EPOC, Guia Clínica

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Global Initiative for Chronic
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Obstructive
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GLOBAL STRATEGY FOR THE DIAGNOSIS,
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MANAGEMENT, AND PREVENTION OF
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CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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REVISED 2011
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GLOBAL INITIATIVE FOR
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CHRONIC OBSTRUCTIVE LUNG DISEASE
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GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND
PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
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(REVISED 2011)
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© 2011 Global Initiative for Chronic Obstructive Lung Disease, Inc.
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GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT,
AND PREVENTION OF COPD (REVISED 2011)
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GOLD BOARD OF DIRECTORS GOLD SCIENCE COMMITTEE*
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Roberto Rodriguez-Roisin, MD, Chair Jørgen Vestbo, MD, Chair
Thorax Institute, Hospital Clinic Hvidovre University Hospital, Hvidovre, Denmark
and University of Manchester
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Univ. Barcelona, Barcelona, Spain
Manchester, England, UK
Antonio Anzueto, MD
(Representing American Thoracic Society) Alvar G. Agusti, MD
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University of Texas Health Science Center Thorax Institute, Hospital Clinic
San Antonio, Texas, USA Univ. Barcelona, Ciberes, Barcelona, Spain
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Jean Bourbeau, MD Antonio Anzueto, MD
McGill University Health Centre University of Texas Health Science Center
Montreal, Quebec, Canada San Antonio, Texas, USA
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Teresita S. deGuia, MD Peter J. Barnes, MD
Philippine Heart Center National Heart and Lung Institute
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Quezon City, Philippines London, England, UK
David S.C. Hui, MD Leonardo M. Fabbri, MD
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The Chinese University of Hong Kong University of Modena & Reggio Emilia
Hong Kong, ROC Modena, Italy
Fernando Martinez, MD
University of Michigan School of Medicine
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Paul Jones, MD
St George’s Hospital Medical School
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Ann Arbor, Michigan, USA London, England, UK
Michiaki Mishima, MD Fernando Martinez, MD
(Representing Asian Pacific Society for Respirology) University of Michigan School of Medicine
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Kyoto University, Kyoto, Japan Ann Arbor, Michigan, USA
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Damilya Nugmanova, MD Masaharu Nishimura, MD
(Representing WONCA) Hokkaido University School of Medicine
Kazakhstan Association of Family Physicians Sapporo, Japan
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Almaty, Kazakhstan
Roberto Rodriguez-Roisin, MD
Alejandra Ramirez, MD Thorax Institute, Hospital Clinic
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(Representing Latin American Thoracic Society) Univ. Barcelona, Barcelona, Spain
Instituto Nacional de Enfermedades Respiratorias
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Calzada de Tlalpan, México Donald Sin, MD
St. Paul’s Hospital
Robert Stockley, MD Vancouver, Canada
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University Hospital, Birmingham, UK
Robert Stockley, MD
Jørgen Vestbo, MD University Hospital
Hvidovre University Hospital, Hvidovre, Denmark Birmingham, UK
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and University of Manchester, Manchester, UK
Claus Vogelmeier, MD
GOLD SCIENCE DIRECTOR University of Giessen and Marburg
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Suzanne S. Hurd, PhD Marburg, Germany
Vancouver, Washington, USA
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*Disclosure forms for GOLD Committees are posted on the GOLD Website, www.goldcopd.org
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GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT,
AND PREVENTION OF COPD (REVISED 2011)
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INVITED REVIEWERS David Price, MD
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University of Aberdeen
Joan-Albert Barbera, MD Aberdeen, Scotland, UK
Hospital Clinic, Universitat de Barcelona
Barcelona Spain Nicolas Roche, MD, PhD
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University Paris Descartes
A. Sonia Buist, MD Paris, France
Oregon Health Sciences University
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Portland, OR, USA Sanjay Sethi, MD
State University of New York
Peter Calverley, MD Buffalo, NY, USA
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University Hospital Aintree
Liverpool, England, UK GOLD NATIONAL LEADERS
(Submitting Comments)
Bart Celli, MD
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Brigham and Women’s Hospital Lorenzo Corbetta, MD
Boston, MA, USA University of Florence
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Florence, Italy
M. W. Elliott, MD
St. James’s University Hospital Alexandru Corlateanu, MD, PhD
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Leeds, England, UK State Medical and Pharmaceutical University
Republic of Moldova
Yoshinosuke Fukuchi, MD
Juntendo University
Tokyo, Japan
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Le Thi Tuyet Lan, MD, PhD
University of Pharmacy and Medicine
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Ho Chi Minh City, Vietnam
Masakazu Ichinose, MD
Wakayama Medical University Fernando Lundgren, MD
Kimiidera, Wakayama, Japan Pernambuco, Brazil
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Christine Jenkins, MD E. M. Irusen, MD
Woolcock Institute of Medical Research University of Stellenbosch
Camperdown. NSW, Australia South Africa
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H. A. M. Kerstjens, MD Timothy J. MacDonald, MD
University of Groningen St. Vincent’s University Hospital
Groningen, The Netherlands Dublin, Ireland
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Peter Lange, MD Takahide Nagase, MD
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Hvidovre University Hospital University of Tokyo
Copenhagen, Denmark Tokyo, Japan
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M.Victorina López Varela, MD Ewa Nizankowska-Mogilnicka, MD, PhD
Universidad de la República Jagiellonian University Medical College
Montevideo, Uruguay Krakow, Poland
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Maria Montes de Oca, MD Magvannorov Oyunchimeg, MD
Hospital Universitario de Caracas Ulannbatar, Mongolia
Caracas, Venezuela
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Mostafizur Rahman, MD
Atsushi Nagai, MD NIDCH
Tokyo Women’s Medical University Mohakhali, Dhaka, Bangladesh
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Tokyo, Japan
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Dennis Niewoehner, MD
Veterans Affairs Medical Center
Minneapolis, MN, USA
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PREFACE
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Chronic Obstructive Pulmonary Disease (COPD) remains will continue to work with the GOLD National Leaders and
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a major public health problem. In 2020, COPD is projected other interested health care professionals to bring COPD to
to rank fifth worldwide in burden of disease, according the attention of governments, public health officials, health
to a study published by the World Bank/World Health care workers, and the general public to raise awareness
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Organization. Although COPD has received increasing of the burden of COPD and to develop programs for early
attention from the medical community in recent years, it is detection, prevention and approaches to management.
still relatively unknown or ignored by the public as well as
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public health and government officials. We are most appreciative of the unrestricted educational
grants from Almirall, AstraZeneca, Boehringer Ingelheim,
In 1998, in an effort to bring more attention to the Chiesi, Dey Pharma, Ferrer International, Forest
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management and prevention of COPD, a committed Laboratories, GlaxoSmithKline, Merck Sharp & Dohme,
group of scientists formed the Global Initiative for Chronic Nonin Medical, Novartis, Nycomed, Pearl Therapeutics,
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Obstructive Lung Disease (GOLD). Among the important and Pfizer that enabled development of this report.
objectives of GOLD are to increase awareness of COPD
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and to help the millions of people who suffer from this Roberto Rodriguez Roisin, MD
disease and die prematurely from it or its complications.
In 2001, the GOLD program released a consensus report,
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Global Strategy for the Diagnosis, Management, and
Prevention of COPD; this document was revised in 2006.
This 2011 revision follows the same format as the 2001 and
2006 reports, but reflects the many publications on COPD Chair, GOLD Executive Committee
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that have appeared since 2006. Professor of Medicine
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Hospital Clínic, Universitat de Barcelona
Based on multiple scientific and clinical achievements in Barcelona, Spain
the ten years since the 2001 GOLD report was published,
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this revised edition provides a new paradigm for treatment Jørgen Vestbo, MD
of stable COPD that is based on the best scientific
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evidence available. We would like to acknowledge the
work of the members of the GOLD Science Committee
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who volunteered their time to review the scientific literature
and prepare the recommendations for care of patients with
COPD that are described in this revised report. In the next
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few years, the GOLD Science Committee will continue Chair, GOLD Science Committee
to work to refine this new approach and, as they have Hvidovre University Hospital
done during the past several years, will review published Hvidovre, Denmark (and)
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literature and prepare an annual updated report. The University of Manchester
Manchester, UK
GOLD has been fortunate to have a network of
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international distinguished health professionals from
multiple disciplines. Many of these experts have initiated
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investigations of the causes and prevalence of COPD in
their countries, and have developed innovative approaches
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for the dissemination and implementation of COPD
management guidelines. We particularly appreciate the
work accomplished by the GOLD National Leaders on
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behalf of their patients with COPD. The GOLD initiative
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TABLE OF CONTENTS
Preface.............................................................. .iv
3. Therapeutic Options 19
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Introduction......................................................vii
Key Points 20
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Smoking Cessation 20
1. Definition and Overview 1 Pharmacotherapies for Smoking Cessation 20
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Key Points COPD 2 Pharmacologic Therapy for Stable 21
Definition 2 Overview of the Medications 21
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Burden Of COPD 2 Bronchodilators 21
Prevalence 3 Corticosteroids 24
Morbidity 3 Phosphodiesterase-4 Inhibitors 25
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Mortality 3 Other Pharmacologic Treatments 25
Economic Burden 3 Non-Pharmacologic Therapies 26
Social Burden 4 Rehabilitation 26
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Factors That Influence Disease Components of Pulmonary Rehabilitation
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Development And Progression 4 Programs 27
Genes 4 Other Treatments 28
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Age and Gender 4 Oxygen Therapy 28
Lung Growth and Development 4 Ventilatory Support 28
Exposure to Particles 5 Surgical Treatments T 29
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Socioeconomic Status 5
Asthma/Bronchial Hyperreactivity 5 4. Management of Stable COPD 31
Chronic Bronchitis 5 Key Points 32
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Infections 5 Introduction 32
6 33
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Pathology, Pathogenesis And Pathophysiology Identify And Reduce Exposure to Risk Factors
Pathology 6 Tobacco Smoke 33
Pathogenesis 6 Occupational Exposures 33
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Pathophysiology Pollution 6 Indoor And Outdoor 33
Treatment of Stable COPD 33
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2. Diagnosis and Assessment 9 Moving from Clinical Trials to Recommendations
Key Points 10 for Routine Practice Considerations 33
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Diagnosis 10 Non-Pharmacologic Treatment 34
Symptoms 11 Smoking Cessation 34
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Medical History 12 Physical Activity 34
Physical Examination 12 Rehabilitation 34
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Spirometry 12 Vaccination
Assessment Of Disease 12 Pharmacologic Treatment 35
Assessment of Symptoms 13 Bronchodilators - Recommendations 35
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Spirometric Assessment 13 Corticosteroids and Phosphodiesterase-4
Assessment of Exacerbation Risk 13 Inhibitors - Recommendations 37
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Assessment of Comorbidities 14 Monitoring And Follow-Up 37
15 Monitor Disease Progression and
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Combined COPD Assessment
Additional Investigations 16 Development of Complications 37
Monitor Pharmacotherapy and
Differential Diagnosis 17
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Other Medical Treatment 37
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Monitor Exacerbation History 37
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Monitor Comorbidities 37 Table 2.4. Modified Medical Research Council
Surgery in the COPD Patient 38 Questionnaire for Assessing the Severity of
5. Management of Exacerbations 39 Breathlessness 13
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Key Points 40 Table 2.5. Classification of Severity of Airflow
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Limitation in COPD (Based on Post-Bronchodilator
Definition 40
Diagnosis 40 FEV1) 14
Table 2.6. RISK IN COPD: Placebo-limb data from
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Assessment 41
TORCH, Uplift, and Eclipse 14
Treatment Options 41
Table 2.7. COPD and its Differential Diagnoses 17
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Treatment Setting 41
Table 3.1. Treating Tobacco Use and Dependence:
Pharmacologic Treatment 41 A Clinical Practice Guideline—Major Findings and
Respiratory Support 43 Recommendations 20
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Hospital Discharge and Follow-up 44 Table 3.2. Brief Strategies to Help the Patient Willing
Home Management of Exacerbations 45 to Quit 21
Prevention of COPD Exacerbations 45 Table 3.3. Formulations and Typical Doses of COPD
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Medications 22
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6. COPD and Comorbidities 47 Table 3.4. Bronchodilators in Stable COPD 23
Key Points 48 Table 3.5. Benefits of Pulmonary Rehabilitation in
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Introduction 48 COPD 26
Cardiovascular Disease 48 Table 4.1. Goals for Treatment of Stable COPD 32
Osteoporosis 49 Table 4.2. Model of Symptom/Risk of Evaluation of
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Anxiety and Depression 33
Lung Cancer 50 Table 4.3. Non-pharmacologic Management
Infections 50 of COPD 34
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Metabolic Syndrome and Diabetes 50 Table 4.4. Initial Pharmacologic Management
of COPD 36
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References 51 Table 5.1. Assessment of COPD Exacerbations:
Medical History 41
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Figures Table 5.2. Assessment of COPD Exacerbations:
Figure 1.1. Mechanisms Underlying Airflow Limitation Signs of Severity 41
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in COPD for Hospital 2 Table 5.3. Potential Indications
Figure 2.1A. Spirometry - Normal Trace 13 Assessment or Admission 41
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Figure 2.1B. Spirometry - Obstructive Disease 13 Table 5.4. Management of Severe but Not
Figure 2.2. Relationship Between Health-Related Life-Threatening Exacerbations 42
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Quality of Life, Post-Bronchodilator FEV1 and Table 5.5. Therapeutic Components of Hospital
GOLD Spirometric Classification 14 Management 42
Figure 2.3. Association Between Symptoms, Table 5.6. Indications for ICU Admission 43
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Spirometric Classification and Future Risk of Table 5.7. Indications for Noninvasive Mechanical
Exacerbations 15 Ventilation 43
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Table 5.8. Indications for Invasive Mechanical
Tables Ventilation 43
Table A. Description of Levels of Evidence ix 44
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Table 5.9. Discharge Criteria
Table 2.1. Key Indicators for Considering Table 5.10. Checklist of items to assess at time of
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a Diagnosis of COPD 10 Discharge from Hospital 44
Table 2.2. Causes of Chronic Cough 11 Table 5.11. Items to Assess at Follow-Up Visit 4-6
Table 2.3. Considerations in Performing Weeks After Discharge from Hospital 44
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Spirometry 12
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GLOBAL STRATEGY FOR THE DIAGNOSIS,
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MANAGEMENT, AND PREVENTION OF COPD
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to the construction of a new approach to management– one
INTRODUCTION that matches assessment to treatment objectives. The new
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management approach can be used in any clinical setting
Much has changed in the 10 years since the first GOLD
anywhere in the world and moves COPD treatment towards
report, Global Strategy for the Diagnosis, Management, and
individualized medicine – matching the patient’s therapy
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Prevention of COPD, was published. This major revision
more closely to his or her needs.
builds on the strengths from the original recommendations
and incorporates new knowledge.
BACKGROUND
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One of the strengths was the treatment objectives. These
Chronic Obstructive Pulmonary Disease (COPD), the fourth
have stood the test of time, but are now organized into two
leading cause of death in the world1, represents an important
groups: objectives that are directed towards immediately
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public health challenge that is both preventable and treatable.
relieving and reducing the impact of symptoms, and
COPD is a major cause of chronic morbidity and mortality
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objectives that reduce the risk of adverse health events
that may affect the patient at some point in the future. throughout the world; many people suffer from this disease
(Exacerbations are an example of such events.) This for years, and die prematurely from it or its complications.
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emphasizes the need for clinicians to maintain a focus on Globally, the COPD burden is projected to increase in coming
both the short-term and long-term impact of COPD on their decades because of continued exposure to COPD risk
patients. factors and aging of the population2.
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A second strength of the original strategy was the simple, In 1998, with the cooperation of the National Heart, Lung,
intuitive system for classifying COPD severity. This was and Blood Institute, NIH and the World Health Organization,
based upon the FEV1 and was called a staging system the Global Initiative for Chronic Obstructive Lung Disease
(GOLD) was implemented. Its goals were to increase
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because it was believed, at the time, that the majority of
awareness of the burden of COPD and to improve prevention
patients followed a path of disease progression in which the
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and management of COPD through a concerted worldwide
severity of the disease tracked the severity of the airflow
effort of people involved in all facets of health care and health
limitation. Much is now known about the characteristics of
care policy. An important and related goal was to encourage
patients in the different GOLD stages – for example, their
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greater research interest in this highly prevalent disease.
level of risk of exacerbations, hospitalization, and death.
However at an individual patient level, the FEV1 is an
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In 2001, GOLD released it first report, Global Strategy for
unreliable marker of the severity of breathlessness, exercise
the Diagnosis, Management, and Prevention of COPD. This
limitation, and health status impairment. This report retains
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report was not intended to be a comprehensive textbook
the GOLD classification system because it is a predictor of
on COPD, but rather to summarize the current state of
future adverse events, but the term “Stage” is now replaced
the field. It was developed by individuals with expertise in
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by “Grade.”
COPD research and patient care and was based on the
best-validated concepts of COPD pathogenesis at that
At the time of the original report, improvement in both
time, along with available evidence on the most appropriate
symptoms and health status was a GOLD treatment
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management and prevention strategies. It provided state-of-
objective, but symptoms assessment did not have a direct
the-art information about COPD for pulmonary specialists
relation to the choice of management, and health status
and other interested physicians and served as a source
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measurement was a complex process largely confined
document for the production of various communications for
to clinical studies. Now, there are simple and reliable
other audiences, including an Executive Summary3, a Pocket
questionnaires designed for use in routine daily clinical
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Guide for Health Care Professionals, and a Patient Guide.
practice. These are available in many languages.
These developments have enabled a new assessment
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Immediately following the release of the first GOLD
system to be developed that draws together a measure of
report in 2001, the GOLD Board of Directors appointed
the impact of the patient’s symptoms and an assessment of
the patient’s risk of having a serious adverse health event a Science Committee, charged with keeping the GOLD
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in the future. In turn, this new assessment system has led documents up-to-date by reviewing published research,
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evaluating the impact of this research on the management
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recommendations in the GOLD documents, and posting
yearly updates of these documents on the GOLD Website. NEW ISSUES PRESENTED
The first update to the GOLD report was posted in July 2003, IN THIS REPORT
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based on publications from January 2001 through December
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2002. A second update appeared in July 2004, and a third 1. This document has been considerably shortened in length
in July 2005, each including the impact of publications from by limiting to Chapter 1 the background information on
January through December of the previous year. In January COPD. Readers who wish to access more comprehensive
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2005, the GOLD Science Committee initiated its work to information about the pathophysiology of COPD are referred
prepare a comprehensively updated version of the GOLD to a variety of excellent textbooks that have appeared in the
report; it was released in 2006. The methodology used to last decade.
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create the annual updated documents, and the 2006 revision,
appears at the front of each volume. 2. Chapter 2 includes information on diagnosis and
assessment of COPD. The definition of COPD has not been
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During the period from 2006 to 2010, again annual updated significantly modified but has been reworded for clarity.
documents were prepared and released on the GOLD
Website, along with the methodology used to prepare the 3. Assessment of COPD is based on the patient’s level
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documents and the list of published literature reviewed to of symptoms, future risk of exacerbations, the severity
examine the impact on recommendations made in the annual of the spirometric abnormality, and the identification of
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updates. In 2009, the GOLD Science Committee recognized comorbidities. Whereas spirometry was previously used to
that considerable new information was available particularly
support a diagnosis of COPD, spirometry is now required to
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related to diagnosis and approaches to management of
make a confident diagnosis of COPD.
COPD that warranted preparation of a significantly revised
report. The work on this new revision was implemented in
mid-2009 while at the same time the Committee prepared the 4. The spirometric classification of airflow limitation is
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2010 update. divided into four Grades (GOLD 1, Mild; GOLD 2, Moderate;
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GOLD 3, Severe; and GOLD 4, Very Severe) using the fixed
ratio, postbronchodilator FEV1/FVC < 0.70, to define airflow
METHODOLOGY limitation. It is recognized that use of the fixed ratio
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In September 2009 and in May and September 2010 while (FEV1/FVC) may lead to more frequent diagnoses of COPD
preparing the annual updated reports (http://www.goldcopd. in older adults with mild COPD as the normal process of
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org), Science Committee members began to identify aging affects lung volumes and flows, and may lead to under-
the literature that impacted on major recommendations, diagnosis in adults younger than 45 years. The concept of
especially for COPD diagnosis and management. Committee staging has been abandoned as a staging system based
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members were assigned chapters to review for proposed on FEV1 alone was inadequate and the evidence for an
modifications and soon reached consensus that the report alternative staging system does not exist. The most severe
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required significant change to reach the target audiences spirometric Grade, GOLD 4, does not include reference to
– the general practitioner and the individuals in clinics respiratory failure as this seemed to be an arbitrary inclusion.
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around the world who first see patients who present with
respiratory symptoms that could lead to a diagnosis of 5. A new chapter (Chapter 3) on therapeutic approaches has
COPD. In the summer of 2010 a writing committee was been added. This includes descriptive information on both
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established to produce an outline of proposed chapters, pharmacologic and non-pharmacologic therapies, identifying
which was first presented in a symposium for the European adverse effects, if any.
Respiratory Society in Barcelona, 2010. The writing
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committee considered recommendations from this session 6. Management of COPD is presented in three chapters:
throughout fall 2010 and spring 2011. During this period Management of Stable COPD (Chapter 4); Management
the GOLD Board of Directors and GOLD National Leaders of COPD Exacerbations (Chapter 5); and COPD and
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were provided summaries of the major new directions
Comorbidities (Chapter 6), covering both management of
recommended. During the summer of 2011 the document
comorbidities in patients with COPD and of COPD in patients
was circulated for review to GOLD National Leaders, and
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with comorbidities.
other COPD opinion leaders in a variety of countries. The
names of the individuals who submitted reviews appear
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in the front of this report. In September 2011 the GOLD 7. In Chapter 4, Management of Stable COPD,
Science Committee reviewed the comments and made recommended approaches to both pharmacologic and
final recommendations. The report was launched during non-pharmacologic treatment of COPD are presented. The
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a symposium hosted by the Asian Pacific Society of chapter begins with the importance of identification and
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Respirology in November 2011. reduction of risk factors. Cigarette smoke continues to be
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identified as the most commonly encountered risk factor for
COPD and elimination of this risk factor is an important step LEVELS OF EVIDENCE
toward prevention and control of COPD. However, more
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Levels of evidence are assigned to management
data are emerging to recognize the importance of other risk recommendations where appropriate. Evidence levels are
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factors for COPD that should be taken into account where indicated in boldface type enclosed in parentheses after the
possible. These include occupational dusts and chemicals, relevant statement e.g., (Evidence A). The methodological
and indoor air pollution from biomass cooking and heating issues concerning the use of evidence from meta-analyses
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in poorly ventilated dwellings – the latter especially among were carefully considered. This evidence level scheme
women in developing countries. (Table A) has been used in previous GOLD reports, and was
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in use throughout the preparation of this document4.
8. In previous GOLD documents, recommendations for
management of COPD were based solely on spirometric
category. However, there is considerable evidence that the
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level of FEV1 is a poor descriptor of disease status and for
this reason the management of stable COPD based on
a strategy considering both disease impact (determined
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mainly by symptom burden and activity limitation) and future
risk of disease progression (especially of exacerbations) is
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recommended.
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9. Chapter 5, Management of Exacerbations, presents a
revised definition of a COPD exacerbation.
10. Chapter 6, Comorbidities and COPD, focuses on
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cardiovascular diseases, osteoporosis, anxiety and
depression, lung cancer, infections, and metabolic syndrome
and diabetes.
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Table A. Description of Levels of Evidence
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Evidence Catagory Sources of Evidence Definition
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Evidence is from endpoints of well-designed RCTs that provide a consistent pattern of
findings in the population for which the recommendation is made.
Randomized controlled trials (RCTs).
A Category A requires substantial numbers of studies involving substantial numbers of
Rich body of data.
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participants.
Evidence is from endpoints of intervention studies that include only a limited number
Randomized controlled trials of patients, posthoc or subgroup analysis of RCTs, or meta-analysis of RCTs. In
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B (RCTs). Limited body of data. 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.
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Nonrandomized trials.
Evidence is from outcomes of uncontrolled or nonrandomized trials or from
C Observational studies.
observational studies
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This category is used only in cases where the provision of some guidance was deemed
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valuable but the clinical literature addressing the subject was deemed insufficient to
D Panel Consensus Judgment. 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
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CHAPTER
OVERVIEW
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DEFINITION
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CHAPTER 1: DEFINITION AND OVERVIEW
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KEY POINTS: Many previous definitions of COPD have emphasized the
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terms “emphysema” and “chronic bronchitis,” which are
• Chronic Obstructive Pulmonary Disease (COPD), not included in the definition used in this or earlier GOLD
a common preventable and treatable disease, is reports. Emphysema, or destruction of the gas-exchanging
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characterized by persistent airflow limitation that is surfaces of the lung (alveoli), is a pathological term that
usually progressive and associated with an enhanced is often (but incorrectly) used clinically and describes
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chronic inflammatory response in the airways and the
lung to noxious particles or gases. Exacerbations Figure 1.1. Mechanisms Underlying
and comorbidities contribute to the overall severity in Airflow Limitation in COPD
Small airways disease
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individual patients.
• COPD is a leading cause of morbidity and mortality Airway inflammation Parenchymal destruction
worldwide and results in an economic and social Airway fibrosis; luminal plugs Loss of alveolar attachments
burden that is both substantial and increasing. Increased airway resistance Decrease of elastic recoil
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• Inhaled cigarette smoke and other noxious particles
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such as smoke from biomass fuels cause lung
inflammation, a normal response that appears to be
modified in patients who develop COPD. This chronic
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inflammatory response may induce parenchymal
tissue destruction (resulting in emphysema), and
disrupt normal repair and defense mechanisms T AIRFLOW LIMITATION
(resulting in small airway fibrosis). These pathological
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changes lead to air trapping and progressive airflow only one of several structural abnormalities present in
limitation, and in turn to breathlessness and other patients with COPD. Chronic bronchitis, or the presence
characteristic symptoms of COPD. of cough and sputum production for at least 3 months in
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each of two consecutive years, remains a clinically and
epidemiologically useful term. However, it is important
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to recognize that chronic cough and sputum production
DEFINITION (chronic bronchitis) is an independent disease entity
that may precede or follow the development of airflow
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Chronic Obstructive Pulmonary Disease (COPD), a common limitation and may be associated with development and/
preventable and treatable disease, is characterized by or acceleration of fixed airflow limitation. Chronic bronchitis
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persistent airflow limitation that is usually progressive and also exists in patients with normal spirometry.
associated with an enhanced chronic inflammatory response
BURDEN OF COPD
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in the airways and the lung to noxious particles or gases.
Exacerbations and comorbidities contribute to the overall
severity in individual patients. COPD is a leading cause of morbidity and mortality
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worldwide and results in an economic and social
The chronic airflow limitation characteristic of COPD is burden that is both substantial and increasing2,5. COPD
caused by a mixture of small airways disease (obstructive prevalence, morbidity, and mortality vary across countries
and across different groups within countries. COPD is the
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bronchiolitis) and parenchymal destruction (emphysema),
the relative contributions of which vary from person result of cumulative exposures over decades. Often, the
to person (Figure 1.1). Chronic inflammation causes prevalence of COPD is directly related to the prevalence
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structural changes and narrowing of the small airways. of tobacco smoking, although in many countries, outdoor,
Destruction of the lung parenchyma, also by inflammatory occupational and indoor air pollution – the latter resulting
processes, leads to the loss of alveolar attachments to the from the burning of wood and other biomass fuels – are
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small airways and decreases lung elastic recoil; in turn, major COPD risk factors6. The prevalence and burden of
these changes diminish the ability of the airways to remain COPD are projected to increase in the coming decades
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open during expiration. Airflow limitation is best measured due to continued exposure to COPD risk factors and the
by spirometry, as this is the most widely available, changing age structure of the world’s population (with more
reproducible test of lung function. people living longer and therefore expressing the long-term
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effects of exposure to COPD risk factors)5. Information
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on the burden of COPD can be found on international
2 DEFINITION AND OVERVIEW

13. CE
Websites such as those of the World Health Organization impairment, diabetes mellitus) that are related to COPD
(WHO) (http://www.who.int) and the World Bank/WHO and may have an impact on the patient’s health status, as
Global Burden of Disease Study (http://www.who.int/topics/ well as interfere with COPD management.
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global_burden_of_disease). Aging itself is a risk factor for
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COPD and aging of the airways and parenchyma mimic Mortality
some of the structural changes associated with COPD7.
The World Health Organization publishes mortality statistics
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Prevalence for selected causes of death annually for all WHO regions;
additional information is available from the WHO Evidence
Existing COPD prevalence data show remarkable variation for Health Policy Department (http://www.who.int/
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due to differences in survey methods, diagnostic criteria, evidence). Data must be interpreted cautiously, however,
and analytic approaches8. The lowest estimates of because of inconsistent use of terminology for COPD. In
prevalence are those based on self-reporting of a doctor the 10th revision of the ICD, deaths from COPD or chronic
OR
diagnosis of COPD or equivalent condition. For example, airways obstruction are included in the broad category of
most national data show that less than 6% of the adult “COPD and allied conditions” (ICD-10 codes J42-46).
population has been told that they have COPD8. This
likely reflects the widespread under-recognition and under- Under-recognition and under-diagnosis of COPD still affect
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diagnosis of COPD9. the accuracy of mortality data14,15. Although COPD is often
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a primary cause of death, it is more likely to be listed as
Despite the complexities, data are emerging that a contributory cause of death or omitted from the death
enable some conclusions to be drawn regarding COPD certificate entirely16. However, it is clear that COPD is one
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prevalence, not least because of increasing data quality of the most important causes of death in most countries.
control. A systematic review and meta-analysis of studies The Global Burden of Disease Study projected that
carried out in 28 countries between 1990 and 20048, and COPD, which ranked sixth as a cause of death in 1990,
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an additional study from Japan10, provide evidence that will become the third leading cause of death worldwide by
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the prevalence of COPD is appreciably higher in smokers 2020; a newer projection estimated COPD will be the fourth
and ex-smokers than in nonsmokers, in those over 40 leading cause of death in 20305. This increased mortality
years of age than those under 40, and in men than in is mainly driven by the expanding epidemic of smoking,
women. The Latin American Project for the Investigation reduced mortality from other common causes of death (e.g.
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of Obstructive Lung Disease (PLATINO)11 examined the ischemic heart disease, infectious diseases), and aging of
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prevalence of post-bronchodilator airflow limitation among the world population.
persons over age 40 in five major Latin American cities,
each in a different country – Brazil, Chile, Mexico, Uruguay, Economic Burden
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and Venezuela. In each country, the prevalence of COPD
increased steeply with age, with the highest prevalence COPD is associated with significant economic burden. In
among those over age 60, ranging in the total population the European Union, the total direct costs of respiratory
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from a low of 7.8% in Mexico City, Mexico to a high of disease are estimated to be about 6% of the total health
19.7% in Montevideo, Uruguay. In all cities/countries the care budget, with COPD accounting for 56% (38.6 billion
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prevalence was appreciably higher in men than in women11, Euros) of this cost of respiratory disease17. In the United
which contrasts with findings from European cities such States the estimated direct costs of COPD are $29.5 billion
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as Salzburg12. The Burden of Obstructive Lung Diseases and the indirect costs $20.4 billion18. COPD exacerbations
program (BOLD) has carried out surveys in several parts of account for the greatest proportion of the total COPD
the world13 and has documented more severe disease than burden on the health care system. Not surprisingly, there is
previously found and a substantial prevalence (3-11%) of a striking direct relationship between the severity of COPD
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COPD among never-smokers. and the cost of care, and the distribution of costs changes
as the disease progresses. For example, hospitalization
Morbidity and ambulatory oxygen costs soar as COPD severity
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increases. Any estimate of direct medical expenditures for
Morbidity measures traditionally include physician visits, home care under-represents the true cost of home care to
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emergency department visits, and hospitalizations. society, because it ignores the economic value of the care
Although COPD databases for these outcome parameters provided to those with COPD by family members.
are less readily available and usually less reliable than
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mortality databases, the limited data available indicate that In developing countries, direct medical costs may be less
morbidity due to COPD increases with age10-12. Morbidity important than the impact of COPD on workplace and
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from COPD may be affected by other comorbid chronic home productivity. Because the health care sector might
conditions (e.g., cardiovascular disease, musculoskeletal
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not provide long-term supportive care services for severely
DEFINITION AND OVERVIEW 3

14. CE
disabled individuals, COPD may force two individuals to and in turn on susceptibility to develop the disease);
leave the workplace—the affected individual and a family and longer life expectancy will allow greater lifetime
member who must now stay home to care for the disabled exposure to risk factors. Understanding the relationships
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relative. Since human capital is often the most important and interactions among risk factors requires further
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national asset for developing countries, the indirect costs of investigation.
COPD may represent a serious threat to their economies.
Genes
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Social Burden
The genetic risk factor that is best documented is a severe
Since mortality offers a limited perspective on the human hereditary deficiency of alpha-1 antitrypsin26, a major
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burden of a disease, it is desirable to find other measures circulating inhibitor of serine proteases. Although alpha-1
of disease burden that are consistent and measurable antitrypsin deficiency is relevant to only a small part of the
across nations. The authors of the Global Burden of world’s population, it illustrates the interaction between
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Disease Study designed a method to estimate the fraction genes and environmental exposures leading to COPD.
of mortality and disability attributable to major diseases
and injuries using a composite measure of the burden A significant familial risk of airflow limitation has
of each health problem, the Disability-Adjusted Life Year been observed in smoking siblings of patients with
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(DALY)2,19,20. The DALYs for a specific condition are the severe COPD27, suggesting that genetic together with
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sum of years lost because of premature mortality and environmental factors could influence this susceptibility.
years of life lived with disability, adjusted for the severity of Single genes such as the gene encoding matrix
disability. In 1990, COPD was the twelfth leading cause of metalloproteinase 12 (MMP12) have been related to
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DALYs lost in the world, responsible for 2.1% of the total. decline in lung function28. Although several genome-
According to the projections, COPD will be the seventh wide association studies indicate a role of the gene for
leading cause of DALYs lost worldwide in 20305. the alpha-nicotinic acetylcholine receptor as well as the
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hedge-hog interacting protein gene and possibly one or two
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others, there remains a discrepancy between findings from
FACTORS THAT INFLUENCE analyses of COPD and lung function as well as between
genome-wide association study analyses and candidate
DISEASE DEVELOPMENT AND gene analyses29-33.
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PROGRESSION
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Age and Gender
Although cigarette smoking is the best-studied COPD Age is often listed as a risk factor for COPD. It is unclear if
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risk factor, it is not the only one and there is consistent healthy aging as such leads to COPD or if age reflects the
evidence from epidemiologic studies that nonsmokers sum of cumulative exposures throughout life. In the past,
may also develop chronic airflow limitation21-24. Much of most studies showed that COPD prevalence and mortality
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the evidence concerning risk factors for COPD comes were greater among men than women but data from
from cross-sectional epidemiological studies that identify developed countries18,34 show that the prevalence of the
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associations rather than cause-and-effect relationships. disease is now almost equal in men and women, probably
Although several longitudinal studies of COPD have reflecting the changing patterns of tobacco smoking.
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followed groups and populations for up to 20 years25, none Some studies have even suggested that women are more
has monitored the progression of the disease through its susceptible to the effects of tobacco smoke than men35-38.
entire course, or has included the pre-and perinatal periods
which may be important in shaping an individual’s future Lung Growth and Development
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COPD risk. Thus, current understanding of risk factors for
COPD is in many respects still incomplete. Lung growth is related to processes occurring during
gestation, birth, and exposures during childhood and
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COPD results from a gene-environment interaction. Among adolescence39,40. Reduced maximal attained lung function
people with the same smoking history, not all will develop (as measured by spirometry) may identify individuals who
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COPD due to differences in genetic predisposition to the are at increased risk for the development of COPD41.
disease, or in how long they live. Risk factors for COPD Any factor that affects lung growth during gestation and
childhood has the potential for increasing an individual’s
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may also be related in more complex ways. For example,
gender may influence whether a person takes up smoking risk of developing COPD. For example, a large study and
or experiences certain occupational or environmental meta-analysis confirmed a positive association between
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exposures; socioeconomic status may be linked to a child’s birth weight and FEV1 in adulthood42, and several studies
birth weight (as it impacts on lung growth and development have found an effect of early childhood lung infections.
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15. CE
A study found that factors in early life termed “childhood Socioeconomic Status
disadvantage factors” were as important as heavy smoking
in predicting lung function in early adult life43. Poverty is clearly a risk factor for COPD but the
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components of poverty that contribute to this are unclear.
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Exposure to Particles There is strong evidence that the risk of developing COPD
is inversely related to socioeconomic status69. It is not
Across the world, cigarette smoking is the most commonly clear, however, whether this pattern reflects exposures
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encountered risk factor for COPD. Cigarette smokers to indoor and outdoor air pollutants, crowding, poor
have a higher prevalence of respiratory symptoms and nutrition, infections, or other factors that are related to low
lung function abnormalities, a greater annual rate of socioeconomic status.
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decline in FEV1, and a greater COPD mortality rate than
nonsmokers44. Other types of tobacco (e.g., pipe, cigar, Asthma/Bronchial Hyperreactivity
water pipe45) and marijuana46 are also risk factors for
COPD47,48. Passive exposure to cigarette smoke (also
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Asthma may be a risk factor for the development of COPD,
known as environmental tobacco smoke or ETS) may although the evidence is not conclusive. In a report from
also contribute to respiratory symptoms49 and COPD50 by a longitudinal cohort of the Tucson Epidemiological Study
increasing the lung’s total burden of inhaled particles and of Airway Obstructive Disease, adults with asthma were
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gases51,52. Smoking during pregnancy may also pose a risk found to have a twelve-fold higher risk of acquiring COPD
for the fetus, by affecting lung growth and development in
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over time than those without asthma, after adjusting for
utero and possibly the priming of the immune system53,54. smoking70. Another longitudinal study of people with
asthma found that around 20% of subjects developed
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Occupational exposures, including organic and irreversible airflow limitation and reduced transfer
inorganic dusts and chemical agents and fumes, are an coefficient71, and in a longitudinal study self-reported
underappreciated risk factor for COPD55-57. An analysis asthma was associated with excess loss of FEV1 in
of the large U.S. population-based NHANES III survey T
the general population72. In the European Community
of almost 10,000 adults aged 30-75 years estimated the
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Respiratory Health Survey, bronchial hyperresponsiveness
fraction of COPD attributable to work was 19.2% overall, was second only to cigarette smoking as the leading risk
and 31.1% among never-smokers58. These estimates are factor for COPD, responsible for 15% of the population
consistent with a statement published by the American attributable risk (smoking had a population attributable
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Thoracic Society that concluded that occupational risk of 39%)73. The pathology of chronic airflow limitation
exposures account for 10-20% of either symptoms or
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in asthmatic nonsmokers and non-asthmatic smokers is
functional impairment consistent with COPD59. The risk
markedly different, suggesting that the two disease entities
from occupational exposures in less regulated areas of the
may remain different even when presenting with similarly
world is likely to be much higher than reported in studies
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reduced lung function74. However, clinically separating
from Europe and North America.
asthma from COPD may not be easy.
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Wood, animal dung, crop residues, and coal, typically
Bronchial hyperreactivity can exist without a clinical
burned in open fires or poorly functioning stoves, may
diagnosis of asthma and has been shown to be an
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lead to very high levels of indoor air pollution. Evidence
independent predictor of COPD in population studies75 as
continues to grow that indoor pollution from biomass
well as an indicator of risk of excess decline in lung function
cooking and heating in poorly ventilated dwellings is an
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in patients with mild COPD76.
important risk factor for COPD60-66. Almost 3 billion people
worldwide use biomass and coal as their main source of
Chronic Bronchitis
energy for cooking, heating, and other household needs, so
the population at risk worldwide is very large63,67.
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In the seminal study by Fletcher and coworkers, chronic
bronchitis was not associated with decline in lung
High levels of urban air pollution are harmful to individuals function77. However, subsequent studies have found an
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with existing heart or lung disease. The role of outdoor association between mucus hypersecretion and FEV1
air pollution in causing COPD is unclear, but appears to decline78, and in younger adults who smoke the presence
be small when compared with that of cigarette smoking. of chronic bronchitis is associated with an increased
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It has also been difficult to assess the effects of single likelihood of developing COPD79,80.
pollutants in long-term exposure to atmospheric pollution.
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However, air pollution from fossil fuel combustion, primarily Infections
from motor vehicle emissions in cities, is associated with
decrements of respiratory function68. The relative effects of A history of severe childhood respiratory infection has
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short-term, high-peak exposures and long-term, low-level been associated with reduced lung function and increased
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exposures are yet to be resolved. respiratory symptoms in adulthood39,73. Susceptibility to
DEFINITION AND OVERVIEW 5

16. CE
infections plays a role in exacerbations of COPD but the increased in the exhaled breath condensate, sputum, and
effect on the development of the disease is less clear. systemic circulation of COPD patients. Oxidative stress is
HIV infection has been shown to accelerate the onset further increased in exacerbations. Oxidants are generated
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of smoking-related emphysema81. Tuberculosis has by cigarette smoke and other inhaled particulates, and
been found to be a risk factor for COPD82,83. In addition,
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released from activated inflammatory cells such as
tuberculosis is both a differential diagnosis to COPD and a macrophages and neutrophils. There may also be a
potential comorbidity83,84. reduction in endogenous antioxidants in COPD patients as
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a result of reduction in a transcription factor called Nrf2 that
regulates many antioxidant genes89.
PATHOLOGY, PATHOGENESIS
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AND PATHOPHYSIOLOGY Protease-Antiprotease Imbalance. There is compelling
evidence for an imbalance in the lungs of COPD patients
between proteases that break down connective tissue
Inhaled cigarette smoke and other noxious particles such
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as smoke from biomass fuels cause lung inflammation, components and antiproteases that protect against this.
a normal response that appears to be modified in Several proteases, derived from inflammatory cells and
patients who develop COPD. This chronic inflammatory epithelial cells, are increased in COPD patients. There
response may induce parenchymal tissue destruction is increasing evidence that they may interact with each
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(resulting in emphysema), and disrupt normal repair and other. Protease-mediated destruction of elastin, a major
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defense mechanisms (resulting in small airway fibrosis). connective tissue component in lung parenchyma, is
These pathological changes lead to air trapping and believed to be an important feature of emphysema and is
progressive airflow limitation. A brief overview follows likely to be irreversible.
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of the pathologic changes in COPD, their cellular and
molecular mechanisms, and how these underlie physiologic Inflammatory Cells. COPD is characterized by a specific
abnormalities and symptoms characteristic of the disease85 pattern of inflammation involving increased numbers of
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CD8+ (cytotoxic) Tc1 lymphocytes present only in smokers
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Pathology that develop the disease85. These cells, together with
neutrophils and macrophages, release inflammatory
Pathological changes characteristic of COPD are mediators and enzymes and interact with structural
found in the airways, lung parenchyma, and pulmonary cells in the airways, lung parenchyma and pulmonary
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vasculature86. The pathological changes include chronic vasculature90.
inflammation, with increased numbers of specific
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inflammatory cell types in different parts of the lung, and Inflammatory Mediators. The wide variety of inflammatory
structural changes resulting from repeated injury and repair. mediators that have been shown to be increased in COPD
In general, the inflammatory and structural changes in
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patients91 attract inflammatory cells from the circulation
the airways increase with disease severity and persist on
(chemotactic factors), amplify the inflammatory process
smoking cessation.
(proinflammatory cytokines), and induce structural changes
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Pathogenesis (growth factors)92.
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The inflammation in the respiratory tract of COPD patients Differences in Inflammation Between COPD and Asthma.
appears to be a modification of the inflammatory response Although both COPD and asthma are associated with
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of the respiratory tract to chronic irritants such as cigarette chronic inflammation of the respiratory tract, there are
smoke. The mechanisms for this amplified inflammation differences in the inflammatory cells and mediators involved
are not yet understood but may be genetically determined. in the two diseases, which in turn account for differences in
Patients can clearly develop COPD without smoking, but physiological effects, symptoms, and response to therapy74.
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the nature of the inflammatory response in these patients is Some patients with COPD have features consistent with
unknown. Oxidative stress and an excess of proteinases in asthma and may have a mixed inflammatory pattern with
the lung further modify lung inflammation. Together, these increased eosinophils.
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mechanisms lead to the characteristic pathological changes
in COPD. Lung inflammation persists after smoking Pathophysiology
cessation through unknown mechanisms, although
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There is now a good understanding of how the underlying
autoantigens and persistent microorganisms may play a disease process in COPD leads to the characteristic
role87. physiologic abnormalities and symptoms. For example,
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inflammation and narrowing of peripheral airways leads
Oxidative Stress. Oxidative stress may be an important to decreased FEV1. Parenchymal destruction due to
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amplifying mechanism in COPD88. Biomarkers of oxidative emphysema also contributes to airflow limitation and leads
stress (e.g., hydrogen peroxide, 8-isoprostane) are to decreased gas transfer.
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6 DEFINITION AND OVERVIEW

17. CE
Airflow Limitation and Air Trapping. The extent of of endothelial cell dysfunction. The loss of the pulmonary
inflammation, fibrosis, and luminal exudates in small capillary bed in emphysema may also contribute
airways is correlated with the reduction in FEV1 and to increased pressure in the pulmonary circulation.
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FEV1/FVC ratio, and probably with the accelerated decline Progressive pulmonary hypertension may lead to right
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in FEV1 characteristic of COPD90. This peripheral airway ventricular hypertrophy and eventually to right-side cardiac
obstruction progressively traps air during expiration, failure.
resulting in hyperinflation. Although emphysema is more
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associated with gas exchange abnormalities than with Exacerbations. Exacerbations of respiratory symptoms
reduced FEV1, it does contribute to gas trapping during often occur in patients with COPD, triggered by infection
expiration. This is especially so as alveolar attachments with bacteria or viruses (which may coexist), environmental
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to small airways are destroyed when the disease becomes pollutants, or unknown factors. Patients with bacterial
more severe. Hyperinflation reduces inspiratory capacity and viral episodes have a characteristic response with
such that functional residual capacity increases, particularly increased inflammation. During respiratory exacerbations
OR
during exercise (dynamic hyperinflation), resulting in there is increased hyperinflation and gas trapping, with
increased dyspnea and limitation of exercise capacity. reduced expiratory flow, thus accounting for the increased
These factors contribute to impairment of the intrinsic dyspnea98. There is also worsening of VA/Q abnormalities,
contractile properties of respiratory muscles; this results which can result in hypoxemia99. Other conditions
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in upregulation of local pro-inflammatory cytokines. It is (pneumonia, thromboembolism, and acute cardiac failure)
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thought that hyperinflation develops early in the disease may mimic or aggravate an exacerbation of COPD.
and is the main mechanism for exertional dyspnea93,94.
Bronchodilators acting on peripheral airways reduce air Systemic Features. It is increasingly recognized that many
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trapping, thereby reducing lung volumes and improving patients with COPD have comorbidities that have a major
symptoms and exercise capacity93. impact on quality of life and survival100. Airflow limitation
and particularly hyperinflation affect cardiac function and
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Gas Exchange Abnormalities. Gas exchange gas exchange101. Inflammatory mediators in the circulation
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abnormalities result in hypoxemia and hypercapnia, may contribute to skeletal muscle wasting and cachexia,
and have several mechanisms in COPD. In general, and may initiate or worsen comorbidities such as ischemic
gas transfer for oxygen and carbon dioxide worsens as heart disease, heart failure, osteoporosis, normocytic
the disease progresses. Reduced ventilation may also anemia, diabetes, metabolic syndrome, and depression.
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be due to reduced ventilatory drive. This may lead to
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carbon dioxide retention when it is combined with reduced
ventilation due to a high work of breathing because
of severe obstruction and hyperinflation coupled with
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ventilatory muscle impairment. The abnormalities in
alveolar ventilation and a reduced pulmonary vascular bed
further worsen the VA/Q abnormalities95.
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Mucus Hypersecretion. Mucus hypersecretion, resulting
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in a chronic productive cough, is a feature of chronic
bronchitis and is not necessarily associated with airflow
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limitation. Conversely, not all patients with COPD have
symptomatic mucus hypersecretion. When present, it is
due to an increased number of goblet cells and enlarged
submucosal glands in response to chronic airway irritation
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by cigarette smoke and other noxious agents. Several
mediators and proteases stimulate mucus hypersecretion
and many of them exert their effects through the activation
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of epidermal growth factor receptor (EGFR)96.
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Pulmonary Hypertension. Pulmonary hypertension may
develop late in the course of COPD and is due mainly
to hypoxic vasoconstriction of small pulmonary arteries,
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eventually resulting in structural changes that include
intimal hyperplasia and later smooth muscle hypertrophy/
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hyperplasia97. There is an inflammatory response in
vessels similar to that seen in the airways and evidence
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DEFINITION AND OVERVIEW 7

18. CO
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