useful: they show ventilatory

replacement, a strategy to reduce lung

Table 2. Clinical presentation and clinical respiratory diagnosis in primary antibody deficiencies

Symptoms and signs

Respiratory clinical diagnosis

Recurrent chest infection

Bronchiectasis

Productive cough

Recurrent chest infection/pneumonia

Wheeze

Asthma

Weight loss

Granulomatous lung disease

Rhinosinusitis

Emphysema

Otitis media

Previous TB

Progressive dyspnoea

Cavitating lung lesion

Hypoxaemia

Rhinosinusitis

TLCO alteration

Polycythaemia

Cyanosis

ERS Handbook: Respiratory Medicine

511

damage should be approached. Prophylactic

Pilette C, et al.

(2001). Lung mucosal

antibiotics, macrolides as anti-inflammatory

immunity: immunoglobulin-A revisited.

agents, inhaled corticosteroids,

Eur Respir J; 18: 571-588.

bronchodilators, mucolytic agents, or

Plebani A, et al. (2002). Clinical, immu-

mechanical or rehabilitative respiratory

nological, and molecular analysis in a

methods need to be considered.

large cohort of patients with X-linked

agammaglobulinemia: an Italian multi-

In conclusion, a PID diagnosis should be

center study. Clin Immunol; 104: 221-230.

considered in patients presenting with

Primary immunodeficiency diseases.

severe and recurrent respiratory infections,

Report of an IUIS Scientific Committee.

International Union of Immunological

with granulomatous diseases or with life-

Societies. Clin Exp Immunol; 118: Suppl.

threatening invasive pulmonary infections

1, 1-28.

(table 2).

Quinti I, et al. (2007). Long-term follow-

up and outcome of a large cohort of

Further reading

patients with common variable immuno-

deficiency. J Clin Immunol; 27: 308-316.

Alachkar H, et al.

(2006). Memory

Quinti I, et al.

(2011). Effectiveness of

switched B cell percentage and not serum

immunoglobulin replacement therapy on

immunoglobulin concentration is asso-

clinical outcome in patients with primary

ciated with clinical complications in

antibody deficiencies: results from a

children and adults with specific antibody

multicenter prospective cohort study. J

deficiency and common variable immu-

Clin Immunol; 31: 315-322.

nodeficiency. Clin Immunol; 120: 310-318.

Sanchez-Ramon S, et al. (2008). Memory

Associazione Italiana Ematologia Oncolgia

B cells in common variable immunodefi-

Pediatrica. www.aeiop.org

ciency: clinical associations and sex

Carsetti R, et al. (2005). The loss of IgM

differences. Clin Immunol; 128: 314-321.

memory B cells correlates with clinical

Serra G, et al.

(2011). Lung MRI as a

disease in common variable immuno-

possible alternative to CT scan for

deficiency. J Allergy Clin Immunol;

115:

patients with primary immune deficien-

412-417.

cies and increased radiosensitivity. Chest;

Costa-Carvalho BT, et al.

(2011).

140: 1581-1589.

Pulmonary complications in patient with

Thickett KM, et al.

(2002). Common

antibody deficiency. Allergol Immunopathol

variable immune deficiency: respiratory

(Madr); 39: 128-132.

manifestations, pulmonary function and

Crooks BN, et al. (2000). Respiratory viral

high-resolution CT scan findings. QJM;

infections in primary immune deficien-

95: 655-662.

cies: significance and relevance to clinical

Vodjgani M, et al.

(2007). Analysis of

outcome in a single BMT unit. Bone

class-switched memory b cells in patients

Marrow Transplant; 26: 1097-1102.

with common variable immunodeficiency

Guillaume B, et al.

(2009). Thoracic

and its clinical implications. J Investig

manifestations of primary humoral

Allergol Clin Immunol; 17: 321-328.

immunodeficiency: a comprehensive

Wood P, et al.

(2007). Recognition,

review. RadioGraphics; 29: 1909-1920.

clinical diagnosis and management of

Notarangelo LD (2010). Primary immu-

patients with primary antibody deficien-

nodeficiencies. J Allergy Clin Immunol;

cies: a systematic review. Clin Exp

125: Suppl. 2, S182-S194.

Immunol; 149: 410-423.

512

ERS Handbook: Respiratory Medicine

HIV-related disease

Marc C.I. Lipman and Rob F. Miller

Most HIV-infected people experience at

Key points

least one significant episode of respiratory

disease during their lifetime. Although the

In populations with access to

widespread use of effective combination

antiretroviral therapy, use of

antiretroviral therapy (CART) has led to a

combination antiretroviral therapy

50-90% fall in the incidence of many HIV-

(CART) has led to a marked reduction

associated opportunistic infections and

in the incidence of many HIV-

some malignancies, the associated

associated pulmonary diseases and

reduction in short-term mortality means that

improved overall outcome following a

people with HIV infection are now living

severe respiratory event.

longer, and so are developing (often at an

increased frequency) noninfectious

Despite CART, bacterial infections

pulmonary conditions usually present in

remain more common in HIV-infected

older age. Thus, HIV patients with

people than in the general population.

respiratory symptoms require careful,

In response to starting CART, there

systematic investigation to exclude a wide

may be an overexuberant and

variety of illnesses and pathogens.

uncontrolled immune response to

This chapter will focus upon common causes

exogenous antigen. This phenomenon

of HIV-related respiratory disease (table 1).

of immune reconstitution disease can

For an individual, the scope and scale of the

mimic a variety of other conditions

problem depends on a number of factors

and may be life threatening.

including their risk of exposure to pathogens

TB may occur at any stage of HIV

(e.g. through geography or lifestyle, such as

infection. Cases should be managed

injecting drug use; their ability to obtain and

in line with appropriate public health

consistently use CART successfully; the use of

and infection control guidance.

specific preventive therapies such as co-

trimoxazole; and co-factors such as cigarette

Noninfectious respiratory

smoking). Unfortunately, there are still a large

complications of HIV are increasingly

number of people who present with severe

recognised in an ageing population.

respiratory disease and undiagnosed HIV

Many of these, such as COPD and

infection. This is avoidable and should be

lung cancer, are linked to smoking,

regarded as a failure of societal medical care.

and can run an accelerated course

compared with the general

In the following sections we use blood

population.

absolute CD4 counts to categorise the

Quitting smoking is an important

stages of HIV infection. This is a reasonably

component of long-term respiratory

accurate measure of systemic and local

health maintenance.

immunity (in HIV-uninfected individuals,

the CD4 count is typically .500 cells?mL^-1).

In HIV-infected subjects with preserved

immunity, typical community-acquired

ERS Handbook: Respiratory Medicine

513

Table 1. Common causes of HIV-associated respiratory disease

Infectious conditions

Non-infectious conditions

Upper respiratory tract infection

Malignancy

Acute sinusitis

Kaposi sarcoma

Chronic sinusitis

Lymphoma

Acute bronchitis

Bronchial carcinoma

Bronchiectasis

Nonmalignant conditions

Bacterial pneumonia

COPD

Streptococcus pneumoniae

HIV-associated pneumonitis e.g. NSIP and LIP

Haemophilus influenzae

Pulmonary arterial hypertension

Viral infection

Pneumothorax

Influenza A

HIV therapy causing respiratory symptoms e.g. IRD

Fungal infection

Pneumocystis pneumonia

Histoplasma capsulatum

Cryptococcus neoformans

NSIP: nonspecific interstitial pneumonitis; LIP: lymphocytic interstitial pneumonitis; IRD: immune

reconstitution disease

infections occur but at a greater frequency

Streptococcus pneumoniae and Haemophilus

than in the general population. With

influenzae. Infection with Staphylococcus

advancing HIV-induced immuno-

aureus and Gram-negative organisms may

suppression (CD4 counts ,200 cells?mL^-1),

occur in advanced HIV disease.

the risk of opportunistic infections and

Mycoplasma, Legionella and Chlamydia

malignancy rapidly increases.

species are probably no more frequent.

Infections

Bacteraemia is reported to be up to 100

times more common in HIV-infected

Bacterial infection Upper respiratory tract

patients with bacterial pneumonia,

infections, acute bronchitis, and acute and

irrespective of blood CD4 count. These data

symptomatic chronic sinusitis occur more

come from studies performed prior to CART.

frequently in HIV-infected patients than in

Even so, it highlights the importance of

the general population.

undertaking a full set of investigations

Bronchiectasis is increasingly recognised in

(including blood cultures) in HIV-infected

patients with advanced HIV disease. It

individuals presenting with community-

probably arises as a consequence of

acquired pneumonia.

recurrent Pneumocystis jiroveci pneumonia or

bacterial infection.

Complications of bacterial infection include

intrapulmonary cavitation, abscess

Compared with HIV-negative populations,

formation and empyema. There is a high

bacterial pneumonia is six to 10 times more

relapse rate, despite appropriate antibiotic

frequent in HIV-infected subjects not using

therapy.

CART. Injecting drug users are particularly

vulnerable (with a risk approximately double

Immunisation with pneumococcal vaccine is

that of other HIV-infected people). The

recommended in all adults and adolescents

presentation of HIV-associated community-

(at diagnosis of HIV infection and after

acquired bacterial pneumonia is similar to

5 years). Conjugate vaccines appear to offer

that in HIV-negative subjects. However, the

better protection than polysaccharide

chest radiograph may be atypical, and

vaccines. Humoral responses and clinical

mimic P. jiroveci pneumonia in up to half of

efficacy are probably impaired in those with

cases. The usual pathogens isolated are

CD4 counts ,200 cells?mL^-1, although

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ERS Handbook: Respiratory Medicine

vaccination can be successfully re-

Once hospitalised, development of

administered to subjects on CART who have

pneumothorax, admission to the intensive

not developed protective immunity from

care unit and the need for mechanical

prior vaccination when not using CART.

ventilation are associated with a worse

outcome.

Viral infection The recent influenza A H1N1

pandemic has served as a reminder that

PCP can be stratified clinically as mild (PaO₂

opportunistic viral infections, such as

.11.0 kPa, SaO₂ .96% breathing air at

Cytomegalovirus pneumonitis, are, for many

rest), moderate (PaO₂ 8.0-11.0 kPa, SaO₂

HIV-infected individuals, much less of an

91-96%) or severe (PaO₂ ,8.0 kPa, SaO₂

issue than common viral pathogens. H1N1

,91%). This categorisation is helpful, as

appears to have a similar presentation and

oral therapy may be given to those with mild

outcome when associated with HIV co-

disease. The first-choice treatment for PCP

infection. CART probably offers little specific

of all severity is high-dose co-trimoxazole

protection and annual influenza

(sulphamethoxazole 100 mg?kg^-1?day^-1 with

immunisation is recommended.

trimethoprim 20 mg?kg^-1?day^-1) in two to

four divided doses orally or intravenously for

Fungal infection P. jiroveci, formerly

21 days. Approximately two-thirds of

P. carinii, is the cause of Pneumocystis

patients will successfully complete this

pneumonia (PCP). It remains a common

regimen. Treatment-limiting drug toxicity

problem in individuals unaware of their HIV

(e.g. intense gastro-intestinal upset, rash,

serostatus and also among HIV-infected

bone marrow suppression, or renal or liver

patients intolerant of, or nonadherent with,

dysfunction) is common, while ,10% who

PCP prophylaxis and/or CART.

tolerate therapy do not respond to treatment

Patients present with nonproductive cough

(defined by deterioration o5 days after

and progressive exertional breathlessness of

initiation).

several days’ to weeks’ duration, with or

without fever. On auscultation, the chest is

In patients with drug toxicity or poor

usually clear; occasionally, end-inspiratory

response to co-trimoxazole, alternative

crackles are audible. In early PCP, the chest

therapy in mild/moderate disease includes

radiograph may be normal (,10% of cases).

clindamycin (450-600 mg four times daily

The most common abnormality is bilateral

orally or i.v.) plus oral primaquine (15 mg

perihilar, interstitial infiltrates, which may

daily), oral dapsone (100 mg daily) with

progress to diffuse alveolar shadowing over

trimethoprim (20 mg?kg^-1?day^-1), or oral

a period of days. Atypical radiographic

atovaquone suspension (750 mg twice

appearances include upper zone infiltrates

daily). In severe disease, alternative therapy

resembling TB, hilar/mediastinal lymph-

is clindamycin with primaquine or i.v.

adenopathy, intrapulmonary nodules and

pentamidine (4 mg?kg^-1 daily).

lobar consolidation (present in up to 20% of

Patients with an admission PaO₂ f9.3 kPa

cases).

should also receive adjunctive gluco-

Treatment is usually started empirically in

corticoids within 72 h of starting specific

patients with typical clinical and radiological

anti-PCP treatment. A frequently used

features and a CD4 count of ,200 cells?mL^-1,

regimen is prednisolone, 40 mg twice daily

pending diagnosis by cytological analysis of

for 5 days, then 40 mg daily on days 6-10,

bronchoalveolar lavage (BAL) fluid or

and 20 mg daily on days 11-21. This has

induced sputum samples.

been shown to reduce mortality. Patients

should be monitored carefully for steroid-

Several factors present at, or soon after,

related adverse events, including hyper-

hospitalisation predict poor outcome from

tension, hyperglycaemia, and local and

PCP. These include increasing patient age, a

systemic viral reactivation.

second or third episode of PCP, hypoxaemia,

low haemoglobin, co-existent pulmonary

Co-trimoxazole, dapsone and primaquine should

Kaposi sarcoma and medical comorbidity.

be avoided in patients with glucose-6-phosphate

ERS Handbook: Respiratory Medicine

515

dehydrogenase deficiency, and testing for

(.200 cells?mL^-1) and undetectable

the enzyme deficiency is recommended as

plasma HIV RNA for o3 months (note

standard practice.

that if CD4 count subsequently falls

below 200 cells?mL^-1 and/or the HIV RNA

Patients are at increased risk of PCP as their

load increases, prophylaxis should be re-

blood CD4 count decreases.

instituted)

Regimens for PCP prophylaxis are listed in

N based on the rates of recurrent PCP noted

table 2.

within observational cohorts, some

clinicians will discontinue treatment if the

Indications for primary prophylaxis are:

HIV load is undetectable and blood CD4

is .100 cells?mL^-1

N blood absolute CD4 count

,200 cells?mL^-1

It is recommended that, if possible, all

N blood CD4 count ,14% of total

patients with an episode of PCP start CART

lymphocyte count

within 2 weeks of completing their anti-

N unexplained fever (.3 weeks’ duration)

Pneumocystis treatment.

N persistent or recurrent oral/pharyngeal

Candida

Tuberculosis All patients with TB and

N history of another AIDS-defining

unknown HIV status should be offered an

diagnosis, e.g. Kaposi sarcoma

HIV test. Active TB is estimated to occur

between 20 and 40 times more frequently in

The indication for secondary prophylaxis is:

HIV-infected subjects. Worldwide, almost

15% of new TB cases occur in HIV-infected

N all patients who have had a previous

subjects. TB accounts for ,25% of all HIV-

episode of PCP

related deaths. TB is also covered in other

Indications for discontinuing secondary

chapters, so here the focus is on issues of

prophylaxis are:

particular relevance in HIV infection.

N patients on CART with a sustained

More than two-thirds of patients with TB

increase in blood CD4 count

and HIV co-infection present with

Table 2. Recommended PCP prophylaxis regimens

Drug

Dosage

Notes

First

Co-trimoxazole

960 mg once

Protects against certain bacterial

choice

(sulphamethoxazole +

daily^#

infections and reactivation of

trimethoprim 5:1)

480 mg once daily

toxoplasmosis

960 mg thrice

Adverse effects include nausea

weekly

(40%), rash (up to 20%), bone

marrow suppression (20%)

Second

Aerosolised pentamidine

300 mg once per

Use once per fortnight if CD4

choice

month via jet

count ,50 cells?mL^-1

nebuliser

Dapsone

100 mg once daily Plus oral pyrimethamine 25 mg

once per week against

reactivation of toxoplasmosis

Third

Atovaquone

Suspension

choice

750 mg twice

daily

Azithromycin

1250 mg once per

week

^#: the use of lower doses of co-trimoxazole may be associated with fewer adverse events.

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ERS Handbook: Respiratory Medicine

pulmonary disease. When blood CD4 counts

patient is shown to have rifampicin

are normal or only slightly reduced (e.g.

resistance using the probe, then an early

.350 cells?mL^-1), clinical features are similar

decision can be made to treat for multidrug-

to adult post-primary disease. Chest

resistant TB in the first instance and

radiography often shows upper lobe

appropriate samples set up for mycobacterial

infiltrates and cavitary changes. Sputum and

culture and sensitivity testing, which may not

BAL fluid are often smear positive.

be a part of local, routine care.

In advanced HIV disease, and/or with a low

Point-of-care rapid antigen assays using

blood CD4 count (,200 cells?mL^-1), the

relatively easily obtained body fluids

presentation is often with nonspecific

(e.g. the mycobacterial cell wall antigen

malaise, fatigue, weight loss and fever.

lipoarabinomannan tested in urine) may be

Chest radiographic abnormalities may not

of more value in HIV-infected than

be specific for TB and include diffuse or

-uninfected individuals with suspected active

miliary-type shadowing, mediastinal/hilar

TB. However, despite good specificity, their

lymphadenopathy and pleural effusions;

sensitivity appears generally low other than in

cavitation is uncommon. Sputum or BAL

patients with TB and advanced HIV infection

fluid is often smear negative though culture

(presumably due to such individuals having a

positive. Extrapulmonary TB is common in

greater mycobacterial load).

patients with CD4 counts ,100 cells?mL^-1.

Local or disseminated infection may involve

The wider use of rapid mycobacterial

lymph nodes and bone marrow, blood

detection systems has led to the discovery

cultures may be positive and it is worth

that ‘subclinical’ TB is common in HIV-

obtaining specimens from as many body

infected subjects from TB endemic areas.

sites or fluids as clinically practical. For

Here, patients are generally well but have

example, the yield from early-morning urine

viable bacilli isolated from, for example,

cultures is reasonable.

sputum and, hence, require treatment for

TB. This has been reported in up to 20% of

If smears or unspeciated mycobacterial

patients being screened for active TB prior

cultures are positive, treatment should

to starting CART. In lower TB prevalence

initially include a four-drug anti-TB regimen

areas, it is less common and probably

with a rifamycin (either rifampicin or

occurs in, at most, 5% of such individuals.

rifabutin) plus isoniazid, pyrazinamide and

ethambutol, until mycobacterial

Short- and long-term response to treatment

identification and drug sensitivities are

with a 6-month four-drug regimen is

known. TB diagnosis using rapid nucleic

generally good, although patients with

acid amplification tests are increasingly

disseminated disease are often treated for

sensitive in HIV infected individuals,

9-12 months. Given the reported increased

although, generally, this remains less than in

risk of developing drug-resistant disease, it

HIV-negative TB patients. The molecular

is recommended that HIV patients with high

probes can distinguish Mycobacterium

mycobacterial loads (e.g. disseminated

tuberculosis from opportunistic mycobacteria

disease, as is often present in patients with

and identify common mutations in the rpoB

low blood CD4 counts) receive daily and not

gene associated with rifampicin resistance,

higher-dose (twice- or thrice-weekly)

as well as isoniazid (katG and inhA genes)

intermittent therapy. Compared with non-

and mutations associated with resistance to

HIV-infected individuals, there is possibly a

other anti-TB drugs, depending on the test

greater incidence of adverse reactions to

kit used.

anti-TB drugs and an increased risk of death.

Rapid molecular diagnostic assays, such as

CART reduces short- and long-term

the Xpert MTB/RIF (Cepheid, Sunnyvale, CA,

mortality in co-infected patients and should

USA), are increasingly simple to use in a field

be started as soon as possible in subjects

setting. They enable often scarce resources to

receiving treatment for active TB. Generally,

be allocated effectively; for example, if a

the lower the blood CD4 count, the more

ERS Handbook: Respiratory Medicine

517

pressing is the clinical need to start CART

nonspecific cough and progressive

(e.g. if blood CD4 ,200 cells?mL^-1, then

dyspnoea; haemoptysis is uncommon.

commence within 2-4 weeks of start of anti-

TB treatment).

As Kaposi sarcoma may involve both the

airways and lung parenchyma; radiological

Issues with early use of CART in TB patients

findings include interstitial or nodular

include:

infiltrates and alveolar consolidation. Hilar/

mediastinal lymphadenopathy occurs in

N high pill burden

,25% of patients and up to 40% have a

N overlapping toxicities, e.g. neuropathy

pleural effusion.

N drug-drug interactions, e.g. CART and

Diagnosis is confirmed at bronchoscopy in

rifamycins

.50% cases by the appearance of multiple,

N poor adherence to complex regimens

raised or flat, red or purple endotracheal and

N increased risk of immune reconstitution

endobronchial lesions. Biopsy is rarely

disease (IRD) (see later, and of particular

performed since cutaneous Kaposi sarcoma

relevance when starting CART within days

is usually present and diagnostic yield from

of anti-TB treatment in cerebral TB)

biopsy is ,20%. CART may induce

Multidrug- and extensively drug-resistant TB

remission of lesions and is used in addition

have been associated epidemiologically with

to chemotherapy.

HIV infection. This is probably due to the

Lymphoma High-grade B-cell non-Hodgkin

rapid development of active (and, hence,

lymphoma is the most common HIV-

infectious) TB in the HIV co-infected

associated thoracic lymphoma and is usually

population exposed to drug-resistant cases

found in association with disease elsewhere.

and, hence, reflects general susceptibility to

Presenting symptoms are nonspecific. Chest

developing mycobacterial disease rather

radiographic abnormalities include

than to infection with specific drug-resistant

mediastinal lymphadenopathy, pleural

strains.

masses or effusions. The prognosis is

considerably better if patients treated with

Given the high risk of latent TB infection

chemotherapy also receive CART.

(LTBI) progressing to active disease, the

World Health Organization recommends

Bronchial carcinoma Lung cancer appears to

that HIV-infected patients with LTBI should

be around twice as common in HIV-infected

receive preventive treatment. As, by

compared with HIV-negative smokers. It is

definition, LTBI diagnosis requires a positive

now more frequently diagnosed than in the

immune response (e.g. tuberculin skin test or

pre-CART era and probably reflects the

blood interferon-c release assay) in an

protection CART offers from other

asymptomatic individual, these assessments

conditions that otherwise would have

can be affected by the immune dysregulation

occurred. The clinical presentation is often

present in HIV co-infected subjects.

late and, despite specific treatment, plus the

use of CART if not already prescribed, the

Malignant conditions

prognosis is, therefore, generally poor.

Kaposi sarcoma Kaposi sarcoma is the most

Nonmalignant, noninfectious conditions

common HIV-associated malignancy. Before

the advent of CART, 15-20% of AIDS

Chronic obstructive pulmonary disease HIV-

diagnoses were due to Kaposi sarcoma. It is

infected smokers are at increased risk

associated with human herpes virus-8 (also

(approximately 20-30%) of developing

called Kaposi sarcoma-associated virus) co-

COPD. Although this does not approach the

infection. Pulmonary Kaposi sarcoma is

relative risk associated with many respiratory

almost always accompanied by cutaneous or

infections, in a similar manner to lung

lymphadenopathic Kaposi sarcoma (palatal

cancer, the onset of symptoms appears to be

disease strongly predicts the presence of

at a younger age. Some studies suggest that

pulmonary lesions). Presentation is with

such individuals have a greater degree of

518

ERS Handbook: Respiratory Medicine

breathlessness and functional disability

means that CART is now a global standard of

compared with HIV-negative COPD patients

care for most HIV-infected people. The

with equivalent lung function.

changes in immunity that occur when it is

first started can be intense. In up to 30%

The large number of HIV-positive ageing

subjects who have documented or subclinical

smokers together with the synergistic effects

co-infection, the immune response may be

of smoking, recurrent bacterial and

overexuberant and manifest as a clinical

opportunistic infections, injecting drug use,

deterioration in health status. This has been

and possibly the direct effect of HIV in the

given several names including immune

lung (plus also the inflammatory response

reconstitution inflammatory syndrome and

generated by use of CART), argue strongly

IRD. It has been reported to occur with a

for scaling up smoking cessation services.

number of conditions, but particularly

This is important as in many developed-

mycobacterial disease and chronic fungal

world settings, smoking rates in HIV-

and viral infections.

infected populations are higher than

national averages. Smoking cessation will

The underlying mechanism is not

also impact on other smoking-related

completely understood, and its clinical

illnesses such as cardiovascular disease,

features represent both innate and acquired

which are increasingly prevalent in HIV-

host responses to exogenous antigen. The

infected communities.

‘paradoxical’ type of IRD is similar to that

seen in non-HIV-infected patients being

HIV-associated pneumonitis Nonspecific

treated for TB but is generally more intense.

pneumonitis mimics PCP but often occurs

Here, subjects with known TB improving on

at higher blood CD4 counts. Diagnosis

treatment start CART and within a median of

requires transbronchial, video-assisted

2-3 weeks develop new clinical

thoracoscopic or open-lung biopsy. Most

manifestations, e.g. peripheral lymph-

episodes are self limiting, but prednisolone

adenopathy, pleural or pericardial effusions

may be beneficial.

or cerebral disease. There is no specific

Lymphocytic interstitial pneumonitis is

diagnostic test and so drug resistance,

generally seen in HIV-infected children and

patient nonadherence to treatment and

clinically resembles idiopathic pulmonary

other disease processes must be actively

fibrosis. Diagnosis requires biopsy.

excluded. It is more likely in people with low

Treatment with CART is often effective.

baseline CD4 counts (,100 cells?mL^-1),

faster suppression of HIV viral load and

Pulmonary arterial hypertension Pulmonary

shorter time between starting anti-TB

arterial hypertension is reported to be six to

therapy and CART. IRD can be severe,

12 times more common in HIV-infected

though is rarely fatal. When this does

populations. The presentation and

happen it is generally due to the pressure

management are similar to

effects associated with a rapid increase in

immunocompetent individuals, although

size of the inflammatory lesions. Hence,

CART is associated with improved

care must be taken with IRD associated with

haemodynamics and survival.

cerebral, pericardial and, sometimes,

Pneumothorax occurs more frequently in

mediastinal disease. Treatment is largely

HIV-infected patients than in the age-

symptomatic and may involve oral

matched general medical population.

glucocorticoid therapy.

Cigarette smoking and receipt of nebulised

A second form of IRD is the ‘unmasking’ of

pentamidine are risk factors. PCP should be

TB. Here, a patient with latent, asymptomatic

excluded in any patient presenting with a

infection will rapidly develop highly

pneumothorax.

inflammatory active TB a median of 3-

HIV therapy causing respiratory symptoms

6 weeks after starting CART. Treatment is

The clear beneficial impact of antiretroviral

generally directed at the underlying

therapy on long-term morbidity and mortality

mycobacterial infection. In TB-endemic areas,

ERS Handbook: Respiratory Medicine

519

such as sub-Saharan Africa and South-East

Crothers K, et al.

(2011). Longitudinal

Asia, screening subjects for subclinical TB

studies of HIV-associated lung infections

prior to CART initiation is important. Studies

and complications in the era of anti-

have indicated that up to one in five of

retroviral therapy. Proc Am Thorac Soc; 8:

individuals who are minimally symptomatic

275-281.

will have sputum culture-positive TB and,

Dockrell DH, et al. (2011). British HIV

hence, require treatment. The use of rapid

Association guidelines for the treatment

of opportunistic infection in HIV-positive

molecular and mycobacterial diagnostic tests

individuals 2010: pulmonary opportunis-

(described earlier in this chapter) are a useful

tic infections. HIV Med;

12: Suppl.

and effective means of excluding TB in people

1-140.

who need to start CART.

Kaplan JE, et al. (2009). Guidelines for

prevention and treatment of opportunis-

The antiretroviral nucleoside analogue

tic infections in HIV-infected adults and

abacavir can cause a hypersensitivity

adolescents: recommendations from

reaction (in up to 3% of subjects) with fever,

CDC, the National Institutes of Health,

rash and pulmonary symptoms. In these

and the HIV Medicine Association of the

cases, recovery occurs if the drug is

Infectious Diseases Society of America.

withdrawn. It should not be given again.

MMWR Recomm Rep; 58: 1-207.

Lipman MCI, et al. An Atlas of Differential

Diagnosis in HIV Disease.

2nd Edn.

Further reading

London, Parthenon Publishing, 2004.

Benfield T. Noninfectious conditions in

Miller RF, et al. Pulmonary infections

patients with human immunodeficiency

in patients with human immunodefi-

virus infection. In: Spiro SG, et al., eds.

ciency virus disease. In: Spiro SG,

Clinical Respiratory Medicine.

4th Edn.

et al.,

eds. Clinical Respiratory

Philadelphia, Elsevier Saunders, 2012.

Medicine.

4th Edn. Philadelphia,

Benfield T, et al.

(2008). Second-line

Elsevier Saunders, 2012.

salvage treatment of AIDS-associated

Pozniak AL, et al.

(2011). British HIV

Pneumocystis jirovecii pneumonia: a case

Association guidelines for the treatment

series and systematic review. J Acquir

of TB/HIV coinfection 2010. HIV Med; 12:

Immune Defic Syndr; 48: 63-67.

517-524.

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ERS Handbook: Respiratory Medicine

Graft versus host disease

Federica Pulvirenti, Cinzia Milito, Maria Anna Digiulio and Isabella Quinti

Pathogenesis

Key points

Graft versus host disease (GVHD) is the

principal complication of allogeneic

Graft versus host disease (GVHD) is

haematopoietic stem cell transplantation

the principal complication of

(HSCT): it limits HSCT success and is fatal

allogeneic HSCT.

to ,15% of transplant recipients. The

number of patients at high risk for GVHD is

Vascular endothelial damage and

increasing, as more HSCTs are performed

increased secretion of pro-

from unrelated donors, mainly in older

inflammatory cytokines are involved

patients. GVHD results from immunological

in the pathogenesis of lung disorders.

attack on target recipient organs or tissues

Acute and subacute patterns of lung

(such as the skin, liver and gut) by donor

injury include: idiopathic interstitial

allogeneic T-cells that are transferred along

pneumonia, bronchiolitis obliterans

with the allograft. The development and

syndrome, organising pneumonia,

severity of GVHD in transplant recipients

alveolar haemorrhage, capillaritis,

depends on many factors, such as recipient

post-transplant lymphoproliferative

age, toxicity of the conditioning regimen,

disorders.

haematopoietic graft source and GVHD

prophylaxis approaches.

CMV infection is the most frequent

viral complication in patients

GVHD is divided into acute and chronic

undergoing HSCT and acute GVHD

forms. Acute GVHD and chronic GVHD

significantly affects active CMV

involve distinct pathological processes:

infection recurrence.

acute GVHD has strong inflammatory

components, whereas chronic GVHD

GVHD has beneficial effect of on the

displays more autoimmune and fibrotic

incidence of leukaemia relapse and

features.

increase the overall survival of

patients with leukaemia: this

Chronic GVHD is defined as occurring after

phenomenon is known as the graft-

the first 100 days post-HSCT and has a

versus-tumour effect.

characteristic clinical presentation, which

New insights from basic immunology,

resembles autoimmune vascular diseases

preclinical models and clinical studies

and is distinct from that observed in acute

have led to novel approaches for

GVHD. Chronic GVHD occurs in 30-65% of

prevention and treatment.

allogeneic HSCT recipients, can be highly

debilitating in its extensive form and has a

5-year mortality rate of 30-50%, mainly due

to immune dysregulation and opportunistic

immune responses, whereas chronic GVHD

infections.

was thought to be predominately medi-ated

Acute GVHD was thought to be a process

by Th2-type responses. Vascular endothelial

driven mainly by T-helper(Th)1- and Th17-type

damage and increased secretion of

ERS Handbook: Respiratory Medicine

521

pro-inflammatory cytokines are involved in

the induction of CD4⁺ T-cell-dependent

systemic disorders post-HSCT, including

acute GVHD. Recent studies have shown

GVHD and cytomegalovirus (CMV) infection.

that host haematopoietic professional APCs

The pathology of acute GVHD can be

in lymphoid organs may have only a limited

considered in a framework of sequential

capacity to induce GVHD, and host

phases. Initially, the recipient-conditioning

dendritic cells (DCs) may not be required.

regimen damages host tissues and causes

Parenchymal tissue cells can acquire APCs

release of pro-inflammatory cytokines; host

functions and they have been shown to

antigen-presenting cells mature, acquire

promote a marked expansion of allo-reactive

adhesion and co-stimulatory molecules that

donor T-cell populations in the

activate mature donor T-cells; these cells

gastrointestinal tract. In the absence of

proliferate and produce additional cytokines

functional host haematopoietic APCs, the

inducing inflammatory and cellular effectors

presentation of minor histocompatibility

that amplify the inflammatory responses that

antigens by donor haematopoietic APCs or

cause tissue damage.

host non-haematopoietic APCs is sufficient

for GVHD induction.

The pivotal role of T-cells in acute GVHD is

supported by the complete abrogation of

The graft versus tumour effect

GVHD following T-cell depletion from the

Obstacles to the improvement of HSCT

graft, an approach that remains the most

treatment include the linkage between

effective in preventing acute GVHD.

GVHD toxicity and the beneficial graft versus

leukaemia effect, as well as the impairment

Tissue damage caused by the cytotoxic

of immune reconstitution leading to life-

T-cells leads to the recruitment of other

threatening infections.

effector cells (including natural killer (NK)

cells and neutrophils), which further

The long-known beneficial effect of GVHD

increase tissue injury and result in a self-

on the incidence of leukaemia relapse and

perpetuating state of GVHD that is difficult

the overall survival of patients with

to control once it is fully initiated

leukaemia is known as the graft versus

tumour (GVT) effect.

Current data implicate the innate immune

response as being responsible for initiating

The role of T-cells in both GVHD and the

or amplify-ing acute GVHD. Molecules such

GVT effect was supported by the finding that

as bacterial lipopoly-saccharide (LPS),

T-cell depletion from the graft eliminates

released from the injured gut during the

GVHD but at the expense of an increased

conditioning regimen, activate innate

leukaemia relapse rate. The major GVT

immune receptors, including Toll-like

effectors are cytotoxic T-cells that recognize

receptors (TLRs), and cause a cytokine

allogeneic histocompatibility antigens and

storm, which favours the devel-opment of

unique tumour antigens. In addition, NK

acute GVHD. Commensal microflora may

cells and NK T-cells can directly recognize

modulate innate response and reduce the

MHC class-I molecules and stress-induced

severity of GVHD by stimulating other TLRs

peptides and mount anti-tumour responses.

(TLR): to re-address the gut flora to make it

less GVHD favourable might be a way to

Current strategies to improve GVT effects

ameliorate GVHD, as suggested by the

are based on selectively targeting tumour-

decreased severity of GVHD and improved

specific killing and inhibiting immune

survival of animals following the

escape mechanisms commonly used by

administration of probiotic bacteria.

tumours. These immune escape

mechanisms include the loss of tumour-

Great progresses have been recently

specific molecules on presented peptides,

achieved in discerning the role of antigen

the downregulation or loss of MHC class-I

presenting cells (APCs) in GVHD: MHC

or co-stimulatory molecules expression by

class II-bearing host haematopoietic APCs

tumour cells, the induction of functional

were previously thought to be essential for

defects in T-cells or NK cells, the production

522

ERS Handbook: Respiratory Medicine

of soluble inhibitors of NK cell function, the

alternative approach to manipulating the

expression of death receptor ligands such as

TH17 cell response is to target the cytokines

CD95 ligand by tumour cells, and tumour

that are involved in the induction of TH17

cell resistance to apoptosis.

cells, such as IL-6. Together with

transforming growth factor (TGF)-b, IL-6

Treatment

promotes the differentiation of naïve T-cells

Systemic corticosteroid therapy, despite its

into TH17 cells. Infusion of an IL-6 receptor-

major shortcomings, remains the standard

specific monoclonal anti-body in a model of

acute GVHD led to increased Treg numbers

primary therapy for GVHD. Patients with

and a reduction in GVHD-induced

steroid-refractory acute GVHD have a

pathological damage, particularly in the gut.

dismal outcome, with long-term mortality

The neutralisation of IL-6 may result in a

rates that can reach 90%.

direct anti-tumour response, particularly in

New and improved therapies are therefore

multiple myeloma.

des-perately needed, particularly in cases of

steroid-refractory chronic GVHD. Most of

Because of the key role for pro-inflammatory

the current therapeutic approaches that are

cytokines in acute GVHD, inhibition of

routinely used for GVHD (like corticosteroid

cytokine-induced signal transduction is an

and the calcineurin inhibitors) are broad-

appealing approach for GVHD treatment.

spectrum approaches that target T-cells and

Janus kinases (JAKs) are cyto-plasmic

are therefore likely have a negative impact

protein tyrosine kinases that initiate

on GVT responses as well as immune

cytokine-triggered signaling events by

reconstitution.

activating the cyto-plasmic latent forms of

STAT proteins. In preclini-cal models, a

Novel approaches to prevent or treat GVHD

small-molecule inhibitor of JAK3 has shown

are linked to the generation of new

great promise in reducing lethality from

monoclonal antibodies, immunomodulatory

GVHD without impeding GVT effects. Small-

therapy, innovative strategies that target

molecule inhibitors of JAK2 or JAK3 may

both soluble and cellular effectors.

therefore prove to be useful in inducing

donor cell tolerance towards the host.

Because of donor CD4⁺ and donor CD8⁺,

T-cells have a crucial role in the

Other tyrosine kinase inhibitors, such as

pathogenesis of GVHD, the most effective

imatinib, which is commonly used to treat

approaches for GVHD prevention and

chronic myeloid leukaemia, have been

therapy focus on the depletion, tolerisation

shown to have marked anti-GVHD effects,

or func-tional incapacitation of donor T-

especially in patients with chronic GVHD.

cells. Recently the role of TH17 cells has

Although the exact mechanism of action of

been highlighted. The TH17 cells are a T-

imatinib in GVHD seems to be independent

lymphocyte helper subset characterised by

of its capacity to inhibit the platelet-derived

the production of interleukin (IL)-17A, IL-

growth factor receptor (PDGFR), imatinib

17F, IL-21 and IL-2; they have been shown to

represents an attractive agent for

have a direct role in GVHD pathogenesis

suppressing chronic GVHD and preserving

and they may yet prove to be a viable target

GVT responses.

for neutralisation in patients with GVHD in

the gut. The TH17-type cytokine, IL-21, is

Proteasome inhibitors, such as bortezomib,

another potential neutralisation target, given

prevent or treat GVHD in mice because they

its role in promoting the activation,

have inhibitory effects on cytokine signaling

differentiation, maturation or expansion of

and nuclear factor (NF)-kB acti-vation.

NK cell, B-cell, T-cell and APC populations.

Bortezomib, even at very low doses, can

Inhibition of IL-21 receptor signaling in vivo

specifically deplete alloreactive T-cells, allow

reduced acute GVHD activity in the gut, and

T-Reg cell survival and attenuate IL-6-

this effect was associated with decreased

mediated T-cell differentia-tion; it can also

TH1 cell and increased regulatory T-cell

inhibit APCs by targeting TLR4-mediated

(Treg) numbers in the gut mucosa. An

activation. Bortezomib and possibly other

ERS Handbook: Respiratory Medicine

523

proteasome inhibitors are attractive

responsible for 50% of transplant related

therapeutic agents and worth testing in

deaths (table 1). Acute and subacute

various clinical HSCT settings.

patterns of lung injury have been

recognised. Idiopathic pneumonia

Modulating the trafficking patterns of

syndrome occurs within the first 120 days

alloreactive T-cells could be an efficacious

after HSCT with a rapidly progressing

mean of ameliorating GVHD. Inhibition of

fulminant course resulting in death in

T-cell homing to inflamed tissues can be

60-80% of patients. By contrast, subacute

accom-plished by interrupting one of four key

noninfectious lung injury (alloimmune lung

stages of T-cell migration: 1) tethering and

syndromes), including idiopathic

rolling on the endothelium; 2) chemokine

pneumonia syndrome, bronchiolitis

ligand-receptor interactions; 3) adhesion to

obliterans syndrome and bronchiolitis

the endothelium; and 4) migration in

obliterans with organising pneumonia, can

response to sphingosine-1-phosphate.

occur in the early post-transplant period or

Other approaches include NK cell infusion

in the months post-HSCT. Although long-

and the in vivo activation of NK cells to

term disease-free survival after HSCT could

promote the deletion of alloreactive T-cells;

exceed 60%, pulmonary infiltrates, due to

infusion of mesenchymal stem cells (MSCs),

either inflammatory or infectious

transfer of donor-derived Treg populations,

pneumonitis, occur in 40-60% of HSCT

infusion of myeloid-derived suppressor cell

recipients causing the 80% of transplant-

(MDSC) populations expanded ex vivo using

related deaths. In children undergoing

granulocyte colony-stimulating factor (G-

HSCT, the incidence of pulmonary

CSF) and granulocyte-macrophage colony-

complications varies from 10% to 25%.

stimulating factor (GM-CSF), sirolimus,

Open lung biopsy has been recommended

anti-tumour necrosis factor and anti-

to make a definitive diagnosis and the

lymphocyte function-associated (anti-LFA)-3

appropriate treatment. Idiopathic interstitial

antibodies, extracorporeal photopheresis.

pneumonitis and CMV pneumonitis are the

most common causes and should be

Non-infectious pulmonary-associated

suspected in patients with diffuse interstitial

complications

infiltrates. Epidemiological data suggest

Common pulmonary complications occur in

that, although GVHD reactions may play an

25-50% of HSCT recipients and are

aetiological role, the major contributing

Table 1. Frequency and mortality due to pulmonary complications after bone marrow transplantation.

Frequency

Mortality

Infectious aetiology

34.3

CMV pneumonitis

71.4

Tuberculosis

33.4

PCP

Aspergillosis

Non infectious aetiology

65.7

30.4

Idiopathic interstitial pneumonitis

14.3

Organising pneumonia

Alveolar haemorrhage

100

Capillaritis

100

Post-transplant lymphoproliferative disorders

100

Data are presented as %. CMV: cytomegalovirus; PCP: Pneumocystis jiroveci pneumonia. Adapted from

Wang et al. (2004)

524

ERS Handbook: Respiratory Medicine

factor is a conditioning-related toxicity.

supplementary factor. Knowledge of these

Moreover, engraftment syndrome, diffuse

complications is now a part of the

alveolar haemorrhage and pulmonary veno-

contemporary practice of pulmonary

occlusive disease are also possible

medicine and no longer isolated to the

complications.

transplant pulmonologists.

Infectious pulmonary-associated

complications

Further reading

Respiratory virus infections in HSCT

Blazar BR, et al. (2012). Advances in graft-

patients are observed in 1-56% of patients.

versus-host disease biology and therapy.

CMV infection is the most frequent viral

Nat Rev Immunol; 12: 443-458.

complication in patients undergoing

Castagnola E, et al.

(2004). Cyto-

HSCT. Despite advanced diagnostic

megalovirus infection after bone marrow

methods and pre-emptive antiviral therapy,

transplantation in children. Human

CMV disease continues to be a life-

Immunol; 65: 416-422.

threatening complication. Clinical

Paczesny S, et al.

(2009). Acute graft-

manifestations could vary from an

versus-host disease: new treatment stra-

asymptomatic infection, defined as active

tegies. Curr Opin Hematol; 16: 427-436.

CMV replication in the blood in the

Takatsuka H, et al. (2000). Complications

absence of clinical manifestations, or

after bone marrow transplantation are

organ failure abnormalities characterised

manifestations of systemic inflammatory

response syndrome. Bone Marrow

by CMV infection with clinical symptoms

Transplant; 26: 419-426.

or organ function abnormalities. Active

Versluys AB, et al. (2010). Strong associa-

CMV infection interacts significantly in

tion between respiratory viral infection

several ways with GVHD. Acute GVHD

early after hematopoietic stem cell trans-

increases the chances of a poor outcome.

plantation and the development of life-

CMV prophylaxis or pre-emptive therapy

threatening acute and chronic alloim-

adopted during the last few years in

mune lung syndromes. Biol Blood

allogeneic HSCT recipients has changed

Marrow Transplant; 16: 782-791.

the natural history of the disease. As

Wang JY, et al. (2004). Diffuse pulmonary

prophylaxis, antiviral drugs are

infiltrates after bone marrow transplanta-

administered before any evidence of the

tion: the role of open lung biopsy. Ann

virus, and in pre-emptive therapy antiviral

Thorac Surg; 78: 267-272.

drugs are administered when there is

Yoshihara S, et al. (2007). Bronchiolitis

laboratory evidence of an active but

obliterans syndrome (BOS), bronchiolitis

asymptomatic infection. Acute GVHD

obliterans

organizing

pneumonia

significantly affects active CMV infection

(BOOP) and other late-onset noninfec-

recurrence. CMV infection recurrence is

tious pulmonary complications following

more frequent with short courses of

allogeneic hematopoietic stem cell trans-

antiviral therapy. The poor bioavailability

plantation. Biol Blood Marrow Transplant;

of oral ganciclovir may account for this;

13: 749-759.

drug resistance may also be a

ERS Handbook: Respiratory Medicine

525

Amyloidosis

Helen J. Lachmann

Amyloidosis is a group of diseases caused

the dye Congo red in a spatially organised

by accumulation of protein as insoluble

manner, which results in the patho-

fibrillar deposits within the extracellular

gnomonic apple-green birefringence when

space. These progressively disrupt the

viewed under cross-polarised light. Amyloid

structure and function of affected tissues.

deposits also always contain the normal

Amyloidosis may be either acquired or

plasma glycoprotein, serum amyloid P

inherited and o26 different proteins can

component (SAP) as a nonfibrillar

form amyloid fibrils in vivo in humans. The

constituent. The universal presence of SAP

ultrastructural morphology and histo-

in amyloid deposits reflects its specific

chemical properties of all amyloid fibrils,

binding to an, as yet, uncharacterised ligand

regardless of the precursor protein type, are

common to all amyloid fibrils, which forms

remarkably similar. Diffraction studies of

the basis for diagnostic scintigraphic

amyloid fibrils have demonstrated a shared

imaging of amyloid with radiolabelled SAP.

common core structure consisting of

Untreated amyloidosis progresses

antiparallel b-strands lying perpendicular to

relentlessly and systemic forms of the

the long axis of the fibril. This extremely

disease are generally fatal, but deposits can

abnormal, highly ordered conformation

regress if the supply of fibril precursors is

underlies the distinctive physicochemical

reduced.

properties of amyloid fibrils: they are

relatively stable and are resistant to

Amyloidosis can present to respiratory

proteolysis, and they all bind molecules of

physicians in a number of ways:

N chronic lung conditions may give rise

Key points

to systemic amyloidosis

N systemic amyloidosis may present with

N Amyloidosis is a protein deposition

respiratory symptoms

disease.

N localised pulmonary and respiratory tract

amyloid deposits may present either

N Diagnosis is by biopsy and Congo red

symptomatically or as an incidental

staining.

finding on imaging

N Systemic amyloidosis is a life

Systemic amyloidosis complicating

threatening condition that usually

respiratory diseases

affects several organs.

AA amyloidosis is a potential complication of

N Localised amyloidosis can present

any sustained inflammatory condition,

with obstructive symptoms,

which usually presents as proteinuric renal

haemoptysis or as an incidental

impairment. The amyloid fibrils are derived

finding on imaging.

from the acute-phase reactant serum

Treatment depends on the type and

amyloid A protein (SAA). The major

distribution of amyloid deposits.

respiratory disease underlying AA

amyloidosis in the industrialised world is

526

ERS Handbook: Respiratory Medicine

longstanding bronchiectasis, which

interstitial pulmonary disease, which may be

underlies 5% of cases. Previously,

steroid responsive.

tuberculosis was common, and other

Amyloidosis localised to the respiratory

associations include lung neoplasia

tract

(Castleman’s tumours, lymphoma and

adenocarcinoma; accounting for 3%

This results either from local production of

of AA amyloidosis cases), CF, sar-

fibril precursors or from properties inherent

coidosis and Kartagener’s syndrome. The

to a particular microenvironment, which

prognosis of AA amyloidosis depends on the

favour fibril formation of a widely distributed

degree of renal damage and whether the

precursor protein. The majority of deposits

underlying inflammatory disease can be

are AL-associated with monoclonal B-cells

completely controlled. Treatment depends

confined to the affected site. Apparently

on the underlying disease and may involve

localised amyloid deposits can be

surgery, antimicrobials or immuno-

manifestations of systemic disease and

suppression.

should always be fully investigated to

Systemic, amyloid light chain (AL)

exclude systemic amyloidosis.

amyloidosis is the commonest type,

Laryngeal amyloidosis

accounting for 60% of cases, and may occur

in association with any B-cell dyscrasia, as

Amyloidosis represents 0.5-1% of benign

the amyloid fibrils are derived from mono-

laryngeal disease and the incidence

clonal immunoglobulin light chains. A

increases with age. It usually presents as

number of chest-localised conditions can

hoarseness and is relatively benign but can

underlie systemic AL amyloidosis, including

be progressive or recur after treatment. Fatal

Sjögren’s syndrome, plasmacytomas and

haemorrhage has been reported.

Castleman’s tumours.

Endoscopic or laser excision is the

Respiratory system symptoms arising from

treatment of choice, aiming to preserve

systemic AL amyloidosis

voice quality and airway patency. Very rarely,

apparently localised laryngeal amyloid

Although lung deposits are universal on post

deposits can be a feature of hereditary

mortem examination, symptoms are rare

apolipoprotein AL amyloidosis.

and dyspnoea generally reflects amyloid

Tracheobronchial amyloidosis

cardiomyopathy. Chest radiographs are

usually normal but can demonstrate diffuse

This typically presents in the fifth or sixth

reticulonodular infiltration. Lung function

decades with dyspnoea, cough and

tests may be restrictive and extensive

haemoptysis. Airway narrowing may cause

alveolar deposits can reduce gas transfer.

pneumonia or lobar collapse and solitary

Persistent pleural effusions are usually due

nodules can mimic endobronchial

to cardiac infiltration by amyloid but can

neoplasia. There is no proven therapy

rarely be caused by amyloidotic disruption of

although chemotherapy has been tried in

the pleura and may require recurrent

patients with progressive disease.

drainage or pleurodesis. Treatment of

Management is dictated by symptoms and

systemic AL amyloidosis is chemotherapy

includes resection, stenting or laser

directed against the underlying B-cell clone.

ablation. Survival is ,45% at 6 years.

Serious pulmonary side-effects from

treatment are rare but fever and asthma-like

Parenchymal pulmonary amyloidosis

symptoms and progression to respiratory

failure with pulmonary infiltrates have been

This is typically an incidental finding on

reported following treatment with the

chest radiography of solitary/multiple

proteasome inhibitor bortezomib. There

nodules or a diffuse alveolar-septal pattern.

have also been descriptions of lung toxicity

Although the lesions must be differentiated

following the use of thalidomide and

from neoplasia, the prognosis is usually

lenalidomide with toxic granulomatous

excellent and no treatment is required.

ERS Handbook: Respiratory Medicine

527

Pulmonary amyloidosis associated with

Gilad R, et al.

(2007). Severe diffuse

Sjögren’s syndrome

systemic amyloidosis with involvement

of the pharynx, larynx, and trachea: CT

This chronic, organ-specific autoimmune

and MR findings. Am J Neuroradiol; 28:

disease predominantly affects females and

1557-1558.

carries a 44-fold increase in lymphoproliferative

Lachmann HJ, et al. (2006). Amyloidosis

disorders. Pulmonary AL amyloidosis is a rare

and the lung. Chron Respir Dis; 3: 203-214.

but well recognised complication, resulting in

Ma L, et al. (2005). Primary localized

cough and dyspnoea.

laryngeal amyloidosis: report of 3 cases

with long-term follow-up and review of

Mediastinal and hilar amyloid

the literature. Arch Pathol Lab Med; 129:

lymphadenopathy

215-218.

O’Regan A, et al.

(2000). Tracheo-

The lymphadenopathy may be massive and

bronchial amyloidosis. The Boston

typically complicates a low-grade lymphoma.

University experience from 1984 to 1999.

Disease progression is slow and calcification

Medicine (Baltimore); 79: 69-79.

frequent. Tracheal compression or superior

Pepys MB, et al. Amyloidosis. In: Warrell

vena cava obstruction occasionally result.

DA, et al., eds. Oxford Textbook of

Medicine.

5th Edn. Oxford, Oxford

Conclusion

University Press, 2010; pp. 1766-1779.

Amyloidosis can both complicate long-

Rajagopala S, et al.

(2010). Pulmonary

standing pulmonary disease and be deposited

amyloidosis in Sjogren’s syndrome: a

within the respiratory system. The

case report and systematic review of the

literature. Respirology; 15: 860-866.

presentation and prognosis of amyloid

Shah P, et al. (2002). The importance of

deposits depend on their aetiology and

complete screening for amyloid fibril type

distribution, and can be benign or life

and systemic disease in patients with

threatening. In most cases of localised

amyloidosis in the respiratory tract.

disease, management is essentially supportive

Sarcoidosis Vasc Diffuse Lung Dis;

19:

or involves resection of symptomatic deposits.

134-142.

In contrast, systemic treatment can be

Travis WD, et al. Non-neoplastic dis-

extremely effective in patients with generalised

orders of the lower respiratory tract. In:

AA and AL amyloidosis.

Travis WD, et al., eds. Atlas of Nontumor

Pathology. Washington DC, American

Registry of Pathology, 2002; pp. 873-881.

Further reading

Turner CA, et al. (2007). CT appearances

Berk JL, et al.

(2002). Pulmonary and

of amyloid lymphadenopathy in a patient

tracheobronchial amyloidosis. Semin

with non-Hodgkin’s lymphoma. Br J

Respir Crit Care Med; 23: 155-165.

Radiol; 80: e250-e252.

528

ERS Handbook: Respiratory Medicine

Pulmonary alveolar

proteinosis

Maurizio Luisetti

Pulmonary alveolar proteinosis (PAP) is a rare

syndrome occurring worldwide with an

Key points

estimated prevalence of 0.1 cases per 100 000

individuals. PAP is characterised by

N PAP is a rare syndrome caused by

accumulation of surfactant within alveolar

surfactant clearance impairment.

macrophages in the alveoli and terminal

.90% of PAP cases are associated

airspaces, with impairment of gas transfer, and

with the presence of neutralising

by a variable clinical course, ranging from

autoantibodies against GM-CSF

spontaneous resolution to progressive

(GMAb; primary autoimmune PAP).

respiratory failure.

N Diagnosis of primary autoimmune

Surfactant clearance impairment is the likely

PAP is based on the following triad:

common pathophysiology of PAP, which can

1) crazy paving pattern on HRCT;

be classified as follows.

2) milky appearance and cytology

of BAL fluid; and 3) elevated serum

Primary PAP is due to disruption of

level of GMAb.

granulocyte-macrophage colony-

stimulating factor (GM-CSF) signalling,

N WLL is the current standard of care of

either by the presence in plasma and

PAP but alternative therapies

lungs of high levels of neutralising anti-

(especially GM-CSF administration)

GM-CSF autoantibodies (GMAb)

are under active investigation.

(autoimmune PAP, formerly known as

idiopathic PAP) or by mutations in the

GM-CSF receptor a or b chains. Passive

transfer of PAP features in monkeys

According to a recently published meta-

inoculated with human GMAb strongly

analysis and large cohort report, .90% of

supports the concept that GMAb are the

immune PAP patients are middle-aged

causative factor of autoimmune PAP.

adults, complaining of progressive

Secondary PAP occurs as a consequence

exertional dyspnoea and cough;

of the presence of several underlying

interestingly, about one-third of a large

diseases associated with PAP, such as

Japanese PAP series was asymptomatic.

haematological disorders (mostly

Physical examination of PAP patients is

myelodysplastic syndrome),

often unremarkable. Pulmonary function

immunodeficiency, dust inhalation or

tests may be normal but, usually, the first

lysinuric protein intolerance.

abnormality is represented by a decrease in

A third group (PAP-like diseases) is

lung diffusing capacity and increased

characterised by surfactant production

exertional alveolar-arterial oxygen tension

impairment and includes genetic disorders

gradient. The classic chest radiographic

due to mutations in the genes encoding

presentation is a diffuse bilateral infiltrate

surfactant protein (SP)-B and SP-C genes,

with a distribution that is sometimes similar

as well as in the ABCA3 (ATP-binding

to that of pulmonary oedema (fig. 1a). More

cassette subfamily A member 3) gene.

typical is the HRCT presentation defined as

ERS Handbook: Respiratory Medicine

529

‘crazy paving’ (thickening of interlobular and

intralobular septa and ground-glass

opacities, with a patchy distribution)

(fig. 1b). Although surgical biopsy is

traditionally considered mandatory to

establish the diagnosis of PAP, more

recently, the triad represented by:

1) typical crazy paving pattern on HRCT

2) macroscopic appearance of milky fluid

and cytology of bronchoalveolar lavage

(BAL) fluid

3) elevated serum level of GMAb (whose

sensitivity and specificity for diagnosing PAP

is ,100%)

is now considered sufficient to establish the

diagnosis of autoimmune PAP. Lung biopsy

should be considered when one or more of

the previous findings are unclear.

Histopathology usually shows well preserved

alveolar wall architecture, and alveolar spaces

filled with lipoproteinaceous, eosinophilic,

Periodic Acid-Schiff-positive material and

foamy macrophages.

Figure

1. a) Radiographic and b) HRCT ‘crazy

The natural history of the PAP has been

paving’ presentation of PAP.

greatly influenced by the treatment. In the

pre-whole-lung lavage (WLL) era,

progressive deterioration occurred in ,30%

the pathophysiology of the disorder, is

of PAP patients. Death occurred mostly

because of irreversible respiratory failure

considered an attractive alternative to WLL.

and, to a lesser extent, respiratory infection.

Unfortunately, limited experience and, more

The latter is a typical complication of the

importantly, difficult access to the drug have

clinical course of PAP: pulmonary and

so far precluded diffusion of this therapeutic

systemic infections due to opportunistic

option. Possible alternatives are plasma-

organisms such as Nocardia, mycobacteria

pheresis or immunosuppressive agents such

and Cryptococcus are often reported.

as rituximab, but data are so far insufficient.

Increased susceptibility to lung infections is

Lung transplantation is considered in end-

traditionally attributed to the impairment of

stage disease but PAP may recur.

alveolar macrophages engulfed by

surfactant but systemic infections have

Further reading

been ascribed more recently to GM-CSF

signalling impairment.

Beccaria M, et al.

(2004). Long-term

durable benefit after whole lung lavage

The adoption of WLL, first described in the

in pulmonary alveolar proteinosis. Eur

mid-1960s, has changed the natural history of

Respir J; 23: 526-531.

PAP by dramatically reducing the death rate. It

Inoue Y, et al. (2008). Characteristics of

is considered the standard of care for PAP and

a large cohort of patients with auto-

95% of PAP patients respond positively to the

immune pulmonary alveolar proteinosis

procedure, although a considerable fraction of

in Japan. Am J Respir Crit Care Med; 177:

patients may show relapses or incomplete

752-762.

resolution. GM-CSF administration, based on

530

ERS Handbook: Respiratory Medicine

Luisetti M, et al. Pulmonary alveolar

Seymour JF, et al.

(2002). Pulmonary

proteinosis. In: Schwarz MI, et al., eds.

alveolar proteinosis: progress in the first

Interstitial Lung Disease,

5th Edn.

44 years. Am J Respir Crit Care Med; 166:

Maidenhead, McGraw-Hill, 2010.

215-235.

Orphanet.

2009 Activity Report. www.

Suzuki T, et al. (2010). Hereditary pulmon-

orpha.net/orphacom/cahiers/docs/GB/

ary alveolar proteinosis: pathogenesis, pre-

ActivityReport2009.pdf

sentation, diagnosis, and therapy. Am J

Ramirez J, et al.

(1963). Pulmonary

Respir Crit Care Med; 182: 1292-1304.

alveolar proteinosis: a new technique

Trapnell BC, et al.

(2003). Pulmonary

and rationale for treatment. Arch Int

alveolar proteinosis. N Engl J Med; 349:

Med; 112: 419-431.

2527-2539.

Sakagami T, et al. (2009). Human GM-

Uchida K, et al. (2007). GM-CSF auto-

CSF autoantibodies and reproduction of

antibodies and neutrophil dysfunction in

pulmonary alveolar proteinosis. N Engl J

Med; 361: 2679-2681.

Med; 356: 567-579.

ERS Handbook: Respiratory Medicine

531

Adult pulmonary Langerhans’

cell histiocytosis

Vincent Cottin, Romain Lazor and Jean-François Cordier

Langerhans’ cells are bone marrow-derived

destruction of the lung parenchyma and

dendritic cells, the physiological function of

respiratory insufficiency.

which is to process and present antigens to

Epidemiology

lymphocytes. Langerhans’ cell histiocytosis

(LCH) is a rare systemic disorder

Pulmonary LCH in adults is a rare disease

characterised by aberrant accumulation of

with an estimated prevalence of less than

Langerhans’ cells in various organs, usually

one case in 200 000. It occurs almost

in the form of granulomas. LCH is part of a

exclusively in smokers, with no sex

spectrum of other histiocytic disorders that

predominance, between the ages of 20 and

includes include LCH, non-Langerhans’

40 years, and is more common in the white

histiocytosis such as Erdheim-Chester

population.

disease and Rosai-Dorfman disease, and

malignant histiocytic disorders. LCH in

Pathologic features

adults may especially involve the lung,

Pulmonary LCH is characterised by

bones, skin and pituitary gland. The

granulomatous bronchiolocentric

presentation in childhood is different, with

organisation of Langerhans’ cells associated

acute disseminated disease and a poor

with inflammatory cells including

prognosis, and, in older children and

eosinophils. Langerhans’ cells do not differ

adolescents, with multifocal involvement

from their normal counterpart in tissues,

including the bone. However, single-system

exhibiting convoluted irregular nuclei with

involvement of LCH is possible. Pulmonary

characteristic Birbeck granules visible by

LCH is characterised by polyclonal

electron microscopy. These cells stain

accumulation of Langerhans’ cells and other

positive with anti-CD1a and anti-CD207

inflammatory cells in the small airways,

(langerin) antibodies. Some features of

resulting in nodular inflammatory lesions

alveolar macrophage pneumonitis

that may evolve into extensive cavitating

(desquamative interstitial pneumonia) or

respiratory bronchiolitis with interstitial lung

disease are often associated with LCH.

Progression of the bronchiolocentric

Key points

granulomatous lesions results in fibrosis

with end-stage stellar fibrotic scars and

Pulmonary LCH is characterised by

adjacent cystic cavities.

cough, dyspnoea on exercise, and

diffuse pulmonary nodules and cysts

Clinical features

on chest imaging in smokers that may

The respiratory manifestations are not

evolve into respiratory failure.

specific, with cough (often overlooked in

Smoking cessation should be

patients who are smokers) and gradually

attained. No medical therapy has

progressive dyspnoea on exercise.

demonstrated efficacy.

Spontaneous pneumothorax is the first

manifestation leading to diagnosis in about

532

ERS Handbook: Respiratory Medicine

10-20% of patients. A number of patients

disease. Pleural effusion and mediastinal

have almost no reported symptoms and the

lymphadenopathy are exceptional.

disease is discovered incidentally on routine

Pulmonary artery enlargement is present in

chest X-ray or CT. Pulmonary LCH is solitary

patients with pulmonary hypertension.

in a large majority of patients; however,

involvement of other systems may be the

Lung function tests

first manifestation of the disease. These

include bone lesions (which are often

Lung function tests may be normal or only

characteristic, well demarcated and

mildly impaired in patients with nodular

osteolytic on imaging; rib involvement with

involvement. However, TLCO is usually

possible chest pain), hypothalamic-pituitary

decreased, including in patients with

involvement resulting in diabetes insipidus

relatively few lesions on imaging. About

(polyuria and polydipsia) and skin lesions.

one-third of patients develop airflow

obstruction with hyperinflation, which may

Imaging

progress to severe obstructive respiratory

insufficiency.

The chest X-ray is usually abnormal, with

micronodular and reticular opacities,

Diagnosis

typically sparing the lower lobes. In

advanced disease, nodules are absent and

The gold standard for diagnosis of LCH is

the chest X-ray may suggest emphysema.

lung biopsy showing the characteristic

features described above. Surgical biopsy is

HRCT of the chest usually shows

characteristic features in early disease with

often obtained during pleurodesis for

disseminated infracentimetric nodules,

recurrent pneumothorax. Because of the

which may show cavitation and may

plurifocal distribution of the lesions in the

spontaneously disappear. The cavitated

lung, the yield of transbronchial lung biopsy

nodules may evolve to thick- then thin-

is usually limited. Bronchoalveolar lavage

walled cysts (fig. 1). The cysts may then

(BAL) is currently considered of little (if any)

enlarge and become confluent, with HRCT

value. It shows an increase in total cell

features resembling emphysema.

counts with a large predominance of

macrophages with possible slight increase

The differential diagnosis includes other

in eosinophils. The CD4⁺/CD8⁺ lymphocyte

multiple cystic lung diseases on imaging,

ratio is decreased. The identification of

especially Birt-Hogg-Dubé syndrome and

Langerhans’ cells in BAL with antibodies

spontaneous familial pneumothorax related

against CD1a has only poor sensitivity and

to FLCN mutations, lymphangio-

specificity, and their proportion is usually

leiomyomatosis, Sjögren’s syndrome, and

similar to that in smokers without LCH.

nonamyloid immunoglobulin deposition

Common laboratory tests do not contribute

to the diagnosis of LCH.

A presumptive diagnosis of pulmonary LCH

may be accepted in patients with

characteristic HRCT features, and limited

symptoms and impaired lung function. Lung

biopsy is indicated in those patients with

significant symptoms and deteriorated or

deteriorating lung function who are

considered for treatment. In patients with

diffuse cystic lesions on HRCT with

irreversible lung function impairment, lung

biopsy is of limited benefit, especially as it

Figure 1. HRCT of the chest demonstrating

may not show characteristic granulomatous

numerous thin-walled cysts in a patient with LCH.

lesions.

ERS Handbook: Respiratory Medicine

533

Evolution

Lung transplantation (single or double

lung, or heart-lung) may be considered in

About half of the patients improve

patients with end stage disease. The

spontaneously or with corticosteroid

majority of them present with moderate-to-

treatment (which has, however, not been

severe pulmonary hypertension. Post-

rigorously evaluated). Poor outcome with

transplant survival is rather good, with

respiratory failure may occur, especially in

10-year survival .50%. However,

older patients with systemic involvement

pulmonary LCH may recur in about

and deteriorating lung function tests.

one-fifth of patients.

Pulmonary hypertension often severe is

common in advanced disease. Lung cancer

may develop resulting from smoking habits.

Further reading

Treatment of pulmonary LCH

Allen TC (2008). Pulmonary Langerhans

cell histiocytosis and other pulmonary

Given the possibility of spontaneous

histiocytic diseases. Arch Pathol Lab Med;

recovery in a number of patients and the

132: 1171-1781.

absence of controlled therapeutic trials,

Caminati A, et al.

(2006). Smoking-

there is currently no evidence of efficacy of

related interstitial pneumonias and pul-

any treatment.

monary Langerhans cell histiocytosis.

Proc Am Thorac Soc; 3: 299-306.

The strong association between pulmonary

Dauriat G, et al. (2006). Lung transplan-

LCH and tobacco smoking suggests a

tation for pulmonary Langerhans’ cell

causal relationship, and numerous

histiocytosis: a multicenter analysis.

observations have reported improvement of

Transplantation; 81: 746-750.

the disease following smoking cessation.

Fartoukh M, et al. (2000). Severe pul-

However, worsening or relapse despite

monary hypertension in histiocytosis X.

smoking cessation has also been described.

Am J Respir Crit Care Med; 161: 216-223.

In any case, smoking cessation is an

Kiakouama L, et al.

(2010). Severe

essential component of management in

pulmonary hypertension in histiocytosis

pulmonary LCH, at least to prevent further

X: long-term improvement with bosentan.

development of COPD and/or lung cancer.

Eur Respir J; 36: 1-3.

Lazor R, et al. (2009). Progressive diffuse

Although without evidence of efficacy,

pulmonary Langerhans cell histiocytosis

corticosteroid treatment is often used in patients

improved by cladribine chemotherapy.

Thorax; 64: 274-275.

with symptomatic disease and worsening lung

Le Pavec J, et al.

(2012). Pulmonary

function, starting with prednisone 0.5-1 mg?kg^-1

Langerhans cell histiocytosis-associated pul-

then tapering over 6-12 months. Whether

monary hypertension: clinical characteristics

improvement, when occurring, results from

and impact of pulmonary arterial hyperten-

treatment efficacy or from spontaneous

sion therapies. Chest; 142: 1150-1157.

improvement cannot be established.

Lorillon G, et al.

(2012). Cladribine is

effective

against cystic pulmonary

Cytotoxic agents (especially vinblastine)

Langerhans cell histiocytosis. Am J

have been occasionally used with no

Respir Crit Care Med; 186: 930-932.

conclusive efficacy. 2-chloro-deoxyadenosine

Mendez JL, et al. (2004). Pneumothorax

(cladribine) has consistently been shown to

in pulmonary Langerhans cell histiocyto-

be efficient in isolated cases. However,

sis. Chest; 125: 1028-1032.

cladribine may induce profound myelo- and

Tazi A (2006).Adult pulmonary Langerhans’

immunosuppression, and should be

cell histiocytosis. Eur Respir J;

27:

administered only in expert centres.

1272-1285.

Vassallo R, et al.

(2000). Pulmonary

Pulmonary hypertension, when present, may

Langerhans’ cell histiocytosis. N Engl

be improved by pulmonary arterial

J Med; 342: 1969-1978.

hypertension treatment in some patients.

534

ERS Handbook: Respiratory Medicine

Lymphangioleiomyomatosis

Vincent Cottin, Romain Lazor and Jean-François Cordier

Epidemiology and genetics

cells (LAM cells). LAM cell proliferation

usually develops around lymphatic vessels

Lymphangioleiomyomatosis (LAM) is a rare

in the lung and, possibly, the axial

(so-called orphan) lung disease affecting

lymphatics and the thoracic duct. LAM cells

about 3.4-7.8 per million adult females

stain with antibodies against smooth

(usually of childbearing age). It may be

muscle actin, desmin and HMB-45

sporadic, or associated with tuberous

(detecting characteristic pre-melanocyte

sclerosis complex (TSC), where it affects 30-

proteins). As LAM cells have been shown to

40% of adult women and exceptionally men.

invade the lymphatic vessels and spread to

selected distant sites such as the lung and

TSC is associated with inherited mutations

kidney, LAM is increasingly considered a

of the TSC1 and TSC2 genes, while acquired

low-grade metastatic tumour. The source

somatic mutations of TSC2 are associated

and physiological counterpart of LAM cells

with sporadic LAM, resulting in constitutive

are currently unknown. LAM cell clusters

activation of the kinase mammalian target of

have recently been found in the uterus of

rapamycin (mTOR) signalling pathway in

90% patients with LAM, suggesting that

affected cells (LAM cells).

these cells could originate from this organ.

Lung pathology

Clinical manifestations and lung function

In LAM, the lung parenchyma is

tests

progressively replaced by cysts associated

Dyspnoea on exertion is the most common

with a proliferation of immature smooth

symptom and pneumothorax the most

muscle cells and perivascular epithelioid

common mode of presentation (often

relapsing and maybe bilateral). Chylous

effusion (chylothorax and chylous ascites)

Key points

may be present.

N LAM is a rare disease occurring in

Lung function tests are characterised by

women of child-bearing age,

airflow obstruction and impaired gas

characterised by dyspnoea on

transfer with a decrease in TLCO. Exercise

exertion, relapsing pneumothorax and

performance and maximal oxygen uptake

numerous thin-walled cysts on chest

are impaired. Hypoxaemia is present in

imaging.

advanced disease.

N Diagnostic criteria have been

Imaging

proposed recently.

N The disease may slowly progress to

Chest X-ray shows reticular opacities, cysts,

respiratory insufficiency.

pleural effusion or pneumothorax.

N No effective therapy is available.

HRCT of the chest plays a major role in

diagnosis. It shows characteristic multiple

round, thin-walled cysts evenly distributed

ERS Handbook: Respiratory Medicine

535

However, the combination of characteristic

HRCT features with AML or other

characteristic features of LAM may obviate

the need for biopsy. The differential

diagnosis comprises other multiple-cystic

lung diseases associated with mutations of

the folliculin gene (FLCN), especially Birt-

Hogg-Dubé syndrome and familial isolated

primary spontaneous pneumothorax,

Langerhans’ cell histiocytosis, cysts

associated with lymphoid interstitial

pneumonia, nonamyloid immunoglobulin

deposition disease, etc. A diagnostic work-

Figure 1. HRCT of the chest demonstrating

up for alternative causes of multiple-cystic

numerous thin-walled cysts in a patient with LAM.

lung disease is mandatory in patients with

probable and especially possible LAM.

throughout the lung parenchyma; these

Levels of vascular endothelial growth factor

cysts may progressively become confluent

(VEGF)-D, a major angiogenic growth factor

(fig. 1).

produced by tumour cells that promotes

formation of lymphatic vessels and spread

Cysts may be associated with small nodules

of tumour cells to lymph nodes, are

in TSC (corresponding to multifocal

increased in the serum of patients with

micronodular pneumocyte hyperplasia),

LAM, as compared with other cystic lung

pleural effusion and pneumothorax. The

diseases and healthy controls. Serum VEGF-

axial lymphatics of the thorax and

D level contributes to the noninvasive

retroperitoneum may be dilated with

diagnosis of LAM if elevated (high positive

lymphadenopathy and abdominal cystic

predictive value if .800 pg?mL^-1) but does

lymphatic collections called lymphangiomas

not rule out the disease if normal.

(in up to 20% of patients) that may result in

abdominal discomfort or compression.

Evolution and prognosis

Angiomyolipoma

Disease progression is variable, with some

patients remaining relatively stable for a

Angiomyolipomas (AMLs) of the kidney are

long time but others deteriorate rapidly with

benign tumours composed of blood vessels,

ensuing respiratory insufficiency. Median

smooth muscle and adipose tissue that are

annual FEV1 decline is around 100 mL?year^-1.

easily identified by HRCT. AMLs are found in

Repeated measurement of FEV1 and TLCO is

,50% of patients with sporadic LAM and

used to assess disease progression with

80% of patients with TSC, in whom they are

arterial oxygen measurement in advanced

more often bilateral and larger. AMLs may

disease. Pulmonary hypertension, usually

slowly enlarge with time and become prone

mild, may develop.

to bleeding, especially when .4 cm or rich

in microaneurysms (percutaneous

The 10-year survival was about 70-90% in

embolisation or, rarely, nephron-sparing

recent large series.

nephrectomy is therefore indicated). Regular

Management

screening for AML is recommended in

patients with LAM.

As LAM occurs in women of childbearing

age, oestrogens have been suspected to

Diagnostic criteria

enhance and progesterone to prevent the

Diagnostic criteria for LAM have recently

development of LAM. However, hormonal

been proposed by a European Respiratory

interventions have not demonstrated

Society Task Force (table 1). The gold

significant advantages. Nevertheless,

standard for diagnosis of LAM is lung

oestrogens (the contraceptive pill or

biopsy fitting the pathological criteria.

hormone replacement) should be avoided.

536

ERS Handbook: Respiratory Medicine

Table 1. European Respiratory Society diagnostic criteria for LAM

Definite LAM

Characteristic^# or compatible^" lung HRCT and lung biopsy fitting the pathological

criteria for LAM#," or

Characteristic^# lung HRCT and any of the following

AML (kidney)⁺

Thoracic or abdominal chylous effusion¹

Lymphangioleiomyoma^e or lymph node involvement of LAM^e

Definite or probable TSC

Probable LAM

Characteristic^# lung HRCT and compatible clinical history^## or

Compatible^" lung HRCT and any of the following

AML (kidney)⁺

Thoracic or abdominal chylous effusion¹

Possible LAM

Characteristic^# or compatible^" lung HRCT

^#: multiple thin-walled, round, well-defined, air-filled cysts;^": only a few (more than two but f10) cysts,

,30 mm in diameter;⁺: diagnosed by characteristic CT features and/or on pathological examination;¹: based

on visual and/or biochemical characteristics of the effusion;^e: based on pathological examination;

^##: compatible clinical features include pneumothorax (especially multiple and/or bilateral) and/or altered

lung function tests as in LAM.

The mTOR inhibitor and

Inhaled bronchodilators should be

immunosuppressive agent sirolimus has

prescribed to patients with airflow

recently been shown to stabilise lung

obstruction and continued if a response is

function in patients with LAM compared with

observed.

placebo. However, significant side-effects

occurred (mouth ulcers, diarrhoea, nausea,

In patients with end-stage LAM, lung

increased blood cholesterol levels, skin rash

transplantation (single or bilateral) is an

and swelling of the extremities) and disease

efficient procedure, with results comparing

progression resumed when sirolimus was

favourably with transplantation for other

stopped. Sirolimus and everolimus also

pulmonary diseases. As many LAM patients

appeared effective on chylous effusion in

are rather young, lung transplantation may

small observational studies, and in AML not

be proposed in the most severe cases with

amenable to embolisation therapy. As mTOR

poor prognosis. Recurrence of LAM on

inhibitors are not currently approved for

transplant is possible but does not affect

LAM, their compassionate use should be

survival.

restricted to expert centres.

There is a greater risk of pneumothorax and

Further reading

chylous effusion during pregnancy. Whether

or not to become pregnant is the patients’

Avila NA, et al.

(2000a). Pulmonary

decision; however, pregnancy may be

lymphangioleiomyomatosis: correlation

of ventilation-perfusion scintigraphy,

discouraged in patients with severe disease.

chest radiography, and CT with pulmonary

Influenza and pneumococcal vaccination

function tests. Radiology; 214: 441-446.

should be offered to patients with LAM.

ERS Handbook: Respiratory Medicine

537

Avila

NA,

al.

(2000b).

Lazor R, et al. (2004). Low initial KCO

Lymphangioleiomyomatosis: abdomino-

predicts rapid FEV1 decline in pulmonary

pelvic CT and US findings. Radiology;

lymphangioleiomyomatosis.

Groupe

216: 147-153.

d’Etudes et de Recherche sur les

Benden C, et al. (2009). Lung transplan-

Maladies

‘‘Orphelines’’ Pulmonaires

tation for lymphangioleiomyomatosis:

(GERM‘‘O’’ P). Respir Med; 98: 536-541.

the European experience. J Heart Lung

McCormac FX, et al. (2011). Efficacy and

Transplant; 28: 1-7.

safety of sirolimus in lymphangioleiomyo-

Bissler JJ, et al.

(2008). Sirolimus for

matosis. New Engl J Med; 364: 1595-1606.

angiomyolipoma in tuberous sclerosis

McCormack FX, et al.

(2012).

complex or lymphangioleiomyomatosis.

Lymphangioleiomyomatosis. Calling it

N Engl J Med; 358: 140-151.

what it is: a low-grade, destructive,

Chang WY, et al. (2012). Clinical utility of

metastasizing neoplasm. Am J Respir

diagnostic guidelines and putative bio-

Crit Care Med; 186: 1210-1212.

markers in lymphangioleiomyomatosis.

Moss J, et al.

(2001). Prevalence and

Respir Res; 13: 34.

clinical characteristics of lymphangioleio-

Cottin V, et al. (2012). Pulmonary hyper-

myomatosis

(LAM) in patients with

tension in lymphangioleiomyomatosis:

tuberous sclerosis complex. Am J Respir

characteristics in 20 patients. Eur Respir J;

Crit Care Med; 164: 669-671.

40: 630-640.

Ryu JH, et al.

(2006). The NHLBI

Harknett EC, et al.

(2011). Use of

Lymphangioleiomyomatosis Registry: char-

variability in national and regional data

acteristics of 230 patients at enrollment. Am

to estimate the prevalence of lymphan-

J Respir Crit Care Med; 173: 105-111.

gioleiomyomatosis. Q J Med;

104:

Taveira-DaSilva AM, et al.

(2011).

971-979.

Changes in lung function and chylous

Hayashi T, et al.

(2011). Prevalence of

effusions in patients with lymphangio-

uterine and adnexal involvement in

leiomyomatosis treated with sirolimus.

pulmonary lymphangioleiomyomatosis:

Ann Intern Med; 154: 797-805.

a clinicopathologic study of 10 patients.

Urban T, et al.

(1999). Pulmonary lym-

Am J Surg Pathol; 35: 1776-1785.

phangioleiomyomatosis. A study of

Johnson SR, et al. (2000). Clinical experi-

patients. Groupe d’Etudes et

ence of lymphangioleiomyomatosis in the

Recherche sur les Maladies ‘‘Orphelines’’

UK. Thorax; 55: 1052-1057.

Pulmonaires

(GERM‘‘O’’P). Medicine

Johnson SR, et al.

(2010). European

(Baltimore); 78: 321-337.

Respiratory Society guidelines for the

Young LR, et al. (2010). Serum vascular

diagnosis and management of lymphan-

endothelial growth factor-D prospectively

gioleiomyomatosis. Eur Respir J;

35:

distinguishes lymphangioleiomyomatosis

14-26.

from other diseases. Chest; 138: 674-681.

538

ERS Handbook: Respiratory Medicine

Respiratory physiotherapy

Julia Bott

Respiratory physiotherapy spans a broad

Physiotherapy is provided across all

range of services, advice and nonphar-

healthcare settings, from the patient’s own

macological interventions, used to help

home to the critical care unit.

patients with a variety of respiratory

Physiotherapists are well qualified to provide

conditions. Its use has been documented for

assessment and monitoring of, for example,

over a century: postural drainage was

ventilatory function and cough effectiveness

reported for secretion removal in

or exercise tolerance, including for

bronchiectasis in 1901, and in 1915,

ambulatory oxygen assessment.

breathing exercises and physical exercise for

Interestingly, there is wide variance in tasks

chest injuries.

undertaken by physiotherapists across

countries; for example, in some, assisting in

General principles of physiotherapy

delivery of pharmacotherapy, oxygen therapy

and NIV is the role of the respiratory

Physiotherapy is aimed at treating or

physiotherapist, while in others, these roles

alleviating problems rather than diseases.

may be provided by other healthcare

Strategies are used to restore, improve or

professionals.

maintain movement and/or function, and

maximise participation in everyday life.

Airway clearance

Physiotherapists are thus vital to the delivery

of effective pulmonary rehabilitation.

To help the patient better manage their

secretions, a range of airway clearance

techniques are available, including:

N independent techniques

Key points

N mechanical or other devices

N postural drainage

Physiotherapy is indicated in most

N nebulised substances (e.g. hypertonic

respiratory conditions, both for groups

saline)

and individuals, for:

N techniques for cough enhancement or

support

N self-management advice and

education on lifestyle modifications,

Physiotherapists’ physiological knowledge

breathlessness management,

and practical skills means they are well

placed to assist in the delivery of

N improvement or maintenance of

pharmacotherapy (inhalers) and their timing

mobility and function,

with respect to the physiotherapy

airway clearance in well-defined cases,

intervention. Physiotherapists can also help

in the delivery and correct application of

N prescription of exercise and exercise

oxygen therapy, including ambulatory

training,

oxygen, as well as in offering improvement

prescription of walking aids.

of poor ventilatory function, including in the

sedated and paralysed patient.

ERS Handbook: Respiratory Medicine

539

Enhancing ventilation and gas exchange

Strategies to enhance ventilation and gas

exchange include:

N Positioning

N Breathing techniques

N Manual hyperinflation

N Intermittent positive pressure breathing

(IPPB)

N CPAP

N NIV

Physiotherapists are considered by many to

be invaluable in the delivery of an effective

NIV service.

Physiotherapy is commonly helpful for

‘Thank you for giving me my life back.’

postural problems and/or musculoskeletal

dysfunction and pain, as well as for

In both the acute and domiciliary settings:

improving continence. With an increased

prevalence compared to that of

N wheeled walking aids (rollator frame)

nonrespiratory populations, this is especially

reduce the ventilatory requirements of

warranted during coughing and forced

ambulation

expiratory manoeuvres.

N wheeled walking aids are especially useful

for those who are more disabled by

Disease-specific physiotherapy

breathlessness and those using

ambulatory oxygen

Chronic obstructive pulmonary disease Taking

N patients severely disabled by breathless-

account of the altered mechanics of

ness may find using a high-gutter rollator

breathing in those with COPD is essential

frame allows some mobility

for effective breathlessness management

N along with occupational therapists,

and advice.

physiotherapists may promote energy

Breathlessness management includes:

conservation strategies to minimise the

work of the activities of daily living

N positioning to fix the shoulder girdle

passively

Airway clearance techniques should be used

N forward-leaning postures to improve the

where indicated and IPPB may be

length/tension ratio of the diaphragm

considered in acute exacerbations of COPD

N breathing techniques help the patient

for patients with retained secretions who are

better control dyspnoea and panic, both

too weak or tired to generate an effective

at rest and during exertion

cough. NIV is now the first-line therapy for

hypercapnic respiratory failure, and both

Physical activity and exercise should be

NIV and oxygen therapy should be delivered

encouraged throughout the course of the

as per current guidance.

disease, including during hospital

admission where possible and

Asthma Some form of breathing retraining,

appropriate. When supervised and carried

using reduced volume and/or frequency with

out at appropriate intensity these

relaxation, is indicated to reduce symptoms

exercises are more effective. Exercise

and improve quality of life, along with

training programs are indicated for

prescribed medication. Several schools

patients who have symptoms and

advocate specific techniques, but it is

impaired physical activities in daily life.

important to stress that these techniques

Selected patients may benefit from

are adjunctive to medication and not a

inspiratory muscle training.

replacement therapy.

540

ERS Handbook: Respiratory Medicine

Routine or regular airway clearance is rarely

N Exercise for the patient with CF must be

indicated in the asthmatic patient

undertaken individually to reduce risk of

cross-infection

Disordered breathing (hyperventilation

syndrome) Breathing exercises, with an

Interstitial lung diseases There is little

emphasis on nasal breathing and either a

published evidence on physiotherapy for

smaller tidal volume or lower respiratory

interstitial lung diseases. Studies on the

rate, or both, to reduce V9E, combined with

effectiveness of engaging in exercise training

relaxation (technique as for asthma), is an

are emerging and patients with interstitial

effective strategy to reduce symptoms once

lung diseases can gain benefit from pulmon-

the diagnosis is confirmed.

ary rehabilitation providing they are referred

early in the disease process. Patients at a

CF and non-CF bronchiectasis Physiotherapy

later stage of disease may benefit from

is integral to the management of patients

wheeled walking aids, ambulatory oxygen,

with bronchiectasis from any cause,

breathlessness management and energy

including CF, with airway clearance and

conservation strategies.

exercise being central to this therapy. The

acceptability of techniques and regimes, to

Community-acquired pneumonia Traditional

enhance concordance with treatment, is

airway clearance techniques are rarely

vital to the success of therapy.

indicated.

A variety of airway clearance techniques,

For patients admitted to hospital with

including those with and without

uncomplicated community-acquired

mechanical assistance if necessary, should

pneumonia (CAP):

be offered to find one that is both acceptable

N Regular use of positive expiratory

and effective. The simplest technique that

pressure may reduce length of stay

impinges the least on the patient’s life is a

N Medical condition permitting, early

good starting point.

mobilisation is indicated

Effective treatment might need to be

N Patients should be encouraged to sit out

supported by inhaled therapies (e.g.

of bed for o20 min on the first day,

bronchodilators or hypertonic saline, oxygen

increasing the time and general mobility

and NIV or IPPB). These supportive

each subsequent day

therapies and postural drainage to enhance

CPAP may be helpful for patients in type I

airway clearance or exercise tolerance

respiratory failure who remain hypoxaemic

should be assessed for benefit on an

despite optimum medical therapy and

individual basis. Regular review is advised to

oxygen, and NIV may be an option for

ensure continuing effectiveness and

selected patients in type II respiratory failure,

concordance with therapy; appropriate

especially those with underlying COPD.

adjustment of treatment can be made if

necessary.

Chest wall disorders Pulmonary rehabilitation

is indicated in a patient with chest wall

N Physiotherapy for patients with CF should

deformity from any cause with reduced

include assessment and treatment for

exercise capacity and/or breathlessness on

musculoskeletal and postural disorders

exertion. The need for ambulatory oxygen or

N Physiotherapists need to be scrupulous

NIV should be assessed before undertaking

about hygiene for infection control in this

exercise. Respiratory muscle training may

population

have a role. Work has yet to establish

N For those with either CF or

whether breathing or thoracic mobility

bronchiectasis, continence problems

exercises are helpful in this client group.

should be identified and treated

N For patients with bronchiectasis,

Neuromuscular disease and spinal cord injury

pulmonary rehabilitation is indicated

Respiratory problems are the most common

when dyspnoea is impacting on exercise

cause of morbidity and mortality for those

tolerance or functional activities

with respiratory muscle weakness;

ERS Handbook: Respiratory Medicine

541

physiotherapy therefore provides vital

functional electrical stimulation may

assistance with airway clearance. Difficulty

enhance muscle strength or VC. Some

clearing secretions may be due to

patients with early neuromuscular disease

inspiratory, expiratory and/or bulbar muscle

may benefit from respiratory muscle training

weakness, depending on the underlying

but caution is advised in Duchenne

condition and stage of disease.

muscular dystrophy.

N Regular monitoring of oxygen saturation,

Patients with critical illness The principles of

vital capacity (VC) and peak cough flow

care remain the same in critically ill patients

can indicate impending problems with

as in other patients; physiotherapists

either ventilation or cough effectiveness

provide rehabilitation for the prevention and

N The use of respiratory aids when these

treatment of the common complications

measures fall may prevent or reduce

associated with prolonged bed rest,

complications

immobility and recumbence, including

deconditioning, weakness and dyspnoea.

Oxygen therapy should be administered with

Physiotherapy is also used to target specific

great care in patients with neuromuscular

respiratory problems, such as retained

disease because of the risk of increasing

airway secretions, atelectasis and weaning

ventilation/perfusion mismatch and

failure.

increasing hypercapnia. In those at risk of

developing hypercapnia, NIV should be

considered. These are done together with

Further reading

the treating physician.

Bott J, et al. Guidelines for the physiother-

Traditional physiotherapy techniques are not

apy management of the adult, medical,

useful in this group of patients. Strategies to

spontaneously breathing patient. Thorax

enhance maximal insufflation capacity

2009; 64: Suppl. 1, i1- i51. Available from:

(MIC) are indicated and include:

www.brit-thoracic.org.uk/Guidelines/

Physiotherapy-Guideline.aspx.

N resuscitation bags

Gosselink R, et al. (2008). Physiotherapy

N NIV

for adult patients with critical illness:

N mechanical insufflation

recommendations of the European

N breath stacking via the above or

Respiratory Society and European

N glossopharyngeal (frog) breathing

Society of Intensive Care Medicine Task

The presence of severe bulbar dysfunction

Force on Physiotherapy for Critically Ill

or paralysis renders breath stacking

Patients. Intensive Care Med;

34:

1188-

ineffective. MIC enhancement, used

1199.

Langer D, et al. (2009). A clinical practice

regularly, is also a means of maintaining

guideline for physiotherapists treating

range of movement in the lungs and chest

patients with chronic obstructive pulmon-

wall. These techniques should be used along

ary disease based on a systematic review

with strategies to enhance cough

of available evidence. Clin Rehabil;

23:

effectiveness: manually assisted coughing or

445-462.

mechanical insufflation-exsufflation.

National Institute for Health and Care

Ventilatory function can be improved with

Excellence. Critial Illness Rehabilitation.

careful positioning to optimise the effect of

www.nice.org.uk/CG83

gravity on weak muscles, as can the use of

Nici L, et al. (2006). American Thoracic

abdominal binders for those with spinal

Society/European Respiratory Society

Statement on Pulmonary Rehabilitation.

cord injury (SCI).

Am J Respir Crit Care Med;

173:

In patients with SCI, exercise should be

1390-1413.

encouraged; respiratory muscle training and

542

ERS Handbook: Respiratory Medicine

Pulmonary rehabilitation

Thierry Troosters, Hans Van Remoortel, Daniel Langer, Marc Decramer and

Rik Gosselink

Definition

programmes. The full rehabilitation

statement of the ATS and ERS, however,

Pulmonary rehabilitation is now a

does provide that insight. In an initial phase,

recognised therapy for patients with

a rehabilitation programme aims to map out

respiratory diseases. Its effectiveness is

and restore the nonrespiratory

supported by countless randomised

consequences of respiratory diseases (i.e.

controlled trials. In 2012, the European

muscle weakness, depressive symptoms,

Respiratory Society (ERS) and American

poor coping with the disease, impaired

Thoracic Society (ATS) defined pulmonary

engagement in physical activities, nutritional

rehabilitation as ‘a comprehensive

deficits, etc.). Subsequently or in parallel, the

intervention based on a thorough patient

rehabilitation programme calls for the self-

assessment followed by patient-tailored

management of patients to engage in a

therapies which include, but are not limited

healthy lifestyle in terms of physical activity,

to, exercise training, education and behavior

nutrition, smoking and coping. The

change, designed to improve the physical

rehabilitation team becomes the patient’s

and psychological condition of people with

coach. In the first phase, exercise training is

chronic respiratory disease and to promote

a crucial part of the rehabilitation

the long-term adherence to health-

programme; later on, the focus can

enhancing behaviors’. This is definition -

gradually shift towards more lifelong

although long - identifies the core

behavioural change. Whereas the science of

components of a rehabilitation programme

the former has reached a very high standard,

(Spruit et al., 2013). The definition per se is

with a clear evidence base, the latter is less

perhaps not as clear as it could be on the

well studied but is probably of equal import-

expected outcomes of rehabilitation

ance and it is expected that progress can be

made in the years ahead. Here, we will

review the different aspects of this

definition:

Key points

N the evidence base and anticipated effects;

N Pulmonary rehabilitation is an

N the selection of patients;

evidence-based treatment that

N the individualisation of the programme;

improves health-related quality of life

and

and symptoms in COPD.

N the mechanisms through which the

Programmes should be tailored to the

programme works (reversing the

patient in terms of content, location,

systemic, extrapulmonary consequences).

duration, frequency and exercise

Importantly, pulmonary rehabilitation

training.

may be an integrated part of other care

In order for the effects to be durable,

plans for COPD patients, such as self-

patients’ everyday activity should be

management programmes, lung transplant-

higher after rehabilitation than before.

ation programmes, NIV or smoking

cessation programmes.

ERS Handbook: Respiratory Medicine

543

The evidence base for pulmonary

efficacy of patients. Self efficacy is the

rehabilitation

confidence patients have in their ability to

carry out a specific task or manage a specific

Several reviews have summarised the

condition (e.g. breathlessness). The

evidence for pulmonary rehabilitation

confidence patients have that they can

(Lacasse et al., 2006; Troosters et al., 2005)

manage dyspnoea improves after pulmonary

and practice guidelines are available (Ries et

rehabilitation and one of the seminal studies

al., 2007). Therefore, a comprehensive

in pulmonary rehabilitation also showed an

review of all evidence for the effectiveness of

improvement of their self efficacy for

pulmonary rehabilitation is beyond the

walking. It is still unclear to what extent this

scope of this short review.

increased self efficacy contributes to an

effective change in behaviour after

Briefly, in patients with COPD, pulmonary

pulmonary rehabilitation.

rehabilitation improves health-related quality

of life and symptoms unequivocally and

Physical activity The amount of activity

clinically significantly. The effect of pulmonary

patients carry out in their daily life is an

rehabilitation on health-related quality of life

important outcome for rehabilitation. The

is similar or even larger than that obtained by

‘systemic consequences’ of COPD, such as

pharmacotherapy in COPD. When exercise

cardiovascular morbidity, muscle weakness

training is provided at adequate intensity,

and osteoporosis, originate, to a large

exercise tolerance is enhanced and functional

extent, directly or indirectly from living an

exercise capacity improves. These

inactive lifestyle. When pulmonary

improvements are also clinically relevant if an

rehabilitation aims to achieve a sustained

appropriate exercise stimulus is provided.

effect, an inactive life style after

Other improvements are also important but,

rehabilitation should be avoided. Currently,

to date, are less studied.

it is unclear what effect pulmonary

rehabilitation programmes have on physical

Psychological improvements A significant

activity levels. Open studies have reported

proportion of patients referred for

conflicting results and randomised

pulmonary rehabilitation suffer from

controlled trials have only studied limited

psychiatric morbidity. Anxiety and

patient numbers in specific situations.

depression are the most common problems.

Changing physical activity behaviour is

Recently, depression was identified as a

challenging and, in general, results are

negative prognostic factor in patients with

somewhat disappointing. While endurance

COPD, particularly in patients who suffered

capacity virtually doubles, physical activity

from exacerbations. A recent meta-analysis

levels increase by about 20% (Troosters

showed the potential small benefit of

et al., 2010a). Our group showed that

multidisciplinary pulmonary rehabilitation

walking time in daily life only modestly

on mood (Coventry et al., 2007). In patients

changed after 3 months of pulmonary

referred to our rehabilitation programme,

rehabilitation. After 6 months, there was a

depressive symptoms were present in 42%

more significant improvement in physical

of patients and symptoms compatible with

activity levels. Changing physical activity may

anxiety in 38% of patients (Trappenburg et

not simply follow the increased exercise

al., 2005). Clearly, one has to take into

capacity. Probst et al. (2011) showed that

account that effects on these variables are

more increased exercise tolerance (by

only to be expected if patients do have

providing higher intensity exercise

symptoms of depression and/or anxiety.

programmes) did not lead to further

Hence, the relatively small effect size

enhanced physical activity levels. Indeed,

reported in the meta-analysis may be

induced by the dilution of the depressed

physical activity levels are a complex

patients in the larger patient pool.

integration of the exercise capacity of

patients and their willingness to use that

Another, even less studied psychological

acquired capacity in a more physically active

effect of rehabilitation is the enhanced self

lifestyle. In recent years, appealing new

544

ERS Handbook: Respiratory Medicine

strategies have been developed that may

terms of the content (the disciplines

potentially help to increase the effects of

contributing), location, duration and

classical rehabilitation on physical activities.

frequency of the programme. These are

First, providing patients real-time feedback

summarised in table 1. Studies that

on their physical activity levels using

compared different modalities of

pedometers may, along with setting

rehabilitation head-to-head are scarce and

achievable goals, enhance daily activity levels

no unequivocal preference has been

within or without the context of pulmonary

reported. Several studies compared

rehabilitation. Second, walking at home has

hospital-based outpatient rehabilitation to

been stimulated effectively using group

rehabilitation at home and found no

activities, such as Nordic walking, or using

differences between them in short-term

modern interfaces, such as mobile phone

outcomes. One study compared, in a

technology that used walking paced to the

randomised controlled design, hospital-

rhythm of music adapted to the abilities of

based outpatient rehabilitation to

the patient. Even more recently, internet-

community-based outpatient rehabilitation

based programmes have become available

and found a trend for a somewhat smaller

that may support rehabilitation programmes,

increase in the exercise tolerance of patients

but need to be further validated in this

after hospital-based rehabilitation. Effects

context. Future research should focus on

on health-related quality of life revealed

further strategies that may help to lead to a

similar nonsignificant trends (Elliott et al.,

sustainable behaviour change.

2004). More research is needed to evaluate

the criteria for assigning patients to a

Utilisation of healthcare resources An

specific form of rehabilitation. In addition, it

important spin-off of pulmonary rehabilitation

remains unclear to what extent home

may be a decrease in the utilisation of

rehabilitation results in more enduring

healthcare recourses. The most important

effects.

source of utilisation of healthcare recourses is

hospital admissions. In one of the first large

The exercise training component is

randomised controlled trials on pulmonary

essential, and the programme needs to be

rehabilitation, there was a trend for a lower

individualised in terms of exercise

number of hospital days and a more recent

modalities, specificity of the training, the

trial showed a significant reduction in the

training intensity and specific inspiratory

number of hospital days (Griffiths et al.,

muscle training. In order to obtain

2000). In a study from Spain, a similar

significant physiological improvements in

nonsignificant trend was observed (Guell et

skeletal muscle function, it is important to

al., 2000). Comparable findings were obtained

train patients at an intensity that is high

in relatively long open studies comparing

relative to the maximum capacity of the

utilisation of healthcare recourses before and

patients. Recently, programmes eliciting

after taking part in pulmonary rehabilitation.

more significant skeletal muscle fatigue

When trials focus on more fragile patients,

were related to better training effects in

such as those recently admitted to hospital

terms of functional exercise tolerance and

and at risk for re-admission.

reduction of symptoms (Burtin et al., 2012).

In order to combine an effective training

A comprehensive intervention: programme

programme with patient comfort, clinicians

content

have the choice of several exercise training

As indicated above, programmes need to be

modalities. These include endurance

individualised, aim to improve the systemic

training, interval training and resistance

consequences (physiological and

training. The duration of an exercise training

psychological) of the underlying respiratory

programme is generally believed to be

disease, and guide the patients and their

minimally 8 weeks and a minimum of three

families towards a long-term change in

sessions is needed, although, admittedly,

physical activity and self-management

solid evidence as to the optimal duration

behaviour. Several options are possible in

remains missing (Spruit et al., 2013). One of

ERS Handbook: Respiratory Medicine

545

Table 1. Choices to be made when prescribing pulmonary rehabilitation

Aspects to be individualised

Possible choices or options

Content

Disciplines typically involved are: chest physicians,

physiotherapists, nurses, exercise specialists, occupational

therapists, psychologists/behavioural coaches, social workers,

dieticians, general practitioners

Location

Rehabilitation centre: inpatient, outpatient or home based but

with close connection to a specialised centre

Community based: outpatient in centre or primary care office

Home-based supervised by primary care team

Duration

o8 weeks, but longer is typically more desirable

Frequency

A minimum of 3 sessions per week of which 2 are supervised

Exercise training component

Exercise modalities (walking, cycling, upper limbs, etc.)

Exercise intensity

Exercise type: interval, endurance, resistance

Additional interventions: inspiratory muscle training, oxygen

therapy, NIV, neuromuscular electrical stimulation

these sessions can be conducted outside the

enhanced exercise capacity and skeletal

formally supervised setting, by the patients,

muscle force will be short lived. Efforts

provided that the session is comparable in

should be made to change physical

terms of duration and intensity to the

activity behaviour during rehabilitation.

supervised sessions.

We showed that longer programmes

were more successful in achieving this

Maintaining the effects of pulmonary

goal than short-term programmes (Pitta

rehabilitation

et al., 2008). However, changes in the

There has been a lot of debate as to whether

programme content, such as providing

the effects of a rehabilitation programme

patients with direct feedback on their

can be maintained or not. From earlier

physical activity levels or using

studies, it can be seen that it is indeed

structured behavioural interventions,

difficult to claim enduring effects of short

may prove to yield results more rapidly.

term (6-8 weeks) pulmonary rehabilitation

Exercise at home should be facilitated.

programmes. Older long-term studies

This can be achieved using feedback on

(using up to 6 months of rehabilitation) did

home exercises or incentives. Such

find more long-term effects.

exercises need to be individually

tailored to achieve effective intensity in

Our current understanding of the

order to provide a continued training

development of systemic consequences of

stimulus. Ideally, the exercises should

COPD may help to design successful longer

be regularly supervised.

term strategies to maintain the effects of

Specific attention should probably be

pulmonary rehabilitation.

paid to patients who suffer from

All efforts should be made to change

exacerbations, as these events acutely

the physical activity behaviour of

reduce muscle force and functional

patients. Physical inactivity is likely to

exercise capacity. Prevention of such

be the most important contributor to

events can be achieved in patients at

the development of systemic

risk by implementing self-management

consequences in COPD. If patients are

strategies and a case manager.

not more active after the rehabilitation

Although it seems intuitively useful,

programme than before, it is likely that

there is currently little evidence for a

the effects of rehabilitation on

short ‘booster’ programme after a

546

ERS Handbook: Respiratory Medicine

hospital admission to maintain the

extrapulmonary consequences of COPD

benefits of rehabilitation. If these

found to be reversible with rehabilitation,

repeated programmes are pre-planned,

symptoms, functional status, the levels of

they seem to contribute little to the

participation in daily life and health-related

overall long-term success of

quality of life. Other factors, such as age, sex

programmes.

and smoking status, are not important

predictors of the outcome of rehabilitation.

Table 2 provides an overview of the different

It is important that patients are screened for

strategies used in the peer-reviewed

pulmonary rehabilitation after establishing

literature to maintain the benefits of a

optimal pharmacotherapy. While being

rehabilitation programme. Many of these

screened for rehabilitation, patients can also

studies were relatively small and, as follow-

be considered for other programmes, such

up becomes longer, the drop-out rate is

as lung transplantation or lung volume

substantial. Altogether, it seems important

reduction, NIV support, or oxygen therapy.

to achieve an enduring change in physical

Such programmes are not exclusion criteria

activity behaviour and patients should

for pulmonary rehabilitation. On the

continue to carry out planned exercises at

contrary, oftentimes, pulmonary

high intensity to maintain the physiological

rehabilitation is strongly recommended for

benefits of rehabilitation. From table 2, it is

these patients. Figure 1 gives an overview of

clear that interventions that are not regular

the selection process for patients with

or are less structured were not successful in

COPD and the design of the programme.

maintaining the benefits of rehabilitation.

Further evidence suggests that exercise

Extrapulmonary consequences of COPD In

maintenance is important to maintain the

the context of exercise training, the most

benefits of rehabilitation. That study,

important systemic consequence of COPD

however, did not find differences between

is skeletal muscle dysfunction. In clinical

supervised and unsupervised exercise

practice, this can be assessed by skeletal

maintenance programmes. Patients were

muscle force or local skeletal muscle

free to choose their preferred form of

endurance, which is often even more

exercise maintenance strategy, which may

affected. Roughly 70% of patients referred to

have led to selection bias. More research is

an outpatient COPD clinic suffer from

needed to identify optimal maintenance

skeletal muscle weakness and skeletal

strategies after pulmonary rehabilitation.

muscle force is acutely further reduced

during acute exacerbations. In patients with

Patient selection: patients with systemic

less severe, newly detected Global Initiative

consequences

for Chronic Obstructive Lung Disease

The 2006 definition of pulmonary

(GOLD) stage II COPD, van Wetering et al.

rehabilitation included the goals of

(2008) suggested quadriceps weakness

rehabilitation: pulmonary rehabilitation is

occurred in 28% of the patients. In these

‘designed to reduce symptoms, optimize

patients, quadriceps force was related to

functional status, increase participation, and

exercise capacity, as was shown previously

reduce health care costs through stabilizing

in more severe patients. In milder patients

or reversing systemic manifestations of the

(FEV1 .80% predicted), muscle weakness

disease’ (Nici et al., 2006). From this, it

was actually a predictor of physical activity

followed that the ideal candidate for

levels (Shrikrishna et al., 2012). Reversal of

rehabilitation is symptomatic, has impaired

skeletal muscle dysfunction is an important

functional status and participation, high

goal of the exercise training component of a

utilisation of healthcare recourses, and

rehabilitation programme and, hence,

should suffer from the ‘systemic

patients suffering from skeletal muscle

consequences of COPD’. Hence, the

weakness are particularly good candidates

selection of patients should not be

for exercise training. Skeletal muscle

performed based on lung function, but

strength can be improved particularly

rather on the proper assessment of the

effectively by including resistance training

ERS Handbook: Respiratory Medicine

547

Table 2. Different maintenance strategies after outpatient (OP) or inpatient (IP) rehabilitation in randomised

controlled trials

Initial

Maintenance strategy

Effect

programme

Moullec

2 sessions per week of structured

Within group: better

et al.

4 weeks

exercise (community gymnasium), group

preserved performance

(2008)

interaction, education sessions versus

Between groups: no

usual care

significant differences

Berry et

15 months continuation of the OP

Longer programme

al. (2003)

12 weeks

programme

more effective

Ries et al.

Weekly telephone calls and monthly

Overall, no major

(2003)

8 weeks

supervised reinforcement sessions

difference between

programmes

Brooks et

IP or OP

Attend monthly 2-h group sessions and

Overall, no major

al. (2002)

6-8 weeks

phone call between visits

difference between

programmes

Steele et

Weeks 1-4: establishing a home- and

Limited effect for the

al. (2008)

8 weeks

community-based exercise programme

duration of the

with emphasis on walking; weeks 5-12:

intervention; no long-

implementing a regular programme of

term benefits at

exercise; weekly phone calls and 1 home

12 weeks

visit over 3 months

Individualised training plan, based on

Enhanced 6MWD and

Moulin et

3 weeks

their last 6MWT and monthly phone call

health-related QoL

al. (2009)

until end of follow-up

at 6 months

Maintenance strategies were compared with a control group receiving usual care in all studies. 6MWT: 6-min

walk test; 6MWD: 6-min walk distance; QoL: quality of life.

exercises in the sessions. When successful

in terms of its intensity, training modalities

muscle force does increase and muscle

and safety. Functional exercise capacity is

oxidative capacity is enhanced.

best assessed using field tests such as the 6-

min walk test. For this test, reference values

More research is needed on pharmaco-

exist, and benchmark improvements for

logical interventions that may assist

programme quality (Lacasse et al., 2006),

pulmonary rehabilitation in order to restore

and clinical and statistical importance have

muscle function more effectively. The short-

been reported. When a patient’s exercise

term benefits of testosterone supplements

tolerance is not abnormal, the indication for

in selected hypogonadal patients in

exercise training is questionable.

combination with resistance training is an

example of how pharmacotherapy and

Another important extrapulmonary

rehabilitation may have synergistic effects.

consequence of COPD is the derangement

Impaired exercise tolerance and functional

of the body composition. Both obesity, as a

exercise capacity are the result of the

consequence of an inactive lifestyle, and

pulmonary and systemic consequences of

cachexia, as observed in other chronic

COPD. In the context of pulmonary

inflammatory disorders, are important to

rehabilitation, exercise tolerance is best

pick up on and treat in pulmonary

formally assessed before the programme

rehabilitation programmes. Obese patients

using an incremental exercise test. This will

may experience less dyspnoea for a given

help guide the exercise training programme

oxygen consumption compared to nonobese

548

ERS Handbook: Respiratory Medicine

Diagnosis of COPD

Anamnesis

Symptoms

Reduced participation

Impaired overall function

Optimise

Frequency exacerbations

Yes

Medical treatment optimal

Systemic consequences?

No indication for rehabilitation

Exercise intolerance (6MWT)

Psychological problems (HADS)

Design programme (table 1)

Yes

Nutritional status (BMI, FFM)

Location

Adaptation in daily life (interview)

Frequency

Exacerbation

Duration

Disciplines involved

Design exercise programme

Exercise limitation (CPET)

Intensity

(Skeletal) muscle weakness (QF)

Training modalities

Additional interventions (NMES, IMT)

Supplements

Figure 1. Flow chart for referral to pulmonary rehabilitation programmes. 6MWT: 6-min walk test; HADS:

hospital anxiety and depression scale; FFM: fat-free mass; CPET: cardiopulmonary exercise test; QF:

quadriceps force; NMES: neuromuscular electrical stimulation; IMT: inspiratory muscle training.

patients due to a favourable mechanical

Symptoms The most disabling symptom in

effect of obesity on the operating lung

COPD is clearly shortness of breath.

volumes. Nevertheless, obesity (defined as a

Patients report dyspnoea, particularly during

BMI .30 kg?m^-2) will limit the functional

exercise or activity as a significant burden.

abilities of patients with limited ventilatory

Another important symptom is fatigue.

capacity, as it increases the ventilatory need

Symptoms can be assessed during exercise

during exercise against gravity. Cachexia, an

using Borg symptom scores or during

involuntary loss of fat-free mass, leads

activities of daily living using specific

questionnaires.

inevitably to skeletal muscle weakness. It is

a complex problem and its origin is not yet

Physical activity The participation of patients

fully understood. Energy imbalance, disuse

in daily activities is not easily assessed. The

atrophy, hormonal imbalance, chronic

methodology to assess physical activity was

hypoxia, accelerated ageing and systemic

reviewed by Pitta et al. (2005). Several

inflammation have been discussed as

questionnaires have been used but,

potential factors contributing to cachexia.

increasingly, activity monitors find their way

The treatment of cachexia is an important

to the clinical arena and validation studies of

aspect of rehabilitation in patients with

several monitors are available (Haskell et al.,

COPD and requires individualised

2007). In the future, it is likely that

interventions by nutritional specialists. In

benchmark values for physical activity will

order to appropriately assess this aspect,

become available for patients with COPD.

body composition should be assessed using

As indicated earlier, patients not meeting

dual-energy X-ray absorptiometry (DEXA) or

current guidelines on healthy physical

bioelectrical impedance measurements.

activity (30 min of moderately intense

ERS Handbook: Respiratory Medicine

549

exercise, 5 days per week) can be considered

Conclusion

candidates for pulmonary rehabilitation

where the focus lies on improving the

Pulmonary rehabilitation is an evidence-

physical activity lifestyle of the patient.

based intervention for patients with COPD.

It is individually tailored to the needs of

Severe exacerbations Patients with COPD

patients, both in terms of the programme

who have been hospitalised with an acute

structure and its components. The aim of

exacerbation are particularly good

the rehabilitation programme is to lead to

candidates for enrolment in pulmonary

an endurable change in physical activity and

rehabilitation programmes. Recent narrative

self-management behaviour. Although the

(Burtin et al., 2011) and systematic (Reid et

short-term effects of rehabilitation are well

al., 2012) reviews exist on the topic. Patients

known, the long term effects are not always

suffering from exacerbations have acutely

guaranteed. Further research should focus

lost muscle force, functional exercise

on the strategies to ensure long-term

tolerance and health-related quality of life as

benefits for patients with COPD. Further

the result of an exacerbation. Physical

knowledge on the processes underlying an

activity levels are also dramatically low

enduring shift in lifestyle, as well as better

during the hospital admission and at least

understanding of the pathophysiological

up to 1 month afterwards. That observation

mechanisms leading to the systemic

prompted investigators to look at the effects

consequences of COPD and its treatments,

of muscle activation during the

may lead to major advances in the future.

hospitalisation phase by means of

resistance training (Troosters et al., 2010b)

Further reading

or neuromuscular electrical stimulation. In

addition, it is well known that patients who

Brooks D, et al.

(2002). The effect of

had a hospital admission for COPD are very

postrehabilitation programmes among

likely to face new hospital admissions in the

individuals with chronic obstructive pul-

monary disease. Eur Respir J; 20: 20-29.

year following the previous admission,

Burtin C, et al. (2011). Rehabilitation and

imposing a high burden of healthcare cost.

acute exacerbations. Eur Respir J; 38: 702-

The risk of re-admission is particularly high

712.

in patients who remain inactive after a

Burtin C, et al. (2012). Effectiveness of

hospitalisation. In these patients, the

exercise training in patients with COPD:

rehabilitation programme may need

the role of muscle fatigue. Eur Respir J; 40:

significant modification. The emphasis

338-344.

should be on acquiring appropriate self-

Coventry PA, et al. (2007). Comprehensive

management skills to prevent subsequent

pulmonary rehabilitation for anxiety and

admissions, and the exercise training

depression in adults with chronic obstruc-

programme may need to be adapted to

tive pulmonary disease: systematic review

more severe ventilatory and/or skeletal

and meta-analysis. J Psychosom Res; 63:

muscle limitation, using resistance training

551-565.

de Voogd JN, et al. (2009). Depressive

or interval training at high intensities.

symptoms as predictors of mortality in

Patients who have experienced an

patients with COPD. Chest; 135: 619-625.

exacerbation are generally excluded from

du Moulin M, et al. (2009). Home-based

clinical studies. A recent meta-analysis of a

exercise training as maintenance after

handful of studies, however, showed that

outpatient pulmonary rehabilitation.

patients who suffered from exacerbations

Respiration; 77: 139-145.

are very good candidates for pulmonary

Elliott M, et al. (2004). Short- and long-term

rehabilitation (Puhan et al., 2011). Clearly,

hospital and community exercise pro-

these patients may impose a higher burden

grammes for patients with chronic obstruc-

on the rehabilitation team and drop-out

tive pulmonary disease. Respirology; 9: 345-

from the programme is a particularly

351.

important problem.

550

ERS Handbook: Respiratory Medicine

Garcia-Aymerich J, et al.

(2003). Risk

Shrikrishna D, et al. (2012). Quadriceps

factors of readmission to hospital for a

wasting and physical inactivity in patients

COPD exacerbation: a prospective study.

with COPD. Eur Respir J; 40: 1115-1122.

Thorax; 58: 100-105.

Spruit MA, et al.

(2013). An Official

Griffiths TL, et al.

(2000). Results at 1

American Thoracic Society/European

year of outpatient multidisciplinary pul-

Respiratory Society Statement: Key con-

monary rehabilitation: a randomised con-

cepts and advances in pulmonary rehabi-

trolled trial. Lancet; 355: 362-368.

litation

- an executive summary. Am J

Lacasse Y, et al.

(2006). Pulmonary

Respir Crit Care Med; [In press].

rehabilitation for chronic obstructive pul-

Trappenburg JC, et al.

(2005).

monary disease. Cochrane Database Syst

Psychosocial conditions do not affect

Rev; 4: CD003793.

short-term outcome of multidisciplinary

Nici L, et al. (2006). American Thoracic

rehabilitation in chronic obstructive pul-

Society/European Respiratory Society

monary disease. Arch Phys Med Rehabil;

statement on pulmonary rehabilitation.

86: 1788-1792.

Am J Respir Crit Care Med; 173: 1390-1413.

Troosters T, et al.

(2005). Pulmonary

Pitta F, et al. (2005). Activity monitoring

rehabilitation in chronic obstructive pul-

for assessment of physical activities in

monary disease. Am J Respir Crit Care

daily life in patients with chronic obstruc-

Med; 172: 19-38.

tive pulmonary disease. Arch Phys Med

Troosters T, et al.

(2010a). Exercise

Rehabil; 86: 1979-1985.

training and pulmonary rehabilitation:

Probst VS, et al.

(2011). Effects of

new insights and remaining challenges.

exercise training programs on physical

Eur Respir Rev; 19: 24-29.

activity in daily life in patients with COPD.

Troosters T, et al.

(2010b). Resistance

Respir Care; 56: 1799-1807.

training prevents deterioration in quad-

Puhan MA, et al. (2008). Interpretation of

riceps muscle function during acute

treatment changes in

6-minute walk

exacerbations of chronic obstructive pul-

distance in patients with COPD. Eur

monary disease. Am J Respir Crit Care

Respir J; 32: 637-643.

Med; 181: 1072-1077.

Reid WD, et al. (2012). Exercise prescrip-

van Wetering CR, et al. (2008). Systemic

tion for hospitalized people with chronic

impairment in relation to disease burden

obstructive pulmonary disease and

in patients with moderate COPD eligible

comorbidities: a synthesis of systematic

for a lifestyle program. Findings from the

reviews. Int J Chron Obstruct Pulmon Dis;

INTERCOM trial. Int J Chron Obstruct

7: 297-320.

Pulmon Dis; 3: 443-451.

Ries AL, et al. (2007). Pulmonary rehabi-

Van RH, et al. (2012). Validity of activity

litation: joint ACCP/AACVPR evidence-

monitors in health and chronic disease: a

based clinical practice guidelines. Chest;

systematic review. Int J Behav Nutr Phys

131: Suppl., 4S-42S.

Act; 9: 84.

ERS Handbook: Respiratory Medicine

551

Palliative care

Sylvia Hartl

Background and definition

The provision of competent caregivers is

part of the implementation of palliative care.

Originally, in end-stage diseases, the term

‘palliation’ was used synonymously with

The methods of palliative care include the

end-of-life support. Today, palliative care is

following.

extended to all patients at any stage of

chronic disease and their relatives. Palliative

N Medication: opioids and other pain

care is defined as prevention and relief of

medication, and anxiolytic,

symptoms, aiming for improved quality of

antidepressant and sedative drugs

life with respect to the needs of the patient

N Psychological counselling, spiritual

and their family. It includes all methods to

support

control symptoms like dyspnoea, pain,

N Dyspnoea management: NIV, oxygen

psychological and spiritual distress, as well

therapy, endoscopic volume reduction

as support in the process of dying and

N Withdrawal or withholding of mechanical

bereavement care (table 1).

ventilation

Bereavement care for the family

Implementation

Pain relief In chronic or progressive pain,

Palliative care is feasible for all progressive

morphine in combination with other pain

chronic diseases or life-threatening diseases

relievers is effective in the control of pain. In

where all curative therapies have been

some patients, the risk of sedation or

applied to maintain quality of life.

depression of central ventilatory drive has to

be discussed and agreed on. In far-advanced

For patients who are able to make decisions,

disease stages, sedation can be a treatment

it is important to discuss their preferences

goal, as end-of-life support.

together with their families at an appropriate

time in their disease. Setting up goals of

Dyspnoea management Chronic severe

care and empowering the patient and their

dyspnoea is very frequent in COPD and other

families to accept or exclude any form of

respiratory diseases. Medication, besides

therapy needs sensitive discussion of all

bronchodilators, does not directly address

symptoms that may cause suffering and

dyspnoea, but treats anxiety and depression.

disability. The palliative support should start

Pulmonary rehabilitation, endoscopic volume

in parallel with the curative approach.

reduction and stenting are used in selected

Table 1. Key processes of palliative care

Pain relief

Key point

Dyspnoea control

Palliative care is a multidisciplinary

Psychological and spiritual support

approach and needs teams of specialists

with experience and training in palliative

End-of-life support

care.

Bereavement care

552

ERS Handbook: Respiratory Medicine

cases. Oxygen therapy and NIV are not

family, who need enough time for

primarily used for dyspnoea reduction, but

bereavement, especially children.

some patients feel relieved by the reduction of

Bereavement therapy It is important to have

the work of breathing. It is feasible to have a

clear treatment goals from the beginning,

trial period and select responders. Caregivers

and support the family and the patient in the

have to be trained well for home therapy.

process of dying before and after death if

Psychosocial support The burden of

needed.

symptoms and the fear of dying lead to

symptoms of depression and/or anxiety.

Further reading

Frequently used antidepressant drugs are

serotonin re-uptake inhibitors and tricyclic

Curtis RJ (2008). Palliative and end-of-life

antidepressants, whereas tranquilisers are

care for patients with severe COPD. Eur

often used as anxiolytic drugs. Effects have

Respir J; 32: 796-803.

to be observed and discussed with the

Curtis RJ, et al.

(2007). Noninvasive

positive pressure ventilation in critical

patient. In every case, psychological

and palliative care settings: understand-

counselling and coaching must accompany

ing the goals of therapy. Crit Care Med; 35:

any drug therapy. The aims of these are for

932-939.

the patient to cope with symptoms and

Halpin DMG, et al. (2009). Palliative and

accept the dying process at the end of life.

end of life care for patients with respira-

Psychological support is also helpful in the

tory disease. Eur Respir Monogr; 43: 327-

creation of advance directives for end-of-life

353.

decisions. Spiritual coaching depends on

Johnson MJ, et al. The evidence base for

the spiritual background of the patient, and

oxygen for chronic refractory breathless-

may be helpful for the patient and the family.

ness: issues, gaps, and a future work

plan. J Pain Symptom Manage 2012; 763-

Withdrawal or withholding of ventilatory

775.

support This is an important goal for life-

Lanken PN, et al.

(2008). An official

threatening diseases and is often discussed

American Thoracic Society clinical policy

in the intensive care unit. If an advance

statement: Palliative care for patients

directive is available, life support may be

with respiratory diseases and critical

withheld or withdrawn, as palliative care

illnesses. Am J Respir Crit Care Med; 177:

does not aim to prolong life. These

912-927.

measures are often difficult to accept for the

ERS Handbook: Respiratory Medicine

553

Measuring the occurrence

and causation of respiratory

diseases

Riccardo Pistelli and Isabella Annesi-Maesano

When reduced to the simplest terms, all

definitions and examples are given in

medical research may be defined as the

table 1.

study of relationships (differences or

Any measurement performed by using an

associations) between variables. A variable

interval or a ratio scale (continuous scales)

is any quality, constituent or characteristic of

can be translated to a category of an ordinal

a person, animal, thing or environment that

can be measured. A variable is, by definition,

or nominal scale (categorical scales). For

example, body temperature above or below a

something that changes and the values

defined point of the Celsius or Fahrenheit

associated with its measurements are

scale can be used to identify subjects

usually grouped in a set or ‘scale’. There are

affected or not by fever, in this way

four basic types of scales of which

translating from an interval to a nominal

scale. Another example is the use of some

values of FEV1 to identify subjects affected

Key points

by different levels of severity of COPD

according to a conventional ordinal scale. In

Occurrence of a health outcome is

general, clinical research is mainly involved

estimated by prevalence (i.e. the

with patient-centred outcomes that are

proportion of subjects affected by the

variables measured using nominal or

health outcome in the considered

ordinal scales (e.g. dichotomous variables

population) and/or incidence (i.e. the

grouping diseased or not diseased, or

proportion of new cases of the health

exposed or not exposed subjects) whereas

outcome in the considered population).

interval or ratio scales are more frequently

The effect of exposure to a risk factor

used in basic research. However, clinicians

on the health outcome and the

should be aware of the basic methods used

associated risk (i.e. the probability that

to study the relationships of variables

the health outcome will occur following

measured using continuous scales, such as

the exposure) is quantified through two

lung function, as well as understanding

measures: the ratio of the measures of

relationships of nominal or ordinal

disease frequency according to the

variables. The aim of this chapter is to

presence or absence of the exposure to

provide basic knowledge about measures

the factor, and the difference between

and methods commonly used to define the

these two measures.

occurrence of clinical conditions, and to

The existence of a statistically

study the relationships between those

significant association between the

variables and other variables that

exposure to a factor and the health

characterise the individual and the

outcome does not imply that the factor

environment. These methods have been

is a cause of the health outcome;

mainly developed for epidemiological

causation must meet several criteria

research but they should be the landmark of

introduced by Austin Bradford Hill.

any clinical reasoning. We hope to improve

the skill of readers of this book by

554

ERS Handbook: Respiratory Medicine

Table 1. Scales grouping measurements of health outcomes and exposure factors

Nominal scale

Uses names or symbols to assign each

Race, sex, geographic area,

measurement to a limited number of

diseased (yes versus no)

categories that cannot be ordered one above

the other

Ordinal scale

Assigns each measurement to a limited

Patient status, cancer stage,

number of categories not equally spaced and

COPD stage

ranked in a graded order

Interval scale

Assigns each measurement to an unlimited

Body temperature

number of categories that are equally spaced

without an absolute zero point

Ratio scale

As the interval scale but measurements can be

Length, time, mass and all

referred to a true zero point

the derived physical units

discussing the relevance of information

long time interval. In many similar cases, the

about the burden of diseases, as assessed

undefined denominator is the entire life

by their distribution, the panel of related risk

span of individuals, but the reader should

or protective factors, and the evaluation of

understand that the life span, which varies

the effectiveness of preventive measures

between individuals and populations, is not

and therapies in respiratory medicine.

the best denominator to produce a broadly

valid measure of risk. Unfortunately, reliable

Measuring occurrence

figures of risk are not available for many

health problems, including many respiratory

Epidemiology is the study of the distribution

diseases.

and determinants of disease frequency in

human populations. The application of this

Incidence and risk Incidence is a measure of

study to determine valid and precise

the risk of developing a new health condition

information about the causes, preventions

or outcome within a specified period of

and treatments of disease in order to control

time, expressed as a proportion or rate. The

health problems is of outstanding clinical

risk, or incidence proportion (also known as

relevance. One of the main goals of any

the cumulative incidence), is the number of

epidemiological study is to measure, for

new cases within a specified time period

instance, the occurrence or frequency of

divided by the size of the population initially

health outcomes, a disease (asthma, COPD,

at risk, and can be expressed by the formula

lung cancer, etc.) or the intake of a

medication. Epidemiological studies allow

Risk~incidence proportion~

(1)

also estimation of the occurrence of

exposure (smoking, air pollution,

in which a is the number of subjects

occupational hazards, etc.). Risk, incidence

developing a health outcome out of N

proportion, and incidence and prevalence

people followed for a time period. Of course,

rates are popular measures of frequency.

any particular noncommunicable disease

They all are proportions and rates, and their

has a very low risk over a very short time

values are meaningless if the denominator is

period and the cumulative risk increases

not clearly and sensibly stated. For example,

with time. However, the risk may change

imagine you read in a newspaper, reported

during the lifetime of individuals. As an

from an important scientific journal, that

example, many chronic respiratory diseases

men who are 40 years old have a .5% risk

are associated with ageing and their risk is

of developing COPD. Of course, the

clearly increasing from the first to the last

dimension of this risk changes according to

decade of life. However, defining risk is not

the time interval used in the denominator:

as simple as it may appear from the above

the risk is high or low according to short or

formula. Actually, the value of N may

ERS Handbook: Respiratory Medicine

555

decrease over the time period for two main

a recurrent event. Readers should be aware

reasons: the competing risk and the loss to

that different results may be produced by the

follow-up. First, let us consider a study

different methods of calculating t for this

aiming to define the risk of death from lung

outcome and that, whichever the choice, its

cancer in a cohort of smokers (i.e. a group of

rationale should be clearly pre-specified in

individuals sharing a particular

clinical trials. The interpretation of incidence

demographic characteristic). It is plausible

rate is not as simple as for the incidence

that, during the follow-up period, many

proportion. The latter is a probability and is

subjects in the cohort will die from many

expressed as a number in the range 0-1;

different diseases and not from lung cancer.

however, the incidence rate may assume any

However, some of these subjects may have

value from 0 to infinity. We may represent the

developed lung cancer but, before clinical

incidence rate as the instantaneous velocity

manifestation, die of another disease. If we

of a vehicle and the incidence proportion as

include those subjects in the denominator,

the proportion of a journey covered by the

the ratio will give an underestimation of the

same vehicle in a defined time period. Using

true risk of death from lung cancer.

this representation, we may suggest that

Secondly, suppose that some subjects

incidence rate and risk for a health outcome

included in the cohort were lost during the

may be related by the formula

follow-up period (this is usual in cohort

studies in which the individuals are followed

Risk 5 incidence rate 6 t

(3)

up for long periods). Those subjects may

We must remember that this formula may

not develop the outcome we are interested

hold for short time intervals but not for

in and their inclusion in the denominator

longer intervals, during which the loss to

will give an underestimation of risk. In

follow-up and the competing risk will

conclusion, it is sensible to pay the same

complicate the relationship between the two

attention to measuring both the numerator

measures of occurrence. It is possible to

and the denominator of a ratio.

find a solution to that complication by

dividing a long time into shorter time

Competing risk or loss to follow-up can be

intervals for which equation 3 may hold, and

managed using a different measure of health

measuring the risk (or probability) of

outcome occurrence: the incidence rate

developing the outcome in each time

expressed as the number of new cases during

some time period, according to the formula

interval. The overall probability will be equal

to the product of probabilities of developing

Incidence rate~^a

(2)

the outcome through all time intervals. This

method is what is generally known as a

survival analysis, and it can be applied to

in which a is the number of incident cases in

any outcome with a well-defined time of

the cohort, as in equation 1, and t is the total

appearance during the follow-up of a cohort.

time interval experienced by the subjects

In respiratory medicine, the results of many

followed. t is calculated by summing the time

trials on chronic disease have been analysed

for which each subject has been at risk of

using the survival analysis approach.

developing the outcome. For events that may

recur during the follow-up period, t is

Prevalence is the proportion of subjects

calculated by adding the contribution of each

affected by a disease (or symptom or

subject according to one of the following

dysfunction) or, more generally, presenting

options the time experienced up to the first

a health outcome in a defined population.

occurrence (in this case, the numerator

Risk and incidence rate are measures of

includes only one occurrence per subject) or

disease onset. Prevalence is a measure of

all the time intervals the subject was at risk of

disease status. The value of prevalence is

getting any of these occurrences (in this case

related not only to disease incidence but

the numerator includes all the occurrences

also to disease duration. The relationship of

experienced by each subject). The

prevalence to incidence and duration of

exacerbation of COPD is a typical example of

disease is expressed by the formula

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ERS Handbook: Respiratory Medicine

Measuring the effects: types of study

ð4Þ

1{P~ID

The second major goal of epidemiology is to

measure the effect of exposure on the health

in which P is prevalence, I is incidence and

outcome and to estimate the associated

D is the mean duration of the health

risk, i.e. the probability that the health

outcome. The ratio on the left side of

outcome will occur following the exposure.

equation 4 is known as the prevalence odds

This is obtained through different types of

(in general, the odds of an event happening

study design, according to the research

is the ratio of the probability that it happens

question. Epidemiological study design is

to the probability that it does not). For a low

divided into:

prevalence, equation 4 may be written as

N experimental studies, which include

P<ID

(5)

clinical or prevention trials (field trials

and community trials)

In this case, the prevalence proportion may

N observational studies, which include

be considered to approximate to the

cross-sectional studies, cohort studies,

product of incidence and duration. It is

case-control studies and panel studies,

clear that prevalence is a good measure of

according to the particular research

the burden of a disease and can be quite

question (table 2)

useful for public health research and

decision making. However, prevalence

In experimental studies, the investigator

cannot be used for causal inference about

assigns subjects to treatments (vaccination,

risk factors for a disease, except in some

treatment, prevention, etc.) and evaluates

rare cases. Factors that may determine a

their effectiveness, whereas in observational

health outcome or may increase its

studies, the researcher observes subjects

duration can be associated with an

and waits for the outcome to happen.

increased prevalence. A well-known

example of this situation in respiratory

Each type of study design represents a

medicine is offered by the prevalence

different way of harvesting data and

studies in asthma published in recent

information. In experimental studies, the

decades. Many factors have been found to

study population is enrolled on the basis of

be associated with an increased prevalence

eligibility criteria that reflect the purpose of

of asthma but, for most of them, the

the prevention or clinical trial, as well as

crucial question ‘is it a cause or a factor

scientific, safety, ethical and practical

that increases the duration of asthma and

considerations. Scientific, safety, ethical and

the reporting of symptoms?’ is still open.

practical considerations are also applied in

Of course, a reliable prevalence proportion

observational studies. An example of a

or ratio depends on both a satisfactory

cross-sectional study is given by the

measurement of population and prevalent

prevalence studies on asthma published in

cases. Sometimes, the definition of a

the past few decades, such as ISAAC

prevalent case for a specific health

(International Study of Asthma and Allergies

outcome may be different among studies

in Childhood). Case-control design was

and this may lead to quite different

used to find risk factors for lung cancer and

prevalence estimates. Prevalence studies

for all the diseases with a low occurrence

on COPD using different clinical

frequency. Cohort studies have provided

definitions (e.g. diagnosis of chronic

proof of the cause-effect relationship

bronchitis or emphysema) or, more

between tobacco smoking and lung cancer.

recently, different cut-off values of

Another type of study is represented by the

spirometric data, are good examples of this

panel study. A panel study is defined as an

situation. Prevalence can be used for

investigation that collects information on

causal inference in the case of genetic

the same individuals at different points in

factors, as genetic background precedes

time. Panels of asthmatics have been

the development of the disease.

involved in the study of the short-term

ERS Handbook: Respiratory Medicine

557

Table 2. Main types of epidemiological study

Type of study

Description

Type of estimation

Experimental studies

Clinical studies

Trial in which subjects are randomly given

Effectiveness of the treatment by

the treatment or placebo.

comparing the two groups (the treatment

and control group, respectively)

Intervention studies

Inference study in which individuals

Estimation of the effect of the intervention

receive an intervention in order to modify

on the health outcome

a supposed causal factor for disease

incidence

Observational studies

Cross-sectional studies

Descriptive study in which health outcome

Prevalence of acute or chronic health

and exposure status are measured

outcomes in a population

simultaneously in a given population

Relationship between exposure and health

It can be thought of as providing a

outcome; however, since exposure and

‘snapshot’ of the frequency and

disease status are measured at the same

characteristics of health and exposure in a

point in time, it may not be possible to

population at a particular point in time

distinguish whether the exposure

preceded or followed the health outcome

and, thus, cause-and-effect relationships

cannot be established

Cohort studies

Longitudinal investigation in which the

Incidence of health outcome

occurrence of a particular health outcome

Relationship between exposure and health

is compared in well-defined groups of

outcomes

people who are alike in most ways but

Causal relationship (through the relative

differ in a certain characteristic, such as

risk) in the case of prospective cohorts.

(but not uniquely) an exposure

Cohort studies are both retrospective

(backward looking) or prospective

(forward looking)

In a prospective investigation, at the

beginning, the individuals do not present

the health outcome

The prospective cohort design can

establish whether having been exposed is

a cause of the disease development

Case-control studies

Investigation that compares two groups of

Relationship between the exposure and

people: those with the disease or

the health outcome (through the odds

condition under study (cases) and a very

ratio)

similar group of people who do not have

the disease or condition (controls)

Medical and lifestyle histories including

exposures of the people in each group are

analysed to learn what factors may be

associated with the disease or condition

Case-control studies are usually

retrospective but they can be prospective

effects of air pollution. A panel study is,

ecological study may look at the association

therefore, a longitudinal study; it differs

between smoking and lung cancer deaths in

from other studies that collect information

different countries. The geographical

over time, such as time series and cohort

information system is a very useful new tool

studies, in that it studies the same persons

that improves the ability of ecological

longitudinally. All these studies are based on

studies to be able to determine a link

individual data for both health outcomes

between health data and a source of

and exposure. Ecological studies also exist,

environmental exposure. These ecological

in which the unit of analysis is a population

studies allow the development of

rather than an individual. For instance, an

hypotheses that provide limited information.

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ERS Handbook: Respiratory Medicine

Quantitative assessment of the relationship

between exposure and health outcome There

are two ways to quantitatively measure the

effect of a factor on the health outcome or the

condition of interest: the ratio of the

measures of disease frequency according to

the presence or absence of the exposure to

the factor, and the difference between these

two measures. The ratio is the measure of the

strength of the association between a factor

and the health outcome, whereas the

difference is an estimate of the health impact

of the factor under the hypothesis that the

Figure 1. Distribution of the individuals according to

association is of cause-effect type and of the

the presence or the absence of a health outcome

consequences of avoiding or diminishing the

and exposure to a factor. a: number of individuals in

exposure to the factor. Specific statistical

the studied sample exposed to the potential risk

tests are necessary to confirm the existence

factor who have experienced the health outcome; b:

number of individuals exposed who have not

of an effect. In the case that both the health

experienced the health outcome; c: number of

outcome and the exposure are dichotomous

individuals unexposed who have experienced the

variables, their relationship can be quantified

health outcome; d: number of individuals

and its statistical significance can be

unexposed who have not experienced the outcome;

established by organising a 262 (two

N: total number of individuals included in the study.

columns and two rows) contingency table, as

represented in table 3.

the health outcome, and the lowest (b) for

individuals who were exposed to the factor

A visual presentation of the relationship

but did not present the health outcome. In

between a factor and a health outcome when

addition, the number of unexposed

both are dichotomous variables is shown in

individuals who did not present the health

figure 1 where, for instance, the highest

outcome (d) is more elevated than the

number (a) is observed for individuals who

number of unexposed individuals presenting

were exposed to the factor and presented

the health outcome (c). All these elements

support the hypothesis that in this case

Table 3. Contingency table presenting the association

there is a relationship between the exposure

data from the case of exposure and disease that are

and the health outcome. The statistical

dichotomous variables

significance of the relationship can be

determined by applying statistical testing.

Health outcome Total

Yes

Ratio In cohort studies where groups of

individuals are identified on the basis of the

Exposure

presence or absence of exposure to a

Exposed

a+b

potential risk factor and then followed-up for

Not exposed

c+d

the appearance of the health outcomes, the

relative risk is used to investigate whether

Total

a+c

b+d

such a risk factor is related to the health

a: number of individuals in the studied sample

outcome. Relative risk estimates the ratio of

exposed to the potential risk factor who have

disease occurrence in the exposed group to

experienced the health outcome; b: number of

that in the unexposed group. If it is not

individuals exposed who have not experienced the

possible to find a completely unexposed

health outcome; c: number of individuals

group to serve as the comparison, then the

unexposed who have experienced the health

least exposed group is used.

outcome; d: number of individuals unexposed

who have not experienced the outcome; N: total

The principal measure of relative risk is the

number of individuals included in the study.

risk ratio or cumulative incidence ratio, which

ERS Handbook: Respiratory Medicine

559

Table 4. Incidence of the health outcome in exposed and unexposed individuals in cohort studies

Health outcome

Incidence 5 risk

Yes

No Total

Exposure

Yes

a+b

azb~incidenceinexposed

c+d

czd~incidenceinunexposed

Total

a+c

b+d

a: number of individuals in the studied sample exposed to the potential risk factor who have experienced the health

outcome; b: number of individuals exposed who have not experienced the health outcome; c: number of individuals

unexposed who have experienced the health outcome; d: number of individuals unexposed who have not experienced

the outcome; N: total number of individuals included in the study.

is the ratio of the cumulative incidence in the

as a negative association between exposure

exposed group (a/(a+b)) to that in the

and outcome at the 5% significance level.

unexposed group (c/(c+d)) (table 4).

In case-control studies in which the

Thereafter, the relative risk is given by the

subjects are selected on the basis of disease

formula

status and the incidence of the health

outcome is not available in the exposed and

unexposed groups, the effect of the

azb

exposure on the health outcome is

RR~

(6)

measured by the ratio of the odds of

czd

exposure among the individuals presenting

the outcome to that among the individuals

A relative risk of 1 means there is no

not presenting the outcome (the odds of the

difference in risk between the two groups, a

event is the quotient p/(1-p), in which p is the

relative risk .1 means the health event is

probability in favour of the event; this value

may be regarded as the relative likelihood

more likely to occur in the exposed group

that the event will happen). This ratio is

than in the unexposed group and a relative

called the odds ratio and is generally

risk ,1 means that the health event is less

estimated as the ratio between the odds in

likely to occur in the unexposed group than

exposed and nonexposed individuals:

in the exposed group. To be statistically

significantly .1, the RR has to belong to a

confidence interval .1. The need to

azb

introduce the confidence interval is due to

the fact that the studied population is

azb

limited and variable due to random errors in

OR~

~ b

~^ad

(7)

selecting it. Similarly, to be statistically

significantly ,1, the RR has to belong to a

czd

confidence interval ,1. The method used to

calculate the 95% confidence interval for a

czd

RR is shown in Appendix 1. The case of a RR

.1 with a 95% confidence interval that does

An odds ratio of 1 indicates that the health

not include 1 has to be interpreted as a

event under study is equally likely to occur in

positive association between the exposure

both groups. An odds ratio .1 with a 95%

and the health outcome at the 5%

confidence interval that does not include 1

significance level, and a RR ,1 with a 95%

indicates that the event is more likely to

confidence interval that does not include 1

occur in the exposed group at the 5%

560

ERS Handbook: Respiratory Medicine

significance level. An odds ratio ,1 with a

95% confidence interval that does not

azb

include 1 indicates that the condition or

RR~

|OR

(8)

event is less likely to occur in the exposed

czd

group at the 5% significance level. It can be

shown that there is a mathematical

As a consequence, when a disease is rare, a

relationship between the odds ratio and the

and c are small, and the odds ratio provides

relative risk:

a valid estimate of the relative risk.

Table 5. Parameters estimating differences between risks

Measure

Definition

Formula

Attributable

The rate (excess risk) of the outcome

AR~

risk (AR)

in exposed individuals that can be

azb

czd

attributed to the exposure

It is given by the difference in

cumulative incidences or incidence

densities of the disease in the exposed

(I_E) and the unexposed individuals (I₀)

AR5(I_E-I₀)

Preventive

The attributable risk in the case

fraction (PF)

that the exposure is preventive,

azb

PF~czd

so that a/(a+b).c/(c+d)

czd

Attributable risk

The attributable risk divided by the

AR%~

|100

percentage or

rate of disease among the exposed

aetiological

azb

fraction

RR{1

|100

(AR%)

Population

The incidence of a disease in a population

azc

PAR~

attributable

that is attributable to the exposure

azbzczd^{

risk (PAR)

Given by the difference between the

rate of the disease in the entire

czd~AR

azc

population (I_TOT) and I₀

PAR5(I_TOT)-(I₀)

or by multiplying the product of the

attributable risk by the proportion of

exposed individuals in the population

(P_E)

PAR5AR6P_E

Combined PAR

The PAR for a combination of risk factors

Combined PAR^#~1{(1{PAR₁

)

is the proportion of the disease that can

(1{PAR₂)(1{PAR₃ ):::

be attributed to any of the risk factors

studied

a: number of individuals in the studied sample exposed to the potential risk factor who have experienced the

health outcome; b: number of individuals exposed who have not experienced the health outcome; c: number

of individuals unexposed who have experienced the health outcome; d: number of individuals unexposed who

have not experienced the outcome;^#: when there is no multiplicative interaction (no departure from

multiplicative scale), combined PAR can be manually calculated by this formula

ERS Handbook: Respiratory Medicine

561

Difference Several types of difference exist

sources of error in collecting clinical data.

between the measures of health outcome

Error can be described as random or

frequency according to the presence or the

systematic. Random error is also known as

absence of exposure to the factor. They

variability, random variation or ‘noise in the

include the attributable risk, preventive

system’. Heterogeneity in the human

fraction and the population attributable risk

population leads to relatively large random

(table 5). It must be noted that these

variation in clinical trials. Random error has

differences have to be computed under the

no preferred direction, so we expect that

assumption that the factor is causally

averaging over a large number of

related to the health outcome, a condition

observations will yield a net effect of zero.

encountered in prospective cohort studies,

The estimate may be imprecise but not

having assessed causation and disposing of

inaccurate. The impact of random error,

the entities like incidences and relative risks

imprecision, can be minimised with large

necessary to compute the differences of

sample sizes. Systematic error, or bias, refers

risks. These differences can be estimated in

to deviations that are not due to chance

several ways, the most used are presented in

alone. There are several types of bias:

table 5.

N recall bias

Statistical association between exposure and

N selection bias

health outcomes The existence of a

N information bias

significant relationship between exposure

N confounding

and health outcome can be established

independently from the estimation of the

Recall bias, selection bias and information

associated risk (odds ratio, relative risk,

bias can be reduced by good protocol.

etc.). The main statistical methods that

Confounding occurs when a variable is

allow the determination of the existence of a

associated with both the exposure and the

significant statistical association between a

health outcome that we are studying. When

factor and the health condition of interest

the effect of an exposure is mixed with the

are indicated in Appendix 2. They depend on

effect of another variable (the confounding

the type of measurement scales used for the

variable), we may incorrectly conclude that

variables.

the disease is caused by the exposure. We

Causation

might then attempt to eliminate the

exposure in the hope that the disease could

The existence of a statistically significant

be prevented. If, however, the association

association between the exposure to a factor

between the exposure and the disease is due

and the health outcome does not imply that

to confounding and is not causal,

the factor is a cause of the health outcome.

elimination of the exposure will have no

Assessing causation implies several criteria

effect on the incidence of the disease. The

introduced by Austin Bradford Hill (table 6).

existence of confounding variables in

Notably, none of the proposed criteria can

smoking studies made it difficult to

bring indisputable evidence for or against

establish a clear causal link between active

the cause-and-effect hypothesis and none

smoking and lung cancer, until appropriate

can be required sine qua non.

methods were used to adjust for the effect of

the confounders. An example of

Bias and errors

confounding variable in the relationship

Occurrence of health outcomes and

between active smoking and lung cancer is

exposure, and measures of associations and

air pollution, which can cause cancer and is

causation are challenged by biases and

also associated with the exposure of

errors. Random error corresponds to

interest, smoking. The effect of a

imprecision and bias to inaccuracy. Error is

confounder can be taken into account by

defined as the difference between the true

adjusting for it with an appropriate

value of a measurement and the recorded

statistical model or matching individuals

value of a measurement. There are many

according to it.

562

ERS Handbook: Respiratory Medicine

Table 6. Criteria for assessing evidence of causation

Strength

The larger the association, the more likely that it is causal

However, a small association does not mean that there is not a causal effect

Consistency

Consistent findings observed by different persons in different places with different samples

strengthen the likelihood of an effect

Specificity

The more specific an association between a factor and an effect, the greater the probability

of a causal relationship

Causation is likely in case of a very specific population at a specific site and disease with no

other likely explanation.

Temporality

The effect has to occur after the cause

Biological gradient

Greater exposure should generally lead to greater incidence of the outcome

Plausibility

A plausible mechanism between cause and effect is helpful although, very often, knowledge

of the mechanism is limited

Coherence

Coherence between epidemiological and laboratory findings increases the likelihood of an

effect of the exposure on the health outcome

Notably, sometimes we lack such laboratory evidence

Experiment

‘Occasionally it is possible to appeal to experimental…evidence.’

Analogy

The effect of similar factors may be considered

Information from Hill (1965).

Bias has a net direction and magnitude so

example, bacille Calmette-Guérin (BCG)

averaging over a large number of

immunisation is an effect modifier for the

observations does not eliminate its effect. In

consequences of exposure to

fact, bias can be large enough to invalidate

Mycobacterium tuberculosis and has to be

any conclusion. Increasing the sample size

taken into account when investigating risk

will not eliminate all bias. In epidemiological

factors for TB. Effect modification is

and clinical studies, bias can be subtle and

detected by varying the selected effect

difficult to detect. A study can be invalidated

measure for the factor under study across

by the presence of bias. Thus, the design of

levels of the other factor. In this example,

clinical or epidemiological trials has to

the modification effect of BCG

focus on removing known biases. Another

immunisation could be estimated by

important element to be introduced in

computing the odds ratio between tobacco

epidemiological investigations is the effect

smoking and TB according to the presence

modifier, a factor that modifies the effect of

or absence of BCG immunisation. The

a putative causal factor under study. Effect

effect of a modifier can be taken into

modification (also known as statistical

account through matching individuals

interaction) occurs when the effect measure

according to different levels of the modifier

depends on the level of another factor. For

(stratification).

ERS Handbook: Respiratory Medicine

563

2) clear definitions of both the health

Table 7. Sensitivity and specificity computation

outcome (or dependent variables) and the

New criterion

Reference criterion results

exposure (or independent variables) to be

results

included in the models.

Positive

Negative

Positive

Further reading

Negative

Hill AB

(1965). The environment and

TP: number of true positive specimens; FP:

disease: association or causation? Proc

number of false positive specimens; FN: number

R Soc Med; 58: 295-300.

of false negative specimens; TN: number of true

Rothman KJ. Epidemiology: An Introduc-

negative specimens.

tion. New York, Oxford University Press,

2002.

Swinscow TDV, et al. Statistics at Square

Sensitivity and specificity

One. London, BMJ Books, 2002.

Swinscow TDV, et al. Statistics at Square

Sensitivity is the probability that the criterion

Two. London, BMJ Books, 2002.

used to define the case will produce a true

positive result when used in a population

Suggested free software

(compared to a reference or ‘gold standard’).

Specificity is the probability that the criterion

Epi Info. Version 3.5.3 (January 26, 2011).

will produce a true negative result when used

Atlanta, Centers for Disease Control and

(as determined by a reference or ‘gold

Prevention, 2011. Available from:

standard’). Using a contingence table

wwwn.cdc.gov/epiinfo/

relating reference and new criterion results

Appendix 1: 95% confidence intervals for

(table 7), the following formulae are obtained

the relative risk and the odds ratio

for sensitivity and specificity

Given the 262 contingency table relating

Sensitivity~

ð9Þ

exposure to health outcome, a common way

TPzFN

to calculate the 95% confidence interval is

as follows.

Specif icity~

ð10Þ

In the case of the relative risk (approximate

TNzFP

estimate):

where TP is the number of true positive

Upper limit 5 elnRR+1.966!vlnRR

(11)

specimens, FP is the number of false positive

specimens, FN is the number of false

Lower limit 5 elnRR-1.966!vlnRR

(12)

negative specimens and TN is the number of

where !vlnRR represents the square root of

true negative specimens. An example of an

the natural log of the risk ratio, defined as

application for sensitivity and specificity

calculation is in the validation of biomarkers.

azb

Conclusion

ln RR~lnB

13Þ

A ð

Epidemiology provides methods for

czd

measuring the occurrence and the causation

of respiratory diseases. In assessing

which is asymptotically normal with variance

occurrence and relationships between

exposure and health outcomes, criteria of

vlnRR~

{

ð14Þ

a^{azbzc

czd

relevance should include:

When there are zeros, a common

1) the representativeness of the studied

convention is to add 1/2 to each cell.

samplesm particularly in studies with

samples of the general population; and

In the case of the odds ratio:

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ERS Handbook: Respiratory Medicine

Table 8. Main statistical methods for assessing the relationship between health outcomes and exposures

Statistical methods

Description

Correlation

A single number that describes the degree of relationship between

two continuous variables

Linear regression

Approach to modelling the relationship between a continuous

variable y and one or more variables denoted x that may be either

continuous or categorical

ANOVA

A statistical test of whether or not the means of several groups are

all equal (i.e. are not statistically significantly different)

Logistic regression model Approach to predicting the probability of occurrence of an event by

fitting data to a logit function

It makes use of several predictor variables that may be either

continuous or categorical

Usually used to estimate the odds ratio between the exposure and

the health outcome after adjustment for potential confounders

Upper limit

variance of lnOR, calculated as (1/a)+(1/b)

lnOR 5 lnOR + 1.96 6 SE(lnOR)

(15)

+(1/c)+(1/d).

Lower limit

Appendix 2: Main methods used to assess

lnOR 5 lnOR - 1.96 6 SE(lnOR)

(16)

the relationship between exposure and

health outcome

which become

We have presented how to assess the

Upper limit OR 5 e^{upperlimitlnOR}

(17)

relationship between the health outcome

and exposure in the case where both

Lower limit OR 5 e^{lowerlimitlnOR}

(18)

variables are dichotomous. Table 8 intro-

where SE(lnOR) is the standard error of the

duces the methods that can be used in other

natural log of the odds ratio, which is the

cases.

ERS Handbook: Respiratory Medicine

565

Index

definition

460

nonsmall cell lung cancer 466

AAT (₁-antitrypsin) deficiency see ₁-proteinase

small cell lung cancer 462

inhibitor (PI) deficiency

advanced lung disease

abacavir 520

gastro-oesophageal reflux 284-285

abscess, lung see lung abscess

see also specific diseases

N-acetylcysteine, idiopathic pulmonary fibrosis therapy

air hunger 53

391

air pollution

345-350

acid-fast stains

256

asthma and 346-348, 349

acid-base disorders 19, 89-90, 91

biological mechanisms 349-350

arterial blood gas analysis 89-90

children and 345, 346

serum electrolyte measurements 90-91, 92

COPD and 289, 294, 346, 349

acquired immune defence 42-43

indoor 347, 348-349

acquired immunodeficiency 207-210, 211, 212

lung cancer and 346, 349

acute bronchitis 279-280

outdoor 346-348

acute chemical pneumonitis 333-335

airway clearance techniques 539

acute cough 45

bronchiectasis 541

acute eosinophilic pneumonia 396, 397, 407

COPD 540

acute exacerbations of chronic obstructive pulmonary

airway resistance 73

disease (AECOPD) 164-165

measurement 73-74

noninvasive ventilation 166-167, 168

airway stenosis

see also chronic obstructive pulmonary disease

impact of interventional bronchoscopy 133-134

(COPD) exacerbations

malignant, interventional pulmonology 131, 133-134

acute hypoxaemic respiratory failure (AHRF) 163

upper see upper airway stenosis (UAS)

noninvasive ventilation 168-169

airway stenting 113, 133, 134

acute inhalation injury 332-336

airways, drug-induced disease 402, 408-409

clinical presentation 332

ALK gene rearrangement 452-453, 464

inhalational fever 332-333

allergen bronchial provocation test 99, 100, 101

pneumonitis see toxic pneumonitis

allergen immunotherapy, asthma 271

sequelae 336

allergic alveolitis see hypersensitivity pneumonitis

acute interstitial pneumonia (AIP) 387

(HP)

bronchoalveolar lavage 116

allergic rhinitis

261-263

high-resolution computed tomography 379

asthma association 261, 263

acute lung injury (ALI) 159-161

definition

261

drug-induced 399, 402, 406

epidemiology 261

inhalation see acute inhalation injury

pathophysiology 262-263

radiation-induced 369

treatment 263

acute mountain sickness (AMS) 361-362, 363, 364

Allergic Rhinitis and Its Impact on Asthma (ARIA)

acute-on-chronic respiratory failure 164, 165

guidelines 262, 263

acute oxygen therapy 171

allergic rhinoconjunctivitis

192

acute respiratory distress syndrome (ARDS) 159-161

allergy tests, asthma 267-268

diagnosis 116

occupational 330

drug-induced 402, 407

alveolar epithelium 8

acute respiratory failure (ARF) 162, 163-164

alveolar haemorrhage, drug-induced 402, 408

neuromuscular disease patients 446

alveolar hypoventilation 23

noninvasive ventilation 166-169

see also pulmonary rehabilitation

287-291

extrapulmonary manifestations 302

altitude effects

364

influenza vaccination 291, 296

asthma versus 265, 267, 269

long-term ventilation 180-181

chronic bronchitis see chronic bronchitis

nutritional support 291

diagnosis and assessment 288-289

oxygen therapy 171, 172, 197, 298, 540

emphysema see emphysema

pharmacological 197, 290, 291, 304-309

exacerbations see chronic obstructive pulmonary

physiotherapy 540

disease (COPD) exacerbations

pulmonary rehabilitation see pulmonary

exercise intolerance 22, 94, 97, 548

rehabilitation

exercise testing 96, 97, 98, 548

see also under chronic obstructive pulmonary dis-

exhaled breath analysis 106, 107

ease (COPD) exacerbations

extrapulmonary effects 300-302, 547-549

chronic renal failure, tuberculosis risk 245

impact on patient care 302

chronic respiratory failure (CRF) 162

local and systemic inflammation 300-302

chronic rhinitis see rhinitis, chronic

therapeutical implications 302

chronic systemic inflammatory syndrome 300, 302

gastro-oesophageal reflux disease association

chronic thromboembolic pulmonary hypertension

282-283

(CTEPH) 423

genetics 289-290

diagnosis 424

HIV association 518-519

Churg-Strauss syndrome 396, 397, 417

hypoventilation 507-508

clinical presentation 418

induced sputum biomarkers 104, 105

diagnosis 418-419

management see chronic obstructive pulmonary

epidemiology 417

disease (COPD) management

pathogenesis 417

pathophysiology 53-55, 287

prognosis 420

role of transforming growth factor- 11

see also pulmonary rehabilitation

cigarette smoke 352

respiratory mechanics 22

cigarette smoking see smoking

risk factors

288, 289-290

ciprofloxacin therapy

air pollution

289, 294, 346, 349

community-acquired pneumonia 201

smoking 280, 287, 289, 290, 354

hospital-acquired pneumonia 205

571

infectious COPD exacerbations 197

congenital central hypoventilation syndrome (CCHS)

pulmonary tuberculosis 236

180, 506-507

cisplatin chemotherapy 462

congenital immunodeficiency see primary

malignant mesothelioma 464

immunodeficiency (PID)

nonsmall cell lung cancer 463

congestive heart failure see heart failure patients

small cell lung cancer 461

consolidation 373-374

citric acid, cough challenge 49

constant work rate (CWR) tests 95

Clara cells

31, 40

continuous positive airway pressure (CPAP) therapy

clarithromycin therapy

central sleep apnoea 494-495, 499-500, 501

nontuberculous mycobacterial infections 253

community-acquired pneumonia 541

pulmonary tuberculosis 237

obstructive sleep apnoea 493-495

Clinical Pulmonary Infection Score (CPIS) 200,

oxygen therapy and 173

205-206

continuous-volume computed tomography scanning

clofazimine therapy, pulmonary tuberculosis 237

141, 142, 143

club cells 31, 40

controllers, asthma 271

co-trimoxazole, Pneumocystis pneumonia

conventional tube thoracostomy, pneumothorax 434

management 515, 516

corpora amylacea 31

coal dust exposure 342-343

corticosteroid-sparing therapy, asthma 309

coal workers' pneumoconiosis (CWP) 343

corticosteroid therapy 307-308

cohort studies 557, 558

asthma 270, 271, 307-308

colchicine, idiopathic pulmonary fibrosis therapy 391

clinical use

307

colon, cystic fibrosis-related disease 322

COPD 197, 290, 291, 296-297, 307

combined antiretroviral therapy (CART) 513

drug-induced respiratory disease 407, 408

respiratory side-effects

519-520

eosinophilic bronchitis 395

tuberculosis patients 517-518, 519

eosinophilic pneumonia 396, 397

common cold 190, 191

graft versus host disease 523

community-acquired pleural infection 215-216

hypereosinophilic syndrome 398

community-acquired pneumonia (CAP) 199-202

hypersensitivity pneumonitis 339

clinical features

200

idiopathic pulmonary fibrosis 389-390

definition

199

Langerhans’ cell histiocytosis 534

diagnosis 200

mode of action 307

see also specific diseases

assessment 61, 63

eosinophilic pneumonia 396-397

evaluation during physical tasks 51-52, 54

drug-induced 406, 407, 409

see also specific diseases

ratio

559-561

dyspnoea threshold 55

sensitivity and specificity

564

statistical association between exposure and health

574

outcomes 562, 565

exogenous lipoid pneumonitis 335

types 557-558

experimental epidemiological studies 557, 558

epidermal growth factor receptor (EGFR) 463

expiration 21-23, 72-73

epidermal growth factor receptor (EGFR)-targeted

expiratory flow limitation (EFL) 67

therapies 463-464

expiratory positive airway pressure (EPAP) 167

epidermal growth factor receptor gene (EGFR)

expiratory reserve volume (ERV) 66, 70

mutations 451, 464

extensively drug-resistant tuberculosis (XDR-TB) 231,

epigenetics 2-3

234

epiglottitis

191

detection 258-259

epithelial barrier

39, 40

HIV association 518

Epworth Sleepiness Scale (ESS) 491, 492

treatment 234

equal pressure point (EPP) 22-23

extracellular matrix (ECM) 7-8

equilibrium coefficient 25

extracorporeal membrane oxygenation (ECMO) 160

ErbB family 451-452

extrapulmonary tuberculosis (EPTB) 241-243

ergots, pleural injury 409

definition

241

erlotinib therapy, nonsmall cell lung cancer 463-464

diagnosis 242

errors 562-563

sites

241-242, 243

erythema nodosum 62, 65

treatment 242-243

etanercept therapy, idiopathic pulmonary fibrosis 392

see also pulmonary rehabilitation

transbronchial see transbronchial fine-needle

exercise training

aspiration (TBNA)

COPD management 291, 540, 547-548, 550

finger clubbing 62, 64

see also pulmonary rehabilitation; respiratory

flow cytometry 30

physiotherapy

flow-volume loop analysis, upper airway stenosis

exertional dyspnoea

131-132, 134

definition

fluid homeostasis 40-41

see also specific diseases

chest 139-140

Geneva score 412, 413

fine-needle biopsy guidance 122

genotyping, Mycobacterium tuberculosis complex

fluticasone, bronchiectasis management 313

259-260

focal lung disease, high-resolution computed

germ cell tumours 489

tomography 148

cytology 37

forced oscillation technique (FOT) 74

goblet cells 30

fractional exhaled nitric oxide measurement 106, 107

gold therapy, asthma 309

asthma 268-269

graft versus host disease (GVHD) 521-525

Framework Convention for Tobacco Control (FCTC)

acute 521, 522

357

chronic 521

functional residual capacity (FRC) 19-20, 66, 67, 69

pathogenesis 521-522

in disease 69

pulmonary complications 524-525

fungal infections

treatment 523-524

bronchiectasis 311

graft versus tumour (GVT) effect 522-523

cytological changes 33

grain handler’s lung 339

immunocompromised hosts 212

Gram stain 29, 30

HIV-infected patients 514, 515-516

sputum 185

post-solid organ transplant 209

granulocyte-macrophage colony-stimulating factor

with primary immunodeficiency 510

(GM-CSF) signalling, disruption in pulmonary alveolar

lung abscess 219

proteinosis 8, 529, 530

see also specific diseases

gases, inhalational injury see acute inhalation injury

granulomatous-lymphocytic interstitial lung disease

gastro-oesophageal reflux (GOR) 281

(GLILD) 511

gastro-oesophageal reflux disease (GORD) 281-286

ground-glass opacities (GGOs) 373

in advanced lung disease 284-285

group A streptococcal pharyngitis 191, 192

comorbidities

gynaecomastia 62, 65

asthma 270, 282-283

COPD 282-283

cough association see gastro-oesophageal reflux-

induced cough

haematopoietic stem cell transplantation (HSCT),

management 285-286

complications

mechanisms of increased reflux 281-282

graft versus host disease 521, 522

pathophysiology 282

pulmonary 208, 524-525

sleep and 285

Haemophilus influenzae infection

symptoms 281

COPD exacerbations 195, 196, 197, 296

upper respiratory tract infections versus 192

diagnosis 183, 184

gastro-oesophageal reflux-induced cough 46, 283-284

hospital-acquired pneumonia 204

management 48, 283-284

Haemophilus influenzae type B (HiB) 191

gastrointestinal disease, cystic fibrosis-related

318, 322

vaccination 192

gefitinib therapy, nonsmall cell lung cancer 463

haemoptysis 49-50

gemcitabine therapy 462

fine-needle biopsy-induced 123

malignant mesothelioma 464

haemorrhage, alveolar, drug-induced 402, 408

nonsmall cell lung cancer 463, 464

haemosiderosis, pulmonary 115

gene mutations 1-2

haemothorax 430, 433-434

gene therapy, cystic fibrosis 324

thoracentesis-induced 130

576

health care resources, effect of pulmonary rehabilitation

histone modifications 2

on utilisation 545

HIV-related disease 513-520

health outcome, measurement see epidemiological

COPD 518-519

studies

infections 209-210, 212, 514-518

healthcare-associated pneumonia (HCAP) 203

bacterial

514-515

see also hospital-acquired pneumonia (HAP)

fungal 514, 515-516

heart disease see cardiovascular disease

see also specific diseases

idiopathic pulmonary arterial hypertension 422, 424,

influenza 192, 222-225

425

chemoprophylaxis 224

idiopathic pulmonary fibrosis (IPF) 375, 386

complications 201, 223

clinical features

387

diagnosis 227-228

diagnosis 388

pandemic 222, 224, 225

bronchoalveolar lavage 116

seasonal 222-225

high-resolution computed tomography 147,

treatment 192, 223-224

375-376, 388

influenza vaccination 192, 224

genetics 3, 387

COPD patients 291, 296

treatment 389-393

lymphangioleiomyomatosis patients 537

578

influenza viruses 222

detection 186

inhalation fever 332-333

Janus kinases (JAKs) 523

hypersensitivity pneumonitis versus 340

Japanese summer-type hypersensitivity pneumonitis

inhalation injury, acute see acute inhalation injury

339

inhaled corticosteroids

joints

asthma management 270, 271, 307

cystic fibrosis-related disease

323

COPD management 197, 290, 291, 296-297, 307

tuberculosis 243

side-effects

307-308

see also specific diseases

community-acquired pneumonia 201

interstitium, anatomy 371-372

hospital-acquired pneumonia 205

interval scale

554, 555

infectious COPD exacerbations 196, 197

interventional lung assist 160

pulmonary tuberculosis 236

interventional pulmonology 131

Lhermitte's syndrome 476

bronchoscopy 112-113, 131, 133-134

Light's criteria

430

intraoperative interventions 175

line probe assay (LiPA) 258-259

intrapleural pressure (PIP) 19-20, 22-23

linezolid therapy, pulmonary tuberculosis 237

ischaemic heart disease, COPD exacerbations and 294

liver, cystic fibrosis-related disease

322

isocapnic hypoxia 84-85

lobectomy 468, 470

isoniazid therapy

pre-operative assessment 175-177

latent tuberculosis 249

local inflammation, in COPD 300, 301

nontuberculous mycobacterial infections 253

Löfgren's syndrome 382, 383, 384

pulmonary tuberculosis 234, 235, 237-238

long-acting antimuscarinics (LAMA)

‘isotime’ measurements 96-97

COPD management 290, 297

579

see also specific diseases

sarcoidosis diagnosis 383

lung elastance 75

transbronchial 111, 112

lung function

lung cancer 451, 455-459

impact of interventional bronchoscopy 133-134

clinical manifestations 455-456

improvement, bronchiectasis 313

CT screening 142

lung function testing

diagnosis 456

asthma 266-267

580

lymphangioleiomyomatosis 535

magnetic resonance imaging (MRI) 142-144

neuromuscular diseases 443-444

computed tomography versus 142-143, 144

pulmonary Langerhans’ cell histiocytosis 533

diffusion-weighted 144

sarcoidosis 383-384

indications 143-144

upper airway stenosis 131-133

male reproductive tract, cystic fibrosis-related disease

see also specific diseases

long-term 181

obstructive sleep apnoea/hypopnoea syndrome

contraindications 167

(OSAHS) 491-496, 503, 504, 506

long-term 178-179

altitude effects

364

neuromuscular disease patients 167, 179-180,

assessment 492

444-445, 446, 542

central sleep apnoea association 492, 498

obesity hypoventilation syndrome 167, 180, 505-506

consequences 492-493

oxygen therapy and 173

definition

491

practicalities of ventilator settings

167

pathophysiology 492, 493

see also continuous positive airway pressure (CPAP)

prevalence 492

therapy

symptoms 491

nonsmall cell lung cancer (NSCLC)

treatment 493-496

diagnosis 456

occupational asthma 327-331

early-stage, definition

467

associated occupations/industries 329

staging 153, 457, 467

diagnosis 328, 330

treatment

management 330

chemotherapy 462-463, 466, 472

sensitising/triggering agents 328, 329

radiotherapy 466, 472, 473-474, 475

socioeconomic impact 330-331

surgical 466-470

symptoms 328

survival rates and 467, 468, 469-470, 473

occurrence, measurement see epidemiological studies

see also specific diseases

Pneumocystis jiroveci, cytological findings 33

pleural biopsy 485-486

Pneumocystis pneumonia 202, 207, 209, 212, 515-516

pleural catheters 487-488

management 212, 515-516

pleural cavity

pneumocytes, type II 31

pleural drainage, pleural effusions 431

pneumomediastinum 433, 434

pleural effusion 428-431

pneumonectomy 467, 468

aetiology 428

alternatives

470

definition

428

pre-operative assessment 175-177

diagnosis 429-430

pneumonia 199-202

laboratory investigations 430

Aspergillus

212, 213

medical thoracoscopy/pleuroscopy 126, 429

aspiration 199, 202

thoracentesis 128, 129, 429

classification

199, 200

transthoracic ultrasonography 155-157

clinical features

200

transudate versus exudate 430

community-acquired see community-acquired

drug-induced 406, 409

pneumonia (CAP)

exudative 429, 430

cytomegalovirus see cytomegalovirus (CMV)

malignant see malignant pleural effusions (MPEs)

pneumonia

management 430-431

eosinophilic see eosinophilic pneumonia

thoracentesis 128, 129, 431

epidemiology 199

pathophysiology 428-429

hospital-acquired see hospital-acquired pneumonia

symptoms 429

(HAP)

transudative 430

idiopathic interstitial see idiopathic interstitial

pleural fluid examination

pneumonias (IIPs)

malignant pleural effusion diagnosis 485

in immunocompromised hosts 199, 201-202,

pleural effusion diagnosis 429-430

211-213

pleural infections 216

HIV-infected patients 514

pleural infection 215-218

as influenza complication 201, 223

bacteriology 215-216

investigations and diagnosis 200

clinical classification

216

see also specific diseases

pulmonary surfactant see surfactant system

ratio, assessment of exposure-health outcome

pulmonary tuberculosis 229-240

relationship 559-561

aetiology 229-230

ratio scale

554, 555

clinical features

231-232

Ravitch technique 449

diagnosis 152, 232-233

re-expansion pulmonary oedema 130

epidemiology 231

reactive airways dysfunction syndrome (RADS) 336

pathogenesis 230-231

real-time PCR, detection of drug resistance in

prevention 238, 240

Mycobacterium tuberculosis complex 259

primary 230, 231-232

rebreathing test 83-84

secondary 230, 232

recall bias

562

treatment 233-238, 239

recoil pressure (PREC) 21, 22

see also pulmonary rehabilitation

residual volume (RV) 66, 67

respiratory polygraphy, neuromuscular disease patients

in disease 67-69

444

respiratory acidosis 89, 90, 91

respiratory quotient (RQ) 18, 19

respiratory alkalosis 89, 90, 91

reduced 23

respiratory bronchiolitis-associated interstitial lung

respiratory syncytial virus (RSV) 33, 186, 187

disease

respiratory system anatomy 13-17

bronchoalveolar lavage 116

respiratory system development 17

high-resolution computed tomography 377-378

respiratory viruses see viral infections

see also idiopathic interstitial pneumonias (IIPs)

restriction fragment length polymorphism (RFLP)

respiratory exchange ratio 18

analysis, Mycobacterium tuberculosis complex 259-260

respiratory failure (RF) 162-165

restrictive lung disease

definition

162

lung volume changes 67, 69

hypercapnic see hypercapnic respiratory failure

see also specific diseases

hypoxaemic see hypoxaemic respiratory failure

RET gene rearrangement 453

idiopathic interstitial pneumonias 387

reticular pattern

372-373

management 165

rhinitis, chronic

261-263

types 162

asthma association 261, 263

see also acute respiratory failure (ARF)

clinical aspects

261-262

respiratory frequency 19, 21, 22

definition

261

respiratory infections

epidemiology 261

bacterial see bacterial infections

pathophysiology 262-263

cystic fibrosis

315, 318

treatment 262, 263

management 318, 319-321

rhinoconjunctivitis, allergic

192

cytological changes 32-34

rhinosinusitis 191

fungal see fungal infections

rib suppression technique 139

HIV-related see under HIV-related disease

rifabutin therapy, pulmonary tuberculosis 236

microbiological diagnosis see microbiological

rifampicin therapy

testing

latent tuberculosis 249

post-bone marrow transplantation 208, 524, 525

nontuberculous mycobacterial infections 253

primary immunodeficiency-associated 509, 510, 511

pulmonary tuberculosis 234, 235, 237-238

smoking association 354

right-to-left shunt

25-26

viral see viral infections

rimantadine 223

see also specific infections; specific pathogens

risk

555-556

respiratory mechanics 19-23, 72-75

roflumilast 309

expiration 21-23, 72-73

ROS1 gene rearrangement 453

inspiration 20-21, 22, 72

Roughton-Forster equation 79

measurement in mechanical ventilation 75

respiratory muscle strength 75

respiratory-muscle work (W) 20

respiratory physiology 18-28

sarcoid granulomas, cytological findings 34

pulmonary gas exchange see pulmonary gas

sarcoidosis 382-385

exchange

clinical presentation 382-383

respiratory mechanics see respiratory mechanics

diagnosis 4, 383-384

ventilatory requirements 18-19

bronchoalveolar lavage 117, 383

respiratory physiotherapy 539-542

high-resolution computed tomography 380-381

airway clearance techniques 539

epidemiology 382

asthma 540-541

genetics 2, 3-4, 308

bronchiectasis 541

induced sputum biomarkers 105

chest wall disorders 541

natural history 384

community-acquired pneumonia 541

prognosis 384

COPD 540

serum angiotensin-converting enzyme levels 4

critically ill patients

542

treatment and follow-up 384-385

cystic fibrosis

541

sarcoma, chest wall 484, 485, 487

hyperventilation syndrome 541

scales 554-555

interstitial lung diseases

541

scintigraphy 60, 151-153

neuromuscular disease 541-542

gallium-67 152

spinal cord injury 541-542

perfusion see perfusion lung scintigraphy (PLS)

ventilation-/gas exchange-enhancing strategies 540

ventilation see ventilation lung scintigraphy (VLS)

588

scoliosis, risk factors for ventilatory decompensation

effect on bronchoalveolar lavage cell counts 120

179

prevention 357-358

seasonal influenza 222-225

protection against hypersensitivity pneumonitis 338