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Gold report 2011 epoc Gold report 2011 epoc Document Transcript

  • CE Global Initiative for Chronic U OD Obstructive PR L ung RE D isease OR R TE AL T NO O -D AL RI TE MA ED GLOBAL STRATEGY FOR THE DIAGNOSIS, HT MANAGEMENT, AND PREVENTION OF IG CHRONIC OBSTRUCTIVE PULMONARY DISEASE YR REVISED 2011 PCO
  • U CE OD GLOBAL INITIATIVE FOR PR CHRONIC OBSTRUCTIVE LUNG DISEASE RE GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE OR (REVISED 2011) R TE AL T NO O -D AL RI TE MA ED HT IG YR PCO © 2011 Global Initiative for Chronic Obstructive Lung Disease, Inc. i
  • 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, www.goldcopd.org P YR CO ii
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 1 RE AND PR CHAPTER OVERVIEW OD DEFINITION UCE
  • 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
  • CEWebsites 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, asGlobal Burden of Disease Study (http://www.who.int/topics/ 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 (http://www.who.int/ 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
  • 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
  • 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
  • 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
  • CEAirflow Limitation and Air Trapping. The extent of of endothelial cell dysfunction. The loss of the pulmonaryinflammation, fibrosis, and luminal exudates in small capillary bed in emphysema may also contributeairways is correlated with the reduction in FEV1 and to increased pressure in the pulmonary circulation. UFEV1/FVC ratio, and probably with the accelerated decline Progressive pulmonary hypertension may lead to right ODin FEV1 characteristic of COPD90. This peripheral airway ventricular hypertrophy and eventually to right-side cardiacobstruction progressively traps air during expiration, failure.resulting in hyperinflation. Although emphysema is more PRassociated with gas exchange abnormalities than with Exacerbations. Exacerbations of respiratory symptomsreduced FEV1, it does contribute to gas trapping during often occur in patients with COPD, triggered by infectionexpiration. This is especially so as alveolar attachments with bacteria or viruses (which may coexist), environmental REto small airways are destroyed when the disease becomes pollutants, or unknown factors. Patients with bacterialmore severe. Hyperinflation reduces inspiratory capacity and viral episodes have a characteristic response withsuch that functional residual capacity increases, particularly increased inflammation. During respiratory exacerbations ORduring exercise (dynamic hyperinflation), resulting in there is increased hyperinflation and gas trapping, withincreased dyspnea and limitation of exercise capacity. reduced expiratory flow, thus accounting for the increasedThese 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 Rin upregulation of local pro-inflammatory cytokines. It is (pneumonia, thromboembolism, and acute cardiac failure) TEthought 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 ALtrapping, thereby reducing lung volumes and improving patients with COPD have comorbidities that have a majorsymptoms and exercise capacity93. impact on quality of life and survival100. Airflow limitation and particularly hyperinflation affect cardiac function and TGas Exchange Abnormalities. Gas exchange gas exchange101. Inflammatory mediators in the circulation NOabnormalities 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 ischemicgas transfer for oxygen and carbon dioxide worsens as heart disease, heart failure, osteoporosis, normocyticthe disease progresses. Reduced ventilation may also anemia, diabetes, metabolic syndrome, and depression. Obe due to reduced ventilatory drive. This may lead to -Dcarbon dioxide retention when it is combined with reducedventilation due to a high work of breathing becauseof severe obstruction and hyperinflation coupled with ALventilatory muscle impairment. The abnormalities inalveolar ventilation and a reduced pulmonary vascular bedfurther worsen the VA/Q abnormalities95. RIMucus Hypersecretion. Mucus hypersecretion, resulting TEin a chronic productive cough, is a feature of chronicbronchitis and is not necessarily associated with airflow MAlimitation. Conversely, not all patients with COPD havesymptomatic mucus hypersecretion. When present, it isdue to an increased number of goblet cells and enlargedsubmucosal glands in response to chronic airway irritation EDby cigarette smoke and other noxious agents. Severalmediators and proteases stimulate mucus hypersecretionand many of them exert their effects through the activation HTof epidermal growth factor receptor (EGFR)96. IGPulmonary Hypertension. Pulmonary hypertension maydevelop late in the course of COPD and is due mainlyto hypoxic vasoconstriction of small pulmonary arteries, YReventually resulting in structural changes that includeintimal hyperplasia and later smooth muscle hypertrophy/ Phyperplasia97. There is an inflammatory response invessels similar to that seen in the airways and evidence CO DEFINITION AND OVERVIEW 7
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR RE PR OD UCE
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 2 RE AND PR CHAPTER OD DIAGNOSIS U ASSESSMENT CE
  • CE CHAPTER 2: DIAGNOSIS AND ASSESSMENT U OD KEY POINTS: longer recommended. The degree of reversibility has never been shown to add to the diagnosis, differential diagnosis with asthma, or to predicting the response to long-term • A clinical diagnosis of COPD should be considered PR treatment with bronchodilators or corticosteroids. in any patient who has dyspnea, chronic cough or sputum production, and/or a history of exposure to Table 2.1. Key Indicators for RE risk factors for the disease. Considering a Diagnosis of COPD • Spirometry is required to make the diagnosis in this clinical context; the presence of a post-bronchodilator Consider COPD, and perform spirometry, if any of these indicators are present FEV1/FVC < 0.70 confirms the presence of persistent OR in an individual over age 40. These indicators are not diagnostic themselves, but airflow limitation and thus of COPD. the presence of multiple key indicators increases the probability of a diagnosis of COPD. Spirometry is required to establish a diagnosis of COPD. • The goals of COPD assessment are to determine the severity of the disease, including the severity R Dyspnea that is: Progressive (worsens over time). of airflow limitation, the impact on the patient’s Characteristically worse with exercise. TE health status, and the risk of future events (such as Persistent. exacerbations, hospital admissions, or death), in order to guide therapy. Chronic cough: May be intermittent and may be unproductive. AL • Comorbidities occur frequently in COPD patients, including cardiovascular disease, skeletal muscle Chronic sputum production: dysfunction, metabolic syndrome, osteoporosis, T Any pattern of chronic sputum production may indicate COPD. depression, and lung cancer. Given that they can NO History of exposure to risk factors: occur in patients with mild, moderate and severe airflow limitation and influence mortality and Tobacco smoke (including popular local preparations). Smoke from home cooking and heating fuels. hospitalizations independently, comorbidities should Occupational dusts and chemicals. O be actively looked for, and treated appropriately if present. -D Family history of COPD The role of screening spirometry in the general populationDIAGNOSIS AL is controversial. Both FEV1 and FVC predict all-cause mortality independent of tobacco smoking, and abnormalA clinical diagnosis of COPD should be considered in lung function identifies a subgroup of smokers at increased RIany patient who has dyspnea, chronic cough or sputum risk for lung cancer. This has been the basis of anproduction, and/or a history of exposure to risk factors for argument that screening spirometry should be employed TEthe disease (Table 2.1). Spirometry is required to make as a global health assessment tool102,103. However,the diagnosis in this clinical context; the presence of a post- there are no data to indicate that screening spirometry is MAbronchodilator FEV1/FVC < 0.70 confirms the presence of effective in directing management decisions or in improvingpersistent airflow limitation and thus of COPD. COPD outcomes in patients who are identified before the development of significant symptoms104. Thus, GOLD EDThe spirometric criterion for airflow limitation remains a advocates active case finding but not screening spirometry.post-bronchodilator fixed ratio of FEV1/FVC < 0.70. Thiscriterion is simple, independent of reference values, The use of the fixed FEV1/FVC ratio to define airflow HTand has been used in numerous clinical trials forming limitation will result in more frequent diagnosis of COPD inthe evidence base from which most of our treatment the elderly105, and less frequent diagnosis in adults youngerrecommendations are drawn. Diagnostic simplicity and than 45 years106, especially of mild disease, compared to IGconsistency are key for the busy non-specialist clinician. using a cutoff based on the lower limit of normal (LLN) values for FEV1/FVC. These LLN values are based on YRWhile post-bronchodilator spirometry is required for the the normal distribution and classify the bottom 5% ofdiagnosis and assessment of severity of COPD, the degree the healthy population as abnormal. From a scientific Pof reversibility of airflow limitation (e.g., measuring FEV1 perspective it is difficult to determine which of these criteriabefore and after bronchodilator or corticosteroids) is no is correct to diagnose COPD107, and no studies exist CO10 DIAGNOSIS AND ASSESSMENT
  • CEcomparing clinical diagnosis based on the two approaches. production in COPD patients. Sputum production is oftenHowever, LLN values are highly dependent on the choice of difficult to evaluate because patients may swallow sputumvalid reference equations using post-bronchodilator FEV1, rather than expectorate it, a habit subject to significant Uand neither longitudinal studies validating the use of the cultural and gender variation. Patients producing large ODLLN nor studies using reference equations in populations volumes of sputum may have underlying bronchiectasis.where smoking is not the major cause of COPD areavailable. The risk of misdiagnosis and over-treatment Table 2.2. Causes of Chronic Cough PRof individual patients using the fixed ratio as a diagnostic Intrathoraciccriterion is limited, as spirometry is only one parameter • Chronic obstructive pulmonary diseasefor establishing the clinical diagnosis of COPD, the others RE • Asthmabeing symptoms and risk factors. • Lung cancer • Tuberculosis • BronchiectasisSymptoms OR • Left heart failure • Interstitial lung diseaseThe characteristic symptoms of COPD are chronic and • Cystic fibrosisprogressive dyspnea, cough, and sputum production. • Idiopathic cough RChronic cough and sputum production may precede Extrathoracicthe development of airflow limitation by many years. TE • Chronic allergic rhinitisIndividuals, particularly those exposed to COPD risk • Upper Airway Cough Syndrome (UACS)factors, who present with these symptoms should be • Gastroesophageal reflux AL • Medication (e.g., ACE inhibitors)examined to search for an underlying cause(s) andappropriate interventions taken. Conversely, significantairflow limitation may develop without chronic cough and The presence of purulent sputum reflects an increase Tsputum production. Although COPD is defined on the basis in inflammatory mediators113, and its development may NOof airflow limitation, in practice the decision to seek medical identify the onset of a bacterial exacerbation114.help (and so permit the diagnosis to be made) is usuallydetermined by the impact of a symptom on a patient’s daily Wheezing and Chest Tightness. Wheezing and chest tightness are nonspecific symptoms that may vary between Olife. A person may seek medical attention either because ofchronic symptoms or because of a first exacerbation. days, and over the course of a single day. Audible -D wheeze may arise at a laryngeal level and need not beDyspnea. Dyspnea, a cardinal symptom of COPD, is a accompanied by auscultatory abnormalities. Alternatively,major cause of disability and anxiety associated with the widespread inspiratory or expiratory wheezes can be ALdisease. Typical COPD patients describe their dyspnea present on listening to the chest. Chest tightness oftenas a sense of increased effort to breathe, heaviness, air follows exertion, is poorly localized, is muscular in RIhunger, or gasping108. However, the terms used to describe character, and may arise from isometric contraction of thedyspnea vary both by individual and by culture109. intercostal muscles. An absence of wheezing or chest TE tightness does not exclude a diagnosis of COPD, nor doesCough. Chronic cough, often the first symptom of COPD the presence of these sypmtoms confirm a diagnosis ofto develop110, is frequently discounted by the patient as an asthma. MAexpected consequence of smoking and/or environmentalexposures. Initially, the cough may be intermittent, but Additional Features in Severe Disease. Fatigue, weightlater is present every day, often throughout the day. The loss and anorexia are common problems in patients with EDchronic cough in COPD may be unproductive111. In some severe and very severe COPD115. They are prognosticallycases, significant airflow limitation may develop without important116 and can also be a sign of other diseases (e.g.,the presence of a cough. Table 2.2 lists some of the other tuberculosis, lung cancer), and therefore should always HTcauses of chronic cough. be investigated. Cough syncope occurs due to rapid increases in intrathoracic pressure during prolonged attacks IGSputum production. COPD patients commonly raise of coughing. Coughing spells may also cause rib fractures,small quantities of tenacious sputum after coughing bouts. which are sometimes asymptomatic. Ankle swelling may YRRegular production of sputum for 3 or more months in 2 be the only symptomatic pointer to the development of corconsecutive years (in the absence of any other conditions pulmonale. Symptoms of depression and/or anxiety meritthat may explain it) is the epidemiological definition of specific enquiry in the clinical history because they are Pchronic bronchitis112, but this is a somewhat arbitrary common in COPD117 and are associated with increased risk COdefinition that does not reflect the range of sputum of exacerbations and poorer health status. DIAGNOSIS AND ASSESSMENT 11
  • CEMedical History Spirometry should measure the volume of air forcibly exhaled from the point of maximal inspiration (forcedA detailed medical history of a new patient known or vital capacity, FVC) and the volume of air exhaled during Uthought to have COPD should assess: the first second of this maneuver (forced expiratory OD volume in one second, FEV1), and the ratio of these two• Patient’s exposure to risk factors, such as smoking and measurements (FEV1/FVC) should be calculated. The occupational or environmental exposures ratio between FEV1 and slow vital capacity (VC), FEV1/ PR• Past medical history, including asthma, allergy, sinusitis, VC, is sometimes measured instead of the FEV1/FVC ratio. or nasal polyps; respiratory infections in childhood; This will often lead to lower values of the ratio, especially in other respiratory diseases pronounced airflow limitation; however, the cut-off point of RE• Family history of COPD or other chronic respiratory disease 0.7 should still be applied. Spirometry measurements are• Pattern of symptom development: COPD typically evaluated by comparison with reference values122 based on develops in adult life and most patients are conscious age, height, sex, and race. OR of increased breathlessness, more frequent or prolonged “winter colds,” and some social restriction for a number of years before seeking medical help Table 2.3. Considerations in Performing Spirometry R• History of exacerbations or previous hospitalizations for Preparation respiratory disorder: Patients may be aware of periodic TE • Spirometers need calibration on a regular basis. worsening of symptoms even if these episodes have • Spirometers should produce hard copy or have a digital display of the not been identified as exacerbations of COPD expiratory curve to permit detection of technical errors or have an automatic AL prompt to identify an unsatisfactory test and the reason for it.• Presence of comorbidities, such as heart disease, • The supervisor of the test needs training in its effective performance. osteoporosis, musculoskeletal disorders, and • Maximal patient effort in performing the test is required to avoid malignancies that may also contribute to restriction of T underestimation of values and hence errors in diagnosis and management. activity118 Bronchodilation NO • Possible dosage protocols are 400 mcg beta2-agonist, 160 mcg anticholinergic,• Impact of disease on patient’s life, including limitation of or the two combined122. FEV1 should be measured 10-15 minutes after a activity, missed work and economic impact, effect on short-acting beta2-agonist is given, or 30-45 minutes after a short-acting family routines, feelings of depression or anxiety, well anticholinergic or a combination. O being and sexual activity Performance • Spirometry should be performed using techniques that meet published• Social and family support available to the patient -D standards123.• Possibilities for reducing risk factors, especially smoking • The expiratory volume/time traces should be smooth and free from irregularities. cessation • The recording should go on long enough for a volume plateau to be reached, which may take more than 15 seconds in severe disease. AL • Both FVC and FEV1 should be the largest value obtained from any of 3Physical Examination technically satisfactory curves and the FVC and FEV1 values in these three curves should vary by no more than 5% or 100 ml, whichever is greater. RIAlthough an important part of patient care, a physical • The FEV1/FVC ratio should be taken from the technically acceptable curve withexamination is rarely diagnostic in COPD. Physical signs the largest sum of FVC and FEV1. Evaluation TEof airflow limitation are usually not present until significant • Spirometry measurements are evaluated by comparison of the results withimpairment of lung function has occurred119,120, and their appropriate reference values based on age, height, sex, and race.detection has a relatively low sensitivity and specificity. A • The presence of a postbronchodilator FEV1/FVC < 0.70 confirms the presence MAnumber of physical signs may be present in COPD, but of airflow limitation.their absence does not exclude the diagnosis. Figure 2.1A shows a normal spirometry tracing; Figure EDSpirometry 2.1B a spirometry tracing typical of a patient with obstructive disease. Patients with COPD typically show aSpirometry is the most reproducible and objective decrease in both FEV1 and FVC. HTmeasurement of airflow limitation available. Peakexpiratory flow measurement alone cannot be reliably used ASSESSMENT OF DISEASE IGas the only diagnostic test, despite its good sensitivity,because of its weak specificity121. Good quality spirometric The goals of COPD assessment are to determine the YRmeasurement is possible in any health care setting and all severity of the disease, its impact on the patient’s healthhealth care workers who care for COPD patients should status and the risk of future events (such as exacerbations,have access to spirometry. Table 2.3 summarizes some of hospital admissions or death), in order to, eventually, guide Pthe factors needed to achieve accurate test results. therapy. To achieve these goals, COPD assessment must CO consider the following aspects of the disease separately:12 DIAGNOSIS AND ASSESSMENT
  • CE Figure 2.1A. Spirometry - Normal Trace Figure 2.1B. Spirometry - Obstructive Disease U OD 5 5 4 4 Vo ume, liters Vo ume, liters FEV1 = 4L 3 PR 3 FEV1 = 1.8L FVC = 5L 2 l FVC = 3.2L Obstructive l 2 FEV1/FVC = 0.8 1 FEV1/FVC = 0.56 RE 1 1 2 3 4 5 6 1 2 3 4 5 6 Time, seconds Time, seconds OR• Current level of patient’s symptoms Table 2.4. Modified Medical Research• Severity of the spirometric abnormality Council Questionnaire for Assessing R• Exacerbation risk the Severity of Breathlessness TE• Presence of comorbidities PLEASE TICK IN THE BOX THAT APPLIES TO YOUAssessment of Symptoms AL (ONE BOX ONLY)There are several validated questionnaires to assess mMRC Grade 0. I only get breathless with strenuous exercise. □symptoms in patients with COPD. GOLD recommends Tthe use of the Modified British Medical Research Council □ NO mMRC Grade 1. I get short of breath when hurrying on the level (mMRC) questionnaire or the COPD Assessment Test or walking up a slight hill.(CAT). The well-known mMRC questionnaire onlyassesses disability due to breathlessness; however, the mMRC Grade 2. I walk slower than people of the same age on the □ OCOPD Assessment Test has a broader coverage of the level because of breathlessness, or I have to stop for breath when -Dimpact of COPD on the patient’s daily life and well-being. walking on my own pace on the level.Breathlessness Measurement using the Modified mMRC Grade 3. I stop for breath after walking about 100 meters or □British Medical Research Council (mMRC) after a few minutes on the level. ALQuestionnaire (Table 2.4). This questionnaire relates wellto other measures of health status91 and predicts future mMRC Grade 4. I am too breathless to leave the house or I am □ RImortality risk92. breathless when dressing or undressing. TECOPD Assessment Test (CAT). The COPD Assessment However, there is only a weak correlation betweenTest is an 8-item unidimensional measure of health status FEV1, symptoms and impairment of a patient’s health- MAimpairment in COPD124. It was developed to be applicable related quality of life. This is illustrated in Figure 2.2worldwide and validated translations are available in a in which health-related quality of life is plotted againstwide range of languages. The score ranges from 0-40; it post-bronchodilator FEV1126,127 with the GOLD spirometriccorrelates very closely with health status measured unsing ED classification superimposed. The figure illustrates that,the St. George Respiratory Questionaire (SGRQ) and is within any given category, patients may have anythingreliable and responsive125 (http://www.catestonline.org). between relatively well preserved to very poor health HT status. For this reason, formal symptomatic assessment isSpirometric Assessment also required. IGTable 2.5 shows the classification of airflow limitation Assessment of Exacerbation Riskseverity in COPD. Specific spirometric cut-points are YRused for purposes of simplicity. Spirometry should be An exacerbation of COPD is defined as an acute eventperformed after the administration of an adequate dose of characterized by a worsening of the patient’s respiratory Pa short-acting inhaled bronchodilator in order to minimize symptoms that is beyond normal day-to-day variations andvariability. CO leads to a change in medication128-130. The rate at which DIAGNOSIS AND ASSESSMENT 13
  • CE the decline in lung function, deterioration in health status Table 2.5. Classification of Severity of Airflow and risk of death, the assessment of exacerbation risk Limitation in COPD can also be seen as an assessment of the risk of poor U (Based on Post-Bronchodilator FEV1) outcomes in general. OD In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 ≥ 80% predicted Table 2.6: RISK IN COPD: Placebo-limb data from PR GOLD 2: Moderate 50% ≤ FEV1 < 80% predicted TORCH134*, Uplift133† and Eclipse132 ≠ RE GOLD 3: Severe 30% ≤ FEV1 < 50% predicted GOLD Exacerbations Hospitalizations 3-year spirometric (per year)*†≠ (per year)* ≠ Mortality*† GOLD 4: Very Severe FEV1 < 30% predicted level GOLD 1: Mild ? ? ? OR GOLD 2: Figure 2.2. Relationship Between 0.7 – 0.9 0.11 – 0.2 11%*† Moderate Health-related Quality of Life, Post-bronchodilator GOLD 3: R FEV1 and GOLD Spirometric Classification 1.1 – 1.3 0.25 – 0.3 15%* Severe (Adapted from Jones127) TE GOLD 4: 1.2 – 2.0 0.4 – 0.54 24%* Very severe AL *Toward a Revolution in COPD Health (TORCH) study134 † Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study133 ≠ Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study132 T NO Assessment of Comorbidities Because COPD often develops in long-time smokers in O middle age, patients frequently have a variety of other -D diseases related to either smoking or aging135. COPD itself also has significant extrapulmonary (systemic) effects including weight loss, nutritional abnormalities and skeletal AL muscle dysfunction. The latter is characterized by bothexacerbations occur varies greatly between patients131. sarcopenia (loss of muscle cells) and abnormal function of RIThe best predictor of having frequent exacerbations (2 the remaining cells136. Its causes are likely multifactorialor more exacerbations per year) is a history of previous (inactivity, poor diet, inflammation, hypoxia) and it can TEtreated events132. In addition, worsening airflow limitation is contribute to exercise intolerance and poor health status inassociated with an increasing prevalence of exacerbations patients with COPD. Importantly, skeletal muscle dysfunctionand risk of death. is a remediable source of exercise intolerance137. MAA large body of data has been accumulated in patients Comorbidities that occur frequently in COPD patientsclassified using GOLD spirometric grading systems. These include cardiovascular disease, skeletal muscle EDshow an increase in risk of exacerbations, hospitalization dysfunction, metabolic syndrome, osteoporosis, depressionand death with worsening of airflow limitation. The data and lung cancer. The existence of COPD may actuallyin Table 2.6 are derived from prospectively collected data increase the risk for other diseases; this is particularly HTfrom large medium-term clinical trials132-134. They are not striking for COPD and lung cancer138-141. Whether thisprecise estimates that apply to each patient, but they association is due to common risk factors (e.g., smoking), IGillustrate clearly the increased risk of exacerbations and involvement of susceptibility genes, or impaired clearancedeath between spirometric levels. Roughly, although up to of carcinogens is not clear. Comorbidities can occur in YR20% of GOLD 2 (Moderate aiflow limitation) patients may patients with mild, moderate or severe airflow limitation131,experience frequent exacerbations requiring treatment with influence mortality and hospitalizations independently142,antibiotics and/or systemic corticosteroids132, the risk of and deserve specific treatment. Therefore, comorbidities Pexacerbations significantly increases in GOLD 3 (Severe) should be looked for routinely, and treated appropriately, in COand GOLD 4 (Very Severe). Since exacerbations increase any patient with COPD. The guidelines for the diagnosis,14 DIAGNOSIS AND ASSESSMENT
  • CEassessment of severity, and management of individual on the individual patient’s history of exacerbations132, withcomorbidities in patients with COPD are the same as two or more exacerbations in the preceding year indicatingfor all other patients. A more detailed description of the high risk. (If there is a discrepancy between the risk Umanagement of COPD and comorbidities is given in category as assessed by spirometric classification and that ODChapter 6. derived from exacerbation history, the assessment pointing to the highest risk should be used.)Combined COPD Assessment PR To use Figure 2.3, first assess symptoms with the mMRCAn understanding of the impact of COPD on an individual or CAT scale and determine if the patient belongs to the leftpatient combines the symptomatic assessment with side of the box – Less Symptoms (mMRC grade 0-1 or CAT REthe patient’s spirometric classification and/or risk of < 10) – or the right side – More Symptoms mMRC grade ≥2exacerbations. This approach to combined assessment is or CAT≥ 10).illustrated in Figure 2.3. OR Next assess the risk of exacerbations to determine if theAs detailed above, the MRC or CAT scale is recommended patient belongs to the lower part of the box – Low Riskfor assessing symptoms, with an mMRC grade ≥2 or a CAT – or the upper part of the box – High Risk. This can be Rscore ≥ 10 indicating a high level of symptoms. (The CAT done by either of two methods: (1) use spirometry toscore is preferred since it provides a more comprehensive determine the GOLD grade of airflow limitation (GOLD 1 TEassessment of the symptomatic impact of the disease; and GOLD 2 categories indicate Low Risk, while GOLDin the absence of a CAT score, mMRC scores provide 3 and GOLD 4 indicate High Risk); or (2) assess the ALan assessment of the impact of dyspnea. However, it is number of exacerbations the patient has had within theunnecessary to use more than one scale.) previous 12 months (0 or 1 indicates Low Risk, while 2 or more exacerbations indicates High Risk). In some patients,There are two methods of assessing exacerbation risk. T these two ways of assessing risk of exacerbations will not lead to the same level of risk; in this case, the risk should NOOne is a population-based method using the GOLD be determined by the method indicating High Risk.spirometric classification (Table 2.5), with GOLD 3 orGOLD 4 categories indicating high risk. The other is based Example: Imagine a patient with a CAT score of 18, FEV1 O of 55% of predicted, and a history of 3 exacerbations within Figure 2.3. Association Between Symptoms, the last 12 months. Symptom assessment using CAT -D Spirometric Classification, shows that the patient is More Symptomatic (CAT≥ 10) and Future Risk of Exacerbations and is therefore either Group B or Group D. Spirometry indicates Low Risk as the patient is GOLD 2 (Moderate AL When assessing risk, choose the highest risk airflow limitation) but as the patient had 3 exacerbations according to GOLD grade or exacerbation history within the last 12 months this indicates High Risk and RI outweighs the lower risk assessment based on spirometry. The patient therefore belongs in Group D. TE The groups can be summarized as follows: MA • Patient Group A – Low Risk, Less Symptoms Typically GOLD 1 or GOLD 2 (Mild or Moderate airflow limitation) and/or 0-1 exacerbation per year and mMRC ED grade 0-1 or CAT score < 10 • Patient Group B – Low Risk, More Symptoms HT Typically GOLD 1 or GOLD 2 (Mild or Moderate airflow limitation) and/or 0-1 exacerbation per year and mMRC IG grade ≥ 2 or CAT score ≥ 10 • Patient Group C – High Risk, Less Symptoms YR Typically GOLD 3 or GOLD 4 (Severe or Very Severe airflow limitation) and/or ≥ 2 exacerbations per year and P mMRC grade 0-1 or CAT score < 10 CO DIAGNOSIS AND ASSESSMENT 15
  • CE• Patient Group D – High Risk, More Symptoms Lung Volumes and Diffusing Capacity. COPD patients Typically GOLD 3 or GOLD 4 (Severe or Very Severe exhibit gas trapping (a rise in residual volume) from airflow limitation) and/or ≥ 2 exacerbations per year and early in the disease, and as airflow limitation worsens U mMRC grade ≥ 2 or CAT score ≥ 10 static hyperinflation (an increase in total lung capacity) OD occurs. These changes can be documented by bodyEvidence to support this classification system includes: plethysmography, or less accurately by helium dilution lung volume measurement. These measurements help PR• Patients with a high risk of exacerbations tend to be characterize the severity of COPD but are not essential to in GOLD categories 3 and 4 (Severe or Very Severe patient management. Measurement of diffusing capacity airflow limitation, Figure 2.3) and can be identified (DLCO) provides information on the functional impact of RE quite reliably from the their own past history132; emphysema in COPD and is often helpful in patients with breathlessness that may seem out of proportion with the• Higher exacerbation rates are associated with faster degree of airflow limitation. OR loss of FEV1143 and greater worsening of health status144. Oximetry and Arterial Blood Gas Measurement. Pulse oximetry can be used to evaluate a patient’s oxygen R• CAT scores ≥ 10 are associated with significantly saturation and need for supplemental oxygen therapy. impaired health status145. Pulse oximetry should be used to assess all stable TE patients with FEV1 < 35% predicted or with clinical signsEven in the absence of frequent exacerbations, patients in suggestive of respiratory failure or right heart failure. If ALGOLD categories 3 and 4 may be at greater risk of hospital peripheral saturation is < 92% arterial blood gases shouldadmission and death (Figure 2.3). These important be assessed147.increased risks form the rationale for including such Tpatients in the “High Risk” groups. Alpha-1 Antitrypsin Deficiency Screening. The World NO Health Organization recommends that COPD patientsThis approach, combined with an assessment of potential from areas with a particularly high prevalence of alpha-1comorbidities, reflects the complexity of COPD better than antitrypsin deficiency should be screened for this geneticthe unidimensional analysis of airflow limitation previously disorder148. However, the typical patient tends to present Oused for staging the disease and forms the basis of the at a younger age (< 45 years) with lower lobe emphysema. -Dguide to individualized management provided in Chapter 4. Family members can be identified and family screening is useful for appropriate counseling. A serum concentrationAdditional Investigations of alpha-1 antitrypsin below 15-20% of the normal value AL is highly suggestive of homozygous alpha-1 antitrypsinThe following additional investigations may be considered deficiency. RIas part of the diagnosis and assessment of COPD: Exercise Testing. Objectively measured exercise TEImaging. A chest X-ray is not useful to establish a impairment, assessed by a reduction in self-paceddiagnosis in COPD, but it is valuable in excluding walking distance149 or during incremental exercise testingalternative diagnoses and establishing the presence of in a laboratory150, is a powerful indicator of health status MAsignificant comorbidities such as concomitant respiratory impairment and predictor of prognosis151. Walking tests can(pulmonary fibrosis, bronchiectasis, pleural diseases), be useful for assessing disability and are used to assessskeletal (e.g., kyphoscoliosis), and cardiac diseases the effectiveness of pulmonary rehabilitation. Both the ED(e.g., cardiomegaly). Radiological changes associated paced shuttle walk tests152,153 and the unpaced 6-minutewith COPD include signs of lung hyperinflation (flattened walk test can be used154. Laboratory testing using cycle ordiaphragm on the lateral chest film, and an increase in treadmill ergometry can identify co-existing or alternative HTthe volume of the retrosternal air space), hyperlucency conditions, e.g., cardiac diagnoses. Monitoring of physicalof the lungs, and rapid tapering of the vascular markings. activity may be more relevant regarding prognosis thanComputed tomography (CT) of the chest is not routinely IG evaluating exercise capacity155. This can be done usingrecommended. However, when there is doubt aboutthe diagnosis of COPD, CT scanning might help in the accelerometers or multisensor instruments. YRdifferential diagnosis where concomitant diseases arepresent. In addition, if a surgical procedure such as lung Composite Scores. Several variables including FEV1,volume reduction is contemplated, a chest CT scan is exercise tolerance assessed by walking distance or Pnecessary since the distribution of emphysema is one of peak oxygen consumption, weight loss, and reduction in COthe most important determinants of surgical suitability146. arterial oxygen tension identify patients at increased risk16 DIAGNOSIS AND ASSESSMENT
  • CEfor mortality. A relatively simple approach to identifyingdisease severity using a combination of most of the above Table 2.7. COPD and its Differential Diagnosesvariables has been proposed. The BODE method gives a Ucomposite score (Body mass index, Obstruction, Dyspnea, Diagnosis Suggestive Features ODand Exercise) that is a better predictor of subsequent COPD Onset in mid-life.survival than any component singly156, and its properties Symptoms slowly progressive.as a measurement tool are under investigation. Simpler History of tobacco smoking or exposure PRalternatives not including an exercise test have been to other types of smoke.suggested but all these approaches need validation acrossa wide range of disease severities and in different clinical Asthma Onset early in life (often childhood). REsettings to confirm that they are suitable for routine clinical Symptoms vary widely from day to day.use157,158. Symptoms worse at night/early morning. Allergy, rhinitis, and/or eczema also ORDifferential Diagnosis present. Family history of asthma.In some patients with chronic asthma, a clear distinction Rfrom COPD is not possible using current imaging andphysiological testing techniques, and it is assumed that Congestive Heart Failure Chest X-ray shows dilated heart, TEasthma and COPD coexist in these patients. In these pulmonary edema.cases, current management will include use of anti- Pulmonary function tests indicate ALinflammatory drugs and other treatments need to be volume restriction, not airflow limitation.individualized. Other potential diagnoses are usually easierto distinguish from COPD (Table 2.7). Bronchiectasis T Large volumes of purulent sputum. Commonly associated with bacterial NO infection. Chest X-ray/CT shows bronchial dilation, bronchial wall thickening. O Tuberculosis Onset all ages. -D Chest X-ray shows lung infiltrate. Microbiological confirmation. High local prevalence of tuberculosis. AL Obliterative Bronchiolitis Onset at younger age, nonsmokers. RI May have history of rheumatoid arthritis or acute fume exposure. TE Seen after lung or bone marrow transplantation. CT on expiration shows hypodense MA areas. Diffuse Panbronchiolitis Predominantly seen in patients of ED Asian descent. Most patients are male and nonsmokers. HT Almost all have chronic sinusitis. Chest X-ray and HRCT show diffuse IG small centrilobular nodular opacities and hyperinflation. YR These features tend to be characteristic of the respective diseases, but are not mandatory. For example, a person who has never smoked may develop COPD (especially in the developing world where other risk factors may be more important than P cigarette smoking); asthma may develop in adult and even in elderly patients. CO DIAGNOSIS AND ASSESSMENT 17
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR RE PR OD UCE
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 3 RE PR OPTIONS CHAPTER OD U THERAPEUTIC CE
  • CE CHAPTER 3: THERAPEUTIC OPTIONS U KEY POINTS: Pharmacologic. Varenicline164, bupropion165 and OD • In patients who smoke, smoking cessation is very nortriptyline have been shown to increase long-term quit important. Pharmacotherapy and nicotine replacement rates161,163,166, but should always be used as one element in a supportive intervention program rather than on their PR reliably increase long-term smoking abstinence rates. • Appropriate pharmacologic therapy can reduce COPD own. Although more studies need to be conducted with symptoms, reduce the frequency and severity of these medications, a randomized controlled trial with RE exacerbations, and improve health status and exercise counseling and support showed quit rates at one year of tolerance. 30% with sustained-release bupropion alone and 35% • To date, none of the existing medications for COPD with sustained-release bupropion plus nicotine patch165. The effectiveness of the antihypertensive drug clonidine is OR has been shown conclusively to modify the long-term decline in lung function. limited by side effects161. • Each pharmacological treatment regimen needs to be patient-specific, guided by severity of symptoms, risk Recommendations for treating tobacco use and R of exacerbations, drug availability, and the patient’s dependence are summarized in Table 3.1. TE response. • Influenza and pneumococcal vaccination should be Table 3.1. Treating Tobacco Use and Dependence: AL offered to every COPD patient; they appear to be more A Clinical Practice Guideline— effective in older patients and those with more severe Major Findings and Recommendations160 disease or cardiac comorbidity. • All patients who get short of breath when walking 1. T Tobacco dependence is a chronic condition that warrants repeated treatment until long-term or permanent abstinence is achieved. NO on their own pace on level ground should be offered 2. Effective treatments for tobacco dependence exist and all tobacco users should rehabilitation; it can improve symptoms, quality of life, be offered these treatments. and physical and emotional participation in everyday 3. Clinicians and health care delivery systems must institutionalize the consistent activities. identification, documentation, and treatment of every tobacco user at every O visit. 4. Brief smoking cessation counseling is effective and every tobacco user should -D be offered such advice at every contact with health care providers.SMOKING CESSATION 5. There is a strong dose-response relation between the intensity of tobacco dependence counseling and its effectiveness. 6. Three types of counseling have been found to be especially effective: practical ALSmoking cessation is the intervention with the greatest counseling, social support as part of treatment, and social support arrangedcapacity to influence the natural history of COPD. outside of treatment.Evaluation of the smoking cessation component in a long- 7. First-line pharmacotherapies for tobacco dependence—varenicline, bupropion RIterm, multicenter study indicates that if effective resources SR, nicotine gum, nicotine inhaler, nicotine nasal spray, and nicotine patch— are effective and at least one of these medications should be prescribed in theand time are dedicated to smoking cessation, 25% long- TE absence of contraindications.term quit rates can be achieved159. 8. Tobacco dependence treatments are cost effective relative to other medical and disease prevention interventions. MAPharmacotherapies for Smoking CessationNicotine Replacement Products. Nicotine replacement A five-step program for intervention (Table 3.2) providestherapy in any form (nicotine gum, inhaler, nasal spray, a strategic framework helpful to health care providers EDtransdermal patch, sublingual tablet, or lozenge) reliably interested in helping their patients stop smoking160,167-169.increases long-term smoking abstinence rates160-162 and is Because tobacco dependence is a chronic disease160,significantly more effective than placebo. Patients need to be clinicians should recognize that relapse is common and HTinformed about the proper use of these products to optimize reflects the chronic nature of dependence and addiction,efficacy. Medical contraindications to nicotine replacement not failure on the part of the clinician or the patient. IGtherapy include unstable coronary artery disease, untreatedpeptic ulcer disease, and recent myocardial infarction or Counseling delivered by physicians and other health YRstroke163. Continuous chewing of nicotine gum produces professionals significantly increases quit rates over self-secretions that are swallowed rather than absorbed through initiated strategies170 (Evidence A). Even a brief (3-minute)the buccal mucosa, results in little absorption, and can cause period of counseling to urge a smoker to quit results in Pnausea. Acidic beverages, particularly coffee, juices, and smoking cessation rates of 5-10%171. There is a strong COsoft drinks, interfere with the absorption of nicotine. dose-response relationship between counseling intensity20 THERAPEUTIC OPTIONS
  • CEand cessation success172,173. Ways to intensify treatment When treatment is given by the inhaled route, attentioninclude increasing the length of the treatment session, the to effective drug delivery and training in inhaler techniquenumber of treatment sessions, and the number of weeks is essential177. The choice of inhaler device will depend Uover which the treatment is delivered. Sustained quit on availability, cost, the prescribing physician, and the ODrates of 10.9% at 6 months have been achieved when skills and ability of the patient. COPD patients mayclinician tutorials and feedback are linked to counseling have problems with coordination and find it hard to use asessions174. With more complex interventions quit rates metered-dose inhaler (MDI). It is essential to ensure that PRcan reach 20-30%172. In a multicenter controlled clinical inhaler technique is correct and to re-check this at eachtrial, a combination of physician advice, group support, visit.skills training, and nicotine replacement therapy achieved a RE Alternative breath-activated or spacer devices arequit rate of 35% at 1 year and a sustained quit rate of 22% available. In general, particle deposition from dry powderat 5 years159. inhalers (DPIs) will tend to be more central with the OR fixed airflow limitation and lower inspiratory flow rates in Table 3.2. Brief Strategies to Help COPD178,179. However, as has been shown in asthma, the Patient Willing to Quit160,167-169 patients are also likely to find the use of some dry powder inhalers difficult. For the MDI, the addition of a large R 1. ASK: Systematically identify all tobacco users at every visit. Implement an or small volume spacer often overcomes coordination TE office-wide system that ensures that, for EVERY patient at EVERY clinic visit, problems, and improves lower airway deposition and tobacco-use status is queried and documented. clinical benefit. Many drugs are available as nebulizer 2. ADVISE: Strongly urge all tobacco users to quit. In a clear, strong, and solutions and, for patients who are severely overinflated AL personalized manner, urge every tobacco user to quit. 3. ASSESS: Determine willingness to make a quit attempt. Ask every tobacco and consequently may have very low inspiratory flow rates, user if he or she is willing to make a quit attempt at this time (e.g., within the there may be theoretical advantages of nebulizer use. next 30 days). However, there is little randomized trial evidence for their T 4. ASSIST: Aid the patient in quitting. Help the patient with a quit plan; provide benefit over other devices, and use of nebulizers will often NO practical counseling; provide intra-treatment social support; help the patient obtain depend on local preference, availability and price. Benefit extra-treatment social support; recommend use of approved pharmacotherapy should be judged symptomatically, since changes in lung except in special circumstances; provide supplementary materials. function may be small and within the limits of repeatability. 5. ARRANGE: Schedule follow-up contact. Schedule follow-up contact, either Nebulized treatment should only be continued if the patient O in person or via telephone. reports clear symptomatic benefit that cannot be achieved -D by simpler, cheaper, and more portable alternatives.PHARMACOLOGIC THERAPY BronchodilatorsFOR STABLE COPD AL Medications that increase the FEV1 or change other spirometric variables, usually by altering airway smooth RI muscle tone, are termed bronchodilators180, since theOverview of the Medications improvements in expiratory flow reflect widening of the TE airways rather than changes in lung elastic recoil. SuchPharmacologic therapy for COPD is used to reduce medications improve emptying of the lungs, tend to reducesymptoms, reduce the frequency and severity of MA dynamic hyperinflation at rest and during exercise181,182,exacerbations, and improve health status and exercise and improve exercise performance. The extent of thesetolerance. To date, none of the existing medications for changes, especially in severe and very severe patients, isCOPD has been conclusively shown to modify the long- not easily predictable from the improvement in FEV1183,184. EDterm decline in lung function when this is tested as aprimary or secondary outcome in clinical trials126,159,175,176. Dose-response relationships using FEV1 as the outcomePost-hoc evidence of such an effect with long-acting are relatively flat with all classes of bronchodilators185-188. HTbronchodilators and/or inhaled corticosteroids133,143 requires Toxicity is also dose-related. Increasing the dose ofconfirmation in specifically designed trials. either a beta2-agonist or an anticholinergic by an order of IG magnitude, especially when given by a nebulizer, appearsThe classes of medications commonly used in treating to provide subjective benefit in acute episodes189 but is notCOPD are shown in Table 3.3. The choice within each necessarily helpful in stable disease190. YRclass depends on the availability and cost of medicationand the patient’s response. Each treatment regimen Bronchodilator medications are given on either an as-needs to be patient-specific as the relationship between P needed basis or a regular basis to prevent or reduceseverity of symptoms, airflow limitation, and severity of symptoms185-188 (Evidence A) (Table 3.4). COexacerbations will differ between patients. THERAPEUTIC OPTIONS 21
  • Table 3.3. Formulations and Typical Doses of COPD Medications* Solution for Vials for Duration of Drug Inhaler (mcg) Nebulizer (mg/ Oral CE Injection (mg) Action (hours) ml) Beta2-agonists U Short-acting OD Fenoterol 100-200 (MDI) 1 0.05% (Syrup) 4-6 Levalbuterol 45-90 (MDI) 0.21, 0.42 6-8 PR 5 mg (Pill), Salbutamol (albuterol) 100, 200 (MDI & DPI) 5 0.1, 0.5 4-6 0.024%(Syrup) RE Terbutaline 400, 500 (DPI) 2.5, 5 mg (Pill) 4-6 Long-acting Formoterol 4.5-12 (MDI & DPI) 0.01¶ 12 OR Arformoterol 0.0075 12 Indacaterol 75-300 (DPI) 24 Salmeterol 25-50 (MDI & DPI) 12 R Tulobuterol 2 mg (transdermal) 24 TE Anticholinergics Short-acting AL Ipratropium bromide 20, 40 (MDI) 0.25-0.5 6-8 Oxitropium bromide 100 (MDI) 1.5 T 7-9 Long-acting NO Tiotropium 18 (DPI), 5 (SMI) 24 Combination short-acting beta2-agonists plus anticholinergic in one inhaler Fenoterol/Ipratropium 200/80 (MDI) 1.25/0.5 O 6-8 Salbutamol/Ipratropium 75/15 (MDI) 0.75/0.5 6-8 -D Methylxanthines Aminophylline 200-600 mg (Pill) 240 Variable, up to 24 AL Theophylline (SR) 100-600 mg (Pill) Variable, up to 24 Inhaled corticosteroids RI Beclomethasone 50-400 (MDI & DPI) 0.2-0.4 TE Budesonide 100, 200, 400 (DPI) 0.20. 0.25, 0.5 Fluticasone 50-500 (MDI & DPI) MA Combination long-acting beta2-agonists plus corticosteroids in one inhaler 4.5/160 (MDI) Formoterol/Budesonide 9/320 (DPI) ED 50/100, 250, 500 (DPI) Salmeterol/Fluticasone 25/50, 125, 250 (MDI) HT Systemic corticosteroids Prednisone 5-60 mg (Pill) Methyl-prednisolone 4, 8, 16 mg (Pill) IG Phosphodiesterase-4 inhibitors YR Roflumilast 500 mcg (Pill) 24MDI=metered dose inhaler; DPI=dry powder inhaler; SMI=smart mist inhaler P*Not all formulations are available in all countries; in some countries, other formulations may be available. CO¶Formoterol nebulized solution is based on the unit dose vial containing 20 mcg in a volume of 2.0 ml22 THERAPEUTIC OPTIONS
  • CEBeta2-agonists. The principal action of beta2-agonists unlike the bronchodilator actions. Mild falls in PaO2 canis to relax airway smooth muscle by stimulating beta2- occur after administration of both short-and long-actingadrenergic receptors, which increases cyclic AMP and beta2-agonists205,206 but the clinical significance of these Uproduces functional antagonism to bronchoconstriction. changes is doubtful. Despite the concerns raised some ODThe bronchodilator effects of short-acting beta2-agonists years ago related to beta2-agonists in the management ofusually wear off within 4 to 6 hours191,192. Regular and as- asthma, further detailed study has found no associationneeded use of short-acting beta-agonists improve FEV1 between beta2-agonist use and an accelerated loss of lung PRand symptoms (Evidence B)193. The use of high doses function or increased mortality in COPD.of short-acting beta2-agonists on an as-needed basis inpatients already treated with long-acting bronchodilators is Anticholinergics. The most important effect in COPD REnot supported by evidence, may be limited by side effects, patients of anticholinergic medications, such as ipratropium,and cannot be recommended. For single-dose, as-needed oxitropium and tiotropium bromide, appears to be blockageuse in COPD, there appears to be no advantage in using of acetylcholine’s effect on muscarinic receptors. Current ORlevalbuterol over conventional bronchodilators194. short-acting drugs block M2 and M3 receptors and modify transmission at the pre-ganglionic junction, although these effects appear less important in COPD207. The long-acting Table 3.4. Bronchodilators in Stable COPD anticholinergic tiotropium has a pharmacokinetic selectivity R for the M3 and M1 receptors208. The bronchodilating • Bronchodilator medications are central to symptom management in TE effect of short-acting inhaled anticholinergics lasts longer COPD. than that of short-acting beta2-agonists, with some • Inhaled therapy is preferred. bronchodilator effect generally apparent up to 8 hours after AL • The choice between beta2-agonist, anticholinergic, theophylline, or administration191. Tiotropium has duration of action of more combination therapy depends on availability and individual patient than 24 hours209-211. Tiotropium reduces exacerbations and response in terms of symptom relief and side effects. related hospitalizations, improves symptoms and health T • Bronchodilators are prescribed on an as-needed or on a regular basis to prevent or reduce symptoms. status212 (Evidence A), and improves the effectiveness NO • Long-acting inhaled bronchodilators are convenient and more of pulmonary rehabilitation213 (Evidence B). In a large, effective at producing maintained symptom relief than short-acting long-term clinical trial on patients with COPD, there was bronchodilators. no effect of tiotropium added to other standard therapies • Combining bronchodilators of different pharmacological classes may on the rate of lung function decline and no evidence of O improve efficacy and decrease the risk of side effects compared to cardiovascular risk214. In another large trial, tiotropium was -D increasing the dose of a single bronchodilator. superior to salmeterol in reducing exacerbations although the difference was small215. ALLong-acting inhaled beta2-agonists show duration of action Adverse effects. Anticholinergic drugs are poorly absorbedof 12 or more hours. Formoterol and salmeterol significantly which limits the troublesome systemic effects seen withimprove FEV1 and lung volumes, dyspnea, health-related atropine216. Extensive use of this class of inhaled agents RIquality of life and exacerbation rate195-200 (Evidence A), in a wide range of doses and clinical settings has shownbut have no effect on mortality and rate of decline of lung them to be very safe. The main side effect is dryness of TEfunction. Salmeterol reduces the rate of hospitalization195 the mouth. Twenty-one days of inhaled tiotropium, 18 mcg/(Evidence B). Indacaterol is a novel long-acting beta2- day as a dry powder, does not retard mucus clearance MAagonist with a duration of action of 24 hours201,202. It from the lungs144. Although occasional prostatic symptomssignificantly improves FEV1, dyspnea, and health-related have been reported, there are no data to prove a truequality of life (Evidence A). causal relationship. Some patients using ipratropium report a bitter, metallic taste. An unexpected small increase in EDAdverse effects. Stimulation of beta2-adrenergic cardiovascular events in COPD patients regularly treatedreceptors can produce resting sinus tachycardia and has with ipratropium bromide has been reported and requiresthe potential to precipitate cardiac rhythm disturbances further investigation217,218. A meta-analysis has indicated HTin susceptible patients, although these seem to have potential toxicity when using tiotropium with the Respimatremarkably few clinical implications. Exaggerated somatic device and requires further comparison with tiotropium IGtremor is troublesome in some older patients treated delivered with the Handihaler219. Use of solutions with awith higher doses of beta2-agonists, whatever the route facemask has been reported to precipitate acute glaucoma,of administration, and this limits the dose that can be probably by a direct effect of the solution on the eye. YRtolerated. Although hypokalemia can occur, especiallywhen treatment is combined with thiazide diuretics203, Methylxanthines. Controversy remains about the Pand oxygen consumption can be increased under resting exact effects of xanthine derivatives. They may act asconditions204, these metabolic effects show tachyphylaxis nonselective phosphodiesterase inhibitors, but have also CO THERAPEUTIC OPTIONS 23
  • CEbeen reported to have a range of non-bronchodilator additional improvements in lung function191,224,228,231-235actions, the significance of which is disputed220-224. Data on and health status191,236. Short-term combination therapyduration of action for conventional, or even slow-release, using formoterol and tiotropium has been shown to have Uxanthine preparations are lacking in COPD. a bigger impact on FEV1 than the single components237,238 OD (Evidence B). Combinations of short-acting beta2-agonistsTheophylline, the most commonly used methylxanthine, is and anticholinergics are also superior compared to eithermetabolized by cytochrome P450 mixed function oxidases. medication alone in improving FEV1 and symptoms231 PRClearance of the drug declines with age. Many other (Evidence B).physiological variables and drugs modify theophyllinemetabolism. Changes in inspiratory muscle function have Corticosteroids REbeen reported in patients treated with theophylline220, butwhether this reflects changes in spirometry or a primary Inhaled Corticosteroids. The dose-responseeffect on the muscle is not clear. All studies that have relationships and long-term safety of inhaled corticosteroids ORshown efficacy of theophylline in COPD were performed in COPD are not known. Only moderate to high doseswith slow-release preparations. have been used in long-term clinical trials. The efficacy and side effects of inhaled corticosteroids in asthma areTheophylline is less effective and less well tolerated dependent on the dose and type of corticosteroid239, but Rthan inhaled long-acting bronchodilators225 and is not whether this is also the case in COPD is unclear. The TErecommended if those drugs are available and affordable. effects of corticosteroids on pulmonary and systemicHowever, there is evidence for a modest bronchodilator inflammation in patients with COPD are controversial, andeffect compared with placebo in stable COPD226 (Evidence their role in the management of stable COPD is limited to ALA). There is also some evidence of symptomatic benefit specific indications.compared to placebo227. Addition of theophylline tosalmeterol produced a greater inprovement in FEV1 and Regular treatment with inhaled corticosteroids improves Tbreathlessness than salmeterol alone228 (Evidence B). symptoms, lung function, and quality of life, and reduces NOLow-dose theophylline reduces exacerbations but does not the frequency of exacerbations144 in COPD patientsimprove post-bronchodilator lung function227 (Evidence B). with an FEV1 < 60% predicted195,240-244 (Evidence A). Withdrawal from treatment with inhaled corticosteroidsAdverse effects. Toxicity is dose-related, a particular may lead to exacerbations in some patients245. Regular Oproblem with the xanthine derivatives because their treatment with inhaled corticosteroids does not modify the -Dtherapeutic ratio is small and most of the benefit long-term decline of FEV1 nor mortality in patients withoccurs only when near-toxic doses are given221,223,229. COPD126,175,176,195,246,247 (Evidence A).Methylxanthines are nonspecific inhibitors of all ALphosphodiesterase enzyme subsets, which explains Adverse effects. Inhaled corticosteroid use is associatedtheir wide range of toxic effects. Problems include the with higher prevalence of oral candidiasis, hoarsedevelopment of atrial and ventricular arrhythmias (which voice, and skin bruising126,175. Treatment with inhaled RIcan prove fatal) and grand mal convulsions (which corticosteroids is associated with an increased risk ofcan occur irrespective of prior epileptic history). Other pneumonia195,246-248. While long-term treatment with TEside effects include headaches, insomnia, nausea, and triamcinolone acetonide is associated with an increasedheartburn, and these may occur within the therapeutic risk of reduced bone density, the evidence with other MArange of serum theophylline. These medications also have inhaled corticosteroids is controversial. One long-termsignificant interactions with commonly used medications study showed no effect of budesonide on bone densitysuch as digitalis, coumadin, etc. Unlike the other and fracture rate175,249, and treatment over a three-yearbronchodilator classes, xanthine derivatives may involve a period with 500 mcg bid fluticasone propionate alone or EDrisk of overdose (either intentional or accidental). in combination with salmeterol was not associated with decreased bone mineral density in a population of COPDCombination Bronchodilator Therapy. Combining patients with high prevalence of osteoporosis250. HTbronchodilators with different mechanisms and durationsof action may increase the degree of bronchodilation Combination Inhaled Corticosteroid/Bronchodilator IGfor equivalent or lesser side effects230. For example, Therapy. An inhaled corticosteroid combined with a long-a combination of a short-acting beta2-agonist and an acting beta2-agonist is more effective than the individualanticholinergic produces greater and more sustained components in improving lung function and health status YRimprovements in FEV1 than either drug alone and does and reducing exacerbations in patients with moderatenot produce evidence of tachyphylaxis over 90 days of (Evidence B) to very severe COPD195,240,243,244,246,251-253 Ptreatment191,231,232. The combination of a beta2-agonist, (Evidence A). A large prospective clinical trial failed toan anticholinergic, and/or theophylline may produce demonstrate a statistically significant effect of combination CO24 THERAPEUTIC OPTIONS
  • CEtherapy on mortality195, but a subsequent meta-analysis Other Pharmacologic Treatmentsfound that combination therapy may reduce mortalitywith a number needed to treat (NNT) of 36254 (Evidence Vaccines. Influenza vaccination can reduce serious UB). Combination therapy is associated with an increased illness (such as lower respiratory tract infections requiring ODrisk of pneumonia255, but no other significant side effect hospitalization267) and death in COPD patients268-270(Evidence A). The addition of a long-acting beta2-agonist/ (Evidence A). Vaccines containing killed or live,inhaled corticosteroid combination to tiotropium improves inactivated viruses are recommended271 as they are more PRlung function and quality of life256,257 and may further reduce effective in elderly patients with COPD272. The strainsexacerbations (Evidence B) but more studies of triple are adjusted each year for appropriate effectivenesstherapy are needed258. and should be given once each year273. Pneumococcal RE polysaccharide vaccine is recommended for COPDOral Corticosteroids. Oral corticosteroids have numerous patients 65 years and older, and also in younger patientsside effects. An important side effect of long-term with significant comorbid conditions such as cardiac disease274-276. In addition, this vaccine has been shown to ORtreatment of COPD with systemic corticosteroids is steroidmyopathy259-261, which contributes to muscle weakness, reduce the incidence of community-acquired pneumonia indecreased functionality, and respiratory failure in subjects COPD patients younger than age 65 with an FEV1 < 40%with very severe COPD. In view of the well-known toxicity predicted277 (Evidence B). Rof long-term treatment with oral corticosteroids, prospective Alpha-1 Antitrypsin Augmentation Therapy. Young TEstudies on the long-term effects of these drugs in COPDare limited262,263. patients with severe hereditary alpha-1 antitrypsin deficiency and established emphysema may be candidates ALPhosphodiesterase-4 Inhibitors for alpha-1 antitrypsin augmentation therapy (Evidence C). However, this therapy is very expensive, is not available inThe principal action of phosphodiesterase-4 inhibitors is most countries, and is not recommended for patients withto reduce inflammation by inhibiting of the breakdown of T COPD that is unrelated to alpha-1 antitrypsin deficiency. NOintracellular cyclic AMP264,265. The phosphodiesterase-4inhibitor roflumilast has been approved for use only in Antibiotics. In older studies prophylactic, continuous usesome countries. It is a once daily oral medication with no of antibiotics was shown to have no effect on the frequencydirect bronchodilator activity, although it has been shown of exacerbations in COPD278-280, and a study that examined Oto improve FEV1 in patients treated with salmeterol or the efficacy of chemoprophylaxis undertaken in winter months over a period of 5 years concluded that there was -Dtiotropium264. Roflumilast reduces moderate and severeexacerbations treated with corticosteroids by 15-20% in no benefit281. Although recent studies have shown somepatients with chronic bronchitis, severe to very severe effects of antibiotics on exacerbation rate282,283, the role ofCOPD, and a history of exacerbations266 (Evidence A). this treatment is unclear. A recent trial of daily azithromycin ALThe effects on lung function are also seen when roflumilast showed efficacy on exacerbation end-points; however,is added to long-acting bronchodilators266 (Evidence A), treatment is not recommended because of an unfavorable RIwhereas the effects on patient-related outcomes and balance between benefits and side effects284. Thus,particularly exacerbations remain controversial265. There the use of antibiotics, other than for treating infectious TEare no comparison or add-on studies of roflumilast and exacerbations of COPD and other bacterial infections, isinhaled corticosteroids. currently not indicated285,286 (Evidence B). MAAdverse effects. Phosphodiesterase-4 inhibitors have Mucolytic (mucokinetic, mucoregulator) andmore adverse effects than inhaled medications for COPD264- Antioxidant Agents (ambroxol, erdosteine,266 . The most frequent adverse effects are nausea, reduced carbocysteine, iodinated glycerol). The regular use EDappetite, abdominal pain, diarrhea, sleep disturbances, and of mucolytics in COPD has been evaluated in a numberheadache. Adverse effects led to increased withdrawal in of long-term studies with controversial results287-289.clinical trials from the group receiving roflumilast. Adverse Although a few patients with viscous sputum may benefit HTeffects seem to occur early during treatment, are reversible, from mucolytics290,291, the overall benefits seem to beand diminish over time with continued treatment. In very small; the widespread use of these agents cannot be recommended at present (Evidence D). Drugs like IGcontrolled studies an average unexplained weight loss of 2kg has been seen and weight monitoring during treatment N-acetylcysteine may have antioxidant effects, leading tois advised as well as avoiding treatment with roflumilast speculation that these medications could have a role in YRin underweight patients. Roflumilast should also be used the treatment of patients with recurrent exacerbations292-295with caution in patients with depression. Roflumilast and (Evidence B). There is some evidence that in COPD patients not receiving inhaled corticosteroids, treatment Ptheophylline should not be given together. with mucolytics such as carbocysteine and N-acetylcysteine CO may reduce exacerbations296,297 (Evidence B). THERAPEUTIC OPTIONS 25
  • CEImmunoregulators (immunostimulators,immunomodulators). Studies using an immunoregulator NON-PHARMACOLOGIC THERAPIESin COPD report a decrease in the severity and frequency U Rehabilitationof exacerbations298,299. However, additional studies to ODexamine the long-term effects of this therapy are required; The principal goals of pulmonary rehabilitation are to reduceat present, its regular use cannot be recommended300. symptoms, improve quality of life, and increase physical and emotional participation in everyday activities313,314. To PRAntitussives. Cough, although sometimes a troublesome accomplish these goals, pulmonary rehabilitation coverssymptom in COPD, has a significant protective role301. The a range of non-pulmonary problems that may not beregular use of antitussives is not recommended in stable adequately addressed by medical therapy for COPD, RECOPD (Evidence D). including exercise de-conditioning, relative social isolation, altered mood states (especially depression), muscle wasting,Vasodilators. The belief that pulmonary hypertension in and weight loss. Pulmonary rehabilitation has been carefully ORCOPD is associated with a poorer prognosis has provoked evaluated in a large number of clinical trials and shownmany attempts to reduce right ventricular afterload, to increase peak workload, peak oxygen consumption,increase cardiac output, and improve oxygen delivery and and endurance time315. Benefits have been reported fromtissue oxygenation. Many agents have been evaluated, R rehabilitation programs conducted in inpatient, outpatient,including inhaled nitric oxide, but the results have been and home settings315,316; considerations of cost and TEuniformly disappointing. In patients with COPD, in whom availability most often determine the choice of setting. Thehypoxemia is caused primarily by ventilation-perfusion various benefits of pulmonary rehabilitation are summarizedmismatching rather than by increased intrapulmonary AL in Table 3.5313,314,317-320.shunt (as in noncardiogenic pulmonary edema), inhalednitric oxide can worsen gas exchange because of alteredhypoxic regulation of ventilation-perfusion balance302,303. Table 3.5. Benefits of Pulmonary Rehabilitation in COPDTherefore, based on the available evidence, nitric oxide T • Improves exercise capacity (Evidence A). NOis contraindicated in stable COPD. Likewise, guidelines • Reduces the perceived intensity of breathlessness (Evidence A).on the treatment of pulmonary hypertension do not • Improves health-related quality of life (Evidence A).recommend the use of endothelium-modulating agents • Reduces the number of hospitalizations and days in the hospitalfor the treatment of pulmonary hypertension associated O (Evidence A).with COPD until data on their safety and efficacy in this • Reduces anxiety and depression associated with COPD (Evidence A). -Dcondition are available304. • Strength and endurance training of the upper limbs improves arm function (Evidence B).Narcotics (morphine). Oral and parenteral opioids are • Benefits extend well beyond the immediate period of training ALeffective for treating dyspnea in COPD patients with very (Evidence B).severe disease. There is insufficient data to conclude • Improves survival (Evidence B).whether nebulized opioids are effective305. However, some • Respiratory muscle training can be beneficial, especially when RIclinical studies suggest that morphine used to control combined with general exercise training (Evidence C).dyspnea may have serious adverse effects and its benefits • Improves recovery after hospitalization for an exacerbation TEmay be limited to a few sensitive subjects306-310. (Evidence B). • Enhances the effect of long-acting bronchodilators (Evidence B). MAOthers. Nedocromil and leukotriene modifiers have notbeen adequately tested in COPD patients and cannot The minimum length of an effective rehabilitation programbe recommended. There was no evidence of benefit— is 6 weeks; the longer the program continues, the moreand some some evidence of harm (malignancy and effective the results321-323. However, as yet, no effective EDpneumonia)—from an anti-TNF-alpha antibody (infliximab) program has been developed to maintain the effectstested in moderate to severe COPD311. There is no over time324. Many physicians advise patients unable toevidence for the effectiveness of herbal medicines in HT participate in a structured program to exercise on their owntreating COPD312 and other alternative healing methods (e.g., walking 20 minutes daily). The benefits of this general(e.g., acupuncture and homeopathy) have not been advice have not been tested, but because observational IGadequately tested. studies have indicated significant benefits of physical activity325,326, and because physical activity is good for so YR many other reasons, it is highly reasonable to offer such advice to patients if a formal program is not available. P CO26 THERAPEUTIC OPTIONS
  • CEComponents of Pulmonary Rehabilitation Programs respiratory muscle weakness335. In contrast, inspiratory muscle training appears to provide additional benefitsThe components of pulmonary rehabilitation vary widely when included in a comprehensive pulmonary rehabilitation Ubut a comprehensive programs includes exercise training, program336-338. The addition of upper limb exercises or other ODsmoking cessation, nutrition counseling, and education. strength training to aerobic training is effective in improving strength, but does not improve quality of life or exerciseExercise training. Exercise tolerance can be assessed tolerance339. PRby either bicycle ergometry or treadmill exercise with themeasurement of a number of physiological variables, The following points summarize current knowledge ofincluding maximum oxygen consumption, maximum heart considerations important in choosing patients for pulmonary RErate, and maximum work performed. A less complex rehabilitation:approach is to use a self-paced, timed walking test (e.g.,6-minute walking distance). These tests require at least one Functional status: Benefits have been seen in patients ORpractice session before data can be interpreted. Shuttle with a wide range of disability, although those who are chair-walking tests offer a compromise: they provide more bound appear less likely to respond even to home visitingcomplete information than an entirely self-paced test, but are programs340 (Evidence B). Rsimpler to perform than a treadmill test153. Severity of dyspnea: Stratification by breathlessness TEExercise training ranges in frequency from daily to weekly, in intensity using the mMRC questionnaire may be helpful induration from 10 minutes to 45 minutes per session, and in selecting patients most likely to benefit from rehabilitation. ALintensity from 50% peak oxygen consumption (VO2 max) to Those with mMRC grade 4 dyspnea may not benefit340maximum tolerated253. The optimum length for an exercise (Evidence B).program has not been investigated in randomized controlled Ttrials but most studies involving fewer than 28 exercise Motivation: Selecting highly motivated participants is NOsessions show inferior results compared to those with longer especially important in the case of outpatient programs341.treatment periods327. In practice, the length depends on theresources available and usually ranges from 4 to 10 weeks, Smoking status: There is no evidence that smokers willwith longer programs resulting in larger effects than shorter benefit less than nonsmokers, although some suggest that Oprograms318. continuing smokers are less likely to complete pulmonary -D rehabilitation programs than nonsmokers341 (Evidence B).In many programs, especially those using simple corridorexercise training, the patient is encouraged to walk to a Education. Most pulmonary rehabilitation programs include ALsymptom-limited maximum, rest, and then continue walking an educational component. The topics that seem mostuntil 20 minutes of exercise have been completed. Where appropriate for an education program include: smoking RIpossible, endurance exercise training to 60-80% of the cessation; basic information about COPD; general approachsymptom-limited maximum is preferred. Endurance training to therapy and specific aspects of medical treatment; self- TEcan be accomplished through continuous or interval exercise management skills; strategies to help minimize dyspnea;programs. The latter involve the patient doing the same advice about when to seek help; decision-making duringtotal work but divided into briefer periods of high-intensity exacerbations; and advance directives and end-of-life issues. MAexercise, which is useful when performance is limited byother comorbidities328,329. Use of a simple wheeled walking The intensity and content of these educational messagesaid seems to improve walking distance and reduces should vary depending on the severity of the patient’s EDbreathlessness in severely disabled COPD patients330-332. disease, although the specific contributions of education toOther approaches to improving outcomes such as use of the improvements seen after pulmonary rehabilitation remainoxygen during exercise333, exercising while breathing heliox unclear. Studies indicate that patient education alone does HTgas mixtures334, or unloading the ventilator muscles while not improve exercise performance or lung function354-357, but itexercising remain experimental at present. can play a role in improving skills, ability to cope with illness, IG and health status358. These outcomes are not traditionallySome programs also include upper limb exercises, usually measured in clinical trials,but they may be most important in YRinvolving an upper limb ergometer or resistive training COPD where even pharmacologic interventions generallywith weights. There are no randomized clinical trial data confer only a small benefit in terms of lung function.to support the routine inclusion of these exercises, but Pthey may be helpful in patients with comorbidities that COrestrict other forms of exercise and those with evidence of THERAPEUTIC OPTIONS 27
  • CEAssessment and Follow-up. Baseline and outcomeassessments of each participant in a pulmonary OTHER TREATMENTSrehabilitation program should be made to quantify individual U Oxygen Therapygains and target areas for improvement. Assessments ODshould include: The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to• Detailed history and physical examination increase survival in patients with severe resting hypoxemia359 PR• Measurement of post-bronchodilator spirometry (Evidence B). Long-term oxygen therapy is indicated for• Assessment of exercise capacity patients who have: RE• Measurement of health status and impact of • PaO2 at or below 7.3 kPa (55 mmHg) or SaO2 at or breathlessness (e.g., CAT and mMRC scales) below 88%, with or without hypercapnia confirmed twice• Assessment of inspiratory and expiratory muscle over a three week period (Evidence B); or OR strength and lower limb strength (e.g., quadriceps) in patients who suffer from muscle wasting • PaO2 between 7.3 kPa (55 mmHg) and 8.0 kPa (60 mmHg), or SaO2 of 88%, if there is evidence of R pulmonary hypertension, peripheral edema suggestingThe first two assessments are important for establishing entry congestive cardiac failure, or polycythemia (hematocrit > TEsuitability and baseline status but are not used in outcome 55%) (Evidence D).assessment. The last three assessments are baseline andoutcome measures. Several detailed questionnaires for AL A decision about the use of long-term oxygen should beassessing health status are available, including some that based on the resting PaO2 or saturation values repeatedare specifically designed for patients with respiratory disease twice over three weeks in the stable patient. Current data(e.g., Chronic Respiratory Disease Questionnaire236, St. T do not support the use of ambulatory oxygen in patientGeorge Respiratory Questionnaire342, Chronic Obstructive populations that do not meet the above criteria360. NOPulmonary Disease Assessment Test124), and there isincreasing evidence that these questionnaires may be useful Although air travel is safe for most patients with chronicin a clinical setting. Health status can also be assessed by respiratory failure who are on long-term oxygen therapy,generic questionnaires, such as the Medical Outcomes Study O patients should ideally be able to maintain an in-flight PaO2Short Form (SF36)343, to enable comparison of quality of life of at least 6.7 kPa (50 mmHg). Studies indicate that this can -Din different diseases. The Hospital Anxiety and Depression be achieved in those with moderate to severe hypoxemiaScale (HADS)344 and the Primary Care Evaluation of Mental at sea level by supplementary oxygen at 3 L/min by nasalDisorders (PRIME-MD) Patient Questionnaire345 have been cannulae or 31% by Venturi facemask361. Those with aused to improve identification and treatment of anxious and AL resting PaO2 at sea level > 9.3 kPa (70 mmHg) are likely todepressed patients. be safe to fly without supplementary oxygen362,363, although RINutrition counseling. Nutritional state is an important it is important to emphasize that a resting PaO2 > 9.3 kPadeterminant of symptoms, disability, and prognosis in COPD; (70 mmHg) at sea level does not exclude the development TEbeing either overweight or underweight can be a problem313. of severe hypoxemia when travelling by air (Evidence C).Approximately 25% of patients with GOLD 2: Moderate Careful consideration should be given to any comorbidityairflow limitation to GOLD 4: Very Severe airflow limitation that may impair oxygen delivery to tissues (e.g., cardiac MAshow a reduction in both their body mass index and fat impairment, anemia). Also, walking along the aisle mayfree mass116,346,347. A reduction in body mass index is an profoundly aggravate hypoxemia364.independent risk factor for mortality in COPD patients116,348,349. Ventilatory Support EDPresent evidence suggests that nutritional supplementationalone may not be a sufficient strategy. Increased calorie Non-invasive ventilation (NIV) is increasingly used in patients HTintake is best accompanied by exercise regimes that have a with stable very severe COPD. The combination of NIV withnonspecific anabolic action, and there is some evidence this long-term oxygen therapy may be of some use in a selectedalso helps even in those patients without severe nutritional subset of patients, particularly in those with pronounced IGdepletion350. Nutritional supplements (e.g., creatine) do not daytime hypercapnia365. It may improve survival but doesaugment the substantial training effect of multidisciplinary not improve quality of life365. However, in patients with both YRpulmonary rehabilitation for patients with COPD351. Anabolic COPD and obstructive sleep apnea there are clear benefitssteroids in COPD patients with weight loss increase body from continuous positive airway pressure (CPAP) in both survival and risk of hospital admission366. Pweight and lean body mass but have little or no effect onexercise capacity352,353. CO28 THERAPEUTIC OPTIONS
  • CESurgical Treatments despite oxygen therapy; and FEV1 < 20% predicted with either DLCO < 20% predicted or homogenous distribution ofLung Volume Reduction Surgery (LVRS). LVRS is a emphysema378 (Evidence C). Usurgical procedure in which parts of the lung are resected to ODreduce hyperinflation367, making respiratory muscles more Bullectomy. Bullectomy is an older surgical procedure foreffective pressure generators by improving their mechanical bullous emphysema. Removal of a large bulla that does notefficiency (as measured by length/tension relationship, contribute to gas exchange decompresses the adjacent lung PRcurvature of the diaphragm, and area of apposition)368,369. parenchyma. Pulmonary hypertension, hypercapnia, andIn addition, LVRS increases the elastic recoil pressure severe emphysema are not absolute contraindications forof the lung and thus improves expiratory flow rates and bullectomy. REreduces exacerbations370. The advantage of surgery overmedical therapy is more significant among patients withpredominantly upper-lobe emphysema and low exercise ORcapacity prior to treatment. A prospective economic analysisindicated that LVRS is costly relative to health-care programsnot including surgery371. In contrast to medical treatment,LVRS has been demonstrated to result in improved survival R(54% vs. 39.7%) in severe emphysema patients with upper- TElobe emphysema and low post-rehabilitation exercisecapacity372 (Evidence A). In similar patients with high post-pulmonary rehabilitation exercise capacity no difference ALin survival was noted after LVRS, although health-relatedquality of life and exercise capacity improved. LVRS hasbeen demonstrated to result in higher mortality than medical Tmanagement in severe emphysema patients with an FEV1 NO≤ 20% predicted and either homogeneous emphysema onhigh resolution computed tomography or a DLCO ≤ 20%predicted373. OBronchoscopic Lung Volume Reduction (BLVR). In -Da post-hoc analysis, BLVR in COPD patients with severeairflow limitation (FEV1 15-45% predicted), heterogeneousemphysema on CT scan, and hyperinflation (TLC > 100% ALand RV > 150% predicted) has been demonstrated to resultin modest improvements in lung function, exercise tolerance,and symptoms at the cost of more frequent exacerbations RIof COPD, pneumonia, and hemoptysis after implantation374.Additional data are required to define the optimal technique TEand patient population. MALung Transplantation. In appropriately selected patientswith very severe COPD, lung transplantation has beenshown to improve quality of life and functional capacity375,376.The common complications seen in COPD patients after EDlung transplantation, apart from post-operative mortality,are acute rejection, bronchiolitis obliterans, opportunisticinfections such as CMV, fungal (Candida, Aspergillus, HTCryptococcus, Pneumocystis) or bacterial (Pseudomonas,Staphylococcus species) infections, and lymphoproliferative IGdisease377. Lung transplantation is limited by the shortageof donor organs and costs. Criteria for referral for lungtransplantation include COPD with a BODE index exceeding YR5. Recommended criteria for listing include a BODE index of7-10 and at least one of the following: history of exacerbation Passociated with acute hypercapnia [PaCO2 > 6.7 kPa (50mmHg)]; pulmonary hypertension, cor pulmonale, or both CO THERAPEUTIC OPTIONS 29
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR RE PR OD UCE
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 4 RE PR CHAPTER OD STABLE COPD UCE MANAGEMENT OF
  • CE CHAPTER 4: MANAGEMENT OF STABLE COPD U ODKEY POINTS: INTRODUCTION PR • Identification and reduction of exposure to risk factors are important steps in the prevention and treatment Once COPD has been diagnosed, effective management RE of COPD. All individuals who smoke should be should be based on an individualized assessment of disease encouraged to quit. in order to reduce both current symptoms and future risks • The level of FEV1 is an inadequate descriptor of the (Table 4.1). These goals should be reached with minimal impact of the disease on patients and for this reason OR side effects from treatment, a particular challenge in COPD individualized assessment of symptoms and future patients because they commonly have comorbidities that risk of exacerbation should also be incorporated into also need to be carefully identified and treated. the management strategy for stable COPD. R • Pharmacologic therapy is used to reduce symptoms, Table 4.1. Goals for Treatment of Stable COPD reduce frequency and severity of exacerbations, TE and improve health status and exercise tolerance. Existing medications for COPD have not been • Relieve symptoms AL conclusively shown to modify the long-term decline in lung function that is the hallmark of this disease. • Improve exercise tolerance • For both beta2-agonists and anticholinergics, long- • Improve health status acting formulations are preferred over short-acting T and NO formulations. Based on efficacy and side effects, inhaled bronchodilators are preferred over oral bronchodilators. • Prevent disease progression • Long-term treatment with inhaled corticosteroids • Prevent and treat exacerbations O added to long-acting bronchodilators is • Reduce mortality -D recommended for patients at high risk of exacerbations. • Long-term monotherapy with oral or inhaled It is crucial for patients with COPD to understand the nature corticosteroids is not recommended in COPD. of their disease, the risk factors for its progression, and AL • The phosphodiesterase-4 inhibitor roflumilast may be their role and that of their health care workers in achieving useful to reduce exacerbations for patients with FEV1 optimal management and health outcomes. The type of RI < 50% predicted, chronic bronchitis, and frequent health care workers seen, and the frequency of visits, will exacerbations. depend on the health care system. Ongoing monitoring TE • Influenza vaccines can reduce the risk of serious should ensure that the goals of treatment are being met and illness (such as hospitalization due to lower should include continuous evaluation of exposure to risk respiratory tract infections) and death in COPD MA factors and monitoring of disease progression, the effect of patients. treatment and possible adverse effects, exacerbation history, • Currently, the use of antibiotics is not indicated and comorbidities. In addition, patients should receive in COPD, other than for treating infectious general advice on healthy living, including diet and the fact ED exacerbations of COPD and other bacterial infections. that physical exercise is safe and encouraged for people with • All COPD patients with breathlessness when walking COPD. HT at their own pace on level ground appear to benefit from rehabilitation and maintenance of physical Identification and reduction of exposure to risk factors are activity, improving their exercise tolerance and quality important in the treatment and prevention of COPD. Since IG of life, and reducing symptoms of dyspnea and cigarette smoking is the most commonly encountered and fatigue. easily identifiable risk factor, smoking cessation should be YR encouraged for all individuals who smoke. Reduction of total personal exposure to occupational dusts, fumes, and gases and to indoor and outdoor air pollutants may be more difficult P but should be attempted. CO32 MANAGEMENT OF STABLE COPD
  • CEIDENTIFY AND REDUCE EXPOSURE TREATMENT OF STABLE COPDTO RISK FACTORS U In previous versions of the GOLD report, COPD treatment recommendations were based on spirometry only. This is in ODTobacco Smoke keeping with the fact that most of the clinical trial evidenceSmoking cessation is the key intervention for all COPD about treatment efficacy in COPD is oriented around baselinepatients who continue to smoke (Evidence A). Health care FEV1. However, FEV1 alone is a poor descriptor of disease PRproviders are important to the delivery of smoking cessation status and for this reason the treatment strategy for stablemessages and interventions and should encourage all COPD should also consider an individual patient’s symptoms and future risk of exacerbations. This individualized REpatients who smoke to quit, even when patients visit a healthcare provider for reasons unrelated to COPD or breathing assessment is summarized in Table 4.2.problems. Moving from Clinical Trials to Recommendations for OROccupational Exposures Routine Practice – ConsiderationsAlthough studies as yet have not been done to demonstrate The guidance for clinical practice presented below is based on evidence from clinical trials, as detailed in the Rwhether interventions to reduce occupational exposuresalso reduce the burden of COPD, it seems common sense discussion of Evidence Levels at the beginning of this TEto advise patients to avoid continued exposures to potential document. However, it is important to recognize that allaggravants, if possible (Evidence D). clinical trials recruit restricted groups of patients; this limits their generalizability. In COPD the key inclusion criteria are: ALIndoor and Outdoor Air Pollution baseline FEV1, acute bronchodilator reversibility, smoking history, symptoms and a prior history of exacerbations. A fewReducing the risk from indoor and outdoor air pollution is general considerations related to these inclusion criteria are Tfeasible and requires a combination of public policy, local discussed below. NOand national resources, cultural changes, and protectivesteps taken by individual patients. Reduction of exposure Baseline FEV1. The evidence for pharmacological treatmentto smoke from biomass fuel, particularly among women of COPD is mostly based on the severity of airflow limitation (FEV1 % predicted), and GOLD spirometry classification Oand children, is a crucial goal to reduce the prevalence ofCOPD worldwide. Efficient ventilation, non-polluting cooking has often been used as an entry criterion for clinical trials. -Dstoves, use of flues, and similar interventions are feasible There is almost no evidence on efficacy of COPD treatmentsand should be recommended379,380 (Evidence B). in patients with FEV1 > 70% predicted (GOLD 1), and no evidence at all concerning anti-inflammatory treatment in patients with FEV1 > 60% predicted. Many studies of ALTable 4.2. Model of Symptom/Risk of Evaluation of COPD combination medications (inhaled corticosteroids plus When assessing risk, choose the highest risk long-acting beta2-agonists) have been limited to GOLD 3-4 RI according to GOLD grade or exacerbation history (Severe-Very Severe airflow limitation) patients. As no trials have been carried out purely in GOLD 2 patients, evidence TE of the efficacy of combination treatment in this group has to be drawn from studies that included such patients as a subset of participants. Large studies such as TORCH195 and MA UPLIFT214 each contained over 2,000 GOLD 2 patients, albeit in the lower stratum of GOLD 2 (FEV1 < 60% predicted). In general, it is important to draw a distinction between absence ED of evidence that a treatment works and presence of evidence that a treatment does not work. HT Acute Bronchodilator Reversibility. Many COPD trials have used low reversibility of airflow limitation as an entry criterion. Acute reversibility is not a reliable measurement381 IG and, in general, acute reversibility in response to bronchodilator is a poor predictor of a treatment’s benefit for YR Patient Characteristics Spirometric Exacerbations mMRC CAT FEV1 after one year382. Thus, this common clinical trial entry A Low Risk, Less Symptoms GOLD 1-2 ≤1 0-1 <10 Category Classification per year criterion has limited impact on the reliability of therapeutic B Low Risk, More Symptoms GOLD 1-2 ≤1 >2 ≥10 recommendations. P C High Risk, Less Symptoms GOLD 3-4 >2 0-1 <10 D High Risk, More Symptoms GOLD 3-4 >2 >2 ≥10 CO MANAGEMENT OF STABLE COPD 33
  • CESymptoms. Almost all studies have included patients withrespiratory symptoms; there are no data on asymptomatic NON-PHARMACOLOGIC TREATMENTpatients. No studies have reported results based upon U Non-pharmacologic management of COPD according to thestratified symptom levels. individualized assessment of symptoms and exacerbation OD risk is shown in Table 4.3.Exacerbation Prevention. Studies in which exacerbationsare a major outcome often “enrich” the patient population Smoking Cessation PRby requiring a history of frequent exacerbations in thepreceding year, as it is often easier to demonstrate an effect Smoking cessation should be considered the most importantof treatment preventing exacerbations if the exacerbations RE intervention for all COPD patients who smoke regardless ofactually occur. However, large trials that have not used this the level of disease severity.entry criterion have also shown reductions in exacerbations,even in patients with less severe airflow limitation195,214. The Physical Activity ORpatient’s own history of exacerbations appears to be themost powerful predictor of future exacerbations132, so the Physical activity is recommended for all patients with COPD.GOLD panel assumed that it is safe to extrapolate evidence There is very little COPD-specific evidence to support Rof efficacy from clinical trials to appropriate patients in routine recommendations for physical activity other than studies ofpractice, regardless of the trial’s entry criteria concerning TE pulmonary rehabilitation (the physical exercise componentprevious exacerbation history. is believed to provide the most benefit). However, given the overall population benefits of physical exercise and its role in ALSub-Group Analysis. Results of clinical trials potentially primary and secondary prevention of cardiovascular disease,apply to every member of the intention-to-treat population, it seems intuitively correct to recommend daily physicalwhether they lie in the center of the distribution of severity or activity. Tat the extremes. Sub-group analysis, whether pre-specified NOor not, must be used with caution. For example, if a treatment Rehabilitationhas no effect in the intention-to-treat population, but appearsto have an effect that is confined to one sub-group, there is a Although more information is needed on criteria forstrong likelihood that one of the other groups would be worse O patient selection for pulmonary rehabilitation programs, allon the treatment. In contrast, subgroup analysis is useful COPD patients appear to benefit from rehabilitation and -Dif it shows that a treatment effect is consistent in size and maintenance of physical activity, improving their exercisedirection across the range of patients recruited to the study. tolerance and experiencing decreased dyspnea andIn summary, sub-group analysis does not provide robust fatigue383 (Evidence A). Several studies have documented ALevidence that a treatment works in a specific subgroup, but an effect of pulmonary rehabilitation in patients withit can provide confidence that the results from the intention- breathlessness, usually mMRC > 1, and following acute RIto-treat population apply to patients who met the study entry exacerbations. Data suggest that these benefits can becriteria. Subgroup analysis can also generate hypotheses to sustained even after a single pulmonary rehabilitation TEbe tested in subsequent trials. program341,384,385. Benefit does wane after a rehabilitation program ends, but if exercise training is maintained at home MA the patient’s health status remains above pre-rehabilitation levels (Evidence B). Vaccination ED Decisions about vaccination in COPD patients depend on HT local policies, availability, and affordability. Table 4.3. Non-Pharmacologic Management of COPD IG Patient Group Essential Recommended Depending on Local Guidelines YR A Smoking cessation (can include pharmacologic treatment) Physical activity Flu vaccination Pneumococcal vaccination P B-D Smoking cessation (can include pharmacologic treatment) Physical activity Flu vaccination Pulmonary rehabilitation Pneumococcal vaccination CO34 MANAGEMENT OF STABLE COPD
  • CE these treatments, which makes differentiation difficult389. PHARMACOLOGIC TREATMENT As second choice, a combination of two long-acting bronchodilators or the combination of inhaled corticosteroid/ UPharmacologic therapy in COPD is used to reducesymptoms, reduce the frequency and severity of long-acting anticholinergic can be used. Both long-acting ODexacerbations, and improve health status and exercise anticholinergic and long-acting beta2-agonist reduce thetolerance. Existing medications for COPD have not been risk of exacerbations212,387, and although good long-termconclusively shown to modify the long-term decline in lung studies are lacking, this principle of combination treatment PRfunction that is the hallmark of this disease126,159,175,176. seems sound (although in many countries expensive). The recommendation for a combination of inhaled corticosteroid/ long-acting anticholinergic is not evidence-based, but this REThe classes of medications commonly used in treatingCOPD are shown in Table 3.3 and a detailed description lack of evidence seems to be the result of lack of interestof the effects of these medications is given in Chapter 3. from the pharmaceutical industry rather than doubts about the rationale. Alternative choices include short- ORThe choice within each class depends on the availability ofmedication and the patient’s response. A proposed model for acting bronchodilators and theophylline if long-actinginitial pharmacological management of COPD according to inhaled bronchodilators are unavailable or unaffordable. Athe individualized assessment of symptoms and exacerbation phosphodiesterase-4 inhibitor could be considered if the Rrisk is shown in Table 4.4. patient has chronic bronchitis264,266. TEGroup A patients have few symptoms and a low risk of Group D patients have many symptoms and a high riskexacerbations. Specific evidence for the effectiveness of of exacerbations. The rationale for the first choice of ALpharmacologic treatments is not available for patients with therapy is the same as that for patients in Group C, asFEV1 > 80% predicted (GOLD 1). However, for all Group reduction of exacerbation risk seems most important. AsA patients a short-acting bronchodilator is recommended second choice a combination of all three classes of drugs Tas first choice based on its effect on lung function and (inhaled corticosteroid/long-acting beta2-agonist/long-acting NObreathlessness. Second choice is a combination of short- anticholinergic) is recommended256, although there areacting bronchodilators or the introduction of a long-acting conflicting findings concerning this treatment257; support for itbronchodilator. The evidence for this step-up is weak; mainly comes from short-term studies390. It is also possible to add a phosphodiesterase-4 inhibitor to the treatment chosen Ofew studies of the combination exist191,386, and most trialsof therapy with long-acting bronchodilators have been as first choice, provided the patient has chronic bronchitis266. -Dperformed in patients with more severe airflow limitation212,387. A phosphodiesterase-4 inhibitor is effective when added to a long-acting bronchodilator264, whereas evidence of its benefitGroup B patients have more significant symptoms but still when added to inhaled corticosteroid comes from less valid ALa low risk of exacerbations. Long-acting bronchodilators secondary analyses. Alternative choices include short-actingare superior to short-acting bronchodilators (taken as bronchodilators, and theophylline or carbocysteine296 can be RIneeded, or prn) and are therefore recommended212,387. used if long-acting inhaled bronchodilators are unavailable orThere is no evidence to recommend one class of long- unaffordable. TEacting bronchodilators over another for initial treatment. Inthe individual patient, the choice should depend on the Bronchodilators – Recommendations MApatient’s perception of symptom relief. For patients withsevere breathlessness, the second choice is a combination • For both beta2-agonists and anticholinergics, long-actingof long-acting bronchodilators237,238. Only short-term studies formulations are preferred over short-acting formulationsof this treatment option have been reported and patients (Evidence A). EDon a combination of long-acting bronchodilators should • The combined use of short- or long-acting beta2-agonistsbe carefully followed and their treatment effect evaluated. and anticholinergics may be considered if symptoms are not improved with single agents (Evidence B). HTAlternative choices include short-acting bronchodilatorsand theophylline, the latter of which can be used if inhaled • Based on efficacy and side effects inhaledbronchodilators are unavailable or unaffordable. bronchodilators are preferred over oral bronchodilators IG (Evidence A).Group C patients have few symptoms but a high risk • Based on evidence of relatively low efficacy and YRof exacerbations. As first choice a fixed combination of more side effects, treatment with theophylline is notinhaled corticosteroid/long-acting beta2-agonist or a long- recommended unless other long-term treatmentacting anticholinergic is recommended195,212,214,240,244,251,388. bronchodilators are unavailable or unaffordable PUnfortunately, there is only one study directly comparing (Evidence B). CO MANAGEMENT OF STABLE COPD 35
  • CE Table 4.4. Initial Pharmacologic Management of COPD* U Patient Group First Choice Second Choice Alternative Choice** OD Long-acting anticholinergic or Short-acting anticholinergic prn Long-acting beta2-agonist PR or A or Theophylline Short-acting beta2-agonist prn Short-acting beta2-agonist and RE short-acting anticholinergic Short-acting beta2-agonist OR Long-acting anticholinergic and/or or Long-acting anticholinergic Short-acting anticholinergic B Long-acting beta2-agonist and long-acting beta2-agonist Theophylline R TE Phosphodiesterase-4 inhibitor AL Inhaled corticosteroid + Long-acting anticholinergic Short-acting beta2-agonist long-acting beta2-agonist and long-acting beta2-agonist and/or C or Short-acting anticholinergic Long-acting anticholinergic T NO Theophylline Inhaled corticosteroid and O long-acting anticholinergic or -D Inhaled corticosteroid + long-acting beta2-agonist and Carbocysteine long-acting anticholinergic AL Inhaled corticosteroid + or Short-acting beta2-agonist long-acting beta2-agonist Inhaled corticosteroid + and/or D RI or long-acting beta2-agonist and Short-acting anticholinergic Long-acting anticholinergic phosphodiesterase-4 inhibitor TE or Theophylline Long-acting anticholinergic and long-acting beta2-agonist MA or Long-acting anticholinergic and phosphodiesterase-4 inhibitor ED*Medications in each box are mentioned in alphabetical order, and therefore not necessarily in order of preference.**Medications in this column can be used alone or in combination with other options in the First and Second columns. HT IG P YR CO36 MANAGEMENT OF STABLE COPD
  • CECorticosteroids and Phosphodiesterase-4 Inhibitors -– Monitor Pharmacotherapy and Other Medical TreatmentRecommendations In order to adjust therapy appropriately as the disease progresses, each follow-up visit should include a discussion U• There is no evidence to recommend a short-term of the current therapeutic regimen. Dosages of various OD therapeutic trial with oral corticosteroids in patients with medications, adherence to the regimen, inhaler technique, COPD to identify those who will respond to inhaled effectiveness of the current regime at controlling symptoms, corticosteroids or other medications. and side effects of treatment should be monitored. PR• Long-term treatment with inhaled corticosteroids Treatment modifications should be recommended is recommended for patients with severe and very as appropriate with a focus on avoiding unnecessary severe COPD and frequent exacerbations that are not polypharmacy. RE adequately controlled by long-acting bronchodilators (Evidence A). At the individual patient level, measurements such as FEV1• Long-term monotherapy with oral corticosteroids is not and questionnaires such as the CAT are useful but are not OR recommended in COPD (Evidence A). completely reliable, because the size of a clinically important• Long-term monotherapy with inhaled corticosteroids is response is smaller than between-assessment variability. For not recommended in COPD because it is less effective this reason, the following questions might be useful when R than the combination of inhaled corticosteroids with long- deciding whether a patient has had a symptomatic response acting beta2-agonists (Evidence A). to treatment: TE• The phosphodiesterase-4 inhibitor, roflumilast, may also be used to reduce exacerbations for patients with chronic • Have you noticed a difference since starting this AL bronchitis, severe and very severe COPD, and frequent treatment? exacerbations that are not adequately controlled by long- • If you are better: acting bronchodilators (Evidence B). T Are you less breathless? Can you do more? NO MONITORING AND FOLLOW-UP Can you sleep better? Describe what difference it has made to you. • Is that change worthwhile to you?Routine follow-up is essential in COPD. Lung function Ocan be expected to worsen over time, even with the best Monitor Exacerbation History -Davailable care. Symptoms and objective measures of airflowlimitation should be monitored to determine when to modify Evaluate the frequency, severity, and likely causes oftherapy and to identify any complications that may develop. any exacerbations391. Increased sputum volume, acutelyAs at the initial assessment, follow-up visits should include a AL worsening dyspnea, and the presence of purulent sputumdiscussion of symptoms, particularly any new or worsening should be noted. Specific inquiry into unscheduled visitssymptoms, and a physical examination. RI to providers, telephone calls for assistance, and use of urgent or emergency care facilities is important. SeverityMonitor Disease Progression and Development of TE of exacerbations can be estimated by the increased needComplications for bronchodilator medication or corticosteroids and by the need for antibiotic treatment. Hospitalizations should be MAMeasurements. Decline in lung function is best tracked byspirometry performed at least once a year to identify patients documented, including the facility, duration of stay, and anywhose lung function is declining quickly. Questionnaires use of critical care or mechanical ventilatory support.such as the COPD Assessment Test (CAT)124 can be EDperformed every two to three months; trends and changes Monitor Comorbiditiesare more valuable than single measurements. Comorbidities are common in COPD, amplify the disability HTSymptoms. At each visit, inquire about changes in associated with COPD, and can potentially complicatesymptoms since the last visit, including cough and sputum, its management. Until more integrated guidance about IGbreathlessness, fatigue, activity limitation, and sleep disease management for specific comorbid problemsdisturbances. becomes available, the focus should be on identification and YR management of these individual problems in line with localSmoking Status. At each visit, determine current smoking treatment guidance (See also Chapter 6).status and smoke exposure; strongly encourage participation Pin programs to reduce and eliminate wherever possible COexposure to COPD risk factors. MANAGEMENT OF STABLE COPD 37
  • CESurgery in the COPD PatientPostoperative pulmonary complications are as important Uand common as postoperative cardiac complications ODand, consequently, are a key component of the increasedrisk posed by surgery in COPD patients392. The principalpotential factors contributing to the risk include smoking, PRpoor general health status, age, obesity, and COPD severity.A comprehensive definition of postoperative pulmonarycomplications should include only major pulmonary RErespiratory complications, namely lung infections, atelectasisand/or increased airflow limitation, which all potentially resultin acute respiratory failure and aggravation of underlying ORCOPD291,393-395.Increased risk of postoperative pulmonary complications Rin COPD patients may vary with the severity of COPD,although the surgical site is the most important predictor; risk TEincreases as the incision approaches the diaphragm394. Mostreports conclude that epidural or spinal anesthesia have a ALlower risk than general anesthesia, although the results arenot totally uniform.For lung resection, the individual patient’s risk factors should T NObe identified by careful history, physical examination, chestradiography, and pulmonary function tests. Although thevalue of pulmonary function tests remains contentious, thereis consensus that all COPD candidates for lung resection Oshould undergo a complete battery of tests, including -Dspirometry with bronchodilator response, static lung volumes,diffusing capacity, and arterial blood gases at rest396,397.COPD patients at high risk for surgical complications due ALto poor lung function should undergo further lung functionassessment, for example, tests of regional distribution of RIperfusion and exercise capacity396,397. TEThe risk of postoperative complications from lung resectionappears to be increased in patients with decreased predictedpostoperative pulmonary function (FEV1 or DLCO < 30-40% MApredicted) or exercise capacity (peak VO2 < 10 ml/kg/min or35% predicted). The final decision to pursue surgery shouldbe made after discussion with the surgeon, pulmonary EDspecialist, primary clinician, and the patient. To preventpostoperative pulmonary complications, stable COPDpatients clinically symptomatic and/or with limited exercise HTcapacity should be treated intensively before surgery, withall the measures already well established for stable COPD IGpatients who are not about to have surgery. Surgery shouldbe postponed if an exacerbation is present. P YR CO38 MANAGEMENT OF STABLE COPD
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 5 OF RE PR CHAPTER OD U MANAGEMENT EXACERBATIONS CE
  • CE CHAPTER 5: MANAGEMENT OF EXACERBATIONS KEY POINTS: In-hospital mortality of patients admitted for a hypercapnic U • An exacerbation of COPD is an acute event exacerbation with acidosis is approximately 10%402. OD characterized by a worsening of the patient’s Mortality reaches 40% at 1 year after discharge in those respiratory symptoms that is beyond normal day-to- needing mechanical support, and all-cause mortality 3 years after hospitalization is as high as 49%401-405. PR day variations and leads to a change in medication. • Exacerbations of COPD can be precipitated by Prevention, early detection, and prompt treatment of several factors. The most common causes appear exacerbations are vital to reduce the burden of COPD406. RE to be viral upper respiratory tract infections and infection of the tracheobronchial tree. Exacerbations of COPD can be precipitated by several • The diagnosis of an exacerbation relies exclusively factors. The most common causes appear to be respiratory tract infections (viral or bacterial). Bronchoscopic studies OR on the clinical presentation of the patient complaining of an acute change of symptoms (baseline dyspnea, have shown that at least 50% of patients have bacteria in cough, and/or sputum production) that is beyond their lower airways during exacerbations of COPD407-409, but normal day-to-day variation. a significant proportion of these patients also have bacteria R • The goal of treatment in COPD exacerbations is to colonizing their lower airways in the stable phase of the TE minimize the impact of the current exacerbation and to disease. On the other hand, there is some indication that prevent the development of subsequent exacerbations. the bacterial burden increases during some exacerbations • Short-acting inhaled beta2-agonists with or without of COPD410-412, and that acquisition of bacterial strains that AL short-acting anticholinergics are usually the preferred are new to the patient is associated with exacerbations of bronchodilators for treatment of an exacerbation. COPD413. Air pollution can also precipitate exacerbations • Systemic corticosteroids and antibiotics can shorten of COPD414-416. However, the cause of about one-third of T recovery time, improve lung function (FEV1) and severe exacerbations of COPD cannot be identified. Some NO arterial hypoxemia (PaO2), and reduce the risk of early patients appear particularly prone to suffer exacerbations relapse, treatment failure, and length of hospital stay. of COPD whereas others do not. Those reporting two or • COPD exacerbations can often be prevented. more exacerbations of COPD per year are often defined as O Smoking cessation, influenza and pneumococcal “frequent exacerbators132,” a phenotype that appears stable vaccination, knowledge of current therapy including over time. -D inhaler technique, and treatment with long- acting inhaled bronchodilators, with or without In addition to infections and exposure to pollutants, inhaled corticosteroids, and treatment with a exacerbations of respiratory symptoms (especially dyspnea) AL phosphodiesterase-4 inhibitor are all interventions in patients with COPD may be due to different mechanisms that reduce the number of exacerbations and that may overlap in the same patients. Conditions that may RI hospitalizations. mimic and/or aggravate exacerbations, including pneumonia, pulmonary embolism, congestive heart failure, cardiac TE DEFINITION arrhythmia, pneumothorax, and pleural effusion, need to be considered in the differential diagnosis and treated if present128,291,398,417. Interruption of maintenance therapy has MAAn exacerbation of COPD is an acute event characterized also been shown to lead to exacerbations.by a worsening of the patient’s respiratory symptoms that isbeyond normal day-to-day variations and leads to a change EDin medication128-130. DIAGNOSISExacerbations of COPD are important events in the course Currently, the diagnosis of an exacerbation relies HTof the disease because they: exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline• Negatively affect a patient’s quality of life144,391 IG dyspnea, cough, and/or sputum production) that is beyond• Have effects on symptoms and lung function that take normal day-to-day variation. In the future, a biomarker or YR several weeks to recover from398 panel of biomarkers that allows a more precise etiologic• Accelerate the rate of decline of lung function399,400 diagnosis would be desirable.• Are associated with significant mortality, particularly in P those requiring hospitalization• CO Have high socioeconomic costs40140 MANAGEMENT OF EXACERBATIONS
  • CE Spirometry is not recommended during an exacerbation ASSESSMENT because it can be difficult to perform and measurements are not accurate enough. UThe assessment of an exacerbation is based on thepatient’s medical history and clinical signs of severity OD(Tables 5.1 and 5.2) and some laboratory tests, if available. TREATMENT OPTIONS PR Table 5.1. Assessment of COPD Exacerbations: Medical History Treatment Setting • Severity of COPD based on degree of airflow limitation The goals of treatment for COPD exacerbations are to RE • Duration of worsening or new symptoms • Number of previous episodes (total/hospitalizations) minimize the impact of the current exacerbation and • Comorbidities prevent the development of subsequent exacerbations419. • Present treatment regimen Depending on the severity of an exacerbation and/or the OR • Previous use of mechanical ventilation severity of the underlying disease, an exacerbation can be managed in an outpatient or inpatient setting. More than Table 5.2. Assessment of COPD Exacerbations: Signs of Severity 80% of exacerbations can be managed on an outpatient R basis132,143,214 with pharmacologic therapies including • Use of accessory respiratory muscles bronchodilators, corticosteroids, and antibiotics. TE • Paradoxical chest wall movements • Worsening or new onset central cyanosis • Development of peripheral edema Table 5.3 shows the indications for hospital assessment AL • Hemodynamic instability and potential admission of a patient with a COPD • Deteriorated mental status exacerbation. When a patient comes to the emergency department the first actions are to provide supplemental TThe following tests may be considered to assess the oxygen therapy and to determine whether the exacerbation NOseverity of an exacerbation: is life-threatening (Table 5.4). If so, the patient should be admitted to the ICU immediately. Otherwise, the patient• Pulse oximetry is useful for tracking and/or adjusting may be managed in the emergency department or hospital as detailed in Table 5.5. In addition to pharmacologic O supplemental oxygen therapy. The measurement of arterial blood gases is vital if the coexistence of acute therapy, hospital management of exacerbations includes -D or acute-on-chronic respiratory failure is suspected respiratory support (oxygen therapy, ventilation) as detailed (PaO2 < 8.0 kPa (60 mmHg) with or without PaCO2 > in Table 5.5. 6.7 kPa (50 mmHg) breathing ambient air). Assessment Table 5.3. Potential Indications for AL of the acid-base status is necessary before initiating mechanical ventilation291,418. Hospital Assessment or Admission*• Chest radiographs are useful in excluding alternative • Marked increase in intensity of symptoms, such as sudden RI diagnoses. development of resting dyspnea• An ECG may aid in the diagnosis of coexisting cardiac • Severe underlying COPD TE problems. • Onset of new physical signs (e.g., cyanosis, peripheral edema)• Whole blood count may identify polycythemia • Failure of an exacerbation to respond to initial medical management (hematocrit > 55%), anemia, or leukocytosis. • Presence of serious comorbidities (e.g., heart failure or newly MA• The presence of purulent sputum during an occurring arrhythmias) exacerbation can be sufficient indication for starting • Frequent exacerbations empirical antibiotic treatment114. Hemophilus influenzae, • Older age ED Streptococcus pneumoniae, and Moraxella catarrhalis • Insufficient home support are the most common bacterial pathogens involved in *Local resources need to be considered. an exacerbation409; in GOLD 3 and GOLD 4 patients Pharmacologic Treatment HT Pseudomonas aeruginosa becomes important. If an infectious exacerbation does not respond to the initial The three classes of medications most commonly antibiotic treatment, a sputum culture and an antibiotic IG sensitivity test should be performed291. used for exacerbations of COPD are bronchodilators,• Biochemical test abnormalities including electrolyte corticosteroids, and antibiotics. YR disturbances and hyperglycemia can be associated with exacerbations. However, these abnormalities can Short-acting Bronchodilators. Although there also be due to associated comorbidities. are no controlled trials, short-acting inhaled beta2- P agonists with or without short-acting anticholinergics CO are usually the preferred bronchodilators for treatment MANAGEMENT OF EXACERBATIONS 41
  • CE Table 5.4. Management of Severe but treatment failure, and length of hospital stay428,430,432. A Not Life-Threatening Exacerbations* dose of 30-40 mg prednisolone per day for 10-14 days is recommended (Evidence D). Therapy with oral U • Assess severity of symptoms, blood gases, chest radiograph prednisolone is preferable433. Nebulised budesonide alone Administer supplemental oxygen therapy and obtain serial arterial blood OD • may be an alternative (although more expensive) to oral gas measurement corticosteroids in the treatment of exacerbations429,434,435. • Bronchodilators: – Increase doses and/or frequency of short-acting bronchodilators PR Antibiotics. Although the infectious agents in COPD – Combine short-acting beta2-agonists and anticholinergics – Use spacers or air-driven nebulizers exacerbations can be viral or bacterial273,436, the use • Add oral or intravenous corticosteroids of antibiotics in exacerbations remains controversial. RE • Consider antibiotics (oral or occasionally intravenous) when signs of The uncertainties originate from studies that did not bacterial infection differentiate between bronchitis (acute or chronic) and • Consider noninvasive mechanical ventilation COPD exacerbations, studies without placebo-control, OR • At all times: and/or studies without chest X-rays in which it was unclear – Monitor fluid balance and nutrition if patients had signs of pneumonia. There is evidence – Consider subcutaneous heparin or low molecular weight heparin supporting the use of antibiotics in exacerbations when – Identify and treat associated conditions (e.g., heart failure, patients have clinical signs of a bacterial infection, e.g., R arrhythmias) – Closely monitor condition of the patient increase in sputum purulence114. A systematic review of the TE*Local resources need to be considered. very few available placebo-controlled studies has shown that antibiotics reduce the risk of short-term mortality by AL Table 5.5. Therapeutic Components of Hospital Management 77%, treatment failure by 53% and sputum purulence by 44%. This review supports antibiotics for only moderately RESPIRATORY SUPPORT or severely ill patients with COPD exacerbations with Oxygen therapy Ventilatory support T increased cough and sputum purulence437,438. In outpatients, NO sputum cultures are not feasible as they take too long (at Noninvasive ventilation least 2 days) and frequently do not give reliable results for Invasive ventilation technical reasons, i.e., more than 4 hours elapse between PHARMACOLOGIC TREATMENT expectoration of sputum and analysis in the microbiology O Bronchodilators lab. Procalcitonin III, a marker that is specific for bacterial -D Corticosteroids infections, may be of value in the decision to use Antibiotics antibiotics439, but this test is expensive and thus not widely Adjunct therapies established. A study in COPD patients with exacerbations ALof an exacerbation290,291 (Evidence C). There are no requiring mechanical ventilation (invasive or noninvasive)clinical studies that have evaluated the use of inhaled indicated that not giving antibiotics was associated withlong-acting bronchodilators (either beta2-agonists or increased mortality and a greater incidence of secondary RIanticholinergics) with or without inhaled corticosteroids nosocomial pneumonia440.during an exacerbation. A systematic review of the TEroute of delivery of short-acting bronchodilators found no In summary, antibiotics should be given to patientssignificant differences in FEV1 between metered-dose with exacerbations of COPD who have three cardinal MAinhalers (with or without a spacer device) and nebulizers420, symptoms – increase in dyspnea, sputum volume, andalthough the latter can be more convenient for sicker sputum purulence (Evidence B); have two of the cardinalpatients. Intravenous methylxanthines (theophylline or symptoms, if increased purulence of sputum is one of EDaminophylline) are considered second-line therapy, only the two symptoms (Evidence C); or require mechanicalto be used in selected cases when there is insufficient ventilation (invasive or noninvasive) (Evidence B)273. Theresponse to short-acting bronchodilators421-425 (Evidence recommended length of antibiotic therapy is usually 5-10 HTB). Side effects of methylxanthines are significant and days (Evidence D).their beneficial effects in terms of lung function and clinicalendpoints are modest and inconsistent426,427. The choice of the antibiotic should be based on the local IG bacterial resistance pattern. Usually initial empiricalCorticosteroids. Data from studies in secondary treatment is an aminopenicillin with or without clavulanic YRhealth care indicate that systemic corticosteroids in acid, macrolide, or tetracycline. In patients with frequentCOPD exacerbations shorten recovery time, improve exacerbations, severe airflow limitation417,441, and/or exacerbations requiring mechanical ventilation412, cultures Plung function (FEV1) and arterial hypoxemia (PaO2)428-431 (Evidence A), and reduce the risk of early relapse, from sputum or other materials from the lung should be CO42 MANAGEMENT OF EXACERBATIONS
  • CEperformed, as gram-negative bacteria (e.g., Pseudomonasspecies) or resistant pathogens that are not sensitive to the Table 5.6. Indications for ICU Admission *above-mentioned antibiotics may be present. The route Uof administration (oral or intravenous) depends on the • Severe dyspnea that responds inadequately to initial emergency therapy ODability of the patient to eat and the pharmacokinetics of theantibiotic, although preferably antibiotics are given orally. • Changes in mental status (confusion, lethargy, coma) • Persistent or worsening hypoxemia (PaO2 < 5.3 kPa, 40 mmHg) and/orImprovements in dyspnea and sputum purulence suggest severe/worsening respiratory acidosis (pH < 7.25) despite supplemental PRclinical success. oxygen and noninvasive ventilation • Need for invasive mechanical ventilationAdjunct Therapies: Depending on the clinical condition • Hemodynamic instability—need for vasopressors REof the patient, an appropriate fluid balance with special *Local resources need to be considered.attention to the administration of diuretics, anticoagulants, Invasive mechanical ventilation. The indicationstreatment of comorbidities and nutritional aspects should for initiating invasive mechanical ventilation during an ORbe considered. At all times, health care providers should exacerbation are shown in Table 5.8, and include failure of anstrongly enforce stringent measures against active cigarette initial trial of NIV450. As experience is being gained with thesmoking. generalized clinical use of NIV in COPD, several indications R for invasive mechanical ventilation are being successfullyRespiratory Support treated with NIV, and in all but a few situations there is TE nothing to be lost by a trial of noninvasive ventilation450.Oxygen therapy. This is a key component of hospital ALtreatment of an exacerbation. Supplemental oxygen shouldbe titrated to improve the patient’s hypoxemia with a target Table 5.7. Indications for Noninvasivesaturation of 88-92%442. Once oxygen is started, arterial Mechanical Ventilation291,445,451,452blood gases should be checked 30-60 minutes later toensure satisfactory oxygenation without carbon dioxide T At least one of the following: NO • Respiratory acidosis (arterial pH ≤ 7.35 and/or PaCO2 ≥ 6.0 kPa, 45retention or acidosis. Venturi masks (high-flow devices) mm Hg)offer more accurate and controlled delivery of oxygen than • Severe dyspnea with clinical signs suggestive of respiratory muscledo nasal prongs but are less likely to be tolerated by the fatigue, increased work of breathing, or both, such as use of respiratory Opatient291. accessory muscles, paradoxical motion of the abdomen, or retraction of the intercostal spaces -DVentilatory Support. Some patients need immediateadmission to an intensive care unit (ICU) (Table 5.6). Table 5.8. Indications for Invasive Mechanical VentilationAdmission of patients with severe exacerbations to ALintermediate or special respiratory care units may be • Unable to tolerate NIV or NIV failureappropriate if personnel, skills, and equipment exist to • Respiratory or cardiac arrest RIidentify and manage acute respiratory failure successfully. • Respiratory pauses with loss of consciousness or gasping for air • Diminished consciousness, psychomotor agitation inadequately controlled TEVentilatory support in an exacerbation can be provided by by sedationeither noninvasive (by nasal or facial mask) or invasive • Massive aspirationventilation (by oro-tracheal tube or tracheostomy). • Persistent inability to remove respiratory secretions MA • Heart rate < 50 min-1 with loss of alertnessRespiratory stimulants are not recommended for acute • Severe hemodynamic instability without response to fluids and vasoactiverespiratory failure290. drugs • Severe ventricular arrhythmiasNoninvasive mechanical ventilation. Noninvasive ED • Life-threatening hypoxemia in patients unable to tolerate NIVmechanical ventilation (NIV) has been studied in severalrandomized controlled trials in acute respiratory failure, HTconsistently providing success rates of 80-85%443-446. The use of invasive ventilation in very severe COPDNIV improves respiratory acidosis (increases pH and patients is influenced by the likely reversibility of thedecreases PaCO2), and decreases respiratory rate, precipitating event, patient’s wishes, and availability of IGseverity of breathlessness, complications such as ventilator intensive care facilities. When possible, a clear statementassociated pneumonia, and length of hospital stay of the patient’s own treatment wishes—an advance YR(Evidence A). More importantly, mortality and intubation directive or “living will”—makes these difficult decisionsrates are reduced by this intervention444,447-449 (Evidence A). much easier to resolve. Major hazards include the risk of ventilator-acquired pneumonia (especially when multi- PTable 5.7 summarizes the indications for NIV443. resistant organisms are prevalent), barotrauma, and failure CO to wean to spontaneous ventilation. MANAGEMENT OF EXACERBATIONS 43
  • CEContrary to some opinions, acute mortality among COPD Table 5.9. Discharge Criteriapatients with respiratory failure is lower than mortalityamong patients ventilated for non-COPD causes453. U • Able to use long acting bronchodilators, either beta2-agonists and/ ODDespite this, there is evidence that patients who might or anticholinergics with or without inhaled corticosteroidsotherwise survive may be denied admission to intensive • Inhaled short-acting beta2-agonist therapy is required no morecare for intubation because of unwarranted prognostic frequently than every 4 hrs PRpessimism454. A study of a large number of COPD patients • Patient, if previously ambulatory, is able to walk across roomwith acute respiratory failure reported in-hospital mortality • Patient is able to eat and sleep without frequent awakening byof 17-49%403. Further deaths were reported over the dyspnea REnext 12 months, particularly among those patients who • Patient has been clinically stable for 12-24 hrshad poor lung function before invasive ventilation (FEV1 • Arterial blood gases have been stable for 12-24 hrs< 30% predicted), had a non-respiratory comorbidity, or • Patient (or home caregiver) fully understands correct use of ORwere housebound. Patients who did not have a previously medicationsdiagnosed comorbidity, had respiratory failure due to a • Follow-up and home care arrangements have been completedpotentially reversible cause (such as an infection), or (e.g., visiting nurse, oxygen delivery, meal provisions) Rwere relatively mobile and not using long-term oxygen did • Patient, family, and physician are confident that the patient cansurprisingly well after ventilatory support. manage successfully at home TEWeaning or discontinuation from mechanical ventilation ALcan be particularly difficult and hazardous in patients withCOPD. The most influential determinant of mechanical Table 5.10. Checklist of Items toventilatory dependency in these patients is the balance Assess at Time of Discharge from Hospitalbetween the respiratory load and the capacity of the T • Assurance of effective home maintenance pharmacotherapy NOrespiratory muscles to cope with this load455. By contrast, regimenpulmonary gas exchange by itself is not a major difficulty • Reassessment of inhaler techniquein patients with COPD456-458. Weaning patients from the • Education regarding role of maintenance regimenventilator can be a very difficult and prolonged process O • Instruction regarding completion of steroid therapy and antibiotics,and the best method (pressure support or a T-piece trial) if prescribed -Dremains a matter of debate459-461. In COPD patients that fail • Assess need for long-term oxygen therapyextubation, NIV facilitates weaning, prevents reintubation, • Assure follow-up visit in 4-6 weeksand reduces mortality451,462. Early NIV after extubation • Provide a management plan for comorbidities and their follow-up ALreduces the risk of respiratory failure and lowers 90-daymortality in patients with hypercapnia during a spontaneous RIbreathing trial457,462. Table 5.11. Items to Assess at Follow-Up Visit 4-6 Weeks After Discharge from Hospital TEHOSPITAL DISCHARGE • Ability to cope in usual environmentAND FOLLOW-UP • Measurement of FEV1 MA • Reassessment of inhaler techniqueInsufficient clinical data exist to establish the optimal • Understanding of recommended treatment regimenduration of hospitalization in individual patients with an • Reassess need for long-term oxygen therapy and/or home EDexacerbation of COPD463-465, although units with more nebulizerrespiratory consultants and better organized care have • Capacity to do physical activity and activities of daily livinglower mortality and reduced length of hospital stay following • CAT or mMRC HTadmission for an exacerbation466. In the hospital prior to • Status of comorbiditiesdischarge, patients should start long-acting bronchodilators, IGeither beta2-agonists and/or anticholinergics with or without cessation, monitor the effectiveness of each medication,inhaled corticosteroids. Consensus and limited data and monitor changes in spirometric parameters467. Prior YRsupport the discharge criteria listed in Table 5.9. Table 5.10 hospital admission, oral corticosteroids, use of long-termprovides a checklist of items to assess at time of discharge oxygen therapy, poor health-related quality of life, and lackand Table 5.11 shows items to assess at follow-up 4 to 6 of routine physical activity have been found to be predictive Pweeks after discharge from the hospital. Thereafter, follow- of readmission468. COup is the same as for stable COPD: supervise smoking44 MANAGEMENT OF EXACERBATIONS
  • CEHome visits by a community nurse may permit earlierdischarge of patients hospitalized with an exacerbationwithout increasing readmission rates291,469-472. Use of a Uwritten action plan increases appropriate therapeutic ODinterventions for an exacerbation, an effect that does notdecrease health-care resource utilization473 (Evidence B)but may shorten recovery time474. PRFor patients who are hypoxemic during an exacerbation,arterial blood gases and/or pulse oximetry should be REevaluated prior to hospital discharge and in the following3 months. If the patient remains hypoxemic, long-termsupplemental oxygen therapy may be required. ORHOME MANAGEMENTOF EXACERBATIONS R TEThe risk of dying from an exacerbation of COPD is closelyrelated to the development of respiratory acidosis, the ALpresence of significant comorbidities, and the need forventilatory support402. Patients lacking these features arenot at high risk of dying. Four randomized clinical trials Thave shown that nurse-administered home care (also NOknown as “hospital-at-home” care) represents an effectiveand practical alternative to hospitalization in selectedpatients with exacerbations of COPD without acidoticrespiratory failure467-470 (Evidence A). However, the exact Ocriteria for this approach as opposed to hospital treatment -Dremain uncertain and will vary by health care setting469,470.Treatment recommendations are the same for hospitalizedpatients. ALPREVENTION OF COPD RIEXACERBATIONS TECOPD exacerbations can often be prevented. Smoking MAcessation, influenza and pneumococcal vaccines, knowledgeof current therapy including inhaler technique, and treatmentwith long-acting inhaled bronchodilators, with or without EDinhaled corticosteroids, and possibly phosphodiesterase-4inhibitors, are all therapies that reduce the number ofexacerbations and hospitalizations133,134,195,214,264,266. Early HToutpatient pulmonary rehabilitation after hospitalization foran exacerbation is safe and results in clinically significant IGimprovements in exercise capacity and health status at3 months475. Patients should be encouraged to maintain YRphysical activity, and anxiety, depression and socialproblems should be discussed. Principal caregivers shouldbe identified if the patient has a significant persisting Pdisability. CO MANAGEMENT OF EXACERBATIONS 45
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR RE PR OD UCE
  • CO PYR IG HT ED MA TE RI AL -D O NO T AL TE R OR 6 RE AND COPD PR CHAPTER OD COMORBIDITIES UCE
  • CE CHAPTER 6: COPD AND COMORBIDITIES U OD may be insufficient for the management of all patients KEY POINTS: and cannot substitute for the use of guidelines for the management of each comorbidity. PR • COPD often coexists with other diseases (comorbidities) that may have a significant impact on Cardiovascular Disease (CVD) prognosis. RE • In general, the presence of comorbidities should not CVD is a major comorbidity in COPD and probably both alter COPD treatment and comorbidities should be the most frequent and most important disease coexisting treated as if the patient did not have COPD. with COPD135,477. Four separate entities within CVD will OR • Cardiovascular disease is a major comorbidity in be considered: ischemic heart disease, heart failure, atrial COPD and probably both the most frequent and most fibrillation and hypertension. important disease coexisting with COPD. R • Osteoporosis and depression are also major Ischemic Heart Disease (IHD): IHD is increased in comorbidities in COPD, are often under-diagnosed, COPD, to some extent because of an unfavourable IHD TE and are associated with poor health status and risk profile in COPD patients478,479. There is evidence that prognosis. myocardial injury is overlooked and IHD is therefore under- AL • Lung cancer is frequently seen in patients with COPD diagnosed in COPD patients480. and has been found to be the most frequent cause of death in patients with mild COPD. Treatment of IHD in patients with COPD: IHD should T be treated according to usual IHD guidelines, as there is NO no evidence that IHD should be treated differently in theINTRODUCTION presence of COPD. In a significant proportion of patients with IHD a beta-blocker will be indicated, either to treat OCOPD often coexists with other diseases (comorbidities) angina or after a myocardial infarction. Treatment withthat may have a significant impact on prognosis100,135,142,476. selective beta1-blockers is considered safe481 but this is -DSome of these arise independently of COPD whereas based on relatively few short-term studies. The benefits ofothers may be causally related, either with shared risk selective beta1-blockers when indicated in IHD are, however,factors or by one disease actually increasing the risk of considerably larger than the potential risks associated with ALanother. It is possible that features of COPD, such as treatment, even in patients with severe COPD.systemic inflammation, are shared with other diseases and RIas such this mechanism represents a link between COPD Treatment of COPD in patients with IHD: COPD shouldand some of its comorbidities477. This risk of comorbid be treated as usual as there is no evidence that COPD TEdisease can be increased by the sequelae of COPD; e.g., should be treated differently in the presence of IHD. Thisreduced physical activity. Whether or not COPD and statement is based on findings from large long-term studiescomorbid diseases are related, management of the COPD in COPD alone195,214,482, but no large long-term studies exist MApatient must include identification and treatment of its in patients with both COPD and IHD. Although no studiescomorbidities. Importantly, comorbidities with symptoms on COPD medications in patients with unstable anginaalso associated with COPD may be overlooked; e.g., heart exist, it seems reasonable to avoid especially high doses of EDfailure and lung cancer (breathlessness) or depression beta-agonists.(fatigue and reduced physical activity). Frequent andtreatable comorbidities should be prioritized. Heart Failure (HF): Heart failure is a common comorbidity HT in COPD. Roughly 30% of patients with stable COPDComorbidities are common at any severity of COPD131 will have some degree of HF483, and worsening of HF is IGand the differential diagnosis can often be difficult. For a significant differential diagnosis to an exacerbation ofexample, in a patient with both COPD and heart failure an COPD. Approximately 30% of patients in a HF clinic have YRexacerbation of COPD may be accompanied by worsening COPD484, and comorbid COPD is often be the cause ofof heart failure. admission for acute HF485 – with significant implications for prognosis as FEV1 is a strong predictor of mortality in HF486. PBelow is a brief guide to management of COPD and some HF, COPD and asthma may be confused because of the COcomorbidities in stable disease. The recommendations common cardinal symptom of breathlessness, and caution48 COPD AND COMORBIDITIES
  • CEis warranted for diagnosis and management of these Hypertension: Hypertension is likely to be the mostcomorbidities. frequently occurring comorbidity in COPD and has implications for prognosis477. UTreatment of HF in patients with COPD: HF should ODbe treated according to usual HF guidelines as there Treatment of hypertension in patients with COPD:is no evidence that HF should be treated differently in Hypertension should be treated according to usualthe presence of COPD. Treatment with selective beta1- hypertension guidelines, as there is no evidence that PRblockers has a significant impact on survival in HF and hypertension should be treated differently in the presencethe presence of COPD is the most significant reason for of COPD. The role of treatment with selective beta-blockerspatients not receiving sufficient therapy487. However, as in is less prominent in recent hypertension guidelines; if these REIHD, treatment with selective beta1-blockers is considered are used in patients with COPD, a selective beta1-blockersafe for heart failure patients who also have COPD481. should be chosen.Studies have shown that treatment with bisoprolol in HF ORwith concomitant COPD decreased FEV1 but without Treatment of COPD in patients with hypertension: COPDdeleterious effects on symptoms and quality of life488 and should be treated as usual as there is no direct evidencethat a selective beta1-blocker is indeed preferable to a non- that COPD should be treated differently in the presence of Rselective beta-blocker in HF with COPD489. The benefits hypertension.of selective beta1-blocker treatment in HF clearly outweigh TEany potential risk associated with treatment even in patients Osteoporosiswith severe COPD. AL Osteoporosis is a major comorbidity in COPD135,477, isTreatment of COPD in patients with HF: COPD should often under-diagnosed492 and is associated with poorbe treated as usual as there is no direct evidence that health status and prognosis. Osteoporosis may be more TCOPD should be treated differently in the presence of closely associated with emphysema than other subgroups NOHF. As for IHD this statement is based on findings from of COPD493. Osteoporosis is more often associated withlarge long-term studies in patients with HF and comorbid decreased body mass index494 and low fat-free mass495.COPD195,214,482. An observational study found an increasedrisk of death and hospital admission among patients with Treatment of osteoporosis in patients with COPD: OHF treated with inhaled beta-agonists490, possibly indicating Osteoporosis should be treated according to usual -Da need for close follow-up of patients with severe HF who osteoporosis guidelines. There is no evidence thatare on this treatment for COPD. osteoporosis should be treated differently in the presence of COPD. ALAtrial Fibrillation (AF): Atrial fibrillation is the mostfrequent cardiac arrhythmia and COPD patients have an Treatment of COPD in patients with osteoporosis: COPD RIincreased incidence of AF491. COPD with AF presents a should be treated as usual, as there is no evidence thatchallenge to clinicians because of the breathlessness and stable COPD should be treated differently in the presence TEdisability resulting from their coexistence. of osteoporosis. Inhaled triamcinolone was associated with increased loss of bone mass in the Lung Health Study II496,Treatment of AF in patients with COPD: AF should be whereas this was not the case for inhaled budesonide in MAtreated according to usual AF guidelines, as there is no the EUROSCOP trial175 or for inhaled fluticasone propionateevidence that patients with COPD should be treated in the TORCH trial250. An association between inhaleddifferently from all other patients. If beta-blockers are used, corticosteroids and fractures has been found in pharmaco- EDbeta1-selective drugs are preferred (see considerations epidemiological studies; however, these studies have notunder IHD and HF above). fully taken severity of COPD or exacerbations and their treatment into account. HTTreatment of COPD in patients with AF: COPD should betreated as usual; however, there are no good data on the Systemic corticosteroids significantly increase the risk IGuse of COPD medication in patients with AF and these of osteoporosis and recurrent courses of systemicpatients have often been excluded from clinical trials. It is corticosteroids for COPD exacerbations should be avoided YRa clinical impression that care should be taken when using if possible.high doses of beta2-agonists as this can make appropriateheart rate control difficult. P CO COPD AND COMORBIDITIES 49
  • CEAnxiety and Depression Treatment of COPD in patients with infections: COPD should be treated as usual as there is no evidence thatAnxiety and depression are major comorbidities in stable COPD should be treated differently in the presence UCOPD117,497-499 and both are associated with a poor of infections. In patients who develop repeated pneumonias ODprognosis498,500. Both are often associated with younger while on inhaled corticosteroids, this medication may beage, female gender, smoking, lower FEV1, cough, higher stopped in order to observe whether this medication couldSGRQ score, and a history of cardiovascular disease117,499. be the cause of repeated infections. PRTreatment of anxiety and depression in patients with Metabolic Syndrome and DiabetesCOPD: Both disorders should be treated according to REusual guidelines, as there is no evidence that anxiety and Studies have shown that the presence of metabolicdepression should be treated differently in the presence of syndrome and manifest diabetes are more frequent inCOPD. Given the large number of patients who have both COPD and the latter is likely to impact on prognosis142. ORdepression and COPD, more research on management ofdepression in COPD patients is needed501. Treatment of diabetes in patients with COPD: Diabetes should be treated according to usual guidelines for RTreatment of COPD in patients with anxiety and diabetes, as there is no evidence that diabetes should bedepression: COPD should be treated as usual as there is treated differently in the presence of COPD. However, for TEno evidence that stable COPD should be treated differently patients with severe COPD, it is not advised to aim for ain the presence of anxiety and depression. The potential body mass index (BMI) less than 21 kg/m2. ALimpact of pulmonary rehabilitation should be stressed asstudies have found that physical exercise has a beneficial Treatment of COPD in patients with diabetes: COPDeffect on depression in general502. should be treated as usual as there is no evidence that T stable COPD should be treated differently in the presence NOLung Cancer of diabetes.Lung cancer is frequently seen in patients with COPD andhas been found to be the most frequent cause of death in Opatients with mild COPD217. -DTreatment of lung cancer in patients with COPD: Lungcancer should be treated according to usual lung cancer ALguidelines, as there is no evidence that lung cancer shouldbe treated differently in the presence of COPD. However,often the reduced lung function of COPD patients will be a RIfactor limiting surgical intervention for lung cancer. TETreatment of COPD in patients with lung cancer: COPDshould be treated as usual as there is no evidence that MAstable COPD should be treated differently in the presenceof lung cancer.Infections EDSerious infections, especially respiratory infections, are HTfrequently seen in patients with COPD503.Treatment of infections in patients with COPD: Macrolide IGantibiotics increase the serum concentration oftheophylline. Apart from this, there is no evidence that YRinfections should be treated differently in the presenceof COPD. However, repeat courses of antibiotics forexacerbations may increase the risk for the presence of Pantibiotic resistant bacterial strains and more extensive COcultures of serious infections may be warranted.50 COPD AND COMORBIDITIES
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