Pulmonary Perspective

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1 Pulmonary Perspective Global Strategy for the Diagnosis, Management, an Prevention of Chronic Obstructive Pulmonary Disease GOLD Executive Summary Jørgen Vestbo 1,2, Suzanne S. Hur 3, Alvar G. Agustí 4, Paul W. Jones 5, Claus Vogelmeier 6, Antonio Anzueto 7, Peter J. Barnes 8, Leonaro M. Fabbri 9, Fernano J. Martinez 10, Masaharu Nishimura 11, Robert A. Stockley 12, Don D. Sin 13, an Roberto Roriguez-Roisin 4 1 Manchester Acaemic Health Sciences Centre, South Manchester University Hospital NHS Founation Trust, Manchester, Unite Kingom; 2 Oense University Hospital an University of Southern Denmark, Oense, Denmark; 3 Global Initiative for Chronic Obstructive Lung Disease, Vancouver, Washington; 4 Hospital Clínic, Universitat e Barcelona, Barcelona, Spain; 5 St George s Hospital Meical School, Lonon, Unite Kingom; 6 University of Gießen an Marburg School of Meicine, Marburg Germany; 7 University of Texas Health Science Center, San Antonio, Texas; 8 National Heart an Lung Institute, Lonon, Unite Kingom; 9 University of Moena an Reggio Emilia, Moena, Italy; 10 University of Michigan School of Meicine, Ann Arbor, Michigan; 11 Hokkaio University School of Meicine, Sapporo, Japan; 12 University Hospitals Birmingham, Birmingham, Unite Kingom; an 13 St Paul s Hospital, Vancouver, Canaa Chronic obstructive pulmonary isease (COPD) is a global health problem, an since 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has publishe its strategy ocument for the iagnosis an management of COPD. This executive summary presents the main contents of the secon 5-year revision of the GOLD ocument that has implemente some of the vast knowlege about COPD accumulate over the last years. Toay, GOLD recommens that spirometry is require for the clinical iagnosis of COPD to avoi misiagnosis an to ensure proper evaluation of severity of airflow limitation. The ocument highlights that the assessment of thepatient with COPDshoul always inclueassessment of (1)symptoms,(2)severity of airflow limitation, (3) history of exacerbations, an (4) comorbiities. Thefirstthreepointscanbeusetoevaluatelevelofsymptomsanrisk offutureexacerbations,anthisisoneinawaythatsplitspatientswith COPD into four categories A, B, C, an D. Nonpharmacologic an pharmacologic management of COPD match this assessment in an evience-base attempt to relieve symptoms an reuce risk of exacerbations. Ientification an treatment of comorbiities must have high priority, an a separate section in the ocument aresses management of comorbiities as well as COPD in the presence of comorbiities. The revise ocument also contains anewsection on exacerbationsof COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholers an will hopefully inspire future national an local guielines on the management of COPD. Keywors: COPD; clinical assessment; COPD management; exacerbations; comorbiities CONTENTS Introuction Summary of New Recommenations Levels of Evience 1. Definition an Overview Author Contributions: All authors have contribute to this report; J.V. wrote the first raft. Corresponence an requests for reprints shoul be aresse to Jørgen Vestbo, D.M.Sc., Manchester Acaemic Sciences Health Centre, Respiratory Research Group, University of Manchester, University Hospital South Manchester, Southmoor Roa, Manchester M23 9LT, UK. jorgen.vestbo@manchester.ac.uk This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Me Vol 187, Iss. 4, pp , Feb 15, 2013 Copyright ª 2013 by the American Thoracic Society Originally Publishe in Press as DOI: /rccm PP on August 9, 2012 Internet aress: Key Points Definition Buren of COPD Factors That Influence Disease Development an Progression Pathology, Pathogenesis, an Pathophysiology 2. Diagnosis an Assessment Key Points Diagnosis Assessment of Disease Differential Diagnosis 3. Therapeutic Options Key Points 4. Management of Stable COPD Key Points Introuction Ientify an Reuce Exposures Treatment of Stable COPD Nonpharmacologic Treatment Pharmacologic Treatment Monitoring an Follow-up 5. Management of Exacerbations Key Points Definition Diagnosis Assessment Treatment Options Hospital Discharge an Follow-up Home Management of Exacerbations Prevention of COPD Exacerbations 6. COPD an Comorbiities Key Points Introuction Cariovascular Diseases Osteoporosis Anxiety an Depression Lung Cancer Infections Metabolic Synrome an Diabetes INTRODUCTION Chronic obstructive pulmonary isease (COPD) is a major public health problem. In 2020, COPD is projecte to rank fifth worlwie

2 348 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL in terms of buren of isease an thir in terms of mortality. Although COPD has receive increasing attention from the meical community in recent years, it is still relatively unknown or ignore by the public as well as public health an government officials. In 1998, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was forme to bring more attention to the management an prevention of COPD. Among the important objectives of GOLD are to increase awareness of COPD an to help the millions of people who suffer from this isease an ie prematurely from it or its complications. In 2001, the GOLD program release a consensus report, Global Strategy for the Diagnosis, Management, an Prevention of COPD; this ocument was revise in 2006, an now we present the 2011 version. The GOLD ocument is a global ocument an for that reason alone shoul not be regare a clinical guieline. It is impossible to make the same guielines for eveloping countries as for, for example, Europe an North America. A strategy ocument provies avice on iagnosis an management that can be implemente in national guielines. It can be expane for rich countries an restricte for poorer ones. It provies guiance on principles an rug classes to be applie, an national guielines can therefore buil on the assessment an management principles suggeste by GOLD an then moify it to fit their country s nees. Base on multiple scientific an clinical achievements in the 10 years since the 2001 GOLD report was publishe, this revise eition provies a new paraigm for treatment of stable COPD. This major revision buils on the strengths from the original recommenations an incorporates new knowlege to make three important new recommenations: 1. One of the strengths was the treatment objectives. These have stoo the test of time, but are now organize into two groups: objectives that are irecte towar immeiately relieving an reucing the impact of symptoms, an objectives that reuce the risk of averse health events in the future. This emphasizes the nee for clinicians to maintain a focus on both the short-term an long-term impact of COPD on their patients. 2. A secon strength of the original strategy was the simple, intuitive system for classifying COPD severity. This was base on the FEV 1 an was calle a staging system because it was believe, at the time, that the majority of patients followe a path of isease progression that tracke the severity of the airflow limitation. Much is now known about the characteristics of patients in the ifferent GOLD stages for example, their level of risk of exacerbations, hospitalization, an eath. However at an iniviual patient level, the FEV 1 is an unreliable marker of the severity of breathlessness, exercise limitation, an health status impairment. This report retains the GOLD classification system of airflow limitation because it is a preictor of future averse events, but the term stage is now replace by grae. 3. At the time of the original report, improvement in both symptoms an health status was a GOLD treatment objective, but symptom assessment i not have a irect relation to the choice of management, an health status measurement was a complex process largely confine to clinical stuies. Now, there are simple an reliable questionnaires esigne for use in routine aily clinical practice. These have been valiate in many languages, which has enable the evelopment of a new assessment system that integrates patient symptoms an their risk for serious averse health events in the future. In turn, this new assessment system has le to the construction of a new approach to management one that matches assessment to treatment objectives. The new management approach can beuseinanyclinical setting anywhere in the worl an moves COPD treatment towar iniviualize meicine matching the patient s therapy more closely to his or her nees. Whereas recommenations on treatment are evience base, a novel assessment system will have to be consensus base, with the aim that future stuies will test the value of this system. Summary of New Recommenations A summary of the new issues presente in this report follows: 1. This ocument has been consierably shortene in length by limiting section 1 to the essential backgroun ata on COPD. Reaers who wish to access more comprehensive information are referre to a variety of excellent textbooks that have appeare in the last ecae. 2. Section 2 inclues information on iagnosis an assessment of COPD. The efinition of COPD has not been significantly moifie but has been rewore for clarity. 3. Assessment of COPD is base on the patient s level of symptoms, exacerbation history, the severity of the spirometric abnormality, an the ientification of comorbiities. Whereas spirometry was previously use to support a iagnosis of COPD, spirometry is now require to make a confient iagnosis of COPD. 4. Airflow limitation as etermine by spirometry is ivie into four graes (GOLD 1, mil; GOLD 2, moerate; GOLD 3, severe; an GOLD 4, very severe) using the fixe ratio, post-bronchoilator FEV 1 /FVC, 0.7, to efine airflow limitation. It is recognize that the use of the fixe ratio (FEV 1 /FVC) may lea to more frequent iagnoses of COPD in oler aults with mil COPD as the normal process of aging affects lung volumes an flows, an may lea to uneriagnosis in aults younger than 45 years. The concept of staging has been abanone because a staging system base on FEV 1 alone was inaequate an the evience for an alternative staging system oes not exist. The most severe spirometric grae, GOLD 4, oes not inclue reference to respiratory failure as this seeme to be an arbitrary inclusion. 5. A new section (section 3) on therapeutic approaches has been ae. This inclues escriptive information on both pharmacologic an nonpharmacologic therapies, an ientifying any averse effects. 6. Management of COPD is presente in three sections: MANAGE- MENT OF STABLE COPD (section 4); MANAGEMENT OF EXACER- BATIONS (section 5); an COPD AND COMORBIDITIES (section 6), covering both management of comorbiities in patients with COPD an of COPD in patients with comorbiities. 7. In section 4, MANAGEMENT OF STABLE COPD, recommene approaches to both pharmacologic an nonpharmacologic treatment of COPD are presente. In previous GOLD ocuments, recommenations for management of COPD were base solely on spirometric category. However, there is consierable evience that the level of FEV 1 is a poor escriptor of isease status, an for this reason, the management of stable COPD base on a strategy consiering both isease impact (etermine mainly by symptom buren an activity limitation) an future risk of isease progression (especially of exacerbations) is recommene. 8. Section 5, MANAGEMENT OF EXACERBATIONS, presents a revise efinition of a COPD exacerbation.

3 GOLD Executive Summary Section 6, COMORBIDITIES AND COPD, focuses on cariovascular iseases, osteoporosis, anxiety an epression, lung cancer, infections, an metabolic synrome an iabetes. Levels of Evience Levels of evience are assigne to management recommenations where appropriate with the system use in previous reports. Evience levels are enclose in parentheses after the relevant statement, for example, (Evience A). Levels of evience use in this ocument have not change with respect to previous releases an are liste in the original ocument ( 1. DEFINITION AND OVERVIEW KEY POINTS COPD, a common preventable an treatable isease, is characterize by persistent airflow limitation that is usually progressive an associate with an enhance chronic inflammatory response in the airways an the lung to noxious particles or gases. Exacerbations an comorbiities contribute to the overall severity in iniviual patients. COPD is a leaing cause of morbiity an mortality worlwie an results in an economic an social buren that is both substantial an increasing. Inhale cigarette smoke an other noxious particles such as smoke from biomass fuels cause lung inflammation, a normal response that appears to be moifie in patients who evelop COPD. This chronic inflammatory response may inuce parenchymal tissue estruction (resulting in emphysema) an isrupt normal repair an efense mechanisms (resulting in small airway fibrosis). These pathological changes lea to air trapping an progressive airflow limitation, an in turn to breathlessness an other characteristic symptoms of COPD. Definition COPD, a common preventable an treatable isease, is characterize by persistent airflow limitation that is usually progressive an associate with an enhance chronic inflammatory response in the airways an the lung to noxious particles or gases. Exacerbations an comorbiities contribute to the overall severity in iniviual patients. The chronic airflow limitation characteristic of COPD is cause by a mixture of small airways isease (obstructive bronchiolitis) an parenchymal estruction (emphysema), the relative contributions of which vary from person to person. Chronic inflammation causes structural changes an narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory processes, leas to the loss of alveolar attachments to the small airways an ecreases lung elastic recoil; in turn, these changes iminish the ability of the airways to remain open uring expiration. Airflow limitation is best measure by spirometry, as this is the most wiely available, reproucible test of lung function. Buren of COPD COPD prevalence, morbiity, an mortality vary across countries an across ifferent groups within countries. COPD is the result of cumulative exposures over ecaes. Often, the prevalence of COPD is irectly relate to the prevalence of tobacco smoking, although in many countries, outoor, occupational, an inoor air pollution the latter resulting from the burning of woo an other biomass fuels are major COPD risk factors (1). The prevalence an buren of COPD are projecte to increase in the coming ecaes ue to continue exposure to COPD risk factors an the aging of the worl s population. Prevalence. Existing COPD prevalence ata show remarkable variation ue to ifferences in survey methos, iagnostic criteria, an analytic approaches (2). Despite the complexities an the wiesprea unerrecognition an uneriagnosis of COPD (3), ata from the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO) an the Buren of Obstructive Lung Diseases program (BOLD) have ocumente more severe isease than previously foun an a substantial prevalence (3 11%) of COPD among never-smokers (4). Morbiity. Morbiity measures traitionally inclue physician visits, emergency epartment visits, an hospitalizations. Morbiity ue to COPD increases with age (5 7) an may be affecte by other comorbi chronic conitions (e.g., cariovascular isease, musculoskeletal impairment, or iabetes mellitus) that are frequent in patients with COPD an may impact on the patient s health status, as well as interfere with COPD management. Mortality. Unerrecognition an uneriagnosis of COPD still affect the accuracy of mortality ata (8, 9) with COPD often liste as a contributory cause of eath or omitte from the eath certificate entirely (10). The Global Buren of Disease Stuy projecte that COPD, which ranke sixth as a cause of eath in 1990, will become the thir leaing cause of eath worlwie by 2020; a newer projection estimate COPD will be the fourth leaing cause of eath in 2030 (11). This increase mortality is mainly riven by the expaning epiemic of smoking, reuce mortality from other common causes of eath, an aging of the worl population. Economic an social buren. COPD is associate with significant economic buren. There is a irect relationship between the severity of COPD an the cost of care, an the istribution of costs changes as the isease progresses. For example, hospitalization an ambulatory oxygen costs soar as COPD severity increases. In eveloping countries, irect meical costs may be less important than the impact of COPD on workplace an home prouctivity. In 1990, COPD was the 12th leaing cause of isability-ajuste life years (DALYs) lost in the worl, responsible for 2.1% of the total. Accoring to the projections, COPD will be the seventh leaing causeofdalyslostworlwiein2030(11). Factors That Influence Disease Development an Progression Although cigarette smoking is the best-stuie COPD risk factor, there is consistent epiemiological evience that nonsmokers may also evelop chronic airflow limitation (5 7, 12). Besies, among people with the same smoking history, not all will evelop COPD, for reasons that are still unclear but likely involve ifferences in genetic backgrouns an other exposures. Across the worl, cigarette smoking is the most commonly encountere risk factor for COPD. Cigarette smokers have a higher prevalence of respiratory symptoms an lung function abnormalities, a greater annual rate of ecline in FEV 1,anagreaterCOPD mortality rate than nonsmokers (13). Other types of tobacco (e.g., pipe, cigar, water pipe [14]) an marijuana (15) are also risk factors for COPD (16, 17). Passive exposure to cigarette smoke (also known as environmental tobacco smoke) may also contribute to respiratory symptoms (18) an COPD (19) by increasing the lung s total buren of inhale particles an gases (20, 21). Smoking uring pregnancy may also pose a risk for the fetus, by affecting lung growth an evelopment in utero an possibly the priming of the immune system (22, 23).

4 350 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Occupational exposures, incluing organic an inorganic usts an chemical agents an fumes, are an unerappreciate risk factor for COPD (24 26). Woo, animal ung, crop resiues, an coal, typically burne in open fires or poorly functioning stoves, may lea to very high levels of inoor air pollution. Evience continues to grow that inoor pollution from biomass cooking an heating in poorly ventilate wellings is an important risk factor for COPD (27 33). Almost 3 billion people worlwie use biomass an coal as their main source of energy for cooking, heating, an other househol nees, so the population at risk worlwie is very large (30, 34). Other factors associate with evelopment an progression of COPD, such as genetics, lung evelopment abnormalities, accelerate aging, bronchial hyperreactivity, an socioeconomic status, among others, are liste in recent reviews an in the full ocument ( Pathology, Pathogenesis, an Pathophysiology 1 Inhale particles (from cigarette smoke or other sources) cause lung inflammation, a normal response that appears to be moifie in iniviuals who evelop COPD. This chronic inflammatory response may inuce parenchymal tissue estruction (resulting in emphysema), an isrupt normal repair an efense mechanisms (resulting in small airway fibrosis), which in turn lea to air trapping an progressive airflow limitation. Pathology. Chronic inflammatory changes with increase numbers of inflammatory cell types, an structural changes resulting from repeate injury an repair, are foun in the airways, lung parenchyma, an pulmonary vasculature of patients with COPD (35). In general, these changes increase with isease severity an persist espite smoking cessation. Pathogenesis. The above-mentione pathological changes appears to be an enhancement of the normal, physiological, inflammatory response of the respiratory tract to chronic irritants. The mechanisms for this amplifie inflammation in COPD are not yet unerstoo but may be genetically etermine. Lung inflammation persists after smoking cessation through unknown mechanisms, although autoantigens an persistent microorganisms may play a role (36). Patients can clearly evelop COPD without smoking, but the nature of the inflammatory response in these patients is unknown. Pathophysiology. AIRFLOW LIMITATION AND GAS TRAPPING. Inflammation an narrowing of peripheral airways leas to ecrease FEV 1. Parenchymal estruction ue to emphysema also contributes to airflow limitation ue to reuce elastic recoil (37). In combination, both progressively lea to gas trapping uring expiration, resulting in hyperinflation. GAS EXCHANGE ABNORMALITIES. Gas exchange abnormalities may result in hypoxemia an hypercapnia, an have several mechanisms in COPD. The main one is ventilation perfusion (V A /Q) abnormalities (38). Reuce ventilatory rive may lea to carbon ioxie retention, particularly when combine with reuce ventilation. MUCUS HYPERSECRETION. Mucus hypersecretion, resulting in a chronic prouctive cough, is a feature of chronic bronchitis an is not necessarily associate with airflow limitation. Conversely, not all patients with COPD have symptomatic mucus hypersecretion. When present, it is ue to an increase number of goblet cells an enlarge submucosal glans in response to chronic airway irritation. PULMONARY HYPERTENSION. Pulmonary hypertension may evelop late in the course of COPD. It can be ue to hypoxic vasoconstriction of small pulmonary arteries, eventually resulting in 1 Illustrations of many of the topics covere in this section can be foun in the Teaching Slie Set on the GOLD website: structural changes that inclue intimal hyperplasia an later smooth muscle hypertrophy/hyperplasia, an/or loss of pulmonary capillary be ue to emphysema (39). In pulmonary vessels, an inflammatory response similar to that seen in the airways (an evience of enothelial ysfunction) has been ientifie. Severe pulmonary hypertension may lea to right ventricular hypertrophy an eventually to right-sie cariac failure. EXACERBATIONS. Exacerbations of respiratory symptoms often occur in patients with COPD, triggere by infection with bacteria or viruses (which may coexist), environmental pollutants, or unknown factors. During exacerbations, there is a flare-up of inflammation, increase hyperinflation an gas trapping, reuce expiratory flow, an increase yspnea (40). There is also worsening of V A /Q abnormalities, which can result in hypoxemia an hypercapnia (41). Other meical conitions (pneumonia, thromboembolism, an acute cariac failure) may mimic or aggravate an exacerbation of COPD. COMORBIDITIES. It is increasingly recognize that many patients with COPD have comorbiities an that these have a major impact on their quality of life an survival (42). The precise pathobiology of this association is uner investigation but may involve mechanical as well as biological or genetic mechanisms. For instance, airflow limitation an hyperinflation affect cariac function an gas exchange (43). 2. DIAGNOSIS AND ASSESSMENT KEY POINTS A clinical iagnosis of COPD shoul be consiere in any patient who has yspnea, chronic cough an/or sputum prouction, an a history of exposure to risk factors for the isease. Spirometry is require to make the iagnosis in this clinical context; the presence of a post-bronchoilator FEV 1 /FVC less than 0.70 confirms the presence of persistent airflow limitation an thus of COPD. The goals of COPD assessment are to etermine: (1) the impact of the isease on the patient s health status, (2) the severity of airflow limitation, an (3) the risk of future exacerbations, in orer to guie therapy. The risk of future exacerbations is estimate by the severity of airflow limitation an the history of previous exacerbations. Comorbiities, incluing cariovascular isease, skeletal muscle ysfunction, metabolic synrome, osteoporosis, epression, an lung cancer, occur frequently in patients with COPD. Comorbiities shoul be actively looke for, an treate appropriately if present. Diagnosis A clinical iagnosis of COPD shoul be consiere in any patient who has yspnea, chronic cough an/or sputum prouction, an a history of exposure to risk factors for the isease. Spirometry is require to make the iagnosis in this clinical context; the presence of a post-bronchoilator FEV 1 /FVC less than 0.70 confirms the presence of persistent airflow limitation an thus of COPD. The spirometric criterion for airflow limitation remains a post-bronchoilator fixe ratio of FEV 1 /FVC less than This criterion is simple, inepenent of reference values, an has been use in numerous clinical trials forming the evience base from which most of our treatment recommenations are rawn. Diagnostic simplicity an consistency are key for the busy nonspecialist clinician. Although post-bronchoilator spirometry

5 GOLD Executive Summary 351 is require for the iagnosis an assessment of severity of COPD, the egree of reversibility of airflow limitation (e.g., measuring FEV 1 before an after bronchoilator or corticosterois) is no longer recommene. Symptoms. The characteristic symptoms of COPD are chronic an progressive yspnea, cough, an sputum prouction. Chronic cough an sputum prouction may precee the evelopment of airflow limitation by many years. Iniviuals, particularly those expose to COPD risk factors, who present with these symptoms shoul be examine to search for an unerlying cause(s) an appropriate interventions taken. Conversely, significant airflow limitation may evelop without chronic cough an sputum prouction. Meical history. A etaile meical history of a new patient known or thought to have COPD shoul assess: Exposure to risk factors Past meical history Family history of COPD or other chronic respiratory isease Pattern of symptom evelopment History of exacerbations or previous hospitalizations for respiratory isorer Presence of comorbiities Impact of the isease on the patient s life Social an family support available to the patient Possibilities for reucing risk factors, especially smoking cessation Physical examination. Although an important part of patient care, a physical examination is rarely iagnostic in COPD. Physical signs of airflow limitation are usually not present until significant impairment of lung function has occurre (44, 45), an their etection has a relatively low sensitivity an specificity. Spirometry. Spirometry is the most reproucible an objective measurement of airflow limitation available. Peak expiratory flow measurement alone cannot be reliably use as the only iagnostic test, espite its goo sensitivity, because of its weak specificity (46). Goo-quality spirometric measurement is possible in any health care setting, an all health care workers who care for patients with COPD shoul have access to spirometry. Assessment of Disease The goals of COPD assessment are to etermine: (1) the impact of the isease on the patient s health status, (2) the severity of airflow limitation, an (3) the risk of future events (such as exacerbations, hospital amissions, or eath), to, eventually, guie therapy. To achieve these goals, COPD assessment must consier the following aspects of the isease separately: Current level of patient s symptoms Severity of airflow limitation Exacerbation risk Presence of comorbiities Assessment of symptoms. There are several valiate questionnaires to assess symptoms in patients with COPD that can be use to istinguish patients with less severe symptoms from patients with more severe symptoms. GOLD primarily recommens the use of the Moifie British Meical Research Council (mmrc) questionnaire on breathlessness or the COPD Assessment Test (CAT), the latter having a broaer coverage of the impact of COPD on the patient s aily life an well-being. Other symptoms scales can be use where available, for example, the Clinical COPD Questionnaire, an future GOLD upates are likely to expan in this area. Assessment of airflow limitation severity. Table 1 shows the classification of airflow limitation severity in COPD. Specific spirometric cut points are use for purposes of simplicity. Spirometry shoul be performe after the aministration of an aequate ose of a short-acting inhale bronchoilator to minimize variability. Worsening airflow limitation is associate with an increasing prevalence of exacerbations (see below) an risk of eath. Assessment of exacerbation risk. An exacerbation of COPD is efine as an acute event characterize by a worsening of the patient s respiratory symptoms that is beyon normal ay-toay variations an leas to a change in meication (47 49). The rate at which exacerbations occur varies greatly between patients (50). The best preictor of having frequent exacerbations (two or more exacerbations per year) is a history of previous treate events (51). Severity of exacerbations is usually classifie as mil when exacerbations of respiratory symptoms require change of inhale treatment by the patient, moerate when exacerbations of respiratory symptoms require meical intervention incluing a short course of antibiotic an/or oral sterois, an severe when exacerbations of respiratory symptoms require hospitalization. Assessment of comorbiities. Comorbiities occur frequently in COPD an inclue cariovascular isease, skeletal muscle ysfunction, metabolic synrome, osteoporosis, epression, an lung cancer. The existence of COPD may actually increase the risk for other concomitant iseases; this is particularly striking for COPD an lung cancer (52 55). Combine COPD assessment. Figure 1 illustrates the propose combine assessment of COPD. The MRC or CAT scale is recommene for assessing symptoms, with an mmrc grae greater than or equal to 2 or a CAT score greater than or equal to 10 inicating a high level of symptoms. These cutoffs shoul be use as inicators; the primary aim is to separate patients with a significant symptom buren from those with less symptoms. There are two methos of assessing exacerbation risk. One is a population-base metho using the GOLD spirometric classification (Table 1), with GOLD 3 or GOLD 4 categories inicating high risk. The other is base on the iniviual patient s history of exacerbations (51, 56), with two or more exacerbations in the preceing year inicating high risk. Given the significance of an exacerbation leaing to hospital amission (57), hospitalization will often be an inicator of high risk as well. If there is a iscrepancy between the risk category as assesse by spirometric classification an that erive from exacerbation history, the assessment pointing to the highest risk shoul be use. To use Figure 1, first assess symptoms an etermine if the patient belongs to the left sie of the box less symptoms (as inicate by mmrc grae 0 1 or CAT, 10) or the right sie more symptoms (as inicate by mmrc > 2 or CAT > 10). Next, assess the risk of exacerbations to etermine if the patient belongs to the TABLE 1. GRADING OF SEVERITY OF AIRFLOW LIMITATION IN COPD (BASED ON POST-BRONCHODILATOR FEV 1 ) In patients with FEV 1 /FVC, 0.70: GOLD 1: Mil FEV 1 > 80% preicte GOLD 2: Moerate 50% < FEV 1, 80% preicte GOLD 3: Severe 30% < FEV 1, 50% preicte GOLD 4: Very severe FEV 1, 30% preicte Definition of abbreviation: COPD ¼ chronic obstructive pulmonary isease; GOLD ¼ Global Initiative for Chronic Obstructive Lung Disease.

6 352 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Combine COPD assessment. When assessing risk, choose the highest risk accoring to GOLD spirometric grae or exacerbation history. lower part of the box low risk or the upper part of the box high risk. This can be one by either of two methos: (1) use spirometry to etermine the GOLD grae of airflow limitation (GOLD 1 an 2 inicate low risk, whereas GOLD 3 an 4 inicate high risk); or (2) assess the number of exacerbations the patient has ha within the previous 12 months (zero or one inicates low risk, whereas two or more exacerbations inicates high risk). In some patients, these two ways of assessing risk of exacerbations will not lea to the same level of risk; in this case, the risk shoul be etermine by the metho inicating high risk. The groups can be summarize as follows: Patient group A low risk, less symptoms GOLD 1 2 (mil or moerate airflow limitation) an 0 1 exacerbation per year an mmrc grae 0 1 or CAT score, 10 Patient group B low risk, more symptoms GOLD 1 2 (mil or moerate airflow limitation) an 0 1 exacerbation per year an mmrc grae > 2or CAT score > 10 Patient group C high risk, less symptoms GOLD 3 4 (severe or very severe airflow limitation) an/or > 2 exacerbations per year an/or > 1 hospitalize exacerbation per year an mmrc grae 0 1 or CAT score, 10 Patient group D high risk, more symptoms GOLD 3 4 (severe or very severe airflow limitation) an/or > 2 exacerbations per year / > 1 hospitalize exacerbation per year an mmrc grae > 2 or CAT score > 10 This approach, combine with an assessment of potential comorbiities, reflects the complexity of COPD better than the uniimensional analysis of airflow limitation previously use for staging the isease an forms the basis of the guie to iniviualize management provie in section 4. Aitional investigations. The following aitional investigations may be consiere as part of the iagnosis an assessment of COPD: IMAGING. A chest X-ray is not useful to establish a iagnosis in COPD, but it is valuable in excluing alternative iagnoses an establishing the presence of significant comorbiities. LUNG VOLUMES AND DIFFUSING CAPACITY. Patients with COPD exhibit gas trapping (a rise in resiual volume) from early in the isease, an as airflow limitation worsens, static hyperinflation (an increase in total lung capacity) occurs. These changes can be ocumente by boy plethysmography, or less accurately by helium ilution lung volume measurement. Diffusing capacity can be assesse by the uptake of carbon monoxie using the single-breath metho. These measurements help characterize the severity of COPD but are not essential to patient management. OXIMETRY AND ARTERIAL BLOOD GAS MEASUREMENT. Pulse oximetry can be use to evaluate a patient s oxygen saturation an nee for supplemental oxygen therapy. Pulse oximetry shoul be use to assess all stable patients with FEV 1 less than 35% preicte or with clinical signs suggestive of respiratory failure or right heart failure. If peripheral saturation is less than 92%, arterial bloo gases shoul be assesse (58). a 1 -ANTITRYPSIN DEFICIENCY SCREENING. The Worl Health Organization recommens that patients with COPD from areas with a particularly high prevalence of a 1 -antitrypsin eficiency shoul be screene for this genetic isorer (59). The typical patient tens to present at a younger age (,45 yr) with lower lobe emphysema. A serum concentration of a 1 -antitrypsin below 15 to 20% of the normal value is highly suggestive of homozygous a 1 -antitrypsin eficiency. EXERCISE TESTING. Objectively measure exercise impairment, assesse by a reuction in self-pace walking istance (60) or uring incremental exercise testing in a laboratory (61), is a powerful inicator of health status impairment an preictor of prognosis (62). Monitoring of physical activity may be more relevant regaring prognosis than evaluating exercise capacity (63). COMPOSITE SCORES. Several variables, incluing age, yspnea, FEV 1, boy mass inex, exercise tolerance assesse by walking istance or peak oxygen consumption, an/or arterial hypoxemia, ientify patients at increase risk for mortality (64 66). Differential Diagnosis In some patients with chronic asthma, a clear istinction from COPD is not possible using current imaging an physiological testing techniques, an it is assume that asthma an COPD coexist in these patients. In these cases, current management will inclue use of antiinflammatory rugs, an other treatments nee to be iniviualize. Other potential iagnoses are usually easier to istinguish from COPD (Table 2). 3. THERAPEUTIC OPTIONS KEY POINTS In patients who continue to smoke, smoking cessation is a key therapeutic measure. Pharmacotherapy an nicotine replacement reliably increase long-term smoking abstinence rates. Appropriate pharmacologic therapy can reuce COPD symptoms, reuce the frequency an severity of exacerbations, an improve health status an exercise tolerance. To ate, none of the existing meications for COPD has been shown conclusively to moify the long-term ecline in lung function. Each pharmacological treatment regimen nees to be patient specific, guie by severity of symptoms, risk of exacerbations, comorbiities, rug availability, an the patient s response. Influenza an pneumococcal vaccination shoul be offere to every patient with COPD; they appear to be more effective in oler patients an those with more severe isease or cariac comorbiity. All patients who get short of breath when walking on their own pace on level groun shoul be offere rehabilitation; it can improve symptoms, quality of life, an physical an emotional participation in everyay activities. All text of this section can be foun in the online supplement.

7 GOLD Executive Summary MANAGEMENT OF STABLE COPD KEY POINTS Ientification an reuction of exposure to risk factors are important in the prevention an treatment of COPD. All iniviuals who smoke shoul be encourage to quit. The level of FEV 1 is an inaequate escriptor of the impact of the isease on patients, an for this reason, iniviualize assessment of symptoms an future risk of exacerbation shoul also be incorporate into the management strategy for stable COPD. Regular physical activity is recommene for all patients with COPD. All patients with COPD with breathlessness when walking at their own pace on level groun benefit from rehabilitation an maintenance of physical activity, improving their exercise tolerance an quality of life, an reucing symptoms of yspnea an fatigue. Pharmacologic therapy is use to reuce symptoms, reuce frequency an severity of exacerbations, an improve health status an exercise tolerance. Existing meications for COPD have not been conclusively shown to moify the long-term ecline in lung function that is the hallmark of this isease. For both b 2 -agonists an anticholinergics, long-acting formulations are preferre over short-acting formulations. Base on efficacy an sie effects, inhale bronchoilators are preferre over oral bronchoilators. Long-term treatment with inhale corticosterois ae to long-acting bronchoilators is recommene for patients at high risk of exacerbations. Long-term monotherapy with oral or inhale corticosterois is not recommene in COPD. The phospoiesterase-4 inhibitor roflumilast may be useful to reuce exacerbations for patients with FEV 1 less than 50% preicte, chronic bronchitis, an frequent exacerbations. Influenza vaccines can reuce the risk of serious illness (such as hospitalization ue to lower respiratory tract infections) an eath in patients with COPD. The routine use of antibiotics is not inicate in patients with clinically stable COPD, other than for treating infectious exacerbations of COPD an other bacterial infections. Introuction Once COPD has been iagnose, effective management shoul be base on an iniviualize assessment of the isease having two goals in min: 1. Reuce current symptoms 2. Reuce the risk of future events (Table 3) These goals shoul be reache with minimal sie effects from treatment, a particular challenge in patients with COPD because they commonly have comorbiities that also nee to be carefully ientifie an treate. Ientify an Reuce Exposures Ientification an reuction of exposure to risk factors are important in the treatment (an prevention) of COPD. Since cigarette smoking is the most commonly encountere an easily ientifiable risk factor, smoking cessation shoul be encourage for all iniviuals who smoke. Reuction of total personal exposure to occupational usts, fumes, an gases an to inoor an outoor air pollutants may be more ifficult but shoul be attempte. Treatment of Stable COPD In previous versions of the GOLD report, COPD treatment recommenations were base on spirometry only. This is in keeping with the fact that most of the clinical trial evience about treatment efficacy in COPD is oriente aroun baseline FEV 1. However, FEV 1 alone is a poor escriptor of isease status, an for this reason, the treatment strategy for stable COPD shoul consier also an iniviual patient s symptoms an future risk of exacerbations as illustrate in Figure 1. Nonpharmacologic Treatment Physical activity. Regular physical activity is recommene for all patients with COPD. Rehabilitation. Although more information is neee on criteria for patient selection for pulmonary rehabilitation programs, all patients with COPD appear to benefit from rehabilitation an maintenance of physical activity, improving their exercise tolerance an experiencing ecrease yspnea an fatigue (67) (Evience A). Vaccination. Decisions about vaccination in patients with COPD epen on local policies, availability, an afforability. Nonpharmacologic management of COPD accoring to the iniviualize assessment of symptoms an exacerbation risk (Figure 1) is shown in Table 4. Pharmacologic Treatment The classes of meications commonly use in treating COPD are shown in Table E1 in the online supplement, an a etaile escription of the effects of these meications is given in section 3 in the online supplement. The choice within each class epens on the availability of meication an the patient s response. A propose moel for initial pharmacological management of COPD accoring to the iniviualize assessment of symptoms an exacerbation risk (Figure 1) is shown in Table 5. Group A. Group A patients have few symptoms an a low risk of exacerbations. Specific evience for the effectiveness of pharmacologic treatments is not available for patients with FEV 1 greater than 80% preicte (GOLD 1). However, for all group A patients, a short-acting bronchoilator is recommene as first choice base on its effect on lung function an breathlessness. Secon choice is a combination of short-acting bronchoilators or the introuction of a long-acting bronchoilator. The evience for this step-up is weak; few stuies of the combination exist (68, 69), an most trials of therapy with long-acting bronchoilators have been performe in patients with more severe airflow limitation (70, 71). Group B. Group B patients have more significant symptoms but still a low risk of exacerbations. Long-acting bronchoilators are superior to short-acting bronchoilators (taken as neee) an are therefore recommene (70, 71). There is no evience to recommen one class of long-acting bronchoilators over another for initial treatment. In the iniviual patient, the choice shoul epen on the patient s perception of symptom relief. For patients with severe breathlessness, the secon choice is a combination of long-acting bronchoilators (72, 73). Only short-term stuies of this treatment option have been reporte, an patients on a combination of long-acting bronchoilators shoul be carefully followe an their treatment effect evaluate.

8 354 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 2. COPD AND ITS DIFFERENTIAL DIAGNOSES Diagnosis COPD Asthma Congestive heart failure Bronchiectasis Tuberculosis Obliterative bronchiolitis Diffuse panbronchiolitis Alternative choices inclue short-acting bronchoilators an theophylline, the latter of which can be use if inhale bronchoilators are unavailable or unafforable. Group C. Group C patients have few symptoms but a high risk of exacerbations. As first choice, a long-acting anticholinergic or a combination of inhale corticosteroi/long-acting b 2 - agonist is recommene (71, 74 79). Unfortunately, there is only one stuy irectly comparing these treatments, which makes ifferentiation ifficult (80). Both long-acting anticholinergic an long-acting b 2 -agonist reuce the risk of exacerbations (70, 71), an although goo long-term stuies are lacking, this principle of combination treatment seems soun (although in many countries expensive). The recommenation for a combination of inhale corticosteroi/long-acting anticholinergic is not evience base. A phosphoiesterase-4 inhibitor may be TABLE 3. GOALS FOR TREATMENT OF STABLE COPD Reuce symptoms Relieve symptoms Improve exercise tolerance Improve health status Reuce risk Prevent isease progression Prevent exacerbations Reuce mortality Suggestive Features Onset in milife Symptoms slowly progressive History of tobacco smoking or exposure to other types of smoke Onset early in life (often chilhoo) Symptoms vary wiely from ay to ay Symptoms worse at night/early morning Allergy, rhinitis, an/or eczema also present Family history of asthma Chest X-ray shows ilate heart, pulmonary eema Pulmonary function tests inicate volume restriction, not airflow limitation Large volumes of purulent sputum Commonly associate with bacterial infection Chest X-ray/CT shows bronchial ilation, bronchial wall thickening Onset all ages Chest X-ray shows lung infiltrate Microbiological confirmation High local prevalence of tuberculosis Onset at younger age, nonsmokers May have history of rheumatoi arthritis or acute fume exposure Seen after lung or bone marrow transplantation CT on expiration shows hypoense areas Preominantly seen in patients of Asian escent Most patients are male an nonsmokers Almost all have chronic sinusitis Chest X-ray an HRCT show iffuse small centrilobular noular opacities an hyperinflation Definition of abbreviations: CT¼ computer tomography; HRCT ¼ high-resolution computer tomography. These features ten to be characteristic of the respective iseases, but are not manatory. For example, a person who has never smoke may evelop COPD (especially in the eveloping worl where other risk factors may be more important than cigarette smoking); asthma may evelop in ault an even in elerly patients. Definition of abbreviation: COPD ¼ chronic obstructive pulmonary isease. consiere if the patient has chronic bronchitis (81, 82). Alternative choices inclue short-acting bronchoilators an theophylline if long-acting inhale bronchoilators are unavailable or unafforable. Group D. Group D patients have many symptoms an a high risk of exacerbations. The rationale for the first choice of therapy is the same as that for patients in group C, as reuction of exacerbation risk seems most important. As secon choice, a combination of all three classes of rugs (inhale corticosteroi/ long-acting b 2 -agonist/long-acting anticholinergic) is recommene (83), although there are conflicting finings concerning this treatment (84); support for it mainly comes from short-term stuies (85). It is also possible to a a phosphoiesterase-4 inhibitor to the treatment chosen as first choice, provie the patient has chronic bronchitis (81). A phosphoiesterase-4 inhibitor is effective when ae to a long-acting bronchoilator (82), whereas evience of its benefit when ae to inhale corticosteroi comes from less vali seconary analyses. Alternative choices inclue short-acting bronchoilators, an theophylline or carbocysteine (86) can be use if long-acting inhale bronchoilators are unavailable or unafforable. Bronchoilators recommenations For both b 2 -agonists an anticholinergics, long-acting formulations are preferre over short-acting formulations (Evience A). The combine use of short- or long-acting b 2 -agonists an anticholinergics may be consiere if symptoms are not improve with single agents (Evience B). Base on efficacy an sie effects, inhale bronchoilators are preferre over oral bronchoilators (Evience A). Base on evience of relatively low efficacy an more sie effects, treatment with theophylline is not recommene unless other long-term treatment bronchoilators are unavailable or unafforable (Evience B). Corticosterois an phosphoiesterase-4 inhibitors recommenations There is no evience to recommen a short-term therapeutic trial with oral corticosterois in patients with COPD to ientify those who will respon to inhale corticosterois or other meications. Long-term treatment with inhale corticosterois is recommene for patients with FEV 1 less than 50% of preicte an/or frequent exacerbations that are not aequately controlle by long-acting bronchoilators (Evience A). Long-term monotherapy with oral corticosterois is not recommene in COPD (Evience A). Long-term monotherapy with inhale corticosterois is not recommene in COPD because it is less effective than the combination of inhale corticosterois with long-acting b 2 -agonists (Evience A). The phosphoiesterase-4 inhibitor roflumilast may also be use to reuce exacerbations for patients with chronic bronchitis, FEV 1 less than 50% of preicte, an frequent exacerbations that are not aequately controlle by longacting bronchoilators (Evience B). Monitoring an Follow-up Routine follow-up is essential in COPD. The frequency of followup visits an type of examinations nees to be iniviualize. In general, the following aspects nee to be consiere:

9 GOLD Executive Summary 355 TABLE 4. NONPHARMACOLOGIC MANAGEMENT OF COPD Patient Group Essential Recommene Depening on Local Guielines A Smoking cessation (can inclue pharmacologic treatment) Physical activity Flu vaccination Pneumococcal vaccination B D Smoking cessation (can inclue pharmacologic treatment) Physical activity Flu vaccination Pulmonary rehabilitation Pneumococcal vaccination Definition of abbreviation: COPD ¼ chronic obstructive pulmonary isease. Symptoms. At each visit, inquire about changes in symptoms since the last visit, incluing cough an sputum, breathlessness, fatigue, activity limitation, an sleep isturbances. Questionnaires such as the CAT (87) can be performe every 2 to 3 months; trens an changes are more valuable than single measurements. Smoking status. At each visit, etermine current smoking status an smoke exposure; strongly encourage participation in programs to reuce an eliminate wherever possible exposure to COPD risk factors. Lung function. It may worsen over time, even with the best available care. Decline in lung function is best tracke by spirometry performe at least once a year to ientify patients whose lung function is eclining quickly. Pharmacotherapy an other meical treatment. To ajust therapy appropriately as the isease progresses, each follow-up visit shoul inclue a iscussion of the current therapeutic regimen. Dosages of various meications, aherence to the regimen, inhaler technique, effectiveness of the current regime at controlling symptoms, an sie effects of treatment shoul be monitore. Treatment moifications shoul be recommene as appropriate with a focus on avoiing unnecessary polypharmacy. Exacerbation history. Evaluate the frequency, severity, an likely causes of any exacerbations (88). Specific inquiry into unscheule visits to proviers, telephone calls for assistance, an use of urgent or emergency care facilities is important. Severity of exacerbations can be estimate by the increase nee for bronchoilator meication or corticosterois, by the nee for antibiotic treatment, or by ocumenting hospitalizations. Comorbiities. Ientification an manage them in line with local treatment guiance (see section 6). Surgery in the patient with COPD. Generalsurgicalriskincreases in patients with COPD ue to smoking, poor general health status, age, obesity, an COPD severity (89). Postoperative pulmonary complications inclue lung infections, atelectasis, an/or increase airflow limitation, which all potentially result in acute respiratory failure (90 93). The surgical site is the most important preictor of postoperative pulmonary complications an risk increases as the incision approaches the iaphragm (92). Epiural or spinal anesthesia appears to have a lower risk than general anesthesia. To prevent postoperative pulmonary complications, patients with COPD shoul be optimally treate before surgery. Surgery shoul be postpone if an exacerbation is present. For lung resection, the iniviual patient s risk factors shoul be ientifie by careful history, physical examination, chest raiography, an a complete battery of pulmonary function tests, incluing spirometry with bronchoilator response, static lung volumes, iffusing capacity, an arterial bloo gases at rest (94, 95). The risk of postoperative complications is particularly high in patients with ecrease preicte postoperative pulmonary function (FEV 1 or DL CO, 30 40% preicte). These patients shoul unergo further lung function assessment, for example, tests of regional istribution of perfusion an exercise capacity (94, 95). Poor exercise capacity (peak VO 2, 10 ml/kg/min or 35% preicte) ientifies a group of patients at very high risk. The final ecision to pursue surgery shoul be mae after iscussion with the surgeon, pulmonary specialist, primary clinician, an the patient. 5. MANAGEMENT OF EXACERBATIONS KEY POINTS An exacerbation of COPD is an acute event characterize by a worsening of the patient s respiratory symptoms that is beyon normal ay-to-ay variations an leas to a change in meication. Exacerbations of COPD can be precipitate by several factors. The most common causes appear to be viral upper respiratory tract infections an infection of the tracheobronchial tree. The iagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline yspnea, cough, an/or sputum prouction) that is beyon normal ayto-ay variation. The goal of treatment in COPD exacerbations is to minimize the impact of the current exacerbation an to prevent the evelopment of subsequent exacerbations. Short-acting inhale b 2 -agonists with or without shortacting anticholinergics are usually the preferre bronchoilators for treatment of an exacerbation. Systemic corticosterois an antibiotics can shorten recovery time, improve lung function (FEV 1 ) an arterial hypoxemia (Pa O2 ), an reuce the risk of early relapse, treatment failure, an length of hospital stay. COPD exacerbations can often be prevente. Smoking cessation, influenza an pneumococcal vaccination, knowlege of current therapy incluing inhaler technique, an appropriate treatment are all interventions that reuce the number of exacerbations an hospitalizations. Definition An exacerbation of COPD is an acute event characterize by a worsening of the patient s respiratory symptoms that is beyon normal ay-to-ay variations an leas to a change in meication (47 49). Exacerbations of COPD are important events in the course of the isease because they: Negatively affect a patient s quality of life (88, 96) Have effects on symptoms an lung function that take several weeks to recover (97) Accelerate the rate of ecline of lung function (98, 99) Are associate with significant mortality, particularly in those requiring hospitalization Have high socioeconomic costs (100) In-hospital mortality of patients amitte for a hypercapnic exacerbation with aciosis is approximately 10% (101). Mortality

10 356 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL reaches 40% at 1 year after ischarge in those neeing mechanical ventilator support, an all-cause mortality 3 years after hospitalization is as high as 49% ( ). Prevention, early etection, an prompt treatment of exacerbations are vital to reuce the buren of COPD (105). Exacerbations of COPD can be precipitate by several factors. The most common causes appear to be respiratory tract infections (viral or bacterial) ( ). Air pollution can also precipitate exacerbations of COPD ( ). However, the cause of about one-thir of severe exacerbations of COPD cannot be ientifie. Some patients appear particularly prone to eveloping exacerbations of COPD, whereas others o not. Those reporting two or more exacerbations of COPD per year are often efine as frequent exacerbators (51, 56), a phenotype that appears stable over time. Severity of exacerbations is usually classifie as mil when exacerbations of respiratory symptoms require change of inhale treatment by the patient, moerate when exacerbations of respiratory symptoms require meical intervention incluing a short course of antibiotic an/ or oral sterois, an severe when exacerbations of respiratory symptoms require hospitalization. In aition to infections an exposure to pollutants, exacerbations of respiratory symptoms (especially yspnea) in patients with COPD may be ue to ifferent mechanisms that may overlap in the same patients. Conitions that may mimic an/or aggravate exacerbations, incluing pneumonia, pulmonary embolism, congestive heart failure, cariac arrhythmia, pneumothorax, an pleural effusion, nee to be consiere in the ifferential iagnosis an treate if present (47, 90, 97, 116). Interruption of maintenance therapy has also been showntoleatoexacerbations. Diagnosis Currently, the iagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline yspnea, cough, an/or sputum prouction) that is beyon normal ay-to-ay variation. In the future, a biomarker or panel of biomarkers that allows a more precise etiologic iagnosis woul be esirable. Assessment The assessment of an exacerbation is base on the patient s meical history an clinical signs of severity an some laboratory tests, if available. The following tests may be consiere to assess the severity of an exacerbation: Pulse oximetry for tracking an/or ajusting supplemental oxygen therapy. The measurement of arterial bloo gases is require if the coexistence of acute or acute-on-chronic respiratory failure is suspecte (Pa O2, 8.0 kpa [60 mm Hg] with or without Pa CO kpa [50 mm Hg] breathing ambient air). Assessment of the aci base status is necessary before initiating mechanical ventilation (90, 117). Chest raiographs are useful in excluing alternative iagnoses. An ECG may ai in the iagnosis of coexisting cariac problems. Whole-bloo count may ientify polycythemia (hematocrit. 55%), anemia, or leukocytosis. The presence of purulent sputum uring an exacerbation can be sufficient inication for starting empirical antibiotic treatment (118). Haemophilus influenzae, Streptococcus pneumoniae, an Moraxella catarrhalis are the most common bacterial pathogens involve in an exacerbation (108); in GOLD 3 an GOLD 4 patients, Pseuomonas aeruginosa becomes important. Biochemical test abnormalities, incluing electrolyte isturbances an hyperglycemia, can be associate with exacerbations. However, these abnormalities can also be ue to associate comorbiities. Spirometry is not recommene uring an exacerbation because it can be ifficult to perform an measurements are not accurate enough. Treatment Options Treatment setting. The goals of treatment for COPD exacerbations are to minimize the impact of the current exacerbation an prevent the evelopment of subsequent exacerbations (119). Depening on the severity of an exacerbation an/or the severity of the unerlying isease, an exacerbation can be manage in an outpatient or inpatient setting. More than 80% of exacerbations can be manage on an outpatient basis (51, 79, 120) with pharmacologic therapies incluing bronchoilators, corticosterois, an antibiotics. Table 6 shows the inications for hospital assessment an potential amission of a patient with a COPD exacerbation. When a patient comes to the emergency epartment, the first actions are to provie controlle oxygen therapy an to etermine whether the exacerbation is life threatening (Table 7). If so, the patient shoul be amitte to the intensive care unit (ICU) immeiately. Otherwise, the patient may be manage in the emergency epartment or hospital. In aition to pharmacologic therapy, hospital management of exacerbations inclues respiratory support (oxygen therapy, ventilation). Pharmacologic treatment. The three classes of meications most commonly use for exacerbations of COPD are bronchoilators, corticosterois, an antibiotics. SHORT-ACTING BRONCHODILATORS. Although there are no controlle trials, short-acting inhale b 2 -agonists with or without short-acting anticholinergics are usually the preferre bronchoilators for treatment of an exacerbation (90, 121) (Evience C). A systematic review of the route of elivery of short-acting bronchoilators foun no significant ifferences in FEV 1 between metere-ose inhalers (with or without a spacer evice) an nebulizers (122), although the latter can be more convenient for sicker or frail patients. Intravenous methylxanthines (theophylline or aminophylline) are only to be use in selecte cases when there is insufficient response to short-acting bronchoilators ( ) (Evience B). Sie effects of methylxanthines are significant, an their beneficial effects in terms of lung function an clinical enpoints are moest an inconsistent (128, 129). CORTICOSTEROIDS. Data from stuies in seconary health care inicate that systemic corticosterois in COPD exacerbations shorten recovery time, improve lung function (FEV 1 )anarterial hypoxemia (Pa O2 ) ( ) (Evience A), an reuce the risk of early relapse, treatment failure, an length of hospital stay (130, 132, 134). A ose of mg prenisolone per ay for ays is recommene (Evience D). Therapy with oral prenisolone is preferable (135). Nebulize buesonie alone may be an alternative (although more expensive) to oral corticosterois in the treatment of exacerbations (131, 136, 137). ANTIBIOTICS. There is evience supporting the use of antibiotics in exacerbations when patients have clinical signs of a bacterial infection, for example, increase in sputum purulence (118). A systematic review of the very few available placebocontrolle stuies has shown that antibiotics reuce the risk of short-term mortality by 77%, treatment failure by 53%, an sputum purulence by 44%. This review supports antibiotics

11 GOLD Executive Summary 357 TABLE 5. INITIAL PHARMACOLOGIC MANAGEMENT OF COPD* Patient Group Recommene First Choice Alternative Choice Other Possible Treatments A Short-acting anticholinergic prn Long-acting anticholinergic Theophylline or or Short-acting b 2 -agonist prn Long-acting b 2 -agonist or Short-acting anticholinergic an short-acting b 2 -agonist B Long-acting anticholinergic Long-acting anticholinergic an or long-acting b 2 -agonist Long-acting b 2 -agonist Short-acting anticholinergic an/or Short-acting b 2 -agonist an/or Theophylline C Inhale corticosteroi an long-acting b 2 -agonist or Long-acting anticholinergic Long-acting anticholinergic an long-acting b 2 -agonist Phosphoiesterase-4 inhibitor an/or Short-acting b 2 -agonist an/or Short-acting anticholinergic an/or Theophylline D Inhale corticosteroi an long-acting b 2 -agonist or Long-acting anticholinergic Inhale corticosteroi, long-acting b 2 -agonist, an long-acting anticholinergic or Inhale corticosteroi, long-acting b 2 -agonist, an phosphoiesterase-4 inhibitor or Long-acting anticholinergic an long-acting b 2 -agonist or Long-acting anticholinergic an phosphoiesterase-4 inhibitor Carbocysteine an/or Short-acting b 2 -agonist an/or Short-acting anticholinergic an/or Theophylline Definition of abbreviation: COPD ¼ chronic obstructive pulmonary isease. * Meications in each cell are mentione in alphabetical orer an therefore not necessarily in orer of preference. y Meications in this column can be use alone or in combination with other options in the First an Alternative Choice columns. for only moerately or severely ill patients with COPD exacerbations with increase cough an sputum purulence (138, 139). Procalcitonin III, a marker that is specific for bacterial infections, may be of value in the ecision to use antibiotics (140), but this test is expensive an thus not wiely establishe. A stuy in patients with COPD with exacerbations requiring mechanical ventilation (invasive or noninvasive) inicate that not giving antibiotics was associate with increase mortality an a greater incience of seconary nosocomial pneumonia (141). In summary, antibiotics shoul be given to patients with exacerbations of COPD who have three carinal symptoms increase in yspnea, sputum volume, an sputum purulence (Evience B); patients who have two of the carinal symptoms, if increase purulence of sputum is one of the two symptoms (Evience C); or require mechanical ventilation (invasive or noninvasive) (Evience B) (142). The recommene length of antibiotic therapy is usually 5 10 ays (Evience D). The choice of the antibiotic shoul be base on the local bacterial resistance pattern. ADJUNCT THERAPIES. Depening on the clinical conition of the patient, an appropriate flui balance with special attention to the aministration of iuretics, anticoagulants, treatment of comorbiities, an nutritional aspects shoul be consiere. At all times, health care proviers shoul strongly enforce stringent measures against active cigarette smoking. Respiratory support. OXYGEN THERAPY. Controlle oxygen shoul be titrate to improve the patient s hypoxemia with a target saturation of 88 92% (143). Once oxygen is starte, arterial bloo gases shoul be checke 30 to 60 minutes later to ensure satisfactory oxygenation without carbon ioxie retention or aciosis. Venturi masks (high-flow evices) offer more accurate an controlle elivery of oxygen than o nasal prongs but are less likelytobetoleratebythepatient(90). VENTILATORY SUPPORT. Some patients nee immeiate amission to an ICU (Table 8). Amission of patients with severe exacerbations to intermeiate or special respiratory care units may be appropriate if personnel, skills, an equipment exist to ientify an manage acute respiratory failure successfully. Ventilatory support in an exacerbation can be provie by either noninvasive (by nasal or facial mask) or invasive (by orotracheal tube or tracheostomy) ventilation. Respiratory stimulants are not recommene for acute respiratory failure (121). NONINVASIVE MECHANICAL VENTILATION. Noninvasive mechanical ventilation (NIV) has been stuie in several ranomize, controlle trials in acute respiratory failure, consistently proviing success rates of 80 to 85% ( ). NIV improves respiratory aciosis (increases ph an ecreases Pa CO2 )an ecreases respiratory rate, severity of breathlessness, complications such as ventilator-associate pneumonia, an length of hospital stay (Evience A). More importantly, mortality an intubation rates are reuce by this intervention (145, ) (Evience A). Table 9 summarizes the inications for NIV (90, 144, 146, 151, 152). INVASIVE MECHANICAL VENTILATION. The inications for initiating invasive mechanical ventilation uring an exacerbation are shown in Table 10, an inclue failure of an initial trial of NIV (153). As experience is being gaine with the generalize clinical use of NIV in COPD, several inications for invasive mechanical ventilation are being successfully treate with NIV, an in all but a few situations, there is nothing to be lost by a trial of noninvasive ventilation (153).

12 358 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 6. POTENTIAL INDICATIONS FOR HOSPITAL ASSESSMENT OR ADMISSION* Marke increase in intensity of symptoms, such as suen evelopment of resting yspnea Severe unerlying COPD Onset of new physical signs (e.g., cyanosis, peripheral eema) Failure of an exacerbation to respon to initial meical management Presence of serious comorbiities (e.g., heart failure or newly occurring arrhythmias) Frequent exacerbations Oler age Insufficient home support Definition of abbreviation: COPD ¼ chronic obstructive pulmonary isease. * Local resources nee to be consiere. The use of invasive ventilation in patients with very severe COPD is influence by the likely reversibility of the precipitating event, the patient s wishes, an availability of intensive care facilities. When possible, a clear statement of the patient s own treatment wishes an avance irective or living will makes these ifficult ecisions much easier to resolve. Major hazars inclue the risk of ventilator-acquire pneumonia (especially when multiresistant organisms are prevalent), barotrauma, an failure to wean to spontaneous ventilation. Contrary to some opinions, acute mortality among patients with COPD with respiratory failure is lower than mortality among patients ventilate for non-copd causes (154). Despite this, there is evience that patients who might otherwise survive may be enie amission to intensive care for intubation because of unwarrante prognostic pessimism (155). Hospital Discharge an Follow-up Insufficient clinical ata exist to establish the optimal uration of hospitalization in iniviual patients with an exacerbation of COPD ( ), although units with more respiratory consultants an better-organize care have lower mortality an reuce length of hospital stay after amission for an exacerbation (159). In the hospital prior to ischarge, patients shoul start longacting bronchoilators, either anticholinergics an/or b 2 -agonists with or without inhale corticosterois. Hospitalization offers a unique winow of opportunity to reinforce smoking cessation measures if necessary. Table 11 provies a checklist of items to assess at time of ischarge an Table 12 shows items to assess at follow-up 4 to 6 weeks after ischarge from the hospital. Home visits by a community nurse may permit earlier ischarge of patients hospitalize with an exacerbation without TABLE 7. MANAGEMENT OF SEVERE BUT NOT LIFE-THREATENING EXACERBATIONS* Assess severity of symptoms, bloo gases, chest raiograph Aminister controlle oxygen therapy an obtain serial arterial bloo gas measurement Bronchoilators: Increase oses an/or frequency of short-acting bronchoilators Combine short-acting b 2 -agonists an anticholinergics Use spacers or air-riven nebulizers A oral or intravenous corticosterois Consier antibiotics (oral or occasionally intravenous) when signs of bacterial infection Consier noninvasive mechanical ventilation At all times: Monitor flui balance an nutrition Consier subcutaneous heparin or low molecular weight heparin Ientify an treat associate conitions (e.g., heart failure, arrhythmias) Closely monitor conition of the patient * Local resources nee to be consiere. increasing reamission rates (90, ). Use of a written action plan increases appropriate therapeutic interventions for an exacerbation, an effect that oes not ecrease health care resource use (164) (Evience B) but may shorten recovery time (165). For patients who are hypoxemic uring an exacerbation, arterial bloo gases an/or pulse oximetry shoul be evaluate prior to hospital ischarge an in the following 3 months. If the patient remains hypoxemic, long-term supplemental oxygen therapy may be require. Home Management of Exacerbations Nurse-aministere home care (also known as hospital-at-home care) represents an effective an practical alternative to hospitalization in selecte patients with exacerbations of COPD without aciotic respiratory failure (160, 161) (Evience A). However, the exact criteria for this approach as oppose to hospital treatment remain uncertain an will vary by health care setting. Treatment recommenations are the same as for hospitalize patients. Prevention of COPD Exacerbations COPD exacerbations can often be prevente. Smoking cessation, influenza an pneumococcal vaccines, knowlege of current therapy incluing inhaler technique, an treatment with longacting inhale bronchoilators, with or without inhale corticosterois, an phosphoiesterase-4 inhibitors are all therapies that reuce the number of exacerbations an hospitalizations (75, 79, 81, 82, 166, 167). Early outpatient pulmonary rehabilitation after hospitalization for an exacerbation is safe an results in clinically significant improvements in exercise capacity an health status at 3 months (168). Patients shoul be encourage to maintain physical activity, an anxiety, epression, an social problems shoul be iscusse. Principal caregivers shoul be ientifie if the patient has a significant persisting isability. 6. COPD AND COMORBIDITIES KEY POINTS COPD often coexists with other iseases (comorbiities) that may have a significant impact on prognosis. In general, the presence of comorbiities shoul not alter COPD treatment, an comorbiities shoul be treate as if the patient i not have COPD. Cariovascular iseases are major comorbiities in COPD an probably both the most frequent an most important iseases coexisting with COPD. Osteoporosis an epression are also major comorbiities in COPD, are often uneriagnose, an are associate with poor health status an prognosis. Lung cancer is frequently seen in patients with COPD an has been foun to be the most frequent cause of eath in patients with mil COPD. Introuction COPD often coexists with other iseases (comorbiities) that may have a significant impact on prognosis (42, ). Comorbiities can occur at any COPD grae (50). Differential iagnosis may be ifficult because comorbiities may mimic COPD

13 GOLD Executive Summary 359 TABLE 8. INDICATIONS FOR ICU ADMISSION* Severe yspnea that respons inaequately to initial emergency therapy Changes in mental status (confusion, lethargy, coma) Persistent or worsening hypoxemia (Pa O2, 5.3 kpa, 40 mm Hg) an/or severe/ worsening respiratory aciosis (ph, 7.25) espite supplemental oxygen an noninvasive ventilation Nee for invasive mechanical ventilation Hemoynamic instability nee for vasopressors * Local resources nee to be consiere. symptoms, for example, heart failure an lung cancer (breathlessness) or epression (fatigue an reuce physical activity). Below is a brief guie to management of COPD an some comorbiities in stable isease. The recommenations reporte in this ocument may be insufficient for the management of all patients an cannot substitute for the use of guielines for the management of each comorbiity. In general, the presence of comorbiities shoul not alter COPD treatment an comorbiities shoul be treate as if the patient i not have COPD. Cariovascular Diseases Cariovascular iseases are the most frequent an important isease coexisting with COPD (171, 172) an inclue four separate entities: ischemic heart isease, heart failure, atrial fibrillation, an hypertension. Ischemic heart isease. The prevalence of ischemic heart isease (IHD) is increase in COPD, to some extent because of an unfavorable IHD risk profile in patients with COPD (173, 174). Yet, it is often uneriagnose in patients with COPD (175). TREATMENT OF IHD IN PATIENTS WITH COPD. IHD shoul be treate accoring to usual IHD guielines, as there is no evience that IHD shoul be treate ifferently in the presence of COPD than recommene in the usual IHD guielines. This inclues treatment with selective b 1 -blockers, which are consiere safe in patients with COPD (176), although this is base on relatively few short-term stuies. The benefits of selective b 1 - blockers when inicate in IHD are, however, consierably larger than the potential risks associate with treatment, even in patients with severe COPD. TREATMENT OF COPD IN PATIENTS WITH IHD. COPD shoul be treate as usual, as there is no evience that COPD shoul be treate ifferently in the presence of IHD (75, 79, 177). Although no large, long-term stuies on COPD meications in patients with unstable angina have been publishe, it seems reasonable to avoi high oses of b-agonists. Heart failure. Roughly 30% of patients with stable COPD will have some egree of heart failure (HF) (178), an worsening of HF is a significant ifferential iagnosis to an exacerbation of COPD. Conversely, approximately 30% of patients in a HF clinic have COPD (179), an comorbi COPD is often the cause of amission for acute HF (180) with significant implications for prognosis as FEV 1 is a strong preictor of mortality in HF (181). HF, COPD, an asthma may be confuse because of the common carinal symptom of breathlessness. TABLE 10. INDICATIONS FOR INVASIVE MECHANICAL VENTILATION Unable to tolerate NIV or NIV failure Respiratory or cariac arrest Respiratory pauses with loss of consciousness or gasping for air Diminishe consciousness, psychomotor agitation inaequately controlle by seation Massive aspiration Persistent inability to remove respiratory secretions Heart rate, 50 min 21 with loss of alertness Severe hemoynamic instability without response to fluis an vasoactive rugs Severe ventricular arrhythmias Life-threatening hypoxemia in patients unable to tolerate NIV Definition of abbreviation: NIV ¼ noninvasive mechanical ventilation. TREATMENT OF HF IN PATIENTS WITH COPD. HF shoul be treate accoring to usual HF guielines as there is no evience that HF shoul be treate ifferently in the presence of COPD. Treatment with selective b 1 -blockers has a significant impact on survival in HF, an the presence of COPD is the most significant reason for patients not receiving sufficient therapy (182). However, as in IHD, treatment with selective b 1 -blockers is consiere safe for heart failure patients who also have COPD (176). The benefits of selective b 1 -blocker treatment in HF clearly outweigh any potential risk associate with treatment even in patients with severe COPD. TREATMENT OF COPD IN PATIENTS WITH HF. COPD shoul be treate as usual, as there is no irect evience that COPD shoul be treate ifferently in the presence of HF. As for IHD, this statement is base on finings from large long-term stuies in patients with HF an comorbi COPD (75, 79, 177). An observational stuy foun an increase risk of eath an hospital amission among patients with HF treate with inhale b-agonists (183), possibly inicating a nee for close follow-up of patients with severe HF who are on this treatment for COPD. Atrial fibrillation. Atrial fibrillation (AF) is the most frequent cariac arrhythmia, an patients with COPD have an increase incience of AF (184). COPD with AF presents a challenge to clinicians because of the breathlessness an isability resulting from their coexistence. TREATMENT OF AF IN PATIENTS WITH COPD. AF shoul be treate accoring to usual AF guielines, as there is no evience that patients with COPD shoul be treate ifferently. If b-blockers are use, b 1 -selective rugs are preferre (see consierations uner IHD an HF above). TREATMENT OF COPD IN PATIENTS WITH AF. COPD shoul be treate as usual; however, there are no goo ata on the use of COPD meication in patients with AF, an these patients have often been exclue from clinical trials. It is a clinical impression that care shoul be taken when using high oses of b 2 - agonists as this can make appropriate heart rate control ifficult. TABLE 11. CHECKLIST AT TIME OF DISCHARGE FROM HOSPITAL TABLE 9. INDICATIONS FOR NONINVASIVE MECHANICAL VENTILATION At least one of the following: Respiratory aciosis (arterial ph < 7.35 an/or Pa CO2 > 6.0 kpa, 45 mm Hg) Severe yspnea with clinical signs suggestive of respiratory muscle fatigue, increase work of breathing, or both, such as use of respiratory accessory muscles, paraoxical motion of the abomen, or retraction of the intercostal spaces Reinforce smoking cessation measures Assure effective home maintenance of pharmacotherapy regimen Reassess inhaler technique Eucate about maintenance regimen Give instruction regaring completion of steroi therapy an antibiotics, if prescribe Assess nee for long-term oxygen therapy Assure follow-up visit in 4 6 wk Provie a management plan for comorbiities an their follow-up

14 360 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 12. ITEMS TO ASSESS AT FOLLOW-UP VISIT 4 6 WEEKS AFTER DISCHARGE FROM HOSPITAL Smoking cessation measures Ability to cope in usual environment Measurement of FEV 1 Inhaler technique Unerstaning of recommene treatment regimen Nee for long-term oxygen therapy an/or home nebulizer Capacity to o physical activity an activities of aily living CAT or mmrc Status of comorbiities Definition of abbreviations: CAT ¼ Chronic Obstructive Pulmonary Disease Assessment Test; mmrc ¼ Moifie British Meical Research Council questionnaire on breathlessness. Hypertension. Hypertension is likely to be the most frequently occurring comorbiity in COPD an has implications for prognosis (172). TREATMENT OF HYPERTENSION IN PATIENTS WITH COPD. Hypertension shoul be treate accoring to usual hypertension guielines, as there is no evience that hypertension shoul be treate ifferently in the presence of COPD. The role of treatment with selective b-blockers is less prominent in recent hypertension guielines; if these are use in patients with COPD, a selective b 1 -blocker shoul be chosen. TREATMENT OF COPD IN PATIENTS WITH HYPERTENSION. COPD shoul be treate as usual, as there is no irect evience that COPD shoul be treate ifferently in the presence of hypertension. Osteoporosis Osteoporosis is a major comorbiity in COPD (171, 172), is often uneriagnose (185), an is associate with poor health status an prognosis. Osteoporosis is more often associate with ecrease boy mass inex (186) an low fat-free mass (187). Treatment of osteoporosis in patients with COPD. Osteoporosis shoul be treate accoring to usual osteoporosis guielines, as there is no evience that osteoporosis shoul be treate ifferently in the presence of COPD. Treatment of COPD in patients with osteoporosis. COPD shoul be treate as usual, as there is no evience that stable COPD shoul be treate ifferently in the presence of osteoporosis. Inhale triamcinolone was associate with increase loss of bone mass in the Lung Health Stuy II (188), whereas this was not the case for inhale buesonie in the EUROSCOP trial (189) or for inhale fluticasone propionate in the TORCH trial (190). An association between inhale corticosterois an fractures has been foun in pharmacoepiemiological stuies; however, these stuies have not fully taken severity of COPD or exacerbations an their treatment into account. Systemic corticosterois significantly increase the risk of osteoporosis, an recurrent courses of systemic corticosterois for COPD exacerbations shoul be avoie if possible. Anxiety an Depression Anxiety an epression are major comorbiities in COPD ( ), an both are associate with a poor prognosis (193, 195). Both are often associate with younger age, female gener, smoking, lower FEV 1, cough, higher St. George s Respiratory Questionnaire score, an a history of cariovascular iseases (191, 194). Treatment of anxiety an epression in patients with COPD. Both isorers shoul be treate accoring to usual guielines, as there is no evience that anxiety an epression shoul be treate ifferently in the presence of COPD. Treatment of COPD in patients with anxiety an epression. COPD shoul be treate as usual, as there is no evience that stable COPD shoul be treate ifferently in the presence of anxiety an epression. The potential impact of pulmonary rehabilitation shoul be stresse, as stuies have foun that physical exercise has a beneficial effect on epression in general (196). Lung Cancer Lung cancer is frequently seen in patients with COPD an has been foun to be the most frequent cause of eath in patients with mil to moerate COPD (197). Treatment of lung cancer in patients with COPD. Lung cancer shoul be treate accoring to usual lung cancer guielines, as there is no evience that lung cancer shoul be treate ifferently in the presence of COPD. However, often the reuce lung function of patients with COPD will be a factor limiting surgical intervention for lung cancer. Treatment of COPD in patients with lung cancer. COPD shoul be treate as usual, as there is no evience that stable COPD shoul be treate ifferently in the presence of lung cancer. Infections Serious infections, especially respiratory infections, are frequently seen in patients with COPD (198). Treatment of infections in patients with COPD. Macrolie antibiotics increase the serum concentration of theophylline. Apart from this, there is no evience that infections shoul be treate ifferently in the presence of COPD. However, repeat courses of antibiotics for exacerbations may increase the risk for the presence of antibiotic resistant bacterial strains, an more extensive cultures may be warrante. Treatment of COPD in patients with infection. COPD shoul be treate as usual, as there is no evience that stable COPD shoul be treate ifferently in the presence of infections. In patients who evelop repeate pneumonias while on inhale corticosterois, this meication may be stoppe to observe whether this meication coul be the cause of repeate infections. Metabolic Synrome an Diabetes Stuies have shown that the metabolic synrome an manifest iabetes are more frequent in COPD, an the latter is likely to impact on prognosis (169). Treatment of iabetes in patients with COPD. Diabetes shoul be treate accoring to usual guielines for iabetes, as there is no evience that iabetes shoul be treate ifferently in the presence of COPD. However, for patients with severe COPD, it is not avise to aim for a boy mass inex less than 21 kg/m 2. Treatment of COPD in patients with iabetes. 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