Chronic ObstructivePulmonary Disease

Professor Robert A. Stockley Professor of MedicineDepartment of MedicineQueen Elizabeth HospitalBirminghamB15 2THUK

Professor Stephen I. RennardPulmonary & Critical Care Medicine SectionUniversity of Nebraska Medical Center985125 Nebraska Medical Center800 South 42nd StreetOmahaNE 68198-5300

Professor Klaus RabeDept of PulmonologyLeiden Universtiy Medical CentreAlbinusdreef 2, C3-PPostbox 96002300 RCLeidenNetherlands

Professor Bartolome Celli Division of Pulmonary and Critical CareSt Elizabeth’s Medical Centre736 Cambridge StreetTufts UniversityBostonMA 02135-2907

Chronic Obstructive Pulmonary Disease

Chronic ObstructivePulmonary Disease

Professor Robert A. Stockley Professor of MedicineDepartment of MedicineQueen Elizabeth HospitalBirminghamB15 2THUK

Professor Stephen I. RennardPulmonary & Critical Care Medicine SectionUniversity of Nebraska Medical Center985125 Nebraska Medical Center800 South 42nd StreetOmahaNE 68198-5300

Professor Klaus RabeDept of PulmonologyLeiden Universtiy Medical CentreAlbinusdreef 2, C3-PPostbox 96002300 RCLeidenNetherlands

Professor Bartolome Celli Division of Pulmonary and Critical CareSt Elizabeth’s Medical Centre736 Cambridge StreetTufts UniversityBostonMA 02135-2907

© 2007 by Blackwell Publishing LtdBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USABlackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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First published 2007

Library of Congress Cataloging-in-Publication Data

Chronic obstructive pulmonary disease / [edited by] Robert Stockley . . . [et al.].p. ; cm.

Includes bibliographical references and index.ISBN-13: 978-1-4051-2289-4ISBN-10: 1-4051-2289-71. Lungs-Diseases, Obstructive. I. Stockley, Robert A.

[DNLM: 1. Pulmonary Disease, Chronic Obstructive. WF 600 C55165 2006]RC776.O3C47423 2006616.2′4–dc22 2005012341

ISBN-13: 978-1-4051-2289-4ISBN-10: 1-4051-2289-7

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Contents

10 The Natural History of COPD, 117Jørgen Vestbo

11 Cystic Fibrosis, 124Marcus P. Kennedy and Michael R. Knowles

12 Bronchiectasis and COPD, 139Robert Wilson

13 Obliterative Bronchiolitis, 148Hélène Levrey Hadden and Marshall I. Hertz

14 Asthma, 154Diana C. Grootendorst and Klaus F. Rabe

15 COPD: Clinical Presentation and Evaluation, 167Bartolome R. Celli

16 Monitoring and Outcomes, 181Paul W. Jones

17 Mucociliary Clearance, 191Souheil El-Chemaly, Adam Wanner and Matthias Salathe

18 Mucosal Immunity, 201Hugues Chanteux, Charles Pilette and Yves Sibille

19 COPD and Pulmonary Surfactant, 212Carola Seifart and Bernd Muller

20 The Macrophage and its Role in the Pathogenesis of COPD, 219Kellie R. Jones and Jordan P. Metcalf

Section 3: Host Defences andInflammation

Section 2: COPD and Allied ConditionsContributors, viii

Preface, xiv

1 Structure–Function Relationships: the Pathophysiology of Airflow Obstruction, 3Dennis E. Niewoehner

2 The Physiology of Breathlessness, 20Donald A. Mahler

3 The Physiology of Muscle, 26Ghislaine Gayan-Ramirez and Marc Decramer

4 Exercise Limitations and Cardiopulmonary ExerciseTesting in COPD, 40Norman R. Morris, Lewis Adams, Bruce D. Johnson and Idelle M. Weisman

5 Clinical Assessment of Control of Breathing, 63Joseph Milic-Emili and Antonia Koutsoukou

6 Physiology and Pathobiology of the Lung Circulation, 75Norbert F. Voelkel

7 Sleep in Patients with COPD, 80Mark W. Elliott

8 The Physiology of Cough, 90Marian Kollarik and Bradley J. Undem

9 The Physiology of Gas Exchange, 102Robert Rodriguez-Roisin, Andrés Echazarreta, Federico P. Gómez and Joan Albert Barberà

Section 1: Physiology

v

21 Eosinophils and COPD, 233Andrew J. Wardlaw

22 Airway Epithelial Defence, Repair and Regeneration, 245Christelle Coraux, Jean-Marie Tournier, Jean-Marie Zahmand Edith Puchelle

23 The Role of the Neutrophil in the Pathogenesis of COPD, 255Ian S. Woolhouse and Robert A. Stockley

24 Lymphocytes, 269Simonetta Baraldo, Maria Elena Zanin, Renzo Zuin and Marina Saetta

25 Cytokines, 275Jack A. Elias and Robert J. Homer

26 Leukotrienes in COPD: The Unexploited Potential, 285Sven-Erik Dahlén

27 Cigarette Smoking, Emphysema and Lung Endothelium, 300Stephanie A. Nonas, Irina Petrache and Joe G.N. Garcia

28 Mesenchymal Cells of the Lung, 308Stephen I. Rennard and J. Graham Sharp

29 Lung Development, 319Cheng Chen, David Warburton and Wei Shi

30 Animal Models, 341Piero A. Martorana, Monica Lucattelli, Barbara Bartalesiand Giuseppe Lungarella

31 Proteinases and COPD, 349Anita L. Sullivan and Robert A. Stockley

32 Oxidants, 367William MacNee

33 Cigarette Smoke-Induced Disease, 385Stephen I. Rennard and Lisa M. Hepp

34 COPD and Air Pollution, 397Kenneth Donaldson, Andrew Churg and William MacNee

35 Viruses in COPD, 408Sam Hibbitts and Colin Gelder

36 Bacteria, 419Sanjay Sethi

37 Genetic Factors, 436Craig P. Hersh and Edwin K. Silverman

Section 4: Pathogenesis

38 α1-Antitrypsin Deficiency, 447Loutfi S. Aboussouan and James K. Stoller

39 Body Weight and Systemic Effects, 460Emile F.M. Wouters

40 Lung Connective Tissue, 467Sarah E. Dunsmore and Geoffrey J. Laurent

41 Aerosols and Delivery Systems, 483Stephen P. Newman

42 Gastro-oesophageal Reflux, 499John K. DiBaise

43 Upper Airway Diseases, 513Maria Rappai and Richard deShazo

44 Acute Pulmonary Embolism, 528Victor F. Tapson

45 COPD and Lung Cancer, 538Stephen G. Spiro and Frank McCaughan

46 Infection Management and Airflow Obstruction, 546Alan M. Fein, Jill P. Karpel and Antonio Anzueto

47 Mechanical Ventilation for Exacerbation of COPD, 559Andrea Rossi, Guido Polese and Lorenzo Appendini

48 Comorbidity, 569Martin Sevenoaks and Robert A. Stockley

49 Primary Care, 579Daryl Freeman and David Price

50 Pulmonary Rehabilitation, 585Richard ZuWallack

51 Social Support, 595Robin Stevenson

52 Long-Term Invasive Mechanical Ventilation, 601Gerard J. Criner

53 Smoking Cessation, 608Philip Tønnesen

54 Oxygen Therapy in COPD, 622Brian Tiep and Rick Carter

55 Surgical Therapy for COPD, 636Fernando J. Martinez

Section 6: Current and Future Treatment

Section 5: Clinical Considerations andComplications

vi CONTENTS

56 Anticholinergics in COPD, 657Theodore J. Witek, Jr

57 β2-Agonists, 669Malcolm Johnson

58 Corticosteroids, 685Olof Selroos

59 Phosphodiesterase 4 Inhibitors in the Treatment ofCOPD, 708Hermann Tenor, Daniela S. Bundschuh, Christian Schudt,Dirk Bredenbröker and Armin Hatzelmann

60 Antibiotic Therapy in Patients with COPD, 728Michael S. Niederman

61 Antioxidants, 747Claudio F. Donner

62 Mucolytics for COPD, 756Duncan F. Rogers and Bruce K. Rubin

63 End-of-Life and Palliative Care for Patients with COPD, 769John E. Heffner and Ann L. Heffner

64 Economic Burden of COPD, 779David H. Au and Sean D. Sullivan

65 Pharmacoepidemiology of COPD, 792Joan B. Soriano

66 Social and Behavioural Impact of COPD – ResearchOpportunities, 805Suzanne S. Hurd and Claude Lenfant

67 Guidelines, 811Peter M.A. Calverley

68 Protease Inhibitors, 823Philip Davies, Malcolm MacCoss and Richard Mumford

69 Retinoids, 845Stephen R. Tudhope

70 Chemokines in COPD, 859Peter J. Barnes

Index, 867

Colour plate section falls between pp. 354 and 355

Section 7: Pharmacotherapy: Developing Therapies

CONTENTS vii

Contributors

Loutfi S. AboussouanAssociate Professor of MedicineDivision of Pulmonary and Critical

Care MedicineWayne State University School of MedicineHarper University Hospital, 3-HudsonDetroit, MichiganUSA

Lewis AdamsSchool of Physiotherapy and Exercise ScienceGriffith University – Gold Coast CampusSouthport, QueenslandAustralia

Antonio AnzuetoAssociate Professor MedicineUniversity of Texas San AntonioDivision of Pulmonary Diseases and

Critical Care MedicineAudie L. Murphy Memorial Veterans HospitalSouth Texas Veterans Healthcare SystemSan Antonio, TexasUSA

Lorenzo AppendiniFondazione Salvatore Maugeri IRCCSVerunoItaly

David H. AuHealth Services Research and DevelopmentVA Puget Sound Health Care SystemDivision of Pulmonary and Critical

Care MedicineUniversity of WashingtonSeattle, WashingtonUSA

Simonetta BaraldoPadua University School of MedicineDepartment of Cardio-Thoracic and

Vascular SciencesSection of Respiratory DiseasesUniversity of PaduaPaduaItaly

Joan Albert BarberàAssociate Professor of MedicinePneumology ServiceHospital ClinicInstitut d’Investigacions Biomèdiques August

Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain

Peter J. BarnesDepartment of Thoracic MedicineNational Heart and Lung InstituteImperial CollegeLondonUK

Barbara BartalesiDepartment of PhysiopathologyExperimental Medicine and Public HealthUniversity of SienaSienaItaly

Dirk BredenbrökerALTANA Pharma AGKonstanzGermany

Daniela S. BundschuhALTANA Pharma AGKonstanzGermany

Peter M. A. CalverleyProfessor of Medicine (Pulmonary and

Rehabilitation)Department of MedicineClinical Sciences CentreUniversity Hospital AintreeLiverpoolUK

Rick CarterChair and ProfessorHealth, Exercise and Sport SciencesTexas Tech UniversityLubbock, TexasUSA

Bartolome R. CelliProfessor of MedicineTufts UniversityChief, Pulmonary Critical Care MedicineCaritas St Elizabeth’s Medical CenterBoston, MassachusettsUSA

Hugues ChanteuxPulmonary and Microbiology DepartmentUniversity of LouvainLouvainBelguim

Cheng ChenDevelopmental Biology ProgramSaban Research Institute of Children’s

HospitalUniversity of Southern California, Los AngelesKeck School of MedicineLos Angeles, CaliforniaUSA andDevelopmental Biology DivisionChina Medical UniversityShenyangChina

viii

Andrew ChurgProfessor of PathologyUniversity of British ColumbiaVancouver, British ColumbiaCanada

Christelle CorauxINSERM UMR-S, 514IFR 53ReimsFrance

Gerard J. CrinerProfessor of MedicineTemple Lung CenterDivision of Pulmonary and Critical Care

MedicineTemple University School of MedicinePhiladelphia, PennsylvaniaUSA

Sven-Erik DahlénExperimental Asthma and Allergy ResearchThe National Institute of Environmental

MedicineThe Centre for Allergy ResearchKarolinska InstitutetStockholmSweden

Philip DaviesDepartment of ImmunologyMerck Research LaboratoriesRahway, New JerseyUSA

Marc DecramerRespiratory Rehabilitation and Respiratory

DivisionUniversity HospitalsKatholieke Universiteit LeuvenLeuvenBelgium

John K. DiBaiseAssociate Professor of MedicineDivision of Gastroenterology and HepatologyMayo ClinicScottsdale, ArizonaUSA

Kenneth DonaldsonProfessor of Respiratory ToxicologyELEGI Colt LaboratoryWilkie BuildingUniversity of Edinburgh Medical SchoolTeviot PlaceEdinburghUK

Claudio F. DonnerMedical DirectorMondo MedicoMultidisciplinary and Rehabilitation

Outpatient ClinicVia Monsignor Cavigioli 10Borgomanero (NO)Italy

Sarah E. DunsmoreDepartment of Medicine (Pulmonary Division)Brigham and Women’s HospitalBoston, MassachusettsUSA

Andrés EchazarretaServicio de NeumonologíaHospital San MartínLa PlataArgentina

Souheil El-ChemalyClinical FellowPulmonary Critical Care Medicine BranchNHLBI, National Institutes of Health10 Center DriveBethesda, MarylandUSA

Jack A. EliasSection of Pulmonary & Critical Care MedicineDept of Internal MedicineYale University School of MedicineNew Haven, ConnecticutUSA

Mark W. ElliottSt James’s University HospitalBeckett StreetLeedsUK

Alan M. FeinProfessor of MedicineNYU School of MedicineChief of Pulmonary, Sleep & Critical Care

MedicineProHealth Care Associates2800 Marcus AvenueSuite 202Lake SuccessNew YorkUSA

Daryl FreemanGeneral Practice Airways Group Research

Fellow in Primary Care Respiratory MedicineGP and GP Specialist in Respiratory MedicineNorth NorfolkUK

Joe G. N. GarciaDivision of Pulmonary and Critical Care

MedicineCenter for Translational Respiratory MedicineJohns Hopkins University School of MedicineBaltimore, MarylandUSA

Ghislaine Gayan-RamirezRespiratory Rehabilitation and Respiratory

DivisionUniversity HospitalsKatholieke Universiteit LeuvenLeuvenBelgium

Colin GelderDepartment of Infection and ImmunityUniversity of Wales College of MedicineHeath ParkCardiffUK

Federico P. GómezPneumology ServiceHospital ClinicInstitut d’Investigacions Biomèdiques August

Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain

Diana C. GrootendorstDepartment of Pulmonology and Clinical

EpidemiologyLeiden University Medical CenterLeidenThe Netherlands

Hélène Levrey HaddenPulmonary, Allergy and Critical Care MedicineUniversity of Minnesota Medical SchoolMinneapolis, MinnesotaUSA

Armin HatzelmannALTANA Pharma AGKonstanzGermany

Ann L. HeffnerDivision of Pulmonary and Critical CareMedical University of South CarolinaCharleston, South CarolinaUSA

John E. HeffnerProfessor of MedicineDivision of Pulmonary and Critical CareMedical University of South CarolinaCharleston, South CarolinaUSA

CONTRIBUTORS ix

Lisa M. HeppPulmonary and Critical Care MedicineUniversity of Nebraska Medical Center

985885 Nebraska Medical CenterOmaha, Nebraska

Craig P. HershChanning LaboratoryDepartment of MedicineBrigham and Women’s HospitalBoston, MassachusettsUSA

Marshall I. HertzPulmonary, Allergy and Critical Care MedicineUniversity of Minnesota Medical SchoolMinneapolis, MinnesotaUSA

Sam HibbittsDepartment of Medical MicrobiologyUniversity of Wales College of MedicineHeath ParkCardiffUK

Robert J. HomerAssociate Professor of PathologyYale University School of MedicineNew Haven, ConnecticutDirector of Anatomic PathologyVA Connecticut HealthCare SystemWest Haven, ConnecticutUSA

Suzanne S. HurdScientific DirectorGlobal Initiative for Chronic Obstructive Lung

Disease (GOLD) Gaithersburg, MarylandUSA

Bruce D. JohnsonDivision of Cardiovascular DiseaseMayo ClinicRochester, MinnesotaUSA

Malcolm JohnsonGlaxoSmithKline Research and DevelopmentGreenfordMiddlesexUK

Kellie R. JonesAssistant ProfessorPulmonary and Critical Care DivisionDepartment of Internal MedicineOklahoma University of Oklahoma Health

Sciences CenterOklahomaUSA

Paul W. JonesProfessor of Respiratory MedicineSt George’s Hospital Medical SchoolLondonUK

Jill P. KarpelProfessor of MedicineAlbert Einstein College of MedicineMedical DirectorBeth Thalheim Asthma CenterDepartment of MedicineNorth Shore-Long Island Jewish Medical

CenterNorth Shore University HospitalNew YorkUSA

Marcus P. KennedyDivision of Pulmonary and Critical Care

MedicineUniversity of North CarolinaChapel Hill, North CarolinaUSA

Michael R. KnowlesDivision of Pulmonary and Critical Care

MedicineUniversity of North CarolinaChapel Hill, North CarolinaUSA

Marian KollarikJohn Hopkins Asthma & Allergy CenterJohn Hopkins School of MedicineBaltimore, MarylandUSA

Antonia KoutsoukouCritical Care Department and Pulmonary

ServicesEvangelismos General HospitalUniversity of Athens Medical SchoolAthensGreece

Geoffrey J. LaurentCentre for Cardiopulmonary Biochemistry

and Respiratory MedicineRoyal Free and University College Medical

SchoolThe Rayne InstituteLondonUK

Claude LenfantFormer DirectorNational Heart, Lung, and Blood InstituteNational Institutes of Health, DHHSBethesda, MarylandUSA

Monica LucattelliDepartment of PhysiopathologyExperimental Medicine and Public HealthUniversity of SienaSienaItaly

Giuseppe LungarellaDepartment of PhysiopathologyExperimental Medicine and Public HealthUniversity of SienaSienaItaly

Malcolm MacCossDepartment of Medicinal ChemistryMerck Research LaboratoriesRahway, New JerseyUSA

William MacNeeProfessor of Respiratory and Environmental

MedicineELEGI, Colt Research LaboratoriesMRC Centre for Inflammation ResearchUniversity of Edinburgh Medical SchoolEdinburghUK

Donald A. MahlerProfessor of MedicineDartmouth Medical SchoolLebanon, New HampshireUSA

Fernando J. MartinezProfessor of MedicineDivision of Pulmonary and Critical Care

MedicineUniversity of Michigan School of MedicineTaubman Center 3916Ann Arbor, MichiganUSA

Piero A. MartoranaDepartment of PhysiopathologyExperimental Medicine and Public HealthUniversity of SienaSienaItaly

Frank McCaughanClinical Research FellowDepartment of Thoracic MedicineUniversity College London NHS TrustLondonUK

x CONTRIBUTORS

Jordan P. MetcalfAssociate ProfessorPulmonary and Critical Care DivisionDepartment of Internal MedicineOklahoma University of Oklahoma Health

Sciences CenterOklahomaUSA

Joseph Milic-EmiliMeakins-Christie LaboratoriesMcGill UniversityMontrealQuebecCanada

Norman R. MorrisSchool of Physiotherapy and Exercise ScienceGriffith University – Gold Coast CampusSouthport, QueenslandAustralia

Bernd MullerLaboratory of Respiratory Cell BiologyUniversity of Giessen and MarburgPhilipps University of Marburg Dept of

Internal MedicineDivision of Respiratory MedicineMarburgGermany

Richard MumfordDepartment of ImmunologyMerck Research LaboratoriesRahway, New JerseyUSA

Stephen P. NewmanScientific ConsultantNottinghamUK

Michael S. NiedermanChairman, Department of MedicineWinthrop-University HospitalMineola, NY andProfessor of MedicineVice-Chairman, Department of MedicineSUNY at Stony Brook, New YorkUSA

Dennis E. NiewoehnerChief Pulmonary SectionMinneapolis Veterans Affairs Medical Center

and Professor of MedicineUniversity of MinnesotaMinneapolis, MinnesotaUSA

Stephanie A. NonasDivision of Pulmonary and Critical Care

MedicineCenter for Translational Respiratory MedicineJohns Hopkins University School of MedicineBaltimore, MarylandUSA

Irina PetracheDivision of Pulmonary and Critical Care

MedicineCenter for Translational Respiratory MedicineJohns Hopkins University School of MedicineBaltimore, MarylandUSA

Charles PilettePulmonary and Microbiology DepartmentUniversity of LouvainLouvainBelguim

Guido PolesePulmonary DivisionOspedali Riuniti di BergamoBergamoItaly

David PriceGeneral Practice Airways Group Professor of

Primary Care Respiratory MedicineDepartment of General Practice and Primary

CareUniversity of AberdeenForesterhill Health CentreAberdeenUK

Edith PuchelleINSERM UMR-S, 514IFR 53ReimsFrance

Klaus F. RabeDepartment of PulmonologyLeiden University Medical CenterLeidenThe Netherlands

Maria RappaiInstructor of MedicineDivision of Pulmonary, Critical Care

and Sleep MedicineDepartment of MedicineUniversity of Mississippi Medical CenterJackson, MississippiUSA

Stephen I. RennardProfessor of MedicinePulmonary and Critical Care Medicine SectionUniversity of Nebraska Medical CenterOmaha, NebraskaUSA

Robert Rodriguez-RoisinProfessor of Medicine Pneumology ServiceHospital ClinicInstitut d’Investigacions Biomèdiques August

Pi i Sunyer (IDIBAPS)University of BarcelonaBarcelonaSpain

Duncan F. RogersThoracic MedicineNational Heart and Lung InstituteImperial College LondonLondonUK

Andrea RossiPulmonary DivisionOspedali Riuniti di BergamoBergamoItaly

Bruce K. RubinProfessor and Associate Chair for ResearchDepartment of PediatricsProfessor of Physiology and PharmacologyWake Forest University School of MedicineWinston-Salem, North CarolinaUSA

Marina SaettaPadua University School of MedicineDepartment of Cardio-Thoracic and Vascular

SciencesSection of Respiratory DiseasesUniversity of PaduaPaduaItaly

Matthias SalatheAssociate Professor of MedicineDivision of Pulmonary and Critical Care

MedicineUniversity of MiamiMiami, FloridaUSA

Christian SchudtALTANA Pharma AGKonstanzGermany

CONTRIBUTORS xi

Carola SeifartUniversity of Giessen and MarburgPhilipps University of MarburgDept of Internal MedicineDivision of Respiratory MedicineMarburgGermany

Olof SelroosAssociate Professor of Pulmonary MedicineHelsinki UniversityHelsinkiFinland

Sanjay SethiAssociate Professor of MedicineDivision of Pulmonary, Critical Care and

Sleep MedicineUniversity of BuffaloState University of New York andVA Western New York Healthcare SystemBuffalo, New YorkUSA

Martin SevenoaksDepartment of MedicineQueen Elizabeth HospitalEdgbastonBirminghamUK

J. Graham SharpProfessorGenetics Cell Biology & AnatomyUniversity of Nebraska Medical Center 986395

Nebraska Medical CenterOmaha, Nebraska

Richard deShazoProfessor of Medicine and PediatricsDivision of Allergy and Clinical ImmunologyDepartment of Medicine and PediatricsUniversity of Mississippi Medical CenterJackson, MississippiUSA

Wei ShiDevelopmental Biology ProgramSaban Research Institute of Children’s

HospitalUniversity of Southern California, Los AngelesKeck School of MedicineLos Angeles, CaliforniaUSA

Yves SibillePulmonary and Microbiology DepartmentUniversity of LouvainLouvainBelguim

Edwin K. SilvermanChanning Laboratory and Division of

Pulmonary and Critical Care MedicineDepartment of MedicineBrigham and Women’s HospitalBoston, MassachusettsUSA

Joan B. SorianoHead, Programme of Epidemiology and

Clinical ResearchFundació Caubet-CIMERA Illes BalearsInternational Centre for Advanced Respiratory

MedicineRecinte Hospital Joan March, Carretera Soller

Km 1207110 Bunyola, Mallorca, Illes BalearsSpain

Stephen G. SpiroDepartment of Thoracic MedicineUniversity College London NHS TrustLondonUK

Robin StevensonDepartment of Respiratory MedicineGlasgow Royal InfirmaryGlasgowUK

Robert A. StockleyProfessor of MedicineDepartment of MedicineQueen Elizabeth HospitalEdgbastonBirminghamUK

James K. StollerProfessor of Medicine, Cleveland Clinic Lerner

School of MedicineVice Chairman, Division of MedicineHead, Section of Respiratory TherapyDepartment of Pulmonary and Critical Care

Medicine, A-190Associate Chief of StaffCleveland Clinic FoundationCleveland, OhioUSA

Anita L. SullivanDepartment of Respiratory MedicineQueen Elizabeth HospitalEdgbastonBirminghamUK

Sean D. SullivanPharmaceutical Outcomes Research and Policy

ProgramDepartment of PharmacyUniversity of WashingtonSeattle, WashingtonUSA

Victor F. TapsonProfessor of MedicineDivision of Pulmonary and Critical CareDuke University Medical CenterDurham, North CarolinaUSA

Hermann TenorALTANA Pharma AGKonstanzGermany

Brian TiepRespiratory Disease Management InstituteIrwindale, CaliforniaWestern University of Health SciencesPomona, CaliforniaPulmonary RehabilitationCity of Hope National Cancer CenterDuarte, CaliforniaUSA

Philip TønnesenChair, Department of Pulmonary MedicineGentofte University HospitalCopenhagenDenmark

Jean-Marie TournierINSERM UMR-S, 514IFR 53ReimsFrance

Stephen R. TudhopeBayer PlcStoke CourtStoke PogesBuckinghamshireUK

Bradley J. UndemJohn Hopkins Asthma & Allergy CenterJohn Hopkins School of MedicineBaltimore, MarylandUSA

xii CONTRIBUTORS

Jørgen VestboProfessor of Respiratory MedicineNorth West Lung CentreSouth Manchester University HospitalSouthmoor RoadManchesterUK andDepartment of Heart and Lung DiseasesHvidovre University HospitalKettegaard Alle 30HvidovreDenmark

Norbert F. VoelkelProfessor of MedicineThe Hart Family Professor of Emphysema

ResearchDirector, COPD CenterPulmonary Hypertension CenterUniversity of Colorado Health Sciences CenterDenver, Colorado

Adam WannerProfessor of MedicineDivision of Pulmonary and Critical Care

MedicineUniversity of MiamiMiami, FloridaUSA

David WarburtonDevelopmental Biology ProgramSaban Research Institute of Children’s

HospitalUniversity of Southern California, Los AngelesKeck School of MedicineLos Angeles, CaliforniaUSA

Andrew J. WardlawProfessor of Respiratory Medicine and Director of Institute for Lung HealthInstitute for Lung HealthDepartment of Infection, Immunity

and InflammationLeicester University Medical SchoolLeicesterUK

Idelle M. WeismanPfizerGlobal PharmaceuticalsPfizer Inc.New YorkUSA

Robert WilsonConsultant PhysicianRoyal Brompton HospitalSydney StreetLondonUK

Theodore J. Witek, JrBoehringer Ingelheim, Lda – PortugalAv. António Augusto de Aguiar no 104-1o

1069-029 LisboaPortugal

Ian S. WoolhouseConsultant Physician and Honorary Senior

Clinical LecturerDepartment of Respiratory MedicineUniversity Hospital BirminghamBirminghamUK

Emile F. M. WoutersProfessor of MedicineDepartment of Respiratory MedicineUniversity Hospital MaastrichtMaastrichtThe Netherlands

Jean-Marie ZahmINSERM UMR-S, 514IFR 53ReimsFrance

Maria Elena ZaninPadua University School of MedicineDepartment of Cardio-Thoracic and

Vascular SciencesSection of Respiratory DiseasesUniversity of PaduaPaduaItaly

Renzo ZuinPadua University School of MedicineDepartment of Cardio-Thoracic and Vascular

SciencesSection of Respiratory DiseasesUniversity of PaduaPaduaItaly

Richard ZuWallackProfessor of Clinical MedicineUniversity of Connecticut School of MedicineAssociate Chief, Pulmonary and Critical CareHartford, ConnecticutUSA

CONTRIBUTORS xiii

However, it became clear that such a book would beextensive and would require the involvement of more editors. For this reason we were very pleased that we persuaded both Bart Celli and Klaus Rabe to join us in thistask. The complexities resulted in a long gestation period,however the persistence of all of the editors and publisherseventually led to the development of this text. We recog-nize that any book of this sort should be regarded as a ‘workin progress’, since the field of COPD research is advancingsteadily, but we greatly appreciate the work of the authorsof the chapters to keep the book as up to date as possible.

We hope this text will provide background and updatenecessary for physicians/scientists/healthcare workers withan interest in COPD.

Robert StockleyStephen Rennard

November 2006

Preface

In recent years COPD has become widely recognised as amajor healthcare problem. This has led to an increase ininterest of the clinical manifestations, management andpathophysiology of the condition. The increase in interesthas been mirrored by dramatic increase in publications andresearch into COPD. Following on from this there has alsobeen an increase in books dedicated to COPD.

Several years ago Steve Rennard and I noted thatalthough there were several textbooks on COPD there were many facets of the condition that required alternativeliterature searches and turning to more books, particularlythose of basic physiology. With this in mind we perceivedthat there was a need for a comprehensive textbook thatcovered normal and abnormal physiology, the latter beingparticularly related to COPD patients and that a spectrumfrom basic to clinical science was missing. Therefore weembarked upon a project to produce as comprehensive abook as possible.

xiv

SECTION 1

Physiology

CHAPTER 1

Structure–function relationships: the pathophysiology of airflow obstruction

Dennis E. Niewoehner

A decrease in maximal expiratory flow rates is the cardinalphysiological abnormality associated with chronic obstruc-tive pulmonary disease (COPD). Expiratory flow obstructionis deemed to be so important that the presence and sever-ity of COPD is commonly defined in terms of the forcedexpiratory pressure in 1 second (FEV1) and of the ratio of the FEV1 to the forced vital capacity (FVC) [1]. The mor-phological features thought responsible for expiratoryairflow obstruction also play a prominent part in the causa-tion of other physiological derangements in COPD, such ashyperinflation and uneven ventilation. These various func-tional abnormalities largely reflect the passive mechanicalproperties of the lung, namely the elastic behaviour of lungparenchyma and airways, and the flow-restrictive char-acteristics of the bronchial tree. The pathological lesionsfound in the lungs of COPD patients have been described insome detail, and they can be broadly classified into thosethat principally affect lung elastic recoil (emphysema) andothers that primarily affect the flow-restrictive properties of the bronchi and bronchioles (airways disease). Ideally,an expert pathologist would be able to estimate accuratelythe degree of airflow obstruction from a comprehensivequantitative assessment of the diseased lung. This can beaccomplished in rather broad terms, but the state-of-the-artfalls well short of the ideal. The physiologist’s assessment of disease severity in the individual case may be markedlydiscrepant from that of the pathologist. These failuresreflect our incomplete understanding of basic pathophy-siology in COPD, as well as the formidable methodologicalproblems in studying an organ so structurally and func-tionally complex as the lung. This chapter describes some of the interrelationships of pathology with physiology inCOPD.

Emphysema

Patients with symptomatic COPD nearly always have someemphysematous involvement of their lungs, although theextent may vary widely among patients who have the samedegree of spirometric impairment. Patients are sometimeslabelled with a clinical diagnosis of ‘emphysema’, but thisusage is discouraged because emphysema has a stricter,pathological definition. An expert committee has definedemphysema as ‘a condition characterized by abnormal en-largement of the airspaces distal to the terminal bronchiole,accompanied by destruction of their walls, and withoutobvious fibrosis’ [1]. Enlargement of the parenchymalairspaces within the gas exchange region of the lung (alve-olus, alveolar duct and respiratory bronchiole) is the seminalfeature of emphysema (Fig. 1.1). Airspace enlargementmay be caused by actual departitioning and fenestration ofthe alveolar walls or by a simpler structural rearrangementof the normal acinus. Airspace enlargement is a normal feature of the ageing lung (‘senile emphysema’), and it may also be observed in diseases such as interstitial fibrosis.Focal areas of fibrosis may be found in many lungs that arejudged to have predominantly emphysema, particularly ofthe centriacinar subtype. Consequently, it may be difficultto ascertain the presence of mild grades of emphysema inthe lungs of older patients, and in some instances there maybe confusion as to whether airspace enlargement should beattributed to emphysema or to a separate disease process.

Pathologists recognize two principal subtypes of emphy-sema. Centriacinar, or centrilobular, emphysema is char-acterized grossly by discrete, enlarged airspaces, usuallymeasuring 1–10 mm in diameter, which tend to be mostprominent in the upper lobes. Microscopically, these

Pathology

3

lesions may be seen in the proximal parts of the respiratorybronchiole, which is the partially alveolated airway imme-diately distal to the terminal bronchiole. Alveolar structuresin the more distal acinus are usually well preserved,although very large centriacinar emphysema lesions mayobliterate much of the acinus. Focal areas of inflammation,fibrosis and carbonaceous pigment are commonly presentin adjacent alveolar and bronchiolar walls.

As the name implies, panacinar, or panlobular, emphy-sema, more uniformly involves the entire acinus. Macro-scopically, mild panacinar emphysema appears as a subtlediffuse enlargement of airspaces, which resembles the aged lung. With progression of the disease, single lesionscoalesce to form airspaces measuring millimeters to centi-meters in diameter; large bullae may form in severe cases.Microscopically, alveolar ducts are diffusely enlarged, andadjacent alveoli become effaced to the extent that indi-vidual units cannot be identified. Panacinar emphysemainvolves all regions of the lung, and some patients, particu-larly those with severe α1-antitrypsin deficiency, may exhibita basal predominance.

When lung sections are appropriately stained, a dense

labyrinth of elastic fibres becomes visible within alveolarwalls and around peripheral airways (Fig. 1.2). This intric-ate elastic fibre network helps maintain normal parenchy-mal structure and contributes importantly to the lung’s distinctive elastic recoil properties. The prevailing theory isthat emphysema develops from an elastase–antielastaseimbalance causing damage to the elastic fibres within thelung parenchyma. Despite their presumed importance inthe pathogenesis of emphysema, surprisingly little is knownabout the state of elastic fibres and other extracellularmatrix components in severe human emphysema. Existingstudies are mostly descriptive and such basic information as the elastin content of the emphysematous lung is notavailable.

Emphysema is an anatomical entity, so that estimates ofprevalence and severity can be directly made only fromspecimens obtained by surgical resection or at autopsy.Because reliable estimates of emphysema severity requirethat specimens be fixed in a uniformly inflated state, wholelungs or lobes are generally more satisfactory than smallerlung samples. The most widely used and accepted methodfor estimating emphysema severity utilizes a standard panel

4 CHAPTER 1

(a) (b)

Figure 1.1 Macroscopic sections of inflation-fixed lungs comparing a normal subject (a) with a COPD patient having moderatelysevere emphysema (b). The emphysema has both centriacinar and panacinar features.

that depicts whole lung sections with increasing degrees of emphysema [2]. The lung section in question is sub-jectively scored by direct comparison against the panel.Determination of a mean linear intercept (average distancebetween alveolar walls) is the preferred method for evalu-ating emphysema severity from histological sections. Thismethod has the advantage of being truly quantitative, but itis time and resource intensive and, because of samplingissues, it is limited in its capability for distinguishing mildemphysema from normal lung [3]. Milder forms of emphy-sema may be focal in their distribution, and can usually bebest appreciated from visualization of whole-lung slices.Estimates of emphysema severity by the picture panel andthe mean linear intercept methods are generally in goodagreement, but for most purposes the picture panel methodis considered the gold standard.

There is now good evidence that reliable estimates ofemphysema severity may be made indirectly from com-puted tomography (CT). Studies to date have consistentlyshown a good correlation between regions of reduced lungtissue density found on CT scan and the presence ofanatomical emphysema [4]. CT scans are highly specific,but they lack sensitivity in detecting very mild grades ofemphysema. This is an evolving technology, with issuesrelating to sensitivity, specificity and standardization cur-rently being addressed.

Airways disease

Much confusion attends the terminology associated withairways disease in COPD. The term ‘chronic bronchitis’ hasbeen widely used but with a variety of meanings. Strictly

speaking, ‘chronic bronchitis’ refers to an inflammatorycondition involving the bronchi, which are the more central, larger and cartilage-containing airways. (The moreperipheral airways without cartilage are termed bronchi-oles.) However, pathologists sometimes refer to bronchialmucous gland enlargement as ‘chronic bronchitis’. To com-plete this rather illogical pattern, the term has also used todefine a ‘clinical disorder characterized by excessive mucussecretion in the bronchial tree, manifested by chronic orrecurrent productive cough on most days for a minimum of 3 months per year for not less than 2 successive years’ [5].Experts arrived at this definition when excess mucus secre-tion was thought to have a central role in the developmentof airflow obstruction in COPD. This is no longer thought tobe the case, but the definition persists to the bewildermentof several generations of medical students and residents. To avoid this confusion, all pathological changes within the bronchial tree that have been implicated in the patho-physiology of COPD will be called simply ‘airways disease’.For reasons that will later become evident, it is appropriateto distinguish pathological changes that primarily involvethe central bronchi from those found in the peripheralbronchioles.

Central airways diseaseMucus lines the airway lumens of the bronchial tree andserves an important role in host defence against the envir-onment. Mucous glands, containing both mucous andserous cells, are found between the epithelial basementmembrane and the cartilage plates of the central bronchialtree. Mucus is actively secreted into the bronchial lumenvia specialized ducts. Modest enlargement of the bronchialmucous glands is found in the lungs of many patients withCOPD but not all. Bronchial mucous gland enlargementcorrelates with cough and excess sputum production [6].The Reid Index was the first described method for quantify-ing the degree of mucous gland enlargement [7]. In thistechnique, the width of the mucous gland is compared withthe width of the bronchial wall between the basal laminaand the perichondrium. This method has been largely sup-planted by better methods which quantify area propor-tions. The volume of bronchial mucous gland may increaseby 50–100% in selected cases of severe COPD (Fig. 1.3).

In addition to the mucous glands, mucus-secreting gobletcells are found in airway epithelium at all levels of the con-ducting airways. The population of epithelial goblet cellsmay expand in the larger airways of COPD patients, butexisting studies are mostly descriptive. Epithelial meta-plasia and loss of cilia have also been described. It is not clearwhether the proportions of smooth muscle and cartilageare abnormal in lungs of COPD patients. COPD is com-monly associated with a low-grade inflammatory responsewithin the epithelium and submucosa of the more central

STRUCTURE–FUNCTION RELATIONSHIPS 5

Figure 1.2 Thick histological section of normal human lungstained for elastic fibres. Elastic fibres appear as a lacy networkof thin dark lines when an alveolar wall is viewed en face.Thicker elastic fibres surround the ostia connecting alveolarducts with individual aveoli. Elastic fibres are majorcontributors to lung elastic recoil.

(Fig. 1.4). The earliest abnormalities seen in lungs fromyoung smokers are focal collections of brown-pigmentedmacrophages in the proximal respiratory bronchioles [9].In older patients with established COPD, the walls of membranous bronchioles frequently contain a low-gradeinflammatory response that includes scattered neutrophils,macrophages and lymphocytes [10]. Additional abnormal-ities include fibrosis, goblet cell and squamous cell meta-plasia of the lining epithelium, smooth muscle enlargementand scattered aggregations of mucus within the lumen.Most of this pathology can probably be directly attributed tothe toxic effects of cigarette smoke, but peripheral airwaysin the lungs of elderly lifelong non-smokers may exhibitsome of the same abnormalities [11].

Measurements in lungs obtained at surgery and atautopsy indicate that the internal calibre of fully distendedperipheral bronchioles is smaller in COPD patients com-pared with normal subjects [11,12]. In addition, the wallsof bronchioles from COPD patients are abnormally thick-ened, with the increased width being caused by epithelial,smooth muscle and connective tissue elements [13].Abnormally thickened airway walls may take on addedfunctional significance at smaller lung volumes, becausethe peripheral airways shorten and narrow as the lungdeflates. Figure 1.5 illustrates this point. In the exampleshown, the abnormal airway has a wall that is twice the

6 CHAPTER 1

Figure 1.3 Histological section of a cartilaginous bronchusfrom a COPD patient with chronic cough and sputumproduction shows marked mucous gland enlargement.Mucous glands normally occupy but a small part of the areabetween cartilage and epithelium. A low-grade inflammatoryreaction commonly accompanies mucous gland enlargement.

(a) (b) (c)

Figure 1.4 Normal terminal bronchiole from a human lung is a thin-walled structure with an internal diameter of approximately0.5 mm (a). Section through the junction of a membranous and respiratory bronchiole from the lung of a young adult shows the typical inflammatory lesion caused by cigarette smoking (b). Clusters of brown-pigmented macrophages are visible in therespiratory bronchiole and a few mixed inflammatory cells are present within the walls of the membranous bronchiole. In patientswith established COPD, membranous bronchioles may exhibit thickened walls and narrowed distorted lumens (c).

bronchi. Neutrophils, macrophages and CD8+ T lympho-cytes are the predominant inflammatory cells [8].

Peripheral airways diseaseThe pathological changes seen in the peripheral airways of COPD patients are multiple and relatively non-specific

normal thickness. For the same change in external dia-meter, the lumen of the abnormal airway wall narrows to afar greater extent because the constant volume of excesstissue tends to bulge inward. This effect is greatly magnifiedat very small lung volumes, where the development of lon-gitudinal folds along the inner surface may predispose tocomplete airway closure.

The accurate assessment of diverse pathological featuresthat are widely distributed among tens of thousands of individual airways presents a formidable problem. Stand-ardized scoring systems and direct quantitative approachesthat measure the dimensions and volume components ofthe airways have largely supplanted earlier descriptivestudies [11,12,14]. However carefully they are performed,assessments of airways in fixed tissues may poorly reflecttheir functional behaviour during the respiratory cycle.There have been efforts to image airways with CT and ultra-sound during life [15,16]. These methods are interestingand promising, but they have yet to be fully validated. Themajor issue is whether they are capable of adequatelyresolving the dimensions of the smaller airways.

Lung elastic recoil

Lung elastic recoil refers to the lung’s intrinsic tendency todeflate after it has been inflated. This relationship is com-monly expressed by plotting lung volume as a function oftranspulmonary pressure under the condition of no airflow

Physiological abnormalities

(Fig. 1.6). Transpulmonary pressure is defined as the pressure differential between the inside and the outside ofthe pleura. Pressure in the pleural space may be roughlyestimated from a balloon catheter placed in the mid-oesophagus. In normal young adults, transpulmonary pressure at total lung capacity (TLC) is typically in excess of 35 cm H2O and at functional residual capacity (FRC) isapproximately 5 cm H2O. Lung elastic recoil is sometimesdefined in terms of compliance, defined as the change in lung volume relative to the change in pressure. The pressure–volume relationship is curvilinear through itsentirety, and as a result, compliance has a unique value ateach lung volume. There has been some success in fittingempirical mathematical models to the pressure–volumecurve so that the entire relationship can be described byestimation of one or two parameters [17,18]. For most purposes lung elastic recoil can be adequately described interms of the transpulmonary pressure at some specifiedlung volumes, TLC and FRC being most commonly used.

Loss of lung elastic recoil is one of the distinguishing features of ageing. This occurs in a manner so predictablethat age can be estimated with fair accuracy from the pressure–volume characteristics of a postmortem lung [17].Age-related losses in lung elasticity probably explain muchof the decrease in spirometric function that occurs withadvancing age.

Lung elastic recoil may be divided into two components:one resulting from tissue elasticity and a second attributable

STRUCTURE–FUNCTION RELATIONSHIPS 7

Normalairway

Abnormalairway

0.85 0.701.0

External airway diameter

Figure 1.5 External airway diameter decreases as lungvolume becomes smaller. Because the volume of the airwaywall remains constant, the wall becomes thicker at smallerlung volumes, with a disproportionate reduction in the calibreof the lumen. At very small lung volumes, longitudinal foldsmay develop along the inner wall of the airway. Abnormallythick airway walls, as occurs in COPD, may exaggerate this effect.

NormalTLC

Emphysema

Normal

NormalRV

Elastic recoil pressure

Lun

gvo

lum

e

Figure 1.6 Lung volume as a function of lung elastic recoilpressure in a normal subject and in a COPD patient withextensive emphysema. At any particular lung volume, lungelastic recoil pressure is reduced with emphysema. In addition,the pressure–volume curve in the emphysema patient exhibitsgreater concavity towards the pressure axis. RV, residualvolume; TLC, total lung capacity.

to the air–liquid interface at the alveolar surface. Tissueelasticity arises from the rich network of elastic fibreswithin lung parenchyma, from other components of theextracellular matrix, and from the geometrical arrange-ments of these elements. Isolated elastic fibres behavemuch like rubber bands, snapping back to their originalposition upon being stretched to twice their resting length.Alveolar structures are sufficiently small that surface ten-sion at the air–liquid interface creates significant pressurewithin the alveolar spaces, even in the presence of the sur-face tension-lowering substance, surfactant. This relation-ship is defined by the law of Laplace, which states that thepressure within a wetted sphere is proportional to the ten-sion within the lining liquid film and inversely proportionalto the radius of curvature. Comparing pressure–volumecurves from air- and fluid-filled lungs delineates the con-tribution of tissue elements and of surface tension. Bothmake substantial contributions in the human lung. Hence,damage to matrix elements and loss of alveolar surface areawould both be expected to reduce lung elastic recoil.

Because damage to elastic fibres and loss of alveolar surface area are the characteristic pathological features ofemphysema, a decrease in lung elastic recoil would beanticipated. This prediction has been fully confirmed andFigure 1.5 illustrates the typical abnormality. Comparedwith normal, the severely emphysematous lung exhibits asubstantial loss in elastic recoil pressure at all lung volumes.In addition, the pressure–volume curve in severe emphy-sema exhibits a shape change, being somewhat more con-vex with respect to the pressure axis. These altered lungelastic properties might be viewed as the primary functionaldefect associated with human emphysema.

Airflow resistance

The human bronchial tree is a complex structure. Startingwith the trachea, conducting airways branch in an irregu-larly dichotomous pattern. Different pathways from tracheato terminal membranous bronchiole may encompass as fewas 10 generations or as many as 25. Further branchingoccurs within the partly alveolated respiratory bronchiolesdistal to the terminal bronchiole. The internal diameter ofthe adult trachea is approximately 2 cm. Airway calibredecreases with each succeeding generation to a miniscule0.5 mm at the level of the terminal bronchiole. Becausethere are approximately 50 000 terminal bronchioles ineach human lung, total cross-sectional area at this level ofthe bronchial tree exceeds that of the trachea by about twoorders of magnitude. Hence, the velocity of airflow duringthe breathing cycle is substantially larger in the central air-ways compared with the peripheral airways.

A pressure differential is necessary to generate airflowthrough a cylinder. The ratio of the longitudinal pressure

difference to the flow rate defines airflow resistance. Themagnitude of airflow resistance varies with the flow profile(laminar versus non-laminar), the physical properties of thegas and the dimensions of the cylinder. The many airwayscomprising the bronchial tree can be viewed as resistive elements existing in series and in parallel.

As is true for lung parenchyma, airways exhibit intrinsicelastic behaviour which allows them to widen or narrow inresponse to traction and pressure differentials. Because ofthe cartilaginous rings within their walls, proximal bronchiare relatively rigid structures. However, the membranousposterior portion is easily deformed, and it will bow inwardto occlude the airway lumen when subjected to large compressive pressures. Peripheral bronchioles have littleinherent rigidity. The relatively thin, cartilage-free walls ofthese airways are embedded within lung parenchyma, and they depend upon the tethering effect from alveolarwall attachments to maintain patent lumens. The outwardtension exerted by alveolar walls is a function of lung volume; the bigger the volume, the larger the lung elasticrecoil, and the greater the tension within each alveolarattachment. If the lung were to exhibit perfect isotropy, a50% reduction in lung volume would be associated with a 21% reduction in airway calibre.

Assessment of airflow resistance requires simultaneousmeasurements of airflow at the mouth and of pressure differential between the mouth and the alveolus. Alveolarpressures can be estimated either with an oesophageal bal-loon or by a plethysmographic method. Figure 1.7 compares

8 CHAPTER 1

NormalTLC

COPD

NormalRV

Normal

Airways resistance

Lun

gvo

lum

e

Figure 1.7 Lung volume as a function of airways resistance in a normal subject and in a COPD patient. In both patientsairways resistance increases as lung volume becomes smaller.At any given lung volume, airways resistance is considerablylarger in the COPD patient. RV, residual volume; TLC, totallung capacity.

typical airflow resistance as a function of lung volume in a normal subject with that in a COPD patient with emphy-sematous lungs. There is a strong volume dependence ofairflow resistance in both subjects, this reflecting thedecrease in lung elastic recoil and consequent reduction inairway calibre at smaller lung volumes. Airflow resistance is substantially higher at comparable lung volumes in thepatient with COPD, and this might be attributed to two dis-tinct mechanisms. At the same lung volumes, lung elasticrecoil would be less in the emphysematous lungs, with theexpectation that airways would be narrower and airflowresistance would be higher. It is possible to negate this effectby comparing airflow resistance in different lungs at thesame lung elastic recoil pressures. Under these conditions,airflow resistance is still substantially higher in COPD com-pared with normal. This strongly suggests structural andfunctional abnormalities inherent to the conducting airwayscause increased airflow resistance in COPD.

The dominant site of airflow resistance within the pul-monary airways is not intuitively obvious. The bronchialtree is a complex structure and pathological changes havebeen described at all levels in lungs from patients withCOPD. The peripheral bronchioles are much smaller thanthe proximal bronchi, but there are a great many of them.Total cross-sectional area at the level of the terminal bron-chiole is larger than the trachea by orders of magnitude.However, this tells us little about the relative flow-resistiveproperties at the two levels, because area changes as thesquare of airway radius while resistance changes as thefourth power or higher.

Studies with a retrograde catheter in excised animal andhuman lungs provide an invaluable clue to the site andnature of increased airflow resistance in COPD [19,20]. Thecatheter was placed at a site in the bronchial tree whereairflow resistance in airways less than 2 mm diameter couldbe partitioned from resistance in airways with a diameter of greater than 2 mm. The first studies were performed innormal dogs and they yielded results that at the time wereconsidered rather surprising [19]. The peripheral compon-ent accounted for only approximately 10% of total airflowresistance, a value much smaller than had been suggestedby earlier studies.

Retrograde catheter studies of central and peripheralairflow resistance were subsequently made in postmortemlungs from subjects with and without COPD [20]. As wasthe case in dog lungs, the peripheral component of totalairflow resistance in normal human lungs appeared quitelow, representing only 10–20% of the total. In lungs fromCOPD patients, the central component of airflow resistancewas only slightly increased from that in normal lungs.However, the peripheral component was increased by factor of between 10 and 20. These observations addedenormously to our understanding of the pathophysiology

of COPD, because they indicated that it was disease in thedistal airways and not the large bronchi that was principallyresponsible for increased airflow resistance in COPD.

The partitioning of airflow resistance in normal and diseased human lungs also led to a novel idea about the natural history of COPD, which in turn spawned a large andmostly futile research effort. The retrograde catheter stud-ies indicated peripheral airflow resistance was negligible innormal lungs, but predominant in severe COPD. Therefore,early stages of the disease might be associated with patho-logical changes in the peripheral airways that had minimaleffect on standard tests of lung function, such as the FEV1.It was further reasoned that these early changes might better be detected with more sensitive, non-standard tests.Considerable effort was expended in developing and evalu-ating newer, so-called ‘tests of small airways disease’,including the frequency dependence of dynamic lung compliance, the single breath nitrogen washout test, andspirometry with exotic gas mixtures. These tests have longbeen abandoned, because a variety of epidemiological andpathological–physiological correlative studies indicated thatthese newer, specialized tests offered little advantage overthe FEV1 in detecting the earliest stages of COPD [21–24].

These newer tests failed in part because they were based on a faulty rationale. Studies by other investigatorsindicated that the original retrograde catheter studies were subject to methodological errors that led to a systematicunderestimate of peripheral airflow resistance in both normal and COPD lungs [25,26]. Repeat measurements in human lungs indicated that the peripheral componentrepresents approximately 90% of total airflow resistance in the normal lung [27]. Additionally, studies in normalpostmortem lungs demonstrated a remarkably good cor-relation between total airflow resistance and the diameterof the peripheral airways, but not with the diameter of theproximal airways [28].

These findings have important implications regardingour understanding of COPD. They lend strong support tothe concept that the peripheral airways, and not the cent-ral airways, are principally responsible for the increasedairflow resistance in COPD. If the peripheral airways deter-mine levels of ventilatory function in the normal lung, itlogically follows that relatively minor pathological changesin those same airways take on added functional significancein disease states.

Maximal expiratory airflow limitation

Spirometry is recommended as the single best test for thediagnosis of COPD. During this procedure maximal expir-atory airflow is measured as a function of time, and theresult is graphically displayed as either a volume–time or flow–volume plot. The two plots contain identical

STRUCTURE–FUNCTION RELATIONSHIPS 9

information. The most common parameters extracted fromthe spirogram are the FEV1 and the FVC. The expiratory flow rate between 200 and 1200 mL of the FVC, the mid-expiratory forced expiratory flow rate between 25% and75% of the FVC, and other less frequently used spirometricparameters contain little additional diagnostic informationand have fallen out of favour. A decrease in the FEV1, bestexpressed as the percentage of predicted, and a decrease inthe ratio of the FEV1 to the FVC (FEV1/FVC) are the hallmarkspirometric abnormalities of COPD.

Figure 1.8 shows representative flow–volume curvesfrom a normal subject and from a patient with COPD. Atany given fraction of VC, maximal expiratory flow rates aresmaller in the COPD patient. In this example, flow rates areshown as a function of absolute lung volume to illustrateanother of the cardinal physiological abnormalities inCOPD. The COPD patient exhibits hyperinflation in thatboth the TLC and residual volume (RV) are shifted to largerlung volumes.

Forced expiratory flow–volume curves exhibit a phenom-enon that is termed airflow limitation. The principle can be demonstrated by having a normal subject perform a series of full inspiratory and expiratory breathingmanoeuvres between RV and TLC, each with a differentstrength of effort. Figure 1.9 depicts these graded efforts (a increasing through e) as a family of flow–volume loops.Greater effort during the inspiratory phase yields largerflow rates, and these increases are roughly proportional at all lung volumes. On the expiratory cycle, greater effortalso generates larger flow rates, but only at the higher lungvolumes. At intermediate and low lung volumes, airflow

increases with added effort, but only up to a certain point.At that point the tracing superimposes those from otherindividual efforts. Over the lower two-thirds of the vitalcapacity a ceiling becomes evident, beyond which airflowdoes not increase further however great the expiratoryeffort. Expiratory flow rates at these lung volumes aresometimes described as being ‘flow limited’ or ‘effort independent’.

The principle of flow limitation can be demonstrated insomewhat better detail from what are called isovolumepressure–flow diagrams (Fig. 1.10). Inspiratory and expir-atory flow are plotted as a function of alveolar pressure atspecified lung volumes. The pressure differential betweenthe mouth and the alveolar space, or driving pressure, gen-erates airflow though the bronchial tree. Alveolar pressureis negative with respect to the mouth during inspirationand positive with expiration. During inspiration, airflowremains linear with driving pressure at each of the indic-ated lung volumes, meaning that airflow resistance remainsnearly constant. Hence, inspiratory flow is largely limitedby the magnitude of the applied pressure, which is largely a function of respiratory muscle strength. Differences in

10 CHAPTER 1

0

9

6

3

12

Flo

w (

loo

ps)

Absolute lung volume (L)9 8 7 6 5 4 3 2 1 0

RV

RV

FVC

FVC

Normal

COPD

Normal

COPD

Figure 1.8 Expiratory flow–volume loops as a function ofabsolute lung volume in a normal subject and in a patient with COPD. This figure illustrates the cardinal functionalabnormalities associated with COPD, expiratory airflowlimitation and hyperinflation. FVC, forced vital capacity; RV, residual volume.

Flo

w r

ate

(lo

op

s)

% Vital capacity80 60 40 20 0100

8

6

4

2

0

a

b

c

d

e

a

b

c

d

e6

4

2

Inspiration

Expiration

Figure 1.9 A normal subject performed a series of fullinspiratory and expiratory manoeuvres with graded effort(a–e). On the expiratory limbs, flow rates are independent ofeffort at smaller lung volumes. This phenomenon, described as ‘flow limitation’ or ‘effort-independence’, is not seen withinspiratory manoeuvres.

the slopes of the pressure–flow relationships at the threedifferent lung volumes indicate that airflow resistancebecomes greater as lung volumes become smaller.

The patterns obtained during expiration are qualitativelydifferent in that relationships between the pressure differ-ential and airflow are curvilinear rather than linear. This ismost obvious at smaller lung volumes where a fairly sharpinflection occurs at a relatively low driving pressure. Beyondthis inflection, the relationship assumes a plateau shape,meaning that airflow is independent of changes in drivingpressure. In other words, greater expiratory effort createsgreater airflow resistance with no increase in airflow.Limitations to expiratory airflow are set by the mechanicalproperties of lung parenchyma and bronchial tree.

The relevance of expiratory airflow limitation to clinicaldisability can be appreciated by comparing flow–volumeloops from a COPD patient with that of a normal subject.Figure 1.11 shows inspiratory and expiratory flow–volumeloops during tidal breathing at rest and with maximal effortin the two subjects. Note that the normal subject has enorm-ous reserve and from the resting state is able to increaseminute ventilation by a large factor in response to increasedmetabolic demands. Consequently, ventilation is not a lim-iting factor, even with very vigorous exercise. In contrast,maximal inspiratory and expiratory flow rates are muchsmaller in the patient with COPD, expiration typically beingmore severely affected than inspiration. Most import-antly, a large portion of the expiratory flow–volume loop

obtained during tidal expiration superimposes that from aforced expiration. Severe COPD patients exhibit flow limita-tion even while meeting the minimal ventilatory require-ments of the resting state. These patients have only limitedcapability for increasing minute ventilation in response toexercise. Their only effective strategy for increasing minute

STRUCTURE–FUNCTION RELATIONSHIPS 11

Negativealveolar pressure

Inspiratoryflow rate

Expiratoryflow rate Large lung

volume

Medium lungvolume

Small lungvolume

Positivealveolar pressure

Figure 1.10 Relationship ofinspiratory and expiratoryairflow rates to alveolar pressureat various lung volumes. Withinspiration, flow increasesproportionally to alveolarpressure. With expiration, flowincreases with alveolar pressureonly to a certain point, beyondwhich flow remains constantdespite greater alveolar pressures.This effect, flow limitation, ismost pronounced at smaller lung volumes.

Lung volume

Normal COPD

Air

flo

w

Insp

irat

ion

Exp

irat

ion

Figure 1.11 Inspiratory and expiratory flow–volume loops ina normal subject and in a patient with severe COPD. The outerloops represent maximal efforts and the loops represent tidalbreathing. In the patient with COPD, expiration is flow limitedeven during a tidal breath.

ventilation is to shift tidal breathing to larger lung volumeswhere higher expiratory flow rates can be achieved.Clinical studies have shown that hyperinflation is a com-mon response to increased workload in COPD patients[29]. Unfortunately, this compensatory mechanism comeswith a price, because the lung and the thoracic cage bothbecome stiffer at larger volumes. This increases the elasticworkload of the respiratory muscles and is an importantcomponent in generating the sensation of breathlessness.

Mechanism of expiratory airflow limitation

Models of varying complexity have been used to analysethe physical behaviour of the lung in an effort to explainflow limitation during forced expiratory manoeuvres. Arelatively simple model is described that provides someinsight into this mechanism. The interested reader is re-ferred elsewhere for more detailed and rigorous approachesto the subject [30–32].

The model shown in Figure 1.12 includes an expand-able balloon to represent lung parenchyma. The balloon iscontained within a box that depicts the thoracic cage. Thespace between the box and the balloon may be viewed asthe pleural space. An airway with semi-rigid walls connectsthe balloon to the exterior. Up or down movement of thepiston, representing the function of respiratory muscles,activates the model by altering intrapleural pressure (Ppl).The centrally directed arrows on the interior of the balloonsymbolize lung elastic recoil.

Figure 1.12(a) shows the model at a fixed volume withno airflow. Under these static conditions, there is no gra-dient along the length of the airway and alveolar pressure(Palv) is equal to the reference pressure at the airway open-ing (Pao). The intrapleural pressure required to keep thelung statically inflated (arbitrarily chosen to be –10 cm H2Oin this example) is equal in magnitude but opposite in signto the lung elastic recoil pressure (Pel). Hence, Palv is thealgebraic sum of Ppl and Pel.

Downward motion of the piston creates a more negativePpl. Palv now becomes negative with respect to Pao and airflows into the lung. On expiration, muscles relax and thelung typically contracts passively because of its inherentelastic recoil. As Ppl becomes less negative (–10 cm H2Oincreasing to –5 cm H2O), Palv becomes positive withrespect to Pao and the lung exhales air (Fig. 1.12b). Duringthe normal tidal breathing cycle, Ppl fluctuates by only afew centimetres H2O and it remains negative even duringexpiration. As a result, pressure at each point within the conducting airway remains positive with respect to Ppl during the entire inspiratory and expiratory cycle.Consequently, an outwardly directed transmural pressuregradient expands the airway along its entire length, aneffect that is greater during inspiration.

However, a forced expiratory effort creates a stronglypositive Ppl that reverses the usual transmural pressure gradient along a segment of the airway. Figure 1.12(c) illus-trates these pressure relationships during a submaximalforced expiration. Respiratory muscles generate sufficientforce to increase Ppl to +10 cm H2O. From the algebraic sumof Ppl and Pel, Palv now becomes +20 cm H2O. The alveolardriving pressure dissipates along the length of airwaylumen and at some point becomes equal to Ppl so that thetransmural pressure gradient is zero. This is sometimesdescribed as the ‘equal-pressure point’ (EPP). The EPP hasno fixed anatomical site. Direct measurements suggest thatthe EPP is located in the central cartilaginous airways dur-ing the early stages of the maximal expiratory manoeuvre,but then migrates peripherally at lower lung volumes.Downstream from the EPP, intraluminal pressures becomenegative with respect to Ppl, creating a compressive forceon the airway. Because the airway is not a rigid tube, compressive pressures narrow the lumen to some degree,thereby increasing airflow resistance. The length of com-pressed airway is referred to as the ‘flow-limiting segment’.

Figure 1.12(d) illustrates the same relationships but witha more forceful expiratory effort. In this example, Pplincreases to +20 cm H2O and the alveolar driving pressure,Palv, now enlarges to +30 cm H2O. Because of the higherPpl, compressive transmural pressures downstream fromthe EPP are now twice as large as in Figure 1.12(c). This further narrows the airway lumen with a correspondingincrease in airflow resistance. In other words, greater expir-atory effort increases the pressure head between alveolusand airway opening, but it also increases flow resistancebecause of greater compression of the airway downstreamfrom the EPP. The result is little net change in expiratoryairflow. This type of feedback mechanism for limiting flowis sometimes referred to as a Starling resistor, of whichthere are examples in other organ systems. It bears em-phasizing that these relationships are exceedingly complexwhen analysed from first principles and no physical lawrequires that changes in Palv and airflow resistance need be strictly proportional. However, empirical observationsindicate that these changes are roughly proportional inmost human subjects.

The illustrated model permits some insight into other fac-tors that might influence the flow-limiting airway segment.It is intuitively evident that a less rigid airway would nar-row to a greater extent in response to the same transmuralcompressive pressure differential. Other conditions beingequal, excessively compliant central airways would fixmaximal expiratory airflow at a lower level. It is unclearfrom existing studies whether bronchial compliance isabnormal in well-defined patients with COPD.

Airflow resistance in more distal portions of the conduct-ing airways may accentuate compressive effects on the

12 CHAPTER 1

more proximal flow-limiting airway segment. This is illus-trated in Figure 1.12(e), which depicts partial obstruction in the most distal part of the airway. Peripheral airway narrowing may occur as a consequence of pathological features such as inflammation and excess mucus. As asresult of the increase in peripheral airflow resistance, a

greater portion of the driving pressure between alveolusand airway dissipates over the obstructed segment of air-way. Hence, the EPP migrates distally and a longer segmentof the more proximal airway is subjected to compressivepressures. Total airway resistance would increase and max-imal expiratory airflow would be expected to decrease.

STRUCTURE–FUNCTION RELATIONSHIPS 13

Chestwall

(a) (b)Respiratory muscles

Airway

Pleural spacePpl = –10cm H2O

Pel = +10

Alveolarspace

Chestwall

Ppl = –5Pel = +10

Palv = +5 +4 +3 +2 +1 0

0

(c) (d)

EPP

Ppl = +10Pel = +10

Ppl = +20

Ppl = +20

Pel= +10

Palv = +30Palv = +20 +10

EPP

+200

0

(e) (f)

Pel = +10

Palv = +30 +20 0

EPP

Ppl = +20Pel= +5

Palv = +25 +20

EPP

Figure 1.12 Model of expiratory flow limitation. Seetext for detailed explanation. (a) Description of static model.(b) Expiration during tidalbreath. (c) Submaximal forcedexpiration. (d) Submaximalforced expiration but withgreater effort than in (c). (e) Forced expiration withincrease in peripheral airwaysresistance. (f) Forced expirationwith decreased lung elastic recoilpressure. EPP, equal-pressurepoint; Palv, alveolar pressure; Pel, elastic recoil pressure; Ppl, intrapleural pressure.

Loss of lung elastic recoil also has an impact on maximalexpiratory airflow limitation. One mechanism relates to theeffects of lung elastic recoil on the diameter of the intra-parenchymal airways, which are not shown in the model. Adecrease in lung elastic recoil at any specified lung volumewill reduce airway calibre and increase peripheral airflowresistance. The effect on maximal expiratory airflow will besimilar to that shown in Figure 1.12(e).

Another effect of elastic recoil on maximal airflow limita-tion is less intuitive. Note that an arbitrary value of 10 cmH2O is assigned to Pel in Figure 1.12(a–e). Note also thatwhen flow limitation becomes evident, as in Figure 1.12(dand e), the difference between Palv and the intra-airwaypressure at the EPP has the same magnitude as Pel (10 cmH2O). Viewed in this manner, lung elastic recoil effectivelykeeps airways open by opposing the high compressive pres-sures that develop in the pleural space during forced expir-ation. Figure 1.12(f) illustrates the effect of decreased lungelastic recoil on flow limitation. In this example, a Pel of 5 cmH2O has been assigned to an ‘emphysematous balloon’.With the same force exerted by respiratory muscles on thepleural space (Ppl = 20 cm H2O), Palv now increases to only25 cm H2O instead of 30 cm H2O. There is a correspondingdecrease in the intra-airway pressure that opposes airwaycompression. Consequently, the EPP migrates distally, thecompressed segment of airway becomes longer, with a corresponding decrease in maximal expiratory airflow.

Lung hyperinflation

A second characteristic and very important physiologicalabnormality in COPD is hyperinflation. This is variablydefined as abnormally large TLC, FRC or RV. Lung volumescan be measured either by the washin or the washout of tracer gases, such as helium, or by plethysmography.Because tracer-gas methods require long equilibrationtimes in the presence of severe COPD, plethysmography isthe more accurate method. In clinical practice the diagnosisof COPD can usually be made from clinical and spirometricfindings alone, but lung volume measurements may beuseful in selected patients.

Figure 1.8 illustrates both the expiratory airflow abnorm-alities and the hyperinflation that are typical of COPD. As the FEV1 and the FVC decrease, RV and TLC increase.Indices of hyperinflation, particularly the RV and RV/TLC,track closely with spirometric measures of expiratory air-flow obstruction across a broad range of COPD severity [33].This suggests that the functional and structural featuresthat relate to expiratory airflow obstruction, namely loss of lung elastic recoil and increased peripheral airway resist-ance, are also responsible for an abnormally large RV.

RV is sometimes termed the ‘volume of trapped air’, adescription that is probably apt. As described previously,

lung volume, lung elastic recoil and peripheral airway resist-ance are intimately interrelated. As lung volume becomessmaller, elastic recoil decreases and the attendant loss ofradial tension causes narrowing of the peripheral airways.At some point, resistance effectively becomes infinite andflow ceases. Several lines of indirect evidence suggest thatperipheral airways in humans may actually close at lungvolumes near RV, a phenomenon that has been directlyobserved in experimental animal lungs [34]. Calculationssuggest that surface tension at the air–liquid interface onthe epithelial surface of peripheral airways may be substan-tial as the lung volume nears RV, so that an intact surfactantsystem may be essential if the terminal bronchioles are toremain patent [35].

Structural correlates of expiratory airflow limitation

Expiratory airflow limitation is functionally related both toa loss of lung elastic recoil and to an increase in airflowresistance through the bronchial tree. Emphysema is pre-sumed to be the morphological equivalent of abnormallung elastic recoil, while a variety of pathological changes,particularly those in the peripheral airways, are thought to be responsible for increased airflow resistance throughthe bronchial tree. Consequently, there is the expectationthat a detailed quantitative assessment of emphysema andairways disease in a lung from a COPD patient should allow a reasonably accurate prediction of spirometric func-tion. Over the past several decades, numerous efforts toshow such pathological and physiological correlations haveyielded rather disappointing results.

Investigators have utilized several approaches whenundertaking correlative structure–function studies, andeach of these has certain advantages and limitations. Mostcommonly, investigators have compared lung tissueobtained at necropsy with function tests performed prior todeath. Patients with severe disease tend to be heavily over-represented in this type of study and the interval betweenthe last pulmonary function test and death is variable.Tissue may also be acquired from patients undergoing lungresection surgery, which is usually performed for localizedcarcinomas. This approach has the major advantage ofallowing detailed pulmonary function testing shortly priorto the scheduled surgery. It has the disadvantage of pro-viding only a limited amount of tissue in most patients,with attendant problems in achieving uniform inflationand fixation. Also, potential surgical candidates must havesufficiently good lung function if they are to tolerate resec-tion, which excludes most patients with severe COPD.Lung-volume-reduction surgery provides new opportun-ities for obtaining resected lung tissue from patients withsevere disease, but the samples are relatively small and they

14 CHAPTER 1