Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease
NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary

ROMAIN A. PAUWELS, A. SONIA BUIST, PETER M. A. CALVERLEY, CHRISTINE R. JENKINS, and SUZANNE S. HURD on behalf of the GOLD Scientific Committee

THIS DOCUMENT WAS ENDORSED BY THE EXECUTIVE COMMITTEE OF THE AMERICAN THORACIC SOCIETY, MARCH 2001

	CONTENTS

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Preface

Introduction

Definition and Classification of Severity

  Definition

  Classification of Severity

  Pathogenesis

  Pathology

  Pathophysiology

Burden of COPD

  Epidemiology

  Economic and Social Burden of COPD

  Risk Factors

The Four Components of COPD Management

  Introduction

  Component 1: Assess and Monitor Disease

    Diagnosis

    Ongoing Monitoring and Assessment

  Component 2: Reduce Risk Factors

    Smoking Prevention and Cessation

    Occupational Exposures

    Indoor/Outdoor Air Pollution

  Component 3: Manage Stable COPD

    Introduction

    Education

    Pharmacologic Treatment

      Bronchodilators

      Glucocorticosteroids

      Other Pharmacologic Treatments

    Nonpharmacologic Treatment

      Rehabilitation

      Oxygen Therapy

      Ventilatory Support

      Surgical Treatments

  Component 4: Manage Exacerbations

    Diagnosis and Assessment of Severity

    Home Management

    Hospital Management

    Hospital Discharge and Follow-up

Future Research

References

	PREFACE

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Chronic obstructive pulmonary disease (COPD) is a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States (1) and is projected to rank fifth in 2020 as a worldwide burden of disease according to a study published by the World Bank/World Health Organization (2). Yet, COPD fails to receive adequate attention from the health care community and government officials. With these concerns in mind, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among GOLD's important objectives are to increase awareness of COPD and to help the thousands of people who suffer from this disease and die prematurely from COPD or its complications.

The first step in the GOLD program was to prepare a consensus Workshop Report, Global Strategy for the Diagnosis, Management, and Prevention of COPD. The GOLD Expert Panel, a distinguished group of health professionals from the fields of respiratory medicine, epidemiology, socioeconomics, public health, and health education, reviewed existing COPD guidelines, as well as new information on pathogenic mechanisms of COPD as they developed a consensus document. Many recommendations will require additional study and evaluation as the GOLD program is implemented.

A major problem is the incomplete information about the causes and prevalence of COPD, especially in developing countries. While cigarette smoking is a major known risk factor, much remains to be learned about other causes of this disease. The GOLD Initiative will bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary to control this major public health problem.

I would like to acknowledge the dedicated individuals who prepared the Workshop Report and the effective leadership of the Workshop Chair, Professor Romain Pauwels. It is a privilege for the National Heart, Lung, and Blood Institute to serve as one of the cosponsors. We look forward to working with the World Health Organization, and all other interested organizations and individuals, to meet the goals of the GOLD Initiative.

Development of the Workshop Report was supported through educational grants to the Department of Respiratory Diseases of the Ghent University Hospital, Belgium (WHO Collaborating Center for the Management of Asthma and COPD) from ASTA Medica, AstraZeneca, Aventis, Bayer, Boehringer-Ingelheim, Byk Gulden, Chiesi, Glaxo Wellcome, Merck, Sharp & Dohme, Mitsubishi-Tokyo, Nikken Chemicals, Novartis, Schering-Plough, SmithKline Beecham, Yamanouchi, and Zambon.

CLAUDE LENFANT, M.D.

Director

National Heart, Lung, and Blood Institute

	INTRODUCTION

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Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. COPD is currently the fourth leading cause of death in the world (3), and further increases in the prevalence and mortality of the disease can be predicted in the coming decades. A unified international effort is required to reverse these trends.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is a collaborative project of the U.S. National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO). Its goals are to increase awareness of COPD and decrease morbidity and mortality from this disease. GOLD aims to improve prevention and management of COPD through a concerted worldwide effort of people involved in all facets of health care and health care policy, and to encourage a renewed research interest in this extremely prevalent disease.

The GOLD Workshop Report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, presents a COPD management plan with four components: (1) Assess and Monitor Disease; (2) Reduce Risk Factors; (3) Manage Stable COPD; (4) Manage Exacerbations. The Workshop Report is based on the best-validated current concepts of COPD pathogenesis and the available evidence on the most appropriate management and prevention strategies. It has been developed by individuals with expertise in COPD research and patient care and extensively reviewed by many experts and scientific societies. Before its release for publication, the Workshop Report was reviewed by the NHLBI and the WHO. This Executive Summary provides key information about COPD; the full Workshop Report provides more details.

In Section 3, Four Components of COPD Management, levels of evidence are assigned to statements, where appropriate, using a system developed by the NHLBI (Table 1). Levels of evidence are indicated in parentheses after the relevant statement, e.g., (Evidence A).

	DEFINITION AND CLASSIFICATION OF SEVERITY

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Definition

COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.

A diagnosis of COPD should be considered in any patient who has symptoms of cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for the disease. The diagnosis is confirmed by spirometry. The presence of a postbronchodilator FEV₁ < 80% of the predicted value in combination with an FEV₁/FVC < 70% confirms the presence of airflow limitation that is not fully reversible. Where spirometry is unavailable, the diagnosis of COPD should be made using all available tools. Clinical symptoms and signs, such as abnormal shortness of breath and increased forced expiratory time, can be used to help with the diagnosis. A low peak flow is consistent with COPD, but has poor specificity because it can be caused by other lung diseases and by poor performance. In the interest of improving the diagnosis of COPD, every effort should be made to provide access to standardized spirometry. Chronic cough and sputum production often precede the development of airflow limitation by many years, although not all individuals with cough and sputum production go on to develop COPD.

Classification of Severity

For educational reasons, a simple classification of disease severity into four stages is recommended (Table 2). The management of COPD is largely symptom-driven, and there is only an imperfect relationship between the degree of airflow limitation and the presence of symptoms. The staging, therefore, is a pragmatic approach aimed at practical implementation and should only be regarded as an educational tool, and a very general indication of the approach to management. All FEV₁ values refer to postbronchodilator FEV₁.

Stage 0: At Risk. Characterized by chronic cough and sputum production. Lung function, as measured by spirometry, is still normal.

Stage I: Mild COPD. Characterized by mild airflow limitation (FEV₁/FVC < 70% but FEV₁  80% predicted) and usually, but not always, by chronic cough and sputum production. At this stage, the individual may not even be aware that his or her lung function is abnormal.

Stage II: Moderate COPD. Characterized by worsening airflow limitation (30%  FEV₁ < 80% predicted) and usually the progression of symptoms, with shortness of breath typically developing on exertion. This is the stage at which patients typically seek medical attention because of dyspnea or an exacerbation of their disease. The division in Stages IIA and IIB is based on the fact that exacerbations are especially seen in patients with an FEV₁ below 50% predicted. The presence of repeated exacerbations has an impact on the quality of life of patients and requires appropriate management.

Stage III: Severe COPD. Characterized by severe airflow limitation (FEV₁ < 30% predicted) or the presence of respiratory failure or clinical signs of right heart failure. Patients may have severe (Stage III) COPD even if the FEV₁ is > 30% predicted, whenever these complications are present. At this stage, quality of life is appreciably impaired and exacerbations may be life-threatening.

Poorly reversible airflow limitation associated with bronchiectasis, cystic fibrosis, tuberculosis, or asthma is not included except insofar as these conditions overlap with COPD. In many developing countries both pulmonary tuberculosis and COPD are common. Therefore, in all subjects with symptoms of COPD, a possible diagnosis of tuberculosis should be considered, especially in areas where this disease is known to be prevalent. In countries in which the prevalence of tuberculosis is greatly diminished, the possible diagnosis of this disease is sometimes overlooked.

Pathogenesis

COPD is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. Macrophages, T lymphocytes (predominately CD8⁺), and neutrophils are increased in various parts of the lung. Activated inflammatory cells release a variety of mediatorsincluding leukotriene B4 (LTB₄) (4), interleukin-8 (IL-8) (5), tumor necrosis factor- (TNF-) (5, 8), and otherscapable of damaging lung structures or sustaining neutrophilic inflammation. In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lung, and oxidative stress. Inflammation of the lungs is caused by exposure to inhaled noxious particles and gases. Cigarette smoke can induce inflammation and directly damage the lungs (9). Although fewer data are available, it is likely that other COPD risk factors initiate a similar inflammatory process (15). It is believed that this inflammation can then lead to COPD.

Pathology

Pathologic changes characteristic of COPD are found in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature. In the central airwaysthe trachea, bronchi, and bronchioles greater than 2 to 4 mm in internal diameterinflammatory cells infiltrate the surface epithelium (9, 20, 21). Enlarged mucus-secreting glands and an increase in the number of goblet cells are associated with mucus hypersecretion. In the peripheral airwayssmall bronchi and bronchioles that have an internal diameter of less than 2 mmchronic inflammation leads to repeated cycles of injury and repair of the airway wall (22). The repair process results in a structural remodeling of the airway wall, with increasing collagen content and scar tissue formation, that narrows the lumen and produces fixed airways obstruction (23).

Destruction of the lung parenchyma in patients with COPD typically occurs as centrilobular emphysema. This involves dilatation and destruction of the respiratory bronchioles (24). These lesions occur more frequently in the upper lung regions in milder cases, but in advanced disease they may appear diffusely throughout the entire lung and also involve destruction of the pulmonary capillary bed. An imbalance of endogenous proteinases and antiproteinases in the lung resulting from genetic factors or the action of inflammatory cells and mediators, is thought to be a major mechanism behind emphysematous lung destruction. Oxidative stress, another consequence of inflammation, may also contribute (25).

Pulmonary vascular changes in COPD are characterized by a thickening of the vessel wall that begins early in the natural history of the disease. Thickening of the intima is the first structural change (26), followed by an increase in smooth muscle and the infiltration of the vessel wall by inflammatory cells (27). As COPD worsens, greater amounts of smooth muscle, proteoglycans, and collagen (28) further thicken the vessel wall.

Pathophysiology

Pathologic changes in the lungs lead to corresponding physiologic changes characteristic of the disease, including mucus hypersecretion, ciliary dysfunction, airflow limitation, pulmonary hyperinflation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale. They usually develop in this order over the course of the disease. Mucus hypersecretion and ciliary dysfunction lead to chronic cough and sputum production. These symptoms can be present for many years before other symptoms or physiologic abnormalities develop. Expiratory airflow limitation, best measured through spirometry, is the hallmark physiologic change of COPD and the key to diagnosis of the disease. It is primarily caused by fixed airway obstruction and the consequent increase in airway resistance. Destruction of alveolar attachments, which inhibits the ability of the small airways to maintain patency, plays a smaller role.

In advanced COPD, peripheral airways obstruction, parenchymal destruction, and pulmonary vascular abnormalities reduce the lung's capacity for gas exchange, producing hypoxemia and, later on, hypercapnia. Pulmonary hypertension, which develops late in the course of COPD (Stage III: Severe COPD), is the major cardiovascular complication of COPD and is associated with the development of cor pulmonale and a poor prognosis (29). The prevalence and natural history of cor pulmonale in COPD are not yet clear.

	BURDEN OF COPD

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Epidemiology

Most of the information available on COPD prevalence, morbidity, and mortality comes from developed countries. Even in these countries, accurate epidemiologic data on COPD are difficult and expensive to collect. Prevalence and morbidity data greatly underestimate the total burden of COPD because the disease is usually not diagnosed until it is clinically apparent and moderately advanced. The imprecise and variable definitions of COPD have made it hard to quantify the morbidity and mortality of this disease in developed (30) and developing countries. Mortality data also underestimate COPD as a cause of death because the disease is more likely to be cited as a contributory than as an underlying cause of death, or may not be cited at all (31).

Prevalence. In the Global Burden of Disease Study conducted under the auspices of the WHO and the World Bank (2, 32), the worldwide prevalence of COPD in 1990 was estimated to be 9.34/1,000 in men and 7.33/1,000 in women. However, these estimates include all ages and underestimate the true prevalence of COPD in older adults. The prevalence of COPD is highest in countries where cigarette smoking has been, or still is, very common, whereas the prevalence is lowest in countries where smoking is less common, or total tobacco consumption per individual is low.

Morbidity. The limited data that are available indicate that morbidity due to COPD increases with age and is greater in men than women (1). COPD is responsible for a significant part of physician visits, emergency department visits, and hospitalizations.

Mortality. COPD is currently the fourth leading cause of death in the world (3), and further increases in the prevalence and mortality of the disease can be predicted in the coming decades (2, 32). In the United States, COPD death rates are very low among people younger than 45 yr of age but then increase with age, and COPD becomes the fourth or fifth leading cause of death among those over 45 (1).

Economic and Social Burden of COPD

Table 3 provides an understanding of the relative economic burden of COPD in four countries with Western styles of medical practice and social or private insurance structures. Similar data from developing countries are not available. The Global Burden of Disease Study (2, 32) estimated the fraction of mortality and disability attributable to major diseases and injuries using a composite measure of the burden of each health problem, the disability-adjusted life year (DALY = the sum of years lost because of premature mortality and years of life lived with disability, adjusted for the severity of disability). According to projections, COPD will be the fifth leading cause of DALYs lost worldwide in 2020 (in 1990 it ranked twelfth), behind ischemic heart disease, major depression, traffic accidents, and cerebrovascular disease (Table 4).

Risk Factors

Risk factors for COPD include both host factors and environmental exposures, and the disease usually arises from an interaction between these two types of factors. The host factor that is best documented is a rare hereditary deficiency of ₁-antitrypsin. Other genes involved in the pathogenesis of COPD have not yet been identified. The major environmental factors are tobacco smoke; heavy exposure to occupational dusts and chemicals (vapors, irritants, and fumes); and indoor/outdoor air pollution. The role of sex as a risk factor for COPD remains unclear. In the past, most studies showed that COPD prevalence and mortality were greater among men than women (33). More recent studies (1, 37) from developed countries show that the prevalence of the disease is almost equal in men and women, which probably reflects changing patterns of tobacco smoking. Some studies have in fact suggested that women are more susceptible to the effects of tobacco smoke than men (35, 38). This is an important question given the increasing rate of smoking among women in both developed and developing countries.

Host Factors

Genes. It is believed that many genetic factors increase (or decrease) a person's risk of developing COPD. The genetic risk factor that is best documented is a rare hereditary deficiency of ₁-antitrypsin (39). Premature and accelerated development of panlobular emphysema and decline in lung function occurs in many smokers and nonsmokers with the severe deficiency, although smoking increases the risk appreciably. Other genes involved in the pathogenesis of COPD have not yet been identified.

Airway hyperresponsiveness. Asthma and airway hyperresponsiveness, identified as risk factors that contribute to the development of COPD (42), are complex disorders related to a number of genetic and environmental factors. How they influence the development of COPD is unknown. Airway hyperresponsiveness may also develop after exposure to tobacco smoke or other environmental insults and thus may be a result of smoking-related airway disease.

Lung growth. Lung growth is related to processes occurring during gestation, birth weight, and exposures during childhood (43). Reduced maximal attained lung function (as measured by spirometry) may identify individuals who are at increased risk for the development of COPD (48).

Exposures

Tobacco smoke. Cigarette smokers have a higher prevalence of lung-function abnormalities and respiratory symptoms, a greater annual rate of decline in FEV₁, and higher death rates for COPD than nonsmokers. Pipe and cigar smokers have higher COPD morbidity and mortality rates than nonsmokers, although their rates are lower than those for cigarette smokers (49). Not all smokers develop clinically significant COPD, which suggests that genetic factors must modify each individual's risk. Passive exposure to cigarette smoke may also contribute to respiratory symptoms and COPD by increasing the lungs' total burden of inhaled particulates and gases (33, 50, 51). Smoking during pregnancy may also pose a risk for the fetus, by affecting lung growth and development in utero and possibly the priming of the immune system (47, 52).

Occupational dusts and chemicals. When the exposures are sufficiently intense or prolonged, occupational dusts and chemicals (vapors, irritants, fumes) can cause COPD independently of cigarette smoking and increase the risk of the disease in the presence of concurrent cigarette smoking (53). Exposure to particulate matter, irritants, organic dusts, and sensitizing agents can cause an increase in airway hyperresponsiveness (54), especially in airways already damaged by other occupational exposures, cigarette smoke, or asthma.

Outdoor and indoor air pollution. High levels of urban air pollution are harmful to persons with existing heart or lung disease. The role of outdoor air pollution in causing COPD is unclear, but appears to be small when compared with cigarette smoking. Indoor air pollution from biomass fuel, burned for cooking and heating in poorly vented dwellings, has been implicated as a risk factor for the development of COPD (55).

Infections. A history of severe childhood respiratory infection has been associated with reduced lung function and increased respiratory symptoms in adulthood (48). However, viral infections may be related to another factor, e.g., low birth weight, that itself is related to COPD.

Socioeconomic status. There is evidence that the risk of developing COPD is inversely related to socioeconomic status (65). It is not clear, however, whether this pattern reflects exposures to indoor and outdoor air pollutants, crowding, poor nutrition, or other factors that are related to socioeconomic status (64, 66).

	THE FOUR COMPONENTS OF COPD MANAGEMENT

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Introduction

An effective COPD management plan includes four components: (1) Assess and Monitor Disease; (2) Reduce Risk Factors; (3) Manage Stable COPD; (4) Manage Exacerbations.

The goals of effective COPD management are to:

• Prevent disease progression
• Relieve symptoms
• Improve exercise tolerance
• Improve health status
• Prevent and treat complications
• Prevent and treat exacerbations
• Reduce mortality

These goals should be reached with a minimum of side effects from treatment, a particular challenge in patients with COPD where comorbidities are common. The extent to which these goals can be realized varies with each individual, and some treatments will produce benefits in more than one area. In selecting a treatment plan, the benefits and risks to the individual and the costs, direct and indirect, to the community must be considered. Patients should be identified before the end stage of the illness, when disability is substantial. However, the benefits of spirometric screening, of either the general population or smokers, are still unclear. Educating patients and physicians to recognize that cough, sputum production, and especially breathlessness are not trivial symptoms is an essential aspect of the public health care of this disease.

Reduction of therapy once symptom control has been achieved is not normally possible in COPD. Further deterioration of lung function usually requires the progressive introduction of more treatments, both pharmacologic and nonpharmacologic, to attempt to limit the impact of these changes. Acute exacerbations of signs and symptoms, a hallmark of COPD, impair patients' quality of life and decrease their health status. Appropriate treatment and measures to prevent further exacerbations should be implemented as quickly as possible.

Component 1: Assess and Monitor Disease

Key Points

• Diagnosis of COPD is based on a history of exposure to risk factors and the presence of airflow limitation that is not fully reversible, with or without the presence of symptoms.
• Patients who have chronic cough and sputum production with a history of exposure to risk factors should be tested for airflow limitation, even if they do not have dyspnea.
• For the diagnosis and assessment of COPD, spirometry is the gold standard as it is the most reproducible, standardized, and objective way of measuring airflow limitation. FEV₁/FVC < 70% and a postbronchodilator FEV₁ < 80% predicted confirms the presence of airflow limitation that is not fully reversible.
• Health care workers involved in the diagnosis and management of patients with COPD should have access to spirometry.
• Measurement of arterial blood gas tensions should be considered in all patients with FEV₁ < 40% predicted or clinical signs suggestive of respiratory failure or right heart failure.

Ongoing Monitoring and Assessment

Monitor disease progression and development of complications. COPD is usually a progressive disease, and a patient's lung function can be expected to worsen over time, even with the best available care. Symptoms and objective measures of airflow limitation should be monitored for development of complications and to determine when to adjust therapy.

Follow-up visits should include a discussion of new or worsening symptoms. Spirometry should be performed if there is a substantial increase in symptoms or a complication. Measurement of arterial blood gas tensions should be performed in all patients with an FEV₁ < 40% predicted or clinical signs of respiratory failure or right heart failure. Elevation of the jugular venous pressure and the presence of pitting ankle edema are often the most useful findings suggestive of right heart failure in clinical practice. Measurement of pulmonary arterial pressure is not recommended in clinical practice as it does not add practical information beyond that obtained from a knowledge of Pa_O2.

Monitor pharmacotherapy and other medical treatment. In order to adjust therapy appropriately as the disease progresses, each follow-up visit should include a discussion of the current therapeutic regimen. Dosages of various medications, adherence to the regimen, inhaler technique, effectiveness of the current regime at controlling symptoms, and side effects of treatment should be monitored.

Monitor exacerbation history. Frequency, severity, and likely causes of exacerbations should be evaluated. Increased sputum volume, acutely worsening dyspnea, and the presence of purulent sputum should be noted. Severity can be estimated by the increased need for bronchodilator medication or glucocorticosteroids and by the need for antibiotic treatment. Hospitalizations should be documented, including the facility, duration of stay, and any use of critical care or intubation.

Monitor comorbidities. In treating patients with COPD, it is important to consider the presence of concomitant conditions such as bronchial carcinoma, tuberculosis, sleep apnea, and left heart failure. The appropriate diagnostic tools (chest radiograph, electrocardiogram [ECG], etc.) should be used whenever symptoms (e.g., hemoptysis) suggest one of these conditions.

Component 2: Reduce Risk Factors

Key Points

• Reduction of total personal exposure to tobacco smoke, occupational dusts and chemicals, and indoor and outdoor air pollutants are important goals to prevent the onset and progression of COPD.
• Smoking cessation is the single most effectiveand cost-effectiveway to reduce the risk of developing COPD and stop its progression (Evidence A).
• Brief tobacco dependence treatment is effective (Evidence A) and every tobacco user should be offered at least this treatment at every visit to a health care provider.
• Three types of counseling are especially effective: practical counseling, social support as part of treatment, and social support arranged outside of treatment (Evidence A).
• Several effective pharmacotherapies for tobacco dependence are available (Evidence A), and at least one of these medications should be added to counseling if necessary and in the absence of contraindications.
• Progression of many occupationally induced respiratory disorders can be reduced or controlled through a variety of strategies aimed at reducing the burden of inhaled particles and gases (Evidence B).

Component 3: Manage Stable COPD

Key Points

• The overall approach to managing stable COPD should be characterized by a stepwise increase in treatment, depending on the severity of the disease.
• For patients with COPD, health education can play a role in improving skills, ability to cope with illness, and health status. It is effective in accomplishing certain goals, including smoking cessation (Evidence A).
• None of the existing medications for COPD has been shown to modify the long-term decline in lung function that is the hallmark of this disease (Evidence A). Therefore, pharmacotherapy for COPD is used to decrease symptoms and complications.
• Bronchodilator medications are central to the symptomatic management of COPD (Evidence A). They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms.
• The principal bronchodilator treatments are ₂-agonists, anticholinergics, theophylline, and a combination of one or more of these drugs (Evidence A).
• Regular treatment with inhaled glucocorticosteroids should only be prescribed for symptomatic patients with COPD with a documented spirometric response to glucocorticosteroids or for those with an FEV₁ < 50% predicted and repeated exacerbations requiring treatment with antibiotics or oral glucocorticosteroids (Evidence B).
• Chronic treatment with systemic glucocorticosteroids should be avoided because of an unfavorable benefit-to-risk ratio (Evidence A).
• All patients with COPD benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A).
• The long-term administration of oxygen (> 15 h per day) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).

Other Pharmacologic Treatments

Vaccines. Influenza vaccines can reduce serious illness and death in patients with COPD by approximately 50% (117). Vaccines containing killed or live, inactivated viruses are recommended (118), and should be given once (in autumn) or twice (in autumn and winter) each year (Evidence A). A pneumococcal vaccine containing 23 virulent serotypes has been used but sufficient data to support its general use in COPD patients are lacking (119) (Evidence B).

₁-Antitrypsin augmentation therapy. Young patients with severe hereditary ₁-antitrypsin deficiency and established emphysema may be candidates for ₁-antitrypsin augmentation therapy. However, this therapy is very expensive, is not available in most countries, and is not recommended for COPD that is not related to ₁-antitrypsin deficiency (Evidence C).

Antibiotics. The use of antibiotics, other than in treating infectious exacerbations of COPD and other bacterial infections, is not recommended (122, 123) (Evidence A).

Mucolytic (mucokinetic, mucoregulator) agents. (ambroxol, erdosteine, carbocysteine, iodinated glycerol): Although a few patients with viscous sputum may benefit from mucolytics (124, 125), the overall benefits seem to be very small. Therefore, the widespread use of these agents cannot be recommended on the basis of the present evidence (Evidence D).

Antioxidant agents. Antioxidants, in particular N-acetylcysteine, have been shown to reduce the frequency of exacerbations and could have a role in the treatment of patients with recurrent exacerbations (126) (Evidence B). However, before their routine use can be recommended, the results of ongoing trials will have to be carefully evaluated.

Immunoregulators (immunostimulators, immunomodulators). A study using an immunostimulator in COPD showed a decrease in the severity (though not in the frequency) of exacerbations (130), but these results have not been duplicated. Thus, the regular use of this therapy cannot be recommended based on the present evidence (131) (Evidence B).

Antitussives. Cough, although sometimes a troublesome symptom in COPD, has a significant protective role (132). Thus, the regular use of antitussives is contraindicated in stable COPD (Evidence D).

Vasodilators. In patients with stable COPD, inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation-balance (133, 134) and thus is contraindicated.

Respiratory stimulants. The use of doxapram, a nonspecific respiratory stimulant available as an intravenous formulation, is not recommended in stable COPD (Evidence D). Almitrine bismesylate is not recommended for regular use in stable COPD patients (135) (Evidence B).

Narcotics. Narcotics are contraindicated in COPD because of their respiratory depressant effects and potential to worsen hypercapnia. Clinical studies suggest that morphine used to control dyspnea may have serious adverse effects and its benefits may be limited to a few sensitive subjects (138). Codeine and other narcotic analgesics should also be avoided.

Others. Nedocromil, leukotriene modifiers, and alternative healing methods (e.g., herbal medicine, acupuncture, homeopathy) have not been adequately tested in COPD patients and thus cannot be recommended at this time.

Nonpharmacologic Treatment

Rehabilitation. The principal goals of pulmonary rehabilitation are to reduce symptoms, improve quality of life, and increase physical and emotional participation in everyday activities. To accomplish these goals, pulmonary rehabilitation covers a range of nonpulmonary problems, including exercise deconditioning, relative social isolation, altered mood states (especially depression), muscle wasting, and weight loss. Patients with COPD at all stages of disease benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (143) (Evidence A). Data suggest that these benefits can be sustained even after a single pulmonary rehabilitation program (144). Benefits have been reported from rehabilitation programs conducted in inpatient, outpatient, and home settings (147).

Ideally, pulmonary rehabilitation should involve several types of health professionals. A comprehensive pulmonary rehabilitation program includes exercise training, nutrition counseling, and education. Baseline and outcome assessments of each participant in a pulmonary rehabilitation program should be made to quantify individual gains and target areas for improvement and should include:

1. Detailed medical history and physical examination.

2. Measurement of spirometry before and after a bronchodilator drug.

3. Assessment of exercise capacity.

4. Measurement of health status and the impact of breathlessness.

5. Assessment of inspiratory and expiratory muscle strength and lower limb strength (e.g., quadriceps) in patients who suffer from muscle wasting (optional).

The first two assessments are important for establishing entry suitability and baseline status but are not used in outcome assessment. The last three assessments are essential baseline and outcome measures.

Oxygen therapy. The long-term administration of oxygen (> 15 h per day) to patients with chronic respiratory failure has been shown to increase survival (123, 124, 150, 151) (Evidence A). It can also have a beneficial impact on hemodynamics, hematologic characteristics, exercise capacity, lung mechanics, and mental state (152). Long-term oxygen therapy is generally introduced in Stage III: Severe COPD for patients who have: (1) Pa_O2 at or below 7.3 kPa (55 mm Hg) or Sa_O2 at or below 88%, with or without hypercapnia; or (2) Pa_O2 between 7.3 kPa (55 mm Hg) and 8.0 kPa (60 mm Hg) or Sa_O2 at or below 89%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythemia (hematocrit > 55%).

The goal of long-term oxygen therapy is to increase the baseline Pa_O2 to at least 8.0 kPa (60 mm Hg) or to produce Sa_O2 at least 90%, which will preserve vital organ function by ensuring an adequate delivery of oxygen. A decision about the use of long-term oxygen should be based on the waking Pa_O2 values. The prescription should always include the source of supplemental oxygen (gas or liquid), the method of delivery, duration of use, and the flow rate at rest, during exercise, and during sleep.

Ventilatory support. To date there is no convincing evidence that mechanical ventilatory support has a role in the routine management of stable COPD.

Surgical Treatments

Bullectomy. In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function (152) (Evidence C). A thoracic CT scan, arterial blood gas measurement, and comprehensive respiratory function tests are essential before making a decision regarding a patient's suitability for resection of a bulla.

Lung volume reduction surgery (LVRS). Although there are some encouraging reports (Evidence C), LVRS is still an unproven palliative surgical procedure (154, 155). Several large randomized studies are now underway to investigate the effectiveness and cost of LVRS in comparison to vigorous conventional therapy (156). Until the results of these studies are known, LVRS cannot be recommended for widespread use.

Lung transplantation. In appropriately selected patients with very advanced COPD, lung transplantation has been shown to improve quality of life and functional capacity (Evidence C) (157). Criteria for referral for lung transplantation include FEV₁ < 35% predicted, Pa_O2 < 7.3 to 8.0 kPa (55 to 60 mm Hg), Pa_CO2 > 6.7 kPa (50 mm Hg), and secondary pulmonary hypertension (161).

Component 4: Manage Exacerbations

Key Points

• Exacerbations of respiratory symptoms requiring medical intervention are important clinical events in COPD.
• The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of approximately one-third of severe exacerbations cannot be identified (Evidence B).
• Inhaled bronchodilators (particularly inhaled ₂-agonists or anticholinergics), theophylline, and systemic, preferably oral, glucocorticosteroids are effective for treatments for acute exacerbations of COPD (Evidence A).
• Patients experiencing COPD exacerbations with clinical signs of airway infection (e.g., increased volume and change of color of sputum, or fever) may benefit from antibiotic treatment (Evidence B).
• Noninvasive positive pressure ventilation (NIPPV) in acute exacerbations improves blood gases and pH, reduces in-hospital mortality, decreases the need for invasive mechanical ventilation and intubation, and decreases the length of hospital stay (Evidence A).

	FUTURE RESEARCH

TOP CONTENTS PREFACE INTRODUCTION DEFINITION AND CLASSIFICATION... BURDEN OF COPD THE FOUR COMPONENTS OF... FUTURE RESEARCH Consultant Reviewers REFERENCES

A better understanding of molecular and cellular pathogenic mechanisms of COPD should lead to many new directions for both basic and clinical investigations. Improved methods for early detection, new approaches for interventions through targeted pharmacotherapy, possible means to identify the "susceptible" smoker, and more effective means of managing exacerbations are needed. Some research recommendations are provided; there are many additional avenues to explore.

1. Until there is a better understanding of the causal mechanisms of COPD, an absolutely rigid definition of COPD, and its relationship to other obstructive airway diseases, will remain controversial. Defining characteristics of COPD should be identified.

2. The stages of COPD and the disease course will vary from one patient to another. The GOLD Report describes four stages; their clinical utility needs to be evaluated.

3. Surrogate markers of inflammation, possibly derived from sputum (cells, mediators, enzymes) or exhaled condensates (lipid mediators, reactive oxygen species, cytokines), that may predict the clinical usefulness of new management and prevention strategies for COPD need to be developed.

4. Information is needed about the cellular and molecular mechanisms of inflammation in stable COPD and in exacerbations. Inflammatory responses in nonsmokers, ex-smokers, and smokers with and without COPD should be compared. The mechanisms responsible for the persistence of the inflammatory response in COPD should be investigated. Why inflammation in COPD is poorly responsive to glucocorticosteroids and what treatments other than glucocorticosteroids are effective in suppressing inflammation in COPD are research topics that could lead to new treatment modalities.

5. There is a pressing need to develop drugs that control symptoms and prevent the progression of COPD. Some progress has been made and there are several classes of drugs that are now in preclinical and clinical development for use in patients with COPD.

6. Standardized methods for tracking trends in COPD prevalence, morbidity, and mortality over time need to be developed so that countries can plan for future increases in the need for health care services in view of predicted increases in COPD. This need is especially urgent in developing countries with limited health care resources.

7. Longitudinal studies demonstrating the course of COPD are needed in a variety of populations exposed to various risk factors. Such studies would provide insight into the pathogenesis of COPD, identify additional genetic bases for COPD, and identify how genetic risk factors interact with environmental risk factors in specific patient populations. Factors that determine why some, but not all, smokers develop COPD need to be identified.

8. Data are needed on the use, cost, and relative distribution of medical and nonmedical resources for COPD, especially in countries where smoking and other risk factors are prevalent. These data are likely to have some impact on health policy and resource allocation decisions. As options for treating COPD grow, more research will be needed to help guide health care providers and health budget managers regarding the most efficient and effective ways of managing this disease. Methods and strategies for implementation of COPD management programs in developing countries will require special attention.

9. While spirometry is recommended to assess and monitor COPD, other measures need to be developed and evaluated in clinical practice. Reproducible and inexpensive exercise-testing methodologies (e.g., stair-climbing tests) suitable for use in developing countries need to be evaluated and their use encouraged. Spirometers need to be developed that can ensure economical and accurate performance when a relatively untrained operator administers the test.

10. Because COPD is not fully reversible (with current therapies) and slowly progressive, it will become ever more important to identify early cases as more effective therapies emerge. Consensus on standard methods for detection and definition of early disease need to be developed. Data to show whether or not screening spirometry is effective in directing management decisions in COPD outcomes are required.

11. Primary prevention of COPD is one of the major objectives of GOLD. Investigations into the most cost-effective ways to reduce the prevalence of tobacco smoking in the general population and more specifically in young people are very much needed. Strategies to prevent people from starting to smoke and methods for smoking cessation require constant evaluation and improvement. Research is required to gauge the impact and reduce the risk from growing air pollution, urbanization, recurrent childhood infections, occupational exposures, and use of local cigarette equivalents. Programs designed to reduce exposure to biomass fuel in countries where this is used for cooking and domestic heating should be explored in an effort to reduce exposure and improve ventilation in the homes.

12. The specific components of effective education for patients with COPD need to be determined. It is not known, for example, whether patients with COPD should be given an individual management plan, or whether these plans are effective in reducing health care costs or improving the outcomes of exacerbations. Developing and evaluating effective tools for physician education concerning prevention, diagnosis, and management of COPD will be important in view of the increasing public health problem presented by COPD.

13. Studies are needed to determine whether education is an essential component of pulmonary rehabilitation. The cost-effectiveness of rehabilitation programs has not been assessed and there is a need to assess the feasibility, resource utilization, and health outcomes of rehabilitation programs that can be delivered outside the major teaching hospital setting. Criteria for selecting individuals for rehabilitation should be evaluated, along with methods to modify programs to suit the needs of individual patients.

14. Collecting and evaluating data to set levels of severity for COPD exacerbations would stimulate standardization of this outcome measure that is so frequently used in clinical trials. Better data on outcomes of COPD exacerbations would allow physicians to provide better advice to patients on possible outcomes and appropriateness of various types of treatment. Further exploration of the ethical principles of life support and greater insights into the behavioral influences that inhibit discussion of end-of-life issues are needed, along with studies to define the needs of patients with end-stage COPD.

	Consultant Reviewers

TOP CONTENTS PREFACE INTRODUCTION DEFINITION AND CLASSIFICATION... BURDEN OF COPD THE FOUR COMPONENTS OF... FUTURE RESEARCH Consultant Reviewers REFERENCES

Individuals Sherwood Burge (UK)

Organizations

American Thoracic Society

Bart Celli

William Martin

Austrian Respiratory Society

Friedriech Kummer

Arab Respiratory Society

Salem El Sayed

Thoracic Society of Australia and New Zealand

Alastair Stewart

David McKenzie

Peter Frith

Australian Lung Foundation

Robert Edwards

Belgian Society of Pneumology

Marc Decramer

Jean-Claude Yernault

British Thoracic Society

Neil Pride

Canadian Thoracic Society

Louis-Philippe Boulet

Kenneth Chapman

Chinese Respiratory Society

Nan-San Zhong

Yuanjue Zhu

Croatian Respiratory Society

Neven Rakusic

Davor Plavec

Czech Thoracic Society

Stanislav Kos

Jaromir Musil

Vladimir Vondra

European Respiratory Society

Marc Decramer (Belgium)

French speaking Pneumological Society

Michel Fournier

Thomas Similovski

Hungarian Respiratory Society

Pal Magyar

Japanese Respiratory Society

Yoshinosuke Fukuchi

Latin American Thoracic Society

Juan Figureoa (Argentina)

Maria Christina Machado (Brasil)

Ilma Paschoal (Brasil)

Jose Jardim (Brasil)

Gisele Borzone (Chile)

Orlando Diaz (Chile)

Patricio Gonzales (Chile)

Carmen Lisboa (Chile)

Rogelio Perez Padilla (Mexico)

Jorge Rodriguez De Marco (Uruguay)

Maria Victorina Lopez (Uruguay)

Roberto Lopez (Uruguay)

Malaysian Thoracic Society

Zin Zainudin

Norwegian Thoracic Society

Amund Gulsvik

Ernst Omenaas

Polish Phthisiopneumonological Society

Michal Pirozynski

Romanian Society of Pulmonary Diseases

Traian Mihaescu

Sabina Antoniu

Singapore Thoracic Society

Alan Ng Wei Keong

Slovakian Pneumological and Phthisiological Society

Ladislav Chovan

Slovenian Respiratory Society

Stanislav Suskovic

South African Thoracic Society

James Joubert

Spanish Society of Pneumology

Teodoro Montemayor Rubio

Victor Sobradillo

Swedish Society for Chest Physicians

Kjell Larsson

Sven Larsson

Claes-Goran Lofdahl

Swiss Pulmonary Society

Philippe Leuenberger

Erich Russi

Thoracic Society of Thailand

Ploysongsang Youngyudh

Vietnam Asthma-Allergology and Clinical   Immunology Association

Nguyen Nang An

	Footnotes

Correspondence and requests for reprints should be addressed to Romain Pauwels, Department of Respiratory Diseases, University Hospital, De Pintelaan 185, B9000 Ghent, Belgium. E-mail: romain.pauwels{at}rug.ac.be

(Received in original form January 10, 2001).

Acknowledgments: The authors thank Sarah DeWeerdt for editorial assistance.

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