Global Initiative for Chronic Obstructive Lung Disease - GOLD

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Global Initiative for Chronic 

Obstructive 

Lung 

Disease 

GLOBAL STRATEGY FOR THE DIAGNOSIS, 

MANAGEMENT, AND PREVENTION OF 

CHRONIC OBSTRUCTIVE PULMONARY DISEASE 

UPDATED 2005

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GLOBAL INITIATIVE FOR 

CHRONIC OBSTRUCTIVE LUNG DISEASE 

GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, 

AND PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE 

Updated 2005 (Based on an April 1998 NHLBI/WHO Workshop) 

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APRIL 1998 WORKSHOP PANEL 

Global Strategy for the Diagnosis, Management, and Prevention of 

Chronic Obstructive Pulmonary Disease: NHLBI/WHO Workshop 

National Heart, Lung, and Blood Institute: Claude Lenfant, MD 

World Health Organization: Nikolai Khaltaev, MD 

Romain Pauwels, MD, PhD, Chair 

Ghent University Hospital 

Ghent, Belgium 

Nicholas Anthonisen, MD 

University of Manitoba 

Winnipeg, Manitoba, Canada 

William C. Bailey, MD 

University of Alabama at Birmingham 

Birmingham, Alabama, US 

Peter J. Barnes, MD 

National Heart & Lung Institute 

London, UK 

A. Sonia Buist, MD 

Oregon Health Sciences University 

Portland, Oregon, US 

Peter Calverley, MD 

University Hospital, Aintree 

Liverpool, UK 

Tim Clark, MD 

Imperial College 

London, UK 

Leonardo Fabbri, MD 

University of Modena & Reggio Emilia 

Modena, Italy 

Yoshinosuke Fukuchi, MD 

Juntendo University 

Tokyo, Japan 

Lawrence Grouse, MD, PhD 

University of Washington 

Seattle, Washington, US 

James C. Hogg, MD 

St. Paul’s Hospital 

Vancouver, British Columbia, Canada 

Christine Jenkins, MD 

Concord Hospital 

Sydney, New South Wales, Australia 

Dirkje S. Postma, MD 

Academic Hospital Groningen 

Groningen, the Netherlands 

Klaus F. Rabe, MD 

Leiden University Medical Center 

Leiden, the Netherlands 

Scott D. Ramsey, MD, PhD 



Stephen I. Rennard, MD 

University of Nebraska Medical Center 

Omaha, Nebraska, US 

Roberto Rodriguez-Roisin, MD 

University of Barcelona 

Barcelona, Spain 

Nikos Siafakas, MD 

University of Crete Medical School 

Heraklion, Greece 

Sean D. Sullivan, PhD 



Wan-Cheng Tan, MD 

National University Hospital 

Singapore 

GOLD Staff 

Sarah DeWeerdt 

Editor 


Suzanne S. Hurd, PhD 

Scientific Director 

Bethesda, Maryland, US 

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ONSULTANT REVIEWERS 

(FOR 1998 WORKSHOP PANEL REPORT) 

Individuals 

Sherwood Burge (UK) 

Moira Chan-Yeung (Hong Kong) 

James Donohue (US) 

Nicholas J. Gross (US) 

Helgo Magnussen (Germany) 

Donald Mahler (US) 

Jean-Francois Muir (France) 

Mrigrendra Pandey (India) 

Peter Pare (Canada) 

Thomas Petty (US) 

Michael Plit (South Africa) 

Sri Ram (US) 

Harold Rea (New Zealand) 

Andrea Rossi (Italy) 

Maureen Rutten-van Molken (The Netherlands) 

Marina Saetta (Italy) 

Raj Singh (India) 

Frank Speizer (US) 

Robert Stockley (UK) 

Donald Tashkin (US) 

Ian Town (New Zealand) 

Paul Vermeire (Belgium) 

Gregory Wagner (US) 

Scott Weiss (US) 

Miel Wouters (The Netherlands) 

Jan Zielinski (Poland) 

Organizations 

American College of Chest Physicians 

Suzanne Pingleton 

American Thoracic Society 

Bart Celli 

William Martin 

Austrian Respiratory Society 

Friedriech Kummer 

Arab Respiratory Society 

Salem El Sayed 

Thoracic Society of Australia and New Zealand 

Alastair Stewart 

David McKenzie 

Peter Frith 

Australian Lung Foundation 

Robert Edwards 

Belgian Society of Pneumology 

Marc Decramer 

Jean-Claude Yernault 

British Thoracic Society 

Neil Pride 

Canadian Thoracic Society 

Louis-Philippe Boulet 

Kenneth Chapman 

Chinese Respiratory Society 

Nan-Shan Zhong 

Yuanjue Zhu 

Croatian Respiratory Society 

Neven Rakusic 

Davor Plavec 

Czech Thoracic Society 

Stanislav Kos 

Jaromir Musil 

Vladimir Vondra 

European Respiratory Society 

Marc Decramer (Belgium) 

French Speaking Pneumological Society 

Michel Fournier 

Thomas Similowski 

Hungarian Respiratory Society 

Pal Magyar 

Japanese Respiratory Society 

Yoshinosuke Fukuchi 

Latin American Thoracic Society 

Juan Figueroa (Argentina) 

Maria Christina Machado (Brazil) 

Ilma Paschoal (Brazil) 

Jose Jardim (Brazil) 

Gisele Borzone (Chile) 

Orlando Diaz (Chile) 

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Patricio Gonzales (Chile) 

Carmen Lisboa (Chile) 

Rogelio Perez Padilla (Mexico) 

Jorge Rodriguez De Marco (Uruguay) 

Maria Victorina Lopez (Uruguay) 

Roberto Lopez (Uruguay) 

Malaysian Thoracic Society 

Zin Zainudin 

Norwegian Thoracic Society 

Amund Gulsvik 

Ernst Omenaas 

Polish Phthisiopneumonological Society 

Michal Pirozynski 

Romanian Society of Pulmonary Diseases 

Traian Mihaescu 

Sabina Antoniu 

Singapore Thoracic Society 

Alan Ng 

Wei Keong 

Slovakian Pneumological and Phthisiological Society 

Ladislav Chovan 

Slovenian Respiratory Society 

Stanislav Suskovic 

South African Thoracic Society 

James Joubert 

Spanish Society of Pneumology 

Teodoro Montemayor Rubio 

Victor Sobradillo 

Swedish Society for Chest Physicians 

Kjell Larsson 

Sven Larsson 

Claes-Goran Lofdahl 

Swiss Pulmonary Society 

Philippe Leuenberger 

Erich Russi 

Thoracic Society of Thailand 

Ploysongsang Youngyudh 

Vietnam Asthma-Allergology and Clinical 

Immunology Association 

Nguyen Nang An 

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PREFACE 

Chronic Obstructive Pulmonary Disease (COPD) is a 

major public health problem. It is the fourth leading 

cause of chronic morbidity and mortality in the United 

States 1 and is projected to rank fifth in 2020 as a worldwide 

burden of disease according to a study published by 

the World Bank/World Health Organization 2 . Yet, COPD 

fails to receive adequate attention from the health care 

community and government officials. With these concerns 

in mind, a committed group of scientists encouraged 

the US National Heart, Lung, and Blood Institute 

and the World Health Organization to form the Global 

Initiative for Chronic Obstructive Lung Disease (GOLD). 

Among GOLD’s important objectives are to increase 

awareness of COPD and to help the thousands of people 

who suffer from this disease and die prematurely from 

COPD or its complications. 

The first step in the GOLD program was to prepare a 

consensus Workshop Report, Global Strategy for the 

Diagnosis, Management, and Prevention of COPD. The 

GOLD Expert Panel, a distinguished group of health 

professionals from the fields of respiratory medicine, 

epidemiology, socioeconomics, public health, and health 

education, reviewed existing COPD guidelines, as well as 

new information on pathogenic mechanisms of COPD as 

they developed a consensus document. Many recommendations 

will require additional study and evaluation as 

the GOLD program is implemented. 

Development of the Workshop Report was supported 

through educational grants from Altana, Andi-Ventis, 

AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, 

Chiesi, GlaxoSmithKline, Merck, Sharp & Dohme, 

Mitsubishi Pharma, Nikken Chemicals, Novartis, Pfizer, 

Schering-Plough, and Zambon. 


Modena, Italy 

Chair, GOLD Executive Committee 

REFERENCES 

1. National Heart, Lung, and Blood Institute. Morbidity & 

mortality: chartbook on cardiovascular, lung, and blood diseases. 

Bethesda, MD: US Department of Health and Human 

Services, Public Health Service, National Institutes of Health; 

1998. Available from: URL: 

www.nhlbi.nih.gov/nhlbi/seiin//other/cht-book/htm 

2. Murray CJL, Lopez AD. Evidence-based health 

policy-lessons from the Global Burden of Disease Study. 

Science 1996; 274:740-3. 

A major problem is the incomplete information about the 

causes and prevalence of COPD, especially in developing 

countries. While cigarette smoking is a major known risk 

factor, much remains to be learned about other causes of 

this disease. The GOLD Initiative will bring COPD to the 

attention of governments, public health officials, health 

care workers, and the general public, but a concerted 

effort by all involved in health care will be necessary to 

control this major public health problem. 

I would like to acknowledge the expert panel that prepared 

the first workshop report, and the GOLD Science Committee 

for its work in preparation of the yearly updated volumes. 

We look forward to our continued work with interested 

organizations and the GOLD National Leaders to meet 

the goals of the GOLD initiative. 

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Methodology and Summary of New Recommendations (2005 Update) 

The GOLD Workshop Report, Global Strategy for 

Diagnosis, Management and Prevention of COPD 

presented in 2001 was based on the scientific literature 

available until mid 2000.. To assure that the recommendations 

for management of COPD remained as current 

as possible, the GOLD Executive Committee established 

a Science Committee* to review published research and 

to post an updated report yearly on the GOLD website. 

The first (2003) and second (2004) updates were posted 

on the GOLD website (www.gold.copd.org) in July 2003 

and July 2004 respectively. This third update (July 2005) 

includes review of publications from January to 

December 2004. This will be the final update of the 2001 

document; a revision of the entire document has been 

implemented and is scheduled to be completed in 2006. 

Methods: The process used for the 2005 update, identical 

to that described for the previous updates, included a 

Pub Med search using fields established by the 

Committee: 1) COPD OR chronic bronchitis OR emphysema, 

All Fields, All Adult, 19+ years, only items with 

abstracts, Clinical Trial, Human, sorted by Authors; and 

2) COPD OR chronic bronchitis OR emphysema AND 

systematic, All fields, All adult, 19+ years, only items 

with abstracts, Human, sorted by Author. In addition, 

publications in peer review journals not captured by Pub 

Med could be submitted to individual members of the 

Committee providing an abstract and the full paper were 

submitted in (or translated into) English. 

All members of the Committee received a summary of 

citations and all abstracts. Each abstract was assigned 

to 2 Committee members (members were not assigned 

to a paper where he/she appears as an author), although 

any member was offered the opportunity to provide an 

opinion on any abstract. Members evaluated the abstract 

or, up to her/his judgment, the full publication, by answering 

specific written questions from a short questionnaire, and 

to indicate if the scientific data presented impacted on 

recommendations in the GOLD report. If so, the member 

was asked to specifically identify modifications that 

should be made. The GOLD Science Committee met 

on a regular basis to discuss each individual publication 

indicated by at least 1 member of the Committee to have 

an impact on COPD management, and to reach a 

consensus on the changes in the report. Disagreements 

were decided by vote. 

*Members: K. Rabe, Chair; P. Barnes, S. Buist, P. Calverley, 

L. Fabbri, Y. Fukuchi, W. MacNee, R. Rodriguez-Roisin, I. Zielinski 

GOLD Workshop Report (2005 Update): 

Summary of Recommendations 

Between January 1 and December 2004, 131 articles met 

the search criteria. Of these, 10 papers were identified to 

have an impact on the GOLD report. Of these, 5 papers 

confirmed an existing statement and were added as a 

reference: 

1. Page 68: Man WD, Mustfa N, Nikoletou D, Kaul S, 

Hart N, Rafferty GF, Donaldson N, Polkey MI, Moxham J. 

Effect of salmeterol on respiratory muscle activity during 

exercise in poorly reversible COPD. Thorax. 2004 

Jun;59(6):471-6. 

2. Page 68: O'Donnell DE, Fluge T, Gerken F, Hamilton 

A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects 

of tiotropium on lung hyperinflation, dyspnoea and exercise 

tolerance in COPD. Eur Respir J. 2004 Jun;23(6):832-40. 

3. Page 68: Oostenbrink JB, Rutten-van Molken MP, Al 

MJ, Van Noord JA, Vincken W. One-year cost-effectiveness 

of tiotropium versus ipratropium to treat chronic obstructive 

pulmonary disease. Eur Respir J. 2004 Feb;23(2):241-9. 

4. Page 71: Spencer S, Calverley PM, Burge PS, Jones 

PW. Impact of preventing exacerbations on deterioration 

of health status in COPD. Eur Respir J. 2004 

May;23(5):698-702. 

5. Page 73: Wongsurakiat P, Maranetra KN, Wasi C, 

Kositanont U, Dejsomritrutai W, Charoenratanakul S. 

Acute respiratory illness in patients with COPD and the 

effectiveness of influenza vaccination: a randomized 

controlled study. Chest. 2004 Jun;125(6):2011-20. 

Five papers introduced information that required a new 

statement to be added to the report: 

1. Page 67 – Add sentence: In a study of mild to moderate 

COPD patients at an out-patient clinic, patient education 

involving one four hour group session followed by one to 

two individual nurse- and physiotherapist-sessions 

improved patient outcomes and reduced costs in a 12- 

month follow-up. 

Reference: Gallefoss F. The effects of patient education 

in COPD in a 1-year follow-up randomised, controlled 

trial. Patient Educ Couns. 2004 Mar;52(3):259-66. 

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2. Page 70 - Add sentence: Twenty-one days of inhaled 

tiotropium, 18 mg/day as a dry powder does not reduce 

mucus clearance from the lungs. 

Reference: Hasani A, Toms N, Agnew JE, Sarno M, 

Harrison AJ, Dilworth P. The effect of inhaled tiotropium 

bromide on lung mucociliary clearance in patients with 

COPD. Chest. 2004 May;125(5):1726-34. 

3. Page 71 – Add sentence: Short-term treatment with 

a combined inhaled glucocorticosteroid and long-acting 

ß 2 -agonist resulted in greater control of lung function and 

symptoms than combined anticholinergic and short-acting 

b2-agonist. 

Reference: Donohue JF, Kalberg C, Emmett A, Merchant 

K, Knobil K. A short-term comparison of fluticasone 

propionate/ salmeterol with ipratropium bromide/albuterol 

for the treatment of COPD. Treat Respir Med. 

2004;3(3):173-81. 

4. Page 73 - Change paragraph on immunoregulators to 

read: Studies using an immunostimulator in COPD show 

a decrease in the severity and frequency of exacerbations 94 

(add new reference). However, additional studies to 

examine the long term effects of this therapy are required 

before regular use can be recommended (Evidence B). 

Reference: Li J, Zheng JP, Yuan JP, Zeng GQ, Zhong 

NS, Lin CY. Protective effect of a bacterial extract against 

acute exacerbation in patients with chronic bronchitis 

accompanied by chronic obstructive pulmonary disease. 

Chin Med J (Engl). 2004 Jun;117(6):828-34. 

An Appendix includes a report on outcome measures 

for COPD to encourage comments and input from the 

scientific community to prepare for the full revision of the 

report, scheduled to appear in mid-2006. The many 

individuals who participated in preparation of this report 

are listed in the document. The GOLD Science 

Committee is grateful to those who contributed to this 

report, particularly the work of Dr. Paul Jones, London, 

England and Dr. Alvar Agusti, Palma de Mallorca, Spain. 

The proposed modifications for the GOLD Workshop 

Report (Updated 2005) were approved by the GOLD 

Executive Committee. 

The GOLD Workshop Report (Updated 2005), the GOLD 

Executive Summary(Updated 2005), and the GOLD 

Pocket Guide (Updated 2005) along with the complete list 

of references examined by the Committee are available 

on the GOLD website (www.goldcopd.org). 

5. Page 93 - Add sentence: Early outpatient pulmonary 

rehabilitation after hospitalization for COPD exacerbation 

results in exercise capacity and health status improvements 

at three months. 

Reference: Man WD, Polkey MI, Donaldson N, Gray BJ, 

Moxham J. Community pulmonary rehabilitation after 

hospitalisation for acute exacerbations of chronic obstructive 

pulmonary disease: randomised controlled study. BMJ. 

2004 Nov 20;329(7476):1209. 

A major new segment appears in Chapter 5-4 on antibiotics 

in treatment of COPD exacerbations (page 94). The 

material was prepared by the GOLD Science Committee 

which gratefully acknowledges the opportunity to review 

a statement on this topic prepared by the European 

Respiratory Society and provided to the Committee by 

Dr. William MacNee and Dr. Mark Woodhead. Prior to its 

release, the material was reviewed by Dr. Sanjay Sethi, 

State University of New York at Buffalo, Buffalo, New York, 

and Dr. Antonio Anzueto, University of San Antonio, San 

Antonio, Texas. 

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TABLE OF CONTENTS 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 

1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . .6 

Definition . . . . . . . . . . . . . . . . . . . . . . . . . . .6 

Natural History . . . . . . . . . . . . . . . . . . . . . . .7 

Classification of Severity . . . . . . . . . . . . . . .7 

Variable Course of COPD . . . . . . . . . . . . . .8 

Scope of the Report . . . . . . . . . . . . . . . . . . .9 

Asthma and COPD . . . . . . . . . . . . . . . . . . .9 

Pulmonary Tuberculosis and COPD . . . . . .9 

References . . . . . . . . . . . . . . . . . . . . . . . . . .9 

2. Burden of COPD . . . . . . . . . . . . . . . . . . . . . . . . .11 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .12 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .12 

Epidemiology . . . . . . . . . . . . . . . . . . . . . . .12 

Prevalence . . . . . . . . . . . . . . . . . . . . . . . .12 

Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . .14 

Mortality . . . . . . . . . . . . . . . . . . . . . . . . . .14 

Economic and Social Burden of COPD . . . .15 

Economic Burden . . . . . . . . . . . . . . . . . . .15 

Social Burden . . . . . . . . . . . . . . . . . . . . . .16 

References . . . . . . . . . . . . . . . . . . . . . . . . .17 

3. Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . .19 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .20 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .20 

Host Factors . . . . . . . . . . . . . . . . . . . . . . . .21 

Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . .21 

Airway Hyperresponsiveness . . . . . . . . . . .21 

Lung Growth . . . . . . . . . . . . . . . . . . . . . . .21 

Exposures . . . . . . . . . . . . . . . . . . . . . . . . . .21 

Tobacco Smoke . . . . . . . . . . . . . . . . . . . .21 

Occupational Dusts and Chemicals . . . . . .22 

Outdoor and Indoor Air Pollution . . . . . . . .22 

Infections . . . . . . . . . . . . . . . . . . . . . . . . .22 

Socioeconomic Status . . . . . . . . . . . . . . . .23 

References . . . . . . . . . . . . . . . . . . . . . . . . .23 

4. Pathogenesis, Pathology, and 

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . .27 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .28 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .28 

Pathogenesis . . . . . . . . . . . . . . . . . . . . . . .28 

Inflammatory Cells . . . . . . . . . . . . . . . . . .29 

Inflammatory Mediators . . . . . . . . . . . . . . .30 

Differences Between Inflammation in 

COPD and Asthma . . . . . . . . . . . . . . . . .31 

Inflammation and COPD Risk Factors . . . . . . .32 

Proteinase-Antiproteinase Imbalance . . . . . . .32 

Oxidative Stress . . . . . . . . . . . . . . . . . . . .33 

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . .33 

Central Airways . . . . . . . . . . . . . . . . . . . . .33 

Peripheral Airways . . . . . . . . . . . . . . . . . .34 

Lung Parenchyma . . . . . . . . . . . . . . . . . . .35 

Pulmonary Vasculature . . . . . . . . . . . . . . .36 

Pathophysiology . . . . . . . . . . . . . . . . . . . . .36 

Mucus Hypersecretion and 

Ciliary Dysfunction . . . . . . . . . . . . . . . . .36 

Airflow Limitation and 

Pulmonary Hyperinflation . . . . . . . . . . . .36 

Gas Exchange Abnormalities . . . . . . . . . . . .37 

Pulmonary Hypertension and 

Cor Pulmonale . . . . . . . . . . . . . . . . . . . .38 

Systemic Effects . . . . . . . . . . . . . . . . . . . .38 

Pathophysiology and the 

Symptoms of COPD . . . . . . . . . . . . . . . .38 

Pathology and Pathophysiology of 

Exacerbations . . . . . . . . . . . . . . . . . . . . . .39 

Pathology . . . . . . . . . . . . . . . . . . . . . . . . .39 

Pathophysiology . . . . . . . . . . . . . . . . . . . .39 

References . . . . . . . . . . . . . . . . . . . . . . . . .39 

5. Management of COPD . . . . . . . . . . . . . . . . . . . . .45 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .46 

Component 1: Assess and Monitor Disease . . .47 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .47 

Initial Diagnosis . . . . . . . . . . . . . . . . . . . . . .47 

Assessment of Symptoms . . . . . . . . . . . . . . .47 

Medical History . . . . . . . . . . . . . . . . . . . . .49 

Physical Examination . . . . . . . . . . . . . . . .50 

Measurement of Airflow Limitation . . . . . . . .50 

Assessment of Severity . . . . . . . . . . . . . . .51 

Additional Investigations . . . . . . . . . . . . . .52 

Differential Diagnosis . . . . . . . . . . . . . . . .53 

Ongoing Monitoring and 

Assessment . . . . . . . . . . . . . . . . . . . . . . .53 

Monitor Disease Progression and 

Development of Complications . . . . . . . .54 

Monitor Pharmacotherapy and 

Other Medical Treatment . . . . . . . . . . . . .55 

Monitor Exacerbation History . . . . . . . . . .55 

Monitor Comorbidities . . . . . . . . . . . . . . . .55 

References . . . . . . . . . . . . . . . . . . . . . . . . .56 

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Component 2: Reduce Risk Factors . . . . . . . . . .58 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .58 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .58 

Tobacco Smoke . . . . . . . . . . . . . . . . . . . . .58 

Smoking Prevention . . . . . . . . . . . . . . . . .58 

Smoking Cessation . . . . . . . . . . . . . . . . . .58 

Occupational Exposures . . . . . . . . . . . . . . .62 

Indoor/Outdoor Air Pollution . . . . . . . . . . . .62 

Regulation of Air Quality . . . . . . . . . . . . . .62 

Patient-Oriented Control . . . . . . . . . . . . . .62 

References . . . . . . . . . . . . . . . . . . . . . . . . .63 

Component 3: Manage Stable COPD . . . . . . . . .65 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .65 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .65 

Education . . . . . . . . . . . . . . . . . . . . . . . . . .65 

Goals and Educational Strategies . . . . . . .66 

Components of an Education Program . . .66 

Cost Effectiveness of Education 

Programs for COPD Patients . . . . . . . . . .67 

Pharmacologic Treatment . . . . . . . . . . . . . .67 

Overview of the Medications . . . . . . . . . . .67 

Bronchodilators . . . . . . . . . . . . . . . . . . . . .67 

Glucocorticosteroids . . . . . . . . . . . . . . . . .71 

Pharmacologic Therapy by Disease Severity . .72 

Other Pharmacologic Treatments . . . . . . .73 

Non-Pharmacologic Treatment . . . . . . . . . . .74 

Rehabilitation . . . . . . . . . . . . . . . . . . . . . .74 

Oxygen Therapy . . . . . . . . . . . . . . . . . . . .76 

Ventilatory Support . . . . . . . . . . . . . . . . . .77 

Surgical Treatments . . . . . . . . . . . . . . . . . .78 

Special Considerations . . . . . . . . . . . . . . .79 

References . . . . . . . . . . . . . . . . . . . . . . . . .80 

Component 4: Manage Exacerbations . . . . . .88 

Key Points . . . . . . . . . . . . . . . . . . . . . . . . . .88 

Introduction . . . . . . . . . . . . . . . . . . . . . . . . .88 

Diagnosis and Assessment of Severity . . . .88 

Medical History . . . . . . . . . . . . . . . . . . . . .88 

Assessment of Severity . . . . . . . . . . . . . . .89 

Home Management . . . . . . . . . . . . . . . . . . .89 

Bronchodilator Therapy . . . . . . . . . . . . . . .90 

Glucocorticosteroids . . . . . . . . . . . . . . . . .90 

Hospital Management . . . . . . . . . . . . . . . . .91 

Emergency Department or Hospital . . . . . .91 

Hospital Discharge and Follow-Up . . . . . . .93 

Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . .94 

References . . . . . . . . . . . . . . . . . . . . . . . . .96 

6. Future Research . . . . . . . . . . . . . . . . . . . . . . . . . .99 

APPENDIX 

Outcomes and Markers in COPD . . . . . . . .103 

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INTRODUCTION 

Chronic Obstructive Pulmonary Disease (COPD) is 

a major cause of chronic morbidity and mortality 

throughout the world. Many people suffer from this 

disease for years and die prematurely from it or its 

complications. COPD is currently the fourth leading 

cause of death in the world 1 , and further increases in its 

prevalence and mortality can be predicted in the coming 

decades 2 . A unified international effort is needed to 

reverse these trends. 

The Global Initiative for Chronic Obstructive Lung 

Disease (GOLD) is conducted in collaboration with the 

US National Heart, Lung, and Blood Institute (NHLBI) 

and the World Health Organization (WHO). Its goals are 

to increase awareness of COPD and decrease morbidity 

and mortality from the disease. GOLD aims to improve 

prevention and management of COPD through a concerted 

worldwide effort of people involved in all facets of health 

care and health care policy, and to encourage a renewed 

research interest in this highly prevalent disease. 

A nihilistic attitude toward COPD has arisen among 

some health care providers, due to the relatively limited 

success of primary and secondary prevention (i.e., 

avoidance of factors that cause COPD or its progression), 

the prevailing notion that COPD is largely a self-inflicted 

disease, and disappointment with available treatment 

options. The GOLD project will work toward combating 

this nihilistic attitude by disseminating information about 

available treatments, both pharmacologic and nonpharmacologic. 

Tobacco smoking is a major cause of COPD, as well as 

of many other diseases. A decline in tobacco smoking 

would result in substantial health benefits and a decrease 

in the prevalence of COPD and other smoking-related 

diseases. There is an urgent need for improved strategies 

to decrease tobacco consumption. However, tobacco 

smoking is not the only cause of COPD and may not 

even be the major cause in some parts of the world. 

Furthermore, not all smokers develop clinically significant 

COPD, which suggests that additional factors are 

involved in determining each individual's susceptibility. 

Thus, investigation of COPD risk factors and ways to 

reduce exposure to these factors is also an important 

area for future research. New research tools have 

recently revealed that inflammation plays a prominent 

role in COPD pathogenesis, but this inflammation is 

different than that involved in asthma. Further study of 

the molecular and cellular mechanisms involved in COPD 

pathogenesis should lead to effective treatments that 

slow or halt the course of the disease. 

GOLD WORKSHOP REPORT: 

GLOBAL STRATEGY FOR THE 

DIAGNOSIS, MANAGEMENT, AND 

PREVENTION OF COPD 

One strategy to help achieve GOLD's objectives is to 

provide health care workers, health care authorities, 

and the general public with state-of-the-art information 

about COPD and specific recommendations on the most 

appropriate management and prevention strategies. 

The GOLD Workshop Report, Global Strategy for the 

Diagnosis, Management, and Prevention of COPD, is 

based on the best-validated current concepts of COPD 

pathogenesis and the available evidence on the most 

appropriate management and prevention strategies. 

The Report has been developed by individuals with 

expertise in COPD research and patient care and extensively 

reviewed by many experts and scientific societies. 

It provides state-of-the-art information about COPD for 

pulmonary specialists and other interested physicians. 

The document will also serve as a source for the production 

of various communications during the implementation 

of the GOLD program, including a practical guide for 

primary care physicians and a document for use in 

developing countries. 

The GOLD Report is not intended to be a comprehensive 

textbook on COPD, but rather to summarize the current 

state of the field. Each chapter starts with Key Points 

that crystallize current knowledge. The chapters on the 

Burden of COPD and Risk Factors demonstrate the 

global importance of COPD and the various causal 

factors involved. The chapter on Pathogenesis, 

Pathology, and Pathophysiology documents the current 

understanding of, and remaining questions about, the 

mechanism(s) that lead to COPD, as well as the 

structural and functional abnormalities of the lungs 

characteristic of the disease. 

A major part of the GOLD Workshop Report is devoted 

to the clinical Management of COPD and presents a 

management plan with four components: (1) Assess 

and Monitor Disease; (2) Reduce Risk Factors; 

(3) Manage Stable COPD; (4) Manage Exacerbations. 

INTRODUCTION 1


Management recommendations are largely symptom 

driven and are presented according to the severity of 

the disease, using a simple classification of severity to 

facilitate the practical implementation of the available 

management options. Where appropriate, information 

about health education for patients is included. 

The final chapter identifies critical gaps in knowledge 

requiring Further Research and provides a summary of 

proposed directions for the development of new therapeutic 

approaches. 

METHODS USED TO DEVELOP 

THIS REPORT 

In January 1997, COPD experts from several countries 

met in Brussels, Belgium to explore the development of a 

Global Initiative for Chronic Obstructive Lung Disease. 

Dr. Romain Pauwels served as Chair; representatives of 

the NHLBI and WHO attended. Participants agreed that 

the project was timely and important, and recommended 

the establishment of a panel with expertise on a wide 

variety of COPD-related topics to prepare an evidencebased 

document on diagnosis, management, and 

prevention of COPD. NHLBI and WHO staff, in concert 

with Dr. Pauwels, identified individuals from many regions 

of the world to serve on the Expert Panel, which included 

health professionals in the areas of respiratory medicine, 

epidemiology, pathology, socioeconomics, public health, 

and health education. 

The first step toward developing the Workshop Report 

was to review the multiple COPD guidelines already 

published. The NHLBI collected these guidelines and 

prepared a summary table of similarities and differences 

between the documents. Where agreement existed, the 

Expert Panel drew on these existing documents for use 

in the Workshop Report. Where major differences existed, 

the Expert Panel agreed to carefully examine the scientific 

evidence to reach an independent conclusion. 

In September 1997, several members of the Expert Panel 

met with a consultant to develop a comprehensive set 

of terms to build a database of COPD literature. The 

database and a computer program to search the world 

literature on COPD have been developed, and they will 

be placed on the Internet and cross-referenced with the 

Workshop Report to help keep the Report current as new 

literature is published. 

In April 1998, the NHLBI and WHO cosponsored a workshop 

to begin the development of the Report. Workshop 

participants were divided into three groups: definition and 

natural history, chaired by Dr. Sonia Buist; pathophysiology, 

risk factors, diagnosis, and classification of severity, 

chaired by Dr. Leonardo Fabbri; and management, 

chaired by Dr. Romain Pauwels. A table of contents 

was developed and writing assignments were made. 

The Panel agreed that clinical recommendations would 

require scientific evidence, or would be clearly labeled as 

"expert opinion." Each chapter would contain a set of the 

most current and representative references. 

In September 1998, the Panel met to evaluate its 

progress. Members reviewed a variety of evidence tables 

and chose to assign levels of evidence to statements 

using the system developed by the NHLBI (Figure A). 

Levels of evidence are assigned to management 

recommendations where appropriate in Chapter 5, 

Management of COPD, and are indicated in boldface 

type enclosed in parentheses after the relevant statement 

- e.g., (Evidence A). The methodological issues 

concerning the use of evidence from meta-analyses were 

carefully considered (e.g., a meta-analysis of a number 

of smaller studies considered to be evidence level B) 2 . 

The panel met in May 1999, September 1999, and May 

2000 in conjunction with meetings of the American 

Thoracic Society (ATS) and the European Respiratory 

Society (ERS). Symposia were held at these meetings to 

present the developing program and to solicit opinion and 

comments. The meeting in May 2000 was the final 

consensus workshop. 

After this workshop, the document was submitted for 

review to individuals and medical societies interested in 

the management of COPD. The reviewers' comments 

were incorporated, as appropriate, into the final document 

by the Chair in cooperation with members of the 

Expert Panel. Prior to its release for publication, the 

Report was reviewed by the NHLBI and the WHO. 

A workshop was held in September, 2000 to begin 

implementation of the GOLD program. 

2 INTRODUCTION


Figure A. Description of Levels of Evidence 

Evidence Category Sources of Evidence Definition 

A 

Randomized controlled 

trials (RCTs). 

Rich body of data. 

Evidence is from endpoints of well-designed RCTs that 

provide a consistent pattern of findings in the population 

for which the recommendation is made. Category A requires 

substantial numbers of studies involving substantial numbers 

of participants. 

B 

Randomized controlled 

trials (RCTs). Limited 

body of data. 

Evidence is from endpoints of intervention studies that 

include only a limited number of patients, posthoc or 

subgroup analysis of RCTs, or meta-analysis of RCTs. 

In general, Category B pertains when few randomized trials 

exist, they are small in size, they were undertaken in a 

population that differs from the target population of the 

recommendation, or the results are somewhat inconsistent. 

C 

Nonrandomized trials. 

Observational studies. 

Evidence is from outcomes of uncontrolled or nonrandomized 

trials or from observational studies. 

D 

Panel Consensus 

Judgment. 

This category is used only in cases where the provision of 

some guidance was deemed valuable but the clinical literature 

addressing the subject was deemed insufficient to justify 

placement in one of the other categories. The Panel 

Consensus is based on clinical experience or knowledge that 

does not meet the above-listed criteria. 

REFERENCES 

1. World Health Organization. World health report. Geneva: World Health Organization; 2000. 

Available from: URL: http://www.who.int/whr/2000/en/statistics.htm 

2. Murray CJL, Lopez AD. Evidence-based health policy - lessons from the Global Burden of Disease Study. 

Science 1996; 274:740-3. 

INTRODUCTION 3


4 INTRODUCTION


CHAPTER 

1 

DEFINITION


CHAPTER 1: DEFINITION 

KEY POINTS: 

• COPD is a disease state characterized by airflow 

limitation that is not fully reversible. The airflow 

limitation is usually both progressive and associated 

with an abnormal inflammatory response of 

the lungs to noxious particles or gases. 

• The four-stage classification of COPD severity 

used throughout this report provides an 

educational tool and a general indication of the 

approach to management. This conceptual 

framework also emphasizes that COPD is usually 

progressive if exposure to the noxious agent is 

continued. 

• The characteristic symptoms of COPD are 

cough, sputum production, and dyspnea upon 

exertion. 

• Chronic cough and sputum production often 

precede the development of airflow limitation 

by many years and these symptoms identify 

individuals at risk of developing COPD. 

• The focus of this Workshop Report is primarily 

on COPD caused by inhaled particles and gases, 

the most common of which worldwide is tobacco 

smoke. 

• COPD can coexist with asthma, the other major 

chronic obstructive airway disease characterized 

by an underlying airway inflammation. However, 

the inflammation characteristic of COPD is distinct 

from that of asthma. 

• Pulmonary tuberculosis may affect lung function 

and symptomatology and, in areas where 

tuberculosis is prevalent, can lead to confusion 

in the diagnosis of COPD. 

DEFINITION 

For years, clinicians, physiologists, pathologists, and 

epidemiologists have struggled with the definitions of 

disorders associated with chronic airflow limitation, 

including chronic bronchitis, emphysema, chronic 

obstructive pulmonary disease (COPD), and asthma. The 

definitions of these terms variably emphasize structure 

and function and are often based on whether the term is 

used for clinical or research purposes. For example, 

epidemiologists have created terminology and criteria, 

based on functional status, that can be monitored in 

population-based studies or studies of physicians' 

diagnoses 1,2 . 

Based on current knowledge, a working definition of COPD 

is a disease state characterized by airflow limitation that 

is not fully reversible. The airflow limitation is usually both 

progressive and associated with an abnormal inflammatory 

response of the lungs to noxious particles or gases. 

Symptoms, functional abnormalities, and complications of 

COPD can all be explained on the basis of this underlying 

inflammation and the resulting pathology (Figure 1-1). 

Figure 1-1. Mechanisms Underlying Airflow 

Limitation in COPD 

Small airway disease 

INFLAMMATION 

Parenchymal destruction 

AIRFLOW LIMITATION 

The chronic airflow limitation characteristic of COPD is 

caused by a mixture of small airway disease (obstructive 

bronchiolitis) and parenchymal destruction (emphysema), 

the relative contributions of which vary from person to 

person. Chronic inflammation causes remodeling and 

narrowing of the small airways. Destruction of the lung 

parenchyma, also by inflammatory processes, leads to 

the loss of alveolar attachments to the small airways and 

decreases lung elastic recoil; in turn, these changes diminish 

the ability of the airways to remain open during expiration. 

Airflow limitation is measured by spirometry, as this is the 

most widely available, reproducible test of lung function. 

Many previous definitions of COPD have emphasized the 

terms "emphysema" and "chronic bronchitis," which are 

no longer included in the definition of COPD used in this 

report. Emphysema, or destruction of the gas-exchanging 

6 DEFINITION


surfaces of the lung (alveoli), is a pathological term that 

is often (but incorrectly) used clinically and describes 

only one of several structural abnormalities present in 

patients with COPD. Chronic bronchitis, or the presence 

of cough and sputum production for at least 3 months in 

each of two consecutive years, remains a clinically and 

epidemiologically useful term. However, it does not 

reflect the major impact of airflow limitation on morbidity 

and mortality in COPD patients. It is also important to 

recognize that cough and sputum production may precede 

the development of airflow limitation; conversely, some 

patients develop significant airflow limitation without 

chronic cough and sputum production. 

NATURAL HISTORY 

COPD has a variable natural history and not all individuals 

follow the same course. However, COPD is generally a 

progressive disease, especially if a patient's exposure 

to noxious agents continues. If exposure is stopped, the 

disease may still progress due to the decline in lung 

function that normally occurs with aging. Nevertheless, 

stopping exposure to noxious agents, even after 

significant airflow limitation is present, can result in 

some improvement in function and will certainly slow or 

even halt the progression of the disease. 

Classification of Severity: Stages of COPD 

For educational reasons, a simple classification of disease 

severity into four stages is recommended (Figure 1-2). 

The staging is based on airflow limitation as measured by 

spirometry, which is essential for diagnosis and provides 

a useful description of the severity of pathological 

changes in COPD. Specific FEV 1 cut-points (e.g., 

< 80% predicted) are used for purposes of simplicity: 

these cut-points have not been clinically validated. 

The impact of COPD on an individual patient depends 

not just on the degree of airflow limitation, but also on 

the severity of symptoms (especially breathlessness and 

decreased exercise capacity) and complications of the 

disease. The management of COPD is largely symptom 

driven, and there is only an imperfect relationship between 

the degree of airflow limitation and the presence of 

symptoms. The staging, therefore, is a pragmatic 

approach aimed at practical implementation and should 

only be regarded as an educational tool, and a very 

Figure 1-2. Classification of Severity of COPD 

Stage 

Characteristics 

0: At Risk • normal spirometry 

• chronic symptoms (cough, sputum production) 

I: Mild COPD • FEV 1 /FVC < 70% 

• FEV 1 ≥ 80% predicted 

• with or without chronic symptoms (cough, sputum production) 

II: Moderate COPD • FEV 1 /FVC < 70% 

• 50% ≤ FEV 1 < 80% predicted 


III: Severe COPD • FEV 1 /FVC < 70% 

• 30% ≤ FEV 1 < 50% predicted 


IV: Very Severe COPD • FEV 1 /FVC < 70% 

• FEV 1 < 30% predicted or FEV 1 < 50% predicted plus chronic respiratory 

failure 

Classification based on postbronchodilator FEV 1 

FEV 1 : forced expiratory volume in one second; FVC: forced vital capacity; respiratory failure: arterial partial pressure of oxygen (PaO 2 ) less than 

8.0 kPa (60 mm Hg) with or without arterial partial pressure of CO 2 (PaCO 2 ) greater than 6.7 kPa (50 mm Hg) while breathing air at sea level. 

DEFINITION 7


general indication of the approach to management. All 

FEV 1 values refer to postbronchodilator FEV 1 . 

Although COPD is defined on the basis of airflow 

limitation, in practice the decision to seek medical help 

(and so permit the diagnosis to be made) is normally 

determined by the impact of a particular symptom on a 

patient's lifestyle. Thus, COPD may be diagnosed at any 

stage of the illness. 

The characteristic symptoms of COPD are cough, 

sputum production, and dyspnea upon exertion. Chronic 

cough and sputum production often precede the 

development of airflow limitation by many years, although 

not all individuals with cough and sputum production go 

on to develop COPD. This pattern offers a unique 

opportunity to identify those at risk for COPD and 

intervene when the disease is not yet a health problem. 

A major objective of GOLD is to increase awareness 

among health care providers and the general public of 

the significance of these symptoms. 

Stage 0: At Risk - Characterized by chronic cough and 

sputum production. Lung function, as measured by 

spirometry, is still normal. 

Stage I: Mild COPD - Characterized by mild airflow 

limitation (FEV 1 /FVC < 70% but FEV 1 > 80% predicted) 

and usually, but not always, by chronic cough and sputum 

production. At this stage, the individual may not even be 

aware that his or her lung function is abnormal. This 

underscores the importance of health care providers 

doing spirometry in all smokers so that their lung function 

can be observed and recorded over time. 

Stage II: Moderate COPD - Characterized by worsening 

airflow limitation (50% < FEV 1 < 80% predicted), and 

usually the progression of symptoms with shortness of 

breath typically developing on exertion. This is the stage 

at which patients typically seek medical attention 

because of dyspnea or an exacerbation of their disease. 

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 edema. Patients may have Stage IV: 

Very Severe COPD even if the FEV 1 is > 30% predicted, 

whenever these complications are present. At this stage, 

quality of life is very appreciably impaired and exacerbations 

may be life threatening. 

Variable Course of COPD 

The common statement that only 15-20% of smokers 

develop clinically significant COPD is misleading. A 

much higher proportion develop abnormal lung function 

at some point if they continue to smoke. Not all individuals 

with COPD follow the classical linear course as outlined 

in the Fletcher and Peto diagram, which is actually the 

mean of many individual courses 3 . 

Figure 1-3 shows four examples of the various courses 

that individual COPD patients may follow. Panel A 

illustrates an individual who has cough and sputum 

production, but never develops abnormal lung function 

(as defined in this Report). Panel B illustrates an 

individual who develops abnormal lung function but who 

may never come to diagnosis. Panel C illustrates a 

person who develops abnormal lung function around 

age 50, then progressively deteriorates over about 15 

years and dies of respiratory failure at age 65. Panel D 

illustrates an individual who develops abnormal lung 

function in mid-adult life and continues to deteriorate 

gradually but never develops respiratory failure and does 

not die as a result of COPD. 

Figure 1-3. Examples of Individual Patient Histories 

Age 

Age 

Stage III: Severe COPD - Characterized by further 

worsening of airflow limitation (30% ≤ FEV 1 < 50% predicted), 

increased shortness of breath, and repeated 

exacerbations which have an impact on patients’ quality 

of life. 

Stage IV: Very Severe COPD - Characterized by severe 

airflow limitation (FEV 1 < 30% predicted) or the presence 

of chronic respiratory failure. Respiratory failure is 

defined as an arterial partial pressure of O 2 (PaO 2 ) less 

than 8.0 kPa (60 mmHg) with or without arterial partial 

pressure of CO 2 (PaCO 2 ) greater than 6.7 kPa (50 mm 

Hg) while breathing air at sea level. Respiratory failure 

A 

Age 

C 

B 

Age 

D 

8 DEFINITION


SCOPE OF THE REPORT 

The focus of this Report is primarily on COPD caused by 

inhaled particles and gases, the most common of which 

worldwide is tobacco smoke. Poorly reversible airflow 

limitation associated with bronchiectasis, cystic fibrosis, 

tuberculosis, or asthma is not included except insofar as 

these conditions overlap with COPD. 

Asthma and COPD 

COPD can coexist with asthma, the other major chronic 

obstructive airway disease characterized by an underlying 

airway inflammation. Asthma and COPD have their major 

symptoms in common, but these are generally more 

variable in asthma than in COPD. The underlying chronic 

airway inflammation is also very different (Figure 1-4): 

that in asthma is mainly eosinophilic and driven by CD4 + 

T lymphocytes, while that in COPD is neutrophilic and 

characterized by the presence of increased numbers of 

macrophages and CD8 + T lymphocytes. In addition, 

airflow limitation in asthma is often completely reversible, 

either spontaneously or with treatment, while in COPD it is 

never fully reversible and is usually progressive if exposure 

to noxious agents continues. Finally, the responses to 

treatment of asthma and COPD are dramatically different, 

in terms of both the overall magnitude of the achievable 

response and the qualitative effects of specific treatments 

such as anticholinergics and glucocorticosteroids. 

However, there is undoubtedly an overlap between 

asthma and COPD. Individuals with asthma who are 

exposed to noxious agents that cause COPD may develop 

a mixture of "asthma-like" inflammation and "COPD-like" 

inflammation. There is also evidence that longstanding 

asthma on its own can lead to airway remodeling and 

partly irreversible airflow limitation. Asthma can usually 

be distinguished from COPD, but until the causal mechanisms 

and pathognomonic markers of these diseases are 

Figure 1-4. Asthma and COPD 

Asthma 

Sensitizing agent 

Asthmatic airway inflammation 

CD4 + T lymphocytes 

Eosinophis 

Completely 

reversible 

Airflow Limitation 

COPD 

Noxious agent 

COPD airway inflammation 

CD8 + T lymphocytes 

Macrophages Neutrophils 

Completely 

irreversible 

better understood it will remain difficult to differentiate the 

two diseases in some individual patients. Given the current 

state of medical and scientific knowledge, an attempt to 

determine an absolutely rigid definition of COPD or asthma 

is bound to end up in semantics. 

Pulmonary Tuberculosis and COPD 

In many developing countries both pulmonary tuberculosis 

and COPD are common. In countries where tuberculosis 

is very common, respiratory abnormalities may be too 

readily attributed to this disease. Conversely, where the 

rate of tuberculosis is greatly diminished, the possible 

diagnosis of this disease is sometimes overlooked. 

Chronic bronchitis/bronchiolitis and emphysema often 

occur as complications of pulmonary tuberculosis and 

are important contributors to the mixed lung function 

changes characteristic of tuberculosis 4 . The degree of 

obstructive airway changes 5 in treated patients with 

pulmonary tuberculosis increases with age, the amount 

of cigarettes smoked, and the extent of the initial 

tuberculous disease 6 . In patients with both diseases, 

COPD adds to the disability of pulmonary tuberculosis, 

and vice versa. 

Therefore, in all subjects with symptoms of COPD, a 

possible diagnosis of tuberculosis should be considered, 

especially in areas where this disease is known to be 

prevalent. Investigations to exclude tuberculosis should 

be a routine part of COPD diagnosis, the intensity of the 

diagnostic procedures depending on the degree of 

suspicion. Chest radiograph and sputum culture are 

helpful in making the differential diagnosis. 

REFERENCES 

1. Samet JM. Definitions and methodology in COPD 

research. In: Hensley M, Saunders N, eds. Clinical epidemiology 

of chronic obstructive pulmonary disease. New 

York: Marcel Dekker; 1989. p. 1-22. 

2. Vermeire PA, Pride NB. A "splitting" look at chronic nonspecific 

lung disease (CNSLD): common features but 

diverse pathogenesis. Eur Respir J 1991; 4:490-6. 

3. Fletcher C, Peto R. The natural history of chronic airflow 

obstruction. BMJ 1977; 1:1645-8. 

4. Leitch AG. Pulmonary tuberculosis: clinical features. In: 

Crofton J, Douglas A, eds. Respiratory diseases. Oxford: 

Blackwell Science; 2000. p. 507-27. 

5. Birath G, Caro J, Malmberg R, Simonsson BG. Airway 

obstruction in pulmonary tuberculosis. Scand J Resp Dis 

1966; 47:27-36. 

6. Snider GL, Doctor L, Demas TA, Shaw AR. Obstructive airway 

disease in patients with treated pulmonary tuberculosis. 

Am Rev Respir Dis 1971; 103:625-40. 

DEFINITION 9


10 DEFINITION


CHAPTER 

2 

BURDEN OF COPD


CHAPTER 2: BURDEN OF COPD 

KEY POINTS: 

• COPD prevalence and morbidity data that are 

available probably greatly underestimate the total 

burden of the disease because it is not usually 

recognized and diagnosed until it is clinically 

apparent and moderately advanced. 

• Prevalence, morbidity, and mortality vary 

appreciably across countries, but in all countries 

where data are available COPD is a significant 

health problem in both men and women. 

• The substantial increase in the global burden 

of COPD projected over the next twenty years 

reflects, in large part, the increasing use of 

tobacco worldwide, and the changing age 

structure of populations in developing countries. 

• Medical expenditures for treating COPD and 

the indirect costs of morbidity can represent a 

substantial economic and social burden for 

societies and public and private payers 

worldwide. Nevertheless, very little economic 

information concerning COPD is available. 

INTRODUCTION 

COPD is a leading cause of morbidity and mortality 

worldwide and results in an economic and social burden 

that is both substantial and increasing. COPD prevalence, 

morbidity, and mortality vary appreciably across countries 

and across different groups within countries, but in general 

are directly related to the prevalence of tobacco smoking. 

Most epidemiological studies have found that COPD 

prevalence, morbidity, and mortality have increased over 

time and are greater in men than in women. Very few 

studies have quantified the economic and social burden 

of COPD. In developed countries, the direct medical 

costs of COPD are substantial because the disease is 

both chronic and highly prevalent. In developing 

countries, the indirect cost of COPD from loss of work 

and productivity may be more important than the direct 

costs of medical care. 

EPIDEMIOLOGY 

Most of the information available on COPD prevalence, 

morbidity, and mortality comes from developed countries. 

Even in these countries, accurate epidemiological data 

on COPD are difficult and expensive to collect. 

Prevalence and morbidity data greatly underestimate the 

total burden of COPD because the disease is usually not 

diagnosed until it is clinically apparent and moderately 

advanced. The imprecise and variable definitions of 

COPD have made it hard to quantify the morbidity and 

mortality of this disease in developed 1 and developing 

countries. Mortality data also underestimate COPD as a 

cause of death because the disease is more likely to be 

cited as a contributory than as an underlying cause of 

death, or may not be cited at all 2 . 

Prevalence 

Available estimates of COPD prevalence have been 

developed by determining either the proportion of the 

population that reports having respiratory symptoms 

and/or airflow limitation, or the proportion that reports 

having been diagnosed with COPD, chronic bronchitis, or 

emphysema by a physician. Each of these approaches 

will yield a different estimate, and may be useful for 

different purposes. For example, studies that ask about 

the full range of COPD symptoms from early to advanced 

disease are useful to estimate the total societal burden of 

the disease. Data on doctor diagnoses of COPD are 

useful to estimate the prevalence of clinically significant 

disease that is of sufficient severity to require health 

services, and therefore is likely to incur significant costs. 

The population surveys necessary to develop accurate 

estimates of COPD prevalence are costly to do and 

therefore have not been conducted in many countries. 

Obtaining reliable prevalence data for COPD in each 

country should be a priority in order to alert those 

responsible for planning prevention services and health 

care delivery to the high prevalence and cost of the 

disease. The prevalence of COPD is likely to vary 

appreciably depending on the prevalence of risk 

factor exposure, age distribution, and prevalence of 

susceptibility genes in different countries. 

Until recently, virtually all population-based studies 

in developed countries showed a markedly greater 

prevalence and mortality of COPD among men 

12 BURDEN OF COPD


compared to women 3-6 . Gender-related differences in 

exposure to risk factors, mostly cigarette smoking, 

probably explain this pattern. In developing countries, 

some studies report a slightly higher prevalence of COPD 

in women than men. This likely reflects exposure to 

indoor air pollution from cooking and heating fuels 

(greater among women) as well as exposure to tobacco 

smoke (greater among men) 7-15 . Recent large populationbased 

studies in the US show a different pattern emerging, 

with the prevalence of COPD almost equal in men and 

women 16,17 . This likely reflects the changing pattern of 

exposure to the most important risk factor, tobacco 

smoke. 

Estimates based on self-report of respiratory symptoms. 

COPD prevalence data based on self-report of respiratory 

symptoms (chronic cough, sputum production, wheezing, 

and shortness of breath) include people at risk for COPD 

(Stage 0) as well as those with airflow limitation, and thus 

yield maximum prevalence estimates. These studies 

reveal sizable variations in the prevalence of respiratory 

symptoms depending on smoking status, age, 

occupational and environmental exposures, country or 

region, and, to a lesser extent, gender and race. The 

data also reveal appreciable variations over time, reflecting 

important temporal changes in populations' exposure to 

risk factors such as smoking, outdoor air pollution, and 

occupational exposures. 

The third National Health and Nutrition Examination 

Survey (NHANES 3) 16 , a large national survey conducted 

in the US between 1988 and 1994, included self-report 

questions about respiratory symptoms. The prevalence 

of respiratory symptoms varied markedly by smoking 

status (current>ex>never). Among white males, chronic 

cough was reported by 24% of smokers, 4.7% of exsmokers, 

and 4.0% of never smokers. The prevalence 

of chronic cough among white women was 20.6% in 

smokers, 6.5% in ex-smokers, and 5.0% in never smokers. 

There was a smaller gradient in the prevalence of chronic 

cough by race (white>black). The prevalence of sputum 

production was similar to that of chronic cough in these 

groups. 

Estimates based on the presence of airflow limitation. 

People may have respiratory symptoms such as cough 

and sputum production for many years before developing 

airflow limitation. Thus, COPD prevalence data based on 

the presence of airflow limitation provide a more accurate 

estimate of the burden of COPD that is, or probably soon 

will be, clinically significant. However, the use of different 

cut points to define airflow limitation makes comparing 

the results of different studies difficult. 

In the NHANES 3 study 16 , airflow limitation was defined 

as an FEV 1 /FVC < 70%. The prevalence of airflow 

limitation was lower than the prevalence of respiratory 

symptoms found in the same study, but both sets of data 

reinforce the view that smoking is the most important 

determinant of COPD prevalence in developed countries. 

Among white males, airflow limitation was present in 

14.2% of current smokers, 6.9% of ex-smokers, and 3.3% 

of never smokers. Among white females, the prevalence 

of airflow limitation was 13.6% in smokers, 6.8% in exsmokers, 

and 3.1% in never smokers. Airflow limitation 

was more common among white smokers than among 

black smokers. 

Estimates based on physician diagnosis of COPD. 

COPD prevalence data based on physician diagnosis 

provide information about the prevalence of clinically 

significant COPD that is of sufficient severity to prompt a 

visit to a physician. Few population-based prevalence 

surveys have been published to provide this information, 

and available data are often confusing because asthma 

and COPD diagnoses are not separated, all age groups 

are considered together, or chronic bronchitis and 

emphysema are considered separately. 

In the UK the General Practice Research Database 18 , 

which is based on 525 practices serving 3.4 million 

patients (6.4% of the total population of England and 

Wales), provides population-based data on physiciandiagnosed 

COPD (Figure 2-1). In 1997, the prevalence 

of COPD was 1.7% among men and 1.4% among 

women. Between 1990 and 1997, the prevalence 

increased by 25% in men and 69% in women. The 

prevalence of COPD among men plateaued in the mid- 

1990s, but continued to increase among women, reaching 

Figure 2-1. Prevalence (%) of Physician-Diagnosed 

COPD in the UK From 1990 to 1997 by Sex 18 

2.0 

1.5 

1.0 

0.5 

0.0 

1990 

1991 

1992 

Men 

1993 

1994 

1995 

1996 

Women 

1997 

Reprinted with permission from Soriano JR, Maier WC, Egger R, Visick G, Thakrar B, Sykes J, 

et al. Thorax 2000; 55:789-94. Copyright 2000 BMJ Publishing Group. 

BURDEN OF COPD 13


in 1997 the level observed in men in 1990. The General 

Practice Research Database includes all ages and thus 

underestimates the true impact of COPD on older adults. 

The Global Burden of Disease Study. The WHO/World 

Bank Global Burden of Disease Study 19,20 used data from 

both published and unpublished studies to estimate the 

prevalence of various diseases in different countries and 

regions around the world (Figure 2-2). Where few data 

for a region were available, experts made informed 

estimates. Where no information was available, preliminary 

estimates were derived from data from other regions that 

were believed to have similar epidemiological patterns. 

Using this approach, the worldwide prevalence of COPD 

in 1990 was estimated at 9.34/1,000 in men and 

7.33/1,000 in women. However, these estimates include 

all ages and underestimate the true prevalence of COPD 

in older adults. 

Figure 2-2. COPD Around the World (All Ages) 19,20 

Region or Country 1990 Prevalence per 1,000 

Males/Females 

Established Market Economies 6.98/3.79 

Formerly Socialist Economies of Europe 7.35/3.45 

India 4.38/3.44 

China* 26.20/23.70 

Other Asia and Islands 2.89/1.79 

Sub-Saharan Africa 4.41/2.49 

Latin America and Caribbean 3.36/2.72 

Middle Eastern Crescent 2.69/2.83 

World 9.34/7.33 

*The prevalence of COPD in China reported in this study has been 

questioned based on recent publications from China 21 - see text. 

Given the striking dearth of population-based data on 

COPD prevalence in many countries of the world, the 

values listed in Figure 2-2 should not be viewed as very 

precise. Nevertheless, some general patterns emerge. 

The prevalence of COPD is highest in countries where 

cigarette smoking has been, or still is, very common, 

while the prevalence is lowest in countries where smoking 

is less common, or total tobacco consumption per capita 

is still low. The lowest COPD prevalence among men 

(2.69/1,000) was found in the Middle Eastern Crescent 

(a group of 36 countries in North Africa and the Middle 

East) and the lowest prevalence among women 

(1.79/1,000) was found in the region referred to as "Other 

Asia and Islands" (a group of 49 countries and islands, 

the largest of which is Indonesia and which includes 

Papua New Guinea, Nepal, Vietnam, Korea, Hong Kong, 

and many small island countries). Except in the Middle 

Eastern Crescent, the prevalence of COPD is higher 

among men than among women. 

The Global Burden of Disease study reported a 

significantly higher prevalence of COPD in China than in 

most of the other regions (26.20/1,000 among men and 

23.70/1,000 among women). A more recent survey 

conducted in three regions of China (Northern: Beijing; 

Northeast: Liao-Ning; and South-Mid: HuBei) in persons 

older than 15 years estimated the prevalence of COPD at 

4.21/1,000 among men and 1.84/1,000 among women 21 . 

Morbidity 

Morbidity includes physician visits, emergency 

department visits, and hospitalizations. COPD databases 

for these outcome parameters are less readily 

available and usually less reliable than mortality databases. 

The limited data available indicate that morbidity 

due to COPD increases with age and is greater in men 

than women 17,22,23 . 

In the UK, general practice consultations for COPD 

during one year ranged from 4.17/1,000 in 45- to 

64-year-olds to 8.86/1,000 in 65- to 74-year-olds to 

10.32/1,000 in 75- to 84-year-olds. These rates are 

2 to 4 times the equivalent rates for chest pain due to 

ischemic heart disease 24 . 

In 1994, according to statistics from the UK Office of 

National Statistics 25 , there were 203,193 hospital 

admissions in Northern Ireland, Scotland, Wales, and 

England for COPD; the average length of hospital stay 

among those admitted for a COPD diagnosis was 

9.9 days. 

US data indicate that in 1997 there were 16.365 million 

(60.6/1,000) ambulatory care visits for COPD and 

448,000 (1.66/1,000) hospitalizations for which COPD 

was the first-listed discharge diagnosis 23 . Hospitalization 

rates for COPD increased with age and were higher 

among men than among women. These data should 

be interpreted cautiously, however, because the ICD-9 

codes for COPD that were in use in 1997, 490-492 and 

494-496, include "bronchitis not specified as acute or 

chronic." Therefore, the data for ambulatory care visits 

are likely to have been inflated by inclusion of visits for 

acute bronchitis 16 . 

Mortality 

Of all of the descriptive epidemiological data for COPD, 

mortality data are the most readily available, and 

probably the most reliable. (The World Health 

Organization publishes mortality statistics for selected 

causes of death annually for all WHO regions 26 ; 

14 BURDEN OF COPD


additional information is available from the WHO 

Evidence for Health Policy Department 27 .) However, 

inconsistent use of terminology for COPD causes 

problems that do not arise for many other diseases. 

For example, prior to about 1968 and the Eighth 

Revision of the ICD, the terms "chronic bronchitis" and 

"emphysema" were used extensively. During the 

1970s, the term "COPD" increasingly replaced those 

terms in the US and some but not all other countries, 

making comparisons of COPD mortality in different 

countries very difficult. However, the situation has 

improved with the Ninth and Tenth Revisions of the 

ICD, in which deaths from COPD or chronic airways 

obstruction are included in the broad category of 

"COPD and allied conditions" (ICD-9 codes 490-496 

and ICD-10 codes J42-46). 

The age-adjusted death rates for COPD by race and 

sex in the US from 1960 to 1996 by ICD code are 

shown in Figure 2-3 17 . COPD death rates are very 

low among people under age 45 in the US, but then 

increase with age, and COPD becomes the fourth or 

fifth leading cause of death among those over 45 17 , a 

pattern that reflects the cumulative effect of cigarette 

smoking 28 . Although appreciable variations in mortality 

across developed countries for both genders have been 

reported 29 , these differences should be interpreted 

cautiously. Differences between countries in death 

certification, diagnostic practices, the structure of 

health care systems, and life expectancy have an 

appreciable impact on reported mortality rates. 

Figure 2-3. Age-Adjusted* Death Rates for 

Chronic Obstructive Pulmonary Disease by 

Race and Sex, US 1960-1996 17 

ECONOMIC AND SOCIAL 

BURDEN OF COPD 

Because COPD is highly prevalent and can be severely 

disabling, direct medical expenditures and the indirect 

costs of morbidity and premature mortality from COPD 

can represent a substantial economic and social burden 

for societies and public and private insurance payers 

worldwide. Nevertheless, very little quantitative information 

concerning the economic and social burden of COPD 

is available in the literature today. 

Economic Burden 

Cost of illness studies provide insight into the economic 

impact of a disease. Some countries attempt to separate 

economic burden into disease-attributable direct and indirect 

costs. The direct cost is the value of health care 

resources devoted to diagnosis and medical management 

of the disease. Indirect costs reflect the monetary 

consequences of disability, missed work and school, 

premature mortality, and caregiver or family costs resulting 

from the illness. Data on these topics from developing 

countries are not available, but data from the US and 

some European countries provide an understanding of 

the economic burden of COPD in developed countries. 

United States. Figure 2-4 compares the estimated costs 

of various lung disorders in the US in 1993. In 1993, the 

annual economic burden of COPD in the US was estimated 

at $23.9 billion 17 , including $14.7 billion in direct expenditures 

for medical care services, $4.7 billion in indirect morbidity 

costs, and $4.5 billion in indirect costs related to premature 

mortality. With an estimated 15.7 million cases of COPD 

in the US 30 , the estimated direct cost of COPD is $1,522 

per COPD patient per year. 

Rate/100,000 Population 

ICD/7 

ICD/8 

ICD/9 

Figure 2-4. Direct and Indirect Costs of 

Lung Diseases, 1993 (US $ Billions) 17 

White Male 

Black Male** 

Condition 

Total 

Cost 

Direct 

Medical 

Cost 

Mortality- 

Related 

Indirect 

Cost 

Morbidity- 

Related 

Indirect 

Cost 

Total 

Indirect 

Cost 

White Female 

Black Female** 

1960 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 1996 

*Age-adjusted to the 2000 standard **Nonwhite from 1960 to 1967. 

COPD 23.9 14.7 4.5 4.7 9.2 

Asthma 12.6 9.8 0.9 0.9 2.8 

Influenza 14.6 1.4 0.1 13.1 13.2 

Pneumonia 7.8 1.7 4.6 1.5 6.1 

Tuberculosis 1.1 0.7 - - 0.4 

Lung Cancer 25.1 5.1 17.1 2.9 20.0 

BURDEN OF COPD 15


In a US study 31 of COPD-related illness costs based on 

the 1987 National Medical Expenditure Survey, per capita 

expenditures for inpatient hospitalizations of COPD 

patients ($5,409 per hospitalization) were 2.7 times the 

expenditures for patients without COPD ($2,001 per 

hospitalization). In 1992, under Medicare, the US 

government health insurance program for individuals 

over 65, annual per capita expenditures for people with 

COPD ($8,482) were nearly 2.5 times higher than annual 

expenditures for people without COPD ($3,511) 32 . 

United Kingdom. In 1996, the direct cost of COPD in 

the UK was approximately £846 million (about US $1.393 

billion) or £1,154 (about US $1,900) per person per year, 

according to data from the National Health Service (NHS) 

Executive 33 . Pharmaceutical expenditures for COPD and 

allied conditions accounted for 11.0% of the total expenditures 

for prescription medications. Only 2% of total 

primary care expenditures were for COPD-related visits. 

In 1996, lost work productivity, disability, and premature 

mortality from COPD in the UK accounted for an estimated 

24 million days of work lost. The indirect cost of the 

disease was estimated at £600 million (about US $960 

million) for attendance and disability living allowance and 

£1.5 billion (about US $2.4 billion) to employers for work 

absence and reduced productivity 24 . 

The Netherlands. In 1993, the direct cost of COPD in 

the Netherlands was estimated to exceed US $256 million, 

or US $813 per patient per year. Assuming constant costs 

and treatment patterns, the direct cost is expected to reach 

US $410 million per year by 2010. In 1993 inpatient 

hospitalizations accounted for 57% of the total direct cost 

of COPD, and medications accounted for an additional 

23%. The indirect cost of COPD in the Netherlands was 

not available 34 . 

Sweden. The direct cost of COPD-related medical care 

in Sweden was estimated at 1.085 billion SEK (about US 

$179.4 million) in 1991. The estimated indirect cost of 

COPD was an additional 1.699 billion SEK (about US 

$280.8 million) 35 . 

Comparison of different countries. Figure 2-5 

provides data on the economic burden of COPD in four 

countries with Western styles of medical practice and 

social or private insurance structures. The data are 

standardized to equivalent year on a per capita basis. 

After adjusting to a common base year and population, 

the costs of COPD were relatively similar. The remaining 

variability in across-country estimates of economic 

burden can be partly explained by several factors, 

including: disease prevalence and demographics, particularly 

smoking patterns; the type and usage patterns of 

health care and non-health care services among patients 

with COPD; the relative prices of health care services; 

employment and wage rates; and the availability of 

medical prevention strategies and treatments for COPD. 

Similar data from developing countries are not available. 

Home care. Individuals with COPD frequently receive 

professional medical care in their homes. In some 

countries, national health insurance plans provide coverage 

for oxygen therapy, visiting nursing services, rehabilitation, 

and even mechanical ventilation in the home, although 

coverage for specific services varies from country to 

country 36 . 

Any estimate of direct medical expenditures for home 

care underrepresents the true cost of home care to society, 

because it ignores the economic value of the care provided 

to those with COPD by family members. In developing 

countries especially, direct medical costs may be less 

important than the impact of COPD on workplace and 

home productivity. Because the health care sector 

might not provide long-term supportive care services for 

severely disabled individuals, COPD may force two 

individuals to leave the workplace - the affected individual 

and a family member who must now stay home to care 

for the disabled relative. Since human capital is often the 

most important national asset for developing countries, 

COPD may represent a serious threat to their economies. 

Social Burden 

Figure 2-5. Four-Country Comparison 

of COPD Direct and Indirect Costs 

Country (ref) Year Direct Cost 

(US$ Millions) 

Indirect Cost 


Total 


Per Capita* 

(US$) 

UK 33 1996 778 3,312 4,090 65 

The Netherlands 34 1993 256 N/A N/A N/A # 

Sweden 35 1991 179 281 460 60 

US 1 1993 14,700 9,200 23,900 87 

* Per capita valuation based on 1993 population estimates from the United 

Nations Population Council and expressed in 1993 US dollars. 

# The authors did not provide estimates of indirect costs. 

Since mortality offers a limited perspective on the human 

burden of a disease, it is desirable to find other measures 

of disease burden that are consistent and measurable 

across nations. The World Bank/WHO Global Burden of 

Disease Study 19 designed a method to estimate the fraction 

of mortality and disability attributable to major diseases 

and injuries using a composite measure of the burden of 

each health problem, the Disability-Adjusted Life Year 

(DALY). The DALYs for a specific condition are the sum 

16 BURDEN OF COPD


Figure 2-6. Leading Causes of Disability-Adjusted Life Years 

(DALYs) Lost Worldwide, 1990 and 2020 (Projected) 19,20 

Disease 

or Injury 

of years lost because of premature mortality and years 

of life lived with disability, adjusted for the severity of 

disability. 

The leading causes of DALYs lost worldwide in 1990 

and 2020 (projected) are shown in Figure 2-6. In 1990, 

COPD was the twelfth leading cause of DALYs lost in the 

world, responsible for 2.1% of the total. According to the 

projections, COPD will be the fifth leading cause of 

DALYs lost worldwide in 2020, behind ischemic heart 

disease, major depression, traffic accidents, and cerebrovascular 

disease. This substantial increase in the 

global burden of COPD projected over the next twenty 

years reflects, in large part, the increasing use of tobacco 

worldwide and the changing age structure of populations 

in developing countries. 

REFERENCES 

Rank 

1990 

Percent of 

Total 

DALYs 

Rank 

2020 

Percent of 

Total 

DALYs 

Lower respiratory infections 1 8.2 6 3.1 

Diarrheal diseases 2 7.2 9 2.7 

Perinatal period conditions 3 6.7 11 2.5 

Unipolar major depression 4 3.7 2 5.7 

Ischemic heart disease 5 3.4 1 5.9 

Cerebrovascular disease 6 2.8 4 4.4 

Tuberculosis 7 2.8 7 3.1 

Measles 8 2.6 25 1.1 

Road traffic accidents 9 2.5 3 5.1 

Congenital anomalies 10 2.4 13 2.2 

Malaria 11 2.3 19 1.5 

COPD 12 2.1 5 4.1 

Trachea, bronchus, lung cancer 33 0.6 15 1.8 

Excerpted with permission from Murray CJL, Lopez AD. Science 1999; 274:740-3. 

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BURDEN OF COPD 17


20. Murray CJL, Lopez AD, eds. The global burden of disease: a 

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18 BURDEN OF COPD


CHAPTER 

3 

RISK FACTORS


CHAPTER 3: RISK FACTORS 

KEY POINTS: 

• Risk factors for COPD include both host factors 

and environmental exposures, and the disease 

usually arises from an interaction between these 

two types of factors. 

• The host factor that is best documented is a rare 

hereditary deficiency of alpha-1 antitrypsin. Other 

genes involved in the pathogenesis of COPD 

have not yet been identified. 

• The major environmental factors are tobacco 

smoke, occupational dusts and chemicals 

(vapors, irritants, fumes), and indoor/outdoor air 

pollution. 

INTRODUCTION 

The identification of risk factors is an important step 

toward developing strategies for prevention and treatment 

of any disease. Identification of cigarette smoking as an 

important risk factor for COPD has led to the incorporation 

of smoking cessation programs as a key element of 

COPD prevention, as well as an important intervention 

for patients who already have the disease. However, 

although smoking is the best-studied COPD risk factor, it 

is not the only one. Further studies of other risk factors 

could lead to similar powerful interventions. 

Much of the evidence concerning risk factors for COPD 

comes from cross-sectional epidemiological studies that 

identify associations rather than cause-and-effect relationships. 

Although several longitudinal studies (which 

are capable of revealing causal relationships) of COPD 

have followed groups and populations for up to 20 years, 

none of them has monitored the progression of the disease 

through its entire course. Thus, current understanding of 

risk factors for COPD is in many respects incomplete. 

Figure 3-1 provides a summary of risk factors for COPD. 

The division into "Host Factors" and "Exposures" reflects 

the current understanding of COPD as resulting from an 

interaction between the two types of factors. Thus, of two 

people with the same smoking history, only one may 

develop COPD due to differences in genetic predisposition 

to the disease, or in how long they live. Risk factors for 

COPD may also be related in more complex ways. For 

example, gender may influence whether a person takes 

up smoking or experiences certain occupational or environmental 

exposures; socioeconomic status may be 

linked to a child's birth weight; longer life expectancy will 

allow greater lifetime exposure to risk factors; etc. 

Understanding the relationships and interactions among 

risk factors is a crucial area of ongoing investigation. 

Host Factors 

Exposures 

Figure 3-1. Risk Factors for COPD 

• Genes (e.g., alpha-1 

antitrypsin deficiency) 

• Airway Hyperresponsiveness 

• Lung Growth 

• Tobacco Smoke 

• Occupational Dusts and 

Chemicals 

• Indoor and Outdoor Air Pollution 

• Infections 

• Socioeconomic Status 

The best-documented host factor is a severe hereditary 

deficiency of alpha-1 antitrypsin. The major environmental 

factors are tobacco smoke, occupational dusts and 

chemicals (vapors, irritants, fumes), and indoor and outdoor 

air pollution. However, it is very difficult to demonstrate that 

a given risk factor is sufficient to cause the disease. 

Data are not available to determine whether the increasing 

prevalence of respiratory symptoms and the accelerated 

rate of lung function decline that occur with age reflect 

the cumulative exposure to respiratory particles, irritants, 

fumes, vapors, etc., or host-related phenomena such as 

the loss of elastic recoil of lung tissue and stiffening of 

the chest wall. The field of normal lung aging has been 

only minimally explored and more work is required. 

The role of gender as a risk factor for COPD remains 

unclear. In the past, most studies showed that COPD 

prevalence and mortality were greater among men than 

women 1-4 . More recent studies 5,6 from developed countries 

show that the prevalence of the disease is almost equal 

in men and women, which probably reflects changing 

patterns of tobacco smoking. Some studies have in fact 

suggested that women are more susceptible to the 

effects of tobacco smoke than men 4,7 . This is an important 

question given the increasing rate of smoking among 

women in both developed and developing countries. 

The role of nutritional status as an independent risk factor 

20 RISK FACTORS


for the development of COPD is unclear. Malnutrition and 

weight loss can reduce respiratory muscle strength and 

endurance, apparently by reducing both respiratory muscle 

mass and the strength of the remaining muscle fibers 8 . 

The association of starvation and anabolic/catabolic 

status with the development of emphysema has been 

shown in experimental studies in animals 9 . 

HOST FACTORS 

Genes 

It is believed that many genetic factors increase (or 

decrease) a person's risk of developing COPD. Studies 

have demonstrated an increased risk of COPD within 

families with COPD probands. Some of this risk may be 

due to shared environmental factors, but several studies 

in diverse populations also suggest a shared genetic risk 10,11 . 

The genetic risk factor that is best documented is a 

severe hereditary deficiency of alpha-1 antitrypsin 12-14 , a 

major circulating inhibitor of serine proteases. This rare 

hereditary deficiency is a recessive trait most commonly 

seen in individuals of Northern European origin. 

Premature and accelerated development of panlobular 

emphysema and decline in lung function occur in both 

smokers and nonsmokers with the severe deficiency, 

although smoking increases the risk appreciably. There 

is considerable variation between individuals in the 

extent and severity of the emphysema and the rate of 

lung function decline. Although alpha-1 antitrypsin 

deficiency is relevant to only a small part of the world's 

population, it illustrates the interaction between host 

factors and environmental exposures leading to COPD. 

In this way, it provides a model for how other genetic risk 

factors are thought to contribute to COPD. 

Exploratory studies have revealed a number of candidate 

genes that may influence a person's risk of COPD, 

including ABO secretor status 15,16 , microsomal epoxide 

hydrolase 17 , glutathione S-transferase 18 , alpha-1 antichymotrypsin 

19 , the complement component GcG 20 , cytokine 

TNF- 21 , and microsatellite instability 22 . However, when 

several studies of a given trait are available, the results 

are often inconsistent. Several of these genes are 

thought to be involved in inflammation, and therefore are 

related to potential pathogenic mechanisms of COPD. 

Airway Hyperresponsiveness 

Asthma and airway hyperresponsiveness, identified as 

risk factors that contribute to the development of COPD, 

are complex disorders related to a number of genetic and 

environmental factors. The relationship between asthma/ 

airway hyperresponsiveness and increased risk of 

developing COPD was originally described by Orie and 

colleagues 23 and termed the "Dutch hypothesis." 

Asthmatics, as a group, experience a slightly accelerated 

loss of lung function 24,25 compared to non-asthmatics, as 

do smokers with airway hyperresponsiveness compared 

to normal smokers 26 . How these trends are related to the 

development of COPD is unknown, however. Airway 

hyperresponsiveness may also develop after exposure to 

tobacco smoke or other environmental insults and thus 

may be a result of smoking-related airway disease. 

Lung Growth 

Lung growth is related to processes occurring during 

gestation, birth weight, and exposures during childhood 27-31 . 

Reduced maximal attained lung function (as measured by 

spirometry) may identify individuals who are at increased 

risk for the development of COPD 32 . 

EXPOSURES 

It may be helpful conceptually to think of a person's 

exposures in terms of his or her total burden of inhaled 

particles (Figure 3-2). Each type of particle, depending 

on its size and composition, may contribute a different 

weight to the risk, and the total risk will depend on the 

integral of the inhaled exposures. Of the many inhalational 

exposures that people may encounter over a lifetime, only 

tobacco smoke 2,33-39 and occupational dusts and chemicals 

(vapors, irritants, and fumes) 40,41 are known to cause 

COPD on their own. Tobacco smoke and occupational 

exposures also appear to act additively to increase a 

person's risk of developing COPD. 

Tobacco Smoke 

Cigarette smoking is by far the most important risk factor 

for COPD and the most important way that tobacco 

contributes to the risk of COPD. Cigarette smokers have 

a higher prevalence of respiratory symptoms and lung 

function abnormalities, a greater annual rate of decline in 

FEV 1 , and a greater COPD mortality rate than nonsmokers. 

These differences between cigarette smokers and nonsmokers 

increase in direct proportion to the quantity of 

smoking. Pipe and cigar smokers have greater COPD 

morbidity and mortality rates than nonsmokers, although 

their rates are lower than those for cigarette smokers 33 . 

Other types of tobacco smoking popular in various 

countries are also risk factors for COPD, although their 

risk relative to cigarette smoking has not been reported. 

Age at starting to smoke, total pack-years smoked, and 

current smoking status are predictive of COPD mortality. 

RISK FACTORS 21


Figure 3-2. Total Burden of Inhaled Particles 

Figure 3-3. Interaction of Smoking 

and Occupational Exposures 41 

Cigarette Smoke 

Occupational Dusts 

& Chemicals 

Environmental Tobacco 

Smoke (ETS) 

Indoor/Outdoor 

Air Pollution 

Not all smokers develop clinically significant COPD, 

which suggests that genetic factors must modify each 

individual's risk. Although it is unclear what percentage 

of smokers develop the disease, the commonly cited 

figure of 15-20% is likely an underestimate because 

COPD is both underdiagnosed and underappreciated. 

Passive exposure to cigarette smoke (also known as 

environmental tobacco smoke or ETS) may also contribute 

to respiratory symptoms and COPD by increasing the 

lungs' total burden of inhaled particles and gases 2,42,43 . 

Smoking during pregnancy may also pose a risk for the 

fetus, by affecting lung growth and development in utero 

and possibly the priming of the immune system 32,44 . 

Occupational Dusts and Chemicals 

Occupational dusts and chemicals (vapors, irritants, 

and fumes) can also cause COPD when the exposures 

are sufficiently intense or prolonged, such as those 

experienced by miners in many countries. These 

exposures can both cause COPD independently of 

cigarette smoking and increase the risk in the presence 

of concurrent cigarette smoking (Figure 3-3) 41 . Exposure 

to coal dust alone in sufficient doses can produce airflow 

limitation 45,46 . 

Exposure to particulate matter, irritants, organic dusts, 

and sensitizing agents can cause an increase in airway 

hyperresponsiveness 47 , especially in airways already 

damaged by other occupational exposures, cigarette 

smoke, or asthma. There is some evidence from 

community studies that a combination of dust exposure 

Excerpted with permission from Kaufmann F, Drouet D, Lellouch J, Brille D. International 

Journal of Epidemiology 1979; 8:201-12. Copyright 1979 Oxford University Press. 

and gas or fume exposure may have an additive effect 

on the risk of COPD 48-50 . 

Indoor and Outdoor Air Pollution 

High levels of urban air pollution are harmful to individuals 

with existing heart or lung disease. The role of outdoor 

air pollution in causing COPD is unclear, but appears to 

be small when compared with that of cigarette smoking. 

The relative effect of short-term, high peak exposures 

and long-term, low-level exposures is a question yet to 

be resolved. 

Over the past two decades, air pollution in most cities in 

developed countries has decreased appreciably. In 

contrast, air pollution has increased markedly in many 

cities in developing countries. Although it is not clear 

which specific elements of ambient air pollution are 

harmful, there is some evidence that particles found in 

polluted air will add to a person's total inhaled burden. 

Indoor air pollution from biomass fuel has been implicated 

as a risk factor for the development of COPD. This exposure 

is greatest in regions where biomass fuel is used for 

cooking and heating in poorly vented dwellings, leading 

to high levels of particulate matter in indoor air 51-61 . 

Infections 

A history of severe childhood infection has been associated 

with reduced lung function and increased respiratory 

symptoms in adulthood 32 . There are several possible 

22 RISK FACTORS


explanations for this association (which are not mutually 

exclusive). There may be an increased diagnosis of 

severe infections in children who have underlying airway 

hyperresponsiveness, itself considered a risk factor for 

COPD. Viral infections may be related to another factor, 

such as birth weight, that is related to COPD. 

HIV infection has been shown to accelerate the onset of 

smoking-induced emphysema; HIV-induced pulmonary 

inflammation may play a role in this process 62-66 . 

Socioeconomic Status 

There is evidence that the risk of developing COPD is 

inversely related to socioeconomic status 65 . It is not clear, 

however, whether this pattern reflects exposures to 

indoor and outdoor air pollutants, crowding, poor nutrition, 

or other factors that are related to low socioeconomic 

status 60,66 . 

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RISK FACTORS 25


26 RISK FACTORS


CHAPTER 

4 

PATHOGENESIS, 

PATHOLOGY, AND 

PATHOPHYSIOLOGY


CHAPTER 4: PATHOGENESIS, PATHOLOGY, 

AND PATHOPHYSIOLOGY 

KEY POINTS: 

• Exposure to inhaled noxious particles and gases 

causes inflammation of the lungs that can lead to 

COPD if the normal protective and/or repair 

mechanisms are overwhelmed or defective. 

• Exacerbations of COPD are associated with an 

increase in airway inflammation. 

• Although inflammation is important in both 

diseases, the inflammatory response in COPD is 

markedly different from that in asthma. 

• In addition to inflammation, two other processes 

thought to be important in the pathogenesis of 

COPD are an imbalance of proteinases and 

antiproteinases in the lung, and oxidative stress. 

• Pathological changes characteristic of COPD are 

found in the central airways, peripheral airways, 

lung parenchyma, and pulmonary vasculature. 

• The peripheral airways become the major site of 

airways obstruction in COPD. The structural 

changes in the airway wall are the most important 

cause of the increase in peripheral airways 

resistance in COPD. Inflammatory changes such 

as airway edema and mucus hypersecretion also 

contribute to airway narrowing. 

• Most common in COPD patients is the 

centrilobular form of emphysema, which involves 

dilatation and destruction of the respiratory 

bronchioles. 

• Physiological changes characteristic of the 

disease include mucus hypersecretion, ciliary 

dysfunction, airflow limitation, pulmonary hyperinflation, 

gas exchange abnormalities, pulmonary 

hypertension, and cor pulmonale, and they 

usually develop in this order over the course of 

the disease. 

• The irreversible component of airflow limitation is 

primarily due to remodeling of the small airways. 

Parenchymal destruction (emphysema) also 

contributes but plays a smaller role. 

• In advanced COPD, peripheral airways obstruction, 

parenchymal destruction, and pulmonary vascular 

abnormalities reduce the lung's capacity for gas 

exchange, producing hypoxemia and, later on, 

hypercapnia. Inequality in the ventilation/perfusion 

ratio (V A /Q) is the major mechanism behind 

hypoxemia in COPD. 

• Pulmonary hypertension develops late in the 

course of COPD. It is the major cardiovascular 

complication of COPD and is associated with a 

poor prognosis. 

• COPD is associated with systemic inflammation 

and skeletal muscle dysfunction that may 

contribute to limitation of exercise capacity and 

decline of health status. 

INTRODUCTION 

Inhaled noxious particles and gases that lead to COPD 

cause lung inflammation, induce tissue destruction, 

impair the defense mechanisms that serve to limit the 

destruction, and disrupt the repair mechanisms that may 

be able to restore tissue structure in the face of some 

injuries. The results of lung tissue damage are mucus 

hypersecretion, airway narrowing and fibrosis, destruction 

of the parenchyma (emphysema), and vascular changes. 

In turn, these pathological changes lead to airflow limitation 

and the other physiological abnormalities characteristic of 

COPD. 

Much of the information concerning the pathogenesis 

of COPD comes from studies in experimental animals or 

in vitro systems. These experimental systems are limited 

as they differ from human disease in a number of 

respects. Studies in human subjects of the pathogenesis, 

pathology, and pathophysiology of COPD are often limited 

by patient selection, small numbers of subjects, and limited 

access to the relevant tissue. Therefore, an evidencebased 

perspective on these topics is in many respects 

incomplete. 

PATHOGENESIS 

COPD is characterized by chronic inflammation throughout 

the airways, parenchyma, and pulmonary vasculature. 

The intensity and cellular and molecular characteristics of 

the inflammation vary as the disease progresses. Over 

28 PATHOGENESIS, PATHOLOGY, AND PATHOPHYSIOLOGY


time, inflammation damages the lungs and leads to the 

pathologic changes characteristic of COPD. 

In addition to inflammation, two other processes thought 

to be important in the pathogenesis of COPD are an 

imbalance of proteinases and antiproteinases in the lung, 

and oxidative stress. These processes may themselves 

be consequences of inflammation, or they may arise from 

environmental (e.g., oxidant compounds in cigarette 

smoke) or genetic (e.g., alpha-1 antitrypsin deficiency) 

factors. Figure 4-1 details the interactions between these 

mechanisms. The multiplicity of cells and mediators 

thought to be involved in the pathogenesis of COPD is 

presented schematically in Figure 4-2. 

Inflammatory Cells 

COPD is characterized by an increase in neutrophils, 

macrophages, and T lymphocytes (especially CD8 + ) in 

various parts of the lung (Figure 4-3). There may also be 

an increase in eosinophils in some patients, particularly 

during exacerbations. These increases are brought about 

by increases in inflammatory cell recruitment, survival, 

and/or activation. Many studies reveal a correlation 

between the number of inflammatory cells of various 

types in the lung and the severity of COPD 1-10 . 

Figure 4-3. Sites of Inflammatory 

Cell Increases in COPD 

Anti-oxidants 

Figure 4-1. Pathogenesis of COPD 

Oxidative stress 

Noxious particles 

and gases 

Lung Inflammation 

Antiproteinases 

Proteinases 

Large Airways 

Small Airways 

Parenchyma 

• Macrophages 

• T lymphocytes (especially CD8 + ) 

• Neutrophils (severe disease only) 

• Eosinophils (in some patients) 



• Eosinophils (in some patients) 



• Neutrophils 

COPD pathology 

Repair mechanisms 

Pulmonary Arteries • T lymphocytes (especially CD8 + ) 

• Neutrophils 

Figure 4-2. Cells and Mediators Involved 

in the Pathogenesis of COPD 

CELLS 

Macrophages 

Neutrophils 

CD8 + lymphocytes 

Eosinophils 

Epithelial cells 

Fibroblasts 

Printed with permission of Dr. Peter J. Barnes. 

MEDIATORS 

LTB4 

IL-8, GRO-1 

MCP-1, MIP-1 

GM-CSF 

4 

Endothelin 

Substance P 

-1 

PROTEINASES 

Neutrophil elastase 

Cathepsins 

Proteinase-3 

MMPs 

EFFECTS 

Mucus hypersecretion 

Fibrosis 

Alveolar wall 

destruction 

Neutrophils. Increased numbers of activated neutrophils 

are found in sputum and bronchoalveolar lavage (BAL) 

fluid of patients with COPD 4,5,8,9 , although the role of 

neutrophils in COPD is not yet clear. Neutrophils are 

also increased in smokers without COPD 11 . However, 

neutrophils are little increased in airway and parenchyma 

tissue sections, which may reflect their rapid transit 

through these parts of the lung. Induced sputum studies 

also show an increase in myeloperoxidase (MPO) 

and human neutrophil lipocalin, indicating neutrophil 

activation 12 . Exacerbations of COPD are characterized by 

a marked increase in the number of neutrophils in BAL 

fluid 13 . Neutrophils secrete several proteinases, including 

neutrophil elastase (NE), neutrophil cathepsin G, and 

neutrophil proteinase-3, which may contribute to 

parenchymal destruction and chronic mucus hypersecretion. 

Macrophages. Increased numbers of macrophages are 

present in the large and small airways and lung 

PATHOGENESIS, PATHOLOGY, AND PATHOPHYSIOLOGY 29


parenchyma of patients with COPD, as reflected in 

histopathology, BAL, bronchial biopsy, and induced 

sputum studies 2,4-6,9 . In patients with emphysema, 

macrophages are localized to sites of alveolar wall 

destruction 1 . Macrophages likely play an orchestrating 

role in COPD inflammation by releasing mediators 

such as tumor necrosis factor- (TNF-), interleukin 

8 (IL-8), and leukotriene B4 (LTB4), which promote 

neutrophilic inflammation. 

T lymphocytes. Histopathology and bronchial biopsy 

studies show an increase in T lymphocytes, especially 

CD8 + (cytotoxic) cells, throughout the lungs of patients 

with COPD 1,2,10,14 . Their role in COPD inflammation is 

not yet fully understood, but one way that CD8 + cells 

may contribute to COPD is by releasing perforin, 

granzyme-B, and TNF-, which can cause the cytolysis 

and apoptosis of alveolar epithelial cells 15 that may be 

responsible for the persistence of inflammation. An 

increased number of lymphocyte-like natural killer (NK) 

cells has also been reported in patients with severe 

COPD 3 . 

Eosinophils. The presence and role of eosinophils 

in COPD are uncertain. Some bronchial biopsy 

studies show eosinophils increased in the airways of 

some patients with stable COPD 6,16 . However, some 

of these patients may have had coexisting asthma, as 

other studies report no increase in eosinophils in 

COPD patients 2 . The levels of eosinophil cationic 

protein (ECP) and eosinophil peroxidase (EPO) in 

induced sputum are elevated in COPD, suggesting 

that eosinophils may be present but degranulated, and 

therefore no longer recognizable by light microscopy 12 . 

The high levels of neutrophil elastase (NE) often found 

in COPD may be responsible for this degranulation 17 . 

Most studies agree that airway eosinophils are 

increased during exacerbations of COPD 18,19 . 

Epithelial cells. Airway and alveolar epithelial cells 

are likely to be important sources of inflammatory 

mediators in COPD, though their role in inflammation 

in this disease has not yet been thoroughly studied. 

Exposure of nasal or bronchial epithelial cells from 

healthy volunteers to nitrogen dioxide (NO 2 ), ozone 

(O 3 ), and diesel exhaust particles results in significant 

synthesis and release of proinflammatory mediators, 

including eicosanoids, cytokines, and adhesion 

molecules 20 . The adhesion molecule E-selectin, 

involved in recruitment and adhesion of neutrophils, is 

up-regulated on airway epithelial cells in COPD patients 21 . 

Cultured human bronchial epithelial cells from COPD 

patients release lower levels of inflammatory mediators 

such as TNF- and IL-8 than similar preparations from 

nonsmokers or smokers without COPD, suggesting 

that some form of down-regulation of inflammatory 

mediator release may occur in epithelial cells of individuals 

with COPD 20 . 

Inflammatory Mediators 

Activated inflammatory cells in COPD release a variety 

of mediators, including a spectrum of potent proteinases 22,23 , 

oxidants 24 , and toxic peptides 25 . Many of the mediators 

thought to be important in the disease – notably LTB4 26 , 

IL-8 4,27 , and TNF- 4,16 – are capable of damaging lung 

structures and/or sustaining neutrophilic inflammation. 

The damage induced by these moieties may further 

potentiate inflammation by releasing chemotactic 

peptides from the extracellular matrix 28 . Little is yet 

known about the specific role of these inflammatory 

mediators in COPD. Studies of the therapeutic use of 

selective mediator antagonists should identify the 

molecules relevant in COPD. 

Leukotriene B4 (LTB4). LTB4, a potent chemoattractant 

of neutrophils, is found at increased levels in the sputum 

of patients with COPD 26 . It is probably derived from 

alveolar macrophages, which secrete more LTB4 in 

patients with COPD. Several potent LTB4 receptor 

antagonists have been developed for clinical studies 

and should elucidate further the role of this mediator 

in COPD. So far there is no evidence that cysteinyl 

leukotrienes (LTC4, LTD4, LTE4) are involved in 

COPD. Selective antagonists of the cysteinyl 

leukotriene 1 receptor (CysLT 1 ) have proven helpful in 

patients with asthma and studies of these drugs in 

COPD patients are now underway. The role of the 

cysteinyl leukotriene 2 receptor (CysLT 2 ) in respiratory 

disease is as yet unknown 29 . 

Interleukin 8 (IL-8). IL-8, a selective chemoattractant 

of neutrophils that may be secreted by macrophages, 

neutrophils, and airway epithelial cells, is present at 

high concentrations in induced sputum and BAL 

fluid of patients with COPD 4,27 . IL-8 may play a 

primary role in the activation of both neutrophils and 

eosinophils in the airways of COPD patients and may 

serve as a marker in evaluating the severity of airway 

inflammation 27 . 

Tumor necrosis factor- (TNF-). TNF- activates 

the transcription factor nuclear factor-B (NF-B), 

which in turn activates the IL-8 gene in epithelial cells 

and macrophages (Figure 4-4). TNF- is present at 

high concentrations in sputum 4 and is detectable in 

bronchial biopsies 16 in patients with COPD. TNF- 

serum levels and production by peripheral blood 

monocytes are increased in weight-losing COPD 

patients, suggesting that this mediator may play a role in 

the cachexia of severe COPD 30 . 



Figure 4-4. Interaction Between 

Macrophages, Neutrophils, and Epithelial Cells 

• Transforming growth factor-ß (TGF-ß) and epidermal 

growth factor (EGF) show increased expression in 

epithelial cells and submucosal cells (eosinophils and 

fibroblasts) in COPD patients 33 . These mediators 

may play a role in airway remodeling (fibrosis and 

narrowing) in COPD 34 . 

• Endothelin-1 (ET-1), a potent endothelium-derived 

vasoconstrictor peptide, is found at increased 

concentrations in induced sputum of patients with 

COPD 35 . Patients with severe COPD also have 

elevated plasma levels of ET-1, which is probably 

related to their chronic hypoxemia 36 . 

Cigarette smoke activates macrophages and epithelial 

cells to produce tumor necrosis factor- (TNF-), 

switching on the gene for interleukin-8 (IL-8), which 

recruits and activates neutrophils. This process occurs 

via the activation of the transcription factor nuclear factor-B 

(NF-B). 


Others. Other inflammatory mediators that may be 

involved in COPD include the following: 

• Macrophage chemotactic protein-1 (MCP-1), a 

potent chemoattractant of monocytes, is increased 

in the BAL fluid of patients with COPD and smokers 

without COPD, but not in ex-smokers or nonsmokers 31 . 

Thus, MCP-1 may be involved in macrophage 

recruitment into the lungs in smokers. 

• Macrophage inflammatory protein-1ß (MIP-1ß) is 

increased in the BAL fluid of patients with COPD 

compared to smokers, ex-smokers, and nonsmokers 31 . 

Macrophage inflammatory protein-1 (MIP-1) 

shows increased expression in airway epithelial cells 

from COPD patients 3 compared to control smokers. 

• Granulocyte-macrophage colony stimulating factor 

(GM-CSF) is found at increased concentrations in 

the BAL fluid of patients with stable COPD and at 

markedly elevated levels during exacerbations 13 . The 

number of GM-CSF-immunoreactive macrophages is 

also increased in sputum of patients with COPD 32 . 

GM-CSF is important for neutrophil survival and may 

play a role in enhancing neutrophilic inflammation. 

• Neuropeptides, such as substance P, calcitonin 

gene-related peptide, and vasoactive intestinal 

peptide (VIP), have potent effects on vascular function 

and mucus secretion. An increased concentration 

of substance P is found in sputum of patients with 

chronic bronchitis 37 . One bronchial biopsy study 

showed an increase in VIP-immunoreactive nerves 

in the vicinity of submucosal glands in patients with 

chronic bronchitis, suggesting that this substance 

may play a role in mucus hypersecretion 38 . However, 

another study showed no significant differences in 

the number of nerves immunoreactive for substance 

P, calcitonin gene-related peptide, or VIP between 

COPD patients and healthy subjects 39 . 

• Complement. Activation of the complement pathway 

via generation of the potent chemotaxin C5a may 

play a significant role in the neutrophil accumulation 

seen in the lungs of patients with COPD 40 . 

Differences Between Inflammation 

in COPD and Asthma 

Although inflammation is important in both diseases, 

the inflammatory response in COPD is markedly different 

from that in asthma, as summarized in Figure 4-5. 

However, some patients with COPD also have asthma, 

and the inflammation in their lungs may show characteristics 

of both diseases. 

Since inflammation is a feature of COPD, it follows that 

anti-inflammatory therapies may have clinical benefit in 

controlling symptoms, preventing exacerbations, and 

slowing the progression of the disease. However, the 

inflammatory response in COPD appears to be poorly 

responsive to the glucocorticosteroids that are effective 

anti-inflammatory medications in asthma. 



Figure 4-5. Characteristics of Inflammation in COPD and Asthma 

COPD 

Asthma 

Cells • Neutrophils • Eosinophils 

• Large increase in macrophages • Small increase in macrophages 

• Increase in CD8 + T lymphocytes • Increase in CD4 + Th2 lymphocytes 

• Activation of mast cells 

Mediators • LTB4 • LTD4 

• IL-8 

• IL-4, IL-5 

• TNF- 

• (Plus many others) 

Consequences • Squamous metaplasia of epithelium • Fragile epithelium 

• Parenchymal destruction 

• Thickening of basement membrane 

• Mucus metaplasia 

• Mucus metaplasia 

• Glandular enlargement 

• Glandular enlargement 

Response to • Glucocorticosteroids have little or • Glucocorticosteroids inhibit 

Treatment no effect inflammation 

Inflammation and COPD Risk Factors 

The connection between cigarette smoke and inflammation 

has been most extensively studied 41-52 . Cigarette smoke 

activates macrophages and epithelial cells to produce 

TNF- and may also cause macrophages to release 

other inflammatory mediators, including IL-8 and LTB4 53,54 . 

Inflammation is present in the lungs of smokers without a 

diagnosis of COPD. This inflammation is similar to, but 

less intense than, the inflammation in the lungs of patients 

with COPD. For example, induced sputum studies show 

that smokers without COPD have a greater proportion of 

neutrophils in their lungs than age-matched nonsmokers, 

but a smaller proportion than COPD patients 4,9 . Thus, the 

inflammation characteristic of COPD is thought to represent 

an exaggeration of a normal, protective response to 

inhalational exposures. 

However, not all smokers develop COPD, and why the 

normal, protective inflammatory response becomes an 

exaggerated, harmful one in some smokers is poorly 

understood. Presumably the inflammation caused by 

cigarette smoking interacts with other host or environmental 

factors to produce the excess decline in lung function 

that results in COPD 55 . Inflammatory changes are also 

present in bronchial biopsies in ex-smokers, suggesting 

that the inflammatory response in COPD may persist even 

in the absence of continuous exposure to risk factors 56 . 

A number of studies have demonstrated that a variety of 

particulates (e.g., diesel exhaust, grain dust) can initiate 

respiratory tract inflammation 57-61 . It is likely that indoor air 

pollution derived from the burning of biomass fuels will 

prove to have similar effects. 

Proteinase-Antiproteinase Imbalance 

Laurell and Eriksson observed in 1963 that individuals 

with a hereditary deficiency of the serum protein alpha-1 

antitrypsin, which inhibits a number of serine proteinases 

such as neutrophil elastase, are at increased risk of 

developing emphysema 62 . Elastin, the target of neutrophil 

elastase, is a major component of alveolar walls, and 

elastin fragments may perpetuate inflammation by acting 

as potent chemotactic agents for macrophages and 

neutrophils. These observations led to the hypothesis 

that an imbalance between proteinases and endogenous 

antiproteinases results in lung destruction. 

Based on many observations, it now seems clear that an 

imbalance of proteinases and antiproteinases may involve 

either increased production or activity of proteinases, or 

inactivation or reduced production of antiproteinases. 

Often, the imbalance is a consequence of the inflammation 

induced by inhalational exposures. For example, 

macrophages, neutrophils, and airway epithelial cells 

release a combination of proteinases. The imbalance 

may also be caused by a decrease of antiproteinase 

activity by oxidative stress (itself a consequence of 



inflammation), cigarette smoke 63,64 , and possibly other 

COPD risk factors. 

The concept has also been expanded to include additional 

proteinases and antiproteinases. While neutrophil elastase 

is likely to be the major proteinase involved in lung 

destruction in alpha-1 antitrypsin deficiency, it may not 

be involved in COPD caused by inhalational exposures. 

Additional proteinases that have been implicated in 

COPD include neutrophil cathepsin G, neutrophil 

proteinase-3, cathepsins released from macrophages 

(specifically cathepsins B, L, and S), and various matrix 

metalloproteinases (MMPs) 65 . These proteinases are 

capable of degrading elastin and also collagen, another 

main component of alveolar walls. Some proteinases, 

such as neutrophil elastase 66 and neutrophil proteinase-3 67 , 

induce mucus secretion, and neutrophil elastase also 

produces mucus gland hyperplasia 68 . Thus, proteinases 

may be involved in mucus hypersecretion as well as 

parenchymal destruction. Antiproteinases thought to 

be involved in COPD include, in addition to alpha-1 

anti-trypsin, secretory leukoproteinase inhibitor (SLPI) 

and tissue inhibitors of MMPs (TIMPs). 

Oxidative Stress 

There is increasing evidence that an oxidant/antioxidant 

imbalance, in favor of oxidants, occurs in COPD. (The 

process is summarized in Figure 4-6.) Markers of 

oxidative stress have been found in the epithelial lining 

fluid, breath, and urine of cigarette smokers and patients 

with COPD. For example, hydrogen peroxide (H 2 O 2 ) 

and nitric oxide (NO) are direct measures of oxidants 

generated by cigarette smoking or released from 

inflammatory leukocytes and epithelial cells. H 2 O 2 is 

increased in the breath of patients with stable COPD and 

during exacerbations 69 , and NO is increased in the breath 

during exacerbations of COPD 70 . A prostaglandin isomer, 

Figure 4-6. Increased Oxidative Stress in COPD 

Antiproteinases 

SLPI 1 -AT 

Proteolysis 

Mucus secretion 

ANTIOXIDANTS 

Glutathione 

Uric acid, bilirubin 

Vitamins C, E 

O - 2 , H 2 O 2 

OH, ONOO 

- 


IL-8 

NF-B 

Neutrophil 

recruitment 

TNF 

Isoprostanes Plasma leak Bronchoconstriction 

isoprostane F 2 -III, which is formed by free radical 

peroxidation of arachidonic acid and believed to be an in 

vivo biomarker of lung oxidative stress, is increased in 

both breath condensates 71 and urine 72 in COPD patients 

compared to healthy controls and is increased even more 

during exacerbations. 

Oxidative stress contributes to COPD in a variety of 

ways. Oxidants can react with, and damage, a variety of 

biological molecules, including proteins, lipids, and nucleic 

acids, and this can lead to cell dysfunction or death, 

as well as damage to the lung extracellular matrix. In 

addition to directly damaging the lung, oxidative stress 

contributes to the proteinase-antiproteinase imbalance 

both by inactivating antiproteinases (such as alpha-1 

antirypsin and SLPI) and by activating proteinases (such 

as MMPs). Oxidants also promote inflammation, for 

example by activating the transcription factor NF-B, 

which orchestrates the expression of multiple inflammatory 

genes thought to be important in COPD such as IL-8 

and TNF-. Finally, oxidative stress may contribute to 

reversible airway narrowing. H 2 O 2 constricts airway 

smooth muscle in vitro and isoprostane F 2 -III is a potent 

constrictor of human airways 73 . 

PATHOLOGY 

Pathological changes characteristic of COPD are found in 

the central airways, peripheral airways, lung parenchyma, 

and pulmonary vasculature 74 . The various lesions are a 

result of chronic inflammation in the lung, which in turn is 

initiated by the inhalation of noxious particles and gases 

such as those present in cigarette smoke. The lung has 

natural defense mechanisms and a considerable capacity 

to repair itself, but the working of these mechanisms may 

be affected by genetic traits (e.g., alpha-1 antitrypsin 

deficiency) or exposure to other environmental risk factors 

(e.g., infection, atmospheric pollution) 75 , as well as by the 

chronic nature of the inflammation and repeated nature of 

the injury. 

Central Airways 

The central airways include the trachea, bronchi, and 

bronchioles greater than 2-4 mm in internal diameter. 

In patients with chronic bronchitis, an inflammatory 

exudate of fluid and cells infiltrates the epithelium lining 

the central airways and associated glands and ducts 2,42 . 

The predominant cells in this inflammatory exudate are 

macrophages and CD8+ T lymphocytes 2,76 . Chronic 

inflammation in the central airways is also associated 

with an increase in the number (metaplasia) of epithelial 

goblet and squamous cells; dysfunction, damage, and/or 

loss of cilia; enlarged submucosal mucus-secreting 



glands 77 ; an increase in the amount of smooth muscle 

and connective tissue in the airway wall 78 ; degeneration 

of the airway cartilage 79,80 ; and mucus hypersecretion. 

The mechanisms of mucus gland hypertrophy and goblet 

cell metaplasia have not yet been identified, but animal 

studies 81,82 show that irritants including cigarette smoke 83 

can produce these changes. The various pathological 

changes in the central airways (Figure 4-7) are responsible 

for the symptoms of chronic cough and sputum production, 

which identify people at risk for COPD and may continue 

to be present throughout the course of the disease. 

Thus, these pathological changes may be present either 

on their own or in combination with the changes in the 

peripheral airways and lung parenchyma described 

below. 

Figure 4-8. Pathological Changes 

of the Peripheral Airways in COPD 

Figure 4-7. Pathological Changes 

of the Central Airways in COPD 

Histological sections of peripheral airways from 

patients who are cigarette smokers. (A) is a 

nearly normal airway; (B) shows a plug of mucoid 

exudate in the lumen with little or no evidence of 

inflammation in the wall; (C) shows the presence of 

an inflammatory exudate in the wall and lumen of 

the airway; and (D) shows an airway with reduced 

lumen, structural reorganization of the airway wall, 

increased smooth muscle, and deposition of peribronchial 

connective tissue. 

Printed with permission of Dr. James C. Hogg and Stuart Greene. 

(A) shows a central bronchus from the lung of a cigarette 

smoker with normal lung function. Only small 

amounts of muscle are present and the epithelial 

glands are small. This contrasts sharply with a diseased 

bronchus (B), where the muscle appears as a 

thick bundle and the glands are enlarged. (C) shows 

these enlarged glands at a higher magnification. There 

is evidence of a chronic inflammatory process involving 

polymorphonuclear (arrowhead) and mononuclear 

cells, including plasma cells (arrow). 


Peripheral Airways 

The peripheral airways include small bronchi and 

bronchioles that have an internal diameter of less than 

2 mm (Figure 4-8). The early decline in lung function 

in COPD is correlated with inflammatory changes in the 

peripheral airways, similar to those that occur in the 

central airways: exudate of fluid and cells in the 

airway wall and lumen, goblet and squamous cell 

metaplasia of the epithelium 43 , edema of the airway 

mucosa due to inflammation, and excess mucus in the 

airways due to goblet cell metaplasia. 

However, the most characteristic change in the peripheral 

airways of patients with COPD is airway narrowing. 

Inflammation initiated by cigarette smoking 45 and other 

risk factors 75 leads to repeated cycles of injury and 

repair of the walls of the peripheral airways. Injury is 

caused either directly by inhaled toxic particles and 

gases such as those found in cigarette smoke, or 

indirectly by the action of inflammatory mediators; this 

injury then initiates repair processes. Although airway 

repair is only partly understood, it seems likely that 

disordered repair processes can lead to tissue 

remodeling with altered structure and function. 

Cigarette smoke may impair lung repair mechanisms, 

thereby further contributing to altered lung structure 84-86 . 

Even normal lung repair mechanisms can lead to airway 



remodeling because tissue repair in the airways, as 

elsewhere in the body, may involve scar tissue formation. 

In any case, this injury-and-repair process results in a 

structural remodeling of the airway wall, with increasing 

collagen content and scar tissue formation, that narrows 

the lumen and produces fixed airways obstruction 87 . 

The peripheral airways become the major site of airways 

obstruction in COPD, and direct measurements of 

peripheral airways resistance 88 show that the structural 

changes in the airway wall are the most important cause 

of the increase in peripheral airways resistance in COPD. 

Inflammatory changes such as airway edema and 

mucus hypersecretion also contribute to airway narrowing 

in COPD. So does loss of elastic recoil, but fibrosis of 

the small airways plays the largest role. 

Fibrosis in the peripheral airways, as elsewhere in the 

body, is characterized by the accumulation of mesenchymal 

cells (fibroblasts and myofibroblasts) and extracellular 

connective tissue matrix. Several cell types including 

mononuclear phagocytes and epithelial cells may produce 

mediators that drive this process. The mediators that 

drive the accumulation of these cells and of the matrix 

are incompletely defined, but it is likely that several 

mediators including TGF-ß, ET-1, Insulin-like growth 

factor-1, fibronectin, platelet-derived growth factor 

(PDGF), and others are involved 89 . 

Figure 4-9. Normal and Emphysematous Lungs 

Figure 4-10. Normal Respiratory Bronchioles 

and Centrilobular Emphysema 

(A) shows a photomicrograph of the pleural surface 

of a normal lung, with a secondary lobule defined by 

a connective tissue septum (solid arrow) and several 

terminal bronchioles (TB) filled with opaque material. 

(B) shows a low-power photomicrograph of a normal 

terminal bronchiole (TB) branching into a respiratory 

bronchiole (RB), which eventually end in alveolar 

ducts (AD). (C) is a schematic diagram of centrilobular 

emphysema and (D) shows the bronchographic 

appearance of this lesion (TB=terminal bronchiole; 

CLE=centrilobular emphysema). 


Photomicrographs of paper-mounted whole lung sections 

prepared from (A) a normal lung, (B) a lung with 

mild centrilobular emphysema, and (C) a lung with 

severe panacinar emphysema. Note that the centrilobular 

form affects mainly the upper lung regions whereas 

the panacinar form is more apparent in the lower 

lung regions. 


Lung Parenchyma 

The lung parenchyma includes the gas exchanging surface 

of the lung (respiratory bronchioles and alveoli) and the 

pulmonary capillary system (Figure 4-9). The most 

common type of parenchymal destruction in COPD 

patients is the centrilobular form of emphysema (Figure 

4-10), which involves dilatation and destruction of the 

respiratory bronchioles 90 . These lesions occur more 

frequently in the upper lung regions in milder cases, but 

in advanced disease they may appear diffusely throughout 

the entire lung and also involve destruction of the pulmonary 

capillary bed. Panacinar emphysema, which extends 

throughout the acinus, is the characteristic lesion seen in 

alpha-1 antitrypsin deficiency and involves dilatation and 

destruction of the alveolar ducts and sacs as well as the 

respiratory bronchioles. It tends to affect the lower more 

than upper lung regions. Because this process usually 

affects all of the acini in the secondary lobule, it is also 

referred to as panlobular emphysema. The primary 

mechanism of lung parenchyma destruction, in both 

smoking-related COPD and alpha-1 antitrypsin deficiency, 

is thought to be an imbalance of endogenous proteinases 

and antiproteinases in the lung. Oxidative stress, another 

consequence of inflammation, may also contribute 91 . 



Figure 4-11. Pathological Changes of the Pulmonary 

Vasculature in COPD 

exercise and then at rest. As COPD worsens, greater 

amounts of smooth muscle, proteoglycans, and collagen 95 

further thicken the vessel wall. In advanced disease, the 

changes in the muscular arteries may be associated with 

emphysematous destruction of the pulmonary capillary bed. 

. 

PATHOPHYSIOLOGY 

Pathological changes in COPD lead to corresponding 

physiological abnormalities that usually become 

evident first on exercise and later also at rest. 

Physiological changes characteristic of the disease 

include mucus hypersecretion, ciliary dysfunction, airflow 

limitation, pulmonary hyperinflation, gas exchange 

abnormalities, pulmonary hypertension, and cor 

pulmonale, and they usually develop in this order 

over the course of the disease. In turn, various 

physiological abnormalities contribute to the 

characteristic symptoms of COPD – chronic cough 

and sputum production and dyspnea. 

Photomicrographs of small (A) and large (B) vessels 

in the lung of a heavy smoker with normal lung function, 

and small (C) and large (D) vessels in the lung of 

a patient with severe emphysema. Note that the smaller 

vessel has thicker walls (compare arrows in A and 

C) and that the larger vessel has a thicker media 

(compare arrows in B and D) in the patient with severe 

emphysema. (L=vessel lumen; magnification 

bars=100µ). 


Pulmonary Vasculature 

Pulmonary vascular changes in COPD (Figure 4-11) are 

characterized by a thickening of the vessel wall that 

begins early in the natural history of the disease, when 

lung function is reasonably well maintained and pulmonary 

vascular pressures are normal at rest 92 . Endothelial 

dysfunction of the pulmonary arteries, which may be 

caused directly by cigarette smoke products 93 or indirectly 

by inflammatory mediators 14 , occurs early in COPD 94 . 

Since endothelium plays an important role in regulating 

vascular tone and cell proliferation, it is likely that 

endothelial dysfunction might initiate the sequence of 

events that results ultimately in structural changes. 

Thickening of the intima is the first structural change 92 , 

followed by an increase in vascular smooth muscle and 

the infiltration of the vessel wall by inflammatory cells, 

including macrophages and CD8 + T lymphocytes 14 . 

These structural changes are correlated with an increase 

in pulmonary vascular pressure that develops first with 

Mucus Hypersecretion 

and Ciliary Dysfunction 

Mucus hypersecretion in COPD is caused by the 

stimulation of the enlarged mucus secreting glands 

and increased number of goblet cells by inflammatory 

mediators such as leukotrienes, proteinases, and 

neuropeptides. Ciliated epithelial cells undergo 

squamous metaplasia leading to impairment in 

mucociliary clearance mechanisms. These changes 

are usually the first physiological abnormalities to 

develop in COPD, and can be present for many years 

before any other physiological abnormalities develop. 

Airflow Limitation and 

Pulmonary Hyperinflation 

Expiratory airflow limitation is the hallmark physiological 

change of COPD. The airflow limitation characteristic 

of COPD is primarily irreversible, with a small reversible 

component. Several pathological characteristics 

contribute to airflow limitation and changes in pulmonary 

mechanics, as summarized in Figure 4-12. The 

irreversible component of airflow limitation is primarily 

due to remodeling 42,43,87,88,96,97 – fibrosis and narrowing – of 

the small airways that produces fixed airways obstruction 

and a consequent increase in airways resistance. The 

sites of airflow limitation in COPD are the smaller 

conducting airways, including bronchi and bronchioles 

less than 2 mm in internal diameter. In the normal lung, 

resistance of these smaller airways makes up a small 

percentage of the total airways resistance 88 . But in 



Figure 4-12. Causes of Airflow Limitation in COPD 

Irreversible 

Reversible 

• Fibrosis and narrowing of airways 

• Loss of elastic recoil due to alveolar 

destruction 

• Destruction of alveolar support that 

maintains patency of small airways 

• Accumulation of inflammatory cells, 

mucus, and plasma exudate in bronchi 

• Smooth muscle contraction in peripheral 

and central airways 

• Dynamic hyperinflation during exercise 

patients with COPD the total lower airways resistance 

approximately doubles, and most of the increase is due 

to a large increase in peripheral airways resistance 88 . 

Although some have argued that a larger proportion of 

the total resistance should be attributed to peripheral airways 

in the normal lung, there is wide agreement that the 

peripheral airways become the major site of obstruction 

in COPD. 

Parenchymal destruction (emphysema) plays a smaller 

role in this irreversible component but contributes to 

expiratory airflow limitation and the increase in airways 

resistance in several ways. Destruction of alveolar 

attachments inhibits the ability of the small airways to 

maintain patency 98 . Alveolar destruction is also associated 

with a loss of elastic recoil of the lung 99,100 , which decreases 

the intra-alveolar pressure driving exhalation. 

Although both the destruction of alveolar attachments to 

the outer wall of the peripheral airways and the loss of 

lung elastic recoil produced by emphysema have been 

implicated in the pathogenesis of peripheral airways 

obstruction 98,100 , direct measurements of peripheral airways 

resistance 88 show that the structural changes in the 

airway wall are the most important cause of the increase 

in peripheral airways resistance in COPD. 

Airway smooth muscle contraction, ongoing airway 

inflammation, and intraluminal accumulation of mucus 

and plasma exudate may be responsible for the small 

part of airflow limitation that is reversible with treatment. 

Inflammation and accumulation of mucus and exudate 

may be particularly important during exacerbations 101 . 

Airflow limitation in COPD is best measured through 

spirometry, which is key to the diagnosis and management 

of the disease. The essential spirometric measurements 

for diagnosis and monitoring of COPD patients are the 

forced expiratory volume in one second (FEV 1 ) and 

forced vital capacity (FVC). As COPD progresses, with 

increased thickness of the airway wall, loss of alveolar 

attachments, and loss of lung elastic recoil, FEV 1 and 

FVC decrease. A decrease in the ratio of FEV 1 to FVC 

is often the first sign of developing airflow limitation. 

FEV 1 declines naturally with age, but the rate of decline 

in COPD patients is generally greater than that in normal 

subjects. 

With increasing severity of airflow limitation, expiration 

becomes flow-limited during tidal breathing. Initially, this 

occurs only during exercise, but later it is also seen at 

rest. In parallel with this, functional residual capacity (FRC) 

increases due to the combination of the decrease in the 

elastic properties of the lungs, premature airway closure, 

and a variable dynamic element reflecting the breathing 

pattern adopted to cope with impaired lung mechanics. 

As airflow limitation develops, the rate of lung emptying is 

slowed and the interval between inspiratory efforts does 

not allow expiration to the relaxation volume of the 

respiratory system; this leads to dynamic pulmonary 

hyperinflation. The increase in FRC can impair inspiratory 

muscle function and coordination, although the contractility 

of the diaphragm, when normalized for lung volume, 

seems to be preserved. These changes occur as the 

disease advances but are almost always seen first during 

exercise, when the greater metabolic stimulus to ventilation 

stresses the ability of the ventilatory pump to maintain 

gas exchange. 

Gas Exchange Abnormalities 

In advanced COPD, peripheral airways obstruction, 

parenchymal destruction, and pulmonary vascular 

abnormalities reduce the lung's capacity for gas 

exchange, producing hypoxemia and, later on, hypercapnia. 

The correlation between routine lung function tests and 

arterial blood gases is poor, but significant hypoxemia or 

hypercapnia is rare when FEV 1 is greater than 1.00 L 102 . 

Hypoxemia is initially only present during exercise, but as 

the disease continues to progress it is also present at rest. 

Inequality in the ventilation/perfusion ratio (V A /Q) is the 

major mechanism behind hypoxemia in COPD, regardless 

of the stage of the disease 103 . In the peripheral airways, 

injury of the airway wall is associated with VA /Q 

mismatching, as indicated by a significant correlation 

between bronchiolar inflammation and the distribution of 

ventilation. In the parenchyma, destruction of the lung 

surface area by emphysema reduces diffusing capacity 

and interferes with gas exchange 104 . High V A /Q units 

probably represent emphysematous regions with alveolar 

destruction and loss of pulmonary vasculature. The 



severity of pulmonary emphysema appears to be related 

to the overall inefficiency of the lung as a gas exchanger. 

This is reflected by the good correlation between the 

diffusing capacity of carbon monoxide per liter of alveolar 

volume (D Lco /V A ) and the severity of macroscopic 

emphysema. Reduced ventilation due to loss of elastic 

recoil in the emphysematous lung, together with the loss 

of the capillary bed and the generalized inhomogeneity 

of ventilation due to the patchy nature of these changes, 

leads to areas of V A /Q mismatching that result in arterial 

hypoxemia. 

The relationship between pulmonary vascular abnormalities 

and V A /Q relationships has been investigated in patients 

with mild COPD. The more severe the vessel wall damage 

is, the less the reversal of hypoxic vasoconstriction by 

oxygen 105 . This suggests that pathology in the pulmonary 

artery wall, particularly when it affects the intimal layer, 

may play a key role in determining the loss of vascular 

response to hypoxia that contributes to V A /Q mismatching. 

Chronic hypercapnia usually reflects inspiratory muscle 

dysfunction and alveolar hypoventilation. 

Pulmonary Hypertension and Cor Pulmonale 

Pulmonary hypertension develops late in the course of 

COPD (Stage IV: Very Severe COPD), usually after the 

development of severe hypoxemia (PaO 2 < 8.0 kPa or 60 

mm Hg) and often hypercapnia as well. It is the major 

cardiovascular complication of COPD and is associated 

with the development of cor pulmonale and with a poor 

prognosis 106 . However, even in patients with severe 

disease, pulmonary arterial pressure is usually only 

modestly elevated at rest, though it may rise markedly 

with exercise. Pulmonary hypertension in COPD is 

believed to progress rather slowly even if left untreated. 

Further studies are required to firmly establish the natural 

history of pulmonary hypertension in COPD. 

Factors that are known to contribute to the development 

of pulmonary hypertension in patients with COPD include 

vasoconstriction; remodeling of pulmonary arteries, 

which thickens the vessel walls and reduces the lumen; 

and destruction of the pulmonary capillary bed by 

emphysema, which further increases the pressure 

required to perfuse the pulmonary vascular bed. 

Vasoconstriction may itself have several causes, including 

hypoxia, which causes pulmonary vascular smooth muscle 

to contract; impaired mechanisms of endothelium-dependent 

vasodilation, such as reduced NO synthesis or release; 

and abnormal secretion of vasoconstrictor peptides (such 

as ET-1, which is produced by inflammatory cells). In 

advanced COPD, hypoxia plays the primary role in 

producing pulmonary hypertension, both by causing 

vasoconstriction of the pulmonary arteries and by 

promoting remodeling of the vessel wall (either by inducing 

the release of growth factors 107 or as a consequence of 

the mechanical stress that results from hypoxic 

vasoconstriction). 

Pulmonary hypertension is associated with the development 

of cor pulmonale, defined as "hypertrophy of the right 

ventricle resulting from diseases affecting the function 

and/or structure of the lungs, except when these pulmonary 

alterations are the result of diseases that primarily affect 

the left side of the heart, as in congenital heart disease." 

This is a pathological definition and the clinical diagnosis 

and assessment of right ventricular hypertrophy is difficult 

in life. 

The prevalence and natural history of cor pulmonale in 

COPD are not yet clear. Pulmonary hypertension and 

reduction of the vascular bed due to emphysema can 

lead to right ventricular hypertrophy and right heart failure, 

but right ventricular function appears to be maintained 

in some patients despite the presence of pulmonary 

hypertension 108 . Right heart failure is associated with 

venous stasis and thrombosis that may result in pulmonary 

embolism and further compromise the pulmonary 

circulation. 

Systemic Effects 

COPD is associated with systemic (i.e., extrapulmonary) 

effects, such as systemic inflammation and skeletal 

muscle dysfunction. Evidence of systemic inflammation 

includes the presence of systemic oxidative stress 109 , 

abnormal concentrations of circulating cytokines 110 , and 

activation of inflammatory cells 111,112 . Evidence of skeletal 

muscle dysfunction includes the progressive loss of 

skeletal muscle mass and the presence of several 

bioenergetic abnormalities 113 . These systemic effects have 

important clinical consequences, as they contribute to the 

limitation of patients' exercise capacity and thus the 

decline of health status in COPD. The presence of these 

systemic effects appears to worsen a patient's prognosis 114 . 

Pathophysiology and the 

Symptoms of COPD 

Chronic cough and sputum production, sometimes labeled 

as chronic bronchitis, are a result of airway inflammation, 

which leads to mucus hypersecretion and dysfunction of 

the normal ciliary clearance mechanisms. Sputum is 

produced in COPD as a result of the inflammatory 

response, and contains plasma proteins exuded from the 

microvessels of the bronchial circulation, inflammatory 

cells, and small amounts of mucus from epithelial goblet 

cells. The volume of sputum produced overpowers clearance 

mechanisms, resulting in cough and expectoration. 



Some pathological abnormalities, such as inflammation of 

the submucosal glands and hyperplasia of goblet cells, 

may contribute to chronic sputum production, although 

these pathological abnormalities are not present in all 

patients with this symptom. 

Dyspnea, an abnormal awareness of the act of breathing, 

usually reflects an imbalance between the neural drive to 

the respiratory muscles and the effectiveness of the 

resulting ventilation. Different individuals use different 

words to describe the feeling of breathlessness, which is 

also influenced by other factors such as mood. In COPD 

patients, dyspnea is mainly the result of impaired lung 

mechanics (increased airways resistance, decreased 

elastic recoil). It is only present on vigorous exercise in 

the early stages of disease but may be present at rest as 

the mechanical impairment becomes severe. 

PATHOLOGY AND 

PATHOPHYSIOLOGY OF 

EXACERBATIONS 

The progressive course of COPD is complicated by 

exacerbations that have many causes and occur with 

increasing frequency as the disease progresses. 

Pathology 

Distinguishing the pathology of these acute events from 

that of the underlying disease is difficult because patients 

experiencing an exacerbation are usually too ill to study. 

The limited evidence available suggests that mild COPD 

exacerbations are associated with increases of both 

neutrophils and eosinophils in sputum and biopsies, while 

severe COPD exacerbations are associated with an 

increase in sputum neutrophils and eosinophils 18,19 . At 

least in sputum, the changes in inflammatory cells during 

exacerbations of COPD are the same as those observed 

during exacerbations of asthma 115-119 . So far no study has 

been conducted examining the pathological abnormalities 

associated with fatal exacerbations of COPD, which can be 

considered the extreme end of the spectrum of severity. 

Pathophysiology 

Expiratory airflow is almost unchanged during mild 

exacerbations 18 , and only slightly reduced during severe 

exacerbations 120,121 . Although the pathophysiology of 

exacerbations is not fully understood, the primary 

physiological change in severe exacerbations is a further 

worsening of gas exchange, primarily produced by 

increased V A /Q inequality. As V A /Q relationships worsen, 

increased work of the respiratory muscles results in 

greater oxygen consumption, decreased mixed venous 

oxygen tension, and further amplification of gas 

exchange abnormalities 120 . Worsening of V A /Q relationships 

has several causes in exacerbations. Airway 

inflammation and edema, mucus hypersecretion, and 

bronchoconstriction may contribute to changes in the 

distribution of ventilation, while hypoxic constriction of 

pulmonary arterioles may modify the distribution of 

perfusion. Additional contributors to worsening gas 

exchange in exacerbations include abnormal patterns of 

breathing and fatigue of the respiratory muscles. These 

can cause further deterioration in blood gases and 

worsening of respiratory acidosis, leading to severe 

respiratory failure and death 120-123 . Alveolar hypoventilation 

also contributes to hypoxemia, hypercapnia, and 

respiratory acidosis. In turn, hypoxemia and respiratory 

acidosis promote pulmonary vasoconstriction, which 

increases pulmonary artery pressures and imposes an 

added load on the right ventricle. 

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CHAPTER 

5 

MANAGEMENT 

OF COPD


CHAPTER 5: MANAGEMENT OF COPD 

INTRODUCTION 

Management of Mild to Moderate COPD (Stages I and II) 

involves the avoidance of risk factors to prevent disease 

progression and pharmacotherapy as needed to control 

symptoms. Severe (Stage III) and very severe (Stage IV) 

disease often require the integration of several different 

disciplines, a variety of treatment approaches, and a 

commitment of the clinician to the continued support of 

the patient as the illness progresses. In addition to 

patient education, health advice, and pharmacotherapy, 

COPD patients may require specific counseling about 

smoking cessation, instruction in physical exercise, 

nutritional advice, and continued nursing support. Not all 

approaches are needed for every patient, and assessing 

the potential benefit of each approach at each stage of 

the illness is a crucial aspect of effective disease 

management. 

An effective COPD management plan includes four 

components: (1) Assess and Monitor Disease; (2) 

Reduce Risk Factors; (3) Manage Stable COPD; (4) 

Manage Exacerbations. 

While disease prevention is the ultimate goal, once 

COPD has been diagnosed, effective management 

should be aimed at the following goals: 

• Prevent disease progression. 

• Relieve symptoms. 

• Improve exercise tolerance. 

• Improve health status. 

• Prevent and treat complications. 

• Prevent and treat exacerbations. 

• Reduce mortality. 

These goals should be reached with minimal side effects 

from treatment, a particular challenge in COPD patients 

because they commonly have comorbidities. The extent 

to which these goals can be realized varies with each 

individual, and some treatments will produce benefits in 

more than one area. In selecting a treatment plan, the 

benefits and risks to the individual, and the costs, direct 

and indirect, to the individual, his or her family, and the 

community must be considered. 

Patients should be identified as early in the course of the 

disease as possible, and certainly before the end stage 

of the illness when disability is substantial. However, the 

benefits of community-based spirometric screening, of 

either the general population or smokers, are still unclear. 

Educating patients and physicians to recognize that 

cough, sputum production, and especially breathlessness 

are not trivial symptoms is an essential aspect of the 

public health care of this disease. 

Reduction of therapy once symptom control has been 

achieved is not normally possible in COPD. Further 

deterioration of lung function usually requires the 

progressive introduction of more treatments, both 

pharmacologic and non-pharmacologic, to attempt to limit 

the impact of these changes. Exacerbations of signs and 

symptoms, a hallmark of COPD, impair patients' quality 

of life and decrease their health status 1,2 . Appropriate 

treatment and measures to prevent further exacerbations 

should be implemented as quickly as possible. 

Important differences exist between countries in the 

approach to chronic illnesses such as COPD and in the 

acceptability of particular forms of therapy. Ethnic 

differences in drug metabolism, especially for oral 

medications, may result in different patient preferences 

in different communities. Little is known about these 

important issues in relationship to COPD. 

REFERENCES 

1. O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and 

radiological characterization of patients diagnosed with 

chronic obstructive pulmonary disease in primary care. 

Thorax 2000; 55:635-42. 

2. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, 

Wedzicha JA. Time course and recovery of exacerbations in 



46 MANAGEMENT OF COPD


COMPONENT 1: ASSESS AND MONITOR DISEASE 

KEY POINTS: 

• Diagnosis of COPD is based on a history of 

exposure to risk factors and the presence of 

airflow limitation that is not fully reversible, with 

or without the presence of symptoms. 

• Patients who have chronic cough and sputum 

production with a history of exposure to risk 

factors should be tested for airflow limitation, 

even if they do not have dyspnea. 

• For the diagnosis and assessment of COPD, 

spirometry is the gold standard as it is the most 

reproducible, standardized, and objective way of 

measuring airflow limitation. FEV 1 /FVC < 70% 

and a postbronchodilator FEV 1 < 80% predicted 

confirms the presence of airflow limitation that is 

not fully reversible. 

• Health care workers involved in the diagnosis 

and management of COPD patients should have 

access to spirometry. 

• Measurement of arterial blood gas tensions 

should be considered in all patients with FEV 1 < 

40% predicted or clinical signs suggestive of 

respiratory failure or right heart failure. 

INITIAL DIAGNOSIS 

A diagnosis of COPD should be considered in any patient 

who has cough, sputum production, or dyspnea, and/or a 

history of exposure to risk factors for the disease (Figure 

5-1-1). The diagnosis is confirmed by spirometry. The 

presence of a postbronchodilator FEV 1 < 80% of the 

predicted value in combination with an FEV 1 /FVC < 70% 

confirms the presence of airflow limitation that is not fully 

reversible. Where spirometry is unavailable, the diagnosis 

of COPD should be made using all available tools. 

Clinical symptoms and signs, such as abnormal shortness 

of breath and increased forced expiratory time, can be 

used to help with the diagnosis. A low peak flow is 

consistent with COPD, but has poor specificity since it 

can be caused by other lung diseases and by poor 

performance. In the interest of improving the diagnosis of 

COPD, every effort should be made to provide access to 

standardized spirometry. 

Assessment of Symptoms 

Although exceptions occur, the general patterns of 

symptom development in COPD are well established. 

The main symptoms among patients in Stage 0: At Risk 

and Stage I: Mild COPD are chronic cough and sputum 

production. These symptoms can be present for many 

years before the development of airflow limitation and 

are often ignored or discounted by patients. As airflow 

limitation develops in Stage II: Moderate COPD, patients 

often experience dyspnea, which may interfere with their 

Figure 5-1-1. Key Indicators for 

Considering a Diagnosis of COPD 

Consider COPD, and perform spirometry, if any of 

these indicators are present. These indicators are not 

diagnostic by themselves, but the presence of multiple 

key indicators increases the probability of a diagnosis 

of COPD. Spirometry is needed to establish a 

diagnosis of COPD. 

Chronic cough: 

Present intermittently or every day. 

Often present throughout the day; 

seldom only nocturnal. 

Chronic sputum Any pattern of chronic sputum 

production: production may indicate COPD. 

Dyspnea that is: 

History of 

exposure to 

risk factors, 

especially: 

Progressive (worsens over time). 

Persistent (present every day). 

Described by the patient as an 

“increased effort to breathe,” 

“heavi-ness,” “air hunger,” or “gasping.” 

Worse on exercise. 

Worse during respiratory infections. 

Tobacco smoke. 

Occupational dusts and chemicals. 

Smoke from home cooking and 

heating fuels. 

MANAGEMENT OF COPD 47


daily activities. Typically, this is the stage at which they 

seek medical attention and are diagnosed with COPD. 

However, some patients do not experience cough, sputum 

production, or dyspnea in Stage I: Mild COPD or 

Stage II: Moderate COPD, and do not come to medical 

attention until their airflow limitation becomes more 

severe or their lung function is worsened acutely by a 

respiratory tract infection. As airflow limitation worsens 

and the patient enters Stage III: Severe COPD, the symptoms 

of cough and sputum production typically continue, 

dyspnea worsens, and additional symptoms heralding 

complications may develop. It is important to note that, 

since COPD may be diagnosed at any stage, any of the 

symptoms described below may be present in a patient 

presenting for the first time. 

Figure 5-1-2. Causes of Chronic Cough 

with a Normal Chest X-ray 

Intrathoracic 

• Chronic obstructive pulmonary disease 

• Bronchial asthma 

• Central bronchial carcinoma 

• Endobronchial tuberculosis 

• Bronchiectasis 

• Left heart failure 

• Interstitial lung disease 

• Cystic fibrosis 

Extrathoracic 

• Postnasal drip 

• Gastroesophageal reflux 

• Drug therapy (e.g., ACE inhibitors) 

Figure 5-1-3. Questionnaire for Assessing the 

Impact of Respiratory Symptoms 6 

WHEEZING 

Does your chest ever sound wheezing or whistling? Yes ❑ 

No ❑ 

IF YOU ANSWERED “YES” TO THIS QUESTION: 

Do you get this on most days – or nights? Yes ❑ 

No ❑ 

Have you ever had attacks of shortness of breath Yes ❑ 

with wheezing? No ❑ 

IF YOU ANSWERED “YES” TO THIS QUESTION: 

Is/was your breathing absolutely normal between Yes ❑ 

attacks? No ❑ 

CHEST ILLNESSES 

During the last three years have you had any chest Yes ❑ 

illnesses which have kept you from your usual No ❑ 

activities for as much as a week? 

IF YOU ANSWERED YES TO THIS QUESTION: 

Did you bring up phlegm more than usual during Yes ❑ 

these illnesses? No ❑ 

IF YOU ANSWERED YES TO THIS QUESTION: 

Have you had more than one illness like this in the Yes ❑ 

past three years? No ❑ 

Cough. Chronic cough, usually the first symptom of 

COPD to develop 1 , is often discounted by the patient as 

an expected consequence of smoking and/or environmental 

exposures. Initially, the cough may be intermittent, 

but later is present every day, often throughout the 

day, and is seldom entirely nocturnal. The chronic cough 

in COPD may be unproductive 2 . In some cases, significant 

airflow limitation may develop without the presence 

of a cough. Figure 5-1-2 lists some of the other causes 

of chronic cough in individuals with a normal chest X-ray. 

Sputum production. COPD patients commonly raise 

small quantities of tenacious sputum after coughing 

bouts. Regular production of sputum for 3 or more 

months in 2 consecutive years is the epidemiological definition 

of chronic bronchitis 3 , but this is a somewhat arbitrary 

definition that does not reflect the range of sputum 

production in COPD patients. Sputum production is often 

BREATHLESSNESS 

PLEASE TICK IN THE BOX THAT APPLIES TO YOU 

(ONE BOX ONLY) 

I only get breathless with strenuous exercise. 

I get short of breath when hurrying on the level or 

walking up a slight hill. 

I walk slower than people of the same age on the level 

because of breathlessness, or I have to stop for breath 

when walking on my own pace on the level. 

I stop for breath after walking about 100 yards or after a 

few minutes on the level. 

I am too breathless to leave the house or I am breathless 

when dressing or undressing. 

❑ 

❑ 

❑ 

❑ 

❑ 



difficult to evaluate because patients may swallow sputum 

rather than expectorate it, a habit subject to significant 

cultural and gender variation. 

Dyspnea. Dyspnea, the hallmark symptom of COPD, is 

the reason most patients seek medical attention and is a 

major cause of disability and anxiety associated with the 

disease. Typical COPD patients describe their dyspnea 

as a sense of increased effort to breathe, heaviness, air 

hunger, or gasping 4 . The terms used to describe dyspnea 

vary both by individual and by culture 5 . It is often possible 

to distinguish the breathlessness of COPD from that due 

to other causes by analysis of the terms used, although 

there is considerable overlap with descriptors of bronchial 

asthma. A simple way to quantify the impact of breathlessness 

on a patient’s health status is the British 

Medical Research Council (MRC) questionnaire (Figure 

5-1-3). This questionnaire relates well to other measures 

of health status 6 . 

Breathlessness in COPD is characteristically persistent 

and progressive. Even on “good days” COPD patients 

experience dyspnea at lower levels of exercise than 

unaffected people of the same age. Initially, breathlessness 

is only noted on unusual effort (e.g., walking or running 

up a flight of stairs) and may be avoided entirely by 

appropriate behavioral change (e.g., using an elevator). 

As lung function deteriorates, breathlessness becomes 

more intrusive, and patients may notice that they are 

unable to walk at the same speed as other people of the 

same age or carry out activities that require use of the 

accessory respiratory muscles (e.g., carrying grocery 

bags) 7 . Eventually, breathlessness is present during 

everyday activities (e.g., dressing, washing) or at rest, 

leaving the patient confined to the home. 

Wheezing and chest tightness. Wheezing and chest 

tightness are relatively non-specific symptoms that may 

vary between days, and over the course of a single day. 

These symptoms may be present in Stage I: Mild COPD, 

but are more characteristic of asthma or Stage III: 

Severe COPD and Stage IV: Very Severe COPD. Audible 

wheeze may arise at a laryngeal level and need not be 

accompanied by ausculatory abnormalities. Alternatively, 

widespread inspiratory or expiratory wheezes can be 

present on listening to the chest. Chest tightness often 

follows exertion, is poorly localized, is muscular in 

character, and may arise from isometric contraction of the 

intercostal muscles. An absence of wheezing or chest 

tightness does not exclude a diagnosis of COPD. 

Additional symptoms in severe disease. Weight loss 

and anorexia are common problems in advanced COPD 8 . 

Hemoptysis can occur during respiratory tract infections 

in COPD patients 9 . However, this can be a sign of other 

diseases (e.g., tuberculosis, bronchial tumors) and 

therefore should always be investigated. Cough syncope 

occurs due to rapid increases in intrathoracic pressure 

during attacks of coughing. Coughing spells may also 

cause ribfractures, which are sometimes asymptomatic. 

Psychiatric morbidity, especially symptoms of depression 

and/or anxiety, is common in advanced COPD 10 . Ankle 

swelling can be the only symptomatic pointer to the 

development of cor pulmonale. 

Medical History 

A detailed medical history of a new patient known or 

thought to have COPD should assess: 

• Patient’s exposure to risk factors, such as smoking 

and occupational or environmental exposures. 

• Past medical history, including asthma, allergy, 

sinusitis or nasal polyps, respiratory infections in 

childhood, other respiratory diseases. 

• Family history of COPD or other chronic respiratory 

disease. 

• Pattern of symptom development: COPD typically 

develops in adult life and most patients are 

conscious of increased breathlessness, more 

frequent “winter colds,” and some social restriction 

for a number of years before seeking medical help. 

• History of exacerbations or previous hospitalizations 

for respiratory disorder: Patients may be aware of 

periodic worsening of symptoms even if these 

episodes have not been identified as exacerbations 

of COPD. 

• Presence of comorbidities, such as heart disease 

and rheumatic disease, which may also contribute to 

restriction of activity. 

• Appropriateness of current medical treatments: 

For example, beta-blockers commonly prescribed 

for heart disease are usually contraindicated in 

COPD. 

• Impact of disease on patient’s life, including limitation 

of activity; missed work and economic impact; effect 

on family routines; feelings of depression or anxiety. 

• Social and family support available to the patient. 

• Possibilities for reducing risk factors, especially 

smoking cessation. 



Physical Examination 

Though an important part of patient care, a physical 

examination is rarely diagnostic in COPD. Physical signs 

of airflow limitation are usually not present until significant 

impairment of lung function has occurred 11,12 , and their 

detection has a relatively low sensitivity and specificity. 

A number of physical signs may be present in COPD, but 

their absence does not exclude the diagnosis. 

Inspection. 

• Central cyanosis, or bluish discoloration of the mucosal 

membranes, may be present but is difficult to detect 

in artificial light and in many racial groups. 

• Common chest wall abnormalities, which reflect the 

pulmonary hyperinflation seen in COPD, include 

relatively horizontal ribs, “barrel- shaped” chest, and 

protruding abdomen. 

• Flattening of the hemi-diaphragms may be associated 

with paradoxical in-drawing of the lower rib cage on 

inspiration, reduced cardiac dullness, and widening 

xiphisternal angle. 

• Resting respiratory rate is often increased to more 

than 20 breaths per minute and breathing can be 

relatively shallow 12 . 

• Patients commonly show pursed-lip breathing, which 

may serve to slow expiratory flow and permit more 

efficient lung emptying. 

• COPD patients often have resting muscle activation 

while lying supine. Use of the scalene and sternocleidomastoid 

muscles is a further indicator of 

respiratory distress. 

• Ankle or lower leg edema can be a sign of right heart 

failure. 

Palpation and percussion. 

• These are often unhelpful in COPD. 

• Detection of the heart apex beat may be difficult due 

to pulmonary hyperinflation. 

• Hyperinflation also leads to downward displacement 

of the liver and an increase in the ability to palpate 

this organ without it being enlarged. 

Auscultation. 

• Patients with COPD often have reduced breath 

sounds, but this finding is not sufficiently characteristic 

to make the diagnosis 13 . 

Figure 5-1-4. Considerations in 

Performing Spirometry 

Preparation 

• Spirometers need calibration on a regular basis. 

• Spirometers should produce hard copy to permit 

detection of technical errors. 

• The supervisor of the test needs training in its effective 

performance. 

• Maximal patient effort in performing the test is 

required to avoid errors in diagnosis and management. 

Performance 

• Spirometry should be performed using techniques that 

meet published standards 14 . 

• The expiratory volume/time traces should be smooth 

and free from irregularities. 

• The recording should go on long enough for a volume 

plateau to be reached, which may take more than 12 

seconds in severe disease. 

• Both FVC and FEV 1 should be the largest value 

obtained from any of 3 technically satisfactory curves 

and the FVC and FEV 1 values in these three curves 

should vary by no more than 5% or 100 ml, whichever 

is greater. 

Evaluation 

• Spirometry measurements are evaluated by comparison 

of the results with appropriate reference values based 

on age, height, sex, and race (e.g., see reference 14). 

• The presence of a postbronchodilator FEV 1 < 80% 

predicted together with an FEV 1 /FVC < 70% confirms 

the presence of airflow limitation that is not fully 

reversible. 

• In patients with FEV 1 > 80% predicted, FEV 1 /FVC < 

70% may be an early indicator of developing airflow 

limitation. 

• The presence of wheezing during quiet breathing is a 

useful pointer to airflow limitation. However, wheezing 

heard only after forced expiration is of no diagnostic 

value. 

• Inspiratory crackles occur in some COPD patients but 

are of little help diagnostically. 

• Heart sounds are best heard over the xiphoid area. 

Measurement of Airflow Limitation 

(Spirometry) 

Spirometry measurements should be undertaken for any 

patient who may have COPD. To help identify individuals 

earlier in the course of the disease, spirometry should be 



performed for patients who have chronic cough and 

sputum production even if they do not have dyspnea. 

Although spirometry does not fully capture the impact of 

COPD on a patient’s health, it remains the gold standard 

for diagnosing the disease and monitoring its progression. 

It is the best standardized, most reproducible, and most 

objective measurement of airflow limitation available. 

Health care workers who care for COPD patients should 

have access to spirometry, which is useful in both diagnosis 

and periodic monitoring. Figure 5-1-4 summarizes some 

considerations that are crucial to achieving consistently 

accurate test results. 

Spirometry should measure the maximal volume of air 

forcibly exhaled from the point of maximal inspiration 

(forced vital capacity, FVC) and the volume of air exhaled 

during the first second of this maneuver (forced expiratory 

volume in one second, FEV 1 ), and the ratio of these two 

measurements (FEV 1 /FVC) should be calculated. 

Spirometry measurements are evaluated by comparison 

with reference values based on age, height, sex, and race 

(use appropriate reference values, e.g., see reference 14). 

Figure 5-1-5 shows a normal spirogram and a spirogram 

typical of patients with mild to moderate COPD. Patients 

with COPD typically show a decrease in both FEV 1 and 

FVC. The degree of spirometric abnormality generally 

reflects the severity of COPD (Figure 1-2). The presence 

of a postbronchodilator FEV 1 < 80% of the predicted 

value in combination with an FEV 1 /FVC < 70% confirms 

Figure 5-1-5. Normal Spirogram and Spirogram 

Typical of Patients with Moderate COPD 

FEV 1 

FVC 

FEV 1 /FVC 

the presence of airflow limitation that is not fully 

reversible. The FEV 1 /FVC on its own is a more sensitive 

measure of airflow limitation, and an FEV 1 /FVC < 70% is 

considered an early sign of airflow limitation in patients 

whose FEV 1 remains normal (≥ 80% predicted). This 

approach to defining airflow limitation is a pragmatic one 

in view of the fact that universally applicable reference 

values for FEV 1 and FVC are not available. 

Peak expiratory flow (PEF) is sometimes used as a measure 

of airflow limitation, but in COPD the relationship between 

PEF and FEV 1 is poor. PEF may underestimate the 

degree of airways obstruction in these patients 15 . If 

spirometry is unavailable, prolongation of the forced 

expiratory time beyond 6 seconds is a crude, but useful, 

guide to the presence of an FEV 1 /FVC ratio < 50% 16,17 . 

The role of screening spirometry in the general population 

or in a population at risk for COPD is controversial. Both 

FEV 1 and FVC predict all-cause mortality independent of 

tobacco smoking, and abnormal lung function identifies a 

subgroup of smokers at increased risk for lung cancer. 

This has been the basis of an argument that screening 

spirometry should be employed as a global health 

assessment tool 18 . However, there are no data to indicate 

that screening spirometry is effective in directing 

management decisions or in improving COPD outcomes. 

Assessment of Severity 

Assessment of COPD severity is based on the patient’s 

level of symptoms, the severity of the spirometric 

abnormality, and the presence of complications such as 

respiratory failure and right heart failure (Figure 1-2). 

The use of specific spirometric cut-points (e.g., 

FEV 1 /FVC


that should be targeted for preventive intervention. Much 

depends on the success of convincing such people, as 

well as health care workers, that minor respiratory 

symptoms may be markers of future ill health. 

The severity of a patient’s breathlessness is important 

and can be gauged by the MRC scale (Figure 5-1-3). 

Arterial blood gases should be measured in all patients 

who have FEV 1 < 40% predicted or clinical signs of 

respiratory failure or right heart failure. 

Additional Investigations 

For patients diagnosed with Stage II: Moderate COPD 

and beyond, the following additional investigations may 

be useful. 

Bronchodilator reversibility testing. Generally performed 

only once, at the time of diagnosis, this test is useful for 

several reasons: 

• To help rule out a diagnosis of asthma. 

If FEV 1 returns to the predicted normal range after 

administration of a bronchodilator, the patient’s airflow 

limitation is likely due to asthma. 

• To establish a patient’s best attainable lung function at 

that point in time. 

• To gauge a patient’s prognosis. 

Some studies show that the postbronchodilator FEV 1 is 

a more reliable prognostic marker than pre-bronchodilator 

FEV 1 

22 

. In addition, the Intermittent Positive Pressure 

Breathing (IPPB) Study, a multicenter clinical trial, 

suggested that the degree of bronchodilator response 

is inversely related to the rate of FEV 1 decline in 

COPD patients 23 . 

• To assess potential response to treatment. 

Patients who show significant improvement in FEV 1 

after administration of a bronchodilator are more likely 

to benefit from treatment with bronchodilators and have 

a positive response to glucocorticosteroids. However, 

individual responses to bronchodilator tests are influenced 

by many factors, and failure of FEV 1 to change by an 

arbitrary amount on one day does not preclude a 

response on another. Moreover, even patients who do 

not show a significant FEV 1 response to a short-acting 

bronchodilator test may benefit symptomatically from 

long-term bronchodilator therapy. 

Figure 5-1-6. Bronchodilator Reversibility Testing 

Preparation 

• Tests should be performed when patients are clinically 

stable and free from respiratory infection. 

• Patients should not have taken inhaled short-acting 

bronchodilators in the previous six hours, long-acting 

ß 2 agonists in the previous 12 hours, or sustainedrelease 

theophyllines in the previous 24 hours. 

Spirometry 

• FEV 1 should be measured before a bronchodilator is 

given. 

• The bronchodilator should be given by metered dose 

inhaler through a spacer device or by nebulizer to be 

certain it has been inhaled. 

• The bronchodilator dose should be selected to be 

high on the dose/response curve. 

• Suitable dosage protocols are 400 g ß 2 -agonist, 

80 g anticholinergic, or the two combined. FEV 1 

should be measured again 30-45 minutes after the 

bronchodilator is given. 

Results 

• An increase in FEV 1 that is both greater than 200 ml 

and 12% above the pre-bronchodilator FEV 1 is considered 

significant. 

Between-day reproducibility of spirometry in the same 

individual is approximately 178 ml 24 . Thus, an acute 

change that exceeds both 200 ml and 12% of the baseline 

measurement is unlikely to have arisen by chance. 

A protocol for bronchodilator reversibility testing is listed 

in Figure 5-1-6. 

Chest X-ray. A chest X-ray is seldom diagnostic in 

COPD unless obvious bullous disease is present, but it is 

valuable in excluding alternative diagnoses. Radiological 

changes associated with COPD include signs of hyperinflation 

(flattened diaphragm on the lateral chest film, and 

an increase in the volume of the retrosternal air space), 



Diagnosis 

COPD 

Figure 5-1-7. Differential Diagnosis of COPD 

Asthma 

Congestive 

Heart Failure 

Bronchiectasis 

Tuberculosis 

Obliterative 

Bronchiolitis 

Diffuse 

Panbronchiolitis 

Suggestive Features* 

Onset in mid-life. 

Symptoms slowly progressive. 

Long smoking history. 

Dyspnea during exercise. 

Largely irreversible airflow limitation. 

Onset early in life (often childhood). 

Symptoms vary from day to day. 

Symptoms at night/early morning. 

Allergy, rhinitis, and/or eczema also 

present. 

Family history of asthma. 

Largely reversible airflow limitation. 

Fine basilar crackles on auscultation. 

Chest X-ray shows dilated heart, 

pulmonary edema. 

Pulmonary function tests indicate 

volume restriction, not airflow limitation. 

Large volumes of purulent sputum. 

Commonly associated with bacterial 

infection. 

Coarse crackles/clubbing on 

auscultation. 

Chest X-ray/CT shows bronchial 

dilation, bronchial wall thickening. 

Onset all ages. 

Chest X-ray shows lung infiltrate. 

Microbiological confirmation. 

High local prevalence of tuberculosis. 

Onset in younger age, nonsmokers. 

May have history of rheumatoid 

arthritis or fume exposure. 

CT on expiration shows hypodense 

areas. 

Most patients are male and nonsmokers. 

Almost all have chronic sinusitis. 

Chest X-ray and HRCT show diffuse 

small centrilobular nodular opacities 

and hyperinflation. 

*These features tend to be characteristic of the respective diseases, 

but do not occur in every case. For example, a person who has 

never smoked may develop COPD (especially in the developing 

world, where other risk factors may be more important than cigarette 

smoking); asthma may develop in adult and even elderly patients. 

hyperlucency of the lungs, and rapid tapering of the vascular 

markings. Computed tomography (CT) of the chest is not 

routinely recommended. However, when there is doubt 

about the diagnosis of COPD, high resolution CT (HRCT) 

might help in the differential diagnosis. In addition, if a 

surgical procedure such as bullectomy or lung volume 

reduction is contemplated, chest CT is helpful. 

Arterial blood gas measurement. In advanced COPD 

measurement of arterial blood gases is important. This 

test should be performed in patients with FEV 1 < 40% 

predicted or with clinical signs suggestive of respiratory 

failure or right heart failure. 

Alpha-1 antitrypsin deficiency screening. In patients 

who develop COPD at a young age (< 45 years) or who 

have a strong family history of the disease, it may be 

valuable to identify coexisting alpha-1 antitrypsin deficiency. 

This could lead to family screening or appropriate 

counseling. A serum concentration of alpha-1 antitrypsin 

below 15-20 % of the normal value is highly suggestive 

of homozygous alpha-1 antitrypsin deficiency. 

Differential Diagnosis 

A major differential diagnosis is asthma. In some patients 

with chronic asthma, a clear distinction from COPD is not 

possible using current imaging and physiological testing 

techniques, and it is assumed that asthma and COPD 

coexist in these patients. In these cases, current 

management is similar to that of asthma. Other potential 

diagnoses are usually easier to distinguish from COPD 

(Figure 5-1-7). 

ONGOING MONITORING 

AND ASSESSMENT 

Visits to health care facilities will increase in frequency 

as COPD progresses. The type of health care workers 

seen, and the frequency of visits, will depend on the 

health care system. Ongoing monitoring and assessment 

in COPD ensures that the goals of treatment are being 

met and should include evaluation of: (1) exposure to 

risk factors, especially tobacco smoke; (2) disease 

progression and development of complications; 

(3) pharmacotherapy and other medical treatment; 

(4) exacerbation history; (5) comorbidities. 

Suggested questions for follow-up visits are listed in 

Figure 5-1-8. The best way to detect changes in 

symptoms and overall health status is to ask the same 

questions at each visit. 



Monitor Disease Progression and 

Development of Complications 

COPD is usually a progressive disease. Lung function 

can be expected to worsen over time, even with the best 

available care. Symptoms and objective measures of 

airflow limitation should be monitored to determine when 

to modify therapy and to identify any complications that 

may develop. As at the initial assessment, follow-up 

visits should include a physical examination and 

discussion of symptoms, particularly any new or 

worsening symptoms. 

Pulmonary function. A patient’s decline in lung function 

is best tracked by periodic spirometry measurements. 

Useful information about lung function decline is unlikely 

from spirometry measurements performed more than 

once a year. Spirometry should be performed if there is 

a substantial increase in symptoms or a complication. 

Other pulmonary function tests, such as flow-volume 

loops, diffusing capacity (D LCO ) measurements, and 

measurement of lung volumes are not needed in a 

routine assessment but can provide information about the 

overall impact of the disease and can be valuable in 

resolving diagnostic uncertainties and assessing patients 

for surgery. 

Arterial blood gas measurement. Measurement of 

arterial blood gas tensions should be performed in all 

patients with FEV 1 < 40% predicted or when clinical 

signs of respiratory failure or right heart failure are 

present. Respiratory failure is indicated by a 

PaO 2 < 8.0 kPa (60 mm Hg) with or without 

PaCO 2 > 6.7 kPa (50 mm Hg) in arterial blood gas 

measurements made while breathing air at sea level. 

Screening patients by pulse oximetry and assessing 

arterial blood gases in those with an oxygen saturation 

(SaO 2 ) < 92% may be a useful way of selecting patients 

for arterial blood gas measurement 27 . However, pulse 

oximetry gives no information about CO 2 tensions. 

Several considerations are important to ensure accurate 

test results. Oxygen pressure in the inspired air (FiO 2 ) 

should be measured, taking note if patient is using an 

O 2 -driven nebulizer. Changes in arterial blood gas tensions 

take time to occur, especially in severe disease. 

Thus, 20-30 minutes should pass before rechecking the 

gas tensions when the FiO 2 has been changed. 

Figure 5-1-8. Suggested Questions 

for Follow-Up Visits* 

Monitor exposure to risk factors: 

• Have you continued to stay off cigarettes? 

• If not, how many cigarettes per day are you smoking? 

• Would you like to quit smoking? 

• Has there been any change in your working 

environment? 

Monitor disease progression and development 

of complications: 

• How much can you do before you get short of breath? 

(Use an everyday example, such as walking up flights 

of stairs, up a hill, or on flat ground.) 

• Has your dyspnea worsened, improved, or stayed the 

same since your last visit? 

• Have you had to reduce your activities because of 

dyspnea or other symptoms? 

• Have any of your symptoms worsened since your 

last visit? 

• Have you experienced any new symptoms since your 

last visit? 

• Has your sleep been disrupted due to dyspnea or other 

symptoms? 

• Since your last visit, have you missed any work 

because of your symptoms? 

Monitor pharmacotherapy and other medical 

treatment: 

• What medications are you taking? 

• How often do you take each medication? 

• How much do you take each time? 

• Have you missed or stopped taking any regular doses 

of your medications for any reason? 

• Have you had trouble filling your prescriptions 

(e.g., for financial reasons, not on formulary)? 

• Please show me how you use your inhaler. 

• Have you tried any other medicines or remedies? 

• Has your medication been effective in controlling 

your symptoms? 

• Has your medication caused you any problems? 

Monitor exacerbation history: 

• Since your last visit, have you had any episodes/times 

when your symptoms were a lot worse than usual? 

• If so, how long did the episode(s) last? What do you 

think caused the symptoms to get worse? What did you 

do to control the symptoms? 

*These questions are examples and do not represent a standardized 

assessment instrument. The validity and reliability of these questions 

have not been assessed. 



Adequate pressure must be applied at the puncture site 

for at least one minute; failure to do so can lead to painful 

bruising. 

Clinical signs of respiratory failure or right heart failure 

include central cyanosis, ankle swelling, and an increase 

in the jugular venous pressure. Clinical signs of hypercapnia 

are extremely nonspecific outside of exacerbations. 

Assessment of pulmonary hemodynamics. Pulmonary 

hypertension is only likely to be important in patients who 

have developed respiratory failure. Measurement of pulmonary 

arterial pressure is not recommended in clinical 

practice as it does not add practical information beyond 

that obtained from a knowledge of PaO 2 . 

Diagnosis of right heart failure or cor pulmonale. 

Elevation of the jugular venous pressure and the presence 

of pitting ankle edema are often the most useful 

findings suggestive of cor pulmonale in clinical practice. 

However, the jugular venous pressure is often difficult to 

assess in patients with COPD, due to large swings in 

intrathoracic pressure. Firm diagnosis of cor pulmonale 

can be made through a number of investigations, including 

radiography, electrocardiography, echocardiography, 

radionucleotide scintigraphy, and magnetic resonance 

imaging. However, all of these measures involve inherent 

inaccuracies of diagnosis. 

CT and ventilation-perfusion scanning. Despite the 

benefits of being able to delineate pathological anatomy, 

routine CT and ventilation-perfusion scanning are currently 

confined to the assessment of COPD patients for surgery. 

HRCT is currently under investigation as a way of visualizing 

airway and parenchymal pathology more precisely. 

Hematocrit. Polycythemia can develop in the presence 

of arterial hypoxemia, especially in continuing smokers 28 . 

Polycythemia can be identified by hematocrit > 55%. 

Respiratory muscle function. Respiratory muscle function 

is usually measured by recording the maximum inspiratory 

and expiratory mouth pressures. More complex 

measurements are confined to research laboratories. 

Measurement of expiratory muscle force is useful in 

assessing patients when dyspnea or hypercapnia is not 

readily explained by lung function testing or when peripheral 

muscle weakness is suspected. This measurement 

may improve in COPD patients when other measurements 

of lung mechanics do not (e.g., after pulmonary 

rehabilitation) 29,30 . 

Sleep studies. Sleep studies may be indicated when 

hypoxemia or right heart failure develops in the presence 

of relatively mild airflow limitation or when the patient has 

symptoms suggesting the presence of sleep apnea. 

Exercise testing. Several types of tests are available to 

measure exercise capacity, but these are primarily used 

in conjunction with pulmonary rehabilitation programs. 

Monitor Pharmacotherapy and Other 

Medical Treatment 

In order to adjust therapy appropriately as the disease 

progresses, each follow-up visit should include a discussion 

of the current therapeutic regimen. Dosages of various 

medications, adherence to the regimen, inhaler technique, 

effectiveness of the current regime at controlling symptoms, 

and side effects of treatment should be monitored. 

Monitor Exacerbation History 

During periodic assessments, health care workers should 

question the patient and evaluate any records of exacerbations, 

both self-treated and those treated by other 

health care providers. Frequency, severity, and likely 

causes of exacerbations should be evaluated. Increased 

sputum volume, acutely worsening dyspnea, and the 

presence of purulent sputum should be noted. Specific 

inquiry into unscheduled visits to providers, telephone 

calls for assistance, and use of urgent or emergency care 

facilities may be helpful. Severity can be estimated by 

the increased need for bronchodilator medication or glucocorticosteroids 

and by the need for antibiotic treatment. 

Hospitalizations should be documented, including the 

facility, duration of stay, and any use of critical care or 

intubation. The clinician then can request summaries of 

all care received to facilitate continuity of care. 

Monitor Comorbidities 

In treating patients with COPD, it is important to consider 

the presence of concomitant conditions such as bronchial 

carcinoma, tuberculosis, sleep apnea, and left heart failure. 

The appropriate diagnostic tools (chest radiograph, 

ECG, etc.) should be used whenever symptoms (e.g., 

hemoptysis) suggest one of these conditions. 



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obstructive lung disease II. Relationships of clinical and 

physiological findings to the severity of airways obstruction. 


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a report to the Medical Research Council by their 

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4. Simon PM, Schwartstein RM, Weiss JW, Fencl V, 

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dyspnea in patients with shortness of breath. Am Rev 

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Guz A. The language of breathlessness. Use of verbal 

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Rev Respir Dis 1991; 144:826-32. 

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Wedzicha JA. Usefulness of the Medical Research 

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Thorax 1999; 54:581-6. 

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during arm but not leg exercise in patients with chronic airflow 

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8. Schols AM, Soeters PB, Dingemans AM, Mostert R, 

Frantzen PJ, Wouters EF. Prevalence and characteristics of 

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for pulmonary rehabilitation. Am Rev Respir Dis 1993; 

147:1151-6. 

9. Johnston RN, Lockhart W, Ritchie RT, Smith DH. 

Haemoptysis. BMJ 1960; 1:592-5. 

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of COPD. Chest 1993; 104:254-8. 

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of breathing pattern with progression of chronic obstructive 

pulmonary disease. Am Rev Respir Dis 1986; 134:930-4. 

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Steiner JF, et al. Can moderate chronic obstructive pulmonary 

disease be diagnosed by history and physical findings 

alone? Am J Med 1993; 94:188-96. 

14. Standardization of spirometry, 1994 update. Am J Respir 

Crit Care Med 1995; 152:1107-36. 

15. Kelly CA, Gibson GJ. Relation between FEV 1 and peak 

expiratory flow in patients with chronic obstructive pulmonary 


16. Lal S, Ferguson AD, Campbell EJM. Forced expiratory time; 

a simple test for airways obstruction. BMJ 1964; 1:814-7. 

17. Swanney MP, Jensen RL, Crichton DA, Beckert LE, Cardno 

LA, Crapo RO. FEV(6) is an acceptable surrogate for FVC 

in the spirometric diagnosis of airway obstruction and 

restriction. Am J Respir Crit Care Med 2000; 162:917-9. 

18. Ferguson GT, Enright PL, Buist AS, Higgins MW. Office 

spirometry for lung health assessment in adults: a consensus 

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Chest 2000; 117:1146-61. 

19. Kanner RE, Connett JE, Williams DE, Buist AS. Effects of 

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in smokers with early chronic obstructive pulmonary 

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Tinker CM, et al. The relevance in adults of airflow obstruction, 

but not of mucus hypersecretion, to mortality from 

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observation. Am Rev Respir Dis 1983; 128:491-500. 

22. Hansen EF, Phanareth K, Laursen LC, KokJensen A, 

Dirksen A. Reversible and irreversible airflow obstruction 

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obstructive pulmonary disease. Am J Respir Crit Care 

Med 1999; 159:1267-71. 

23. Anthonisen NR, Wright EC. Bronchodilator response in 

chronic obstructive pulmonary disease. Am Rev Respir 

Dis 1986; 133:814-9. 

24. Sourk RL, Nugent KM. Bronchodilator testing: confidence 

intervals derived from placebo inhalations. Am Rev Respir 

Dis 1983; 128:153-7. 

25. Reis AL. Response to bronchodilators. In: Clausen J, ed. 

Pulmonary function testing: guidelines and controversies. 

New York: Academic Press; 1982. p. 215-221. 

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27. Roberts CM, Bugler JR, Melchor R, Hetzel ML, Spiro SG. 

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Cigarette smoking and secondary polycythemia in hypoxic 

cor pulmonale. Am Rev Respir Dis 1982; 125:507-10. 



29. Dekhuijzen PNR, Folgering HT, van Herwaarden CLA. 

Target-flow inspiratory muscle training during pulmonary 

rehabilitation in patients with COPD. Chest 1991; 99:128-33. 

30. Heijdra YF, Dekhuijzen PN, van Herwaarden CLA, 

Forlgering H. Nocturnal saturation improves by target-flow 

inspiratory muscle training in patients with COPD. Am J 




COMPONENT 2: REDUCE RISK FACTORS 

KEY POINTS: 

• Reduction of total personal exposure to tobacco 

smoke, occupational dusts and chemicals, and 

indoor and outdoor air pollutants are important 

goals to prevent the onset and progression of 

COPD. 

• Smoking cessation is the single most effective - 

and cost effective - way in most people to reduce 

the risk of developing COPD and stop its progression 

(Evidence A). 

• Brief tobacco dependence counseling is effective 

(Evidence A) and every tobacco user should be 

offered at least this treatment at every visit to a 

health care provider. 

• Three types of counseling are especially effective: 

practical counseling, social support as part of 

treatment, and social support arranged outside of 

treatment (Evidence A). 

• Several effective pharmacotherapies for tobacco 

dependence are available (Evidence A), and at 

least one of these medications should be added 

to counseling if necessary and in the absence of 

contraindications (Evidence A). 

• Progression of many occupationally induced 

respiratory disorders can be reduced or controlled 

through a variety of strategies aimed at reducing 

the burden of inhaled particles and gases 

(Evidence B). 

INTRODUCTION 

Identification, reduction, and control of risk factors are 

important steps toward prevention and treatment of any 

disease. In the case of COPD, these factors include 

tobacco smoke, occupational exposures, and indoor and 

outdoor air pollution and irritants. 

Since cigarette smoking is the major risk factor for COPD 

worldwide, smoking prevention programs should be 

implemented and smoking cessation programs should 

be readily available and encouraged for all individuals 

who smoke. Reduction of total personal exposure to 

occupational dust, fumes, and gases and to indoor and 

outdoor air pollutants is also an important goal to prevent 

the onset and progression of COPD 1 . 

TOBACCO SMOKE 

Smoking Prevention 

Comprehensive tobacco control policies and programs 

with clear, consistent, and repeated nonsmoking 

messages should be delivered through every feasible 

channel, including health care providers, schools, and 

radio, television, and print media. National and local 

campaigns should be undertaken to reduce exposure to 

tobacco smoke in public forums. Legislation to establish 

smoke-free schools, public facilities, and work environments 

should be encouraged by government officials, public 

health workers, and the public. Smoking prevention 

programs should target all ages, including young children, 

adolescents, young adults, and pregnant women. 

Physicians and public health officials should encourage 

smoke-free homes. 

The first exposure to cigarette smoke may begin in utero 

when the fetus is exposed to blood-borne metabolites 

from the mother 2,3 . Neonates and infants may be 

exposed passively to tobacco smoke in the home if a 

family member smokes. Children less than 2 years old 

who are passively exposed to cigarette smoke have an 

increased prevalence of respiratory infections, and are at 

a greater risk of developing chronic respiratory symptoms 

later in life 4 . 

Smoking Cessation 

Smoking cessation is the single most effective - and cost 

effective - way to reduce exposure to COPD risk factors. 

Quitting smoking can prevent or delay the development of 

airflow limitation or reduce its progression 5 . A statement 

by the WHO (Figure 5-2-1) 6 emphasizes the health and 

economic benefits to be gained from smoking cessation. 

All smokers - including those who may be at risk for 

COPD as well as those who already have the disease - 

should be offered the most intensive smoking cessation 

intervention feasible. 



Figure 5-2-1. World Health Organization Statement 

on Smoking Cessation 6 

Smoking cessation is a critical step toward substantially 

reducing the health risks run by current smokers, 

thereby improving world health. Tobacco has been 

shown to cause about 25 life-threatening diseases, 

or groups of diseases, many of which can be prevented, 

delayed, or mitigated by smoking cessation. As life 

expectancy increases in developing countries, the 

morbidity and mortality burden of chronic diseases 

will increase still further. This projected concentration 

of tobacco-related disease burden can be lightened 

by intensive efforts at smoking cessation. Studies 

have shown that 75-80% of smokers want to quit, 

while one-third have made at least three serious 

cessation attempts. Cessation efforts cannot be 

ignored in favor of primary prevention; rather, both 

efforts must be made in conjunction with one another. 

If only small portions of today's 1.1 billion smokers 

were able to stop, the long-term health and economic 

benefits would be immense. Governments, 

communities, organizations, schools, families and 

individuals are called upon to help current smokers 

stop their addictive and damaging habit. 

Smoking cessation interventions are effective in both 

genders, in all racial and ethnic groups, and in pregnant 

women. Age influences quit rates, with young people 

less likely to quit, but nevertheless smoking cessation 

programs can be effective in all age groups. 

International data on the economic impact of smoking 

cessation are strikingly consistent: investing resources in 

smoking cessation programs is cost effective in terms of 

medical costs per life year gained. Interventions that 

have been investigated include nicotine replacement with 

transdermal patch, counseling from physicians and other 

health professionals (with and without nicotine patch), 

self-help and group programs, and community-based 

stop-smoking contests. A review of data from a number 

of countries estimated the median societal cost of various 

smoking cessation interventions at $990 to $13,000 (US) 

per life year gained 7 . Smoking cessation programs are a 

particularly good value for the UK National Health 

Service, with costs from £212 to £873 (US $320 to 

$1,400) per life year gained 8 . 

The role of health care providers in smoking cessation. 

A successful smoking cessation strategy requires a 

multifaceted approach, including public policy, information 

dissemination programs, and health education through 

the media and schools 9 . However, health care providers, 

including physicians, nurses, dentists, psychologists, 

pharmacists, and others, are key to the delivery of smoking 

cessation messages and interventions. Involving as 

many of these individuals as possible will help. Health 

care workers should encourage all patients who smoke 

to quit, even those patients who come to the health care 

provider for unrelated reasons and do not have symptoms 

of COPD or evidence of airflow limitation. 

Guidelines for smoking cessation entitled Treating 

Tobacco Use and Dependence: A Clinical Practice 

Guideline were published by the US Public Health 

Service 10 . The major conclusions are summarized in 

Figure 5-2-2. 

Figure 5-2-2. Public Health Service Report: Treating 

Tobacco Use and Dependence: A Clinical Practice 

Guideline - Major Findings and Recommendations 10 

1. Tobacco dependence is a chronic condition that 

warrants repeated treatment until long-term or 

permanent abstinence is achieved. 

2. Effective treatments for tobacco dependence exist 

and all tobacco users should be offered these 

treatments. 

3. Clinicians and health care delivery systems 

must institutionalize the consistent identification, 

documentation and treatment of every tobacco 

user at every visit. 

4. Brief tobacco dependence treatment is effective 

and every tobacco user should be offered at least 

brief treatment. 

5. There is a strong dose-response relation between the 

intensity of tobacco dependence counseling and its 

effectiveness. 

6. Three types of counseling were found to be especially 

effective: practical counseling, social support as part 

of treatment, and social support arranged outside of 

treatment. 

7. Five first-line pharmacotherapies for tobacco dependence 

- bupropion SR, nicotine gum, nicotine inhaler, nicotine 

nasal spray, and nicotine patch - are effective and at 

least one of these medications should be prescribed 

in the absence of contraindications. 

8. Tobacco dependence treatments are cost effective 

relative to other medical and disease prevention 

interventions. 



Figure 5-2-3. Brief Strategies to Help the 

Patient Willing to Quit 10-13 

1. ASK: Systematically identify all tobacco users at 

every visit. 

Implement an office-wide system that ensures that, 

for EVERY patient at EVERY clinic visit, tobacco-use 

status is queried and documented. 

The Public Health Service Guidelines recommend a 

five-step program for intervention (Figure 5-2-3), which 

provides a strategic framework helpful to health care 

providers interested in helping their patients stop 

smoking 10-13 . The guidelines emphasize that tobacco 

dependence is a chronic disease (Figure 5-2-4) 10 and 

urge clinicians to recognize that relapse is common and 

reflects the chronic nature of dependence, not failure on 

the part of the clinician or the patient. 

2. ADVISE: Strongly urge all tobacco users to quit. 

In a clear, strong, and personalized manner, urge 

every tobacco user to quit. 

Figure 5-2-5. 

Stages of Change Model 

3. ASSESS: Determine willingness to make a quit 

Precontemplation 

attempt. 

Ask every tobacco user if he or she is willing to make 

a quit attempt at this time (e.g., within the next 30 days). 

4. ASSIST: Aid the patient in quitting. 

Help the patient with a quit plan; provide practical 

counseling; provide intra-treatment social support; help the 

Relapse 

Slipping Back 

Contemplation 

Recycling 

patient obtain extra-treatment social support; recommend 

Short-Term 

use of approved pharmacotherapy except in special 

Maintenance 

circumstances; provide supplementary materials. 

Sustained 

5. ARRANGE: Schedule follow-up contact. 

Maintenance 

Schedule follow-up contact, either in person or via 

telephone. 

Printed with permission of Dr. Peter M.A. Calverley. 

Figure 5-2-4. Tobacco Dependence 

• For most people, tobacco dependence results in 

true drug dependence comparable to dependence 

caused by opiates, amphetamines, and cocaine. 

• Tobacco dependence is almost always a chronic 

disorder that warrants long-term clinical intervention 

as do other addictive disorders. Failure to appreciate 

the chronic nature of tobacco dependence may 

impair the clinician's motivation to treat tobacco use 

consistently in a long-term fashion. 

• Clinicians must understand that this is a chronic 

condition comparable to diabetes, hypertension, 

or hyperlipidemia requiring simple counseling advice, 

support, and appropriate pharmacotherapy. 

• Relapse is common, which is the nature of dependence 

and not the failure of the clinician or the patient. 

Preparation 

Action 

Most individuals go through several stages before they 

stop smoking (Figure 5-2-5) 9 . It is often helpful for the 

clinician to assess a patient's readiness to quit in order to 

determine the most effective course of action at that time. 

The clinician should initiate treatment if the patient is 

ready to quit. For a patient not ready to make a quit 

attempt, the clinician should provide a brief intervention 

designed to promote the motivation to quit. 

Counseling. Counseling delivered by physicians and 

other health professionals significantly increases quit 

rates over self-initiated strategies 14 . Even a brief 

(3-minute) period of counseling to urge a smoker to quit 

results in smoking cessation rates of 5-10% 15 . At the very 

least, this should be done for every smoker at every 

health care provider visit 15,16 . 

However, there is a strong dose-response relationship 

between counseling intensity and cessation success 17,18 . 

Ways to make the treatment more intense include 

increasing the length of the treatment session, the 

number of treatment sessions, and the number of weeks 

over which the treatment is delivered. Counseling 



sessions of 3 to 10 minutes result in cessation rates of 

around 12% 10 . With more complex interventions (for 

example, controlled clinical trials that include skills training, 

problem solving, and psychosocial support), quit rates can 

reach 20-30% 17 . In one multicenter controlled clinical trial, 

a combination of physician advice, group support, skills 

training, and nicotine replacement therapy achieved a 

quit rate of 35% at one year and a sustained quit rate of 

22% at 5 years 5 . 

Both individual and group counseling are effective formats 

for smoking cessation. Several particular items of 

counseling content seem to be especially effective, 

including problem solving, general skills training, and 

provision of intra-treatment support. The important 

elements in the support aspect of successful treatment 

programs are shown in Figure 5-2-6 9,10 . The common 

subjects covered in successful problem solving/skills 

training programs include: 

• Recognition of danger signals likely to be associated 

with the risk of relapse, such as being around other 

smokers, being under time pressure, getting into an 

argument, drinking alcohol, and negative moods. 

• Enhancement of skills needed to handle these 

situations, such as learning to anticipate and avoid a 

particular stress. 

• Basic information about smoking and successful 

quitting, such as the nature and time course of 

withdrawal, the addictive nature of smoking, and the 

fact that any return to smoking, including even a single 

puff, increases the likelihood of a relapse. 

Pharmacotherapy. Numerous effective pharmacotherapies 

for smoking cessation now exist 9-11 (Evidence A), and 

pharmacotherapy is recommended when counseling is not 

sufficient to help patients quit smoking. Special consideration 

should be given before using pharmacotherapy in selected 

populations: people with medical contraindications, light 

smokers (fewer than 10 cigarettes/day), and pregnant 

and adolescent smokers. 

Nicotine replacement products. Numerous studies indicate 

that nicotine replacement therapy in any form (nicotine 

gum, inhaler, nasal spray, transdermal patch, sublingual 

tablet, or lozenge) reliably increases long-term smoking 

abstinence rates 10,19 . Nicotine replacement therapy is 

more effective when combined with counseling and 

behavior therapy 20 , although nicotine patch or nicotine 

gum consistently increases smoking cessation rates 

regardless of the level of additional behavioral or 

Figure 5-2-6. Patient Support in 

Smoking Cessation Programs 9,10 

• Encourage the patient in the quit attempt. 

Indicate that effective cessation treatments are now 

available and, in fact, half of all people who smoked 

have now quit. Communicate your confidence in the 

patient's ability to quit. 

• Communicate care and concern. Ask how the 

patient feels about smoking and whether he/she 

wants to quit, expressing concern along with the 

ability and willingness to help. Be open to the 

patient's fears of quitting. 

• Encourage the patient to talk about the quitting 

process. Talk to the patient about the reasons 

he/she wants to quit, difficulty encountered while 

quitting, success the patient has achieved, and concerns 

and worries about quitting. 

• Provide basic information about smoking, the 

risks of continuing, the benefits of quitting, and 

the techniques that optimize success. Outline the 

nature, symptoms, and time course of withdrawal 

and techniques for dealing with withdrawal. 

psychosocial interventions. Medical contraindications to 

nicotine replacement therapy include unstable coronary 

artery disease, untreated peptic ulcer disease, and recent 

myocardial infarction or stroke 9 . Specific studies to date 

do not support the use of nicotine replacement therapy 

for longer than 8 weeks 21 , although some patients may 

require extended use to prevent relapse. 

All forms of nicotine replacement therapy are significantly 

more effective than placebo. Every effort should be 

made to tailor the choice of replacement therapy to the 

individual's culture and lifestyle to improve adherence. 

The patch is generally favored over the gum because it 

requires less training for effective use and is associated 

with fewer compliance problems. 

No data are available to help clinicians tailor nicotine 

patch regimens to the intensity of cigarette smoking. In 

all cases it seems generally appropriate to start with the 

higher dose patch. For most patches, which come in 

three different doses, patients should use the highest 

dose for the first four weeks and drop to progressively 

lower doses over an eight-week period. Where only two 

doses are available, the higher dose should be used for 

the first four weeks and the lower dose for the second 

four weeks. 



When using nicotine gum, the patient needs to be advised 

that absorption occurs through the buccal mucosa. For 

this reason, the patient should be advised to chew the 

gum for a while and then put the gum against the inside 

of the cheek to allow absorption to occur and prolong 

the release of nicotine. Continuous chewing produces 

secretions that are swallowed, results in little absorption, 

and can cause nausea. Acidic beverages, particularly 

coffee, juices, and soft drinks, interfere with the absorption 

of nicotine. Thus, the patient needs to be advised that 

eating or drinking anything except water should be avoided 

for 15 minutes before and during chewing. Although 

nicotine gum is an effective smoking cessation treatment, 

problems with compliance, ease of use, social acceptability, 

risk of developing temporo-mandibular joint symptoms, 

and unpleasant taste have been noted. In highly dependent 

smokers, the 4 mg gum is more effective than the 2 mg 

gum 22 . 

Other pharmacotherapy. The antidepressants bupropion 23 

and nortriptyline have also been shown to increase longterm 

quit rates 9,19,24 . Although more studies need to be 

conducted with these medications, a randomized 

controlled trial with counseling and support showed quit 

rates at one year of 30% with sustained-release bupropion 

alone and 35% with sustained-release bupropion plus 

nicotine patch 23 . The effectiveness of the antihypertensive 

drug clonidine is limited by side effects 19 . 

OCCUPATIONAL EXPOSURES 

Although it is not known how many individuals are at risk 

of developing respiratory disease from occupational 

exposures in either developing or developed countries, 

many occupationally induced respiratory disorders can be 

reduced or controlled through a variety of strategies aimed 

at reducing the burden of inhaled particles and gases 25 : 

● 

● 

● 

Implement and enforce strict, legally mandated control 

of airborne exposure in the workplace. 

Initiate intensive and continuing education of exposed 

workers, industrial managers, health care workers, 

primary care physicians, and legislators. 

Educate workers and policymakers on how cigarette 

smoking aggravates occupational lung diseases and 

why efforts to reduce smoking where a hazard exists 

are important. 

The main emphasis should be on primary prevention, 

which is best achieved by the elimination or reduction of 

exposures to various substances in the workplace. 

Secondary prevention, achieved through surveillance and 

early case detection, is also of great importance. Both 

approaches are necessary to improve the present situation 

and to reduce the burden of lung disease. 

INDOOR AND OUTDOOR 

AIR POLLUTION 

Individuals experience diverse indoor and outdoor 

environments throughout the day, each of which has its 

own unique set of air contaminants. Although outdoor 

and indoor air pollution are generally thought of separately, 

the concept of total personal exposure may be more 

relevant for COPD. Reducing the risk from indoor and 

outdoor air pollution requires a combination of public 

policy and protective steps taken by individual patients. 

Regulation of Air Quality 

At the national level, achieving a set level of air quality 

should be a high priority; this goal will normally require 

legislative action. Details on setting and maintaining air 

quality goals are beyond the scope of this document. 

Understanding health risks posed by local air pollution 

sources may be difficult and requires skills in community 

health, toxicology, and epidemiology. Local physicians may 

become involved through concerns about the health of their 

patients or as advocates for the community's environment. 

Patient-Oriented Control 

The health care provider should consider susceptibility 

(including family history and exposure to indoor/outdoor 

pollution) for each individual patient. 

● 

● 

● 

Patients should be counseled concerning the nature 

and degree of their susceptibility. Those who are at 

high risk should avoid vigorous exercise outdoors 

during pollution episodes. 

If various solid fuels are used for cooking and heating, 

adequate ventilation should be encouraged. 

Persons with severe COPD should monitor public 

announcements of air quality and should stay indoors 

when air quality is poor. 



● 

● 

● 

The use of medication should follow the usual clinical 

indications; therapeutic regimes should not be adjusted 

because of the occurrence of a pollution episode 

without evidence of worsening of symptoms or function. 

Respiratory protective equipment has been developed 

for use in the workplace in order to minimize exposure 

to toxic gases and particles. However, under most 

circumstances, health care providers should not suggest 

respiratory protection as a method for reducing the 

risks of ambient air pollution. 

Air cleaners have not been shown to have health 

benefits, whether directed at pollutants generated by 

indoor sources or at those brought in with outdoor air. 

REFERENCES 

1. Samet J, Utell MJ. Ambient air pollution. In: Rosenstock L, 

Cullen M, eds. Textbook of occupational and environmental 

medicine. Philadelphia: WB Saunders; 1994. p. 53-60. 

2. Jeffery PK. Cigarette smoke-induced damage of airway 

mucosa. In: Chretien J, Dusser D, eds. Environmental 

impact on the airways: from injury to repair. Lung biology 

in health and disease. Vol. 93. New York: Marcel Dekker; 

1996. p. 299-354. 

3. Helms PJ. Lung growth: implications for the development of 

disease [editorial]. Thorax 1994; 49:440-1. 

4. Colley JR, Holland WW, Corkhill RT. Influence of passive 

smoking and parental phlegm on pneumonia and bronchitis 

in early childhood. Lancet 1974; 2:1031-4. 




rate of decline of FEV 1 . The Lung Health Study. JAMA 

1994; 272:1497-505. 

6. World Health Organization. Tobacco free initiative: 

policies for public health. Geneva: World Health 

Organization; 1999. Available from: URL: 

www.who/int/toh/worldnottobacco99 

7. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, 

Weinstein MC, et al. Five-hundred life-saving interventions 

and their cost-effectiveness. Risk Anal 1995; 15:369-90. 

8. Parrott S, Godfrey C, Raw M, West R, McNeill A. Guidance 

for commissioners on the cost effectiveness of smoking 

cessation interventions. Health Educational Authority. 

Thorax 1998; 53 (Suppl 5 Pt 2): S1-38. 

9. Fiore MC, Bailey WC, Cohen SJ. Smoking cessation: information 

for specialists. Rockville, MD: US Department of 

Health and Human Services, Public Health Service, 

Agency for Health Care Policy and Research and Centers 

for Disease Control and Prevention; 1996. AHCPR 


10. The Tobacco Use and Dependence Clinical Practice 

Guideline Panel, Staff, and Consortium Representatives. 

A clinical practice guideline for treating tobacco use and 

dependence. JAMA 2000; 283:244-54. 

11. American Medical Association. Guidelines for the diagnosis 

and treatment of nicotine dependence: how to help 

patients stop smoking. Washington, DC: American Medical 

Association; 1994. 

12. Glynn TJ, Manley MW. How to help your patients stop 

smoking. A National Cancer Institute manual for physicians. 

Bethesda, MD: US Department of Health and 

Human Services, Public Health Service, National Institutes 

of Health, National Cancer Institute; 1990. NIH Publication 

No. 90-3064. 

13. Glynn TJ, Manley MW, Pechacek TF. Physician-initiated 

smoking cessation program: the National Cancer Institute 

trials. Prog Clin Biol Res 1990; 339:11-25. 

14. Baillie AJ, Mattick RP, Hall W, Webster P. Meta-analytic 

review of the efficacy of smoking cessation interventions. 

Drug and Alcohol Review 1994; 13:157-70. 

15. Wilson DH, Wakefield MA, Steven ID, Rohrsheim RA, 

Esterman AJ, Graham NM. "Sick of smoking": evaluation of 

a targeted minimal smoking cessation intervention in general 

practice. Med J Aust 1990; 152:518-21. 

16. Britton J, Knox A. Helping people to stop smoking: the new 

smoking cessation guidelines [editorial]. Thorax 1999; 

54:1-2. 

17. Kottke TE, Battista RN, DeFriese GH, Brekke ML. 

Attributes of successful smoking cessation interventions in 

medical practice. A meta-analysis of 39 controlled trials. 

JAMA 1988; 259:2883-9. 

18. Ockene JK, Kristeller J, Goldberg R, Amick TL, Pekow PS, 

Hosmer D, et al. Increasing the efficacy of physician-delivered 

smoking interventions: a randomized clinical trial. J 

Gen Intern Med 1991; 6:1-8. 

19. Lancaster T, Stead L, Silagy C, Sowden A. Effectiveness of 

interventions to help people stop smoking: findings from 

the Cochrane Library. BMJ 2000; 321:355-8. 

20. Schwartz JL. Review and evaluation of smoking cessation 

methods: United States and Canada, 1978-1985. 

Bethesda, MD: National Institutes of Health; 1987. NIH 


21. Fiore MC, Smith SS, Jorenby DE, Baker TB. The effectiveness 

of the nicotine patch for smoking cessation. A metaanalysis. 

JAMA 1994; 271:1940-7. 

22. Sachs DP, Benowitz NL. Individualizing medical treatment 

for tobacco dependence [editorial; comment]. Eur Respir J 

1996; 9:629-31. 

23. Tashkin D, Kanner R, Bailey W, Buist S, Anderson P, Nides 

M, Gonzales D, Dozier G, Patel MK, Jamerson B. Smoking 

cessation in patients with chronic obstructive pulmonary 

disease: a double-blind, placebo-controlled, randomised 

trial. Lancet 2001: 19;357 (9268): 1571-5 



24. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, 

Johnston JA, Hughes AR, et al. A controlled trial of sustained-release 

bupropion, a nicotine patch, or both for 

smoking cessation. N Engl J Med 1999; 340:685-91. 

25. The COPD Guidelines Group of the Standards of Care 

Committee of the BTS. BTS guidelines for the management 

of chronic obstructive pulmonary disease. Thorax 

1997; 52 Suppl 5:S1-28. 



COMPONENT 3: MANAGE STABLE COPD 

KEY POINTS: 

• The overall approach to managing stable COPD 

should be characterized by a stepwise increase in 

treatment, depending on the severity of the disease. 

• For patients with COPD, health education can play 

a role in improving skills, ability to cope with illness, 

and health status. It is effective in accomplishing 

certain goals, including smoking cessation 

(Evidence A). 

• None of the existing medications for COPD have 

been shown to modify the long-term decline in lung 

function that is the hallmark of this disease 

(Evidence A). Therefore, pharmacotherapy for 

COPD is used to decrease symptoms and/or 

complications. 

• Bronchodilator medications are central to the 

symptomatic management of COPD (Evidence A). 

They are given on an as-needed basis or on a 

regular basis to prevent or reduce symptoms. 

• The principal bronchodilator treatments are 

ß 2 -agonists, anticholinergics, theophylline, and a 

combination of these drugs (Evidence A). 

• Regular treatment with long-acting bronchodilators 

is more effective and convenient than treatment with 

short-acting bronchodilators, but more expensive 

(Evidence A). 

• The addition of regular treatment with inhaled 

glucocorticosteroids to bronchodilator treatment is 

appropriate for symptomatic COPD patients with an 

FEV1 < 50% predicted (Stage III: Severe COPD 

and Stage IV: Very Severe COPD) and repeated 

exacerbations (Evidence A). 

• Chronic treatment with systemic glucocorticosteroids 

should be avoided because of an unfavorable 

benefit-to-risk ratio (Evidence A). 

• All COPD patients benefit from exercise training 

programs, improving with respect to both exercise 

tolerance and symptoms of dyspnea and fatigue 

(Evidence A). 

• The long-term administration of oxygen (> 15 hours 

per day) to patients with chronic respiratory failure 

has been shown to increase survival (Evidence A). 

INTRODUCTION 

The overall approach to managing stable COPD should 

be characterized by a stepwise increase in treatment, 

depending on the severity of the disease. The step-down 

approach used in the chronic treatment of asthma is not 

applicable to COPD since COPD is usually stable and 

very often progressive. Management of COPD involves 

several objectives (see Chapter 5, Introduction) that 

should be met with minimal side effects from treatment. 

It is based on an individualized assessment of disease 

severity (Figure 5-3-1) and response to various therapies. 

Figure 5-3-1. Factors Affecting the Severity of COPD 

• Severity of symptoms 

• Severity of airflow limitation 

• Frequency and severity of exacerbations 

• Presence of one or more complications 

• Presence of respiratory failure 

• Presence of comorbid conditions 

• General health status 

• Number of medications needed to manage the disease 

The classification of severity (Figure 1-2) of stable COPD 

incorporates an individualized assessment of disease 

severity and therapeutic response into the management 

strategy. This classification is a guide that should help 

health care workers make decisions about the management 

of COPD in individual patients. Treatment depends on 

the patient’s educational level and willingness to apply 

the recommended management, on cultural and local 

conditions, and on the availability of medications. 

EDUCATION 

Although patient education is generally regarded as an 

essential component of care for any chronic disease, the 

role of education in COPD has been poorly studied. 

Assessment of the value of education in COPD may be 

difficult because of the relatively long time required to 

achieve improvements in objective measurements of lung 

function. 

Studies that have been done indicate that patient education 

alone does not improve exercise performance or lung 

function 1-4 (Evidence B), but it can play a role in improving 

skills, ability to cope with illness, and health status 5 . 



These outcomes are not traditionally measured in clinical 

trials, but they may be most important in COPD where 

even pharmacologic interventions generally confer only a 

small benefit in terms of lung function. 

Patient education regarding smoking cessation has the 

greatest capacity to influence the natural history of 

COPD. Evaluation of the smoking cessation component 

in a long-term, multicenter study indicates that if effective 

resources and time are dedicated to smoking cessation, 

25% long-term quit rates can be maintained 6 (Evidence 

A). Education also improves patient response to 

exacerbations 7,8 (Evidence B). Prospective end-of-life 

discussions can lead to understanding of advance 

directives and effective therapeutic decisions at the end 

of life 9 (Evidence B). 

Ideally, educational messages should be incorporated 

into all aspects of care for COPD and may take place 

in many settings: consultations with physicians or other 

health care workers, home-care or outreach programs, 

and comprehensive pulmonary rehabilitation programs. 

Goals and Educational Strategies 

It is vital for patients with COPD to understand the nature 

of their disease, risk factors for progression, and their role 

and the role of health care workers in achieving optimal 

management and health outcomes. Education should be 

tailored to the needs and environment of the individual 

patient, interactive, directed at improving quality of life, 

simple to follow, practical, and appropriate to the intellectual 

and social skills of the patient and the caregivers. 

In managing COPD, open communication between patient 

and physician is essential. In addition to being empathic, 

attentive and communicative, health professionals should 

pay attention to patients’ fears and apprehensions, focus 

on educational goals, tailor treatment regimens to each 

individual patient, anticipate the effect of functional 

decline, and optimize patients’ practical skills. 

Several specific education strategies have been shown to 

improve patient adherence to medication and management 

regimens. In COPD, adherence does not simply refer to 

whether patients take their medication appropriately. It 

also covers a range of non-pharmacologic treatments - 

e.g., maintaining an exercise program after pulmonary 

rehabilitation, undertaking and sustaining smoking 

cessation, and using devices such as nebulizers, spacers, 

and oxygen concentrators properly. 

Components of an Education Program 

The topics that seem most appropriate for an education 

program include: smoking cessation; basic information 

about COPD and pathophysiology of the disease; general 

approach to therapy and specific aspects of medical 

treatment; self-management skills; strategies to help 

minimize dyspnea; advice about when to seek help; selfmanagement 

and decision-making during exacerbations; 

and advance directives and end-of-life issues (Figure 5-3-2). 

Education should be part of consultations with health 

care workers beginning at the time of first assessment for 

Figure 5-3-2. Topics for Patient Education 

Stage 0: At Risk 

• Information and advice about reducing risk factors 

Stage I: Mild COPD through Stage III: Severe COPD 

Above topic, plus: 

• Information about the nature of COPD 

• Instruction on how to use inhalers and other treatments 

• Recognition and treatment of exacerbations 

• Strategies for minimizing dyspnea 

Stage IV: Very Severe COPD 

Above topics, plus: 

• Information about complications 

• Information about oxygen treatment 

• Advance directives and end-of-life decisions 

COPD and continuing with each follow-up visit. The 

intensity and content of these educational messages 

should vary depending on the severity of the patient’s 

disease. In practice, a patient often poses a series of 

questions to the physician (Figure 5-3-3). It is important 

to answer these questions fully and clearly, as this may 

help make treatment more effective. 

There are several different types of educational programs, 

ranging from simple distribution of printed materials, to 

teaching sessions designed to convey information about 

COPD, to workshops designed to train patients in specific 

skills (e.g., self-management, peak flow monitoring). 

Although printed materials may be a useful adjunct to 

other educational messages, passive dissemination of 

printed materials alone does not improve skills or health 

outcomes. Education is most effective when it is interactive 

and conducted in small workshops 4 (Evidence B) 

designed to improve both knowledge and skills. 

Behavioral approaches such as cognitive therapy and 

behavior modification lead to more effective selfmanagement 

skills and maintenance of exercise programs. 



Figure 5-3-3. Examples of Patient Questions 

• What is COPD? 

• What causes COPD? 

• How will it affect me? 

• Can it be treated? 

• What will happen if my disease gets worse? 

• What will happen if I need to be admitted to the 

hospital? 

• How will I know when I need oxygen at home? 

• What if I do not wish to be admitted to intensive 

care for ventilation? 

Answers to these questions can be developed from this document 

and will depend on local circumstances. In all cases, it is important 

that answers are clear and use terminology that the patient understands. 

Cost Effectiveness of Education Programs 

for COPD Patients 

The cost effectiveness of education programs for COPD 

patients is highly dependent on local factors that influence 

the cost of access to medical services and that will vary 

substantially between countries. In one cost-benefit 

analysis of education provided to hospital inpatients with 

COPD 10 , an information package resulted in increased 

knowledge of COPD and reduced use of health services, 

including reductions of hospital readmissions and general 

practice consultations. The education package involved 

training patients to increase knowledge of COPD, 

medication usage, precautions for exacerbations, and 

peak flow monitoring technique. However, this study 

was undertaken in a heterogeneous group of patients - 

65% were smokers and 88% were judged to have an 

asthmatic component to their disease - and these 

findings may not hold true for a “pure” COPD population. 

In a study of mild to moderate COPD patients at an outpatient 

clinic, patient education involving one four hour 

group session followed by one to two individual nurseand 

physiotherapist-sessions improved patient outcomes 

and reduced costs in a 12-month follow-up 220 . 

Although a healthy lifestyle is important, and should be 

encouraged, additional studies are needed to identify 

specific components of self-management programs that 

are effective 200 . 

PHARMACOLOGIC TREATMENT 

Overview of the Medications 

Pharmacologic therapy is used to prevent and control 

symptoms, reduce the frequency and severity of 

exacerbations, improve health status, and improve 

exercise tolerance. None of the existing medications for 

COPD have been shown to modify the long-term decline 

in lung function that is the hallmark of this disease 6,11-13 

(Evidence A). However, this should not preclude efforts 

to use medications to control symptoms. Since COPD 

is usually progressive, recommendations for the 

pharmacological treatment of COPD reflect the following 

general principles: 

• There should be a stepwise increase in treatment, 

depending on the severity of the disease. (The 

step-down approach used in the chronic treatment 

of asthma is not applicable to COPD.) 

• Regular treatment needs to be maintained at the same 

level for long periods of time unless significant side 

effects occur or the disease worsens. 

• Treatment response of an individual patient is variable 

and should be monitored closely and adjusted frequently. 

The medications are presented in the order in which they 

would normally be introduced in patient care, based on 

the level of disease severity. However, each treatment 

regimen needs to be patient-specific as the relationship 

between the severity of symptoms and the severity of airflow 

limitation is influenced by other factors, such as the 

frequency and severity of exacerbations, the presence of 

one or more complications, the presence of respiratory 

failure, comorbidities (cardiovascular disease, sleep-related 

disorders, etc.), and general health status. 

Bronchodilators 

Medications that increase the FEV 1 or change other 

spirometric variables, usually by altering airway smooth 

muscle tone, are termed bronchodilators 14 , since the 

improvements in expiratory flow reflect widening of the 

airways rather than changes in lung elastic recoil. Such 

drugs improve emptying of the lungs, tend to reduce 

dynamic hyperinflation at rest and during exercise 15 , 

and improve exercise performance. The extent of these 

changes, especially in moderate to severe disease, is 

not easily predictable from the improvement in FEV 1 

16,17 

. 

Regular bronchodilation with drugs that act primarily on 

airway smooth muscle does not modify the decline of 

function in mild COPD and, by inference, the prognosis 

of the disease 6 (Evidence B). 

Bronchodilator medications are central to the symptomatic 

management of COPD 18-21 (Evidence A). They are given 

either on an as-needed basis for relief of persistent or 

worsening symptoms, or on a regular basis to prevent or 

reduce symptoms. The side effects of bronchodilator 

therapy are pharmacologically predictable and dose 

dependent. Adverse effects are less likely, and resolve 

more rapidly after treatment withdrawal, with inhaled than 



with oral treatment. However, COPD patients tend to be 

older than asthma patients and more likely to have 

comorbidities, so their risk of developing side effects is 

greater. 

When treatment is given by the inhaled route, attention to 

effective drug delivery and training in inhaler technique is 

essential. COPD patients may have more problems in 

effective coordination and find it harder to use a simple 

Metered Dose Inhaler (MDI) than do healthy volunteers 

or younger asthmatics. It is essential to ensure that inhaler 

technique is correct and to re-check this at each visit. 

Alternative breath-activated or spacer devices are available 

for most formulations. Dry powder inhalers may be more 

convenient and possibly provide improved drug deposition, 

although this has not been established in COPD. In 

general, particle deposition will tend to be more central 

with the fixed airflow limitation and lower inspiratory flow 

rates in COPD 22,23 . 

Wet nebulizers are not recommended for regular treatment 

because they are more expensive and require appropriate 

maintenance 24 . A list of currently available inhaler devices 

is provided at http://www.goldcopd.org/inhalers/. The 

choice will depend on availability, cost, the prescribing 

physician, and the skills and ability of the patient. 

Dose-response relationships using the FEV 1 as the 

outcome are relatively flat with all classes of 

bronchodilators 18-21 . The dose-response relationships for 

short-acting anticholinergics and ß 2 -agonists are shown 

in Figure 5-3-5 21 . Toxicity is also dose related. 

Increasing the dose of either a ß 2 -agonist or an anticholinergic 

by an order of magnitude, especially when 

given by a wet nebulizer, appears to provide subjective 

benefit in acute episodes 25 (Evidence B) but is not 

necessarily helpful in stable disease 26 (Evidence C). 

Inhaled ß 2 -agonists have a relatively rapid onset of 

bronchodilator effect although this is probably slower in 

COPD than in asthma. The bronchodilator effects of 

short-acting ß 2 -agonists usually wear off within 4 to 6 

hours 27,28 (Evidence A). For single-dose, as needed use 

in COPD, there appears to be no advantage in using levalbuterol 

over conventional nebulized bronchodilators 201 . 

Long-acting inhaled ß 2 -agonists, such as salmeterol and 

formoterol, show a duration of effect of 12 hours or more 

with no loss of effectiveness overnight or with regular use 

in COPD patients 29-32 (Evidence A). The long-acting 

inhaled anticholinergic, tiotropium, has a duration of 

action of more than 24 hours (Evidence A) 33-35 . 

All categories of bronchodilators have been shown to 

increase exercise capacity in COPD, without necessarily 

producing significant changes in FEV 1 

36,37,221,222 

(Evidence A). 

Regular treatment with long-acting bronchodilators is 

more effective and convenient than treatment with 

short-acting bronchodilators, but more expensive 34,38,39,223 

(Evidence A). 

Figure 5-3-5. Dose-Response 

Relationships for Short-acting Bronchodilators 21 

Figure 5-3-4. Bronchodilators in Stable COPD 

• Bronchodilator medications are central to symptom 

management in COPD. 

• Inhaled therapy is preferred. 

• The choice between ß 2 -agonist, anticholinergic, 

theophylline, or combination therapy depends on 

availability and individual response in terms of 

symptom relief and side effects. 

• Bronchodilators are prescribed on an as-needed or 

on a regular basis to prevent or reduce symptoms. 

• Long-acting inhaled bronchodilators are more 

effective and convenient, but more expensive. 

• Combining bronchodilators may improve efficacy 

and decrease the risk of side effects compared to 

increasing the dose of a single bronchodilator. 

Cumulative dose (µg) 

Open symbols - salbutamol (ß 2 -agonist) 

Closed symbols - ipratropium (anticholinergic) 

Squares - patients with asthma 

Triangles - patients with COPD 

Printed with permission from Higgins BG, Powell RM, Cooper S, Tattersfield AE. European 

Respiratory Journal 1991; 4:415-20. Copyright 1991 European Respiratory Society Journals, Ltd. 



Drug 

2 -agonists 

Short-acting 

Fenoterol 

Salbutamol (albuterol) 

Terbutaline 

Long-acting 

Formoterol 

Salmeterol 

Anticholinergics 

Short-acting 

Ipratropium bromide 

Oxitropium bromide 

Long-acting 

Fenoterol/Ipratropium 

Salbutamol/Ipratropium 

Aminophylline 

Theophylline (SR) 

Beclomethasone 

Budesonide 

Fluticasone 

Triamcinolone 

Prednisone 

Methyl-prednisolone 

Figure 5-3-6. Commonly Used Formulations of Drugs used in COPD 

Inhaler 

(g) 

100-200 (MDI) 

100, 200 (MDI & DPI) 

400, 500 (DPI) 

4.5–12 (MDI & DPI) 

25-50 (MDI & DPI) 

20, 40 (MDI) 

100 (MDI) 

200/80 (MDI) 

75/15 (MDI) 

50-400 (MDI & DPI) 

100, 200, 400 (DPI) 

50-500 (MDI & DPI) 

100 (MDI) 

Formoterol/Budesonide 4.5/80, 160 (DPI) 

(9/320) (DPI) 

Salmeterol/Fluticasone 50/100, 250, 500 (DPI) 

25/50, 125, 250 (MDI) 

Systemic glucocorticosteroids 

10-2000 mg 

MDI=metered dose inhaler; DPI=dry powder inhaler 

Solution for 

Nebulizer (mg/ml) 

1 

5 

– 

0.25-0.5 

1.5 

1.25/0.5 

0.75/4.5 

Oral 

0.05% (Syrup) 

5mg (Pill) 

Syrup 0.024% 

2.5, 5 (Pill) 

200-600 mg (Pill) 

100-600 mg (Pill) 

5-60 mg (Pill) 

4, 8, 16 mg (Pill) 

Vials for Injection 

(mg) 

0.1, 0.5 

0.2, 0.25 

Duration of Action 

(hours) 

Tiotropium 18 (DPI) 24+ 

Combination short-acting 2 -agonists plus anticholinergic in one inhaler 

Methylxanthines 

Inhaled glucocorticosteroids 

0.2-0.4 

0.20, 0.25, 0.5 

40 40 

Combination long-acting 2 -agonists plus glucocorticosteroids in one inhaler 

4-6 

4-6 

4-6 

12+ 

12+ 

6-8 

7-9 

6-8 

6-8 

240 mg Variable, up to 24 

Variable, up to 24 

Regular use of a long-acting ß 2 -agonist 38 or a short- or 

long-acting anticholinergic improves health status 34,38,39 . 

Theophylline is effective in COPD, but due to its potential 

toxicity inhaled bronchodilators are preferred when available. 

All studies that have shown efficacy of theophylline in 

COPD were done with slow-release preparations. The 

classes of bronchodilator drugs commonly used in treating 

COPD, ß 2 -agonists, anticholinergics, and methylxanthines, 

are shown in Figure 5-3-6. The choice depends on the 

availability of medication and the patient’s response. 

ß 2 -agonists. The principal action of ß 2 -agonists is to 

relax airway smooth muscle by stimulating ß 2 -adrenergic 

receptors, which increases cyclic AMP and produces 



functional antagonism to bronchoconstriction. Oral 

therapy is slower in onset and has more side effects than 

inhaled treatment 40 (Evidence A). 

Adverse effects. Stimulation of ß 2 -receptors can produce 

resting sinus tachycardia and has the potential to precipitate 

cardiac rhythm disturbances in very susceptible patients, 

although this appears to be a remarkably rare event with 

inhaled therapy. Exaggerated somatic tremor is troublesome 

in some older patients treated with higher doses of 

ß 2 -agonists, whatever the route of administration, and 

this limits the dose that can be tolerated. Although 

hypokalemia can occur, especially when treatment is 

combined with thiazide diuretics 41 , and oxygen consumption 

can be increased under resting conditions 42 , these metabolic 

effects show tachyphylaxis unlike the bronchodilator actions. 

Mild falls in PaO 2 occur after administration of both shortand 

long-acting ß 2 -agonists 43 , but the clinical significance 

of these changes is doubtful. Despite the concerns 

raised some years ago, further detailed study has found 

no association between ß 2 -agonist use and an accelerated 

loss of lung function or increased mortality in COPD. 

Anticholinergics. The most important effect of 

anticholinergic medications in COPD patients appears 

to be blockage of acetylcholine’s effect on M3 receptors. 

Current short-acting drugs also block M2 receptors and 

modify transmission at the pre-ganglionic junction, 

although these effects appear less important in COPD 44 . 

The long-acting tiotropium has a pharmacokinetic 

selectivity for the M3 and the M1 receptor 45 . 

The bronchodilating effect of short-acting inhaled 

anticholinergics lasts longer than that of short-acting 

ß 2 -agonists, with some bronchodilator effect generally 

apparent up to 8 hours after administration 27 (Evidence 

A). The long-acting inhaled anticholinergic, tiotropium, 

has a duration of action of more than 24 hours 33-35 

(Evidence A). 

Adverse effects. Anticholinergic drugs, such as ipratropium, 

oxitropium and tiotropium bromide, are poorly absorbed 

which limits the otherwise troublesome systemic effects 

seen with atropine. Extensive use of this class of inhaled 

agents in a wide range of doses and clinical settings has 

shown them to be very safe. The main side effect is dryness 

of the mouth. Twenty-one days of inhaled tiotropium, 18 

µg day as a dry powder, does not retard mucus clearance 

from the lungs 224 . Although occasional prostatic symptoms 

have been reported, there are no data to prove a true 

causal relationship. A bitter, metallic taste is reported 

by some patients using ipratropium. An unexpected 

small increase in cardiovascular events in COPD patients 

regularly treated with ipratropium bromide has been 

reported and requires further investigation 46 . 

Use of wet nebulizer solutions with a face mask has been 

reported to precipitate acute glaucoma, probably by a 

direct effect of the solution on the eye. Mucociliary 

clearance is unaffected by these drugs, and respiratory 

infection rates are not increased. 

Methylxanthines. Controversy remains about the exact 

effects of xanthine derivatives. They may act as nonselective 

phosphodiesterase inhibitors, but have also 

been reported to have a range of non-bronchodilator 

actions, the significance of which is disputed 47-51 . Data on 

duration of action for conventional, or even slow-release, 

xanthine preparations are lacking in COPD. Changes in 

inspiratory muscle function have been reported in 

patients treated with theophylline 47 , but whether this 

reflects changes in dynamic lung volumes or a primary 

effect on the muscle is not clear (Evidence B). All studies 

that have shown efficacy of theophylline in COPD were 

done with slow-release preparations. Theophylline is 

effective in COPD but, due to its potential toxicity, inhaled 

bronchodilators are preferred when available. 

Adverse effects. Toxicity is dose related, a particular 

problem with the xanthine derivatives because their 

therapeutic ratio is small and most of the benefit occurs 

only when near-toxic doses are given 49,50 (Evidence A). 

Methylxanthines are nonspecific inhibitors of all phosphodiesterase 

enzyme subsets, which explains their 

Figure 5-3-7. Drugs and Physiological Variables 

that Affect Theophylline Metabolism in COPD 

Increased 

• Tobacco smoking 

• Anticonvulsant drugs 

• Rifampicin 

• Alcohol 

Decreased 

• Old age 

• Arterial hypoxemia 

(PaO 2 < 6.0 kPa, 45 

mm Hg) 

• Respiratory acidosis 

• Congestive cardiac 

failure 

• Liver cirrhosis 

• Erythromycin 

• Quinolone antibiotics 

• Cimetidine 

(not ranitidine) 

• Viral infections 

• Herbal remedies 

(St. John’s Wort) 



wide range of toxic effects. Problems include the 

development of atrial and ventricular arrhythmias (which 

can prove fatal) and grand mal convulsions (which can 

occur irrespective of prior epileptic history). More 

common and less dramatic side effects include 

headaches, insomnia, nausea, and heartburn, and 

these may occur within the therapeutic range of serum 

theophylline. Unlike the other bronchodilator classes, 

xanthine derivatives may involve a risk of overdose 

(either intentional or accidental). 

Theophylline, the most commonly used methylxanthine, 

is metabolized by cytochrome P450 mixed function 

oxidases. Clearance of the drug declines with age. 

Many other physiological variables and drugs modify 

theophylline metabolism; some of the potentially 

important interactions are listed in Figure 5-3-7. 

Combination bronchodilator therapy. Combining 

bronchodilators with different mechanisms and durations 

of action may increase the degree of bronchodilation for 

equivalent or lesser side effects. A combination of a 

short-acting ß 2 -agonist and an anticholinergic produces 

greater and more sustained improvements in FEV 1 

than either drug alone and does not produce evidence 

of tachyphylaxis over 90 days of treatment 27,52,53 

(Evidence A). 

The combination of a ß 2 -agonist, an anticholinergic, 

and/or theophylline may produce additional improvements 

in lung function 27,51,54-56 and health status 27,57 . Increasing 

the number of drugs usually increases costs, and an 

equivalent benefit may occur by increasing the dose of 

one bronchodilator when side effects are not a limiting 

factor. Detailed assessments of this approach have not 

been carried out. 

Glucocorticosteroids 

The effects of oral and inhaled glucocorticosteroids in 

COPD are much less dramatic than in asthma, and their 

role in the management of stable COPD is limited to very 

specific indications. The use of glucocorticosteroids for 

the treatment of acute exacerbations is described in 

Component 4: Manage Exacerbations. 

Oral glucocorticosteroids - short-term. Many existing 

COPD guidelines recommend the use of a short course 

(two weeks) of oral glucocorticosteroids to identify COPD 

patients who might benefit from long-term treatment with 

oral or inhaled glucocorticosteroids. This recommendation 

is based on evidence 58 that short-term effects predict 

long-term effects of oral glucocorticosteroids on FEV 1 , 

and evidence that asthma patients with airflow limitation 

might not respond acutely to an inhaled bronchodilator 

but do show significant bronchodilation after a short 

course of oral glucocorticosteroids. 

There is mounting evidence, however, that a short course 

of oral glucocorticosteroids is a poor predictor of the longterm 

response to inhaled glucocorticosteroids in COPD 13,59 . 

For this reason, there appears to be insuffi-cient evidence 

to recommend a therapeutic trial with oralglucocorticosteroids 

in patients with Stage II: Moderate COPD, Stage 

III: Severe COPD, or Stage IV: Very Severe COPD and 

poor response to an inhaled bronchodilator. 

Oral glucocorticosteroids - long-term. Two retrospective 

studies 60,61 analyzed the effects of treatment with oral 

glucocorticosteroids on long-term FEV 1 changes in clinic 

populations of patients with moderate to very severe 

COPD. The retrospective nature of these studies, the lack 

of a true control group, and the imprecise definition of 

COPD are reasons for a cautious interpretation of the 

data and conclusions. 

A side effect of long-term treatment with systemic 

glucocorticosteroids is steroid myopathy 62-64 , which 

contributes to muscle weakness, decreased functionality, 

and respiratory failure in subjects with advanced COPD. 

In view of the well-known toxicity of long-term treatment 

with oral glucocorticosteroids, it is not surprising that no 

prospective studies have been performed on the longterm 

effects of these drugs in COPD. 

Therefore, based on the lack of evidence of benefit, and 

the large body of evidence on side effects, long-term 

treatment with oral glucocorticosteroids is not recommended 

in COPD (Evidence A). 

Inhaled glucocorticosteroids. Regular treatment with 

inhaled glucocorticosteroids does not modify the longterm 

decline of FEV 1 in patients with COPD 11-13,65 . 

However, regular treatment with inhaled glucocorticosteroids 

is appropriate for symptomatic COPD patients 

with an FEV 1 < 50% predicted (Stage III: Severe COPD 

and Stage IV: Very Severe COPD) and repeated 

exacerbations (for example, 3 in the last three years) 66-69 

(Evidence A). This treatment has been shown to reduce 

the frequency of exacerbations and thus improve health 

status 224 (Evidence A), and withdrawal from treatment 

with inhaled glucocorticosteroids can lead to exacerbations 

in some patients 202 . Inhaled glucocorticosteroid combined 

with a long-acting ß 2 -agonist is more effective than the 

individual components 66,68,69,203,204 (Evidence A). Shortterm 

treatment with a combined inhaled glucocorticosteroid 

and long-acting ß 2 -agonist resulted in greater control of 

lung function and symptoms than combined anticholinergic 

and short-acting ß 2 -agonist 225 . 



Figure 5-3-8. Therapy at Each Stage of COPD 

Old 0: At Risk I: Mild II: Moderate III: Severe 

IIA 

IIB 

New 0: At Risk I: Mild II: Moderate III: Severe IV: Very Severe 

Characteristics • Chronic symptoms 

• Exposure to risk 

factors 

• Normal spirometry 

• FEV 1 /FVC < 70% 

• FEV 1 ≥ 80% 

• With or without 

symptoms 

• FEV 1 /FVC < 70% 

• 50% ≤ FEV 1 < 80% 


symptoms 

• FEV 1 /FVC < 70% 

• 30% ≤ FEV 1 < 50% 


symptoms 

• FEV 1 /FVC < 70% 

• FEV 1 < 30% or FEV 1 < 50% 

predicted plus chronic 

respiratory failure 

Avoidance of risk factor(s); influenza vaccination 

Add short-acting bronchodilator when needed 

Add regular treatment with one or more 

long-acting bronchodilators 

Add rehabilitation 

Add inhaled glucocorticosteroids 

if repeated exacerbations 

Add long-term 

oxygen if chronic 

respiratory 

failure 

Consider surgical 

treatments 

The dose-response relationships and long-term safety 

of inhaled glucocorticosteroids in COPD are not known. 

Only moderate to high doses have been used in long- term 

clinical trials. Two studies showed an increased incidence 

of skin bruising in a small percentage of the COPD 

patients 11,13 . One long-term study showed no effect of 

budesonide on bone density and fracture rate 11,70 , while 

another study showed that treatment with triamcinolone 

acetonide was associated with a decrease in bone 

density 65 . The efficacy and side effects of inhaled 

glucocorticosteroids in asthma are dependent on the dose 

and type of glucocorticosteroid 71 . This pattern can also 

be expected in COPD and needs documentation in this 

patient population. Treatment with inhaled glucocorticosteroids 

can be recommended for patients with more 

advanced COPD and repeated exacerbations. 

Pharmacologic Therapy by Disease Severity 

Figure 5-3-8 provides a summary of recommended 

treatment at each stage of COPD. For patients with few 

or intermittent symptoms (Stage I: Mild COPD), shortacting 

inhaled therapy as needed to control dyspnea or 

coughing spasms is sufficient. If inhaled bronchodilators 

are not available, regular treatment with slow-release 

theophylline should be considered. 

In patients with Stage II: Moderate COPD to Stage IV: 

Very Severe COPD) whose symptoms are not adequately 

controlled with as-needed short-acting bronchodilators, 

adding regular treatment with a long-acting inhaled 

bronchodilator is recommended (Evidence A). Regular 

treatment with long-acting bronchodilators is more effective 

and convenient than treatment with short-acting 



bronchodilators, but more expensive (Evidence A). There 

is insufficient evidence to favor one or the other longacting 

bronchodilator. For patients who need additional 

symptom control, adding theophylline leads to additional 

benefits. 

Patients with Stage II: Moderate COPD to Stage IV: 

Very Severe COPD who are on regular short- or longacting 

bronchodilator therapy may also use a short-acting 

bronchodilator as needed. 

Some patients may request regular treatment with 

high-dose nebulized bronchodilators, especially if they 

have experienced subjective benefit from this treatment 

during an acute exacerbation. Clear scientific evidence 

for this approach is lacking, but one suggested option is 

to examine the improvement in mean daily peak 

expiratory flow recording during two weeks of treatment 

in the home and continue with nebulizer therapy if a 

significant change occurs 24 . In general, nebulized therapy 

for a stable patient is not appropriate unless it has been 

shown to be better than conventional dose therapy. 

In patients with a postbronchodilator FEV 1 < 50% 

predicted (Stage III: Severe COPD to Stage IV: Very 

Severe COPD) and a history of repeated exacerbations 

(for example, three in the last three years), regular 

treatment with inhaled glucocorticosteroids reduce 

frequency of exacerbations and improve health status. 

In these patients, regular treatment with an inhaled 

glucocorticosteroid should be added to regular 

bronchodilator treatment. Chronic treatment with oral 

glucocorticosteroids should be avoided. 

Other Pharmacologic Treatments 

Vaccines. Influenza vaccines can reduce serious 

illness 226 72, 205 

and death in COPD patients by about 50% 

(Evidence A). Vaccines containing killed or live, inactivated 

viruses are recommended 73 as they are more effective in 

elderly patients with COPD 74 . The strains are adjusted 

each year for appropriate effectiveness and should be 

given once (in autumn) or twice (in autumn and winter) 

each year. A pneumococcal vaccine containing 23 

virulent serotypes has been used, but sufficient data to 

support its general use in COPD patients are lacking 75-77 

(Evidence B). 

Alpha-1 antitrypsin augmentation therapy. Young 

patients with severe hereditary alpha-1 antitrypsin 

deficiency and established emphysema may be 

candidates for alpha-1 antitrypsin augmentation therapy. 

However, this therapy is very expensive, is not available 

in most countries, and is not recommended for patients 

with COPD that is unrelated to alpha-1 antitrypsin 

deficiency (Evidence C). 

Antibiotics. In several large-scale controlled studies 78-80 , 

prophylactic, continuous use of antibiotics was shown 

to have no effect on the frequency of exacerbations in 

COPD. Another study examined the efficacy of winter 

chemoprophylaxis over a period of 5 years and concluded 

that there was no benefit 81 . Thus, on the present evidence, 

the use of antibiotics, other than for treating infectious 

exacerbations of COPD and other bacterial infections, is 

not recommended 82,83 (Evidence A). 

Mucolytic (mucokinetic, mucoregulator) agents 

(ambroxol, erdosteine, carbocysteine, iodinated glycerol). 

The regular use of mucolytics in COPD has been 

evaluated in a number of long-term studies with 

controversial results 84-86 . The majority showed no effect 

of mucolytics on lung function or symptoms, although 

some have reported a reduction in the frequency of 

exacerbations. A Cochrane collaborative review 

performed a meta-analysis of all the available data, 

including that from a number of abstracts 87 . A statistically 

significant reduction in the number of episodes of chronic 

bronchitis was found in patients treated with mucolytics 

compared to those receiving placebo. However, these 

data are not easy to interpret, as the follow-up ranged 

from 2 to 6 months and the patients all had an FEV 1 > 

50% predicted. Although a few patients with viscous 

sputum may benefit from mucolytics 88,89 , the overall 

benefits seem to be very small. Therefore, the widespread 

use of these agents cannot be recommended 

on the basis of the present evidence (Evidence D). 

Antioxidant agents. Antioxidants, in particular 

N-acetylcysteine, have been shown to reduce the 

frequency of exacerbations and could have a role in the 

treatment of patients with recurrent exacerbations 90-93 

(Evidence B). However, before their routine use can be 

recommended, the results of ongoing trials will have to 

be carefully evaluated. 

Immunoregulators (immunostimulators, 

immunomodulators). Studies using an immunostimulator 

in COPD show a decrease in the severity and frequency 

of exacerbations 94,227 . However, additional studies to 

examine the long term effects of this therapy are required 

before regular use can be recommended 95 (Evidence B). 

Antitussives. Cough, although sometimes a troublesome 

symptom in COPD, has a significant protective role 96 . 

Thus the regular use of antitussives is contraindicated in 

stable COPD (Evidence D). 

Vasodilators. The belief that pulmonary hypertension 

in COPD is associated with a poorer prognosis has 

provoked many attempts to reduce right ventricular 

afterload, increase cardiac output, and improve oxygen 



delivery and tissue oxygenation. Many agents have 

been evaluated, including inhaled nitric oxide, but the 

results have been uniformly disappointing. In patients 

with COPD, in whom hypoxemia is caused primarily by 

venti-lation-perfusion mismatching rather than by 

increased intrapulmonary shunt (as in noncardiogenic 

pulmonary edema), inhaled nitric oxide can worsen gas 

exchange because of altered hypoxic regulation of 

ventilation-perfusion balance 97,98 . Therefore, based on 

the available evidence, nitric oxide is contraindicated in 

stable COPD. 

Respiratory stimulants. Almitrine bismesylate, a relatively 

specific peripheral chemoreceptor stimulant that increases 

ventilation at any level of CO 2 under hypoxemic conditions, 

has been studied in both stable respiratory failure and 

exacerbations. It improves ventilation-perfusion relationships 

by modifying the hypoxic vasoconstrictor response. 

Oral almitrine has been shown to improve oxygenation, 

but to a lesser degree than low doses of inspired O 2 . 

There is no evidence that almitrine improves survival or 

quality of life, and in large clinical trials it was associated 

with a number of significant side effects, particularly 

peripheral neuropathy 99-101 . Therefore, on the present 

evidence almitrine is not recommended for regular use in 

stable COPD patients (Evidence B). The use of 

doxapram, a non-specific but relatively safe respiratory 

stimulant available as an intravenous formulation, is not 

recommended in stable COPD (Evidence D). 

Narcotics (morphine). The use of oral and parenteral 

opioids are effective for treating dyspnea in COPD 

patients with advanced disease. There are insufficient 

data to conclude whether nebulized opioids are 

effective 102 . However, some clinical studies suggest that 

morphine used to control dyspnea may have serious 

adverse effects and its benefits may be limited to a few 

sensitive subjects 103-107 . 

Others. Nedocromil, leukotriene modifiers, and alternative 

healing methods (e.g., herbal medicine, acupunture, 

homeopathy) have not been adequately tested in COPD 

patients and thus cannot be recommended at this time. 

NON-PHARMACOLOGIC TREATMENT 

Rehabilitation 

The principal goals of pulmonary rehabilitation are to 

reduce symptoms, improve quality of life, and increase 

physical and emotional participation in everyday activities. 

To accomplish these goals, pulmonary rehabilitation 

covers a range of non-pulmonary problems that may not 

be adequately addressed by medical therapy for COPD. 

Such problems, which especially affect patients with 

Figure 5-3-9. The Cycle of Physical, Social, and 

Psychosocial Consequences of COPD 

COPD 

Dyspnea 

Depression 

Lack of Fitness 

Immobility 

Social Isolation 

Stage II: Moderate COPD, Stage III: Severe COPD, 

and Stage IV: Very Severe COPD, include exercise 

deconditioning, relative social isolation, altered mood 

states (especially depression), muscle wasting, and 

weight loss. These problems have complex interrelationships 

and improvement in any one of these interlinked 

processes can interrupt the “vicious circle” in COPD so 

that positive gains occur in all aspects of the illness 

(Figure 5-3-9). 

Figure 5-3-10. Benefits of Pulmonary Rehabilitation 

in COPD 5,110-120 

• Improves exercise capacity (Evidence A). 

• Reduces the perceived intensity of breathlessness 

(Evidence A). 

• Can improve health-related quality of life (Evidence A). 

• Reduces the number of hospitalizations and days in 

the hospital (Evidence A). 

• Reduces anxiety and depression associated with 

COPD (Evidence A). 

• Strength and endurance training of the upper limbs 

improves arm function (Evidence B). 

• Benefits extend well beyond the immediate period of 

training (Evidence B). 

• Improves survival (Evidence B). 

• Respiratory muscle training is beneficial, especially 

when combined with general exercise training 

(Evidence C). 

• Psychosocial intervention is helpful (Evidence C). 



Pulmonary rehabilitation has been carefully evaluated in 

a large number of clinical trials; the various benefits are 

summarized in Figure 5-3-10 5,108-118 . 

Patient selection and program design. Although 

more information is needed on criteria for patient 

selection for pulmonary rehabilitation programs, COPD 

patients at all stages of disease appear to benefit from 

exercise training programs, improving with respect to 

both exercise tolerance and symptoms of dyspnea and 

fatigue 119 (Evidence A). Data suggest that these 

benefits can be sustained even after a single pulmonary 

rehabilitation program 120-122 . 

Benefit does wane after a rehabilitation program ends, 

but if exercise training is maintained at home the patient’s 

health status remains above pre-rehabilitation levels 

(Evidence B). To date there is no consensus on whether 

repeated rehabilitation courses enable patients to sustain 

the benefits gained through the initial course. 

Ideally, pulmonary rehabilitation should involve several 

types of health professionals. Significant benefits can 

also occur with more limited personnel, as long as 

dedicated professionals are aware of the needs of each 

patient. Benefits have been reported from rehabilitation 

programs conducted in inpatient, outpatient, and home 

settings 112,113,123 . Considerations of cost and availability 

most often determine the choice of setting. The 

educational and exercise training components of 

rehabilitation are usually conducted in groups, normally 

with 6 to 8 individuals per class (Evidence D). 

The following points summarize current knowledge of 

considerations important in choosing patients: 

Functional status: Benefits have been seen in patients 

with a wide range of disability, although those who are 

chair-bound appear unlikely to respond even to home visiting 

programs 124 (Evidence A). 

Severity of dyspnea: Stratification by breathlessness 

intensity using the MRC questionnaire (Figure 5-1-3) 

may be helpful in selecting patients most likely to benefit 

from rehabilitation. Those with MRC grade 5 dyspnea 

may not benefit 124 (Evidence B). 

Motivation: Selecting highly motivated participants is 

especially important in the case of outpatient programs 121 . 

Smoking status: There is no evidence that smokers will 

benefit less than nonsmokers, but many clinicians 

believe that inclusion of a smoker in a rehabilitation 

program should be conditional on their participation in a 

smoking cessation program. Some data indicate that continuing 

smokers are less likely to complete pulmonary 

rehabilitation programs than nonsmokers 121 (Evidence B). 

Components of pulmonary rehabilitation programs. 

The components of pulmonary rehabilitation vary 

widely from program to program but a comprehensive 

pulmonary rehabilitation program includes exercise 

training, nutrition counseling, and education. 

Exercise training. Exercise tolerance can be assessed 

by either bicycle ergometry or treadmill exercise with the 

measurement of a number of physiological variables, 

including maximum oxygen consumption, maximum heart 

rate, and maximum work performed. A less complex 

approach is to use a self-paced, timed walking test 

(e.g., 6-minute walking distance). These tests require at 

least one practice session before data can be interpreted. 

Shuttle walking tests offer a compromise: they provide 

more complete information than an entirely self-paced 

test, but are simpler to perform than a treadmill test 125 . 

Exercise training ranges in frequency from daily to 

weekly, in duration from 10 minutes to 45 minutes per 

session, and in intensity from 50% peak oxygen 

consumption (VO 2 max) to maximum tolerated 126 . The 

optimum length for an exercise program has not been 

investigated in randomized, controlled trials. Thus, the 

length depends on the resources available and usually 

ranges from 4 to 10 weeks, with longer programs 

resulting in larger effects than shorter programs 111 . 

Participants are often encouraged to achieve a 

predetermined target heart rate 127 , but this goal may have 

limitations in COPD. In many programs, especially those 

using simple corridor exercise training, the patient is 

encouraged to walk to a symptom-limited maximum, rest, 

and then continue walking until 20 minutes of exercise 

have been completed. Use of a simple wheeled walkingaid 

seems to improve walking distance and reduces 

breathlessness in severely disabled COPD patients 

(Evidence C) 206-208 . The minimum length of an effective 

rehabilitation program is two months; the longer the 

program continues, the more effective the results 

(Evidence B) 128-130 . However, as yet, no effective program 

has been developed to maintain the effects over time 131 . 

Many physicians advise patients unable to participate in 

a structured program to exercise on their own (e.g., walking 

20 minutes daily). The benefits of this general advice 

have not been tested, but it is reasonable to offer such 

advice to patients if a formal program is not available. 

Some programs also include upper limb exercises, 

usually involving an upper limb ergometer or resistive 

training with weights. There are no randomized clinical 

trial data to support the routine inclusion of these 

exercises, but they may be helpful in patients with 

comorbidities that restrict other forms of exercise and 

those with evidence of respiratory muscle weakness 132,133 . 

The addition of upper limb exercises or other strength 



training to aerobic training is effective in improving strength, 

but does not improve quality of life or exercise tolerance 134 . 

Nutrition counseling. Nutritional state is an important 

determinant of symptoms, disability, and prognosis in 

COPD; both overweight and underweight can be a 

problem. Specific nutritional recommendations for 

patients with COPD are based on expert opinion and 

some small randomized clinical trials 209 . Approximately 

25% of patients with Stage II: Moderate COPD to Stage 

IV: Very Severe COPD show a reduction in both their 

body mass index and fat free mass 135-137 . A reduction in 

body mass index is an independent risk factor for 

mortality in COPD patients 138-140 (Evidence A). 

Health care workers should identify and correct the 

reasons for reduced calorie intake in COPD patients. 

Patients who become breathless while eating should be 

advised to take small, frequent meals. Poor dentition 

should be corrected and comorbidities (pulmonary sepsis, 

lung tumors, etc.) should be managed appropriately. 

Improving the nutritional state of weight-losing COPD 

patients can lead to improved respiratory muscle 

strength 141-143 . However, controversy remains as to 

whether this additional effort is cost effective 141,142 . Present 

evidence suggests that nutritional supplementa-tion alone 

may not be a sufficient strategy. Increased calorie intake 

is best accompanied by exercise regimes that have a 

nonspecific anabolic action. This approach has not been 

formally tested in large numbers of subjects. Anabolic 

steroids in patients with COPD with weight loss increase 

body weight and lean body mass but have little or no 

effect on exercise capacity 144,145 

Education. Most pulmonary rehabilitation programs 

include an educational component, but the specific 

contributions of education to the improvements seen after 

pulmonary rehabilitation remain unclear. 

Assessment and follow-up. Baseline and outcome 

assessments of each participant in a pulmonary 

rehabilitation program should be made to quantify 

individual gains and target areas for improvement. 

Assessments should include: 

• Detailed history and physical examination. 

• Measurement of spirometry before and after a 

bronchodilator drug. 

• Assessment of exercise capacity. 

• Measurement of health status and impact of 

breathlessness. 

• Assessment of inspiratory and expiratory muscle 

strength and lower limb strength (e.g., quadriceps) in 

patients who suffer from muscle wasting. 

The first two assessments are important for establishing 

entry suitability and baseline status but are not used in 

outcome assessment. The last three assessments are 

baseline and outcome measures. 

Several detailed questionnaires for assessing health 

status are available, including some that are specifically 

designed for patients with respiratory disease (e.g., 

Chronic Respiratory Disease Questionnaire 57 , St. George 

Respiratory Questionnaire 146 ), and there is increasing 

evidence that these questionnaires may be useful in a 

clinical setting. Health status can also be assessed by 

generic questionnaires, such as the Medical Outcomes 

Study Short Form (SF36) 147 , to enable comparison of 

quality of life in different diseases. 

Economic cost of rehabilitation programs. A 

Canadian study showing statistically significant improvements 

in dyspnea, fatigue, emotional health, and mastery 

found that the incremental cost of pulmonary rehabilitation 

was $11,597 (CDN) per person 148 . A study from the 

UK provided evidence that an intensive (6-week, 18-visit) 

multidisciplinary rehabilitation program was effective in 

decreasing use of health services 122 (Evidence B). 

Although there was no difference in the number of 

hospital admissions between patients with disabling 

COPD in a control group and those who participated in 

the rehabilitation program, the number of days the 

rehabilitation group spent in the hospital was significantly 

lower. The rehabilitation group had more primary-care 

consultations at the general practitioner’s premises than 

did the control group, but fewer primary-care home visits. 

Compared with the control group, the rehabilitation group 

also showed greater improvements in walking ability and 

in general and disease-specific health status. 

Oxygen Therapy 

Oxygen therapy, one of the principal non-pharmacologic 

treatments for patients with Stage IV: Very Severe 

COPD 88,149 , can be administered in three ways: long-term 

continuous therapy, during exercise, and to relieve acute 

dyspnea. The primary goal of oxygen therapy is to 

increase the baseline PaO 2 to at least 8.0 kPa (60 mm 

Hg) at sea level and rest, and/or produce an SaO 2 at 

least 90%, which will preserve vital organ function by 

ensuring adequate delivery of oxygen. 

The long-term administration of oxygen (> 15 hours per 

day) to patients with chronic respiratory failure has 

been shown to increase survival 150,152 . It can also have a 

beneficial impact on hemodynamics, hematologic 

characteristics, exercise capacity, lung mechanics, and 

mental state 151 . Continuous oxygen therapy decreased 

resting pulmonary artery pressure in one study 150 but not 



in another study 152 . Several controlled prospective 

studies have shown that the primary hemodynamic effect 

of oxygen therapy is preventing the progression of 

pulmonary hypertension 153,154 . Long-term oxygen therapy 

improves general alertness, motor speed, and hand grip, 

although the data are less clear about changes in quality 

of life and emotional state. The possibility of walking 

while using some oxygen devices may help to improve 

physical conditioning and have a beneficial influence on 

the psychological state of patients 155 . 

Long-term oxygen therapy is generally introduced in 

Stage IV: Very Severe COPD for patients who have: 

• PaO 2 at or below 7.3 kPa (55 mm Hg) or SaO 2 at or 

below 88%, with or without hypercapnia (Evidence A); or 

• PaO 2 between 7.3 kPa (55 mm Hg) and 8.0 kPa 

(60 mm Hg), or SaO 2 of 89%, if there is evidence of 

pulmonary hypertension, peripheral edema 

suggesting congestive cardiac failure, or polycythemia 

(hematocrit > 55%) (Evidence D). 

A decision about the use of long-term oxygen should be 

based on the waking PaO 2 values. The prescription 

should always include the source of supplemental oxygen 

(gas or liquid), method of delivery, duration of use, and 

flow rate at rest, during exercise, and during sleep. 

Oxygen therapy given during exercise increases walking 

distance and endurance, optimizing oxygen delivery to 

tissues and utilization by muscles. However, there are no 

data to suggest that long-term oxygen therapy changes 

exercise capacity per se. Where available, this treatment 

is usually restricted to patients who meet the criteria for 

continuous oxygen therapy, or experience significant 

oxygen desaturation during exercise (Evidence C). 

Oxygen therapy reduces the oxygen cost of breathing 

and minute ventilation, a mechanism that although still 

disputed helps to minimize the sensation of dyspnea. 

This has led to the use of short burst therapy to control 

severe dyspnea such as occurs after climbing stairs. 

However, there is no benefit from using short burst 

oxygen for symptomatic relief before or after exercise 210,211 

(Evidence B). 

Cost considerations. Supplemental home oxygen is 

usually the most costly component of outpatient therapy 

for adults with COPD who require this therapy 156 . Studies 

of the cost effectiveness of alternative outpatient oxygen 

delivery methods in the US and Europe suggest that 

oxygen concentrator devices may be more cost effective 

than cylinder delivery systems 157,158 . 

Oxygen use in air travel. Although air travel is safe for 

most patients with chronic respiratory failure who are on 

long-term oxygen therapy, patients should be instructed 

to increase the flow by 1-2 L/min during the flight 159 . 

Ideally, patients who fly should be able to maintain an 

inflight PaO 2 of at least 6.7 kPa (50 mm Hg). Studies 

indicate that this can be achieved in those with moderate 

to severe hypoxemia at sea level by supplementary 

oxygen at 3 L/min by nasal cannulae or 31% by Venturi 

facemask 160 . Those with a resting PaO 2 at sea level of 

> 9.3 kPa (70 mm Hg) are likely to be safe to fly without 

supplementary oxygen 159,161 , although it is important to 

emphasize that a resting PaO 2 > 9.3 kPa (70 mm Hg) at 

sea level does not exclude the development of severe 

hypoxemia when travelling by air (Evidence C). Careful 

consideration should be given to any comorbidity that 

may impair oxygen delivery to tissues (e.g., cardiac 

impairment, anemia). Also, walking along the aisle may 

profoundly aggravate hypoxemia 162 . 

Ventilatory Support 

Although both noninvasive ventilation (using either 

negative or positive pressure devices) and invasive 

(conventional) mechanical ventilation are essentially 

designed to manage and treat acute episodes of COPD, 

for years noninvasive ventilation has been applied in 

patients with Stage IV: Very Severe COPD and chronic 

respiratory failure. This has followed the successful use of 

noninvasive ventilation in other forms of chronic 

respiratory failure due to chest wall deformities and/or 

neuromuscular disorders. Several scientific studies have 

examined the use of ventilatory support and there is no 

convincing evidence that this therapy has a role in the 

management of stable COPD. It is possible that some 

patients with chronic hypercapnia may benefit from this 

form of treatment, but no randomized controlled study 

has yet been reported. 

Noninvasive mechanical ventilation. This modality of 

ventilatory support is applied when endotracheal and 

nasotracheal ventilation are not needed, using either 

negative pressure ventilation (nPV) or noninvasive 

intermittent positive pressure ventilation (NIPPV). 

Noninvasive negative pressure ventilation (nPV). The use 

of tank respirators, cuirass, or poncho ventilation is largely 

of historical interest in COPD. Problems with patient 

comfort and limited access restrict future use of nPV 163,164 . 

When this treatment is used in chronic respiratory failure, 

some patients develop upper airway obstruction during 

sleep 165 . A comparison of domiciliary active and sham 

nPV in patients with chronic respiratory failure due to 

COPD showed no differences in shortness of breath, 

exercise tolerance, arterial blood gases, respiratory 

muscle strength, or quality of life between the two 

treatments 166 . 



Noninvasive intermittent positive pressure ventilation 

(NIPPV). The role of NIPPV in chronic respiratory failure 

remains unsettled, although this is now the standard 

means of providing noninvasive ventilatory support in 

other instances of chronic respiratory failure not directly 

related to COPD. NIPPV can be delivered by different 

types of ventilators: volume-controlled, pressure-controlled, 

bilevel positive airway pressure, or continuous positive 

airway pressure. New devices with lower cost, greater 

ease of operation, and greater portability are constantly 

being developed 167 . Recent technical improvements have 

facilitated the use of NIPPV while reducing the possibility 

of air leaking through face or nasal masks. 

A study of NIPPV compared to conventional therapy in a 

population with end-stage COPD using a randomized, 

crossover design for a 3-month period found that the 

noninvasive approach is not well tolerated and is 

associated with marginal clinical and functional 

improvements 168 (Evidence B). Although preliminary 

studies have suggested that combining NIPPV with 

long-term oxygen therapy could be beneficial on certain 

outcome variables, based on a 12-month study 169 and a 

24-month study 170 in stable COPD patients with chronic 

respiratory failure, its widespread use cannot be 

advocated as yet 171 . However, compared with long-term 

oxygen therapy alone, the addition of NIPPV has some 

effect on carbon dioxide retention and improved 

shortness of breath 170 . 

Given this conflicting evidence, long-term NIPPV cannot 

be recommended for the routine treatment of patients 

with chronic respiratory failure due to COPD. Nonetheless, 

the combination of NIPPV with long-term oxygen 

therapy may be of some use in a selected subset of 

patients, particularly in those with pronounced daytime 

hypercapnia 172 . 

Invasive (conventional) mechanical ventilation. 

The appropriateness of using invasive (conventional) 

ventilation in end-stage COPD continues to be debated. 

There are no guidelines to define which patients will 

benefit. 

Surgical Treatments 

Bullectomy. Bullectomy is an older surgical procedure 

for bullous emphysema. By removing a large bulla that 

does not contribute to gas exchange, the adjacent lung 

parenchyma is decompressed. Bullectomy can be 

performed thoracoscopically. In carefully selected 

patients, this procedure is effective in reducing dyspnea 

and improving lung function 173 (Evidence C). 

Bullae may be removed to alleviate local symptoms 

such as hemoptysis, infection, or chest pain, and to allow 

re-expansion of a compressed lung region. This is the 

usual indication in patients with COPD. In considering the 

possible benefit of surgery it is crucial to estimate the 

effect of the bulla on the lung and the function of the 

nonbullous lung. A thoracic CT scan, arterial blood gas 

measurement, and comprehensive respiratory function 

tests are essential before making a decision regarding 

suitability for resection of a bulla. Normal or minimally 

reduced diffusing capacity, absence of significant 

hypoxemia, and evidence of regional reduction in perfusion 

with good perfusion in the remaining lung are indications 

a patient will likely benefit from surgery 174 . However, 

pulmonary hypertension, hypercapnia, and severe 

emphysema are not absolute contraindications for 

bullectomy. Some investigators have recommended that 

the bulla must occupy 50% or more of the hemithorax 

and produce definite displacement of the adjacent lung 

before surgery is performed 175 . 

Lung volume reduction surgery (LVRS). LVRS is a 

surgical procedure in which parts of the lung are resected 

to reduce hyperinflation 176 , making respiratory muscles 

more effective pressure generators by improving their 

mechanical efficiency (as measured by length/tension 

relationship, curvature of the diaphragm, and area of 

apposition) 177,178 . In addition, LVRS increases the elastic 

recoil pressure of the lung and thus improves expiratory 

flow rates 179 . 

LVRS does not improve life expectancy but improves 

exercise capacity in patients with predominant upper lobe 

emphysema and a low post-rehabilitation exercise 

capacity 212 , and may improve global health status in 

patients with heterogeneous emphysema 213 . 

In some centers with adequate experience, perioperative 

mortality of LVRS has been reported to be less than 5%. 

Results have been reported following bilateral (upper 

parts) resection using median sternotomy 180,181 or 

video-assisted thoracoscopy (VATS) 182 . Most studies 

select patients with FEV 1 < 35% predicted, PaCO 2 

< 6.0 kPa (45 mm Hg), predominant upper lobe 

emphysema on CT scan, and a residual volume of > 

200% predicted. The average increase in FEV 1 following 

LVRS has ranged from 32% to 93%, and the decrease in 

TLC from 15% to 20% 180,183 . LVRS appears to improve 

exercise capacity as well as quality of life in some patients. 

There are reports of these effects lasting more than one 

year 180-182 . Patients with an FEV 1 < 20 % predicted 

and either homogeneous emphysema on HRCT or a 

DLCO < 20 % predicted are at high risk for death after 

LVRS and unlikely to benefit from the intervention 184 . 



Hospital costs associated with LVRS in 52 consecutive 

patients 185 ranged from $11,712 to $121,829 (US). 

Hospital charges in 23 consecutive patients admitted for 

LVRS at a single institution 186 ranged from $20,032 to 

$75,561 with a median charge of $26,669 (US). A small 

number of individuals incurred extraordinary costs 

because of complications. Advanced age was a significant 

factor leading to higher expected total hospital costs. 

Although there are some encouraging reports 187 , LVRS 

is still an experimental palliative surgical procedure 188 . 

Most results (Evidence C) reported to date are from 

uncontrolled studies; several large randomized multicenter 

studies are underway to investigate the effectiveness and 

cost of LVRS in comparison to vigorous conventional 

therapy 189 . Until the results of these controlled studies are 

known, LVRS cannot be recommended for widespread 

use. 

Lung transplantation. In appropriately selected patients 

with very advanced COPD, lung transplantation has 

been shown to improve quality of life and functional 

capacity 190-193 (Evidence C), although the Joint United 

Network for Organ Sharing in 1998 found that lung 

transplantation does not confer a survival benefit in 

patients with end-stage emphysema after two years 192 . 

Criteria for referral for lung transplantation include FEV 1 

< 35% predicted, PaO 2 < 7.3-8.0 kPa (55-60 mm Hg), 

PaCO 2 > 6.7 kPa (50 mm Hg), and secondary pulmonary 

hypertension 194,195 . 

Lung transplantation is limited by the shortage of donor 

organs, which has led some centers to adopt the single 

lung technique. The common complications seen in 

COPD patients after lung transplantation, apart from 

operative mortality, are acute rejection and bronchiolitis 

obliterans, CMV, other opportunistic fungal (Candida, 

Aspergillus, Cryptococcus, Carini) or bacterial 

(Pseudomonas, Staphylococcus species) infections, 

lymphoproliferative disease, and lymphomas 191 . 

Another limitation of lung transplantation is its cost. 

Hospitalization costs associated with lung transplantation 

have ranged from $110,000 to well over $200,000 

(US). Costs remain elevated for months to years after 

surgery due to the high cost of complications and the 

immunosuppressive regimens 196-199 that must be initiated 

during or immediately after surgery. 

Special Considerations 

Surgery in COPD. Postoperative pulmonary complications 

are as important and common as postoperative cardiac 

complications and, consequently, are a key component 

of increased risk of surgery in COPD patients. The principal 

potential factors contributing to the risk include smoking, 

poor general health status, age, obesity and COPD severity. 

A comprehensive definition of postoperative pulmonary 

complications should include only major pulmonary 

respiratory complications, namely lung infections, 

atelectasis and/or increased airflow obstruction, all 

potentially resulting in acute respiratory failure and 

aggravation of underlying COPD 214-219 . 

The incidence of increased risk of postoperative pulmonary 

complications in COPD patients may vary according to 

the definition of postoperative pulmonary complications 

and the severity of COPD, with relative ranges of the 

order of 2.7 and 4.7 214 . The surgical site is the most 

important predictor, and risk increases as the incision 

approaches the diaphragm. Upper abdominal and thoracic 

surgery represents the greatest risk, the latter being 

uncommon after interventions outside the thorax or 

abdomen. Most reports conclude that epidural or spinal 

anesthesia have a lower risk than with general anesthesia, 

although the results are not totally uniform. 

Patient-risk factors are identified by careful history, physical 

examination, chest radiography, and pulmonary function 

tests. Although the value of pulmonary function tests 

remains contentious, there is consensus that all COPD 

candidates for lung resection should undergo a complete 

battery, including forced spirometry with bronchodilator 

response, static lung volumes, diffusing capacity and 

arterial blood gases at rest. One theoretical rationale 

behind the assessment of pulmonary function measurement 

is the identification of COPD patients in whom the risk is 

so elevated that surgery should be contraindicated. 

Several studies in high risk COPD patients suggest that 

there is threshold beyond which the risk of surgery is 

prohibitive. The risk of postoperative respiratory failure 

appears to be in patients undergoing pneumonectomy 

with a preoperative FEV 1 < 2 L or 50% predicted and/or 

a DLCO < 50% predicted 218 . COPD patients at high risk 

due to poor lung function should undergo further lung 

function assessment, for example, regional distribution 

of perfusion and exercise capacity 219 . To prevent 

postoperative pulmonary complications, stable COPD 

patients clinically symptomatic and/or with limited exercise 

capacity should be treated, before surgery, intensely with 

all the measures already well established for stable 

COPD patients who are not about to have surgery. 

Surgery should be postponed if an exacerbation is present. 

Surgery in patients with COPD needs to be differentiated 

from that aimed to improve function and symptoms for 

COPD. This includes bullectomy, lung volume reduction 

surgery and lung transplantation 219 . 



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COMPONENT 4: MANAGE EXACERBATIONS 

KEY POINTS: 

• Exacerbations of respiratory symptoms requiring medical 

intervention are important clinical events in COPD. 

• The most common causes of an exacerbation are 

infection of the tracheobronchial tree and air pollution, 

but the cause of about one-third of severe exacerbations 

cannot be identified (Evidence B). 

• Inhaled bronchodilators (particularly inhaled ß 2 - 

agonists and/or anticholinergics), theophylline, and 

systemic, preferably oral, glucocorticosteroids are 

effective treatments for exacerbations of COPD 

(Evidence A). 

• Patients experiencing COPD exacerbations with 

clinical signs of airway infection (e.g., increased 

volume and change of color of sputum, and/or fever) 

may benefit from antibiotic treatment (Evidence B). 

• Noninvasive intermittent positive pressure ventilation 

(NIPPV) in exacerbations improves blood gases 

and pH, reduces in-hospital mortality, decreases the 

need for invasive mechanical ventilation and 

intubation, and decreases the length of hospital 

stay (Evidence A). 

INTRODUCTION 

COPD is often associated with exacerbations of symptoms 

1-4. In patients with Stage I: Mild COPD to Stage II: 

Moderate COPD, an exacerbation is associated with 

increased breathlessness, often accompanied by 

increased cough and sputum production, and may 

require medical attention outside of the hospital 5 . The 

need for medical intervention intensifies as the airflow 

limitation worsens. Exacerbations in Stage IV: Very 

Severe COPD are associated with acute respiratory failure, 

representing a significant burden on the health care 

system. Hospital mortality of patients admitted for an 

exacerbation of COPD is approximately 10%, and the 

long-term outcome is poor. Mortality reaches 40% in one 

year 6-9 , and is even higher (up to 59%) for patients older 

than 65 years 9 . These figures vary from country to country 

depending on the health care system and the availability 

of intensive care unit (ICU) beds. 

The most common causes of an exacerbation are infection 

of the tracheobronchial tree and air pollution 10 , but the 

cause of about one-third of severe exacerbations cannot 

be identified. The role of bacterial infections is controversial, 

but recent investigations with newer research techniques 

have begun to provide important information. 

Bronchoscopic studies have shown that at least 50% of 

patients have bacteria in high concentrations in their lower 

airways during exacerbations 11 . However, a significant 

proportion of these patients also have bacteria colonizing 

their lower airways in the stable phase of the disease. 

There is some indication that the bacterial burden 

increases during exacerbations 11 , and that acquisition 

of strains of the bacteria that are new to the patient is 

associated with exacerbations 12 . Development of specific 

immune responses to the infecting bacterial strains, and 

the association of neutrophilic inflammation with bacterial 

exacerbations also support the bacterial causation of a 

proportion of exacerbations 13-16 . Conditions that may 

mimic an exacerbation include pneumonia, congestive 

heart failure, pneumothorax, pleural effusion, pulmonary 

embolism, and arrhythmia. Recommendations for use of 

antibiotics for COPD exacerbations are provided at the 

end of this chapter. 

DIAGNOSIS AND ASSESSMENT 

OF SEVERITY 


Increased breathlessness, the main symptom of an 

exacerbation, is often accompanied by wheezing and 

chest tightness, increased cough and sputum, change 

of the color and/or tenacity of sputum, and fever. 

Exacerbations may also be accompanied by a number 

of nonspecific complaints, such as malaise, insomnia, 

sleepiness, fatigue, depression, and confusion. A 

decrease in exercise tolerance, fever, and/or new radiological 

anomalies suggestive of pulmonary disease may 

herald a COPD exacerbation. An increase in sputum 

volume and purulence points to a bacterial cause, as 

does prior history of chronic sputum production 4,14 . 

Assessment of Severity 

Assessment of the severity of an exacerbation is based 

on the patient’s medical history before the exacerbation, 

symptoms, physical examination, lung function tests, 

arterial blood gas measurements, and other laboratory 

tests (Figure 5-4-1). Specific information is required on 



the frequency and severity of attacks of breathlessness 

and cough, sputum volume and color, and limitation 

of daily activities. When available, prior tests of lung 

function and arterial blood gases are extremely useful for 

comparison with those made during the acute episode, 

as an acute change in these tests is more important than 

their absolute values. Thus, where possible, physicians 

should instruct their patients to bring the summary of 

their last evaluation when they come to the hospital with 

an exacerbation. In patients with very severe COPD, the 

most important sign of a severe exacerbation is a change 

in the alertness of the patient and this signals a need for 

immediate evaluation in the hospital. 

Lung function tests. Even simple lung function tests 

can be difficult for a sick patient to perform properly. In 

general, a PEF < 100 L/min or an FEV 1 < 1.00 L 

indicates a severe exacerbation 21-23 , except in patients 

with chronically severe airflow limitation. For instance, 

an FEV 1 of 0.75 L, or a PaO 2 /FiO 2 (FiO 2 = fractional 

concentration of oxygen in dry inspired gas) of 32 kPa 

(240 mm Hg) may be well tolerated by a subject with 

severe COPD who copes with these values in stable 

conditions, whereas they may reflect a severe 

exacerbation for a subject with slightly higher values, e.g., 

an FEV 1 of 0.90 L or a PaO 2 /FiO 2 of 38 kPa (282 mm 

Hg) in stable conditions 24 . 

Figure 5-4-1. Medical History and Signs of 

Severity of Exacerbations of COPD 


• Duration of worsening or 

new symptoms. 

• Number of previous 

episodes 

(exacerbations/hospitalizations). 

• Present treatment regimen. 

Signs of Severity 

• Use of accessory respiratory 

muscles. 

• Paradoxical chest wall 

movements. 

• Worsening or new onset 

central cyanosis. 

• Development of peripheral 

edema. 

• Hemodynamic instability. 

• Signs of right heart failure. 

• Reduced alertness. 

Arterial blood gases. In the hospital, measurement of 

arterial blood gases is essential to assess the severity of 

an exacerbation. A PaO 2 < 8.0 kPa (60 mm Hg) and/or 

SaO 2 < 90% with or without PaCO 2 > 6.7 kPa, (50 mm Hg) 

when breathing room air indicate respiratory failure. In 

addition, a PaO 2 < 6.7 kPa (50 mm Hg), PaCO 2 > 9.3 

kPa (70 mm Hg), and pH < 7.30 point toward a life-threatening 

episode that needs critical management 25 . 

Chest X-ray and ECG. Chest radiographs 

(posterior/anterior plus lateral) are useful in identifying 

alternative diagnoses that can mimic the symptoms of an 

exacerbation. Although the history and physical signs 

can be confusing, especially when pulmonary hyperinflation 

masks coexisting cardiac signs, most problems are 

resolved by the chest X-ray and ECG. An ECG aids in 

the diagnosis of right heart hypertrophy, arrhythmias, and 

ischemic episodes. Pulmonary embolism can be very 

difficult to distinguish from an exacerbation, especially in 

severe COPD, because right ventricular hypertrophy and 

large pulmonary arteries lead to confusing ECG and 

radiographic results. Spiral CT scanning and angiography, 

and perhaps specific D-dimer assays, are the best 

tools presently available for the diagnosis of pulmonary 

embolism in patients with COPD, but ventilation-perfusion 

scanning is of no value. A low systolic blood pressure 

and an inability to increase the PaO 2 above 8.0 kPa 

(60 mm Hg) despite high-flow oxygen also suggest 

pulmonary embolism. If there are strong indications that 

pulmonary embolism has occurred, it is best to treat for 

this along with the exacerbation. 

Other laboratory tests. The whole blood count may 

identify polycythemia (hematocrit > 55%) or bleeding. 

White blood cell counts are usually not very informative. 

The presence of purulent sputum during an exacerbation 

of symptoms is sufficient indication for starting empirical 

antibiotic treatment. Streptococcus pneumoniae, 

Hemophilis influenzae, and Moraxella catarrhalis are the 

most common bacterial pathogens involved in COPD 

exacerbations. If an infectious exacerbation does not 

respond to the initial antibiotic treatment, a sputum 

culture and an antibiogram should be performed. 

Biochemical tests can reveal whether the cause of 

the exacerbation is an electrolyte disturbance(s) 

(hyponatremia, hypokalemia, etc.), a diabetic crisis, or 

poor nutrition (low proteins), and may suggest a 

metabolic acid-base disorder. 

HOME MANAGEMENT 

There is increasing interest in home care for end-stage 

COPD patients, although economic studies of home-care 

services have yielded mixed results. Four randomized 

clinical trials have shown nurse administered home care 

represents an effective and practical alternative to 

hospitalization in selected patients with exacerbations of 

COPD without acidotic respiratory failure. However, the 

exact criteria for home vs hospital treatment remains 

uncertain and will vary by health care setting 26-29 . A major 

outstanding issue is when to treat an exacerbation at 

home and when to hospitalize the patient. 



Figure 5-4-2. Algorithm for the Management 

of an Exacerbation of COPD at Home 

Initiate or increase bronchodilator therapy 

Consider antibiotics 

Resolution or improvement 

of signs and symptoms 

Continue management 

Step down when possible 

Review long-term management 

The algorithm reported in Figure 5-4-2 may assist in 

the management of an exacerbation at home; a stepwise 

therapeutic approach is recommended 30-33 . 

Bronchodilator Therapy 

Home management of COPD exacerbations involves 

increasing the dose and/or frequency of existing 

bronchodilator therapy (Evidence A). If not already 

used, an anticholinergic can be added until the symptoms 

improve. In more severe cases, high-dose nebulizer 

therapy can be given on an as-needed basis for several 

days and if a suitable nebulizer is available. However, 

long-term use of nebulizer therapy after an acute episode 

is not routinely recommended. 

Glucocorticosteroids 

Reassess within hours 

No resolution or improvement 

Add oral corticosteroids 

Reassess within hours 

Worsening of signs/symptoms 

Refer to hospital 

Systemic glucocorticosteroids are beneficial in the 

management of exacerbations of COPD. They shorten 

recovery time and help to restore lung function more 

quickly 34-36 (Evidence A) and may reduce the risk of early 

relapse 73 . They should be considered in addition to 

bronchodilators if the patient’s baseline FEV 1 is < 50% 

predicted. A dose of 40 mg prednisolone per day for 10 

days is recommended (Evidence D). One large study 

indicates that nebulized budesonide may be an alternative 

to oral glucocorticosteroids in the treatment 

of nonacidotic exacerbations 37 . 

HOSPITAL MANAGEMENT 

The risk of dying from an exacerbation of COPD is 

closely related to the development of respiratory acidosis, 

the presence of significant comorbidities, and the need 

for ventilatory support 6 . Patients lacking these features 

are not at high risk of dying, but those with severe 

underlying COPD often require hospitalization in any case. 

Attempts at managing such patients entirely in the 

community have met with only limited success 38 , but 

returning them to their homes with increased social 

support and a supervised medical care package after 

initial emergency room assessment has been much more 

successful 39 . Several randomized controlled trials have 

confirmed that this is a safe alternative to hospitalization, 

although it probably only applies to about 25% of COPD 

admissions. Savings on inpatient expenditures 40 offset the 

additional costs of maintaining a community-based 

COPD nursing team. However, detailed cost-benefit 

analyses of these approaches are awaited. 

Figure 5-4-3. Indications for Hospital Assessment 

or Admission for Exacerbations of COPD* 

• Marked increase in intensity of symptoms, 

such as sudden development of resting dyspnea. 

• Severe background COPD. 

• Onset of new physical signs (e.g., cyanosis, 

peripheral edema). 

• Failure of exacerbation to respond to initial 

medical management. 

• Significant comorbidities. 

• Newly occurring arrhythmias. 

• Diagnostic uncertainty. 

• Older age. 

• Insufficient home support. 

Figure 5-4-4. Indications for ICU Admission of 

Patients with Exacerbations of COPD* 

• Severe dyspnea that responds inadequately to 

initial emergency therapy. 

• Confusion, lethargy, coma. 

• Persistent or worsening hypoxemia (PaO 2 

< 5.3 kPa, 40 mm Hg), and/or severe/worsening 

hypercapnia (PaCO 2 > 8.0 kPa, 60 mm Hg), and/or 

severe/worsening respiratory acidosis (pH < 7.25) 

despite supplemental oxygen and NIPPV. 

*Local resources need to be considered. 



Figure 5-4-5. Management of Severe but 

Not Life-Threatening Exacerbations of COPD in the 

Emergency Department or the Hospital* 

• Assess severity of symptoms, blood gases, chest 

X-ray. 

• Administer controlled oxygen therapy and repeat 

arterial blood gas measurement after 30 minutes. 

• Bronchodilators: 

– Increase doses or frequency. 

– Combine ß 2 -agonists and anticholinergics. 

– Use spacers or air-driven nebulizers. 

– Consider adding intravenous aminophylline, if 

needed. 

• Add oral or intravenous glucocorticosteroids. 

• Consider antibiotics: 

– When signs of bacterial infection, oral or 

occasionally intravenous. 

• Consider noninvasive mechanical ventilation. 

• At all times: 

– Monitor fluid balance and nutrition. 

– Consider subcutaneous heparin. 

– Identify and treat associated conditions 

(e.g., heart failure, arrhythmias). 

– Closely monitor condition of the patient. 

*Local resources need to be considered. 

A range of criteria to consider for hospital assessment/ 

admission for exacerbations of COPD are shown in 

Figure 5-4-3. Some patients need immediate admission 

to an intensive care unit (ICU) (Figure 5-4-4). Admission 

of patients with severe COPD exacerbations to intermediate 

or special respiratory care units may be appropriate if 

personnel, skills, and equipment exist to identify and 

manage acute respiratory failure successfully. 

Emergency Department or Hospital 

The first actions when a patient reaches the emergency 

department are to provide controlled oxygen therapy 

and to determine whether the exacerbation is life 

threatening. If so, the patient should be admitted to the 

ICU immediately. Otherwise, the patient may be 

managed in the emergency department or hospital as 

detailed in Figure 5-4-5. 

Controlled oxygen therapy. Oxygen therapy is the 

cornerstone of hospital treatment of COPD exacerbations. 

Adequate levels of oxygenation (PaO 2 > 8.0 kPa, 

60 mm Hg, or SaO 2 > 90%) are easy to achieve in 

uncomplicated exacerbations, but CO 2 retention can 

occur insidiously with little change in symptoms. Once 

oxygen is started, arterial blood gases should be checked 

30 minutes later to ensure satisfactory oxygenation 

without CO 2 retention or acidosis. Venturi masks are 

more accurate sources of controlled oxygen than are 

nasal prongs but are more likely to be removed by the 

patient. 

Bronchodilator therapy. Short-acting inhaled 

2 -agonists are usually the preferred bronchodilators for 

treatment of exacerbations of COPD 30,31,41 (Evidence A). If 

a prompt response to these drugs does not occur, the 

addition of an anticholinergic is recommended, even 

though evidence concerning the effectiveness of this 

combination is controversial. Despite its wide-spread 

clinical use, the role of aminophylline in the treatment of 

exacerbations of COPD remains controversial. Most 

studies of aminophylline have demonstrated minor 

improvements in lung volumes without showing gas 

exchange deterioration 42,43 . In more severe exacerbations, 

addition of an oral or intravenous methylxanthine to the 

treatment can be considered. However, close monitoring 

of serum theophylline is recommended to avoid the side 

effects of these drugs 42,44-46 . Possible beneficial effects in 

lung function, and clinical endpoints, are modest and 

inconsistent, whereas adverse effects are significantly 

increased 74 . 

Glucocorticosteroids. Oral or intravenous glucocorticosteroids 

are recommended as an addition to 

bronchodilator therapy (plus eventually antibiotics 

and oxygen therapy) in the hospital management of 

exacerbations of COPD 35-36 (Evidence A). The exact 

dose that should be recommended is not known, but high 

doses are associated with a significant risk of side effects. 

Thirty to 40 mg of oral prednisolone daily for 10 to 14 

days is a reasonable compromise between efficacy and 

safety (Evidence D). Prolonged treatment does not result 

in greater efficacy and increases the risk of side effects. 

Ventilatory support. The primary objectives of 

mechanical support in patients with exacerbations in 

Stage IV: Very Severe COPD are to decrease mortality 

and morbidity and to relieve symptoms. Ventilatory 

support includes both noninvasive mechanical ventilation 

using either negative or positive pressure devices, and 

invasive (conventional) mechanical ventilation by 

oro/naso-tracheal tube or tracheostomy. 



Figure 5-4-6. Indications and Relative 

Contraindications for NIPPV 47,56 

Selection criteria 

• Moderate to severe dyspnea with use of accessory 

muscles and paradoxical abdominal motion. 

• Moderate to severe acidosis (pH ≤ 7.35) and 

hypercapnia (PaCO 2 > 6.0 kPa, 45 mm Hg) 57 . 

• Respiratory frequency > 25 breaths per minute. 

Exclusion criteria (any may be present) 

• Respiratory arrest. 

• Cardiovascular instability (hypotension, 

arrhythmias, myocardial infarction). 

• Somnolence, impaired mental status, 

uncooperative patient. 

• High aspiration risk; viscous or copious secretions. 

• Recent facial or gastroesophageal surgery. 

• Craniofacial trauma, fixed nasopharyngeal 

abnormalities. 

• Burns. 

• Extreme obesity. 

Noninvasive mechanical ventilation. Noninvasive 

intermittent positive pressure ventilation (NIPPV) has 

been studied in many uncontrolled and five randomized 

controlled trials in acute respiratory failure 47,48 . The 

studies show consistently positive results with success 

rates of 80-85% 49 . Taken together they provide evidence 

that NIPPV increases pH, reduces PaCO 2 , reduces 

the severity of breathlessness in the first 4 hours of 

treatment, and decreases the length of hospital stay 

(Evidence A). More importantly, mortality - or its surrogate, 

intubation rate - is reduced by this intervention 50-53 . 

However, NIPPV is not appropriate for all patients, as 

summarized in Figure 5-4-6 49 . 

Invasive (conventional) mechanical ventilation. During 

exacerbations of COPD the events occurring within the 

lungs include bronchoconstriction, airway inflammation, 

increased mucous secretions, and loss of elastic recoil, 

all of which prevent the respiratory system from reaching 

its passive functional residual capacity at the end of 

expiration, enhancing dynamic hyperinflation 54 . As a 

result of these processes, an elastic threshold load, 

referred to as intrinsic or auto-positive end-expiratory 

pressure (PEEPi), is imposed on the inspiratory muscles 

at the beginning of inspiration and increases the work of 

breathing. For these reasons, patients who show 

impending acute respiratory failure and those with 

Figure 5-4-7. Indications for 

Invasive Mechanical Ventilation 

• Severe dyspnea with use of accessory muscles 

and paradoxical abdominal motion. 

• Respiratory frequency > 35 breaths per minute. 

• Life-threatening hypoxemia (PaO 2 < 5.3 kPa, 

40 mm Hg or PaO 2 /FiO 2 < 200 mm Hg). 

• Severe acidosis (pH < 7.25) and hypercapnia 

(PaCO 2 > 8.0 kPa, 60 mm Hg). 

• Respiratory arrest. 

• Somnolence, impaired mental status. 

• Cardiovascular complications (hypotension, 

shock, heart failure). 

• Other complications (metabolic abnormalities, 

sepsis, pneumonia, pulmonary embolism, 

barotrauma, massive pleural effusion). 

• NIPPV failure (or exclusion criteria, 

see Figure 5-4-7). 

FiO 2 : Fractional concentration of oxygen in dry inspired gas. 

Figure 5-4-8. Factors Determining 

Benefit from Invasive Ventilation 

• Cultural attitudes toward chronic disability. 

• Expectations of therapy. 

• Financial resources (especially the provision 

of ICU facilities). 

• Perceived likelihood of recovery. 

• Customary medical practice. 

• Wishes, if known, of the patient. 

life-threatening acid-base status abnormalities and/or 

altered mental status despite aggressive pharmacologic 

therapy are likely to be the best candidates for invasive 

(conventional) mechanical ventilation. The indications for 

initiating mechanical ventilation during exacerbations of 

COPD are shown in Figure 5-4-7, the first being the 

commonest and most important reason. Figure 5-4-8 

details the factors determining benefit from invasive 

ventilation. The three ventilatory modes most widely 

used are assisted-control ventilation, and pressure 

support ventilation alone or in combination with intermittent 

mandatory ventilation 55 . 

The use of invasive ventilation in end-stage COPD 

patients is influenced by the likely reversibility of the 

precipitating event, the patient’s wishes, and the availability 



of intensive care facilities. Major hazards include the risk 

of ventilator-acquired pneumonia (especially when 

multi-resistant organisms are prevalent), barotrauma, 

and failure to wean to spontaneous ventilation. Contrary 

to some opinions, mortality among COPD patients with 

respiratory failure is no greater than mortality among 

patients ventilated for non-COPD causes. 

A review of a large number of North American COPD 

patients ventilated for respiratory failure indicated an in 

hospital mortality of 17-30% 58 . Further attrition over the 

next 12 months was particularly high among those 

patients who had poor lung function before ventilation 

(FEV 1 < 30% predicted), had a non-respiratory comorbidity, 

or were housebound. Patients who did not have a 

previously diagnosed underlying disease, had respiratory 

failure due to a potentially reversible cause (such as an 

infection), or were relatively mobile and not using longterm 

oxygen did surprisingly well with ventilatory support. 

When possible, a clear statement of the patient’s own 

treatment wishes - an advance directive or “living will” - 

makes these difficult decisions much easier to resolve. 

Weaning or discontinuation from mechanical ventilation 

can be particularly difficult and hazardous in patients with 

COPD. The most influential determinant of mechanical 

ventilatory dependency in these patients is the balance 

between the respiratory load and the capacity of the 

respiratory muscles to cope with this load 59 . By contrast, 

pulmonary gas exchange by itself is not a major difficulty 

in patients with COPD 60-62 . Weaning patients from the 

ventilator can be a very difficult and prolonged process 

and the best method remains a matter of debate 63,64 . 

Whether pressure support or a T-piece trial is used, 

weaning is shortened when a clinical protocol is adopted 

(Evidence A). Noninvasive ventilation has been applied 

to facilitate the weaning process in COPD patients with 

acute or chronic respiratory failure 58 . Compared with 

invasive pressure support ventilation, noninvasive 

intermittent positive pressure ventilation (NIPPV) during 

weaning shortened weaning time, reduced the stay in 

the intensive care unit, decreased the incidence of 

nosocomial pneumonia, and improved 60-day survival 

rates. Similar findings have been reported when NIPPV is 

used after extubation for hypercapnic respiratory failure 65 

(Evidence C). 

Other measures. Further treatments that can be used in 

the hospital include: fluid administration (accurate monitoring 

of fluid balance is essential); nutrition (supplementary 

when the patient is too dyspneic to eat); low molecular 

heparin in immobilized, polycythemic, or dehydrated 

patients with or without a history of thromboembolic 

disease; and sputum clearance (by stimulating coughing 

and low-volume forced expirations as in home management). 

Manual or mechanical chest percussion and 

postural drainage may be beneficial in patients producing 

> 25 ml sputum per day or with lobar atelectasis. 

Hospital Discharge and Follow-Up 

Insufficient clinical data exist to establish the optimal 

duration of hospitalization in individual patients 

developing an exacerbation of COPD 1,66,67 . Consensus 

and limited data support the discharge criteria listed in 

Figure 5-4-9. Figure 5-4-10 provides items to include in 

a follow-up assessment 4 to 6 weeks after discharge from 

the hospital. Thereafter, follow-up is the same as for 

stable COPD, including supervising smoking cessation, 

monitoring the effectiveness of each drug treatment, and 

monitoring changes in spirometric parameters 39 . Home 

visits by a community nurse may permit earlier discharge 

of patients hospitalized with an exacerbation of COPD, 

without increasing readmission rate 29,68-70 . Early outpatient 

pulmonary rehabilitation after hospitalization for COPD 

exacerbation results in exercise capacity and health 

status improvements at three months 75 . 

If hypoxemia developed during the exacerbation, arterial 

blood gases should be rechecked at discharge and at 

the follow-up visit. If the patient remains hypoxemic, 

long-term oxygen therapy should be instituted. Decisions 

about suitability for continuous domiciliary oxygen based 

on the severity of the acute hypoxemia during an 

exacerbation are frequently misleading. 

The opportunities for prevention of future exacerbations 

should be reviewed before discharge, with particular 

Figure 5-4-9. Discharge Criteria for 

Patients with Exacerbations of COPD 

• Inhaled ß 2 -agonist therapy is required no more 

frequently than every 4 hrs. 

• Patient, if previously ambulatory, is able to walk 

across room. 

• Patient is able to eat and sleep without frequent 

awakening by dyspnea. 

• Patient has been clinically stable for 12-24 hrs. 

• Arterial blood gases have been stable for 12-24 hrs. 

• Patient (or home caregiver) fully understands correct 

use of medications. 

• Follow-up and home care arrangements have been 

completed (e.g., visiting nurse, oxygen delivery, meal 

provisions). 

• Patient, family, and physician are confident patient 

can manage successfully. 



Figure 5-4-10. Follow-Up Assessment 4-6 Weeks 

After Discharge from Hospital for 

Exacerbations of COPD 

• Ability to cope in usual environment. 

• Measurement of FEV 1 . 

• Reassessment of inhaler technique. 

• Understanding of recommended treatment regimen. 

• Need for long-term oxygen therapy and/or home 

nebulizer (for patients with very severe COPD). 

attention to future influenza vaccination plans, knowledge 

about current therapy including inhaler technique 71,72 , and 

how to recognize symptoms of exacerbations. 

Pharmacotherapy known to reduce the number of 

exacerbations should be considered. Social problems 

should be discussed and principal caregivers identified if 

the patient has a significant persisting disability. 

Antibiotics 

Randomised placebo controlled studies of antibiotic 

treatment in exacerbations of COPD have demonstrated 

a small beneficial effect of antibiotics on lung function 76 , 

and one randomised controlled trial has provided evidence 

for a significant beneficial effect of antibiotics in COPD 

patients who presented with an increase in all three of the 

following cardinal symptoms: dyspnea, sputum volume, 

sputum purulence 77 . There was also some benefit in 

those patients with an increase in only two of these cardinal 

symptoms. 

A study on non-hospitalized patients with exacerbations 

of COPD showed a relationship between the purulence of 

the sputum and the presence of bacteria 78 , suggesting 

that these patients should be treated with antibiotics if 

they also have at least one of the other two cardinal 

symptoms (dyspnea or sputum volume). However, 

these criteria for exacerbations of COPD have not been 

validated in other studies. A study in COPD patients 

with exacerbations requiring mechanical ventilation 

(invasive and non-invasive) indicated that not giving 

antibiotics was associated with increased mortality and 

a greater incidence of secondary intra-hospital pneumonia 79 . 

• Patients with exacerbations of COPD with two of the 

cardinal symptoms, if increased purulence of sputum 

is one of the two symptoms. (Evidence C) 

• Patients with a severe exacerbation of COPD that 

requires invasive mechanical ventilation (invasive and 

non-invasive). (Evidence B) 

The predominant bacterial organisms recovered in the 

lower airways of patients with mild exacerbations are 

H. influenzae, S. pneumoniae and M. catarrhalis 11,80 . 

In contrast, studies in patients requiring mechanical 

ventilation with severe underlying COPD 81,82 have shown 

that other microorganisms, such as enteric gram negative 

bacilli and P. aeruginosa may be more frequent. Other 

studies have shown that the severity of the COPD is an 

important determinant of the type of microorganism 83,84 . 

In patients with mild COPD, S. pneumoniae is predominant. 

When the FEV 1 is lower, H. influenzae and M. catarrhalis 

are more frequent and P. aeruginosa may appear in 

patients with a more severe degree of airways obstruction 

(Figure 5-4-11). The risk factors for P. aeruginosa infection 

are recent hospitalisation, frequent administration of antibiotics 

(4 courses in the last year, very severe COPD (Stage IV), 

and isolation of P. aeruginosa during a previous 

exacerbation or colonization during a stable period 83,84 . 

There is no clear information about when to use oral or 

intravenous route of administration in hospitalized 

patients. The route of administration depends on the 

ability of the patient to eat, and the pharmacokinetics of 

the antibiotic. The oral route is preferred. Otherwise, 

the IV route has to be used, switching to oral when there 

is clinical stabilization. Antibiotic treatment in patients 

with exacerbations of COPD should be maintained for 3 

to 10 days. Figure 5-4-12 provides recommended 

antibiotic treatment in exacerbations of COPD. 

Ten to thirty percent of COPD exacerbated patients do 

not respond to empiric antimicrobial treatment 80 . In such 

cases the patient should be re-evaluated for complications 

that can aggravate symptoms and mimic exacerbations 

(e.g., cardiac failure, pulmonary embolism, non-compliance 

with prescribed medications); microbiological reassessment 

of these patients is recommended. 

Based on the current available evidence, antibiotics 

should be given to: 

• Patients with exacerbations of COPD with three of 

the following cardinal symptoms: increased dyspnea, 

increased sputum volume, increased sputum purulence. 

(Evidence B) 



Figure 5-4-11: Stratification of patients with COPD exacerbated for antibiotic 

treatment and potential microorganisms involved in each group 

Group a Definition b Microorganisms 

Group A: Patients not requiring 

hospitalization (Stage I: Mild COPD) 

Mild exacerbation 

H. influenzae 

S. pneumoniae 

M. catarrhalis 

Chlamydia pneumoniae c 

Viruses 

Group B: Patients admitted to hospital 

(Stages II-IV: Moderate to Very Severe 

COPD) 

Group C: Patients admitted to hospital 

(Stages II-IV: Moderate to Very Severe 

COPD) 

Moderate-severe exacerbation without 

risk factors for P. aeruginosa infection 

Moderate-severe exacerbation with risk 

factors for P. aeruginosa infection 

Group A plus: 

Enterobacteriaceae (K.pneumoniae, 

E. coli, Proteus, Enterobacter, etc) 

Group B plus: 

P. aeruginosa 

a. In some settings, patients with moderate to severe exacerbations may be treated as outpatients. In this case, patients may best be stratified into 

two groups: an uncomplicated group without any risk factors and a complicated group that has one or more ‘risk factors’ (co-morbidity, severe COPD, 

frequent exacerbations, antimicrobial use within last 3 months). The uncomplicated group: use Group A recommendations Figure 5-4-12. 

Complicated group: use Group B or C recommendations (oral therapy) Figure 5-4-12 217-19 . 

b. Severity refers to the exacerbation, though this is intertwined with the severity of the underlying COPD. 

c. Chlamydia pneumonia (or Chlamidophila pneumoniae) has not been confirmed as a cause of exacerbations in some areas (e.g., UK). 

Group A 

Group B 

Group C 

Oral Treatment 

(No particular order) 

Figure 5-4-12: Antibiotic treatment in exacerbations of COPD a,b 

Patients with only one cardinal symptom 

should not receive antibiotics 

If indication then: 

• ß-lactam (Ampicillin/Amoxicillin c ) 

• Tetracycline 

• Trimethoprim/Sulfamethoxazole 

• ß-lactam/b-lactamase inhibitor 

(Co-amoxiclav) 

• Fluoroquinolones (Ciprofloxacin, 

Levofloxacin - high dose e ) 

Alternative 


• ß-lactam/ß-lactamase inhibitor 

(Co-amoxiclav) 

• Macrolides (Azithromycin, 

Clarithromycin, Roxithromycin d ) 

• Cephalosporins - 2nd or 3rd generation 

• Ketolides (Telithromycin) 

• Fluoroquinolones d (Gatifloxacin, 

Gemifloxacin, Levofloxacin, 

Moxifloxacin) 

Parental Treatment 


• ß-lactam/b-lactamase inhibitor 

(Co-amoxiclav, ampicillin/sulbactam) 

• Cephalosporins - 2nd or 

3rd generation 

• Fluoroquinolones d (Gatifloxacin, 

Levofloxacin, Moxifloxacin) 

• Fluoroquinolones (Ciprofloxacin, 

Levofloxacin - high dose e ) or 

• ß-lactam with P.aeruginosa activity 

a. All patients with symptoms of a COPD exacerbation should be treated with additional bronchodilators ± glucocorticosteroids. 

b. Classes of antibiotics are provided (with specific agents in parentheses). In countries with high incidence of S. pneumoniae resistant to penicillin, 

high dosages of Amoxicillin or Co-Amoxiclav are recommended. (See Table 1 for definition of Groups A, B, C.) 

c. This antibiotic is not appropriate in areas where there is increased prevalence of ß-lactamase producing H. influenzae and M. catarrhalis and/or of 

S. pneumoniae resistant to penicillin. 

d. Not available in all areas of the world. 

e. Dose 750 mgs effective against P. aeruginosa. 



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98 FUTURE RESEARCH


CHAPTER 

6 

FUTURE 

RESEARCH


CHAPTER 6: FUTURE RESEARCH 

A better understanding of the molecular and cellular 

pathogenic mechanisms of COPD should lead to many 

new directions for both basic and clinical investigations. 

Improved methods of early detection, new approaches for 

interventions through targeted pharmacotherapy, possible 

means to identify the “susceptible” smoker, and more 

effective means of managing exacerbations are needed. 

Some research recommendations and future program 

goals are provided to stimulate the efforts of investigators 

around the world. There are many additional avenues to 

explore. 

❥ Until there is a better understanding of the causal 

mechanisms of COPD, an absolutely rigid definition of 

COPD, and its relationship to other obstructive airways 

diseases, will remain controversial. The defining 

characteristics of COPD should be better identified. 

❥ The stages and natural history of COPD vary from one 

patient to another. The clinical utility of the four-stage 

classification of severity used in the GOLD Report needs 

to be evaluated. 

❥ Surrogate markers of inflammation, possibly derived 

from the analysis of sputum (cells, mediators, enzymes) 

or exhaled condensates (lipid mediators, reactive oxygen 

species, cytokines), that may predict the clinical usefulness 

of new management and prevention strategies for COPD 

need to be developed. 

❥ Longitudinal studies demonstrating the course of 

COPD are needed in a variety of populations exposed to 

various risk factors. Such studies would provide insight 

into the pathogenesis of COPD, identify additional genetic 

bases for COPD, and identify how genetic risk factors 

interact with environmental risk factors in specific patient 

populations. Factors that determine why some, but not 

all, smokers develop COPD need to be identified. 

❥ Data are needed on the use, cost, and relative distribution 

of medical and non-medical resources for COPD, especially 

in countries where smoking and other risk factors are 

prevalent. These data are likely to have some impact 

on health policy and resource allocation decisions. As 

options for treating COPD grow, more research will be 

needed to help guide health care workers and health 

budget managers regarding the most efficient and effective 

ways of managing this disease. Methods and strategies 

for implementation of COPD management programs in 

developing countries will require special attention. 

❥ While spirometry is recommended to assess and 

monitor COPD, other measures need to be developed 

and evaluated in clinical practice. Reproducible and 

inexpensive exercise-testing methodologies (e.g., stairclimbing 

tests) suitable for use in developing countries 

need to be evaluated and their use encouraged. 

Spirometers need to be developed that can ensure e 

conomical and accurate performance when a relatively 

untrained operator administers the test. 

❥ Information is needed about the cellular and molecular 

mechanisms involved in inflammation in stable COPD 

and exacerbations. Inflammatory responses in nonsmokers, 

ex-smokers, and smokers with and without COPD should 

be compared. The mechanisms responsible for the 

persistence of the inflammatory response in COPD should 

be investigated. Why inflammation in COPD is poorly 

responsive to glucocorticosteroids and what treatments 

other than glucocorticosteroids are effective in suppressing 

inflammation in COPD are research topics that could lead 

to new treatment modalities. 

❥ Standardized methods for tracking trends in COPD 

prevalence, morbidity, and mortality over time need to be 

developed so that countries can plan for future increases 

in the need for health care services in view of predicted 

increases in COPD. This need is especially urgent in 

developing countries with limited health care resources. 

❥ Since COPD is not fully reversible (with current 

therapies) and slowly progressive, it will become ever 

more important to identify early cases as more effective 

therapies emerge. Consensus on standard methods for 

detection and definition of early disease need to be 

developed. Data to show whether or not screening is 

effective in directing management decisions in COPD 

outcomes are required. 

❥ Primary prevention of COPD is one of the major 

objectives of GOLD. Investigations into the most costeffective 

ways to reduce the prevalence of tobacco smoking 

in the general population and more specifically in young 

people are very much needed. Strategies to prevent people 

from starting to smoke and methods for smoking cessation 

require constant evaluation and improvement. Research 

is required to gauge the impact and reduce the risk from 

increasing air pollution, urbanization, recurrent childhood 

100 FUTURE RESEARCH


infections, occupational exposures, and use of local 

cigarette equivalents. Programs designed to reduce 

exposure to biomass fuel in countries where this is used 

for cooking and domestic heating should be explored in an 

effort to reduce exposure and improve ventilation in homes. 

❥ The specific components of effective education for 

COPD patients need to be determined. It is not known, 

for example, whether COPD patients should be given an 

individual management plan, or whether these plans are 

effective in reducing health care costs or improving the 

outcomes of exacerbations. Developing and evaluating 

effective tools for physician education concerning prevention, 

diagnosis, and management of COPD will be important in 

view of the increasing public health problem presented by 

COPD. 

❥ Studies are needed to determine whether education is 

an essential component of pulmonary rehabilitation. The 

cost effectiveness of rehabilitation programs has not been 

assessed and there is a need to assess the feasibility, 

resource utilization, and health outcomes of rehabilitation 

programs that are delivered outside the major teaching 

hospital setting. Criteria for selecting individuals for 

rehabilitation should be evaluated, along with methods to 

modify programs to suit the needs of individual patients. 

❥ Collecting and evaluating data to classify COPD 

exacerbations by severity would stimulate standardization 

of this outcome measure that is so frequently used in 

clinical trials. Further exploration of the ethical principles 

of life support and greater insight into the behavioral 

influences that inhibit discussion of such intangible issues 

are needed, along with studies to define the needs of 

end-stage COPD patients. 

❥ There is a pressing need to develop drugs that control 

symptoms and prevent the progression of COPD. Some 

progress has been made and there are several classes of 

drugs that are now in preclinical and clinical development 

for use in COPD patients. 

Bronchodilators: Bronchodilators are the mainstay of 

symptomatic therapy and new short-acting and long-acting 

bronchodilators are anticipated. With the recognition that 

there are different subtypes of muscarinic receptors, 

there has been a search for more selective antagonists. 

Tiotropium bromide, a new drug in advanced clinical trials, 

is a quaternary ammonium compound like ipratropium 

bromide, but with the unique property of kinetic selectivity 

and very long duration of action. Selective phosphodiesterase 

type IV inhibitors might combine bronchodilator 

and anti-inflammatory activity. 

Mediator antagonists: Attention has largely focused 

on mediators involved in recruitment and activation of 

neutrophils, and reactive oxygen species. In this category 

are the LTB4 antagonists, lipoxygenase inhibitors, 

chemokine inhibitors, and TNF- inhibitors. 

Antioxidants: Oxidative stress is increased in patients 

with COPD, particularly during exacerbations. Oxidants 

are present in cigarette smoke and are produced 

endogenously by activated inflammatory cells, including 

neutrophils and alveolar macrophages, suggesting that 

antioxidants may be of use in therapy for COPD. 

Anti-inflammatory drugs: The limited value of glucocorticosteroids 

in reducing inflammation in COPD suggests 

that novel types of nonsteroidal anti-inflammatory treatment 

may be needed. There are several new approaches to 

anti-inflammatory treatment in COPD including, for example, 

phosphodiesterase inhibitors, transcription factor NF-B 

inhibitors, and adhesion molecule blockers. 

Proteinase inhibitors: There is compelling evidence 

that an imbalance between proteinases that digest elastin 

(and other structural proteins) and antiproteinases that 

protect against this digestion exists in COPD. 

Considerable progress has been made in identifying the 

enzymes involved in elastolytic activity in emphysema 

and in characterizing the endogenous antiproteinases 

that counteract this activity, including neutrophil elastase 

inhibitors, cathepsin G and proteinase 3 inhibitors, and 

matrix metalloproteinase inhibitors. Other serine proteinase 

inhibitors (serpins), such as elafin, may also be 

important in counteracting elastolytic activity in the lung. 

Mucoregulators: It may be important to develop drugs 

that inhibit the hypersecretion of mucus, without 

suppressing the normal secretion of mucus or impairing 

mucociliary clearance. There are several types of 

mucoregulatory drugs in development including tachykinin 

antagonists, sensory neuropeptide inhibitors, mediator 

and enzyme inhibitors, mucin gene suppressors, mucolytic 

agents, macrolide antibiotics, and purinoceptor blockers. 

Alveolar repair: A major mechanism of airway obstruction 

in COPD is loss of elastic recoil due to proteolytic 

destruction of the lung parenchyma. Thus, it seems 

unlikely that this obstruction can be reversed by drug 

therapy, although it might be possible to reduce the rate 

of progression by preventing the inflammatory and 

enzymatic disease processes. It is even possible that 

drugs might be developed to stimulate regrowth of alveoli. 

Retinoic acid increases the number of alveoli in rats and, 

remarkably, reverses the histological and physiological 

FUTURE RESEARCH 101


changes induced by elastase treatment. The molecular 

mechanisms involved and whether this can be extrapolated 

to humans are not yet known. Several retinoic acid 

receptor subtype agonists have now been developed that 

may have a greater selectivity for this effect. Hepatocyte 

growth factor (HGF) has a major effect on the growth of 

alveoli in the fetal lung, and it is possible that in the future 

drugs might be developed that switch on responsiveness 

to HGF in adult lung or mimic the action of HGF. 

Route of delivery: Many inhalers that deliver bronchodilators 

have been optimized to deliver drugs to the 

respiratory tract in asthma. Methods to quickly and safely 

deliver medications to target sites of inflammation and 

tissue destruction in COPD need to be evaluated. 

102 FUTURE RESEARCH


Note: This segment on Outcomes and Markers in COPD is presented by the GOLD Science 

Committee as an Abstract to the GOLD Workshop Report (updated 2005) as a “work in 

progress.” Comments may be sent to the GOLD Science Committee (shurd@prodigy.net). 

The GOLD Science Committee intends to include segments from this document in the full 

revision of the report, scheduled to appear in mid-2006. 

OUTCOMES AND MARKERS IN COPD 

TABLE OF CONTENTS 

PARTICIPANTS ................................................................................................................................................................. 2 

PREFACE.......................................................................................................................................................................... 3 

I. INTRODUCTION......................................................................................................................................................... 4 

II. TERMINOLOGY AND DEFINITIONS .......................................................................................................................... 4 

A. Clinical outcome.................................................................................................................................................. 4 

B Marker................................................................................................................................................................. 4 

C. Relationship between markers and outcomes.................................................................................................... 5 

D. Clinical outcomes, markers and modifiers in COPD........................................................................................... 6 

E Worked example ................................................................................................................................................. 6 

III. CLINICAL OUTCOMES ............................................................................................................................................... 6 

A. Mortality ............................................................................................................................................................. 6 

B. Symptoms and quality of life.............................................................................................................................. 7 

C. Exercise tolerance ............................................................................................................................................. 7 

D. Exacerbations and acute respiratory failure ...................................................................................................... 7 

E. Weight loss......................................................................................................................................................... 7 

F. Use of health care and non-health care resources ............................................................................................ 8 

IV. MARKERS.................................................................................................................................................................... 8 

A. Mortality .............................................................................................................................................................. 8 

B. Symptoms and health status............................................................................................................................... 8 

C. Exacerbations and acute respiratory failure ....................................................................................................... 9 

D. Lung function....................................................................................................................................................... 9 

E. Exercise capacity ................................................................................................................................................ 10 

F. Weight Loss ......................................................................................................................................................... 10 

G. Imaging ............................................................................................................................................................... 10 

H. Resource utilization............................................................................................................................................. 11 

I. Biomarkers .......................................................................................................................................................... 11 

J. Composite markers.............................................................................................................................................. 11 

V. SUMMARY AND CONCLUSIONS ............................................................................................................................... 11 

TABLE 1. PROPERTIES OF THE IDEAL MARKER ......................................................................................................... 12 

TABLE 2. OUTCOME MEASURES FOR COPD............................................................................................................... 13 

TABLE 3. MARKERS FOR STABLE COPD ...................................................................................................................... 14 

TABLE 4: MARKERS FOR EXACERBATIONS OF COPD .............................................................................................. 15 

REFERENCES.................................................................................................................................................................. 15 

OUTCOME AND MARKERS 103



PARTICIPANTS 

EXECUTIVE COMMITTEE: L. Fabbri, Chair: A. Agusti, S. Buist, P. Calverley, S. Hurd, C. Jenkins, P. Jones, K. Rabe, 

R. Rodriguez-Roisin 

WORKING GROUPS: Provided materials to develop the report and invited to participate 

in review. 

A. Mortality: B. Celli, Chair, Boston, Massachusetts, US 

J. Vestbo, Hvidore, Denmark 

E. Wouters, Maastricht, The Netherlands 

T. Oga, Kyoto, Japan 

B. Exacerbation, respiratory failure: C. Jenkins, Chair, NSW Australia 

R. Rodriguez Roisin, Barcelona, Spain 

S. Sethi, Buffalo, New York, US 

J. A. Wedzicha, London, UK 

A. Rossi, Verona, Italy 

C. Symptoms, quality of life: S. Rennard, Chair, Omaha, Nebraska, US 

H. Schunemann, Buffalo, New York, US 

P. Jones, Tonbridge, Kent, UK 

D. Lung Function: L. Fabbri, Chair, Modena, Italy 

A. S. Buist, Portland, Oregon, US 

P. Sterk, Leiden, The Netherlands 

E. Exercise: P. Calverley, Chair, Liverpool, UK 

K. Nishimura, Kyoto, Japan 

Jose Albert Jardim, Sao Paulo, Brazil 

F. Imaging: K. Rabe, Chair, Leiden, The Netherlands 

G. Biomarkers: S. Rennard, Chair, Omaha, Nebraska, US 

A. G. Agusti, Palma de Mallorca, Spain 

H. Health Care Utilization: S. Sullivan, Seattle, Washington, US 

GOLD NATIONAL LEADERS: Invited to participate in review. 

104 OUTCOME AND MARKERS



PREFACE 

The lack of generally accepted outcome measures in 

COPD (other than FEV1) that can be used as criteria 

for the evaluation of novel treatments and for approval 

of new medications greatly hinders research and clinical 

practice. This problem has been long recognized by 

research scientists, clinical investigators, industry 

representatives, and regulatory authorities worldwide. 

recommendations are expected to be incorporated into the 

management section of the revised GOLD guidelines that 

will be available by the end of 2006. 


Chair, GOLD Executive Committee 

July 31, 2005 

In 2001, the Global Initiative for Chronic Obstructive Lung 

Disease (GOLD) developed, and widely distributed, 

evidence-based guidelines for COPD therapy titled Global 

Strategy for Diagnosis, Management and Prevention of 

COPD 1 . These guidelines have been updated each year 

2 to assure that recommendations for COPD treatment 

and management are based on current published literature. 

In 2004, under the leadership of Professor Romain 

Pauwels, GOLD convened an expert panel to review data 

on outcome measures and to identify those that could be 

used to evaluate management of COPD as described in 

the GOLD guidelines. The panel was also asked to 

provide guidance about additional research that may be 

needed to confirm the validity of the use of other 

outcome measures. 

With the GOLD guidelines as the foundation of this 

project, and the consultation and support of respected 

experts from several regions of the world, we hope that 

the recommendations provided in this report will stimulate 

discussion in the scientific community as well as additional 

research to fill the several gaps in knowledge. We strongly 

believe that the process initiated by this “working” document 

will eventually benefit clinical practice, clinical research 

concerning new COPD medications, regulatory decision 

making, and patient welfare. 

We are indebted to Dr. Romain Pauwels for initiation of 

this project. His untimely death occurred before he could 

have significant input into this report. We are grateful for 

the expert consultation provided in particular by Dr. Paul 

Jones and Dr. Alvar Agusti who, along with other 

colleagues on the panel, provided the recommendations 

to the GOLD Executive Committee. During the 12-month 

period beginning July 1, 2005, this report will be included 

as an Appendix to the 2005 update of the Global 

Strategy for Diagnosis, Management and Prevention of 

COPD and posted on the GOLD website: 

http://www.goldcopd.org for comments. The final 



I. INTRODUCTION 

Patients with COPD are heterogeneous in terms of their 

clinical presentation, co-morbidities, underlying lung 

pathology, disease severity, and rate of disease progression. 

Thus it is highly unlikely that a single measure can 

accurately assess the severity of COPD, predict patient 

prognosis, and evaluate the effectiveness of therapy, 

thereby measuring all the dimensions of the disease 3 . 

Yet traditionally, the forced expiratory volume in one 

second (FEV 1 ) has been used extensively as a global 

measurement for COPD. While the long term excessive 

decline of FEV 1 is the pathognomonic abnormality of 

COPD and may indeed relate to mortality, FEV 1 varies 

little over short periods of time, even during exacerbations, 

and it relates weakly to other clinical manifestations such 

as quality of life or exercise tolerance. It is clear, therefore, 

that other measures (besides FEV 1 ) need to be identified 

and validated to allow a more complete and clinically 

relevant assessment of patients with COPD 3 . 

The terms “clinical outcome” and “marker” have been 

increasingly used over the past few years in relation to 

COPD, yet considerable confusion and misuse of these 

terms exists. The goals of this document are to: 

• clarify the meaning of the terms “clinical outcome” and 

“marker” and suggest how these terms can contribute 

to COPD management described in GOLD 1 ; 

• review the available evidence supporting the use of 

different clinical outcomes/markers in the overall 

assessment of a treatment or intervention in COPD 

patients; 

• identify existing gaps of knowledge where further 

research is required. 

II. TERMINOLOGY AND DEFINITIONS 

A. Clinical Outcome 

A clinical outcome is a consequence of COPD 

experienced by the patient (symptoms, weight loss, 

exorcise intolerance, exacerbations, health care 

resource use, mortality). 

The meaning of the term “outcome” varies depending 

on the context. For instance, in clinical trials, the term 

“outcome variable” refers to the main variable of interest, 

irrespective of its nature or type (e.g., FEV 1 , FEV 1 

decline, exacerbations). In this document, “outcome” will 

be used in the context of the clinical assessment of 

COPD. 

B. Marker 

A marker is a measurement associated with one or 

more clinical outcomes. 

The term “marker” is used in a number of contexts: 

• Diagnostic marker - used as a dichotomous variable 

- present or absent. It may not be measured on a 

dichotomous scale, but is assigned to one of two 

states, based on ranges defined from experience; 

e.g., alpha 1 -antitrypsin level, or FEV 1 when used for 

COPD diagnosis. 

• Marker of disease severity - describes different 

levels of disease severity by categorizing levels of 

the marker into predefined ranges, e.g., Body Mass 

Index (BMI), or FEV 1 as used in GOLD staging. 

• Marker of disease progression - used to assess 

the course of the disease (e.g., rate of decline in 

FEV 1 or rate of deterioration in health status). 

• Marker of treatment effect - used to measure 

response to treatment (e.g., dyspnea score, lean 

body mass, exercise capacity, health status, FEV 1 , 

etc.). In clinical trials these markers are usually 

termed ‘outcome variables’. 

• Biomarker – a measurement of chemical or biological 

material that reflects a disease process, e.g. a biomarker 

for inflammation. 

• Surrogate marker – applies when one marker is 

used as a substitute for the marker of primary interest, 

e.g., High resolution computed tomography (HRCT) 

scan densitometry measurement as a surrogate 

marker for the presence of emphysema. 

Regardless of these different uses, the ideal marker 

should have the properties shown in Table 1. 

C. Relationship between markers and outcomes 

The relationship between markers and outcomes is not 

straightforward. The following factors need to be 

considered: 

• A clinical outcome may have multiple markers (e.g., 

BMI, FEV 1 and exercise capacity are all independent 

predictors of mortality). 



• The relationship between a marker and a clinical 

outcome may be altered by modifiers that are not 

directly related to the disease but may have a 

significant impact on its clinical outcomes. Modifiers 

in COPD include co-morbidity, level of social support, 

and ease of access to the health care system. 

• A small number of markers may be so well 

characterized and understood that they can substitute 

effectively for a clinical outcome and become an 

outcome of treatment in itself. For instance, in the 

treatment of cardiovascular disease a reduction in 

blood pressure (a marker) has become an accepted 

clinical outcome since it is known to reduce the 

probability of cardiovascular morbidity and mortality. 

• Occasionally a marker may be used both as a marker 

of disease severity and as a clinically relevant 

outcome in itself. One example, weight loss, is 

particularly prevalent among patients with severe 

COP 4 , but influences prognosis independently of the 

level of lung function impairment 5,6 . Thus, it is both 

an outcome that affects the patient (e.g., in terms 

of body image) and a marker of underlying disease 

activity. 

D. Clinical outcomes, markers and modifiers in COPD 

Tables 2-4 summarize currently accepted clinical outcomes, 

markers, and modifiers in COPD, and the potential use of 

different markers in patients with stable and exacerbated 

COPD. Once appropriately validated, some current 

markers (e.g., HRCT) may become clinical outcomes in 

themselves (as in the example of blood pressure cited 

above). 

While clinical trials in patients with COPD have mainly 

focused on changes in lung function as a marker of 

treatment effect and/or disease progression, the 

importance of measuring clinical outcomes such as 

symptoms, exacerbations, and health-related quality of 

life (and their associated markers) is gaining increasing 

recognition because these outcomes are important to 

patients. Lung function is only weakly related to these 

outcomes (i.e., it is a poor surrogate marker). 

E. Worked example 

A simple worked example of clinical outcomes, markers, 

surrogate markers, and modifiers: 

• Clinical outcome: exercise tolerance 

• Marker: exercise capacity measured in laboratory 

• Surrogate marker for exercise capacity: FEV 1 

• Modifier: co-morbidity (e.g., heart failure) 

The correlation between exercise capacity and FEV 1 is 

not always strong. This is often the case with surrogate 

markers, and, as a general rule, they should be used only 

when it is not possible to use the relevant marker. In a 

clinical trial, exercise capacity may be used as the primary 

outcome variable, because it is a valid marker of exercise 

tolerance (the clinical outcome of interest in this example). 

III. CLINICAL OUTCOMES 

A. Mortality 

Mortality as a clinical outcome for COPD can be measured, 

is meaningful, and is obviously clinically relevant to the 

disease process, in particular to the end-stage disease 7 . 

A drawback to using mortality as an outcome in COPD is 

that it is often not listed on the death certificate, or may 

only be listed as a contributory cause of death. However, 

in clinical studies, particularly those in which participants 

are followed over time and in which there is supporting 

clinical information about markers of disease severity, 

mortality provides a very important clinical outcome 

measure. In studies that use COPD mortality as a clinical 

outcome, an adequate adjudication process for all deaths 

must be followed so that COPD (as either a primary or a 

contributory cause of death) is coded as accurately as 

possible 8 . 

B. Symptoms and quality of life 

The most frequent symptoms in COPD patients are 

dyspnea, cough, sputum production, and fatigue. 

Although fatigue is poorly specific for COPD, it has a 

very high prevalence but is rarely reported spontaneously 

by COPD patients 9 . Symptoms contribute significantly 

to other relevant clinical outcomes such as disability, 

restriction of normal daily activities, and emotional and 

social disturbances. In turn, symptoms impair quality of 

life, although the impact will be unique to each patient. 

C. Exercise tolerance 

The ability to exercise is significantly impaired in many 

COPD patients and is an important determinant of 

health-related quality of life 10,11 . as it impairs the ability to 

carry out daily activities. The ability of exercise to provoke 

breathlessness is used in the Medical Research Council 

(MRC) dyspnea scale to estimate symptom intensity 12 . 

It is difficult to make reliable measurements of a patient’s 

daily activity, so physiological measurements in the 



exercise laboratory are used as markers of impaired 

activity. Exercise capacity is not only a marker of exercise 

tolerance, but also an important predictor of mortality 13,14 . 

D. Exacerbations and acute respiratory failure 

A COPD exacerbation is a sustained worsening of the 

patient’s condition from the stable state and beyond normal 

day-to-day variation that is acute in onset and may warrant 

additional treatment 15 . Patients with exacerbations of 

COPD typically present with increased breathlessness 

with or without cough, changes in sputum volume and 

purulence, wheezing, and chest tightness. Exacerbations 

are an important clinical outcome of the disease as well 

as an important marker of disease severity. 

Severe exacerbations may be accompanied by acute 

respiratory failure, defined as decreased arterial PO2 

(arterial deoxygenation) with or without increased arterial 

PCO2. Acute respiratory failure is a common clinical 

outcome in severe exacerbations of COPD. Acute 

respiratory failure is perceived by the patient as severe 

dyspnea often associated with agitation, confusion, 

tachycardia and sweating 15 . Mortality ranges between 

11% 16 and 20% 17 in patients needing mechanical ventilation. 

E. Weight loss 

Patients with moderate to severe COPD have a depletion 

of fat-free mass, particularly skeletal muscle, that is 

reflected by weight loss 18,19 . Weight loss is a predictor 

of mortality in patients with COPD, and survival may 

improve with an increase in body-mass index. In addition 

to the relation of low body weight and mortality, weight 

loss is an important determinant of impaired muscle 

strength, exercise capacity, exercise response, and health 

status, as well as increased morbidity (e.g., recurrent 

exacerbations and readmission to hospital) in patients 

with COPD 18,19 . 

F. Use of health care and non-health care resources 

Between 60 and 75 percent of medical expenditures for 

COPD are a direct consequence of exacerbations 20-23 , so 

use of health care resources is an important outcome in 

COPD representing treatment failure and progression of 

disease 24 . In clinical trials, use of emergency treatment, 

alone or in combination with symptom and lung function 

data, is customarily used to characterize an exacerbation 

especially when the primary study outcome is reduction 

in the frequency or time to an exacerbation event. 

Emergency treatment data can be obtained from the 

patient or care-giver, and from clinical or billing records 25 . 

Data on preventive pharmacotherapy, diagnostic 

investigations, and clinical follow-up are required to 

supplement data on emergency treatments in order to 

provide a more comprehensive assessment of health 

resource use and costs. Assessment of patient and 

care-giver travel and waiting time, disability, absence from 

work, and productivity while at work comprise additional 

and important non-health care resource consumption 

measures in COPD 20 . 

IV. MARKERS 

A. Mortality 

To establish a precise cause of death is difficult for chronic 

diseases (including COPD) that often are associated with 

other diseases. While all-cause mortality in COPD can 

be assessed, death caused specifically by COPD heavily 

relies on accuracy of death certificate. Predictors of 

mortality from COPD include lung function (FEV 1 , forced 

vital capacity [FVC], inspiratory capacity/total lung capacity 

[IC/TLC]), blood gases (both PaO2 and PaCO2), respiratory 

symptoms 26 , exercise capacity, BMI 6 , exacerbations and 

combinations 27,28 . Of these, lung function is a marker of 

all-cause mortality and is associated with COPD mortality 

even in the early stages of disease 7 . 

B. Symptoms and health status 

Dyspnea is currently the only COPD symptom that can 

be measured in a standardized manner, through the use 

of Borg or Visual Analogue Scales usually applied during 

laboratory exercise tests. The Borg scale has standardized 

descriptors that allow more direct comparisons between 

studies than Visual Analogue Scale scores. Other 

measures of dyspnea do not assess this symptom directly, 

as they quantify self-reported activity limitation in daily 

life. All dyspnea instruments listed in Table 3 (except the 

Transitional dyspnea index [TDI]) can distinguish between 

different degrees of breathlessness-induced disability, 

although the MRC scale is simplest and most widely 

used. The TDI and University of California San Diego 

(UCSD) instruments can respond to changes with 

treatment but there are currently too few data to make 

an assessment as to whether they can track long-term 

disease progression 29 . 

Health-related quality of life is a clinical outcome of 

COPD that will be unique to each patient, so it cannot 

be quantified in a standardized manner. Instead, health 

status questionnaires are used as markers of the impact 



of the disease on patients’ health, daily life and sense of 

well-being. All three health status questionnaires (chronic 

respiratory questionnaire [CRQ], St. Georges respiratory 

questionnaire [SGRQ], 36 item short form [SF-36]) can 

distinguish between different degrees of severity. The 

disease-specific CRQ and SGRQ are sensitive to 

treatment, but the generic SF-36 is not consistently 

responsive to worthwhile therapeutic effects. The SGRQ 

and SF-36 have been shown to be responsive to longterm 

disease progression, but similar evidence is not 

currently available for the CRQ 30 . 

C Exacerbations and acute respiratory failure 

Exacerbations of COPD are clinical outcomes when 

evaluating the impact of interventions. Exacerbation 

frequency and severity are also used as markers of 

COPD severity, progression, impact on quality of life, 

and mortality 16,31 . Exacerbations are more frequent and 

severe in advanced disease 32 , and exacerbation frequency 

is related to the decline in quality of life experienced 

by the COPD patient 30,33,34 . There are a few clinical 

classifications of exacerbation severity, mostly ranging 

from mild to life-threatening, and based essentially on 

either symptom-driven 35 or event-driven definitions 36 . 

Major difficulties are currently encountered in studies 

that use exacerbations as endpoint primary outcome for 

assessing interventions because of the lack of a widely 

acknowledged definition of COPD exacerbations. In most 

studies, exacerbations have been defined on the basis 

of increase in symptoms, requiring patient perception 

and a reaction to this perception. Both vary significantly 

between patients and may be influenced by a number of 

modifiers, such as access to the health care system, and 

the presence or absence of family or social support. 

Definitions of exacerbations based on the need for therapy 

can be useful indicators of severity, but may also be 

insensitive in some settings given that exacerbation 

therapies vary throughout the world. Patients with COPD 

exacerbations do not always seek medical care and are 

increasingly using self-management strategies that may 

exclude visiting the primary care physician unless critically 

ill. When a hospital admission occurs, objective measures 

of severity may be included. Symptoms, volume and 

color of sputum, use of health resources, lung function, 

and blood gases may be considered the most relevant 

markers of COPD exacerbations (Table 4). Arterial pH 

and blood gases are the only proven markers of acute 

respiratory failure in COPD 37 . Oxygen saturation by pulse 

oximetry can also be used, although less accurately, and 

does not provide information on arterial PCO 2 . 

D. Lung function 

Lung function may act as a marker for clinical outcomes 

such as symptoms, quality of life, exercise tolerance, 

health care utilization, and mortality 1,38 . However, lung 

function measures relate weakly to these clinical 

outcomes 30 . Lung function measures have been used 

extensively for the diagnosis and assessment of severity 

of COPD 1 ; FEV 1 is the most readily available and 

reproducible. Other parameters of lung function add 

little to FEV 1 , being either less reproducible or less 

sensitive 39,40 . Post-bronchodilator FEV 1 and FEV 1 /FVC 

are essential markers for the diagnosis and assessment 

of severity of COPD 1 . Because of its unimodal distribution 

and poor reproducibility, short-term reversibility testing 

to bronchodilator or glucocorticosteroids add little to 

baseline lung function for diagnosis 41,42 , prediction of 

disease progression 15 , or response to treatment 43 . 

Repeated measurements of FEV 1 over a period of time 

have been used to study the natural progression of 

disease 44,45 . Follow-up studies have shown that the annual 

decline in post-bronchodilator FEV 1 may be more 

reproducible than pre-bronchodilator as a parameter of 

lung function to assess progression 45,46 . Additional lung 

function measures such as lung volumes and capacities 

(residual volume [RV], functional residual capacity [FRC], 

inspiratory capacity [IC], and total lung capacity [TLC]), 

carbon monoxide diffusion capacity, and arterial blood 

gases may be helpful to assess severity (e.g., severe 

COPD, exacerbations), and to predict the response to 

specific treatments (e.g., lung volume reduction 

surgery) 19,47 , but have not been shown to add much to 

FEV 1 , being either less reproducible or less sensitive 

E. Exercise capacity 

Exercise capacity is a marker for clinical outcomes such 

as symptoms, quality of life, exercise tolerance, health 

care utilization, and mortality. Exercise capacity can be 

evaluated by making detailed physiological measurements 

in the exercise laboratory (minute ventilation, breathing 

pattern, oxygen consumption, carbon dioxide production, 

oxygen saturation, and oxygen pulse - all during exercise) 

or by using simpler field tests where the duration of 

exercise or the distance covered in a fixed time period is 

recorded (e.g., six-minute walking test). Measures of 

exercise capacity are close to the ideal marker (Table 1), 

as they have good validity, specificity, reliability, 

repeatability 48 , predictive ability 14 , discriminative ability 

and evaluative ability 47 . 



F. Weight loss 

Weight loss is a marker for clinical outcomes such as 

symptoms, quality of life, exercise tolerance, health care 

utilization, and mortality. Serial measurements of body 

weight can disclose progressive involuntary weight loss, 

generally considered to be clinically relevant when it 

exceeds 5% over a month or 10% over 6 months 49 . 

Actual body weight can be related to the ideal bodyweight 

as derived from height, frame size, and gender. 

Nutritional depletion is generally and arbitrarily defined 

as body weight of less than 90% of the ideal 4 . Body 

weight can be corrected for body size by calculation of 

body-mass index; a value lower than 20 kg/m 2 is generally 

taken as abnormal 4,50 . The assessment of nutritional 

status according to body weight provides no qualitative 

information on body tissues. A fat-free-mass index 

(fat-free mass in kg divided by height squared) of less 

than 16 kg/m 2 in men and 15 kg/m 2 in women is taken 

as an indicator of active body-tissue depletion 18,19 . 

G. Imaging 

Chest imaging can provide useful information for diagnosis 

and disease severity 51 . The chest x-ray is seldom 

diagnostic in COPD, but is valuable in the differential 

diagnosis to exclude other diseases. A chest x-ray 

may also be helpful in phenotyping COPD in term of 

bronchiolitis or emphysema 52 . There is no evidence of the 

value of chest x-ray to assess disease progression or 

treatment effect. HRCT scan is progressively replacing 

the regular chest x-ray for differential diagnosis of COPD, 

phenotyping of COPD (bronchiolitis vs. emphysema), and 

assessment of COPD severity. Densitometric analysis of 

a CT-scan or HRCT scan be used to assess the presence 

and severity of emphysema 53 , and thus is potentially useful 

in assessing the progression of the disease, and the effect 

of specific treatments (e.g., retinoids) on progression of 

emphysema 54,55 . 

H. Resource utilization 

The presence and frequency of health care resource 

utilization are good markers of COPD exacerbations, 

disease severity, and progression of disease 22 . In general, 

and for patients with chronic disease specifically, increasing 

age and female gender are positively related to resource 

consumption and costs. The general health status question 

on the SF-36, when adjusted for age and gender, has 

been shown to predict mortality and health care resource 

utilization. 

I. Biomarkers 

COPD is characterized by chronic inflammation 56 . 

Inflammatory cells (e.g., T cells, neutrophils, and 

eosinophils), mediators (e.g., IL-8, TNFa, LTB4, proteases 

and antiproteases, C-reactive protein [CRP]), and 

components of exhaled air or condensate involved in this 

complex inflammatory cascade have been identified as 

potential biomarkers of the disease process, and have 

been examined as markers for diagnosis 57 , assessment of 

severity of stable COPD 58 , diagnosis/assessment of COPD 

exacerbations 59 , and evaluation of the effect of treatment 60,61 . 

However, no single or combination of biomarkers has yet 

been identified that can be reliably used in clinical practice 

in the diagnosis, staging, or monitoring of COPD. 

J. Composite markers 

Because COPD is a multi-system, multi-component 

disease 62 , there has been increased interest in the use 

of composite markers that reflect the overall effect of the 

disease. Two markers in particular may fulfill this function: 

exercise testing, which reflects cardiopulmonary and 

skeletal muscle function, and health status measurements, 

which assess a wide range of symptomatic effects of the 

disease. A composite score derived from four established 

clinical markers - BMI, MRC Dyspnea Grade, FEV 1 and 

6-minute walking distance (all included in Table 3) - has 

been created and validated (the BODE Index: Bodymass 

index (B), the degree of airflow obstruction (O), 

dyspnea (D), exercise capacity (E) 27 ). The components 

of this instrument are all markers of mortality, and this 

instrument validated against mortality proved to be a 

better predictor than FEV 1 alone. 

V. SUMMARY AND CONCLUSIONS 

Based on available evidence, definitions of clinical outcome 

and markers in COPD have been proposed. Most published 

investigations have concentrated on COPD as a respiratory 

disease, and particularly on respiratory symptoms and 

lung function, although more comprehensive approaches 

addressing health-related quality of life and exercise testing 

have recently appeared. The judicious use of many of the 

outcomes and markers described in this report should 

greatly enhance the development of new therapeutic 

strategies that may eventually contribute to improve the 

management of COPD. The increasing evidence that 

COPD is a multi-component, complex disease suggests the 

need for the identification and use of more comprehensive 

clinical outcomes and more accurate markers or biomarkers 

to assess disease severity, prognosis, and response to 

therapy. This should be an important goal for future 

clinical research investigations. 



TABLE 1. PROPERTIES OF THE IDEAL MARKER 

PROPERTY 

Validity 

Specificity 

Reliability 

Repeatability 

Predictive ability 

Discriminative ability 

Evaluative ability 

Simplicity 

Cost-effective 

DEFINITION 

Strong relationship to underlying disease mechanisms and well-being 

Absence of confounding effects of co-morbidities or other factors 

Performs consistently in different settings. 

Measurements do not change in the stable state 

Predicts clinical outcomes 

Identifies differences in severity between patients 

Sensitive to changes within patients. 

Routine or research procedure 

Savings from improved management offset the cost 

TABLE 2. OUTCOME MEASURE FOR COPD 

Outcome Clinical Relevance Markers Modifiers 

Mortality 

End of life 

FEV 1 

BMI 

MRC dyspnea 

Exercise capacity 

BODE 

PaO 2 , PaCO 2 

Exacerbations 

Health status 

Co-morbidity 

Age 

Social/family support 

Access to health care system 

Symptoms 

Quality of Life 

Health status 

Dyspnea 

Health status 

Dyspnea scales 

Co-morbidity 

Exacerbations 

Mortality 

Health status 

Lung function decline 

Weight loss 

Previous frequency 

FEV 1 

PaCO 2 

Bronchial colonization 

Inflammatory markers 

Co-morbidity 

Age 



Exercise Tolerance 

Health status 

Exacerbations 

FEV 1 

PaO 2 

BMI 

Co-morbidity 

Age 

Weight Loss 

Survival 

Exercise tolerance 

Health status 

Exacerbations 

Weight 

PaO 2 ,PaCO 2 

DLCO 

CT-emphysema 

Co-morbidity 

Age 


Health Care Utilization 

Health status 

Economic cost 

FEV 1 

PaO 2 ,PaCO 2 

BMI 

Exercise tolerance 

Health status 

Age 

Co-morbidity 

Active smoking 







FEV 1 [% pred] 

TABLE 4. MARKERS FOR EXACERBATIONS OF COPD 

Markers Diagnosis Assessment of 

Severity 

Assessment of 

Treatment 

Effects 

Predictor 

NO YES ? YES ? YES 

PaO 2 /PaCO 2 /SaO 2 (%) NO YES [?] YES /////////// 

Sputum volume/color YES YES YES /////////// 

Imaging 

Inflammatory markers /////////// /////////// /////////// YES ? 

///////// indicates insufficient evidence 

? (differential 

diagnosis) 

NO NO NO 

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