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Gold report 2011 epoc

  3. 3. CE GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (REVISED 2011) UGOLD BOARD OF DIRECTORS GOLD SCIENCE COMMITTEE* ODRoberto Rodriguez-Roisin, MD, Chair Jørgen Vestbo, MD, ChairThorax Institute, Hospital Clinic Hvidovre University Hospital, Hvidovre, Denmark and University of Manchester PRUniv. Barcelona, Barcelona, Spain Manchester, England, UKAntonio Anzueto, MD(Representing American Thoracic Society) Alvar G. Agusti, MD REUniversity of Texas Health Science Center Thorax Institute, Hospital ClinicSan Antonio, Texas, USA Univ. Barcelona, Ciberes, Barcelona, Spain ORJean Bourbeau, MD Antonio Anzueto, MDMcGill University Health Centre University of Texas Health Science CenterMontreal, Quebec, Canada San Antonio, Texas, USA RTeresita S. deGuia, MD Peter J. Barnes, MDPhilippine Heart Center National Heart and Lung Institute TEQuezon City, Philippines London, England, UKDavid S.C. Hui, MD Leonardo M. Fabbri, MD ALThe Chinese University of Hong Kong University of Modena & Reggio EmiliaHong Kong, ROC Modena, ItalyFernando Martinez, MDUniversity of Michigan School of Medicine T Paul Jones, MD St George’s Hospital Medical School NOAnn Arbor, Michigan, USA London, England, UKMichiaki Mishima, MD Fernando Martinez, MD(Representing Asian Pacific Society for Respirology) University of Michigan School of Medicine OKyoto University, Kyoto, Japan Ann Arbor, Michigan, USA -DDamilya Nugmanova, MD Masaharu Nishimura, MD(Representing WONCA) Hokkaido University School of MedicineKazakhstan Association of Family Physicians Sapporo, Japan ALAlmaty, Kazakhstan Roberto Rodriguez-Roisin, MDAlejandra Ramirez, MD Thorax Institute, Hospital Clinic RI(Representing Latin American Thoracic Society) Univ. Barcelona, Barcelona, SpainInstituto Nacional de Enfermedades Respiratorias TECalzada de Tlalpan, México Donald Sin, MD St. Paul’s HospitalRobert Stockley, MD Vancouver, Canada MAUniversity Hospital, Birmingham, UK Robert Stockley, MDJørgen Vestbo, MD University HospitalHvidovre University Hospital, Hvidovre, Denmark Birmingham, UK EDand University of Manchester, Manchester, UK Claus Vogelmeier, MDGOLD SCIENCE DIRECTOR University of Giessen and Marburg HTSuzanne S. Hurd, PhD Marburg, GermanyVancouver, Washington, USA IG *Disclosure forms for GOLD Committees are posted on the GOLD Website, P YR CO ii
  4. 4. CE GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD (REVISED 2011) UINVITED REVIEWERS David Price, MD OD University of AberdeenJoan-Albert Barbera, MD Aberdeen, Scotland, UKHospital Clinic, Universitat de Barcelona Barcelona Spain Nicolas Roche, MD, PhD PR University Paris DescartesA. Sonia Buist, MD Paris, FranceOregon Health Sciences University REPortland, OR, USA Sanjay Sethi, MD State University of New YorkPeter Calverley, MD Buffalo, NY, USA ORUniversity Hospital AintreeLiverpool, England, UK GOLD NATIONAL LEADERS (Submitting Comments)Bart Celli, MD RBrigham and Women’s Hospital Lorenzo Corbetta, MDBoston, MA, USA University of Florence TE Florence, ItalyM. W. Elliott, MDSt. James’s University Hospital Alexandru Corlateanu, MD, PhD ALLeeds, England, UK State Medical and Pharmaceutical University Republic of MoldovaYoshinosuke Fukuchi, MDJuntendo UniversityTokyo, Japan T Le Thi Tuyet Lan, MD, PhD University of Pharmacy and Medicine NO Ho Chi Minh City, VietnamMasakazu Ichinose, MDWakayama Medical University Fernando Lundgren, MDKimiidera, Wakayama, Japan Pernambuco, Brazil O -DChristine Jenkins, MD E. M. Irusen, MDWoolcock Institute of Medical Research University of StellenboschCamperdown. NSW, Australia South Africa ALH. A. M. Kerstjens, MD Timothy J. MacDonald, MDUniversity of Groningen St. Vincent’s University HospitalGroningen, The Netherlands Dublin, Ireland RIPeter Lange, MD Takahide Nagase, MD TEHvidovre University Hospital University of TokyoCopenhagen, Denmark Tokyo, Japan MAM.Victorina López Varela, MD Ewa Nizankowska-Mogilnicka, MD, PhDUniversidad de la República Jagiellonian University Medical CollegeMontevideo, Uruguay Krakow, Poland EDMaria Montes de Oca, MD Magvannorov Oyunchimeg, MDHospital Universitario de Caracas Ulannbatar, MongoliaCaracas, Venezuela HT Mostafizur Rahman, MDAtsushi Nagai, MD NIDCHTokyo Women’s Medical University Mohakhali, Dhaka, Bangladesh IGTokyo, Japan YRDennis Niewoehner, MDVeterans Affairs Medical CenterMinneapolis, MN, USA P CO iii
  5. 5. CE PREFACE U ODChronic Obstructive Pulmonary Disease (COPD) remains will continue to work with the GOLD National Leaders and PRa major public health problem. In 2020, COPD is projected other interested health care professionals to bring COPD toto rank fifth worldwide in burden of disease, according the attention of governments, public health officials, healthto a study published by the World Bank/World Health care workers, and the general public to raise awareness REOrganization. Although COPD has received increasing of the burden of COPD and to develop programs for earlyattention 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 ORpublic 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 Rmanagement 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, TEObstructive Lung Disease (GOLD). Among the important and Pfizer that enabled development of this report.objectives of GOLD are to increase awareness of COPD ALand to help the millions of people who suffer from this Roberto Rodriguez Roisin, MDdisease and die prematurely from it or its complications.In 2001, the GOLD program released a consensus report, T NOGlobal Strategy for the Diagnosis, Management, andPrevention of COPD; this document was revised in 2006.This 2011 revision follows the same format as the 2001 and2006 reports, but reflects the many publications on COPD Chair, GOLD Executive Committee Othat have appeared since 2006. Professor of Medicine -D Hospital Clínic, Universitat de BarcelonaBased on multiple scientific and clinical achievements in Barcelona, Spainthe ten years since the 2001 GOLD report was published, ALthis revised edition provides a new paradigm for treatment Jørgen Vestbo, MDof stable COPD that is based on the best scientific RIevidence available. We would like to acknowledge thework of the members of the GOLD Science Committee TEwho volunteered their time to review the scientific literatureand prepare the recommendations for care of patients withCOPD that are described in this revised report. In the next MAfew years, the GOLD Science Committee will continue Chair, GOLD Science Committeeto work to refine this new approach and, as they have Hvidovre University Hospitaldone during the past several years, will review published Hvidovre, Denmark (and) EDliterature and prepare an annual updated report. The University of Manchester Manchester, UKGOLD has been fortunate to have a network of HTinternational distinguished health professionals frommultiple disciplines. Many of these experts have initiated IGinvestigations of the causes and prevalence of COPD intheir countries, and have developed innovative approaches YRfor the dissemination and implementation of COPDmanagement guidelines. We particularly appreciate thework accomplished by the GOLD National Leaders on Pbehalf of their patients with COPD. The GOLD initiative CO iv
  6. 6. CE TABLE OF CONTENTSPreface.............................................................. .iv 3. Therapeutic Options 19 UIntroduction......................................................vii Key Points 20 OD Smoking Cessation 201. Definition and Overview 1 Pharmacotherapies for Smoking Cessation 20 PRKey Points COPD 2 Pharmacologic Therapy for Stable 21Definition 2 Overview of the Medications 21 REBurden Of COPD 2 Bronchodilators 21 Prevalence 3 Corticosteroids 24 Morbidity 3 Phosphodiesterase-4 Inhibitors 25 OR Mortality 3 Other Pharmacologic Treatments 25 Economic Burden 3 Non-Pharmacologic Therapies 26 Social Burden 4 Rehabilitation 26 RFactors That Influence Disease Components of Pulmonary Rehabilitation TEDevelopment And Progression 4 Programs 27 Genes 4 Other Treatments 28 AL Age and Gender 4 Oxygen Therapy 28 Lung Growth and Development 4 Ventilatory Support 28 Exposure to Particles 5 Surgical Treatments T 29 NO Socioeconomic Status 5 Asthma/Bronchial Hyperreactivity 5 4. Management of Stable COPD 31 Chronic Bronchitis 5 Key Points 32 O Infections 5 Introduction 32 6 33 -DPathology, Pathogenesis And Pathophysiology Identify And Reduce Exposure to Risk Factors Pathology 6 Tobacco Smoke 33 Pathogenesis 6 Occupational Exposures 33 AL Pathophysiology Pollution 6 Indoor And Outdoor 33 Treatment of Stable COPD 33 RI2. Diagnosis and Assessment 9 Moving from Clinical Trials to Recommendations Key Points 10 for Routine Practice Considerations 33 TEDiagnosis 10 Non-Pharmacologic Treatment 34 Symptoms 11 Smoking Cessation 34 MA Medical History 12 Physical Activity 34 Physical Examination 12 Rehabilitation 34 34 ED Spirometry 12 Vaccination Assessment Of Disease 12 Pharmacologic Treatment 35 Assessment of Symptoms 13 Bronchodilators - Recommendations 35 HT Spirometric Assessment 13 Corticosteroids and Phosphodiesterase-4 Assessment of Exacerbation Risk 13 Inhibitors - Recommendations 37 IG Assessment of Comorbidities 14 Monitoring And Follow-Up 37 15 Monitor Disease Progression and YR Combined COPD Assessment Additional Investigations 16 Development of Complications 37 Monitor Pharmacotherapy andDifferential Diagnosis 17 P Other Medical Treatment 37 CO Monitor Exacerbation History 37 v
  7. 7. CE 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 UKey Points 40 Table 2.5. Classification of Severity of Airflow OD Limitation in COPD (Based on Post-Bronchodilator Definition 40Diagnosis 40 FEV1) 14 Table 2.6. RISK IN COPD: Placebo-limb data from PRAssessment 41 TORCH, Uplift, and Eclipse 14Treatment Options 41 Table 2.7. COPD and its Differential Diagnoses 17 RE 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 ORHospital Discharge and Follow-up 44 Table 3.2. Brief Strategies to Help the Patient Willing Home Management of Exacerbations 45 to Quit 21Prevention of COPD Exacerbations 45 Table 3.3. Formulations and Typical Doses of COPD R Medications 22 TE6. COPD and Comorbidities 47 Table 3.4. Bronchodilators in Stable COPD 23Key Points 48 Table 3.5. Benefits of Pulmonary Rehabilitation in ALIntroduction 48 COPD 26Cardiovascular Disease 48 Table 4.1. Goals for Treatment of Stable COPD 32Osteoporosis 49 Table 4.2. Model of Symptom/Risk of Evaluation of T 50 COPD NOAnxiety and Depression 33Lung Cancer 50 Table 4.3. Non-pharmacologic ManagementInfections 50 of COPD 34 OMetabolic Syndrome and Diabetes 50 Table 4.4. Initial Pharmacologic Management of COPD 36 -DReferences 51 Table 5.1. Assessment of COPD Exacerbations: Medical History 41 ALFigures Table 5.2. Assessment of COPD Exacerbations:Figure 1.1. Mechanisms Underlying Airflow Limitation Signs of Severity 41 RI in COPD for Hospital 2 Table 5.3. Potential IndicationsFigure 2.1A. Spirometry - Normal Trace 13 Assessment or Admission 41 TEFigure 2.1B. Spirometry - Obstructive Disease 13 Table 5.4. Management of Severe but NotFigure 2.2. Relationship Between Health-Related Life-Threatening Exacerbations 42 MA Quality of Life, Post-Bronchodilator FEV1 and Table 5.5. Therapeutic Components of Hospital GOLD Spirometric Classification 14 Management 42Figure 2.3. Association Between Symptoms, Table 5.6. Indications for ICU Admission 43 ED Spirometric Classification and Future Risk of Table 5.7. Indications for Noninvasive Mechanical Exacerbations 15 Ventilation 43 HT Table 5.8. Indications for Invasive Mechanical Tables Ventilation 43Table A. Description of Levels of Evidence   ix 44 IG Table 5.9. Discharge Criteria Table 2.1. Key Indicators for Considering Table 5.10. Checklist of items to assess at time of YR a Diagnosis of COPD 10 Discharge from Hospital 44Table 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 P Spirometry 12 CO vi
  8. 8. CE GLOBAL STRATEGY FOR THE DIAGNOSIS, U MANAGEMENT, AND PREVENTION OF COPD OD to the construction of a new approach to management– oneINTRODUCTION that matches assessment to treatment objectives. The new PR management approach can be used in any clinical settingMuch has changed in the 10 years since the first GOLD anywhere in the world and moves COPD treatment towardsreport, Global Strategy for the Diagnosis, Management, and individualized medicine – matching the patient’s therapy REPrevention of COPD, was published. This major revision more closely to his or her needs.builds on the strengths from the original recommendationsand incorporates new knowledge. BACKGROUND OROne of the strengths was the treatment objectives. These Chronic Obstructive Pulmonary Disease (COPD), the fourthhave stood the test of time, but are now organized into two leading cause of death in the world1, represents an importantgroups: objectives that are directed towards immediately R 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 TEobjectives that reduce the risk of adverse health eventsthat 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. ALemphasizes the need for clinicians to maintain a focus on Globally, the COPD burden is projected to increase in comingboth the short-term and long-term impact of COPD on their decades because of continued exposure to COPD riskpatients. factors and aging of the population2. T NOA 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 Obecause it was believed, at the time, that the majority of awareness of the burden of COPD and to improve preventionpatients followed a path of disease progression in which the -D and management of COPD through a concerted worldwideseverity of the disease tracked the severity of the airflow effort of people involved in all facets of health care and healthlimitation. Much is now known about the characteristics of care policy. An important and related goal was to encouragepatients in the different GOLD stages – for example, their AL 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 RI In 2001, GOLD released it first report, Global Strategy forunreliable marker of the severity of breathlessness, exercise the Diagnosis, Management, and Prevention of COPD. Thislimitation, and health status impairment. This report retains TE report was not intended to be a comprehensive textbookthe GOLD classification system because it is a predictor of on COPD, but rather to summarize the current state offuture adverse events, but the term “Stage” is now replaced the field. It was developed by individuals with expertise in MAby “Grade.” COPD research and patient care and was based on the best-validated concepts of COPD pathogenesis at thatAt the time of the original report, improvement in both time, along with available evidence on the most appropriatesymptoms and health status was a GOLD treatment ED management and prevention strategies. It provided state-of-objective, but symptoms assessment did not have a direct the-art information about COPD for pulmonary specialistsrelation to the choice of management, and health status and other interested physicians and served as a source HTmeasurement was a complex process largely confined document for the production of various communications forto clinical studies. Now, there are simple and reliable other audiences, including an Executive Summary3, a Pocketquestionnaires designed for use in routine daily clinical IG Guide for Health Care Professionals, and a Patient Guide.practice. These are available in many languages.These developments have enabled a new assessment YR Immediately following the release of the first GOLDsystem to be developed that draws together a measure of report in 2001, the GOLD Board of Directors appointedthe impact of the patient’s symptoms and an assessment ofthe patient’s risk of having a serious adverse health event a Science Committee, charged with keeping the GOLD Pin the future. In turn, this new assessment system has led documents up-to-date by reviewing published research, CO evaluating the impact of this research on the management vii
  9. 9. CErecommendations in the GOLD documents, and postingyearly updates of these documents on the GOLD Website. NEW ISSUES PRESENTEDThe first update to the GOLD report was posted in July 2003, IN THIS REPORT Ubased on publications from January 2001 through December OD2002. A second update appeared in July 2004, and a third 1. This document has been considerably shortened in lengthin July 2005, each including the impact of publications from by limiting to Chapter 1 the background information onJanuary through December of the previous year. In January COPD. Readers who wish to access more comprehensive PR2005, the GOLD Science Committee initiated its work to information about the pathophysiology of COPD are referredprepare a comprehensively updated version of the GOLD to a variety of excellent textbooks that have appeared in thereport; it was released in 2006. The methodology used to last decade. REcreate 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 ORDuring the period from 2006 to 2010, again annual updated significantly modified but has been reworded for clarity.documents were prepared and released on the GOLDWebsite, along with the methodology used to prepare the 3. Assessment of COPD is based on the patient’s level Rdocuments and the list of published literature reviewed to of symptoms, future risk of exacerbations, the severityexamine the impact on recommendations made in the annual of the spirometric abnormality, and the identification of TEupdates. In 2009, the GOLD Science Committee recognized comorbidities. Whereas spirometry was previously used tothat considerable new information was available particularly support a diagnosis of COPD, spirometry is now required to ALrelated to diagnosis and approaches to management of make a confident diagnosis of COPD.COPD that warranted preparation of a significantly revisedreport. The work on this new revision was implemented inmid-2009 while at the same time the Committee prepared the 4. The spirometric classification of airflow limitation is T2010 update. divided into four Grades (GOLD 1, Mild; GOLD 2, Moderate; NO GOLD 3, Severe; and GOLD 4, Very Severe) using the fixed ratio, postbronchodilator FEV1/FVC < 0.70, to define airflowMETHODOLOGY limitation. It is recognized that use of the fixed ratio OIn September 2009 and in May and September 2010 while (FEV1/FVC) may lead to more frequent diagnoses of COPDpreparing the annual updated reports (http://www.goldcopd. in older adults with mild COPD as the normal process of -Dorg), 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 ofespecially for COPD diagnosis and management. Committee staging has been abandoned as a staging system based ALmembers were assigned chapters to review for proposed on FEV1 alone was inadequate and the evidence for anmodifications and soon reached consensus that the report alternative staging system does not exist. The most severe RIrequired 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. TEaround the world who first see patients who present withrespiratory symptoms that could lead to a diagnosis of 5. A new chapter (Chapter 3) on therapeutic approaches hasCOPD. In the summer of 2010 a writing committee was been added. This includes descriptive information on both MAestablished to produce an outline of proposed chapters, pharmacologic and non-pharmacologic therapies, identifyingwhich was first presented in a symposium for the European adverse effects, if any.Respiratory Society in Barcelona, 2010. The writing EDcommittee 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); Managementthe GOLD Board of Directors and GOLD National Leaders of COPD Exacerbations (Chapter 5); and COPD and HTwere provided summaries of the major new directions Comorbidities (Chapter 6), covering both management ofrecommended. During the summer of 2011 the document comorbidities in patients with COPD and of COPD in patientswas circulated for review to GOLD National Leaders, and IG with comorbidities.other COPD opinion leaders in a variety of countries. Thenames of the individuals who submitted reviews appear YRin 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 andfinal recommendations. The report was launched during non-pharmacologic treatment of COPD are presented. The Pa symposium hosted by the Asian Pacific Society of chapter begins with the importance of identification and CORespirology in November 2011. reduction of risk factors. Cigarette smoke continues to be viii
  10. 10. CEidentified as the most commonly encountered risk factor forCOPD and elimination of this risk factor is an important step LEVELS OF EVIDENCEtoward prevention and control of COPD. However, more U Levels of evidence are assigned to managementdata are emerging to recognize the importance of other risk recommendations where appropriate. Evidence levels are ODfactors for COPD that should be taken into account where indicated in boldface type enclosed in parentheses after thepossible. These include occupational dusts and chemicals, relevant statement e.g., (Evidence A). The methodologicaland indoor air pollution from biomass cooking and heating issues concerning the use of evidence from meta-analyses PRin poorly ventilated dwellings – the latter especially among were carefully considered. This evidence level schemewomen in developing countries. (Table A) has been used in previous GOLD reports, and was RE in use throughout the preparation of this document4.8. In previous GOLD documents, recommendations formanagement of COPD were based solely on spirometriccategory. However, there is considerable evidence that the ORlevel of FEV1 is a poor descriptor of disease status and forthis reason the management of stable COPD based ona strategy considering both disease impact (determined Rmainly by symptom burden and activity limitation) and futurerisk of disease progression (especially of exacerbations) is TErecommended. AL9. Chapter 5, Management of Exacerbations, presents arevised definition of a COPD exacerbation.10. Chapter 6, Comorbidities and COPD, focuses on T NOcardiovascular diseases, osteoporosis, anxiety anddepression, lung cancer, infections, and metabolic syndromeand diabetes. O -D AL Table A. Description of Levels of Evidence RI Evidence Catagory Sources of Evidence Definition TE 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. MA 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 ED 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. HT Nonrandomized trials. Evidence is from outcomes of uncontrolled or nonrandomized trials or from C Observational studies. observational studies IG This category is used only in cases where the provision of some guidance was deemed YR 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 P CO ix
  12. 12. CE CHAPTER 1: DEFINITION AND OVERVIEW U KEY POINTS: Many previous definitions of COPD have emphasized the OD 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 PR 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 RE 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 OR 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 R • Inhaled cigarette smoke and other noxious particles TE such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be modified in patients who develop COPD. This chronic AL 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 NO 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 O each of two consecutive years, remains a clinically and epidemiologically useful term. However, it is important -D to recognize that chronic cough and sputum productionDEFINITION (chronic bronchitis) is an independent disease entity that may precede or follow the development of airflow ALChronic 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 RIpersistent airflow limitation that is usually progressive and also exists in patients with normal spirometry.associated with an enhanced chronic inflammatory response BURDEN OF COPD TEin the airways and the lung to noxious particles or gases.Exacerbations and comorbidities contribute to the overallseverity in individual patients. COPD is a leading cause of morbidity and mortality MA worldwide and results in an economic and socialThe chronic airflow limitation characteristic of COPD is burden that is both substantial and increasing2,5. COPDcaused by a mixture of small airways disease (obstructive prevalence, morbidity, and mortality vary across countries and across different groups within countries. COPD is the EDbronchiolitis) and parenchymal destruction (emphysema),the relative contributions of which vary from person result of cumulative exposures over decades. Often, theto person (Figure 1.1). Chronic inflammation causes prevalence of COPD is directly related to the prevalence HTstructural 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 resultingprocesses, leads to the loss of alveolar attachments to the from the burning of wood and other biomass fuels – are IGsmall airways and decreases lung elastic recoil; in turn, major COPD risk factors6. The prevalence and burden ofthese changes diminish the ability of the airways to remain COPD are projected to increase in the coming decades YRopen during expiration. Airflow limitation is best measured due to continued exposure to COPD risk factors and theby spirometry, as this is the most widely available, changing age structure of the world’s population (with morereproducible test of lung function. people living longer and therefore expressing the long-term P effects of exposure to COPD risk factors)5. Information CO on the burden of COPD can be found on international2 DEFINITION AND OVERVIEW
  13. 13. CEWebsites such as those of the World Health Organization impairment, diabetes mellitus) that are related to COPD(WHO) ( and the World Bank/WHO and may have an impact on the patient’s health status, asGlobal Burden of Disease Study ( well as interfere with COPD management. Uglobal_burden_of_disease). Aging itself is a risk factor for ODCOPD and aging of the airways and parenchyma mimic Mortalitysome of the structural changes associated with COPD7. The World Health Organization publishes mortality statistics PRPrevalence for selected causes of death annually for all WHO regions; additional information is available from the WHO EvidenceExisting COPD prevalence data show remarkable variation for Health Policy Department ( REdue 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. Inprevalence are those based on self-reporting of a doctor the 10th revision of the ICD, deaths from COPD or chronic ORdiagnosis of COPD or equivalent condition. For example, airways obstruction are included in the broad category ofmost 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. Thislikely reflects the widespread under-recognition and under- Under-recognition and under-diagnosis of COPD still affect Rdiagnosis of COPD9. the accuracy of mortality data14,15. Although COPD is often TE a primary cause of death, it is more likely to be listed asDespite the complexities, data are emerging that a contributory cause of death or omitted from the deathenable some conclusions to be drawn regarding COPD certificate entirely16. However, it is clear that COPD is one ALprevalence, 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 thatcarried out in 28 countries between 1990 and 20048, and COPD, which ranked sixth as a cause of death in 1990, Tan additional study from Japan10, provide evidence that will become the third leading cause of death worldwide by NOthe prevalence of COPD is appreciably higher in smokers 2020; a newer projection estimated COPD will be the fourthand ex-smokers than in nonsmokers, in those over 40 leading cause of death in 20305. This increased mortalityyears 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. Oof Obstructive Lung Disease (PLATINO)11 examined the ischemic heart disease, infectious diseases), and aging of -Dprevalence 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 ALand Venezuela. In each country, the prevalence of COPDincreased steeply with age, with the highest prevalence COPD is associated with significant economic burden. Inamong those over age 60, ranging in the total population the European Union, the total direct costs of respiratory RIfrom a low of 7.8% in Mexico City, Mexico to a high of disease are estimated to be about 6% of the total health19.7% in Montevideo, Uruguay. In all cities/countries the care budget, with COPD accounting for 56% (38.6 billion TEprevalence was appreciably higher in men than in women11, Euros) of this cost of respiratory disease17. In the Unitedwhich contrasts with findings from European cities such States the estimated direct costs of COPD are $29.5 billion MAas Salzburg12. The Burden of Obstructive Lung Diseases and the indirect costs $20.4 billion18. COPD exacerbationsprogram (BOLD) has carried out surveys in several parts of account for the greatest proportion of the total COPDthe world13 and has documented more severe disease than burden on the health care system. Not surprisingly, there ispreviously found and a substantial prevalence (3-11%) of a striking direct relationship between the severity of COPD EDCOPD among never-smokers. and the cost of care, and the distribution of costs changes as the disease progresses. For example, hospitalizationMorbidity and ambulatory oxygen costs soar as COPD severity HT increases. Any estimate of direct medical expenditures forMorbidity measures traditionally include physician visits, home care under-represents the true cost of home care to IGemergency department visits, and hospitalizations. society, because it ignores the economic value of the careAlthough COPD databases for these outcome parameters provided to those with COPD by family members.are less readily available and usually less reliable than YRmortality databases, the limited data available indicate that In developing countries, direct medical costs may be lessmorbidity due to COPD increases with age10-12. Morbidity important than the impact of COPD on workplace and Pfrom COPD may be affected by other comorbid chronic home productivity. Because the health care sector mightconditions (e.g., cardiovascular disease, musculoskeletal CO not provide long-term supportive care services for severely DEFINITION AND OVERVIEW 3
  14. 14. CEdisabled 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 lifetimemember who must now stay home to care for the disabled exposure to risk factors. Understanding the relationships Urelative. Since human capital is often the most important and interactions among risk factors requires further ODnational asset for developing countries, the indirect costs of investigation.COPD may represent a serious threat to their economies. Genes PRSocial Burden The genetic risk factor that is best documented is a severeSince mortality offers a limited perspective on the human hereditary deficiency of alpha-1 antitrypsin26, a major REburden of a disease, it is desirable to find other measures circulating inhibitor of serine proteases. Although alpha-1of disease burden that are consistent and measurable antitrypsin deficiency is relevant to only a small part of theacross nations. The authors of the Global Burden of world’s population, it illustrates the interaction between ORDisease Study designed a method to estimate the fraction genes and environmental exposures leading to COPD.of mortality and disability attributable to major diseasesand injuries using a composite measure of the burden A significant familial risk of airflow limitation hasof each health problem, the Disability-Adjusted Life Year been observed in smoking siblings of patients with R(DALY)2,19,20. The DALYs for a specific condition are the severe COPD27, suggesting that genetic together with TEsum 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 matrixdisability. In 1990, COPD was the twelfth leading cause of metalloproteinase 12 (MMP12) have been related to ALDALYs 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 forleading cause of DALYs lost worldwide in 20305. the alpha-nicotinic acetylcholine receptor as well as the T hedge-hog interacting protein gene and possibly one or two NO 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. O PROGRESSION -D Age and GenderAlthough cigarette smoking is the best-studied COPD Age is often listed as a risk factor for COPD. It is unclear if ALrisk factor, it is not the only one and there is consistent healthy aging as such leads to COPD or if age reflects theevidence 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 RIthe evidence concerning risk factors for COPD comes were greater among men than women but data fromfrom cross-sectional epidemiological studies that identify developed countries18,34 show that the prevalence of the TEassociations rather than cause-and-effect relationships. disease is now almost equal in men and women, probablyAlthough several longitudinal studies of COPD have reflecting the changing patterns of tobacco smoking. MAfollowed groups and populations for up to 20 years25, none Some studies have even suggested that women are morehas 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 periodswhich may be important in shaping an individual’s future Lung Growth and Development EDCOPD risk. Thus, current understanding of risk factors forCOPD is in many respects still incomplete. Lung growth is related to processes occurring during gestation, birth, and exposures during childhood and HTCOPD results from a gene-environment interaction. Among adolescence39,40. Reduced maximal attained lung functionpeople with the same smoking history, not all will develop (as measured by spirometry) may identify individuals who IGCOPD 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 YRmay 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 andor experiences certain occupational or environmental meta-analysis confirmed a positive association between Pexposures; socioeconomic status may be linked to a child’s birth weight and FEV1 in adulthood42, and several studiesbirth weight (as it impacts on lung growth and development have found an effect of early childhood lung infections. CO4 DEFINITION AND OVERVIEW
  15. 15. CEA study found that factors in early life termed “childhood Socioeconomic Statusdisadvantage factors” were as important as heavy smokingin predicting lung function in early adult life43. Poverty is clearly a risk factor for COPD but the U components of poverty that contribute to this are unclear. ODExposure to Particles There is strong evidence that the risk of developing COPD is inversely related to socioeconomic status69. It is notAcross the world, cigarette smoking is the most commonly clear, however, whether this pattern reflects exposures PRencountered risk factor for COPD. Cigarette smokers to indoor and outdoor air pollutants, crowding, poorhave a higher prevalence of respiratory symptoms and nutrition, infections, or other factors that are related to lowlung function abnormalities, a greater annual rate of socioeconomic status. REdecline in FEV1, and a greater COPD mortality rate thannonsmokers44. Other types of tobacco (e.g., pipe, cigar, Asthma/Bronchial Hyperreactivitywater pipe45) and marijuana46 are also risk factors forCOPD47,48. Passive exposure to cigarette smoke (also OR 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 fromalso contribute to respiratory symptoms49 and COPD50 by a longitudinal cohort of the Tucson Epidemiological Studyincreasing the lung’s total burden of inhaled particles and of Airway Obstructive Disease, adults with asthma were Rgases51,52. Smoking during pregnancy may also pose a risk found to have a twelve-fold higher risk of acquiring COPDfor the fetus, by affecting lung growth and development in TE over time than those without asthma, after adjusting forutero and possibly the priming of the immune system53,54. smoking70. Another longitudinal study of people with asthma found that around 20% of subjects developed ALOccupational exposures, including organic and irreversible airflow limitation and reduced transferinorganic dusts and chemical agents and fumes, are an coefficient71, and in a longitudinal study self-reportedunderappreciated risk factor for COPD55-57. An analysis asthma was associated with excess loss of FEV1 inof the large U.S. population-based NHANES III survey T the general population72. In the European Communityof almost 10,000 adults aged 30-75 years estimated the NO Respiratory Health Survey, bronchial hyperresponsivenessfraction of COPD attributable to work was 19.2% overall, was second only to cigarette smoking as the leading riskand 31.1% among never-smokers58. These estimates are factor for COPD, responsible for 15% of the populationconsistent with a statement published by the American attributable risk (smoking had a population attributable OThoracic Society that concluded that occupational risk of 39%)73. The pathology of chronic airflow limitationexposures account for 10-20% of either symptoms or -D in asthmatic nonsmokers and non-asthmatic smokers isfunctional impairment consistent with COPD59. The risk markedly different, suggesting that the two disease entitiesfrom occupational exposures in less regulated areas of the may remain different even when presenting with similarlyworld is likely to be much higher than reported in studies AL reduced lung function74. However, clinically separatingfrom Europe and North America. asthma from COPD may not be easy. RIWood, animal dung, crop residues, and coal, typically Bronchial hyperreactivity can exist without a clinicalburned in open fires or poorly functioning stoves, may diagnosis of asthma and has been shown to be an TElead to very high levels of indoor air pollution. Evidence independent predictor of COPD in population studies75 ascontinues to grow that indoor pollution from biomass well as an indicator of risk of excess decline in lung functioncooking and heating in poorly ventilated dwellings is an MA in patients with mild COPD76.important risk factor for COPD60-66. Almost 3 billion peopleworldwide use biomass and coal as their main source of Chronic Bronchitisenergy for cooking, heating, and other household needs, sothe population at risk worldwide is very large63,67. ED In the seminal study by Fletcher and coworkers, chronic bronchitis was not associated with decline in lungHigh levels of urban air pollution are harmful to individuals function77. However, subsequent studies have found an HTwith existing heart or lung disease. The role of outdoor association between mucus hypersecretion and FEV1air pollution in causing COPD is unclear, but appears to decline78, and in younger adults who smoke the presencebe small when compared with that of cigarette smoking. of chronic bronchitis is associated with an increased IGIt has also been difficult to assess the effects of single likelihood of developing COPD79,80.pollutants in long-term exposure to atmospheric pollution. YRHowever, air pollution from fossil fuel combustion, primarily Infectionsfrom motor vehicle emissions in cities, is associated withdecrements of respiratory function68. The relative effects of A history of severe childhood respiratory infection has Pshort-term, high-peak exposures and long-term, low-level been associated with reduced lung function and increased COexposures are yet to be resolved. respiratory symptoms in adulthood39,73. Susceptibility to DEFINITION AND OVERVIEW 5
  16. 16. CEinfections plays a role in exacerbations of COPD but the increased in the exhaled breath condensate, sputum, andeffect on the development of the disease is less clear. systemic circulation of COPD patients. Oxidative stress isHIV infection has been shown to accelerate the onset further increased in exacerbations. Oxidants are generated Uof smoking-related emphysema81. Tuberculosis has by cigarette smoke and other inhaled particulates, andbeen found to be a risk factor for COPD82,83. In addition, OD released from activated inflammatory cells such astuberculosis is both a differential diagnosis to COPD and a macrophages and neutrophils. There may also be apotential comorbidity83,84. reduction in endogenous antioxidants in COPD patients as PR a result of reduction in a transcription factor called Nrf2 that regulates many antioxidant genes89.PATHOLOGY, PATHOGENESIS REAND PATHOPHYSIOLOGY Protease-Antiprotease Imbalance. There is compelling evidence for an imbalance in the lungs of COPD patients between proteases that break down connective tissueInhaled cigarette smoke and other noxious particles such ORas 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 andpatients who develop COPD. This chronic inflammatory epithelial cells, are increased in COPD patients. Thereresponse may induce parenchymal tissue destruction is increasing evidence that they may interact with each R(resulting in emphysema), and disrupt normal repair and other. Protease-mediated destruction of elastin, a major TEdefense mechanisms (resulting in small airway fibrosis). connective tissue component in lung parenchyma, isThese pathological changes lead to air trapping and believed to be an important feature of emphysema and isprogressive airflow limitation. A brief overview follows likely to be irreversible. ALof the pathologic changes in COPD, their cellular andmolecular mechanisms, and how these underlie physiologic Inflammatory Cells. COPD is characterized by a specificabnormalities and symptoms characteristic of the disease85 pattern of inflammation involving increased numbers of T CD8+ (cytotoxic) Tc1 lymphocytes present only in smokers NOPathology that develop the disease85. These cells, together with neutrophils and macrophages, release inflammatoryPathological changes characteristic of COPD are mediators and enzymes and interact with structuralfound in the airways, lung parenchyma, and pulmonary cells in the airways, lung parenchyma and pulmonary Ovasculature86. The pathological changes include chronic vasculature90.inflammation, with increased numbers of specific -Dinflammatory cell types in different parts of the lung, and Inflammatory Mediators. The wide variety of inflammatorystructural changes resulting from repeated injury and repair. mediators that have been shown to be increased in COPDIn general, the inflammatory and structural changes in AL patients91 attract inflammatory cells from the circulationthe airways increase with disease severity and persist on (chemotactic factors), amplify the inflammatory processsmoking cessation. (proinflammatory cytokines), and induce structural changes RIPathogenesis (growth factors)92. TEThe 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 MAof the respiratory tract to chronic irritants such as cigarette chronic inflammation of the respiratory tract, there aresmoke. The mechanisms for this amplified inflammation differences in the inflammatory cells and mediators involvedare not yet understood but may be genetically determined. in the two diseases, which in turn account for differences inPatients can clearly develop COPD without smoking, but physiological effects, symptoms, and response to therapy74. EDthe nature of the inflammatory response in these patients is Some patients with COPD have features consistent withunknown. Oxidative stress and an excess of proteinases in asthma and may have a mixed inflammatory pattern withthe lung further modify lung inflammation. Together, these increased eosinophils. HTmechanisms lead to the characteristic pathological changesin COPD. Lung inflammation persists after smoking Pathophysiologycessation through unknown mechanisms, although IG There is now a good understanding of how the underlyingautoantigens and persistent microorganisms may play a disease process in COPD leads to the characteristicrole87. physiologic abnormalities and symptoms. For example, YR inflammation and narrowing of peripheral airways leadsOxidative Stress. Oxidative stress may be an important to decreased FEV1. Parenchymal destruction due to Pamplifying mechanism in COPD88. Biomarkers of oxidative emphysema also contributes to airflow limitation and leadsstress (e.g., hydrogen peroxide, 8-isoprostane) are to decreased gas transfer. CO6 DEFINITION AND OVERVIEW