Upon successful completion of this course, you will be able to:

• Define what is meant by Chronic Obstructive Pulmonary Disease (COPD)
• Discuss the scope and prevalence of COPD internationally
• Identify and explain the epidemiology and etiology of the disease
• Explain the techniques for diagnosing the disease
• List and discuss the key treatment/management/prevention strategies currently recommended
• Identify the key medications currently in recommended for COPD patients.

Chronic obstructive pulmonary disease (COPD) is a term referring to two lung diseases, chronic bronchitis and emphysema, that are characterized by obstruction to airflow that interferes with normal breathing. Both of these conditions frequently co-exist, hence physicians prefer the term COPD. The quality of life for a person suffering from COPD diminishes as the disease progresses. At the onset, there is minimal shortness of breath. People with COPD may eventually require supplemental oxygen and may have to rely on mechanical respiratory assistance.

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 States1 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 Organization2. 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 US 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, socio-economics, 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, GlaxoSmithKline, Merck, Sharp & Dohme, Mitsubishi-Tokyo, Nikken Chemicals, Novartis, Schering-Plough, Yamanouchi, and Zambon.

Claude Lenfant, MD
Director
National Heart, Lung, and Blood Institute

REFERENCES

1. National Heart, Lung, and Blood Institute. Morbidity & mortality: Chartbook on cardiovascular, lung, and blood diseases. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 1998. Available from: URL: www.nhlbi.nih.gov/nhlbi/seiin//other/cht-book/htm
2. Murray CJL, Lopez AD. Evidence-based health policy-lessons from the Global Burden of Disease Study, Science 1996; 274:740-3.

Human Respiratory System

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. Many people suffer from this disease for years and die prematurely from it or its complications. COPD is currently the fourth leading cause of death in the world1, and further increases in its prevalence and mortality can be predicted in the coming decades2. A unified international effort is needed to reverse these trends.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is conducted in collaboration with the US 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 the 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 highly prevalent disease.

A nihilistic attitude toward COPD has arisen among some health care providers, due to the relatively limited success of primary and secondary prevention (i.e., avoidance of factors that cause COPD or its progression), the prevailing notion that COPD is largely a self-inflicted disease, and disappointment with available treatment options. The GOLD project will work toward combating this nihilistic attitude by disseminating information about available treatments, both pharmacologic and non-pharmacologic.

Tobacco smoking is a major cause of COPD, as well as of many other diseases. A decline in tobacco smoking would result in substantial health benefits and a decrease in the prevalence of COPD and other smoking-related diseases. There is an urgent need for improved strategies to decrease tobacco consumption. However, tobacco smoking is not the only cause of COPD and may not even be the major cause in some parts of the world. Furthermore, not all smokers develop clinically significant COPD, which suggests that additional factors are involved in determining each individual's susceptibility. Thus, investigation of COPD risk factors and ways to reduce exposure to these factors is also an important area for future research. New research tools have recently revealed that inflammation plays a prominent role in COPD pathogenesis, but this inflammation is different than that involved in asthma. Further study of the molecular and cellular mechanisms involved in COPD pathogenesis should lead to effective treatments that slow or halt the course of the disease.

GOLD WORKSHOP REPORT: GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF COPD

One strategy to help achieve GOLD's objectives is to provide health care workers, health care authorities, and the general public with state-of-the-art information about COPD and specific recommendations on the most appropriate management and prevention strategies. The GOLD Workshop Report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, is based on the best-validated current concepts of COPD pathogenesis and the available evidence on the most appropriate management and prevention strategies. The Report has been developed by individuals with expertise in COPD research and patient care and extensively reviewed by many experts and scientific societies. It provides state-of-the-art information about COPD for pulmonary specialists and other interested physicians. The document will also serve as a source for the production of various communications during the implementation of the GOLD program, including a practical guide for primary care physicians and a document for use in developing countries.

The GOLD Report is not intended to be a comprehensive textbook on COPD, but rather to summarize the current state of the field. Each chapter starts with Key Points that crystallize current knowledge. The chapters on the Burden of COPD and Risk Factors demonstrate the global importance of COPD and the various causal factors involved. The chapter on Pathogenesis, Pathology, and Pathophysiology documents the current understanding of, and remaining questions about, the mechanism(s) that lead to COPD, as well as the structural and functional abnormalities of the lungs characteristic of the disease.

A major part of the GOLD Workshop Report is devoted to the clinical Management of COPD and presents a management plan with four components:

1. Assess and Monitor Disease;
2. Reduce Risk Factors;
3. Manage Stable COPD;
4. Manage Acute Exacerbations.

Management recommendations are largely symptom driven and are presented according to the severity of the disease, using a simple classification of severity to facilitate the practical implementation of the available management options. Where appropriate, information about health education for patients is included.

The final chapter identifies critical gaps in knowledge requiring Further Research and provides a summary of proposed directions for the development of new therapeutic approaches.

METHODS USED TO DEVELOP THIS REPORT

In January, 1997, COPD experts from several countries met in Brussels, Belgium to explore the development of a Global Initiative for Chronic Obstructive Lung Disease. Dr. Romain Pauwels served as Chair; representatives of the NHLBI and WHO attended. Participants agreed that the project was timely and important, and recommended the establishment of a panel with expertise on a wide variety of COPD-related topics to prepare an evidence-based document on diagnosis, management, and prevention of COPD. NHLBI and WHO staff, in concert with Dr. Pauwels, identified individuals from many regions of the world to serve on the Expert Panel, which included health professionals in the areas of respiratory medicine, epidemiology, pathology, socio-economics, public health, and health education. The first step toward developing the Workshop Report was to review the multiple COPD guidelines already published. The NHLBI collected these guidelines and prepared a summary table of similarities and differences between the documents. Where agreement existed, the Expert Panel drew on these existing documents for use in the Workshop Report. Where major differences existed, the Expert Panel agreed to carefully examine the scientific evidence to reach an independent conclusion.

In September, 1997, several members of the Expert Panel met with a consultant to develop a comprehensive set of terms to build a database of COPD literature. The database and a computer program to search the world literature on COPD have been developed, and they will be placed on the Internet and cross-referenced with the Workshop Report to help keep the Report current as new literature is published.

In April, 1998, the NHLBI and WHO cosponsored a workshop to begin the development of the Report. Workshop participants were divided into three groups: definition and natural history, chaired by Dr. Sonia Buist; pathophysiology, risk factors, diagnosis, and classification of severity, chaired by Dr. Leonardo Fabbri; and management, chaired by Dr. Romain Pauwels. A table of contents was developed and writing assignments were made. The Panel agreed that clinical recommendations would require scientific evidence, or would be clearly labeled as "expert opinion." Each chapter would contain a set of the most current and representative references.

In September, 1998, the Panel met to evaluate its progress. Members reviewed a variety of evidence tables and chose to assign levels of evidence to statements using the system developed by the NHLBI (Figure A). Levels of evidence are assigned to management recommendations where appropriate in Chapter 5, Management of COPD, and are indicated in boldface type enclosed in parentheses after the relevant statement - e.g., (Evidence A). The methodological issues concerning the use of evidence from meta-analyses were carefully considered (e.g., a meta-analysis of a number of smaller studies was considered to be evidence level B)2. The panel met in May, 1999, September, 1999, and May, 2000 in conjunction with meetings of the American Thoracic Society (ATS) and the European Respiratory Society (ERS). Symposia were held at these meetings to present the developing program and to solicit opinion and comments. The meeting in May, 2000 was the final consensus workshop.

After this workshop, the document was submitted for review to individuals and medical societies interested in the management of COPD. The reviewers' comments were incorporated, as appropriate, into the final document by the Chair in cooperation with members of the Expert Panel. Prior to its release for publication, the Report was reviewed by the NHLBI and the WHO. A workshop was held in September, 2000 to begin implementation of the GOLD program.

REFERENCES

1. World Health Organization. World health report. Geneva: World Health Organization; 2000. Available from: URL: http://www.who.int/whr/2000/en/statistics.htm
2. Murray CJL, Lopez AD. Evidence-based health policy - lessons from the Global Burden of Disease Study. Science 1996; 274:740-

KEY POINTS:

• 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.
• The four-stage classification of COPD severity used throughout this report provides an educational tool and a general indication of the approach to management. This conceptual framework also emphasizes that COPD is usually progressive if exposure to the noxious agent is continued.
• The characteristic symptoms of COPD are cough, sputum production, and dyspnea upon exertion.
• Chronic cough and sputum production often precede the development of airflow limitation by many years and these symptoms identify individuals at risk of developing COPD.
• The focus of this Workshop Report is primarily on COPD caused by inhaled particles and gases, the most common of which worldwide is tobacco smoke.
• COPD can coexist with asthma, the other major chronic obstructive airway disease characterized by an underlying airway inflammation. However, the inflammation characteristic of COPD is distinct from that of asthma.
• Pulmonary tuberculosis may affect lung function and symptomatology and, in areas where tuberculosis is prevalent, can lead to confusion in the diagnosis of COPD.

DEFINITION

For years, clinicians, physiologists, pathologists, and epidemiologists have struggled with the definitions of disorders associated with chronic airflow limitation, including chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), and asthma. The definitions of these terms variably emphasize structure and function and are often based on whether the term is used for clinical or research purposes. For example, epidemiologists have created terminology and criteria, based on functional status, that can be monitored in population-based studies or studies of physicians' diagnoses1,2.

Based on current knowledge, a working definition of 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. Symptoms, functional abnormalities, and complications of COPD can all be explained on the basis on this underlying inflammation and the resulting pathology.

The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from person to person. Chronic inflammation causes remodeling and narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory processes, leads to the loss of alveolar attachments to the small airways and decreases lung elastic recoil; in turn, these changes diminish the ability of the airways to remain open during expiration. Airflow limitation is measured by spirometry, as this is the most widely available, reproducible test of lung function.

Many previous definitions of COPD have emphasized the terms "emphysema" and "chronic bronchitis," which are no longer included in the definition of COPD used in this report. Emphysema, or destruction of the gas-exchanging surfaces of the lung (alveoli), is a pathological term that is often (but incorrectly) used clinically and describes only one of several structural abnormalities present in patients with COPD. Chronic bronchitis, or the presence of cough and sputum production for at least 3 months in each of two consecutive years, remains a clinically and epidemiologically useful term. However, it does not reflect the major impact of airflow limitation on morbidity and mortality in COPD patients. It is also important to recognize that cough and sputum production may precede the development of airflow limitation; conversely, some patients develop significant airflow limitation without chronic cough and sputum production.

NATURAL HISTORY

COPD has a variable natural history and not all individuals follow the same course. However, COPD is generally a progressive disease, especially if a patient's exposure to noxious agents continues. If exposure is stopped, the disease may still progress due to the decline in lung function that normally occurs with aging. Nevertheless, stopping exposure to noxious agents, even after significant airflow limitation is present, can result in some improvement in function and will certainly slow or even halt the progression of the disease.

Classification of Severity: Stages of COPD

For educational reasons, a simple classification of disease severity into four stages is recommended (Figure 1-2). The staging is based on airflow limitation as measured by spirometry, which is essential for diagnosis and provides a useful description of the severity of pathological changes in COPD. Specific FEV1 cut-points (e.g.,< 80% predicted) are used for purposes of simplicity: these cut-points have not been clinically validated.

The impact of COPD on an individual patient depends not just on the degree of airflow limitation, but also on the severity of symptoms (especially breathlessness and decreased exercise capacity) and complications of the disease. A wide range of FEV1 values are included in Stage II: Moderate COPD, reflecting the major contribution of these additional factors to the disability caused by COPD. For the purposes of management, this category is subdivided into two segments (IIA and IIB), as discussed in Chapter 5.3, Manage Stable COPD, and Figure 5-3-8. 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 post-bronchodilator FEV1."

Although COPD is defined on the basis of airflow limitation, in practice the decision to seek medical help (and so permit the diagnosis to be made) is normally determined by the impact of a particular symptom on a patient's lifestyle. Thus, COPD may be diagnosed at any stage of the illness.

The characteristic symptoms of COPD are cough, sputum production, and dyspnea upon exertion. 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. This pattern offers a unique opportunity to identify those at risk for COPD and intervene when the disease is not yet a health problem. A major objective of GOLD is to increase awareness among health care providers and the general public of the significance of these symptoms.

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. This underscores the importance of health care providers doing spirometry in all smokers so that their lung function can be observed and recorded over time.

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 into 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 patients’ quality of life 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. Respiratory failure is defined as an arterial partial pressure of oxygen (PaO2) less than 8.0 kPa (60 mm Hg) with or without arterial partial pressure of CO2 (PaCO2) greater than 6.7 kPa (50 mm Hg) while breathing air at sea level. Respiratory failure may also lead to effects on the heart such as cor pulmonale (right heart failure). Clinical signs of cor pulmonale include elevation of the jugular venous pressure and pitting ankle edema. "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 very appreciably impaired and exacerbations may be life threatening.

Variable Course of COPD
The common statement that only 15-20% of smokers develop clinically significant COPD is misleading. A much higher proportion develops abnormal lung function at some point if they continue to smoke. Not all individuals with COPD follow the classical linear course as outlined in the Fletcher and Peto diagram, which is actually the mean of many individual courses3.

Figure 1-3 shows four examples of the various courses that individual COPD patients may follow. Panel A illustrates an individual who has cough and sputum production, but never develops abnormal lung function (as defined in this Report). Panel B illustrates an individual who develops abnormal lung function but who may never come to diagnosis. Panel C illustrates a person who develops abnormal lung function around age 50, then progressively deteriorates over about 15 years and dies of respiratory failure at age 65. Panel D illustrates an individual who develops abnormal lung function in mid-adult life and continues to deteriorate gradually but never develops respiratory failure and does not die as a result of COPD.

SCOPE OF THE REPORT

The focus of this Report is primarily on COPD caused by inhaled particles and gases, the most common of which worldwide is tobacco smoke. Poorly reversible airflow limitation associated with bronchiectasis, cystic fibrosis, tuberculosis, or asthma is not included except insofar as these conditions overlap with COPD.

Asthma and COPD

COPD can coexist with asthma, the other major chronic obstructive airway disease characterized by an underlying airway inflammation. Asthma and COPD have their major symptoms in common, but these are generally more variable in asthma than in COPD. The underlying chronic airway inflammation is also very different (Figure 1-4): that in asthma is mainly eosinophilic and driven by CD4+ T lymphocytes, while that in COPD is neutrophilic and characterized by the presence of increased numbers of macrophages and CD8+ T lymphocytes. In addition, airflow limitation in asthma is often completely reversible, either spontaneously or with treatment, while in COPD it is never fully reversible and is usually progressive if exposure to noxious agents continues. Finally, the responses to treatment of asthma and COPD are dramatically different, in terms of both the overall magnitude of the achievable response and the qualitative effects of specific treatments such as anticholinergics and glucocorticosteroids. However, there is undoubtedly an overlap between asthma and COPD. Individuals with asthma who are exposed to noxious agents that cause COPD may develop a mixture of "asthma-like" inflammation and "COPD-like" inflammation. There is also evidence that longstanding asthma on its own can lead to airway remodeling and partly irreversible airflow limitation. Asthma can usually be distinguished from COPD, but until the causal mechanisms and pathognomonic markers of these diseases are better understood it will remain difficult to differentiate the two diseases in some individual patients. Given the current state of medical and scientific knowledge, an attempt to determine an absolutely rigid definition of COPD or asthma is bound to end up in semantics.

Pulmonary Tuberculosis and COPD

In many developing countries both pulmonary tuberculosis and COPD are common. In countries where tuberculosis is very common, respiratory abnormalities may be too readily attributed to this disease. Conversely, where the rate of tuberculosis is greatly diminished, the possible diagnosis of this disease is sometimes overlooked.

Chronic bronchitis/bronchiolitis and emphysema often occur as complications of pulmonary tuberculosis and are important contributors to the mixed lung function changes characteristic of tuberculosis4. The degree of obstructive airway changes5 in treated patients with pulmonary tuberculosis increases with age, the amount of cigarettes smoked, and the extent of the initial tuberculosis disease. In patients with both diseases, COPD adds to the disability of pulmonary tuberculosis, and vice versa.

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. Investigations to exclude tuberculosis should be a routine part of COPD diagnosis, the intensity of the diagnostic procedures depending on the degree of suspicion. Chest radiograph and sputum culture are helpful in making the differential diagnosis.

REFERENCES

1. Samet JM. Definitions and methodology in COPD research. In: Hensley M, Saunders N, eds. Clinical epidemiology of chronic obstructive pulmonary disease. New York: Marcel Dekker; 1989. p. 1-22.
2. Vermeire PA, Pride NB. A "splitting" look at chronic non-specific lung disease (CNSLD): common features but diverse pathogenesis. Eur Respir J 1991; 4:490-6.
3. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977; 1:1645-8.
4. Leitch AG. Pulmonary tuberculosis: clinical features. In: Crofton J, Douglas A, eds. Respiratory diseases. Oxford: Blackwell Science; 2000. p. 507-27.
5. Birath G, Caro J, Malmberg R, Simonsson BG. Airway obstruction in pulmonary tuberculosis. Scand J Resp Dis 1966; 47:27-36.
6. Snider GL, Doctor L, Demas TA, Shaw AR. Obstructive airway disease in patients with treated pulmonary tuberculosis. Am Rev Respir Dis 1971; 103:625-40.

KEY POINTS:

• COPD prevalence and morbidity data that are available probably greatly underestimate the total burden of the disease because it is not usually recognized and diagnosed until it is clinically apparent and moderately advanced.
• Prevalence, morbidity, and mortality vary appreciably across countries, but in all countries where data are available COPD is a significant health problem in both men and women.
• The substantial increase in the global burden of COPD projected over the next twenty years reflects, in large part, the increasing use of tobacco worldwide, and the changing age structure of populations in developing countries.
• Medical expenditures for treating COPD and the indirect costs of morbidity can represent a substantial economic and social burden for societies and public and private payers worldwide. Nevertheless, very little economic information concerning COPD is available.

INTRODUCTION
COPD is a leading cause of morbidity and mortality worldwide and results in an economic and social burden that is both substantial and increasing. COPD prevalence, morbidity, and mortality vary appreciably across countries and across different groups within countries, but in general are directly related to the prevalence of tobacco smoking. Most epidemiological studies have found that COPD prevalence, morbidity, and mortality have increased over time and are greater in men than in women. Very few studies have quantified the economic and social burden of COPD. In developed countries, the direct medical costs of COPD are substantial because the disease is both chronic and highly prevalent. In developing countries, the indirect cost of COPD from loss of work and productivity may be more important than the direct costs of medical care.

EPIDEMIOLOGY

Most of the information available on COPD prevalence, morbidity, and mortality comes from developed countries. Even in these countries, accurate epidemiological 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 developed1 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.

Prevalence
Available estimates of COPD prevalence have been developed by determining either the proportion of the population that reports having respiratory symptoms and/or airflow limitation, or the proportion that reports having been diagnosed with COPD, chronic bronchitis, or emphysema by a physician. Each of these approaches will yield a different estimate, and may be useful for different purposes. For example, studies that ask about the full range of COPD symptoms from early to advanced disease are useful to estimate the total societal burden of the disease. Data on doctor diagnoses of COPD are useful to estimate the prevalence of clinically significant disease that is of sufficient severity to require health services, and therefore is likely to incur significant costs.

The population surveys necessary to develop accurate estimates of COPD prevalence are costly to do and therefore have not been conducted in many countries. Obtaining reliable prevalence data for COPD in each country should be a priority in order to alert those responsible for planning prevention services and health care delivery to the high prevalence and cost of the disease. The prevalence of COPD is likely to vary appreciably depending on the prevalence of risk factor exposure, age distribution, and prevalence of susceptibility genes in different countries.

Until recently, virtually all population-based studies in developed countries showed a markedly greater prevalence and mortality of COPD among men compared to women3-6. Gender-related differences in exposure to risk factors, mostly cigarette smoking, probably explain this pattern. In developing countries, some studies report a slightly higher prevalence of COPD in women than men. This likely reflects exposure to indoor air pollution from cooking and heating fuels (greater among women) as well as exposure to tobacco smoke (greater among men)7-15. Recent large population-based studies in the US show a different pattern emerging, with the prevalence of COPD almost equal in men and women16,17. This likely reflects the changing pattern of exposure to the most important risk factor, tobacco smoke.
Estimates based on self-report of respiratory symptoms. COPD prevalence data based on self-report of respiratory symptoms (chronic cough, sputum production, wheezing, and shortness of breath) include people at risk for COPD (Stage 0) as well as those with airflow limitation, and thus yield maximum prevalence estimates. These studies reveal sizable variations in the prevalence of respiratory symptoms depending on smoking status, age, occupational and environmental exposures, country or region, and, to a lesser extent, gender and race. The data also reveal appreciable variations over time, reflecting important temporal changes in populations' exposure to risk factors such as smoking, outdoor air pollution, and occupational exposures.

The third National Health and Nutrition Examination Survey (NHANES 3)16, a large national survey conducted in the US between 1988 and 1994, included self-report questions about respiratory symptoms. The prevalence of respiratory symptoms varied markedly by smoking status (current>ex>never). Among white males, chronic cough was reported by 24% of smokers, 4.7% of ex-smokers, and 4.0% of never smokers. The prevalence of chronic cough among white women was 20.6% in smokers, 6.5% in ex-smokers, and 5.0% in never smokers. There was a smaller gradient in the prevalence of chronic cough by race (white>black). The prevalence of sputum production was similar to that of chronic cough in these groups.

Estimates based on the presence of airflow limitation. People may have respiratory symptoms such as cough and sputum production for many years before developing airflow limitation. Thus, COPD prevalence data based on the presence of airflow limitation provide a more accurate estimate of the burden of COPD that is, or probably soon will be, clinically significant. However, the use of different cut points to define airflow limitation makes comparing the results of different studies difficult.

In the NHANES study, airflow limitation was defined as an FEV1/FVC < 70%. The prevalence of airflow limitation was lower than the prevalence of respiratory symptoms found in the same study, but both sets of data reinforce the view that smoking is the most important determinant of COPD prevalence in developed countries. Among white males, airflow limitation was present in 14.2% of current smokers, 6.9% of ex-smokers, and 3.3% of never smokers. Among white females, the prevalence of airflow limitation was 13.6% in smokers, 6.8% in ex-smokers, and 3.1% in never smokers. Airflow limitation was more common among white smokers than among black smokers.

Estimates based on physician diagnosis of COPD. COPD prevalence data based on physician diagnosis provide information about the prevalence of clinically significant COPD that is of sufficient severity to prompt a visit to a physician. Few population-based prevalence surveys have been published to provide this information, and available data are often confusing because asthma and COPD diagnoses are not separated, all age groups are considered together, or chronic bronchitis and emphysema are considered separately.

In the UK the General Practice Research Database18, which is based on 525 practices serving 3.4 million patients (6.4% of the total population of England and Wales), provides population-based data on physician-diagnosed COPD (Figure 2-1). In 1997, the prevalence of COPD was 1.7% among men and 1.4% among women. Between 1990 and 1997, the prevalence increased by 25% in men and 69% in women. The prevalence of COPD among men plateaued in the mid-1990s, but continued to increase among women, reaching in 1997 the level observed in men in 1990. The General Practice Research Database includes all ages and thus underestimates the true impact of COPD on older adults.

The Global Burden of Disease Study. The WHO/World Bank Global Burden of Disease Study19,20 used data from both published and unpublished studies to estimate the prevalence of various diseases in different countries and regions around the world (Figure 2-2). Where few data for a region were available, experts made informed estimates. Where no information was available, preliminary estimates were derived from data from other regions that were believed to have similar epidemiological patterns. Using this approach, the worldwide prevalence of COPD in 1990 was estimated at 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.

Figure 2.2 COPD Around the World (All Ages)

Given the striking dearth of population-based data on COPD prevalence in many countries of the world, the values listed in Figure 2-2 should not be viewed as very precise. Nevertheless, some general patterns emerge. The prevalence of COPD is highest in countries where cigarette smoking has been, or still is, very common, while the prevalence is lowest in countries where smoking is less common, or total tobacco consumption per capita is still low. The lowest COPD prevalence among men (2.69/1,000) was found in the Middle Eastern Crescent (a group of 36 countries in North Africa and the Middle East) and the lowest prevalence among women (1.79/1,000) was found in the region referred to as "Other Asia and Islands" (a group of 49 countries and islands, the largest of which is Indonesia and which includes Papua New Guinea, Nepal, Vietnam, Korea, Hong Kong, and many small island countries). Except in the Middle Eastern Crescent, the prevalence of COPD is higher among men than among women.

The Global Burden of Disease study reported a significantly higher prevalence of COPD in China than in most of the other regions (26.20/1,000 among men and 23.70/1,000 among women). A more recent survey conducted in three regions of China (Northern: Beijing; Northeast: Liao-Ning; and South-Mid: HuBei) in persons older than 15 years estimated the prevalence of COPD at 4.21/1,000 among men and 1.84/1,000 among women

Morbidity

Morbidity includes physician visits, emergency department visits, and hospitalizations. COPD databases for these outcome parameters are less readily available and usually less reliable than mortality databases. The limited data available indicate that morbidity due to COPD increases with age and is greater in men than women17,22,23.

In the UK, general practice consultations for COPD during one year ranged from 4.17/1,000 in 45- to 64-year-olds to 8.86/1,000 in 65- to 74-year-olds to 10.32/1,000 in 75- to 84-year-olds. These rates are 2 to 4 times the equivalent rates for chest pain due to ischemic heart disease.

In 1994, according to statistics from the UK Office of National Statistics25, there were 203,193 hospital admissions in Northern Ireland, Scotland, Wales, and England for COPD; the average length of hospital stay among those admitted for a COPD diagnosis was 9.9 days.

US data indicate that in 1997 there were 16.365 million (60.6/1,000) ambulatory care visits for COPD and 448,000 (1.66/1,000) hospitalizations for which COPD was the first-listed discharge diagnosis23. Hospitalization rates for COPD increased with age and were higher among men than among women. These data should be interpreted cautiously, however, because the ICD-9 codes for COPD that were in use in 1997, 490-492 and 494-496, include "bronchitis not specified as acute or chronic." Therefore, the data for ambulatory care visits are likely to have been inflated by inclusion of visits for acute bronchitis.

Mortality

Of all of the descriptive epidemiological data for COPD, mortality data are the most readily available, and probably the most reliable. (The World Health Organization publishes mortality statistics for selected causes of death annually for all WHO regions26; additional information is available from the WHO Evidence for Health Policy Department27.) However, inconsistent use of terminology for COPD causes problems that do not arise for many other diseases. For example, prior to about 1968 and the Eighth Revision of the ICD, the terms "chronic bronchitis" and "emphysema" were used extensively. During the 1970s, the term "COPD" increasingly replaced those terms in the US and some but not all other countries, making comparisons of COPD mortality in different countries very difficult. However, the situation has improved with the Ninth and Tenth Revisions of the ICD, in which deaths from COPD or chronic airways obstruction are included in the broad category of "COPD and allied conditions" (ICD-9 codes 490-496 and ICD-10 codes J42-46).

The age-adjusted death rates for COPD by race and sex in the US from 1960 to 1996 by ICD code are shown in Figure 2-317. COPD death rates are very low among people under age 45 in the US, but then increase with age, and COPD becomes the fourth or fifth leading cause of death among those over 4517, a pattern that reflects the cumulative effect of cigarette smoking28. Although appreciable variations in mortality across developed countries for both genders have been reported29, these differences should be interpreted cautiously. Differences between countries in death certification, diagnostic practices, the structure of health care systems, and life expectancy have an appreciable impact on reported mortality rates.

Figure 2.3 Age-Adjusted Death Rates for
COPD by Race and Sex, US 1960-96

Rate 100,000 Population

ECONOMIC AND SOCIAL BURDEN OF COPD

Because COPD is highly prevalent and can be severely disabling, direct medical expenditures and the indirect costs of morbidity and premature mortality from COPD can represent a substantial economic and social burden for societies and public and private insurance payers worldwide. Nevertheless, very little quantitative information concerning the economic and social burden of COPD is available in the literature today.

Economic Burden

Cost of illness studies provide insight into the economic impact of a disease. Some countries attempt to separate economic burden into disease-attributable direct and indirect costs. The direct cost is the value of health care resources devoted to diagnosis and medical management of the disease. Indirect costs reflect the monetary consequences of disability, missed work and school, premature mortality, and caregiver or family costs resulting from the illness. Data on these topics from developing countries are not available, but data from the US and some European countries provide an understanding of the economic burden of COPD in developed countries.

United States. Figure 2-4 compares the estimated costs of various lung disorders in the US in 1993. In 1993, the annual economic burden of COPD in the US was estimated at $23.9 billion17, including $14.7 billion in direct expenditures for medical care services, $4.7 billion in indirect morbidity costs, and $4.5 billion in indirect costs related to premature mortality. With an estimated 15.7 million cases of COPD in the US30, the estimated direct cost of COPD is $1,522 per COPD patient per year.

Figure 2.4
Direct and Indirect Costs of Lung Diseases, 1993 (US$ Billions)

In a US study31 of COPD-related illness costs based on the 1987 National Medical Expenditure Survey, per capita expenditures for inpatient hospitalizations of COPD patients ($5,409 per hospitalization) were 2.7 times the expenditures for patients without COPD ($2,001 per hospitalization). In 1992, under Medicare, the US government health insurance program for individuals over 65, annual per capita expenditures for people with COPD ($8,482) were nearly 2.5 times higher than annual expenditures for people without COPD ($3,511)32.

United Kingdom. In 1996, the direct cost of COPD in the UK was approximately £846 million (about US $1.393 billion) or £1,154 (about US $1,900) per person per year, according to data from the National Health Service (NHS) Executive33. Pharmaceutical expenditures for COPD and allied conditions accounted for 11.0% of the total expenditures for prescription medications Only 2% of total primary care expenditures were for COPD-related visits.

In 1996, lost work productivity, disability, and premature mortality from COPD in the UK accounted for an estimated 24 million days of work lost. The indirect cost of the disease was estimated at £600 million (about US $960 million) for attendance and disability living allowance and £1.5 billion (about US $2.4 billion) to employers for work absence and reduced productivity24.

The Netherlands. In 1993, the direct cost of COPD in the Netherlands was estimated to exceed US $256 million, or US $813 per patient per year. Assuming constant costs and treatment patterns, the direct cost is expected to reach US $410 million per year by 2010. In 1993 inpatient hospitalizations accounted for 57% of the total direct cost of COPD, and medications accounted for an additional 23%. The indirect cost of COPD in the Netherlands was not available34.

Sweden. The direct cost of COPD-related medical care in Sweden was estimated at 1.085 billion SEK (about US $179.4 million) in 1991. The estimated indirect cost of COPD was an additional 1.699 billion SEK (about US $280.8 million)35.

Comparison of different countries. Figure 2-5 provides data on the economic burden of COPD in four countries with Western styles of medical practice and social or private insurance structures. The data are standardized to equivalent year on a per capita basis. After adjusting to a common base year and population, the costs of COPD were relatively similar. The remaining variability in across-country estimates of economic burden can be partly explained by several factors, including: disease prevalence and demographics, particularly smoking patterns; the type and usage patterns of health care and non-health care services among patients with COPD; the relative prices of health care services; employment and wage rates; and the availability of medical prevention strategies and treatments for COPD. Similar data from developing countries are not available.

Figure 2.5 Four-Country Comparison of COPD Direct and Indirect Costs

Home care. Individuals with COPD frequently receive professional medical care in their homes. In some countries, national health insurance plans provide coverage for oxygen therapy, visiting nursing services, rehabilitation, and even mechanical ventilation in the home, although coverage for specific services varies from country to country36.

Any estimate of direct medical expenditures for home care under-represents the true cost of home care to society, because it ignores the economic value of the care provided to those with COPD by family members. In developing countries especially, direct medical costs may be less important than the impact of COPD on workplace and home productivity. Because the health care sector might not provide long-term supportive care services for severely disabled individuals, COPD may force two individuals to leave the workplace - the affected individual and a family member who must now stay home to care for the disabled relative. Since human capital is often the most important national asset for developing countries, COPD may represent a serious threat to their economies.

Social Burden

Figure 2.6 - Leading Causes of Disability-Adjusted Life Years (DALYs) Lost Worldwide: 1990 and 2020 (Projected)2,32

Since mortality offers a limited perspective on the human burden of a disease, it is desirable
to find other measures of disease burden that are consistent and measurable across nations. The World Bank/WHO Global Burden of Disease Study19 designed a method to estimate 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 DALYs for a specific condition are the sum of years lost because of premature mortality and years of life lived with disability, adjusted for the severity of disability.

The leading causes of DALYs lost worldwide in 1990 and 2020 (projected) are shown in Figure 2-6. In 1990, COPD was the twelfth leading cause of DALYs lost in the world, responsible for 2.1% of the total. According to the projections, COPD will be the fifth leading cause of DALYs lost worldwide in 2020, behind ischemic heart disease, major depression, traffic accidents, and cerebrovascular disease. This substantial increase in the global burden of COPD projected over the next twenty years reflects, in large part, the increasing use of tobacco worldwide and the changing age structure of populations in developing countries.

REFERENCES

1. Pride NB, Vermeire P, Allegra L. Diagnostic labels applied to model case histories of chronic airflow obstruction. Responses to a questionnaire in 11 North American and Western European countries. Eur Respir J 1989; 2:702-9.
2. Mannino DM, Brown C, Giovino GA. Obstructive lung disease deaths in the United States from 1979 through 1993. An analysis using multiple-cause mortality data. Am J Respir Crit Care Med 1997; 156:814-8.
3. Buist AS, Vollmer WM. Smoking and other risk factors. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders Co.; 1994. p. 1259-87.
4. Thom TJ. International comparisons in COPD mortality. Am Rev Respir Dis 1989; 140:S27-34.
5. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J 1994; 7:1056-61.
6. Feinleib M, Rosenberg HM, Collins JG, Delozier JE, Pokras R, Chevarley FM. Trends in COPD morbidity and mortality in the United States. Am Rev Respir Dis 1989; 140:S9-18.
7. Chen JC, Mannino MD. Worldwide epidemiology of chronic obstructive pulmonary disease. Current Opinion in Pulmonary Medicine 1999; 5:93-9.
8. Dossing M, Khan J, al-Rabiah F. Risk factors for chronic obstructive lung disease in Saudi Arabia. Respiratory Med 1994; 88:519-22.
9. Dennis R, Maldonado D, Norman S, Baena E, Martinez G. Woodsmoke exposure and risk for obstructive airways disease among women. Chest 1996; 109:115-9.
10. Perez-Padilla R, Regalado U, Vedal S, Pare P, Chapela R, Sansores R, et al. Exposure to biomass smoke and chronic airway disease in Mexican women. Am J Respir Crit Care Med 1996; 154:701-6.
11. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels. Chest 1991; 100:385-8.
12. Amoli K. Bronchopulmonary disease in Iranian housewives chronically exposed to indoor smoke. Eur Respir J 1998; 11:659-63.
13. Pandey MR. Prevalence of chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax 1984; 39:331-6.
14. Pandey MR. Domestic smoke pollution and chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax 1984; 39:337-9.
15. Samet JM, Marbury M, Spengler J. Health effects and sources of indoor air pollution. Am Rev Respir Dis 1987; 136:1486-508.
16. National Center for Health Statistics. Current estimates from the National Health Interview Survey, United States, 1995. Washington, DC: Department of Health and Human Services, Public Health Service, Vital and Health Statistics; 1995. Publication No. 96-1527.
17. National Heart, Lung, and Blood Institute. Morbidity & mortality: chartbook on cardiovascular, lung, and blood diseases. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 1998. Available from: URL: www.nhlbi.nih.gov/nhlbi/seiin/other/cht-book/htm
18. Soriano JR, Maier WC, Egger P, Visick G, Thakrar B, Sykes J, et al. Recent trends in physician diagnosed COPD in women and men in the UK. Thorax 2000; 55:789-94.
19. Murray CJL, Lopez AD. Evidence-based health policy - lessons from the Global Burden of Disease Study. Science 1996; 274:740-3.
20. Murray CJL, Lopez AD, eds. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge, MA: Harvard University Press; 1996.
21. Xian Sheng Chen. Analysis of basic data of the study on prevention and treatment of COPD. Chin J Tuber Respiratory Dis 1998; 21:749-52 (with English abstract).
22. Higgins MW, Thom T. Incidence, prevalence, and mortality: intra- and inter-country differences. In: Hensley M, Saunders N, eds. Clinical epidemiology of chronic obstructive pulmonary disease. New York: Marcel Dekker.; 1989. p. 23-43.
23. National Center for Health Statistics. National hospital interview survey. Vital and health statistics, series 10 (issues from 1974 to 1995).
24. Calverley PMA. Chronic obstructive pulmonary disease: the key facts. London: British Lung Foundation; 1998.
25. Office of National Statistics. Mortality statistics (revised) 1994, England and Wales. London: Her Majesty’s Stationery Office; 1996.
26. World Health Organization. World health statistics annual 1995. Geneva: World Health Organization; 1995.
27. World Health Organization, Geneva. Available from: URL: www.who.int
28. Renzetti AD, McClement JH, Litt BD. The Veterans Administration Cooperative Study of Pulmonary Function. III: Mortality in relation to respiratory function in chronic obstructive pulmonary disease. Am J Med 1966; 41:115-29.
29. Incalzi RA, Fuso L, De Rosa M, Forastiere F, Rapiti E, Nardecchia B, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J1997; 10:2794-800.
30. Singh GK, Matthews TJ, Clarke SC. Annual summary of births, marriages, divorces, and deaths: United States, 1994. Monthly Vital Statistics Report 14 (13). National Center for Health Statistics, Hyattsville, MD.
31. Sullivan SD, Strassels S, Smith DH. Characterization of the incidence and cost of COPD in the US. Eur Respir J 1996; 9:S421.
32. Grasso ME, Weller WE, Shaffer TJ, Diette GB, Anderson GF. Capitation, managed care, and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:133-8.
33. National Health Service Executive. Burdens of disease: a discussion document. London: Department of Health; 1996.
34. Rutten-van Molken MP, Postma MJ, Joore MA, Van Genugten ML, Leidl R, Jager JC. Current and future medical costs of asthma and chronic obstructive pulmonary disease in the Netherlands. Respir Med 1999; 93:779-87.
35. Jacobson L, Hertzman P, Lofdahl C-G, Skoogh B-E, Lindgren B. The economic impact of asthma and COPD in Sweden 1980 and 1991. Respir Med 2000; 94:247-55.
36. Fauroux B, Howard P, Muir JF. Home treatment for chronic respiratory insufficiency: the situation in Europe in 1992. The European Working Group on Home Treatment for Chronic Respiratory Insufficiency. Eur Respir J 1994; 7:1721-6.

    Top

KEY POINTS:

• 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 alpha-1 antitrypsin. Other genes involved in the pathogenesis of COPD have not yet been identified.
• The major environmental factors are tobacco smoke, occupational dusts and chemicals (vapors, irritants, fumes), and indoor/outdoor air pollution.

INTRODUCTION

The identification of risk factors is an important step toward developing strategies for prevention and treatment of any disease. Identification of cigarette smoking as an important risk factor for COPD has led to the incorporation of smoking cessation programs as a key element of COPD prevention, as well as an important intervention for patients who already have the disease. However, although smoking is the best-studied COPD risk factor, it is not the only one. Further studies of other risk factors could lead to similar powerful interventions.

Much of the evidence concerning risk factors for COPD comes from cross-sectional epidemiological studies that identify associations rather than cause-and-effect relationships. Although several longitudinal studies (which are capable of revealing causal relationships) of COPD have followed groups and populations for up to 20 years, none of them has monitored the progression of the disease through its entire course. Thus, current understanding of risk factors for COPD is in many respects incomplete.

The division into "Host Factors" and "Exposures" reflects the current understanding of COPD as resulting from an interaction between the two types of factors. Thus, of two people with the same smoking history, only one may develop COPD due to differences in genetic predisposition to the disease, or in how long they live. Risk factors for COPD may also be related in more complex ways. For example, gender may influence whether a person takes up smoking or experiences certain occupational or environmental exposures; socioeconomic status may be linked to a child's birth weight; longer life expectancy will allow greater lifetime exposure to risk factors; etc. Understanding the relationships and interactions among risk factors is a crucial area of ongoing investigation.

The best-documented host factor is a severe hereditary deficiency of alpha-1 antitrypsin. The major environmental factors are tobacco smoke, occupational dusts and chemicals (vapors, irritants, fumes), and indoor and outdoor air pollution. However, it is very difficult to demonstrate that a given risk factor is sufficient to cause the disease.

Data are not available to determine whether the increasing prevalence of respiratory symptoms and the accelerated rate of lung function decline that occur with age reflect the cumulative exposure to respiratory particles, irritants, fumes, vapors, etc., or host-related phenomena such as the loss of elastic recoil of lung tissue and stiffening of the chest wall. The field of normal lung aging has been only minimally explored and more work is required.

The role of gender as a risk factor for COPD remains unclear. In the past, most studies showed that COPD prevalence and mortality were greater among men than women1-4. More recent studies5,6 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 men4,7. This is an important question given the increasing rate of smoking among women in both developed and developing countries.

The role of nutritional status as an independent risk factor for the development of COPD is unclear. Malnutrition and weight loss can reduce respiratory muscle strength and endurance, apparently by reducing both respiratory muscle mass and the strength of the remaining muscle fibers8. The association of starvation and anabolic/catabolic status with the development of emphysema has been shown in experimental studies in animals9.

HOST FACTORS

Genes

It is believed that many genetic factors increase (or decrease) a person's risk of developing COPD. Studies have demonstrated an increased risk of COPD within families with COPD probands. Some of this risk may be due to shared environmental factors, but several studies in diverse populations also suggest a shared genetic risk10,11.

The genetic risk factor that is best documented is a severe hereditary deficiency of alpha-1 antitrypsin12-14, a major circulating inhibitor of serine proteases. This rare hereditary deficiency is a recessive trait most commonly seen in individuals of Northern European origin. Premature and accelerated development of panlobular emphysema and decline in lung function occur in both smokers and nonsmokers with the severe deficiency, although smoking increases the risk appreciably. There is considerable variation between individuals in the extent and severity of the emphysema and the rate of lung function decline. Although alpha-1 antitrypsin deficiency is relevant to only a small part of the world's population, it illustrates the interaction between host factors and environmental exposures leading to COPD. In this way, it provides a model for how other genetic risk factors are thought to contribute to COPD.

Exploratory studies have revealed a number of candidate genes that may influence a person's risk of COPD, including ABO secretor status15,16, microsomal epoxide hydrolase17, glutathione S-transferase18, alpha-1 antichymotrypsin19, the complement component GcG20, cytokine TNF- 21, and micro-satellite instability22. However, when several studies of a given trait are available, the results are often inconsistent. Several of these genes are thought to be involved in inflammation, and therefore are related to potential pathogenic mechanisms of COPD.

Airway Hyper-responsiveness

Asthma and airway hyper-responsiveness, identified as risk factors that contribute to the development of COPD, are complex disorders related to a number of genetic and environmental factors. The relationship between asthma/airway hyper-responsiveness and increased risk of developing COPD was originally described by Orie and colleagues23 and termed the "Dutch hypothesis." Asthmatics, as a group, experience a slightly accelerated loss of lung function24,25 compared to non-asthmatics, as do smokers with airway hyper-responsiveness compared to normal smokers26. How these trends are related to the development of COPD is unknown, however. Airway hyper-responsiveness 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 childhood27-31. Reduced maximal attained lung function (as measured by spirometry) may identify individuals who are at increased risk for the development of COPD32.

EXPOSURES

It may be helpful conceptually to think of a person's exposures in terms of his or her total burden of inhaled particles. Each type of particle, depending on its size and composition, may contribute a different weight to the risk, and the total risk will depend on the integral of the inhaled exposures. Of the many inhalational exposures that people may encounter over a lifetime, only tobacco smoke2,33-39 and occupational dusts and chemicals (vapors, irritants, and fumes)40,41 are known to cause COPD on their own. Tobacco smoke and occupational exposures also appear to act additively to increase a person's risk of developing COPD.

Tobacco Smoke

Cigarette smoking is by far the most important risk factor for COPD and the most important way that tobacco contributes to the risk of COPD. Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities, a greater annual rate of decline in FEV1, and a greater COPD mortality rate than nonsmokers. These differences between cigarette smokers and nonsmokers increase in direct proportion to the quantity of smoking. Pipe and cigar smokers have greater COPD morbidity and mortality rates than nonsmokers, although their rates are lower than those for cigarette smokers33.

Other types of tobacco smoking popular in various countries are also risk factors for COPD, although their risk relative to cigarette smoking has not been reported.
Age at starting to smoke, total pack-years smoked, and current smoking status are predictive of COPD mortality. Not all smokers develop clinically significant COPD, which suggests that genetic factors must modify each individual's risk. Although it is unclear what percentage of smokers develop the disease, the commonly cited figure of 15-20% is likely an underestimate because COPD is both under-diagnosed and under-appreciated.

Passive exposure to cigarette smoke (also known as environmental tobacco smoke or ETS) may also contribute to respiratory symptoms and COPD by increasing the lungs' total burden of inhaled particles and gases2,42,43. 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 system32,44.

Occupational Dusts and Chemicals

Figure 3.3 Interaction of Smoking and Occupational Exposures

Occupational dusts and chemicals (vapors, irritants, and fumes) can also cause COPD when the exposures are sufficiently intense or prolonged, such as those experienced by miners in many countries. These exposures can both cause COPD independently of cigarette smoking and increase the risk in the presence of concurrent cigarette smoking 41. Exposure to coal dust alone in sufficient doses can produce airflow limitation45,46.

Exposure to particulate matter, irritants, organic dusts, and sensitizing agents can cause an increase in airway hyperresponsiveness47, especially in airways already damaged by other occupational exposures, cigarette smoke, or asthma. There is some evidence from community studies that a combination of dust exposure and gas or fume exposure may have an additive effect on the risk of COPD48-50.

Indoor and Outdoor Air Pollution

High levels of urban air pollution are harmful to individuals 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 that of cigarette smoking. The relative effect of short-term, high peak exposures and long-term, low-level exposures is a question yet to be resolved.

Over the past two decades, air pollution in most cities in developed countries has decreased appreciably. In contrast, air pollution has increased markedly in many cities in developing countries. Although it is not clear which specific elements of ambient air pollution are harmful, there is some evidence that particles found in polluted air will add to a person's total inhaled burden. Indoor air pollution from biomass fuel has been implicated as a risk factor for the development of COPD. This exposure is greatest in regions where biomass fuel is used for cooking and heating in poorly vented dwellings, leading to high levels of particulate matter in indoor air51-61.

Infections
A history of severe childhood infection has been associated with reduced lung function and increased respiratory symptoms in adulthood32. There are several possible explanations for this association (which are not mutually exclusive). There may be an increased diagnosis of severe infections in children who have underlying airway hyper-responsiveness, itself considered a risk factor for COPD. Viral infections may be related to another factor, such as birth weight, that is related to COPD.

HIV infection has been shown to accelerate the onset of smoking-induced emphysema; HIV-induced pulmonary inflammation may play a role in this process62-66.

Socioeconomic Status

There is evidence that the risk of developing COPD is inversely related to socioeconomic status65. 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 low socioeconomic status60,65.

REFERENCES

1. Feinleib M, Rosenberg HM, Collins JG, Delozier JE, Pokras R, Chevarley FM. Trends in COPD morbidity and mortality in the United States. Am Rev Respir Dis 1989; 140:S9-18.
2. Buist AS, Vollmer WM. Smoking and other risk factors. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders Co; 1994. p. 1259-87.
3. Thom TJ. International comparisons in COPD mortality. Am Rev Respir Dis 1989; 140:S27-34.
4. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J 1994; 7:1056-61.
5. National Center for Health Statistics. Current estimates from the National Health Interview Survey, United States, 1995. Washington, DC: Department of Health and Human Services, Public Health Service, Vital and Health Statistics; 1995. Publication No. 96-1527.
6. National Heart, Lung, and Blood Institute. Morbidity & mortality: chartbook on cardiovascular, lung, and blood diseases. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 1998. Available from: URL: www.nhlbi.nih.gov/nhlbi/seiin/other/cht-book/htm
7. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497-505.
8. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis 1989; 139:1435-8.
9. Sahebjami H, Vassallo CL. Influence of starvation on enzyme-induced emphysema. J Appl Physiol 1980; 48:284-8.
10. Silverman EK, Speizer FE. Risk factors for the development of chronic obstructive pulmonary disease. Med Clin North Am 1996; 80:501-22.
11. Chen Y. Genetics and pulmonary medicine.10: Genetic epidemiology of pulmonary function. Thorax 1999; 54:818-24.
12. Laurell CB, Eriksson S. The electrophoretic alpha-1 globulin pattern of serum in alpha-1 antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15:132-40.
13. Hubbard RC, Crystal RG. Antiproteases. In: Crystal RB, West JB, Barnes PJ, Cherniack NS, Weibel ER, eds. The lung: scientific foundations. New York: Raven Press; 1991. p. 1775-87.
14. McElvaney NG, Crystal RG. Inherited susceptibility of the lung to proteolytic injury. In: Crystal RG, West JB, Weibel ER, Barnes PJ, eds. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1997. p. 2537-53.
15. Khoury MJ, Beaty TH, Newill CA, Bryant S, Cohen BH. Genetic-environmental interactions in chronic airways obstruction. Int J Epidemiol 1986; 15:65-72.
16. Cohen BH, Bias WB, Chase GA, Diamond EL, Graves CG, Levy DA, et al. Is ABH non-secretor status a risk factor for obstructive lung disease? Am J Epidemiol 1980; 111:285-91.
17. Smith CA, Harrison DJ. Association between polymorphism in gene for microsomal epoxide hydrolase and susceptibility to emphysema. Lancet 1997; 350:630-3.
18. Harrison DJ, Cantlay AM, Rae F, Lamb D, Smith CA. Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer. Hum Exp Toxicol 1997; 16:356-60.
19. Faber JP, Poller W, Olek K, Baumann U, Carlson J, Lindmark B, et al. The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease. J Hepatol 1993; 18:313-21.
20. Schellenberg D, Pare PD, Weir TD, Spinelli JJ, Walker BA, Sandford AJ. Vitamin D binding protein variants and the risk of COPD. Am J Respir Crit Care Med 1998; 157:957-61.
21. Huang SL, Su CH, Chang SC. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 1997; 156:1436-9.
22. Siafakas NM, Tzortzaki EG, Sourvinos G, Bouros D, Tzanakis N, Kafatos A, et al. Microsatellite DNA instability in COPD. Chest 1999; 116:47-51.
23. Orie NGM, Sluiter HJ, De Vreis K, Tammerling K, Wikop J. The host factor in bronchitis. In: Orie NGM, Sluiter HJ, eds. Bronchitis, an international symposium. Assen, Netherlands: Royal Vangorcum; 1961. p. 43-59.
24. Peat JK, Woolcock AJ, Cullen K. Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987; 70:171-9.
25. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med 1998; 339:1194-200.
26. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996; 153:1802-11.
27. Morgan WJ. Maternal smoking and infant lung function. Further evidence for an in utero effect [editorial; comment]. Am J Respir Crit Care Med 1998; 158:689-90.
28. Hagstrom B, Nyberg P, Nilsson PM. Asthma in adult life - is there an association with birth weight? Scand J Prim Health Care 1998; 16:117-20.
29. Svanes C, Omenaas E, Heuch JM, Irgens LM, Gulsvik A. Birth characteristics and asthma symptoms in young adults: results from a population-based cohort study in Norway. Eur Respir J 1998; 12:1366-70.
30. Todisco T, de Benedictis FM, Iannacci L, Baglioni S, Eslami A, Todisco E, et al. Mild prematurity and respiratory functions. Eur J Pediatr 1993; 152:55-8.
31. Stein CE, Kumaran K, Fall CH, Shaheen SO, Osmond C, Barker DJ. Relation of fetal growth to adult lung function in South India. Thorax 1997; 52:895-9.
32. Tager IB, Segal MR, Speizer FE, Weiss ST. The natural history of forced expiratory volumes. Effect of cigarette smoking and respiratory symptoms. Am Rev Respir Dis 1988; 138:837-49.
33. US Surgeon General. The health consequences of smoking: chronic obstructive pulmonary disease. Washington, D.C: US Department of Health and Human Services; 1984. Publication No. 84-50205.
34. Higgins MW, Thom T. Incidence, prevalence, and mortality: intra- and inter-country differences. In: Hensley M, Saunders N, eds. Clinical epidemiology of chronic obstructive pulmonary disease. New York: Marcel Dekker; 1989. p. 23-43.
35. Sherrill DL, Lebowitz MD, Burrows B. Epidemiology of chronic obstructive pulmonary disease. Clin Chest Med 1990; 11:375-87.
36. Auerbach O, Hammond EC, Garfinkel L, Benante C. Relation of smoking and age to emphysema. Whole-lung section study. N Engl J Med 1972; 286:853-7.
37. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis 1977; 115:195-205.
38. Lebowitz MD, Burrows B. Quantitative relationships between cigarette smoking and chronic productive cough. Int J Epidemiol 1977; 6:107-13.
39. Higgins MW, Keller JB, Becker M, Howatt W, Landis JR, Rotman H, et al. An index of risk for obstructive airways disease. Am Rev Respir Dis 1982; 125:144-51.
40. Becklake MR. Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:S85-91.
41. Kauffmann F, Drouet D, Lellouch J, Brille D. Twelve years spirometric changes among Paris area workers. Int J Epidemiol 1979; 8:201-12.
42. Leuenberger P, Schwartz J, Ackermann-Liebrich U, Blaser K, Bolognini G, Bongard JP, et al. Passive smoking exposure in adults and chronic respiratory symptoms (SAPALDIA Study). Swiss Study on Air Pollution and Lung Diseases in Adults, SAPALDIA Team. Am J Respir Crit Care Med 1994; 150:1222-8.
43. Dayal HH, Khuder S, Sharrar R, Trieff N. Passive smoking in obstructive respiratory disease in an industrialized urban population. Environ Res 1994; 65:161-71.
44. Holt PG. Immune and inflammatory function in cigarette smokers. Thorax 1987; 42:241-9.
45. US Centers for Disease Control and Prevention. Criteria for a recommended standard: occupational exposure to respirable coal mine dust. Morgantown, WV: National Institute of Occupational Safety and Health; 1995. Publication No. 95-106.
46. Heppleston AG. Prevalence and pathogenesis of pneumoconiosis in coal workers. Environ Health Perspect 1988; 78:159-70.
47. Niewoehner DE. Anatomic and pathophysiological correlations in COPD. In: Baum GL, Crapo JD, Celli BR, Karlinsky JB, eds. Textbook of pulmonary diseases. Philadelphia: Lippincott-Raven; 1998. p. 823-42.
48. Bakke S, Baste V, Hanoa R, Gulsvik A. Prevalence of obstructive lung disease in a general population: relation to occupational title and exposure to some airborne agents. Thorax 1991; 46:863-70.
49. Humerfelt S, Gulsvik A, Skjaerven R, Nilssen S, Kvale G, Sulheim O, et al. Decline in FEV1 and airflow limitation related to occupational exposures in men of an urban community. Eur Respir J 1993; 6:1095-103.
50. Humerfelt S, Eide GE, Gulsvik A. Association of years of occupational quartz exposure with spirometric airflow limitation in Norwegian men aged 30-46 years. Thorax 1998; 53:649-55.
51. Chen JC, Mannino MD. Worldwide epidemiology of chronic obstructive pulmonary disease. Current Opinion in Pulmonary Medicine 1999; 5:93-9.
52. Perez-Padilla R, Regalado U, Vedal S, Pare P, Chapela R, Sansores R, et al. Exposure to biomass smoke and chronic airway disease in Mexican women. Am J Respir Crit Care Med 1996; 154:701-6.
53. Dossing M, Khan J, al-Rabiah F. Risk factors for chronic obstructive lung disease in Saudi Arabia. Respiratory Med 1994; 88:519-22.
54. Behera D, Jindal SK. Respiratory symptoms in Indian women using domestic cooking fuels. Chest 1991; 100:385-8.
55. Amoli K. Bronchopulmonary disease in Iranian housewives chronically exposed to indoor smoke. Eur Respir J 1998; 11:659-63.
56. Dennis R, Maldonado D, Norman S, Baena E, Martinez G. Woodsmoke exposure and risk for obstructive airways disease among women. Chest 1996; 109:115-9.
57. Pandey MR. Prevalence of chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax 1984; 39:331-6.
58. Pandey MR. Domestic smoke pollution and chronic bronchitis in a rural community of the Hill Region of Nepal. Thorax 1984; 39:337-9.
59. Samet JM, Marbury M, Spengler J. Health effects and sources of indoor air pollution. Am Rev Respir Dis 1987; 136:1486-508.
60. Tao X, Hong CJ, Yu S, Chen B, Zhu H, Yang M. Priority among air pollution factors for preventing chronic obstructive pulmonary disease in Shanghai. Sci Total Environ 1992; 127:57-67.
61. Smith KR. National burden of disease in India from indoor air pollution. Proc Natl Acad Sci USA 2000; 97:13286-93.
62. Diaz PT, Clanton TL, Pacht ER. Emphysema-like pulmonary disease associated with human immunodeficiency virus infection. Ann Intern Med 1992; 116:124-8.
63. Diaz PT, King MA, Pacht ER, Wewers MD, Gadek JE, Nagaraja HN, et al. Increased susceptibility to pulmonary emphysema among HIV-seropositive smokers. Ann Intern Med 2000; 132:369-72.
64. Diaz PT, King MA, Pacht ER, Wewers MD, Gadek JE, Neal D, et al. The pathophysiology of pulmonary diffusion impairment in human immunodeficiency virus infection. Am J Respir Crit Care Med 1999; 160:272-7.
65. Prescott E, Lange P, Vestbo J. Socioeconomic status, lung function and admission to hospital for COPD: results from the Copenhagen City Heart Study. Eur Respir J 1999; 13:1109-14.
66. Strachan DP. Epidemiology: a British perspective. In: Calverley PMA, Pride NB, eds. Chronic obstructive pulmonary disease. London: Chapman and Hall; 1995. p. 47

    Top

KEY POINTS:

• Exposure to inhaled noxious particles and gases causes inflammation of the lungs that can lead to COPD if the normal protective and/or repair mechanisms are overwhelmed or defective.
• Exacerbations of COPD are associated with an increase in airway inflammation.
• Although inflammation is important in both diseases, the inflammatory response in COPD is markedly different from that in asthma.
• In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and anti-proteinases in the lung, and oxidative stress.
• Pathological changes characteristic of COPD are found in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature.
• The peripheral airways become the major site of airways obstruction in COPD. The structural changes in the airway wall are the most important cause of the increase in peripheral airways resistance in COPD. Inflammatory changes such as airway edema and mucus hypersecretion also contribute to airway narrowing.
• Most common in COPD patients is the centrilobular form of emphysema, which involves dilatation and destruction of the respiratory bronchioles.
• Physiological changes characteristic of the disease include mucus hypersecretion, ciliary dysfunction, airflow limitation, pulmonary hyperinflation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale, and they usually develop in this order over the course of the disease.
• The irreversible component of airflow limitation is primarily due to remodeling of the small airways. Parenchymal destruction (emphysema) also contributes but 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. Inequality in the ventilation/perfusion ration (VA/Q) is the major mechanism behind hypoxemia in COPD.
• Pulmonary hypertension develops late in the course of COPD. It is the major cardiovascular complication of COPD and is associated with a poor prognosis.
• COPD is associated with systemic inflammation and skeletal muscle dysfunction that may contribute to limitation of exercise capacity and decline of health status.

INTRODUCTION

Inhaled noxious particles and gases that lead to COPD cause lung inflammation, induce tissue destruction, impair the defense mechanisms that serve to limit the destruction, and disrupt the repair mechanisms that may be able to restore tissue structure in the face of some injuries. The results of lung tissue damage are mucus hypersecretion, airway narrowing and fibrosis, destruction of the parenchyma (emphysema), and vascular changes. In turn, these pathological changes lead to airflow limitation and the other physiological abnormalities characteristic of COPD.

Much of the information concerning the pathogenesis of COPD comes from studies in experimental animals or in vitro systems. These experimental systems are limited as they differ from human disease in a number of respects. Studies in human subjects of the pathogenesis, pathology, and pathophysiology of COPD are often limited by patient selection, small numbers of subjects, and limited access to the relevant tissue. Therefore, an evidence-based perspective on these topics is in many respects incomplete.

PATHOGENESIS

COPD is characterized by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The intensity and cellular and molecular characteristics of the inflammation vary as the disease progresses. Over time, inflammation damages the lungs and leads to the pathologic changes characteristic of COPD.

In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and anti-proteinases in the lung, and oxidative stress. These processes may themselves be consequences of inflammation, or they may arise from environmental (e.g., oxidant compounds in cigarette smoke) or genetic (e.g., alpha-1 antitrypsin deficiency) factors. Figure 4-1 details the interactions between these mechanisms. The multiplicity of cells and mediators thought to be involved in the pathogenesis of COPD is presented schematically in Figure 4-2.

Figure 4.1 Pathogenesis of COPD

Inflammatory Cells

Figure 4.3 Sites of Inflammatory Cell Increases in COPD

COPD is characterized by an increase in neutrophils, macrophages, and T lymphocytes (especially CD8+) in various parts of the lung (Figure 4-3). There may also be an increase in eosinophils in some patients, particularly during exacerbations. These increases are brought about by increases in inflammatory cell recruitment, survival, and/or activation. Many studies reveal a correlation between the number of inflammatory cells of various types in the lung and the severity of COPD1-10.

Neutrophils. Increased numbers of activated neutrophils are found in sputum and bronchoalveolar lavage (BAL) fluid of patients with COPD4,5,8,9, although the role of neutrophils in COPD is not yet clear. Neutrophils are also increased in smokers without COPD11. However, neutrophils are little increased in airway and parenchyma tissue sections, which may reflect their rapid transit through these parts of the lung. Induced sputum studies also show an increase in myeloperoxidase (MPO) and human neutrophil lipocalin, indicating neutrophil activation12. Acute exacerbations of COPD are characterized by a marked increase in the number of neutrophils in BAL fluid13. Neutrophils secrete several proteinases, including neutrophil elastase (NE), neutrophil cathepsin G, and neutrophil proteinase-3, which may contribute to parenchymal destruction and chronic mucus hypersecretion.

Macrophages. Increased numbers of macrophages are present in the large and small airways and lung parenchyma of patients with COPD, as reflected in histopathology, BAL, bronchial biopsy, and induced sputum studies2,4-9. In patients with emphysema, macrophages are localized to sites of alveolar wall destruction1. Macrophages likely play an orchestrating role in COPD inflammation by releasing mediators such as tumor necrosis factor-a (TNF- ), interleukin 8 (IL-8), and leukotriene B4 (LTB4), which promote neutrophilic inflammation.

T lymphocytes. Histopathology and bronchial biopsy studies show an increase in T lymphocytes, especially CD8+ (cytotoxic) cells, throughout the lungs of patients with COPD1,2,10,14. Their role in COPD inflammation is not yet fully understood, but one way that CD8+ cells may contribute to COPD is by releasing perforin, granzyme-B, and TNF-a, which can cause the cytolysis and apoptosis of alveolar epithelial cells15 that may be responsible for the persistence of inflammation. An increased number of lymphocyte-like natural killer (NK) cells has also been reported in patients with severe COPD3.

Eosinophils. The presence and role of eosinophils in COPD are uncertain. Some bronchial biopsy studies show eosinophils increased in the airways of some patients with stable COPD6,16. However, some of these patients may have had coexisting asthma, as other studies report no increase in eosinophils in COPD patients2. The levels of eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) in induced sputum are elevated in COPD, suggesting that eosinophils may be present but degranulated, and therefore no longer recognizable by light microscopy12. The high levels of neutrophil elastase (NE) often found in COPD may be responsible for this degranulation17. Most studies agree that airway eosinophils are increased during acute exacerbations of COPD18,19.

Epithelial cells. Airway and alveolar epithelial cells are likely to be important sources of inflammatory mediators in COPD, though their role in inflammation in this disease has not yet been thoroughly studied. Exposure of nasal or bronchial epithelial cells from healthy volunteers to nitrogen dioxide (NO2), ozone (O3), and diesel exhaust particles results in significant synthesis and release of pro-inflammatory mediators, including eicosanoids, cytokines, and adhesion molecules20. The adhesion molecule E-selectin, involved in recruitment and adhesion of neutrophils, is up-regulated on airway epithelial cells in COPD patients21. Cultured human bronchial epithelial cells from COPD patients release lower levels of inflammatory mediators such as TNF-a and IL-8 than similar preparations from nonsmokers or smokers without COPD, suggesting that some form of down-regulation of inflammatory mediator release may occur in epithelial cells of individuals with COPD20.

Inflammatory Mediators

Activated inflammatory cells in COPD release a variety of mediators, including a spectrum of potent proteinases22,23, oxidants24, and toxic peptides25. Many of the mediators thought to be important in the disease — notably LTB426, IL-84,7,27, and TNF- 4,16 — are capable of damaging lung structures and/or sustaining neutrophilic inflammation. The damage induced by these moieties may further potentiate inflammation by releasing chemotactic peptides from the extracellular matrix28. Little is yet known about the specific role of these inflammatory mediators in COPD. Studies of the therapeutic use of selective mediator antagonists should identify the molecules relevant in COPD.

Leukotriene B4 (LTB4). LTB4, a potent chemoattractant of neutrophils, is found at increased levels in the sputum of patients with COPD26. It is probably derived from alveolar macrophages, which secrete more LTB4 in patients with COPD. Several potent LTB4 receptor antagonists have been developed for clinical studies and should elucidate further the role of this mediator in COPD. So far there is no evidence that cysteinyl leukotrienes (LTC4, LTD4, LTE4) are involved in COPD. Selective antagonists of the cysteinyl leukotriene 1 receptor (CysLT1) have proven helpful in patients with asthma and studies of these drugs in COPD patients are now underway. The role of the cysteinyl leukotriene 2 receptor (CysLT2) in respiratory disease is as yet unknown29.

Interleukin 8 (IL-8). IL-8, a selective chemoattractant of neutrophils that may be secreted by macrophages, neutrophils, and airway epithelial cells, is present at high concentrations in induced sputum and BAL fluid of patients with COPD,4,7,27. IL-8 may play a primary role in the activation of both neutrophils and eosinophils in the airways of COPD patients and may serve as a marker in evaluating the severity of airway inflammation27.

Tumor necrosis factor- (TNF- ). TNF-xx activates the transcription factor nuclear factor-kB (NF-kB), which in turn activates the IL-8 gene in epithelial cells and macrophages (Figure 4-4). TNF-a is present at high concentrations in sputum4 and is detectable in bronchial biopsies16 in patients with COPD. TNF- serum levels and production by peripheral blood monocytes are increased in weight-losing COPD patients, suggesting that this mediator may play a role in the cachexia of severe COPD30.

Cigarette smoke activates macrophages and epithelial cells to produce tumor necrosis factor ? (TNF-?), switching on the gene for interleukin 8 (IL-8), which recruits and activates neutrophils. This process occurs via activation of the transcription factor nuclear factor - ?B (NF-?B).

Others. Other inflammatory mediators that may be involved in COPD include the following:

• Macrophage chemotactic protein-1 (MCP-1), a potent chemoattractant of monocytes, is increased in the BAL fluid of patients with COPD and smokers without COPD, but not in ex-smokers or nonsmokers31. Thus, MCP-1 may be involved in macrophage recruitment into the lungs in smokers.
• Macrophage inflammatory protein-1ß (MIP-1ß) is increased in the BAL fluid of patients with COPD compared to smokers, ex-smokers, and nonsmokers31. Macrophage inflammatory protein-1 (MIP-1 ) shows increased expression in airway epithelial cells from COPD patients3 compared to control smokers.
• Granulocyte-macrophage colony stimulating factor (GM-CSF) is found at increased concentrations in the BAL fluid of patients with stable COPD and at markedly elevated levels during exacerbations13. The number of GM-CSF-immunoreactive macrophages is also increased in sputum of patients with COPD32. GM-CSF is important for neutrophil survival and may play a role in enhancing neutrophilic inflammation.
• Transforming growth factor-ß (TGF-ß) and epidermal growth factor (EGF) show increased expression in epithelial cells and sub-mucosal cells (eosinophils and fibroblasts) in COPD patients33. These mediators may play a role in airway remodeling (fibrosis and narrowing) in COPD34.
• Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is found at increased concentrations in induced sputum of patients with COPD35. Patients with severe COPD also have elevated plasma levels of ET-1, which is probably related to their chronic hypoxemia36.
• Neuropeptides, such as substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide (VIP), have potent effects on vascular function and mucus secretion. An increased concentration of substance P is found in sputum of patients with chronic bronchitis37. One bronchial biopsy study showed an increase in VIP-immunoreactive nerves in the vicinity of sub-mucosal glands in patients with chronic bronchitis, suggesting that this substance may play a role in mucus hypersecretion38. However, another study showed no significant differences in the number of nerves immunoreactive for substance P, calcitonin gene-related peptide, or VIP between COPD patients and healthy subjects39.
• Complement. Activation of the complement pathway via generation of the potent chemotaxin C5a may play a significant role in the neutrophil accumulation seen in the lungs of patients with COPD40.

Differences Between Inflammation in COPD and Asthma

Although inflammation is important in both diseases, the inflammatory response in COPD is markedly different from that in asthma, as summarized in Figure 4-5. However, some patients with COPD also have asthma, and the inflammation in their lungs may show characteristics of both diseases.

Figure 4.5 Characteristics of Inflammation in COPD and Asthma

COPD Asthma     Cells • Neutrophils • Large increases in macrophages • Increase in CD8+ lymphocytes • Eosinophils • Small increase in macrophages • Increase in CD4+ Th2 lymphocytes • Activation of mast cells     Mediators • LTB4 • IL-8 • TNF- • LTD4 • IL-4, IL-5 • Plus many others     Consequences • Squamous metaplasia of epithelium • Parenchymal destruction • Mucus metaplasia • Glandular enlargement • Fragile epithelium • Thickening of basement membrane • Mucus metaplasia • Glandular enlargement     Response to treatment • Glucocorticosteroids have little or no effect • Glucocorticosteroids inhibit inflammation

Since inflammation is a feature of COPD, it follows that anti-inflammatory therapies may have clinical benefit in controlling symptoms, preventing exacerbations, and slowing the progression of the disease. However, the inflammatory response in COPD appears to be poorly responsive to the glucocorticosteroids that are effective anti-inflammatory medications in asthma.

Inflammation and COPD Risk Factors

The connection between cigarette smoke and inflammation has been most extensively studied41-52. Cigarette smoke activates macrophages and epithelial cells to produce TNF- and may also cause macrophages to release other inflammatory mediators, including IL-8 and LTB453,54.

Inflammation is present in the lungs of smokers without a diagnosis of COPD. This inflammation is similar to, but less intense than, the inflammation in the lungs of patients with COPD. For example, induced sputum studies show that smokers without COPD have a greater proportion of neutrophils in their lungs than age-matched nonsmokers, but a smaller proportion than COPD patients4,9. Thus, the inflammation characteristic of COPD is thought to represent an exaggeration of a normal, protective response to inhalational exposures.

However, not all smokers develop COPD, and why the normal, protective inflammatory response becomes an exaggerated, harmful one in some smokers is poorly understood. Presumably the inflammation caused by cigarette smoking interacts with other host or environmental factors to produce the excess decline in lung function that results in COPD55. Inflammatory changes are also present in bronchial biopsies in ex-smokers, suggesting that the inflammatory response in COPD may persist even in the absence of continuous exposure to risk factors56.

A number of studies have demonstrated that a variety of particulates (e.g., diesel exhaust, grain dust) can initiate respiratory tract inflammation57-61. It is likely that indoor air pollution derived from the burning of biomass fuels will prove to have similar effects.

Proteinase-Antiproteinase Imbalance

Laurell and Eriksson observed in 1963 that individuals with a hereditary deficiency of the serum protein alpha-1 antitrypsin, which inhibits a number of serine proteinases such as neutrophil elastase, are at increased risk of developing emphysema62. Elastin, the target of neutrophil elastase, is a major component of alveolar walls, and elastin fragments may perpetuate inflammation by acting as potent chemotactic agents for macrophages and neutrophils. These observations led to the hypothesis that an imbalance between proteinases and endogenous anti-proteinases results in lung destruction.

Based on many observations, it now seems clear that an imbalance of proteinases and anti-proteinases may involve either increased production or activity of proteinases, or inactivation or reduced production of anti-proteinases. Often, the imbalance is a consequence of the inflammation induced by inhalational exposures. For example, macrophages, neutrophils, and airway epithelial cells release a combination of proteinases. The imbalance may also be caused by a decrease of anti-proteinase activity by oxidative stress (itself a consequence of inflammation), cigarette smoke63,64, and possibly other COPD risk factors.

The concept has also been expanded to include additional proteinases and anti-proteinases. While neutrophil elastase is likely to be the major proteinase involved in lung destruction in alpha-1 antitrypsin deficiency, it may not be involved in COPD caused by inhalational exposures. Additional proteinases that have been implicated in COPD include neutrophil cathepsin G, neutrophil proteinase-3, cathepsins released from macrophages (specifically cathepsins B, L, and S), and various matrix metalloproteinases (MMPs)65. These proteinases are capable of degrading elastin and also collagen, another main component of alveolar walls. Some proteinases, such as neutrophil elastase66 and neutrophil proteinase-367, induce mucus secretion, and neutrophil elastase also produces mucus gland hyperplasia68. Thus, proteinases may be involved in mucus hypersecretion as well as parenchymal destruction. Anti-proteinases thought to be involved in COPD include, in addition to alpha-1 antitrypsin, secretory leukoproteinase inhibitor (SLPI) and tissue inhibitors of MMPs (TIMPs).

Oxidative Stress

There is increasing evidence that an oxidant/antioxidant imbalance, in favor of oxidants, occurs in COPD. (The process is summarized in Figure 4-6.) Markers of oxidative stress have been found in the epithelial lining fluid, breath, and urine of cigarette smokers and patients with COPD. For example, hydrogen peroxide (H2O2) and nitric oxide (NO) are direct measures of oxidants generated by cigarette smoking or released from inflammatory leukocytes and epithelial cells. H2O2 is increased in the breath of patients with stable COPD and during acute exacerbations69, and NO is increased in the breath during exacerbations of COPD70. A prostaglandin isomer, isoprostane F2 -III, which is formed by free radical peroxidation of arachidonic acid and believed to be an in vivo biomarker of lung oxidative stress, is increased in both breath condensates71 and urine72 in COPD patients compared to healthy controls and is increased even more during exacerbations.

Oxidative stress contributes to COPD in a variety of ways. Oxidants can react with, and damage, a variety of biological molecules, including proteins, lipids, and nucleic acids, and this can lead to cell dysfunction or death, as well as damage to the lung extracellular matrix. In addition to directly damaging the lung, oxidative stress contributes to the proteinase-anti-proteinase imbalance both by inactivating anti-proteinases (such as alpha-1 antitrypsin and SLPI) and by activating proteinases (such as MMPs). Oxidants also promote inflammation, for example by activating the transcription factor NF-kB, which orchestrates the expression of multiple inflammatory genes thought to be important in COPD such as IL-8 and TNF- . Finally, oxidative stress may contribute to reversible airway narrowing. H2O2 constricts airway smooth muscle in vitro and isoprostane F2 -III is a potent constrictor of human airways73.

PATHOLOGY

Pathological changes characteristic of COPD are found in the central airways, peripheral airways, lung parenchyma, and pulmonary vasculature74. The various lesions are a result of chronic inflammation in the lung, which in turn is initiated by the inhalation of noxious particles and gases such as those present in cigarette smoke. The lung has natural defense mechanisms and a considerable capacity to repair itself, but the working of these mechanisms may be affected by genetic traits (e.g., alpha-1 antitrypsin deficiency) or exposure to other environmental risk factors (e.g., infection, atmospheric pollution) 75, as well as by the chronic nature of the inflammation and repeated nature of the injury.

Central Airways

The central airways include the trachea, bronchi, and bronchioles greater than 2-4 mm in internal diameter. In patients with chronic bronchitis, an inflammatory exudate of fluid and cells infiltrates the epithelium lining the central airways and associated glands and ducts2,42. The predominant cells in this inflammatory exudate are macrophages and CD8+T lymphocytes2,76. Chronic inflammation in the central airways is also associated with an increase in the number (metaplasia) of epithelial goblet and squamous cells; dysfunction, damage, and/or loss of cilia; enlarged sub-mucosal mucus-secreting glands77; an increase in the amount of smooth muscle and connective tissue in the airway wall78; degeneration of the airway cartilage79,80; and mucus hypersecretion. The mechanisms of mucus gland hypertrophy and goblet cell metaplasia have not yet been identified, but animal studies 81, 82 show that irritants including cigarette smoke83 can produce these changes. The various pathological changes in the central airways are responsible for the symptoms of chronic cough and sputum production, which identify people at risk for COPD and may continue to be present throughout the course of the disease. Thus, these pathological changes may be present either on their own or in combination with the changes in the peripheral airways and lung parenchyma described below.

Peripheral Airways

The peripheral airways include small bronchi and bronchioles that have an internal diameter of less than 2 mm (Figure 4-8). The early decline in lung function in COPD is correlated with inflammatory changes in the peripheral airways, similar to those that occur in the central airways: exudate of fluid and cells in the airway wall and lumen, goblet and squamous cell metaplasia of the epithelium43, edema of the airway mucosa due to inflammation, and excess mucus in the airways due to goblet cell metaplasia.

However, the most characteristic change in the peripheral airways of patients with COPD is airway narrowing. Inflammation initiated by cigarette smoking45 and other risk factors75 leads to repeated cycles of injury and repair of the walls of the peripheral airways. Injury is caused either directly by inhaled toxic particles and gases such as those found in cigarette smoke, or indirectly by the action of inflammatory mediators; this injury then initiates repair processes. Although airway repair is only partly understood, it seems likely that disordered repair processes can lead to tissue remodeling with altered structure and function. Cigarette smoke may impair lung repair mechanisms, thereby further contributing to altered lung structure84-86. Even normal lung repair mechanisms can lead to airway remodeling because tissue repair in the airways, as elsewhere in the body, may involve scar tissue formation. In any case, this injury-and-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 obstruction87.

The peripheral airways become the major site of airways obstruction in COPD, and direct measurements of peripheral airways resistance88 show that the structural changes in the airway wall are the most important cause of the increase in peripheral airways resistance in COPD. Inflammatory changes such as airway edema and mucus hypersecretion also contribute to airway narrowing in COPD. So does loss of elastic recoil, but fibrosis of the small airways plays the largest role.

Fibrosis in the peripheral airways, as elsewhere in the body, is characterized by the accumulation of mesenchymal cells (fibroblasts and myofibroblasts) and extracellular connective tissue matrix. Several cell types including mononuclear phagocytes and epithelial cells may produce mediators that drive this process. The mediators that drive the accumulation of these cells and of the matrix are incompletely defined, but it is likely that several mediators including TGF-ß, ET-1, Insulin-like growth factor-1, fibronectin, platelet-derived growth factor (PDGF), and others are involved89.

Lung Parenchyma

The lung parenchyma includes the gas exchanging surface of the lung (respiratory bronchioles and alveoli) and the pulmonary capillary system (Figure 4-9). The most common type of parenchymal destruction in COPD patients is the centrilobular form of emphysema which involves dilatation and destruction of the respiratory bronchioles90. 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. Panacinar emphysema, which extends throughout the acinus, is the characteristic lesion seen in alpha-1 antitrypsin deficiency and involves dilatation and destruction of the alveolar ducts and sacs as well as the respiratory bronchioles. It tends to affect the lower more than upper lung regions. Because this process usually affects all of the acini in the secondary lobule, it is also referred to as panlobular emphysema. The primary mechanism of lung parenchyma destruction, in both smoking-related COPD and alpha-1 antitrypsin deficiency, is thought to be an imbalance of endogenous proteinases and anti-proteinases in the lung. Oxidative stress, another consequence of inflammation, may also contribute91.

Pulmonary Vasculature

Pulmonary vascular changes in COPD (Figure 4-11) are characterized by a thickening of the vessel wall that begins early in the natural history of the disease, when lung function is reasonably well maintained and pulmonary vascular pressures are normal at rest92. Endothelial dysfunction of the pulmonary arteries, which may be caused directly by cigarette smoke products93 or indirectly by inflammatory mediators14, occurs early in COPD 94. Since endothelium plays an important role in regulating vascular tone and cell proliferation, it is likely that endothelial dysfunction might initiate the sequence of events that results ultimately in structural changes. Thickening of the intima is the first structural change92, followed by an increase in vascular smooth muscle and the infiltration of the vessel wall by inflammatory cells, including macrophages and CD8+ T lymphocytes14. These structural changes are correlated with an increase in pulmonary vascular pressure that develops first with exercise and then at rest. As COPD worsens, greater amounts of smooth muscle, proteoglycans, and collagen95 further thicken the vessel wall. In advanced disease, the changes in the muscular arteries may be associated with emphysematous destruction of the pulmonary capillary bed.

PATHOPHYSIOLOGY

Pathological changes in COPD lead to corresponding physiological abnormalities that usually become evident first on exercise and later also at rest. Physiological changes characteristic of the disease include mucus hypersecretion, ciliary dysfunction, airflow limitation, pulmonary hyperinflation, gas exchange abnormalities, pulmonary hypertension, and cor pulmonale, and they usually develop in this order over the course of the disease. In turn, various physiological abnormalities contribute to the characteristic symptoms of COPD — chronic cough and sputum production and dyspnea.

Mucus Hypersecretion and Ciliary Dysfunction

Mucus hypersecretion in COPD is caused by the stimulation of the enlarged mucus secreting glands and increased number of goblet cells by inflammatory mediators such as leukotrienes, proteinases, and neuropeptides. Ciliated epithelial cells undergo squamous metaplasia leading to impairment in mucociliary clearance mechanisms. These changes are usually the first physiological abnormalities to develop in COPD, and can be present for many years before any other physiological abnormalities develop.

Airflow Limitation and Pulmonary Hyperinflation

Expiratory airflow limitation is the hallmark physiological change of COPD. The airflow limitation characteristic of COPD is primarily irreversible, with a small reversible component. Several pathological characteristics contribute to airflow limitation and changes in pulmonary mechanics, as summarized in Figure 4-12. The irreversible component of airflow limitation is primarily due to remodeling42,43,87,88,96,97 — fibrosis and narrowing — of the small airways that produces fixed airways obstruction and a consequent increase in airways resistance. The sites of airflow limitation in COPD are the smaller conducting airways, including bronchi and bronchioles less than 2 mm in internal diameter. In the normal lung, resistance of these smaller airways makes up a small percentage of the total airways resistance88. But in patients with COPD the total lower airways resistance approximately doubles, and most of the increase is due to a large increase in peripheral airways resistance88. Although some have argued that a larger proportion of the total resistance should be attributed to peripheral airways in the normal lung, there is wide agreement that the peripheral airways become the major site of obstruction in COPD.

Figure 4.12 Causes of Airflow Limitation in COPD

Parenchymal destruction (emphysema) plays a smaller role in this irreversible component but contributes to expiratory airflow limitation and the increase in airways resistance in several ways. Destruction of alveolar attachments inhibits the ability of the small airways to maintain patency98. Alveolar destruction is also associated with a loss of elastic recoil of the lung99,100, which decreases the intra-alveolar pressure driving exhalation.

Although both the destruction of alveolar attachments to the outer wall of the peripheral airways and the loss of lung elastic recoil produced by emphysema have been implicated in the pathogenesis of peripheral airways obstruction98,100, direct measurements of peripheral airways resistance88 show that the structural changes in the airway wall are the most important cause of the increase in peripheral airways resistance in COPD.

Airway smooth muscle contraction, ongoing airway inflammation, and intraluminal accumulation of mucus and plasma exudate may be responsible for the small part of airflow limitation that is reversible with treatment. Inflammation and accumulation of mucus and exudate may be particularly important during exacerbations101.

Airflow limitation in COPD is best measured through spirometry, which is key to the diagnosis and management of the disease. The essential spirometric measurements for diagnosis and monitoring of COPD patients are the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). As COPD progresses, with increased thickness of the airway wall, loss of alveolar attachments, and loss of lung elastic recoil, FEV1 and FVC decrease. A decrease in the ratio of FEV1 to FVC is often the first sign of developing airflow limitation. FEV1 declines naturally with age, but the rate of decline in COPD patients is generally greater than that in normal subjects.

With increasing severity of airflow limitation, expiration becomes flow-limited during tidal breathing. Initially, this occurs only during exercise, but later it is also seen at rest. In parallel with this, functional residual capacity (FRC) increases due to the combination of the decrease in the elastic properties of the lungs, premature airway closure, and a variable dynamic element reflecting the breathing pattern adopted to cope with impaired lung mechanics. As airflow limitation develops, the rate of lung emptying is slowed and the interval between inspiratory efforts does not allow expiration to the relaxation volume of the respiratory system; this leads to dynamic pulmonary hyperinflation. The increase in FRC can impair inspiratory muscle function and coordination, although the contractility of the diaphragm, when normalized for lung volume, seems to be preserved. These changes occur as the disease advances but are almost always seen first during exercise, when the greater metabolic stimulus to ventilation stresses the ability of the ventilatory pump to maintain gas exchange.

Gas Exchange Abnormalities

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. The correlation between routine lung function tests and arterial blood gases is poor, but significant hypoxemia or hypercapnia is rare when FEV1 is greater than 1.00 L102. Hypoxemia is initially only present during exercise, but as the disease continues to progress it is also present at rest.

Inequality in the ventilation/perfusion ratio (VA/Q) is the major mechanism behind hypoxemia in COPD, regardless of the stage of the disease103. In the peripheral airways, injury of the airway wall is associated with VA/Q mismatching, as indicated by a significant correlation between bronchiolar inflammation and the distribution of ventilation. In the parenchyma, destruction of the lung surface area by emphysema reduces diffusing capacity and interferes with gas exchange104. High VA/Q units probably represent emphysematous regions with alveolar destruction and loss of pulmonary vasculature. The severity of pulmonary emphysema appears to be related to the overall inefficiency of the lung as a gas exchanger. This is reflected by the good correlation between the diffusing capacity of carbon monoxide per liter of alveolar volume (DLco/VA) and the severity of macroscopic emphysema. Reduced ventilation due to loss of elastic recoil in the emphysematous lung, together with the loss of the capillary bed and the generalized inhomogeneity of ventilation due to the patchy nature of these changes, leads to areas of VA/Q mismatching that result in arterial hypoxemia.

The relationship between pulmonary vascular abnormalities and VA/Q relationships has been investigated in patients with mild COPD. The more severe the vessel wall damage is, the less the reversal of hypoxic vasoconstriction by oxygen105. This suggests that pathology in the pulmonary artery wall, particularly when it affects the intimal layer, may play a key role in determining the loss of vascular response to hypoxia that contributes to VA/Q mismatching. Chronic hypercapnia usually reflects inspiratory muscle dysfunction and alveolar hypoventilation.

Pulmonary Hypertension and Cor Pulmonale

Pulmonary hypertension develops late in the course of COPD (Stage III: Severe COPD), usually after the development of severe hypoxemia (PaO2 < 8.0 kPa or 60 mm Hg) and often hypercapnia as well. It is the major cardiovascular complication of COPD and is associated with the development of cor pulmonale and with a poor prognosis106. However, even in patients with severe disease, pulmonary arterial pressure is usually only modestly elevated at rest, though it may rise markedly with exercise. Pulmonary hypertension in COPD is believed to progress rather slowly even if left untreated. Further studies are required to firmly establish the natural history of pulmonary hypertension in COPD.

Factors that are known to contribute to the development of pulmonary hypertension in patients with COPD include vasoconstriction; remodeling of pulmonary arteries, which thickens the vessel walls and reduces the lumen; and destruction of the pulmonary capillary bed by emphysema, which further increases the pressure required to perfuse the pulmonary vascular bed. Vasoconstriction may itself have several causes, including hypoxia, which causes pulmonary vascular smooth muscle to contract; impaired mechanisms of endothelium-dependent vasodilation, such as reduced NO synthesis or release; and abnormal secretion of vasoconstrictor peptides (such as ET-1, which is produced by inflammatory cells). In advanced COPD, hypoxia plays the primary role in producing pulmonary hypertension, both by causing vasoconstriction of the pulmonary arteries and by promoting remodeling of the vessel wall (either by inducing the release of growth factors107 or as a consequence of the mechanical stress that results from hypoxic vasoconstriction).

Pulmonary hypertension is associated with the development of cor pulmonale, defined as "hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lungs, except when these pulmonary alterations are the result of diseases that primarily affect the left side of the heart, as in congenital heart disease." This is a pathological definition and the clinical diagnosis and assessment of right ventricular hypertrophy is difficult in life.

The prevalence and natural history of cor pulmonale in COPD are not yet clear. Pulmonary hypertension and reduction of the vascular bed due to emphysema can lead to right ventricular hypertrophy and right heart failure, but right ventricular function appears to be maintained in some patients despite the presence of pulmonary hypertension108. Right heart failure is associated with venous stasis and thrombosis that may result in pulmonary embolism and further compromise the pulmonary circulation.

Systemic Effects

COPD is associated with systemic (i.e., extrapulmonary) effects, such as systemic inflammation and skeletal muscle dysfunction. Evidence of systemic inflammation includes the presence of systemic oxidative stress109, abnormal concentrations of circulating cytokines110, and activation of inflammatory cells111,112. Evidence of skeletal muscle dysfunction includes the progressive loss of skeletal muscle mass and the presence of several bioenergetic abnormalities113. These systemic effects have important clinical consequences, as they contribute to the limitation of patients' exercise capacity and thus the decline of health status in COPD. The presence of these systemic effects appears to worsen a patient's prognosis114.

Pathophysiology and the Symptoms of COPD

Chronic cough and sputum production, sometimes labeled as chronic bronchitis, are a result of airway inflammation, which leads to mucus hypersecretion and dysfunction of the normal ciliary clearance mechanisms. Sputum is produced in COPD as a result of the inflammatory response, and contains plasma proteins exuded from the microvessels of the bronchial circulation, inflammatory cells, and small amounts of mucus from epithelial goblet cells. The volume of sputum produced overpowers clearance mechanisms, resulting in cough and expectoration. Some pathological abnormalities, such as inflammation of the sub-mucosal glands and hyperplasia of goblet cells, may contribute to chronic sputum production, although these pathological abnormalities are not present in all patients with this symptom.

Dyspnea, an abnormal awareness of the act of breathing, usually reflects an imbalance between the neural drive to the respiratory muscles and the effectiveness of the resulting ventilation. Different individuals use different words to describe the feeling of breathlessness, which is also influenced by other factors such as mood. In COPD patients, dyspnea is mainly the result of impaired lung mechanics (increased airways resistance, decreased elastic recoil). It is only present on vigorous exercise in the early stages of disease but may be present at rest as the mechanical impairment becomes severe.

PATHOLOGY AND PATHOPHYSIOLOGY OF ACUTE EXACERBATIONS

The progressive course of COPD is complicated by acute exacerbations that have many causes and occur with increasing frequency as the disease progresses.

Pathology

Distinguishing the pathology of these acute events from that of the underlying disease is difficult because patients experiencing an exacerbation are usually too ill to study. The limited evidence available suggests that mild COPD exacerbations are associated with increases of both neutrophils and eosinophils in sputum and biopsies, while severe COPD exacerbations are associated with an increase in sputum neutrophils and eosinophils18,19. At least in sputum, the changes in inflammatory cells during exacerbations of COPD are the same as those observed during exacerbations of asthma115-119. So far no study has been conducted examining the pathological abnormalities associated with fatal exacerbations of COPD, which can be considered the extreme end of the spectrum of severity.

Pathophysiology

Expiratory airflow is almost unchanged during mild exacerbations18, and only slightly reduced during severe exacerbations120,121. Although the pathophysiology of acute exacerbations is not fully understood, the primary physiological change in severe acute exacerbations is a further worsening of gas exchange, primarily produced by increased VA/Q inequality. As VA/Q relationships worsen, increased work of the respiratory muscles results in greater oxygen consumption, decreased mixed venous oxygen tension, and further amplification of gas exchange abnormalities120. Worsening of VA/Q relationships has several causes in acute exacerbations. Airway inflammation and edema, mucus hypersecretion, and bronchoconstriction may contribute to changes in the distribution of ventilation, while hypoxic constriction of pulmonary arterioles may modify the distribution of perfusion. Additional contributors to worsening gas exchange in acute exacerbations include abnormal patterns of breathing and fatigue of the respiratory muscles. These can cause further deterioration in blood gases and worsening of respiratory acidosis, leading to severe respiratory failure and death120-123. Alveolar hypoventilation also contributes to hypoxemia, hypercapnia, and respiratory acidosis. In turn, hypoxemia and respiratory acidosis promote pulmonary vasoconstriction, which increases pulmonary artery pressures and imposes an added load on the right ventricle.

REFERENCES

1. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 1995; 152:1666-72.
2. O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med 1997; 155:852-7.
3. Di Stefano A, Capelli A, Lusuardi M, Balbo P, Vecchio C, Maestrelli P, et al. Severity of airflow limitation is associated with severity of airway inflammation in smokers. Am J Respir Crit Care Med 1998; 158:1277-85.
4. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153:530-4.
5. Thompson AB, Daughton D, Robbins RA, Ghafouri MA, Oehlerking M, Rennard SI. Intraluminal airway inflammation in chronic bronchitis. Characterization and correlation with clinical parameters. Am Rev Respir Dis 1989; 140:1527-37.
6. Lacoste JY, Bousquet J, Chanez P, Van Vyve T, Simony-Lafontaine J, Lequeu N, et al. Eosinophilic and neutrophilic inflammation in asthma, chronic bronchitis, and chronic obstructive pulmonary disease. J Allergy Clin Immunol 1993; 92:537-48.
7. Pesci A, Balbi B, Majori M, Cacciani G, Bertacco S, Alciato P, et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12:380-6.
8. Pesci A, Majori M, Cuomo A, Borciani N, Bertacco S, Cacciani G, et al. Neutrophils infiltrating bronchial epithelium in chronic obstructive pulmonary disease. Respir Med 1998; 92:863-70.
9. Peleman RA, Rytila PH, Kips JC, Joos GF, Pauwels RA. The cellular composition of induced sputum in chronic obstructive pulmonary disease. Eur Respir J 1999; 13:839-43.
10. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:822-6.
11. Roth MD, Arora A, Barsky SH, Kleerup EC, Simmons M, Tashkin DP. Airway inflammation in young marijuana and tobacco smokers. Am J Respir Crit Care Med 1998; 157:928-37.
12. Keatings VM, Barnes PJ. Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 1997; 155:449-53.
13. Balbi B, Bason C, Balleari E, Fiasella F, Pesci A, Ghio R, et al. Increased bronchoalveolar granulocytes and granulocyte/macrophage colony-stimulating factor during exacerbations of chronic bronchitis. Eur Respir J 1997; 10:846-50.
14. Peinado VI, Barbera JA, Abate P, Ramirez J, Roca J, Santos S, et al. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:1605-11.
15. Liu AN, Mohammed AZ, Rice WR, Fiedeldey DT, Liebermann JS, Whitsett JA, et al. Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am J Respir Cell Mol Biol 1999; 20:849-58.
16. Mueller R, Chanez P, Campbell AM, Bousquet J, Heusser C, Bullock GR. Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis. Respir Med 1996; 90:79-85.
17. Liu H, Lazarus SC, Caughey GH, Fahy JV. Neutrophil elastase and elastase-rich cystic fibrosis sputum degranulate human eosinophils in vitro. Am J Physiol 1999; 276:L28-34.
18. Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994; 150:1646-52.
19. Saetta M, Di Stefano A, Maestrelli P, Turato G, Mapp CE, Pieno M, et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin Exp Allergy 1996; 26:766-74.
20. Mills PR, Davies RJ, Devalia JL. Airway epithelial cells, cytokines, and pollutants. Am J Respir Crit Care Med 1999; 160:S38-43.
21. Di Stefano A, Maestrelli P, Roggeri A, Turato G, Calabro S, Potena A, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994; 149:803-10.
22. McElvaney NG, Crystal RG. Proteases and lung injury. In: Crystal RG, West JB, eds. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1997. p. 2205-18.
23. Shapiro SD. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr Opin Cell Biol 1998; 10:602-8.
24. Warren JS, Ward PA. Consequences of oxidant injury. In: Crystal RG, West JB, eds. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1997. p. 2279-88.
25. Ganz T, Lehrer RI. Defensins. Curr Opin Immunol 1994; 6:584-9.
26. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 1999; 160:893-8.
27. Yamamoto C, Yoneda T, Yoshikawa M, Fu A, Tokuyama T, Tsukaguchi K, et al. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 1997; 112:505-10.
28. Senior RM, Griffin GL, Mecham RP. Chemotactic activity of elastin-derived peptides. J Clin Invest 1980; 66:859-62.
29. Heise CE, O'Dowd BF, Figueroa DJ, Sawyer N, Nguyen T, Im DS, et al. Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000; 275:30531-6.
30. de Godoy I, Donahoe M, Calhoun WJ, Mancino J, Rogers RM. Elevated TNF-alpha production by peripheral blood monocytes of weight-losing COPD patients. Am J Respir Crit Care Med 1996; 153:633-7.
31. Capelli A, Di Stefano A, Gnemmi I, Balbo P, Cerutti CG, Balbi B, et al. Increased MCP-1 and MIP-1beta in bronchoalveolar lavage fluid of chronic bronchitics. Eur Respir J 1999; 14:160-5.
32. Hoshi H, Ohno I, Honma M, Tanno Y, Yamauchi K, Tamura G, et al. IL-5, IL-8 and GM-CSF immunostaining of sputum cells in bronchial asthma and chronic bronchitis. Clin Exp Allergy 1995; 25:720-8.
33. Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, et al. Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 1997; 156:591-9.
34. de Boer WI, van Schadewijk A, Sont JK, Sharma HS, Stolk J, Hiemstra PS, et al. Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158:1951-7.
35. Chalmers GW, Macleod KJ, Sriram S, Thomson LJ, McSharry C, Stack BH, et al. Sputum endothelin-1 is increased in cystic fibrosis and chronic obstructive pulmonary disease. Eur Respir J 1999; 13:1288-92.
36. Fujii T, Otsuka T, Tanaka S, Kanazawa H, Hirata K, Kohno M, et al. Plasma endothelin-1 level in chronic obstructive pulmonary disease: relationship with natriuretic peptide. Respiration 1999; 66:212-9.
37. Tomaki M, Ichinose M, Miura M, Hirayama Y, Yamauchi H, Nakajima N, et al. Elevated substance P content in induced sputum from patients with asthma and patients with chronic bronchitis. Am J Respir Crit Care Med 1995; 151:613-7.
38. Lucchini RE, Facchini F, Turato G, Saetta M, Caramori G, Ciaccia A, et al. Increased VIP-positive nerve fibers in the mucous glands of subjects with chronic bronchitis. Am J Respir Crit Care Med 1997; 156:1963-8.
39. Chanez P, Springall D, Vignola AM, Moradoghi-Hattvani A, Polak JM, Godard P, et al. Bronchial mucosal immunoreactivity of sensory neuropeptides in severe airway diseases. Am J Respir Crit Care Med 1998; 158:985-90.
40. Metcalf JP, Thompson AB, Gossman GL, Nelson KJ, Koyama S, Rennard SI, et al. Gcglobulin functions as a cochemotaxin in the lower respiratory tract. A potential mechanism for lung neutrophil recruitment in cigarette smokers. Am Rev Respir Dis 1991; 143:844-9.
41. Wright JL, Lawson LM, Pare PD, Wiggs BJ, Kennedy S, Hogg JC. Morphology of peripheral airways in current smokers and ex-smokers. Am Rev Respir Dis 1983; 127:474-7.
42. Mullen JB, Wright JL, Wiggs BR, Pare PD, Hogg JC. Reassessment of inflammation of airways in chronic bronchitis. BMJ (Clin Res Ed) 1985; 291:1235-9.
43. Cosio M, Ghezzo H, Hogg JC, Corbin R, Loveland M, Dosman J, et al. The relations between structural changes in small airways and pulmonary-function tests. N Engl J Med 1978; 298:1277-81.
44. McLean KA. Pathogenesis of pulmonary emphysema. Am J Med 1958; 25:62-74.
45. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974; 291:755-8.
46. Auerbach O, Garfinkel L, Hammond EC. Relation of smoking and age to findings in lung parenchyma: a microscopic study. Chest 1974; 65:29-35.
47. Auerbach O, Hammond EC, Garfinkel L, Benante C. Relation of smoking and age to emphysema. Whole-lung section study. N Engl J Med 1972; 286:853-7.
48. Petty TL, Silvers GW, Stanford RE, Baird MD, Mitchell RS. Small airway pathology is related to increased closing capacity and abnormal slope of phase III in excised human lungs. Am Rev Respir Dis 1980; 121:449-56.
49. Ollerenshaw SL, Woolcock AJ. Characteristics of the inflammation in biopsies from large airways of subjects with asthma and subjects with chronic airflow limitation. Am Rev Respir Dis 1992; 145:922-7.
50. Gadek JE, Fells GA, Crystal RG. Cigarette smoking induces functional antiprotease deficiency in the lower respiratory tract of humans. Science 1979; 206:1315-6.
51. Stone PJ, Calore JD, McGowan SE, Bernardo J, Snider GL, Franzblau C. Functional alpha 1-protease inhibitor in the lower respiratory tract of cigarette smokers is not decreased. Science 1983; 221:1187-9.
52. Hunninghake GW, Crystal RG. Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis 1983; 128:833-8.
53. Mio T, Romberger DJ, Thompson AB, Robbins RA, Heires A, Rennard SI. Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells. Am J Respir Crit Care Med 1997; 155:1770-6.
54. Masubuchi T, Koyama S, Sato E, Takamizawa A, Kubo K, Sekiguchi M, et al. Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity. Am J Pathol 1998; 153:1903-12.
55. Speizer FE, Tager IB. Epidemiology of chronic mucus hypersecretion and obstructive airways disease. Epidemiol Rev 1979; 1:124-42.
56. Turato G, Di Stefano A, Maestrelli P, Mapp CE, Ruggieri MP, Roggeri A, et al. Effect of smoking cessation on airway inflammation in chronic bronchitis. Am J Respir Crit Care Med 1995; 152:1262-7.
57. . Li XY, Brown D, Smith S, MacNee W, Donaldson K. Short-term inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats Inhal Toxicol 1999; 11:709-31.
58. Monn C, Becker S. Cytotoxicity and induction of proinflammatory cytokines from human monocytes exposed to fine (PM2.5) and coarse particles (PM10-2.5) in outdoor and indoor air. Toxicol Appl Pharmacol1999; 155:245-52.
59. Salvi S, Blomberg A, Rudell B, Kelly F, Sandstrom T, Holgate ST, et al. Acute inflammatory responses in the airways and peripheral blood after short-term exposure to diesel exhaust in healthy human volunteers. Am J Respir Crit Care Med 1999; 159:702-9.
60. Von Essen SG, O'Neill DP, McGranaghan S, Olenchock SA, Rennard SI. Neutrophilic respiratory tract inflammation and peripheral blood neutrophilia after grain sorghum dust extract challenge. Chest 1995; 108:1425-33.
61. Von Essen SG, Robbins RA, Thompson AB, Ertl RF, Linder J, Rennard SI. Mechanisms of neutrophil recruitment to the lung by grain dust exposure [published erratum appears in Am Rev Respir Dis 1989; 139:1065]. Am Rev Respir Dis 1988; 138:921-7.
62. Laurell CB, Eriksson S. The electrophoretic alpha-1 globulin pattern of serum in alpha-1 antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15:132-40.
63. Carp H, Miller F, Hoidal JR, Janoff A. Potential mechanism of emphysema: alpha 1-proteinase inhibitor recovered from lungs of cigarette smokers contains oxidized methionine and has decreased elastase inhibitory capacity. Proc Natl Acad Sci U S A 1982; 79:2041-5.
64. Cohen AB, James HL. Reduction of the elastase inhibitory capacity of alpha 1-antitrypsin by peroxides in cigarette smoke: an analysis of brands and filters. Am Rev Respir Dis 1982; 126:25-30.
65. Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med 1994; 150:S160-4.
66. Sommerhoff CP, Nadel JA, Basbaum CB, Caughey GH. Neutrophil elastase and cathepsin G stimulate secretion from cultured bovine airway gland serous cells. J Clin Invest 1990; 85:682-9.
67. Witko-Sarsat V, Halbwachs-Mecarelli L, Schuster A, Nusbaum P, Ueki I, Canteloup S, et al. Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum. Am J Respir Cell Mol Biol 1999; 20:729-36.
68. Christensen TG, Korthy AL, Snider GL, Hayes JA. Irreversible bronchial goblet cell metaplasia in hamsters with elastase-induced panacinar emphysema. J Clin Invest 1977; 59:397-404.
69. Dekhuijzen PN, Aben KK, Dekker I, Aarts LP, Wielders PL, van Herwaarden CL, et al. Increased exhalation of hydrogen peroxide in patients with stable and unstable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 154:813-6.
70. Maziak W, Loukides S, Culpitt S, Sullivan P, Kharitonov SA, Barnes PJ. Exhaled nitric oxide in chronic obstructive pulmonary disease.Am J Respir Crit Care Med 1998; 157:998-1002.
71. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, et al. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 2000; 162:1175-7.
72. Pratico D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald GA. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 1998; 158:1709-14.
73. Kawikova I, Barnes PJ, Takahashi T, Tadjkarimi S, Yacoub MH, Belvisi MG. 8-Epi-PGF2 alpha, a novel noncyclooxygenase-derived prostaglandin, constricts airways in vitro. Am J Respir Crit Care Med 1996; 153:590-6.
74. Ciba Guest Symposium Report. Terminiology, definitions and classifications of chronic pulmonary emphysema and related conditions. Thorax 1959; 14:286-99.
75. Pride NB, Burrows B. Development of impaired lung function: natural history and risk factors. In: Calverley PM, Pride NB, eds. Chronic obstructive lung disease. London and Glasgow: Chapman and Hall Medical; 1995. p. 69-71.
76. Saetta M, Di Stefano A, Maestrelli P, Ferraresso A, Drigo R, Potena A, et al. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis 1993; 147:301-6.
77. Reid L. Measurement of the bronchial mucous gland layer: a diagnostic yardstick in chronic bronchitis. Thorax 1960; 15:132-41.
78. Jamal K, Cooney TP, Fleetham JA, Thurlbeck WM. Chronic bronchitis. Correlation of morphologic findings to sputum production and flow rates. Am Rev Respir Dis 1984; 129:719-22.
79. Haraguchi M, Shimura S, Shirato K. Morphometric analysis of bronchial cartilage in chronic obstructive pulmonary disease and bronchial asthma.Am J Respir Crit Care Med 1999; 159:1005-13.
80. Thurlbeck WM, Pun R, Toth J, Frazer RG. Bronchial cartilage in chronic obstructive lung disease. Am Rev Respir Dis 1974; 109:73-80.
81. Snider GL. Parker B. Francis Lecture. Animal models of chronic airways injury. Chest 1992; 101:74-9S.
82. Snider GL, Faling LJ, Rennard SI. Chronic bronchitis and emphysema. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders; 2000. p. 1187-246.
83. Rogers DF, Jeffery PK. Inhibition by oral N-acetylcysteine of cigarette smoke-induced "bronchitis" in the rat. Exp Lung Res 1986; 10:267-83.
84. Nakamura Y, Romberger DJ, Tate L, Ertl RF, Kawamoto M, Adachi Y, et al. Cigarette smoke inhibits lung fibroblast proliferation and chemotaxis. Am J Respir Crit Care Med 1995; 151:1497-503.
85. Osman M, Cantor JO, Roffman S, Keller S, Turino GM, Mandl I. Cigarette smoke impairs elastin resynthesis in lungs of hamsters with elastase-induced emphysema. Am Rev Respir Dis 1985; 132:640-3.
86. Laurent P, Janoff A, Kagan HM. Cigarette smoke blocks cross-linking of elastin in vitro. Chest 1983; 83:63-5S.
87. Matsuba K, Thurlbeck WM. The number and dimensions of small airways in emphysematous lungs. Am J Pathol 1972; 67:265-75.
88. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968; 278:1355-60.
89. Rennard SI. Inflammation and repair processes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:S12-6.
90. Leopold JG, Goeff J. Centrilobular form of hypertrophic emphysema and its relation to chronic bronchitis. Thorax 1957; 12:219-35.
91. Repine JE, Bast A, Lankhorst I. Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Respir Crit Care Med 1997; 156:341-57.
92. Wright JL, Lawson L, Pare PD, Hooper RO, Peretz DI, Nelems JM, et al. The structure and function of the pulmonary vasculature in mild chronic obstructive pulmonary disease. The effect of oxygen and exercise. Am Rev Respir Dis 1983; 128:702-7.
93. Sekhon HS, Wright JL, Churg A. Cigarette smoke causes rapid cell proliferation in small airways and associated pulmonary arteries. Am J Physiol 1994; 267:L557-63.
94. Peinado VI, Barbera JA, Ramirez J, Gomez FP, Roca J, Jover L, et al. Endothelial dysfunction in pulmonary arteries of patients with mild COPD. Am J Physiol 1998; 274:L908-13.
95. Riley DJ, Thakker-Varia S, Poiani GJ, Tozzi CA. Vascular remodeling. In: Crystal RG, West JB, Barnes PJ, Weibel ER, eds. The lung: scientific foundations. Philadelphia: Lippincott-Raven; 1977. p. 1589-97.
96. Kuwano K, Bosken CH, Pare PD, Bai TR, Wiggs BR, Hogg JC. Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993; 148:1220-5.
97. Matsuba K, Wright JL, Wiggs BR, Pare PD, Hogg JC. The changes in airways structure associated with reduced forced expiratory volume in one second. Eur Respir J 1989; 2:834-9.
98. Dayman H. Mechanics of airflow in health and emphysema. J Clin Invest 1951; 30:1175-90.
99. Butler J, Caro C, Alkaler R, Dubois AB. Physiological factors affecting airway resistance in normal subjects and in patients with obstructive airways disease. J Clin Invest 1960; 39:584-91.
100. Mead J, Turner JM, Macklem PT, Little JB. Significance of the relationship between lung recoil and maximum expiratory flow. J Appl Physiol 1967; 22:95-108.
101. Burnett D, Stockley RA. Serum and sputum alpha 2 macroglobulin in patients with chronic obstructive airways disease. Thorax 1981; 36:512-6.
102. Lane DJ, Howell JB, Giblin B. Relation between airways obstruction and CO2 tension in chronic obstructive airways disease. BMJ 1968; 3:707-9.
103. Rodriguez-Roisin R, MacNee W. Pathophysiology of chronic obstructive pulmonary disease. In: Postma DS, Siafakas NM, eds. Management of chronic obstructive pulmonary disease. European Respiratory Monograph 1998; 3:107-26.
104. McLean A, Warren PM, Gillooly M, MacNee W, Lamb D. Microscopic and macroscopic measurements of emphysema: relation to carbon monoxide gas transfer. Thorax 1992; 47:144-9.
105. Barbera JA, Riverola A, Roca J, Ramirez J, Wagner PD, Ros D, et al. Pulmonary vascular abnormalities and ventilation-perfusion relationships in mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994; 149:423-9.
106. MacNee W. Pathophysiology of cor pulmonale in chronic obstructive pulmonary disease. Part two. Am J Respir Crit Care Med 1994; 150:1158-68.
107. Knighton DR, Hunt TK, Scheuenstuhl H, Halliday BJ, Werb Z, Banda MJ. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science 1983; 221:1283-5.
108. Biernacki W, Flenley DC, Muir AL, MacNee W. Pulmonary hypertension and right ventricular function in patients with COPD. Chest 1988; 94:1169-75.
109. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996; 154:1055-60.
110. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996; 51:819-24.
111. Sauleda J, Garcia-Palmer FJ, Gonzalez G, Palou A, Agusti AG. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000; 161:32-5.
112. Sauleda J, Garcia-Palmer F, Wiesner RJ, Tarraga S, Harting I, Tomas P, et al. Cytochrome oxidase activity and mitochondrial gene expression in skeletal muscle of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1413-7.
113. American Thoracic Society and European Respiratory Society. Skeletal muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:S1-40.
114. Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1791-7.
115. Pizzichini MM, Pizzichini E, Efthimiadis A, Clelland L, Mahony JB, Dolovich J, et al. Markers of inflammation in induced sputum in acute bronchitis caused by Chlamydia pneumoniae. Thorax 1997; 52:929-31; discussion 6-7.
116. Pizzichini E, Pizzichini MM, Gibson P, Parameswaran K, Gleich GJ, Berman L, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med 1998; 158:1511-7.
117. Maestrelli P, Saetta M, Di Stefano A, Calcagni PG, Turato G, Ruggieri MP, et al. Comparison of leukocyte counts in sputum, bronchial biopsies, and bronchoalveolar lavage. Am J Respir Crit Care Med 1995; 152:1926-31.
118. Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave FE. Exacerbations of asthma without sputum eosinophilia. Thorax 1995; 50:1057-61.
119. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputum from subjects with asthma exacerbation. J Allergy Clin Immunol 1995; 95:843-52.
120. Barbera JA, Roca J, Ferrer A, Felez MA, Diaz O, Roger N, et al. Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1997; 10:1285-91.
121. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1608-13.
122. Schmidt GA, Hall JB. Acute or chronic respiratory failure. Assessment and management of patients with COPD in the emergency setting. JAMA 1989; 261:3444-53.
     123.Rodriguez-Roisin R. Pulmonary gas exchange in acute respiratory failure. Eur J Anaesthesiol 1994; 11:5-13.

     Top

INTRODUCTION

Management of Mild to Moderate COPD (Stages I and II) involves the avoidance of risk factors to prevent disease progression and pharmacotherapy as needed to control symptoms. Severe disease (Stage III) often requires the integration of several different disciplines, a variety of treatment approaches, and a commitment of the clinician to the continued support of the patient as the illness progresses. In addition to patient education, health advice, and pharmacotherapy, COPD patients may require specific counseling about smoking cessation, instruction in physical exercise, nutritional advice, and continued nursing support. Not all approaches are needed for every patient, and assessing the potential benefit of each approach at each stage of the illness is a crucial aspect of effective disease management.

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

While disease prevention is the ultimate goal, once COPD has been diagnosed, effective management should be aimed at the following goals:

• 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 minimal side effects from treatment, a particular challenge in COPD patients because they commonly have co-morbidities. 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 individual, his or her family, and the community must be considered.

Patients should be identified as early in the course of the disease as possible, and certainly before the end stage of the illness when disability is substantial. However, the benefits of community-based 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 non-pharmacologic, 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 status1,2. Appropriate treatment and measures to prevent further exacerbations should be implemented as quickly as possible.

Important differences exist between countries in the approach to chronic illnesses such as COPD and in the acceptability of particular forms of therapy. Ethnic differences in drug metabolism, especially for oral medications, may result in different patient preferences in different communities. Little is known about these important issues in relationship to COPD.

References

1. O'Brien C, Guest PJ, Hill SL, Stockley RA. Physiological and radiological characterization of patients diagnosed with chronic obstructive pulmonary disease in primary care. Thorax 2000; 55:635-42.
2. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time cour
3. se and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161:1608-13.

   Top

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 post-bronchodilator FEV1 < 80% predicted confirms the presence of airflow limitation that is not fully reversible.
• Health care workers involved in the diagnosis and management of COPD patients 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.

INITIAL DIAGNOSIS

A diagnosis of COPD should be considered in any patient who has cough, sputum production, or dyspnea, and/or a history of exposure to risk factors for the disease (Figure 5-1-1). The diagnosis is confirmed by spirometry. The presence of a post-bronchodilator 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 since 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.

Assessment of Symptoms

Although exceptions occur, the general patterns of symptom development in COPD are well established. The main symptoms among patients in Stage 0: At Risk and Stage I: Mild COPD are chronic cough and sputum production. These symptoms can be present for many years before the development of airflow limitation and are often ignored or discounted by patients. As airflow limitation develops in Stage II: Moderate COPD, patients often experience dyspnea, which may interfere with their daily activities. Typically, this is the stage at which they seek medical attention and are diagnosed with COPD. However, some patients do not experience cough, sputum production, or dyspnea in Stage I: Mild COPD or Stage II: Moderate COPD, and do not come to medical attention until their airflow limitation becomes more severe or their lung function is worsened acutely by a respiratory tract infection. As airflow limitation worsens and the patient enters Stage III: Severe COPD, the symptoms of cough and sputum production typically continue, dyspnea worsens, and additional symptoms heralding complications may develop. It is important to note that, since COPD may be diagnosed at any stage, any of the symptoms described below may be present in a patient presenting for the first time.

Cough: Chronic cough, usually the first symptom of COPD to develop1, is often discounted by the patient as an expected consequence of smoking and/or environmental exposures. Initially, the cough may be intermittent, but later is present every day, often throughout the day, and is seldom entirely nocturnal. The chronic cough in COPD may be unproductive2. In some cases, significant airflow limitation may develop without the presence of a cough. Figure 5-1-2 lists some of the other causes of chronic cough in individuals with a normal chest X-ray.

Sputum production. COPD patients commonly raise small quantities of tenacious sputum after coughing bouts. Regular production of sputum for 3 or more months in 2 consecutive years is the epidemiological definition of chronic bronchitis3, but this is a somewhat arbitrary definition that does not reflect the range of sputum production in COPD patients. Sputum production is often difficult to evaluate because patients may swallow sputum rather than expectorate it, a habit subject to significant cultural and gender variation.

Dyspnea. Dyspnea, the hallmark symptom of COPD, is the reason most patients seek medical attention and is a major cause of disability and anxiety associated with the disease. Typical COPD patients describe their dyspnea as a sense of increased effort to breathe, heaviness, air hunger, or gasping4. The terms used to describe dyspnea vary both by individual and by culture5. It is often possible to distinguish the breathlessness of COPD from that due to other causes by analysis of the terms used, although there is considerable overlap with descriptors of bronchial asthma. A simple way to quantify the impact of breathlessness on a patient’s health status is the British Medical Research Council (MRC) questionnaire (Figure 5-1-3). This questionnaire relates well to other measures of health status6.

Breathlessness in COPD is characteristically persistent and progressive. Even on "good days" COPD patients experience dyspnea at lower levels of exercise than unaffected people of the same age. Initially, breathlessness is only noted on unusual effort (e.g., walking or running up a flight of stairs) and may be avoided entirely by appropriate behavioral change (e.g., using an elevator). As lung function deteriorates, breathlessness becomes more intrusive, and patients may notice that they are unable to walk at the same speed as other people of the same age or carry out activities that require use of the accessory respiratory muscles (e.g., carrying grocery bags)7. Eventually, breathlessness is present during everyday activities (e.g., dressing, washing) or at rest, leaving the patient confined to the home.

Wheezing and chest tightness. Wheezing and chest tightness are relatively non-specific symptoms that may vary between days, and over the course of a single day. These symptoms may be present in Stage I: Mild COPD, but are more characteristic of asthma or Stage III: Severe COPD. Audible wheeze may arise at a laryngeal level and need not be accompanied by auscultatory abnormalities. Alternatively, widespread inspiratory or expiratory wheezes can be present on listening to the chest. Chest tightness often follows exertion, is poorly localized, is muscular in character, and may arise from isometric contraction of the intercostal muscles. An absence of wheezing or chest tightness does not exclude a diagnosis of COPD.

Additional symptoms in severe disease. Weight loss and anorexia are common problems in advanced COPD8. Hemoptysis can occur during respiratory tract infections in COPD patients9. However, this can be a sign of other diseases (e.g., tuberculosis, bronchial tumors) and therefore should always be investigated. Cough syncope occurs due to rapid increases in intrathoracic pressure during attacks of coughing. Coughing spells may also cause rib fractures, which are sometimes asymptomatic. Psychiatric morbidity, especially symptoms of depression and/or anxiety, is common in advanced COPD10. Ankle swelling can be the only symptomatic pointer to the development of cor pulmonale.

Medical History

A detailed medical history of a new patient known or thought to have COPD should assess:

• Patient’s exposure to risk factors: such as smoking and occupational or environmental exposures.
• Past medical history: including asthma, allergy, sinusitis or nasal polyps, respiratory infections in childhood, other respiratory diseases.
• Family history of COPD or other chronic respiratory disease.
• Pattern of symptom development: COPD typically develops in adult life and most patients are conscious of increased breathlessness, more frequent "winter colds," and some social restriction for a number of years before seeking medical help.
• History of exacerbations or previous hospitalizations for respiratory disorder: Patients may be aware of periodic worsening of symptoms even if these episodes have not been identified as acute exacerbations of COPD.
• Presence of co-morbidities: such as heart disease and rheumatic disease, which may also contribute to restriction of activity.
• Appropriateness of current medical treatments: For example, beta-blockers commonly prescribed for heart disease are usually contraindicated in COPD.
• Impact of disease on patient’s life: including limitation of activity; missed work and economic impact; effect on family routines; feelings of depression or anxiety.
• Social and family support available to the patient.
• Possibilities for reducing risk factors, especially smoking cessation.

Physical Examination

Though an important part of patient care, a physical examination is rarely diagnostic in COPD. Physical signs of airflow limitation are usually not present until significant impairment of lung function has occurred11,12, and their detection has a relatively low sensitivity and specificity. A number of physical signs may be present in COPD, but their absence does not exclude the diagnosis.

Inspection.

• Central cyanosis, or bluish discoloration of the mucosal membranes, may be present but is difficult to detect in artificial light and in many racial groups.
• Common chest wall abnormalities, which reflect the pulmonary hyperinflation seen in COPD, include relatively horizontal ribs, "barrel- shaped" chest, and protruding abdomen.
• Flattening of the hemi-diaphragms may be associated with paradoxical in-drawing of the lower rib cage on inspiration, reduced cardiac dullness, and widening xiphisternal angle.
• Resting respiratory rate is often increased to more than 20 breaths per minute and breathing can be relatively shallow12.
• Patients commonly show pursed-lip breathing, which may serve to slow expiratory flow and permit more efficient lung emptying.
• COPD patients often have resting muscle activation while lying supine. Use of the scalene and sternocleidomastoid muscles is a further indicator of respiratory distress.
• Ankle or lower leg edema can be a sign of right heart failure.

Palpation and percussion.

• These are often unhelpful in COPD.
• Detection of the heart apex beat may be difficult due to pulmonary hyperinflation.
• Hyperinflation also leads to downward displacement of the liver and an increase in the ability to palpate this organ without it being enlarged.

Auscultation.

• Patients with COPD often have reduced breath sounds, but this finding is not sufficiently characteristic to make the diagnosis13.
• The presence of wheezing during quiet breathing is a useful pointer to airflow limitation. However, wheezing heard only after forced expiration is of no diagnostic value.
• Inspiratory crackles occur in some COPD patients but are of little help diagnostically.
• Heart sounds are best heard over the xiphoid area. Measurement of Airflow Limitation (Spirometry)

Measurement of Airflow Limitation (Spirometry)

Spirometry measurements should be undertaken for any patient who may have COPD. To help identify individuals earlier in the course of the disease, spirometry should be performed for patients who have chronic cough and sputum production even if they do not have dyspnea. Although spirometry does not fully capture the impact of COPD on a patient’s health, it remains the gold standard for diagnosing the disease and monitoring its progression. It is the best standardized, most reproducible, and most objective measurement of airflow limitation available. Health care workers who care for COPD patients should have access to spirometry, which is useful in both diagnosis and periodic monitoring. Figure 5-1-4 summarizes some considerations that are crucial to achieving consistently accurate test results.

Spirometry should measure the maximal volume of air forcibly exhaled from the point of maximal inspiration (forced vital capacity, FVC) and the volume of air exhaled during the first second of this maneuver (forced expiratory volume in one second, FEV1), and the ratio of these two measurements (FEV1/FVC) should be calculated. Spirometry measurements are evaluated by comparison with reference values based on age, height, sex, and race (use appropriate reference values, e.g., see reference 14).

Figure 5-1-5 shows a normal spirogram and a spirogram typical of patients with mild to moderate COPD. Patients with COPD typically show a decrease in both FEV1 and FVC. The degree of spirometric abnormality generally reflects the severity of COPD (Figure 1-2). The presence of a post-bronchodilator FEV1 < 80% of the predicted value in combination with an FEV1/FVC < 70% confirms the presence of airflow limitation that is not fully reversible. The FEV1/FVC on its own is a more sensitive measure of airflow limitation, and an FEV1/FVC < 70% is considered an early sign of airflow limitation in patients whose FEV1 remains normal ( 80% predicted). This approach to defining airflow limitation is a pragmatic one in view of the fact that universally applicable reference values for FEV1 and FVC are not available.

Peak expiratory flow (PEF) is sometimes used as a measure of airflow limitation, but in COPD the relationship between PEF and FEV1 is poor. PEF may underestimate the degree of airways obstruction in these patients15. If spirometry is unavailable, prolongation of the forced expiratory time beyond 6 seconds is a crude, but useful, guide to the presence of an FEV1/FVC ratio < 50%16,17.
The role of screening spirometry in the general population or in a population at risk for COPD is controversial. Both FEV1 and FVC predict all-cause mortality independent of tobacco smoking, and abnormal lung function identifies a subgroup of smokers at increased risk for lung cancer. This has been the basis of an argument that screening spirometry should be employed as a global health assessment tool18.

However, there are no data to indicate that screening spirometry is effective in directing management decisions or in improving COPD outcomes.

Assessment of Severity

Assessment of COPD severity is based on the patient’s level of symptoms, the severity of the spirometric abnormality, and the presence of complications such as respiratory failure and right heart failure (Figure 1-2). The use of specific spirometric cut-points (e.g., FEV1 80% predicted) to define different stages of COPD is for purposes of simplicity; these cut-points have not been clinically validated and may underestimate the prevalence of COPD in some groups, such as the elderly.

Although the presence of airflow limitation is key to the current understanding of COPD, it may be valuable from a public health perspective to identify individuals at risk for the disease before significant airflow limitation develops (Stage 0, At Risk). A majority of people with early COPD identified in large studies complained of at least one respiratory symptom, such as cough, sputum production, wheezing, or breathlessness19,20. These symptoms may be present at a time of relatively minor or even no spirometric abnormality. While not all individuals with such symptoms will go on to develop COPD21, the presence of these symptoms should help define a high-risk population that should be targeted for preventive intervention. Much depends on the success of convincing such people, as well as health care workers, that minor respiratory symptoms may be markers of future ill health.

The severity of a patient’s breathlessness is important and can be gauged by the MRC scale (Figure 5-1-3). Arterial blood gases should be measured in all patients who have FEV1 < 40% predicted or clinical signs of respiratory failure or right heart failure.

Additional Investigations

For patients diagnosed with Stage II: Moderate COPD and beyond, the following additional investigations may be useful.

Bronchodilator reversibility testing. Generally performed only once, at the time of diagnosis, this test is useful for several reasons:

• To help rule out a diagnosis of asthma. If FEV1 returns to the predicted normal range after administration of a bronchodilator, the patient’s airflow limitation is likely due to asthma.
• To establish a patient’s best attainable lung function at that point in time.
• To gauge a patient’s prognosis. Some studies show that the post-bronchodilator FEV1 is a more reliable prognostic marker than pre-bronchodilator FEV122. In addition, the Intermittent Positive Pressure Breathing (IPPB) Study, a multicenter clinical trial, suggested that the degree of bronchodilator response is inversely related to the rate of FEV1 decline in COPD patients23.
• To assess potential response to treatment. Patients who show significant improvement in FEV1 after administration of a bronchodilator are more likely to benefit from treatment with bronchodilators and have a positive response to glucocorticosteroids. However, individual responses to bronchodilator tests are influenced by many factors, and failure of FEV1 to change by an arbitrary amount on one day does not preclude a response on another. Moreover, even patients who do not show a significant FEV1 response to a short-acting bronchodilator test may benefit symptomatically from long-term bronchodilator therapy.

Between-day reproducibility of spirometry in the same individual is approximately 178 ml24. Thus, an acute change that exceeds both 200 ml and 12% of the base line measurement is unlikely to have arisen by chance. A protocol for bronchodilator reversibility testing is listed in Figure 5-1-6.

Glucocorticosteroid reversibility testing. Long-term glucocorticosteroid treatment in COPD can at present only be justified in patients with a consistent, significant FEV1 response to glucocorticosteroids, or in those with repeated exacerbations. The simplest, and potentially safest, way to identify these patients is by a treatment trial with inhaled glucocorticosteroids for 6 weeks to 3 months, using as criteria for glucocorticosteroid reversibility an FEV1 increase of 200 ml and 15% above baseline25,26. The response to glucocorticosteroids should be evaluated with respect to the post-bronchodilator FEV1 (i.e., the effect of treatment with inhaled glucocortico-steroids should be in addition to that of regular treatment with a bronchodilator). Where treatment with glucocorticosteroids is restricted for economic reasons to patients with a substantial spirometric response, a trial of oral glucocorticosteroid therapy may help select those with the largest response. However, prolonged oral glucocorticosteroid treatment beyond 2 weeks is NOT recommended in clinically stable patients.

Chest X-ray. A chest X-ray is seldom diagnostic in COPD unless obvious bullous disease is present, but it is valuable in excluding alternative diagnoses. Radiological changes associated with COPD include signs of hyperinflation (flattened diaphragm on the lateral chest film, and an increase in the volume of the retrosternal air space), hyperlucency of the lungs, and rapid tapering of the vascular markings. Computed tomography (CT) of the chest is not routinely recommended. However, when there is doubt about the diagnosis of COPD, high resolution CT (HRCT) might help in the differential diagnosis. In addition, if a surgical procedure such as bullectomy or lung volume reduction is contemplated, chest CT is helpful.

Arterial blood gas measurement. In advanced COPD measurement of arterial blood gases is important. This test should be performed in patients with FEV1 < 40% predicted or with clinical signs suggestive of respiratory failure or right heart failure.

Alpha-1 antitrypsin deficiency screening. In patients who develop COPD at a young age (< 45 years) or who have a strong family history of the disease, it may be valuable to identify coexisting alpha-1 antitrypsin deficiency. This could lead to family screening or appropriate counseling. A serum concentration of alpha-1 antitrypsin below 15-20 % of the normal value is highly suggestive of homozygous alpha-1 antitrypsin deficiency.

Differential Diagnosis

A major differential diagnosis is asthma. In some patients with chronic asthma, a clear distinction from COPD is not possible using current imaging and physiological testing techniques, and it is assumed that asthma and COPD coexist in these patients. In these cases, current management is similar to that of asthma. Other potential diagnoses are usually easier to distinguish from COPD.

ONGOING MONITORING AND ASSESSMENT

Visits to health care facilities will increase in frequency as COPD progresses. The type of health care workers seen, and the frequency of visits, will depend on the health care system. Ongoing monitoring and assessment in COPD ensures that the goals of treatment are being met and should include evaluation of: (1) exposure to risk factors, especially tobacco smoke; (2) disease progression and development of complications; (3) pharmacotherapy and other medical treatment; (4) exacerbation history; (5) co-morbidities. Suggested questions for follow-up visits are listed in Figure 5-1-8. The best way to detect changes in symptoms and overall health status is to ask the same questions at each visit.

Monitor Disease Progression and Development of Complications

COPD is usually a progressive disease. 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 to determine when to modify therapy and to identify any complications that may develop. As at the initial assessment, follow-up visits should include a physical examination and discussion of symptoms, particularly any new or worsening symptoms.

Pulmonary function. A patient’s decline in lung function is best tracked by periodic spirometry measurements. Useful information about lung function decline is unlikely from spirometry measurements performed more than once a year. Spirometry should be performed if there is a substantial increase in symptoms or a complication.

Other pulmonary function tests, such as flow-volume loops, diffusing capacity (DLCO) measurements, and measurement of lung volumes are not needed in a routine assessment but can provide information about the overall impact of the disease and can be valuable in resolving diagnostic uncertainties and assessing patients for surgery.

Arterial blood gas measurement. Measurement of arterial blood gas tensions should be performed in all patients with FEV1 < 40% predicted or when clinical signs of respiratory failure or right heart failure are present. Respiratory failure is indicated by a PaO2 < 8.0 kPa (60 mm Hg) with or without PaCO2 > 6.0 kPa (45 mm Hg) in arterial blood gas measurements made while breathing air at sea level.

Screening patients by pulse oximetry and assessing arterial blood gases in those with an oxygen saturation (SaO2) < 92% may be a useful way of selecting patients for arterial blood gas measurement27. However, pulse oximetry gives no information about CO2 tensions.

Several considerations are important to ensure accurate test results. Oxygen pressure in the inspired air (FiO2) should be measured, taking note if patient is using an O2-driven nebulizer. Changes in arterial blood gas tensions take time to occur, especially in severe disease. Thus, 20-30 minutes should pass before rechecking the gas tensions when the FiO2 has been changed.
Adequate pressure must be applied at the puncture site for at least one minute; failure to do so can lead to painful bruising.

Clinical signs of respiratory failure or right heart failure include central cyanosis, ankle swelling, and an increase in the jugular venous pressure. Clinical signs of hypercapnia are extremely nonspecific outside of acute exacerbations.

Assessment of pulmonary hemodynamics. Pulmonary hypertension is only likely to be important in patients who have developed respiratory failure. 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 PaO2.

Diagnosis of right heart failure or cor pulmonale. Elevation of the jugular venous pressure and the presence of pitting ankle edema are often the most useful findings suggestive of cor pulmonale in clinical practice. However, the jugular venous pressure is often difficult to assess in patients with COPD, due to large swings in intrathoracic pressure. Firm diagnosis of cor pulmonale can be made through a number of investigations, including radiography, electrocardiography, echocardiography, radionucleotide scintigraphy, and magnetic resonance imaging. However, all of these measures involve inherent inaccuracies of diagnosis.

CT and ventilation-perfusion scanning. Despite the benefits of being able to delineate pathological anatomy, routine CT and ventilation-perfusion scanning are currently confined to the assessment of COPD patients for surgery. HRCT is currently under investigation as a way of visualizing airway and parenchymal pathology more precisely.

Hematocrit. Polycythemia can develop in the presence of arterial hypoxemia, especially in continuing smokers28. Polycythemia can be identified by hematocrit > 55%.

Respiratory muscle function. Respiratory muscle function is usually measured by recording the maximum inspiratory and expiratory mouth pressures. More complex measurements are confined to research laboratories. Measurement of expiratory muscle force is useful in assessing patients when dyspnea or hypercapnia is not readily explained by lung function testing or when peripheral muscle weakness is suspected. This measurement may improve in COPD patients when other measurements of lung mechanics do not (e.g., after pulmonary rehabilitation)29,30.

Sleep studies. Sleep studies may be indicated when hypoxemia or right heart failure develops in the presence of relatively mild airflow limitation or when the patient has symptoms suggesting the presence of sleep apnea.

Exercise testing. Several types of tests are available to measure exercise capacity, but these are primarily used in conjunction with pulmonary rehabilitation programs.

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

During periodic assessments, health care workers should question the patient and evaluate any records of exacerbations, both self-treated and those treated by other health care providers. 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. Specific inquiry into unscheduled visits to providers, telephone calls for assistance, and use of urgent or emergency care facilities may be helpful. 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 incubation. The clinician then can request summaries of all care received to facilitate continuity of care.

Monitor Co-morbidities
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, ECG, etc.) should be used whenever symptoms (e.g., hemoptysis) suggest one of these conditions.

REFERENCES

1. Georgopoulos D, Anthonisen NR. Symptoms and signs of COPD. In: Cherniack NS, ed. Chronic obstructive pulmonary disease. Toronto: WB Saunders; 1991. p. 357-63.
2. Burrows B, Niden AH, Barclay WR, Kasik JE. Chronic obstructive lung disease II. Relationships of clinical and physiological findings to the severity of airways obstruction. Am Rev Respir Dis 1965; 91:665-78.
3. Medical Research Council. Definition and classification of chronic bronchitis for clinical and epidemiological purposes: a report to the Medical Research Council by their Committee on the etiology of Chronic Bronchitis. Lancet 1965; 1: 775-80.
4. Simon PM, Schwartstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009-14.
5. Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz A. The language of breathlessness. Use of verbal descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 1991; 144:826-32.
6. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54:581-6.
7. Celli BR, Rassulo J, Make BJ. Dyssynchronous breathing during arm but not leg exercise in patients with chronic airflow obstruction. N Engl J Med 1986; 314:1485-90.
8. Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993; 147:1151-6.
9. Johnston RN, Lockhart W, Ritchie RT, Smith DH. Haemoptysis. BMJ 1960; 1:592-5.
10. Calverley PM. Neuropsychological deficits in chronic obstructive pulmonary disease. Monaldi Archives for Chest Disease 1996; 51:5-6.
11. Kesten S, Chapman KR. Physician perceptions and management of COPD. Chest 1993; 104:254-8.
12. Loveridge B, West P, Kryger MH, Anthonisen NR. Alteration of breathing pattern with progression of chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 134:930-4.
13. Badgett RC, Tanaka DV, Hunt DK, Jelley MJ, Feinberg LE, Steiner JF, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by history and physical findings alone? Am J Med 1993; 94:188-96.
14. Standardization of spirometry, 1994 update. American Thoracic Society. Am J Respir Crit Care Med 1995; 152:1107-36.
15. Kelly CA, Gibson GJ. Relation between FEV1 and peak expiratory flow in patients with chronic obstructive pulmonary disease. Thorax 1988; 43:335-6.
16. Lal S, Ferguson AD, Campbell EJM. Forced expiratory time; a simple test for airways obstruction. BMJ 1964; 1:814-7.
17. Swanney MP, Jensen RL, Crichton DA, Beckert LE, Cardno LA, Crapo RO. FEV(6) is an acceptable surrogate for FVC in the spirometric diagnosis of airway obstruction and restriction. Am J Respir Crit Care Med 2000; 162:917-9.
18. Ferguson GT, Enright PL, Buist AS, Higgins MW. Office spirometry for lung health assessment in adults: a consensus statement from the national lung health education program. Chest 2000; 117:1146-61.
19. Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med 1999; 106:410-6.
20. Lofdahl CG, Postma DS, Laitinen LA, Ohlsson SV, Pauwels RA, Pride NB. The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): recruitment methods and strategies. Respir Med 1998; 92:467-72.
21. Peto R, Speizer FE, Cochrane AL, Moore F, fletcher CM, Tinker CM, et al. The relevance in adults of airflow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease: results from twenty years of prospective observation. Am Rev Respir Dis 1983; 128:491-500.
22. Hansen EF, Phanareth K, Laursen LC, KokJensen A, Dirksen A. Reversible and irreversible airflow obstruction as predictor of overall mortality in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:1267-71.
23. Anthonisen NR, Wright EC. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 133:814-9.
24. Sourk RL, Nugent KM. Bronchodilator testing: confidence intervals derived from placebo inhalations. Am Rev Respir Dis 1983; 128:153-7.
25. Reis AL. Response to bronchodilators. In: Clausen J, ed. Pulmonary function testing: guidelines and controversies. New York: Academic Press; 1982. p. 215-221.
26. American Thoracic Society-Lung function testing: selection of reference values and interpretative strategies. Am Rev Respir Dis 1991; 144:1202-18.
27. Roberts CM, Bugler JR, Melchor R, Hetzel ML, Spiro SG. Value of pulse oximetry for long-term oxygen therapy requirement. Eur Respir J 1993; 6:559-62.
28. Calverley PM, Leggett RJ, McElderry L, Flenley DC. Cigarette smoking and secondary polycythemia in hypoxic cor pulmonale. Am Rev Respir Dis 1982; 125:507-10.
29. Dekhuijzen PNR, Folgering HT, van Herwaarden CLA. Target-flow inspiratory muscle training during pulmonary rehabilitation in patients with COPD. Chest 1991; 99:128-33.
30. Heijdra YF, Dekhuijzen PN, van Herwaarden CLA, Forlgering H. Nocturnal saturation improves by target-flow inspiratory muscle training in patients with COPD. Am J Respir Crit Care Med 1996; 153:260-5.

    Top

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 effective - and cost effective - way in most people to reduce the risk of developing COPD and stop its progression (Evidence A).
• Brief tobacco dependence counseling 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). S
• 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 (Evidence A).
• 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).

INTRODUCTION

Identification, reduction, and control of risk factors are important steps toward prevention and treatment of any disease. In the case of COPD, these factors include tobacco smoke, occupational exposures, and indoor and outdoor air pollution and irritants.

Since cigarette smoking is the major risk factor for COPD worldwide, smoking prevention programs should be implemented and smoking cessation programs should be readily available and encouraged for all individuals who smoke. Reduction of total personal exposure to occupational dust, fumes, and gases and to indoor and outdoor air pollutants is also an important goal to prevent the onset and progression of COPD1.

TOBACCO SMOKE

Smoking Prevention

Comprehensive tobacco control policies and programs with clear, consistent, and repeated nonsmoking messages should be delivered through every feasible channel, including health care providers, schools, and radio, television, and print media. National and local campaigns should be undertaken to reduce exposure to tobacco smoke in public forums. Legislation to establish smoke-free schools, public facilities, and work environments should be encouraged by government officials, public health workers, and the public. Smoking prevention programs should target all ages, including young children, adolescents, young adults, and pregnant women. Physicians and public health officials should encourage smoke-free homes.

The first exposure to cigarette smoke may begin in utero when the fetus is exposed to blood-borne metabolites from the mother2,3. Neonates and infants may be exposed passively to tobacco smoke in the home if a family member smokes. Children less than 2 years old who are passively exposed to cigarette smoke have an increased prevalence of respiratory infections, and are at a greater risk of developing chronic respiratory symptoms later in life4.

Smoking Cessation

Smoking cessation is the single most effective - and cost effective - way to reduce exposure to COPD risk factors. Quitting smoking can prevent or delay the development of airflow limitation or reduce its progression5. A statement by the WHO (Figure 5-2-1)6 emphasizes the health and economic benefits to be gained from smoking cessation. All smokers - including those who may be at risk for COPD as well as those who already have the disease - should be offered the most intensive smoking cessation intervention feasible.

Smoking cessation interventions are effective in both genders, in all racial and ethnic groups, and in pregnant women. Age influences quit rates, with young people less likely to quit, but nevertheless smoking cessation programs can be effective in all age groups.

International data on the economic impact of smoking cessation are strikingly consistent: investing resources in smoking cessation programs is cost effective in terms of medical costs per life year gained. Interventions that have been investigated include nicotine replacement with transdermal patch, counseling from physicians and other health professionals (with and without nicotine patch), self-help and group programs, and community-based stop-smoking contests. A review of data from a number of countries estimated the median societal cost of various smoking cessation interventions at $990 to $13,000 (US) per life year gained7. Smoking cessation programs are a particularly good value for the UK National Health Service, with costs from £212 to £873 (US $320 to $1,400) per life year gained8.

The role of health care providers in smoking cessation. A successful smoking cessation strategy requires a multifaceted approach, including public policy, information dissemination programs, and health education through the media and schools9. However, health care providers, including physicians, nurses, dentists, psychologists, pharmacists, and others, are key to the delivery of smoking cessation messages and interventions. Involving as many of these individuals as possible will help. Health care workers should encourage all patients who smoke to quit, even those patients who come to the health care provider for unrelated reasons and do not have symptoms of COPD or evidence of airflow limitation.

Guidelines for smoking cessation entitled Treating Tobacco Use and Dependence: A Clinical Practice Guideline were published by the US Public Health Service10. The major conclusions are summarized in Figure 5-2-2.

The Public Health Service Guidelines recommend a five-step program for intervention (Figure 5-2-3), which provides a strategic framework helpful to health care providers interested in helping their patients stop smoking10-13. The guidelines emphasize that tobacco dependence is a chronic disease (Figure 5-2-4)10 and urge clinicians to recognize that relapse is common and reflects the chronic nature of dependence, not failure on the part of the clinician or the patient.

Most individuals go through several stages before they stop smoking (Figure 5-2-5)9. It is often helpful for the clinician to assess a patient's readiness to quit in order to determine the most effective course of action at that time. The clinician should initiate treatment if the patient is ready to quit. For a patient not ready to make a quit attempt, the clinician should provide a brief intervention designed to promote the motivation to quit.

Counseling. Counseling delivered by physicians and other health professionals significantly increases quit rates over self-initiated strategies14. Even a brief (3-minute) period of counseling to urge a smoker to quit results in smoking cessation rates of 5-10%15. At the very least, this should be done for every smoker at every health care provider visit15,16.

However, there is a strong dose-response relationship between counseling intensity and cessation success17,18. Ways to make the treatment more intense include increasing the length of the treatment session, the number of treatment sessions, and the number of weeks over which the treatment is delivered. Counseling sessions of 3 to 10 minutes result in cessation rates of around 12%10. With more complex interventions (for example, controlled clinical trials that include skills training, problem solving, and psychosocial support), quit rates can reach 20-30%17. In one multicenter controlled clinical trial, a combination of physician advice, group support, skills training, and nicotine replacement therapy achieved a quit rate of 35% at one year and a sustained quit rate of 22% at 5 years5.

Both individual and group counseling are effective formats for smoking cessation. Several particular items of counseling content seem to be especially effective, including problem solving, general skills training, and provision of intra-treatment support. The important elements in the support aspect of successful treatment programs are shown in Figure 5-2-69,10. The common subjects covered in successful problem solving/skills training programs include:

• Recognition of danger signals likely to be associated with the risk of relapse, such as being around other smokers, being under time pressure, getting into an argument, drinking alcohol, and negative moods.
• Enhancement of skills needed to handle these situations, such as learning to anticipate and avoid a particular stress.
• Basic information about smoking and successful quitting, such as the nature and time course of withdrawal, the addictive nature of smoking, and the fact that any return to smoking, including even a single puff, increases the likelihood of a relapse.

Pharmacotherapy. Numerous effective pharmacotherapies for smoking cessation now exist9-11 (Evidence A), and pharmacotherapy is recommended when counseling is not sufficient to help patients quit smoking. Special consideration should be given before using pharmacotherapy in selected populations: people with medical contraindications, light smokers (fewer than 10 cigarettes/day), and pregnant and adolescent smokers.

Nicotine replacement products. Numerous studies indicate that nicotine replacement therapy in any form (nicotine gum, inhaler, nasal spray, transdermal patch, sublingual tablet, or lozenge) reliably increases long-term smoking abstinence rates10,19. Nicotine replacement therapy is more effective when combined with counseling and behavior therapy20, although nicotine patch or nicotine gum consistently increases smoking cessation rates regardless of the level of additional behavioral or psychosocial interventions. Medical contraindications to nicotine replacement therapy include unstable coronary artery disease, untreated peptic ulcer disease, and recent myocardial infarction or stroke9. Specific studies to date do not support the use of nicotine replacement therapy for longer than 8 weeks21, although some patients may require extended use to prevent relapse.

All forms of nicotine replacement therapy are significantly more effective than placebo. Every effort should be made to tailor the choice of replacement therapy to the individual's culture and lifestyle to improve adherence. The patch is generally favored over the gum because it requires less training for effective use and is associated with fewer compliance problems.
No data are available to help clinicians tailor nicotine patch regimens to the intensity of cigarette smoking. In all cases it seems generally appropriate to start with the higher dose patch. For most patches, which come in three different doses, patients should use the highest dose for the first four weeks and drop to progressively lower doses over an eight-week period. Where only two doses are available, the higher dose should be used for the first four weeks and the lower dose for the second four weeks.

When using nicotine gum, the patient needs to be advised that absorption occurs through the buccal mucosa. For this reason, the patient should be advised to chew the gum for a while and then put the gum against the inside of the cheek to allow absorption to occur and prolong the release of nicotine. Continuous chewing produces secretions that are swallowed, results in little absorption, and can cause nausea. Acidic beverages, particularly coffee, juices, and soft drinks, interfere with the absorption of nicotine. Thus, the patient needs to be advised that eating or drinking anything except water should be avoided for 15 minutes before and during chewing. Although nicotine gum is an effective smoking cessation treatment, problems with compliance, ease of use, social acceptability, risk of developing temporo-mandibular joint symptoms, and unpleasant taste have been noted. In highly dependent smokers, the 4 mg gum is more effective than the 2 mg gum22.

Other pharmacotherapy. The antidepressants bupropion and nortriptyline have also been shown to increase long-term quit rates9,19,23. Although more studies need to be conducted with these medications, a randomized controlled trial with counseling and support showed quit rates at one year of 30% with sustained-release bupropion alone and 35% with sustained-release bupropion plus nicotine patch23. The effectiveness of the antihypertensive drug clonidine is limited by side effects19.

OCCUPATIONAL EXPOSURES

Although it is not known how many individuals are at risk of developing respiratory disease from occupational exposures in either developing or developed countries, many occupationally induced respiratory disorders can be reduced or controlled through a variety of strategies aimed at reducing the burden of inhaled particles and gases24:

• Implement and enforce strict, legally mandated control of airborne exposure in the workplace.
• Initiate intensive and continuing education of exposed workers, industrial managers, health care workers, primary care physicians, and legislators.
• Educate workers and policy-makers on how cigarette smoking aggravates occupational lung diseases and why efforts to reduce smoking where a hazard exists are important.

The main emphasis should be on primary prevention, which is best achieved by the elimination or reduction of exposures to various substances in the workplace. Secondary prevention, achieved through surveillance and early case detection, is also of great importance. Both approaches are necessary to improve the present situation and to reduce the burden of lung disease.

INDOOR AND OUTDOOR AIR POLLUTION

Individuals experience diverse indoor and outdoor environments throughout the day, each of which has its own unique set of air contaminants. Although outdoor and indoor air pollution are generally thought of separately, the concept of total personal exposure may be more relevant for COPD. Reducing the risk from indoor and outdoor air pollution requires a combination of public policy and protective steps taken by individual patients.

Regulation of Air Quality

At the national level, achieving a set level of air quality should be a high priority; this goal will normally require legislative action. Details on setting and maintaining air quality goals are beyond the scope of this document.

Understanding health risks posed by local air pollution sources may be difficult and requires skills in community health, toxicology, and epidemiology. Local physicians may become involved through concerns about the health of their patients or as advocates for the community's environment.

Patient-Oriented Control

The health care provider should consider susceptibility (including family history and exposure to indoor/outdoor pollution) for each individual patient.

• Patients should be counseled concerning the nature and degree of their susceptibility. Those who are at high risk should avoid vigorous exercise outdoors during pollution episodes.
• If various solid fuels are used for cooking and heating, adequate ventilation should be encouraged.
• Persons with severe COPD should monitor public announcements of air quality and should stay indoors when air quality is poor.
• The use of medication should follow the usual clinical indications; therapeutic regimes should not be adjusted because of the occurrence of a pollution episode without evidence of worsening of symptoms or function.
• Respiratory protective equipment has been developed for use in the workplace in order to minimize exposure to toxic gases and particles. However, under most circumstances, health care providers should not suggest respiratory protection as a method for reducing the risks of ambient air pollution.
• Air cleaners have not been shown to have health benefits, whether directed at pollutants generated by indoor sources or at those brought in with outdoor air.

  Top

REFERENCES

1. Samet J, Utell MJ. Ambient air pollution. In: Rosenstock L, Cullen M, eds. Textbook of occupational and environmental medicine. Philadelphia: WB Saunders; 1994. p. 53-60.
2. Jeffery PK. Cigarette smoke-induced damage of airway mucosa. In: Chretien J, Dusser D, eds. Environmental impact on the airways: from injury to repair. Lung biology in health and disease. Vol. 93. New York: Marcel Dekker;1996. p. 299-354.
3. Helms PJ. Lung growth: implications for the development of disease [editorial]. Thorax 1994; 49:440-1.
4. Colley JR, Holland WW, Corkhill RT. Influence of passive smoking and parental phlegm on pneumonia and bronchitis in early childhood. Lancet 1974; 2:1031-4.
5. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497-505.
6. World Health Organization. Tobacco free initiative: policies for public health. Geneva: World Health Organization; 1999. Available from: URL: www.who/int/toh/worldnottobacco99
7. Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, Weinstein MC, et al. Five-hundred life-saving interventions and their cost-effectiveness. Risk Anal 1995; 15:369-90.
8. Parrott S, Godfrey C, Raw M, West R, McNeill A. Guidance for commissioners on the cost effectiveness of smoking cessation interventions. Health Educational Authority. Thorax 1998; 53 (Suppl 5 Pt 2): S1-38.
9. Fiore MC, Bailey WC, Cohen SJ. Smoking cessation: information for specialists. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research and Centers for Disease Control and Prevention; 1996. AHCPR Publication No. 96-0694.
10. The Tobacco Use and Dependence Clinical Practice Guideline Panel, Staff, and Consortium Representatives. A clinical practice guideline for treating tobacco use and dependence. JAMA 2000; 28:3244-54.
11. American Medical Association. Guidelines for the diagnosis and treatment of nicotine dependence: how to help patients stop smoking. Washington, DC: American Medical Association; 1994.
12. Glynn TJ, Manley MW. How to help your patients stop smoking. A National Cancer Institute manual for physicians. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute; 1990. NIH Publication No. 90-3064.
13. Glynn TJ, Manley MW, Pechacek TF. Physician-initiated smoking cessation program: the National Cancer Institute trials. Prog Clin Biol Res 1990; 339:11-25.
14. Baillie AJ, Mattick RP, Hall W, Webster P. Meta-analytic review of the efficacy of smoking cessation interventions. Drug and Alcohol Review 1994; 13:157-70.
15. Wilson DH, Wakefield MA, Steven ID, Rohrsheim RA, Esterman AJ, Graham NM. "Sick of smoking": evaluation of a targeted minimal smoking cessation intervention in general practice. Med J Aust 1990; 152:518-21.
16. Britton J, Knox A. Helping people to stop smoking: the new smoking cessation guidelines [editorial]. Thorax 1999; 54:1-2.
17. Kottke TE, Battista RN, DeFriese GH, Brekke ML. Attributes of successful smoking cessation interventions in medical practice. A meta-analysis of 39 controlled trials.JAMA 1988; 259:2883-9.
18. Ockene JK, Kristeller J, Goldberg R, Amick TL, Pekow PS, Hosmer D, et al. Increasing the efficacy of physician-delivered smoking interventions: a randomized clinical trial. J Gen Intern Med 1991; 6:1-8.
19. Lancaster T, Stead L, Silagy C, Sowden A. Effectiveness of interventions to help people stop smoking: findings from the Cochrane Library. BMJ 2000; 321:355-8.
20. Schwartz JL. Review and evaluation of smoking cessation methods: United States and Canada, 1978-1985. Bethesda, MD: National Institutes of Health; 1987. NIH Publication No. 87-2940.
21. Fiore MC, Smith SS, Jorenby DE, Baker TB. The effectiveness of the nicotine patch for smoking cessation. A meta-analysis. JAMA 1994; 271:1940-7.
22. Sachs DP, Benowitz NL. Individualizing medical treatment for tobacco dependence [editorial; comment]. Eur Respir J 1996; 9:629-31.
23. Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, et al. A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999; 340:685-91.
24. The COPD Guidelines Group of the Standards of Care Committee of the BTS. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52 Suppl 5:S1-28.

    Top

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/or 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 ß2-agonists, anticholinergics, theophylline, and a combination of these drugs (Evidence A).
• Regular treatment with inhaled glucocorticosteroids should only be prescribed for symptomatic COPD patients with a documented spirometric response to glucocorticosteroids or in 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 COPD patients 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 hours per day) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).

INTRODUCTION
The overall approach to managing stable COPD should be characterized by a stepwise increase in treatment, depending on the severity of the disease. The step-down approach used in the chronic treatment of asthma is not applicable to COPD since COPD is usually stable and very often progressive. Management of COPD involves several objectives (see Chapter 5, Introduction) that should be met with minimal side effects from treatment. It is based on an individualized assessment of disease severity (Figure 5-3-1) and response to various therapies.

The classification of severity (Figure 1-2) of stable COPD incorporates an individualized assessment of disease severity and therapeutic response into the management strategy. This classification is a guide that should help health care workers make decisions about the management of COPD in individual patients. Treatment depends on the patient's educational level and willingness to apply the recommended management, on cultural and local conditions, and on the availability of medications.

EDUCATION
Although patient education is generally regarded as an essential component of care for any chronic disease, the role of education in COPD has been poorly studied. Assessment of the value of education in COPD may be difficult because of the relatively long time required to achieve improvements in objective measurements of lung function.

Studies that have been done indicate that patient education alone does not improve exercise performance or lung function1-4 (Evidence B), but it can play a role in improving skills, ability to cope with illness, and health status5. These outcomes are not traditionally measured in clinical trials, but they may be most important in COPD where even pharmacologic interventions generally confer only a small benefit in terms of lung function.

Patient education regarding smoking cessation has the greatest capacity to influence the natural history of COPD. Evaluation of the smoking cessation component in a long-term, multicenter study indicates that if effective resources and time are dedicated to smoking cessation, 25% long-term quit rates can be maintained6 (Evidence A). Education also improves patient response to acute exacerbations7,8 (Evidence B). Prospective end-of-life discussions can lead to understanding of advance directives and effective therapeutic decisions at the end of life9 (Evidence B).

Ideally, educational messages should be incorporated into all aspects of care for COPD and may take place in many settings: consultations with physicians or other health care workers, home-care or outreach programs, and comprehensive pulmonary rehabilitation programs.

Goals and Educational Strategies

It is vital for patients with COPD to understand the nature of their disease, risk factors for progression, and their role and the role of health care workers in achieving optimal management and health outcomes. Education should be tailored to the needs and environment of the individual patient, interactive, directed at improving quality of life, simple to follow, practical, and appropriate to the intellectual and social skills of the patient and the caregivers.

In managing COPD, open communication between patient and physician is essential. In addition to being empathic, attentive and communicative, health professionals should pay attention to patients' fears and apprehensions, focus on educational goals, tailor treatment regimens to each individual patient, anticipate the effect of functional decline, and optimize patients' practical skills.

Several specific education strategies have been shown to improve patient adherence to medication and management regimens. In COPD, adherence does not simply refer to whether patients take their medication appropriately. It also covers a range of non-pharmacologic treatments - e.g., maintaining an exercise program after pulmonary rehabilitation, undertaking and sustaining smoking cessation, and using devices such as nebulizers, spacers, and oxygen concentrators properly.

Components of an Education Program

The topics that seem most appropriate for an education program include: smoking cessation; basic information about COPD and pathophysiology of the disease; general approach to therapy and specific aspects of medical treatment; self-management skills; strategies to help minimize dyspnea advice about when to seek help; self-management and decision-making during exacerbations; and advance directives and end-of-life issues (Figure 5-3-2).

Education should be part of consultations with health care workers beginning at the time of first assessment for COPD and continuing with each follow-up visit. The intensity and content of these educational messages should vary depending on the severity of the patient's disease. In practice, a patient often poses a series of questions to the physician (Figure 5-3-3). It is important to answer these questions fully and clearly, as this may help make treatment more effective.

T here are several different types of educational programs, ranging from simple distribution of printed materials, to teaching sessions designed to convey information about COPD, to workshops designed to train patients in specific skills (e.g., self-management, peak flow monitoring).

Although printed materials may be a useful adjunct to other educational messages, passive dissemination of printed materials alone does not improve skills or health outcomes. Education is most effective when it is interactive and conducted in small workshops4 (Evidence B) designed to improve both knowledge and skills. Behavioral approaches such as cognitive therapy and behavior modification lead to more effective self-management skills and maintenance of exercise programs.

Cost Effectiveness of Education Programs for COPD Patients

The cost effectiveness of education programs for COPD patients is highly dependent on local factors that influence the cost of access to medical services and that will vary substantially between countries. In one cost-benefit analysis of education provided to hospital inpatients with COPD10, an information package resulted in increased knowledge of COPD and reduced use of health services, including reductions of hospital readmissions and general practice consultations. The education package involved training patients to increase knowledge of COPD, medication usage, precautions for exacerbations, and peak flow monitoring technique. However, this study was undertaken in a heterogeneous group of patients - 65% were smokers and 88% were judged to have an asthmatic component to their disease - and these findings may not hold true for a "pure" COPD population.

PHARMACOLOGIC TREATMENT

Overview of the Medications

Pharmacologic therapy is used to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. 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 disease6,11,12,13 (Evidence A). However, this should not preclude efforts to use medications to control symptoms. Since COPD is usually progressive, recommendations for the pharmacological treatment of COPD reflect the following general principles:

• There should be a stepwise increase in treatment, depending on the severity of the disease. (The step-down approach used in the chronic treatment of asthma is not applicable to COPD.)
• Regular treatment needs to be maintained at the same level for long periods of time unless significant side effects occur or the disease worsens.
• Treatment response of an individual patient is variable and should be monitored closely and adjusted frequently.

The medications are presented in the order in which they would normally be introduced in patient care, based on the level of disease severity. However, each treatment regimen needs to be patient-specific as the relationship between the severity of symptoms and the severity of airflow limitation is influenced by other factors, such as the frequency and severity of exacerbations, the presence of one or more complications, the presence of respiratory failure, co-morbidities (cardiovascular disease, sleep-related disorders, etc.), and general health status.

Bronchodilators

Medications that increase the FEV1 or change other spirometric variables, usually by altering airway smooth muscle tone, are termed bronchodilators14, since the improvements in expiratory flow reflect widening of the airways rather than changes in lung elastic recoil. Such drugs improve emptying of the lungs, tend to reduce dynamic hyperinflation at rest and during exercise15, and improve exercise performance. The extent of these changes, especially in moderate to severe disease, is not easily predictable from the improvement in FEV116,17. Regular bronchodilation with drugs that act primarily on airway smooth muscle does not modify the decline of function in mild COPD and, by inference, the prognosis of the disease6 (Evidence B).

Bronchodilator medications are central to the symptomatic management of COPD18-21 (Evidence A). They are given either on an as-needed basis for relief of persistent or worsening symptoms, or on a regular basis to prevent or reduce symptoms. The side effects of bronchodilator therapy are pharmacologically predictable and dose dependent. Adverse effects are less likely, and resolve more rapidly after treatment withdrawal, with inhaled than with oral treatment. However, COPD patients tend to be older than asthma patients and more likely to have co-morbidities, so their risk of developing side effects is greater. A summary of bronchodilator therapy in COPD is provided in Figure 5-3-4.

When treatment is given by the inhaled route, attention to effective drug delivery and training in inhaler technique is essential. COPD patients may have more problems in effective coordination and find it harder to use a simple Metered Dose Inhaler (MDI) than do healthy volunteers or younger asthmatics. It is essential to ensure that inhaler technique is correct and to re-check this at each visit.
Alternative breath-activated or spacer devices are available for most formulations. Dry powder inhalers may be more convenient and possibly provide improved drug deposition, although this has not been established in COPD. In general, particle deposition will tend to be more central with the fixed airflow limitation and lower inspiratory flow rates in COPD22,23.

Wet nebulizers are not recommended for regular treatment because they are more expensive and require appropriate maintenance. A list of currently available inhaler devices is provided at http://www.goldcopd.com/inhalers/. The choice will depend on availability, cost, the prescribing physician, and the skills and ability of the patient.

Dose-response relationships using the FEV1 as the outcome are relatively flat with all classes of bronchodilators18-21. The dose-response relationships for anticholinergics and ß2-agonists are shown in Figure 5-3-5 21. Toxicity is also dose related. Increasing the dose of either a ß2-agonist or an anticholinergic by an order of magnitude, especially when given by a wet nebulizer, appears to provide subjective benefit in acute episodes24 (Evidence B) but is not necessarily helpful in stable disease25 (Evidence C).

Inhaled ß2-agonists have a relatively rapid onset of bronchodilator effect although this is probably slower in COPD than in asthma. The bronchodilator effects of short-acting ß2-agonists usually wear off within 4 to 6 hours26,27 (Evidence A). Long-acting inhaled ß2-agonists, such as salmeterol and formoterol, show a duration of effect of 12 hours or more with no loss of effectiveness overnight or with regular use in COPD patients28-30 (Evidence A).

All categories of bronchodilators have been shown to increase exercise capacity in COPD, without necessarily producing significant changes in FEV125,31,32 (Evidence A). Regular treatment with short-acting bronchodilators is cheaper but less convenient than treatment with long-acting bronchodilators. In doses of 50 µg twice daily, but not 100 µg twice daily33 (Evidence B), the long-acting inhaled ß2-agonist salmeterol has been shown to improve health status significantly. Similar data for short-acting ß2-agonists are not available. Use of inhaled ipratropium (an anticholinergic) four times daily also improves health status34 (Evidence B). Theophylline is effective in COPD, but due to its potential toxicity inhaled bronchodilators are preferred when available. All studies that have shown efficacy of theophylline in COPD were done with slow-release preparations. The classes of bronchodilator drugs commonly used in treating COPD, ß2-agonists, anticholinergics, and methylxanthines, are shown in Figure 5-3-6. The choice depends on the availability of medication and the patient's response.

ß2-agonists. The principal action of ß2-agonists is to relax airway smooth muscle by stimulating ß2-adrenergic receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstriction. Oral therapy is slower in onset and has more side effects than inhaled treatment35 (Evidence A).

Adverse effects. Stimulation of ß2-receptors can produce resting sinus tachycardia and has the potential to precipitate cardiac rhythm disturbances in very susceptible patients, although this appears to be a remarkably rare event with inhaled therapy. Exaggerated somatic tremor is troublesome in some older patients treated with higher doses of ß2-agonists, whatever the route of administration, and this limits the dose that can be tolerated.

Although hypokalemia can occur, especially when treatment is combined with thiazide diuretics36, and oxygen consumption can be increased under resting conditions37, these metabolic effects show tachyphylaxis unlike the bronchodilator actions. Mild falls in PaO2 occur after administration of both short- and long-acting ß2-agonists38, but the clinical significance of these changes is doubtful. Despite the concerns raised some years ago, further detailed study has found no association between ß2-agonist use and an accelerated loss of lung function or increased mortality in COPD.

Anticholinergics. The most important effect of anticholinergic medications in COPD patients appears to be blockage of acetylcholine's effect on M3 receptors. Current drugs also block M2 receptors and modify transmission at the pre-ganglionic junction, although these effects appear less important in COPD39.

The bronchodilating effect of short-acting inhaled anticholinergics lasts longer than that of short-acting ß2-agonists, with some bronchodilator effect generally apparent up to 8 hours after administration26 (Evidence A).

Adverse effects. Anticholinergic drugs, such as ipratropium bromide, are poorly absorbed, which limits the troublesome systemic effects seen with atropine. Extensive use of this class of inhaled agents in a wide range of doses and clinical settings has shown them to be very safe. Although occasional prostatic symptoms have been reported, there are no data to prove a true causal relationship. A bitter, metallic taste is reported by some patients using ipratropium.

Use of wet nebulizer solutions with a face mask has been reported to precipitate acute glaucoma, probably by a direct effect of the solution on the eye. Mucociliary clearance is unaffected by these drugs, and respiratory infection rates are not increased.

Methylxanthines. Controversy remains about the exact effects of xanthine derivatives. They may act as non-selective phosphodiesterase inhibitors, but have also been reported to have a range of non-bronchodilator actions, the significance of which is disputed31,40-44. Data on duration of action for conventional, or even slow-release, xanthine preparations are lacking in COPD. Changes in inspiratory muscle function have been reported in patients treated with theophylline40, but whether this reflects changes in dynamic lung volumes or a primary effect on the muscle is not clear (Evidence B). All studies that have shown efficacy of theophylline in COPD were done with slow-release preparations. Theophylline is effective in COPD but, due to its potential toxicity, inhaled bronchodilators are preferred when available.

Adverse effects. Toxicity is dose related, a particular problem with the xanthine derivatives because their therapeutic ratio is small and most of the benefit occurs only when near-toxic doses are given42,43 (Evidence A). Methylxanthines are nonspecific inhibitors of all phosphodiesterase enzyme subsets, which explains their wide range of toxic effects. Problems include the development of atrial and ventricular arrhythmias (which can prove fatal) and grand mal convulsions (which can occur irrespective of prior epileptic history). More common and less dramatic side effects include headaches, insomnia, nausea, and heartburn, and these may occur within the therapeutic range of serum theophylline. Unlike the other bronchodilator classes, xanthine derivatives may involve a risk of overdose (either intentional or accidental).

Theophylline, the most commonly used methylxanthine, is metabolized by cytochrome P450 mixed function oxidases. Clearance of the drug declines with age. Many other physiological variables and drugs modify theophylline metabolism; some of the potentially important interactions are listed in Figure 5-3-7.

Combination therapy. Combining drugs with different mechanisms and durations of action may increase the degree of bronchodilation for equivalent or lesser side effects. A combination of a short-acting ß2-agonist and the anticholinergic drug ipratropium in stable COPD produces greater and more sustained improvements in FEV1 than either drug alone and does not produce evidence of tachyphylaxis over 90 days of treatment26,45,46 (Evidence A).

The combination of a ß2-agonist, an anticholinergic, and/or theophylline may produce additional improvements in lung function26,28,44,47 and health status26,28,42,48. Increasing the number of drugs usually increases costs, and an equivalent benefit may occur by increasing the dose of one bronchodilator when side effects are not a limiting factor. Detailed assessments of this approach have not been carried out.

Bronchodilator therapy by disease severity. Figure 5-3-8 provides a summary of bronchodilator and other treatment at each stage of COPD. For patients with few or intermittent symptoms (Stage I: Mild COPD), short-acting inhaled therapy as needed to control dyspnea or coughing spasms is sufficient. If inhaled bronchodilators are not available, regular treatment with slow-release theophylline should be considered. ß2-agonists and anticholinergics taken by inhalation are generally equipotent49, with some studies suggesting that the latter are more likely to be effective in a given clinical setting7 (Evidence A). Consideration of costs and possible side effects will determine the choice of drug for monotherapy, but for patients with Stage I: Mild COPD or Stage II: Moderate COPD as-needed treatment with either is a reasonable first step. Failure of one of these bronchodilator classes to control symptoms should prompt a trial of the other class, and if symptoms are still troublesome, regular treatment with a combination of drugs is appropriate. One post-hoc review has suggested that hospitalization days are reduced in patients whose treatment regimens contain an inhaled anticholinergic50 (Evidence C), but this issue requires prospective study as it would be of considerable economic importance if confirmed. One-time, objective changes in spirometry are a poor guide to the long-term, subjective benefit of bronchodilator treatment. Empirical treatment trials, rather than a laboratory assessment of bronchodilator response, should be used to determine whether treatment should continue.

Patients with Stage II: Moderate COPD to Stage III: Severe COPD who are on regular short- or long-acting bronchodilator therapy may also use a short-acting bronchodilator as needed.

For patients who remain highly symptomatic, the addition of oral slow-release theophylline can be tried, but it should be titrated against directly measured plasma theophylline levels to reduce the risk of serious side effects and obtain maximum benefit. Some patients may request regular treatment with high-dose nebulized bronchodilators51, especially if they have experienced subjective benefit from this treatment during an acute exacerbation. Clear scientific evidence for this approach is lacking, but one option is to examine the improvement in mean daily peak expiratory flow recording during two weeks of treatment in the home and continue with nebulizer therapy if a significant change occurs51. In general, nebulized therapy for a stable patient is not appropriate unless it has been shown to be better than conventional dose therapy.

Glucocorticosteroids

The effects of oral and inhaled glucocorticosteroids in COPD are much less dramatic than in asthma, and their role in the management of stable COPD is limited to very specific indications. The use of glucocorticosteroids for the treatment of acute exacerbations is described in Component 4: Manage Exacerbations.

Oral glucocorticosteroids - short-term. Many existing COPD guidelines recommend the use of a short course (two weeks) of oral glucocorticosteroids to identify COPD patients who might benefit from long-term treatment with oral or inhaled glucocorticosteroids. This recommendation is based on evidence52 that short-term effects predict long-term effects of oral glucocorticosteroids on FEV1, and evidence that asthma patients with airflow limitation might not respond acutely to an inhaled bronchodilator but do show significant bronchodilation after a short course of oral glucocorticosteroids.

There is mounting evidence, however, that a short course of oral glucocorticosteroids is a poor predictor of the long-term response to inhaled glucocorticosteroids in COPD13,53. For this reason, there appears to be insufficient evidence to recommend a therapeutic trial with oral glucocorticosteroids in patients with Stage II: Moderate COPD or Stage III: Severe COPD and poor response to an inhaled bronchodilator.

Oral glucocorticosteroids - long-term. Two retrospective studies54,55 analyzed the effects of treatment with oral glucocorticosteroids on long-term FEV1 changes in clinic populations of patients with moderate to severe COPD. The retrospective nature of these studies, the lack of a true control group, and the imprecise definition of COPD are reasons for a cautious interpretation of the data and conclusions.

A side effect of long-term treatment with systemic glucocorticosteroids is steroid myopathy56-58, which contributes to muscle weakness, decreased functionality, and respiratory failure in subjects with advanced COPD. In view of the well-known toxicity of long-term treatment with oral glucocorticosteroids, it is not surprising that no prospective studies have been performed on the long-term effects of these drugs in COPD.

Therefore, based on the lack of evidence of benefit, and the large body of evidence on side effects, long-term treatment with oral glucocorticosteroids is not recommended in COPD (Evidence A).

Inhaled glucocorticosteroids. Many studies have looked at the short-term effect of inhaled glucocorticosteroids on pulmonary function parameters in COPD. While some studies have shown a significant improvement, others have not59-72. The major problems with most studies are the small number of subjects and the short duration of treatment. However, data from four large studies on the long-term effects of inhaled glucocorticosteroids in COPD (Copenhagen City12, EUROSCOP11, ISOLDE13, Lung Health Study II73) provide evidence that regular treatment with inhaled glucocorticosteroids is only appropriate for symptomatic COPD patients with a documented spirometric response to inhaled glucocortico-steroids (see Component 1: Assess and Monitor Disease) or in those with an FEV1 < 50% predicted (Stage IIB: Moderate COPD and Stage III: Severe COPD) and repeated exacerbations requiring treatment with antibiotics or oral glucocorticosteroids (Evidence B).

The dose-response relationships and long-term safety of inhaled glucocorticosteroids in COPD are not known. Only moderate to high doses have been used in long-term clinical trials. Two studies showed an increased incidence of skin bruising in a small percentage of the COPD patients11,13. One long-term study showed no effect of budesonide on bone density and fracture rate11, while another study showed that treatment with triamcinolone acetamide was associated with a decrease in bone density73. The efficacy and side effects of inhaled glucocorticosteroids in asthma are dependent on the dose and type of glucocorticosteroid74. This pattern can also be expected in COPD and needs documentation in this patient population. Treatment with inhaled glucocorticosteroids can be recommended for patients with more advanced COPD and repeated acute exacerbations as described in Component 4: Manage Exacerbations.

Other Pharmacologic Treatments

Vaccines. Influenza vaccines can reduce serious illness and death in COPD patients by about 50%75 (Evidence A). Vaccines containing killed or live, inactivated viruses are recommended76 as they are more effective in elderly patients with COPD77. The strains are adjusted each year for appropriate effectiveness and should be given once (in Autumn) or twice (in Autumn and Winter) each year. A pneumococcal vaccine containing 23 virulent serotypes has been used, but sufficient data to support its general use in COPD patients are lacking78-80 (Evidence B).

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

Antibiotics. In several large-scale controlled studies81-83, prophylactic, continuous use of antibiotics was shown to have no effect on the frequency of acute exacerbations in COPD. Another study examined the efficacy of winter chemoprophylaxis over a period of 5 years and concluded that there was no benefit84. Thus, on the present evidence, the use of antibiotics, other than for treating infectious exacerbations of COPD and other bacterial infections, is not recommended85,86 (Evidence A).

Mucolytic (mucokinetic, mucoregulator) agents (ambroxol, erdosteine, carbocysteine, iodinated glycerol). The regular use of mucolytics in COPD has been evaluated in a number of long-term studies with controversial results87-89. The majority showed no effect of mucolytics on lung function or symptoms, although some have reported a reduction in the frequency of acute exacerbations. A Cochrane collaborative review performed a meta-analysis of all the available data, including that from a number of abstracts90. A statistically significant reduction in the number of episodes of chronic bronchitis was found in patients treated with mucolytics compared to those receiving placebo. However, these data are not easy to interpret, as the follow-up ranged from 2 to 6 months and the patients all had an FEV1 > 50% predicted. Although a few patients with viscous sputum may benefit from mucolytics91,92, 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 exacerbations93-96 (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 exacerbations97, but these results have not been duplicated. Thus, the regular use of this therapy cannot be recommended based on the present evidence98 (Evidence B).

Antitussives. Cough, although sometimes a troublesome symptom in COPD, has a significant protective role99. Thus the regular use of antitussives is contraindicated in stable COPD (Evidence D).

Vasodilators. The belief that pulmonary hypertension in COPD is associated with a poorer prognosis has provoked many attempts to reduce right ventricular afterload, increase cardiac output, and improve oxygen delivery and tissue oxygenation. Many agents have been evaluated, including inhaled nitric oxide, but the results have been uniformly disappointing. In patients with COPD, in whom hypoxemia is caused primarily by ventilation-perfusion mismatching rather than by increased intrapulmonary shunt (as in noncardiogenic pulmonary edema), inhaled nitric oxide can worsen gas exchange because of altered hypoxic regulation of ventilation-perfusion balance100,101. Therefore, based on the available evidence, nitric oxide is contraindicated in stable COPD.

Respiratory stimulants. Almitrine bismesylate, a relatively specific peripheral chemoreceptor stimulant that increases ventilation at any level of CO2 under hypoxemic conditions, has been studied in both stable respiratory failure and acute exacerbations. It improves ventilation-perfusion relationships by modifying the hypoxic vasoconstrictor response. Oral almitrine has been shown to improve oxygenation, but to a lesser degree than low doses of inspired O2. There is no evidence that almitrine improves survival or quality of life, and in large clinical trials it was associated with a number of significant side effects, particularly peripheral neuropathy102-104. Therefore, on the present evidence almitrine is not recommended for regular use in stable COPD patients (Evidence B). The use of doxapram, a non-specific but relatively safe respiratory stimulant available as an intravenous formulation, is not recommended in stable COPD (Evidence D).

Narcotics (morphine). 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 subjects105-109. 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.

NON-PHARMACOLOGIC 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 non-pulmonary problems that may not be adequately addressed by medical therapy for COPD. Such problems, which especially affect patients with Stage II: Moderate COPD and Stage III: Severe COPD, include exercise de-conditioning, relative social isolation, altered mood states (especially depression), muscle wasting, and weight loss. These problems have complex interrelationships and improvement in any one of these inter-linked processes can interrupt the "vicious circle" in COPD so that positive gains occur in all aspects of the illness (Figure 5-3-9).

Pulmonary rehabilitation has been carefully evaluated in a large number of clinical trials; the various benefits are summarized in Figure 5-3-105,110-120.

Patient selection and program design. Although more information is needed on criteria for patient selection for pulmonary rehabilitation programs, COPD patients at all stages of disease appear to benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue121 (Evidence A). Data suggest that these benefits can be sustained even after a single pulmonary rehabilitation program122-124. Benefit does wane after a rehabilitation program ends, but if exercise training is maintained at home the patient's health status remains above pre-rehabilitation levels (Evidence B). To date there is no consensus on whether repeated rehabilitation courses enable patients to sustain the benefits gained through the initial course.

Ideally, pulmonary rehabilitation should involve several types of health professionals. Significant benefits can also occur with more limited personnel, as long as dedicated professionals are aware of the needs of each patient. Benefits have been reported from rehabilitation programs conducted in inpatient, outpatient, and home settings114,115,125. Considerations of cost and availability most often determine the choice of setting. The educational and exercise training components of rehabilitation are usually conducted in groups, normally with 6 to 8 individuals per class (Evidence D).

The following points summarize current knowledge of considerations important in choosing patients:

Functional status: Benefits have been seen in patients with a wide range of disability, although those who are chair-bound appear unlikely to respond even to home visiting programs126 (Evidence A).
Severity of dyspnea: Stratification by breathlessness intensity using the MRC questionnaire (Figure 5-1-3) may be helpful in selecting patients most likely to benefit from rehabilitation. Those with MRC grade 5 dyspnea may not benefit126 (Evidence B).

Motivation: Selecting highly motivated participants is especially important in the case of outpatient programs123.

Smoking status: There is no evidence that smokers will benefit less than nonsmokers, but many clinicians believe that inclusion of a smoker in a rehabilitation program should be conditional on their participation in a smoking cessation program. Some data indicate that continuing smokers are less likely to complete pulmonary rehabilitation programs than nonsmokers123 (Evidence B).

Components of pulmonary rehabilitation programs. The components of pulmonary rehabilitation vary widely from program to program but a comprehensive pulmonary rehabilitation program includes exercise training, nutrition counseling, and education.

Exercise training. Exercise tolerance can be assessed by either bicycle ergometry or treadmill exercise with the measurement of a number of physiological variables, including maximum oxygen consumption, maximum heart rate, and maximum work performed. A less complex approach is to use a self-paced, timed walking test (e.g., 6-minute walking distance). These tests require at least one practice session before data can be interpreted. Shuttle walking tests offer a compromise: they provide more complete information than an entirely self-paced test, but are simpler to perform than a treadmill test127.

Exercise training ranges in frequency from daily to weekly, in duration from 10 minutes to 45 minutes per session, and in intensity from 50% peak oxygen consumption (VO2 max) to maximum tolerated128. The optimum length for an exercise program has not been investigated in randomized, controlled trials. Thus, the length depends on the resources available and usually ranges from 4 to 10 weeks, with longer programs resulting in larger effects than shorter programs113.

Participants are often encouraged to achieve a predetermined target heart rate129, but this goal may have limitations in COPD. In many programs, especially those using simple corridor exercise training, the patient is encouraged to walk to a symptom-limited maximum, rest, and then continue walking until 20 minutes of exercise have been completed. Many physicians advise patients unable to participate in a structured program to exercise on their own (e.g., walking 20 minutes daily). The benefits of this general advice have not been tested, but it is reasonable to offer such advice to patients if a formal program is not available.

Some programs also include upper limb exercises, usually involving an upper limb ergometer or resistive training with weights. There are no randomized clinical trial data to support the routine inclusion of these exercises, but they may be helpful in patients with co-morbidities that restrict other forms of exercise130,131. The addition of upper limb exercises or other strength training to aerobic training is effective in improving strength, but does not improve quality of life or exercise tolerance132.

Nutrition counseling. Nutritional state is an important determinant of symptoms, disability, and prognosis in COPD; both overweight and underweight can be a problem. Specific nutritional recommendations for patients with COPD are based on expert opinion and some small randomized clinical trials. Approximately 25% of patients with Stage II: Moderate COPD to Stage III: Severe COPD show a reduction in both their body mass index and fat free mass133-135. A reduction in body mass index is an independent risk factor for mortality in COPD patients136-138 (Evidence A).

Health care workers should identify and correct the reasons for reduced calorie intake in COPD patients. Patients who become breathless while eating should be advised to take small, frequent meals. Poor dentition should be corrected and co-morbidities (pulmonary sepsis, lung tumors, etc.) should be managed appropriately.

Improving the nutritional state of weight-losing COPD patients can lead to improved respiratory muscle strength139-141. However, controversy remains as to whether this additional effort is cost effective139,140. Present evidence suggests that nutritional supplementation alone may not be a sufficient strategy. Increased calorie intake is best accompanied by exercise regimes that have a nonspecific anabolic action. This approach has not been formally tested in large numbers of subjects.

Education. Most pulmonary rehabilitation programs include an educational component, but the specific contributions of education to the improvements seen after pulmonary rehabilitation remain unclear.

Assessment and follow-up. Baseline and outcome assessments of each participant in a pulmonary rehabilitation program should be made to quantify individual gains and target areas for improvement. Assessments should include:

• Detailed history and physical examination.
• Measurement of spirometry before and after a bronchodilator drug.
• Assessment of exercise capacity.
• Measurement of health status and impact of breathlessness.
• Assessment of inspiratory and expiratory muscle strength and lower limb strength (e.g., quadriceps) in patients who suffer from muscle wasting.

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 baseline and outcome measures.
Several detailed questionnaires for assessing health status are available, including some that are specifically designed for patients with respiratory disease (e.g., Chronic Respiratory Disease Questionnaire48, St. George Respiratory Questionnaire142), and there is increasing evidence that these questionnaires may be useful in a clinical setting. Health status can also be assessed by generic questionnaires, such as the Medical Outcomes Study Short Form (SF36)143, to enable comparison of quality of life in different diseases.

Economic cost of rehabilitation programs. A Canadian study showing statistically significant improvements in dyspnea, fatigue, emotional health, and mastery found that the incremental cost of pulmonary rehabilitation was $11,597 (CDN) per person144. A study from the UK provided evidence that an intensive (6-week, 18-visit) multidisciplinary rehabilitation program was effective in decreasing use of health services124 (Evidence B). Although there was no difference in the number of hospital admissions between patients with disabling COPD in a control group and those who participated in the rehabilitation program, the number of days the rehabilitation group spent in the hospital was significantly lower. The rehabilitation group had more primary-care consultations at the general practitioner's premises than did the control group, but fewer primary-care home visits. Compared with the control group, the rehabilitation group also showed greater improvements in walking ability and in general and disease-specific health status.

Oxygen Therapy

Oxygen therapy, one of the principal non-pharmacologic treatments for patients with Stage III: Severe COPD91,145, can be administered in three ways: long-term continuous therapy, during exercise, and to relieve acute dyspnea. The primary goal of oxygen therapy is to increase the baseline PaO2 to at least 8.0 kPa (60 mm Hg) at sea level and rest, and/or produce an SaO2 at least 90%, which will preserve vital organ function by ensuring adequate delivery of oxygen.

The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival91,146. It can also have a beneficial impact on hemodynamics, hematologic characteristics, exercise capacity, lung mechanics, and mental state147. Continuous oxygen therapy decreased resting pulmonary artery pressure in one study146 but not in another study148. Several controlled prospective studies have shown that the primary hemodynamic effect of oxygen therapy is preventing the progression of pulmonary hypertension149,150. Long-term oxygen therapy improves general alertness, motor speed, and hand grip, although the data are less clear about changes in quality of life and emotional state. The possibility of walking while using some oxygen devices may help to improve physical conditioning and have a beneficial influence on the psychological state of patients151.

Long-term oxygen therapy is generally introduced in Stage III: Severe COPD for patients who have:

• PaO2 at or below 7.3 kPa (55 mm Hg) or SaO2 at or below 88%, with or without hypercapnia (Evidence A); or
• PaO2 between 7.3 kPa (55 mm Hg) and 8.0 kPa (60 mm Hg), or SaO2 of 89%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit > 55%) (Evidence D). A decision about the use of long-term oxygen should be based on the waking PaO2 values. The prescription should always include the source of supplemental oxygen (gas or liquid), method of delivery, duration of use, and flow rate at rest, during exercise, and during sleep.

Oxygen therapy given during exercise increases walking distance and endurance, optimizing oxygen delivery to tissues and utilization by muscles. However, there are no data to suggest that long-term oxygen therapy changes exercise capacity per se. Where available, this treatment is usually restricted to patients who meet the criteria for continuous oxygen therapy, or experience significant oxygen desaturation during exercise(Evidence C).

Oxygen therapy reduces the oxygen cost of breathing and minute ventilation, a mechanism that although still disputed helps to minimize the sensation of dyspnea. This has led to the use of short burst therapy to control severe dyspnea such as occurs after climbing stairs. Often the patient keeps a cylinder of oxygen at home to use as needed. Whether this is of physiological, psychological, or any benefit at all is not known (Evidence C).

Cost considerations. Supplemental home oxygen is usually the most costly component of outpatient therapy for adults with COPD who require this therapy152. Studies of the cost effectiveness of alternative outpatient oxygen delivery methods in the US and Europe suggest that oxygen concentrator devices may be more cost effective than cylinder delivery systems153,154.

Oxygen use in air travel. Although air travel is safe for most patients with chronic respiratory failure who are on long-term oxygen therapy, patients should be instructed to increase the flow by 1-2 L/min during the flight155. Ideally, patients who fly should be able to maintain an in-flight PaO2 of at least 6.7 kPa (50 mm Hg). Studies indicate that this can be achieved in those with moderate to severe hypoxemia at sea level by supplementary oxygen at 3 L/min by nasal cannulae or 31% by Venturi face mask156. Those with a resting PaO2 at sea level of > 9.3 kPa (70 mm Hg) are likely to be safe to fly without supplementary oxygen155,157, although it is important to emphasize that a resting PaO2 > 9.3 kPa (70 mm Hg) at sea level does not exclude the development of severe hypoxemia when traveling by air (Evidence C). Careful consideration should be given to any comorbidity that may impair oxygen delivery to tissues (e.g., cardiac impairment, anemia). Also, walking along the aisle may profoundly aggravate hypoxemia158.

Ventilatory Support

Although both noninvasive ventilation (using either negative or positive pressure devices) and invasive (conventional) mechanical ventilation are essentially designed to manage and treat acute episodes of COPD, for years noninvasive ventilation has been applied in patients with Stage III: Severe COPD and chronic respiratory failure. This has followed the successful use of noninvasive ventilation in other forms of chronic respiratory failure due to chest wall deformities and/or neuromuscular disorders. Several scientific studies have examined the use of ventilatory support and there is no convincing evidence that this therapy has a role in the management of stable COPD. It is possible that some patients with chronic hypercapnia may benefit from this form of treatment, but no randomized controlled study has yet been reported.

Noninvasive mechanical ventilation. This modality of ventilatory support is applied when endotracheal and nasotracheal ventilation are not needed, using either negative pressure ventilation (nPV) or noninvasive intermittent positive pressure ventilation (NIPPV).

Noninvasive negative pressure ventilation (nPV). The use of tank respirators, cuirass, or poncho ventilation is largely of historical interest in COPD. Problems with patient comfort and limited access restrict future use of nPV159,160. When this treatment is used in chronic respiratory failure, some patients develop upper airway obstruction during sleep161. A comparison of domiciliary active and sham nPV in patients with chronic respiratory failure due to COPD showed no differences in shortness of breath, exercise tolerance, arterial blood gases, respiratory muscle strength, or quality of life between the two treatments162.

Noninvasive intermittent positive pressure ventilation (NIPPV). The role of NIPPV in chronic respiratory failure remains unsettled, although this is now the standard means of providing noninvasive ventilatory support in other instances of chronic respiratory failure not directly related to COPD. NIPPV can be delivered by different types of ventilators: volume-controlled, pressure-controlled, bilevel positive airway pressure, or continuous positive airway pressure. New devices with lower cost, greater ease of operation, and greater portability are constantly being developed163. Recent technical improvements have facilitated the use of NIPPV while reducing the possibility of air leaking through face or nasal masks.

A study of NIPPV compared to conventional therapy in a population with end-stage COPD using a randomized, crossover design for a 3-month period found that the noninvasive approach is not well tolerated and is associated with marginal clinical and functional improvements164 (Evidence B). The use of NIPPV together with long-term oxygen therapy in a randomized crossover study in a small subset of patients produced a significant improvement in daytime arterial blood gases, total sleep time, sleep efficiency, quality of life, and overnight PaCO2 compared with oxygen therapy alone, indicating that NIPPV may be a useful addition to long-term oxygen therapy165 (Evidence B). However, a similar approach in a larger series of patients concluded that NIPPV plus long-term oxygen therapy does not improve long-term survival. In this study, however, intensive care admissions were reduced and exercise capacity was improved166 (Evidence C).

Given this conflicting evidence, long-term NIPPV cannot be recommended for the routine treatment of patients with chronic respiratory failure due to COPD. Nonetheless, the combination of NIPPV with long-term oxygen therapy may be of some use in a selected subset of patients, particularly in those with pronounced daytime hypercapnia167.

Invasive (conventional) mechanical ventilation. The appropriateness of using invasive (conventional) ventilation in end-stage COPD continues to be debated. There are no guidelines to define which patients will benefit.

Surgical Treatments

Bullectomy. Bullectomy is an older surgical procedure for bullous emphysema. By removing a large bulla that does not contribute to gas exchange, the adjacent lung parenchyma is decompressed. Bullectomy can be performed thoracoscopically. In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function168 (Evidence C).

Bullae may be removed to alleviate local symptoms such as hemoptysis, infection, or chest pain, and to allow re-expansion of a compressed lung region. This is the usual indication in patients with COPD. In considering the possible benefit of surgery it is crucial to estimate the effect of the bulla on the lung and the function of the non-bullous lung. A thoracic CT scan, arterial blood gas measurement, and comprehensive respiratory function tests are essential before making a decision regarding suitability for resection of a bulla. Normal or minimally reduced diffusing capacity, absence of significant hypoxemia, and evidence of regional reduction in perfusion with good perfusion in the remaining lung are indications a patient will likely benefit from surgery169. However, pulmonary hypertension, hypercapnia, and severe emphysema are not absolute contraindications for bullectomy. Some investigators have recommended that the bulla must occupy 50% or more of the hemithorax and produce definite displacement of the adjacent lung before surgery is performed170.

Lung volume reduction surgery (LVRS). LVRS is a surgical procedure in which parts of the lung are resected to reduce hyperinflation171, making respiratory muscles more effective pressure generators by improving their mechanical efficiency (as measured by length/tension relationship, curvature of the diaphragm, and area of apposition)172,173. In addition, LVRS increases the elastic recoil pressure of the lung and thus improves expiratory flow rates174.

In some centers with adequate experience, perioperative mortality of LVRS has been reported to be less than 5%. Results have been reported following bilateral (upper parts) resection using median sternotomy175,176 or video-assisted thoracoscopy (VATS)177. Most studies select patients with FEV1 < 35% predicted, PaCO2 < 6.0 kPa (45 mm Hg), predominant upper lobe emphysema on CT scan, and a residual volume of > 200% predicted. The average increase in FEV1 following LVRS has ranged from 32% to 93%, and the decrease in TLC from 15% to 20%175,178. LVRS appears to improve exercise capacity as well as quality of life in some patients. There are reports of these effects lasting more than one year175-177.

Hospital costs associated with LVRS in 52 consecutive patients179 ranged from $11,712 to $121,829 (US). Hospital charges in 23 consecutive patients admitted for LVRS at a single institution180 ranged from $20,032 to $75,561 with a median charge of $26,669 (US). A small number of individuals incurred extraordinary costs because of complications. Advanced age was a significant factor leading to higher expected total hospital costs.

Although there are some encouraging reports181, LVRS is still an experimental palliative surgical procedure182. Most results (Evidence C) reported to date are from uncontrolled studies; several large randomized multicenter studies are underway to investigate the effectiveness and cost of LVRS in comparison to vigorous conventional therapy183. Until the results of these controlled studies are known, LVRS can- not 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 capacity184-187(Evidence C), although the Joint United Network for Organ Sharing in 1998 found that lung transplantation does not confer a survival benefit in patients with end-stage emphysema after two years186. Criteria for referral for lung transplantation include FEV1 < 35% predicted, PaO2 < 7.3-8.0 kPa (55-60 mm Hg), PaCO2 > 6.7 kPa (50 mm Hg), and secondary pulmonary hypertension188,189.

Lung transplantation is limited by the shortage of donor organs, which has led some centers to adopt the single lung technique. The common complications seen in COPD patients after lung transplantation, apart from operative mortality, are acute rejection and bronchiolitis obliterans, CMV, other opportunistic fungal (Candida, Aspergillus, Cryptococcus, Carini) or bacterial (Pseudomonas, Staphylococcus species) infections, lymphoproliferative disease, and lymphomas185.

Another limitation of lung transplantation is its cost. Hospitalization costs associated with lung transplantation have ranged from $110,000 to well over $200,000 (US). Costs remain elevated for months to years after surgery due to the high cost of complications and the immunosuppressive regimens190-193 that must be initiated during or immediately after surgery.

REFERENCES

1. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med 1995; 122:823-32.
2. Janelli LM, Scherer YK, Schmieder LE. Can a pulmonary health teaching program alter patients' ability to cope with COPD? Rehabil Nurs 1991; 16:199-202.
3. Ashikaga T, Vacek PM, Lewis SO. Evaluation of a community-based education program for individuals with chronic obstructive pulmonary disease. J Rehabil 1980; 46:23-7.
4. Toshima MT, Kaplan RM, Ries AL. Experimental evaluation of rehabilitation in chronic obstructive pulmonary disease: short-term effects on exercise endurance and health status. Health Psychol 1990; 9:237-52.
5. Celli BR. Pulmonary rehabilitation in patients with COPD. Am J Respir Crit Care Med 1995; 152:861-4.
6. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272:1497-505.
7. Stewart MA. Effective physician-patient communication and health outcomes: a review. CMAJ 1995; 152:1423-33.
8. Clark NM, Nothwehr F, Gong M, Evans D, Maiman LA, Hurwitz ME, et al. Physician-patient partnership in managing chronic illness. Acad Med 1995; 70:957-9.
9. Heffner JE, Fahy B, Hilling L, Barbieri C. Outcomes of advance directive education of pulmonary rehabilitation patients. Am J Respir Crit Care Med 1997; 155:1055-9.
10. Tougaard L, Krone T, Sorknaes A, Ellegaard H. Economic benefits of teaching patients with chronic obstructive pulmonary disease about their illness. The PASTMA Group. Lancet 1992; 339:1517-20.
11. Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, et al. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999; 340:1948-53.
12. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353:1819-23.
13. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320:1297-303.
14. Calverley PMA. Symptomatic bronchodilator treatment. In: Calverley PMA, Pride NB, eds. Chronic obstructive pulmonary disease. London: Chapman and Hall; 1995. p. 419-45.
15. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic hyperinflation during exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:967-75.
16. Berger R, Smith D. Effect of inhaled metaproterenol on exercise performance in patients with stable "fixed" airway obstruction. Am Rev Respir Dis 1988; 138:624-9.
17. Hay JG, Stone P, Carter J, Church S, Eyre-Brook A, Pearson MG, et al. Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive pulmonary disease. Eur Respir J 1992; 5:659-64.
18. Vathenen AS, Britton JR, Ebden P, Cookson JB, Wharrad HJ, Tattersfield AE. High-dose inhaled albuterol in severe chronic airflow limitation. Am Rev Respir Dis 1988; 138:850-5.
19. Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers GW, Donohue JF. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am Rev Respir Dis 1989; 139:1188-91.
20. Chrystyn H, Mulley BA, Peake MD. Dose response relation to oral theophylline in severe chronic obstructive airways disease. BMJ 1988; 297:1506-10.
21. Higgins BG, Powell RM, Cooper S, Tattersfield AE. Effect of salbutamol and ipratropium bromide on airway calibre and bronchial reactivity in asthma and chronic bronchitis. Eur Respir J 1991; 4:415-20.
22. Ericsson CH, Svartengren K, Svartengren M, Mossberg B, Philipson K, Blomquist M, et al. Repeatability of airway deposition and tracheobronchial clearance rate over three days in chronic bronchitis. Eur Respir J 1995; 8:1886-93.
23. Kim CS, Kang TC. Comparative measurement of lung deposition of inhaled fine particles in normal subjects and patients with obstructive airway disease. Am J Respir Crit Care Med 1997; 155:899-905.
24. O'Driscoll BR, Kay EA, Taylor RJ, Weatherby H, Chetty MC, Bernstein A. A long-term prospective assessment of home nebulizer treatment. Respir Med 1992; 86:317-25.
25. Jenkins SC, Heaton RW, Fulton TJ, Moxham J. Comparison of domiciliary nebulized salbutamol and salbutamol from a metered-dose inhaler in stable chronic airflow limitation. Chest 1987; 91:804-7.
26. COMBIVENT Inhalation Aerosol Study Group. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. Chest 1994; 105:1411-9.
27. van Schayck CP, Folgering H, Harbers H, Maas KL, van Weel C. Effects of allergy and age on responses to salbutamol and ipratropium bromide in moderate asthma and chronic bronchitis.Thorax 1991; 46:355-9.
28. Ulrik CS. Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomised, double blind, placebo controlled, crossover study.Thorax 1995; 50:750-4.
29. Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD) [published erratum appears in Eur Respir J 1997; 10:1696]. Eur Respir J 1997; 10:815-21.
30. Cazzola M, Matera MG, Santangelo G, Vinciguerra A, Rossi F, D'Amato G. Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose-response study. Respir Med 1995; 89:357-62.
31. Ikeda A, Nishimura K, Koyama H, Izumi T. Bronchodilating effects of combined therapy with clinical dosages of ipratropium bromide and salbutamol for stable COPD: comparison with ipratropium bromide alone. Chest 1995; 107:401-5.
32. Guyatt GH, Townsend M, Pugsley SO, Keller JL, Short HD, Taylor DW, et al. Bronchodilators in chronic air-flow limitation. Effects on airway function, exercise capacity, and quality of life. Am Rev Respir Dis 1987; 135:1069-74.
33. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155:1283-9.
34. Mahler DA, Donohue JF, Barbee RA, Goldman MD, Gross NJ, Wisniewski ME, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115:957-65.
35. Shim CS, Williams MH Jr. Bronchodilator response to oral aminophylline and terbutaline versus aerosol albuterol in patients with chronic obstructive pulmonary disease. Am J Med 1983; 75:697-701.
36. Lipworth BJ, McDevitt DG, Struthers AD. Hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy. Protection by conventional doses of spironolactone but not triamterene. Chest 1990; 98:811-5.
37. Uren NG, Davies SW, Jordan SL, Lipkin DP. Inhaled bronchodilators increase maximum oxygen consumption in chronic left ventricular failure. Eur Heart J 1993; 14:744-50.
38. Khoukaz G, Gross NJ. Effects of salmeterol on arterial blood gases in patients with stable chronic obstructive pulmonary disease. Comparison with albuterol and ipratropium. Am J Respir Crit Care Med 1999; 160:1028-30.
39. Barnes PJ. Bronchodilators: basic pharmacology. In: Calverley PMA, Pride NB, eds. Chronic obstructive pulmonary disease. London: Chapman and Hall; 1995. p. 391-417.
40. Aubier M. Pharmacotherapy of respiratory muscles. Clin Chest Med 1988; 9:311-24.
41. Moxham J. Aminophylline and the respiratory muscles: an alternative view. Clin Chest Med 1988; 9:325-36.
42. Murciano D, Auclair MH, Pariente R, Aubier M. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989; 320:1521-5.
43. McKay SE, Howie CA, Thomson AH, Whiting B, Addis GJ. Value of theophylline treatment in patients handicapped by chronic obstructive lung disease.Thorax 1993; 48:227-32.
44. Taylor DR, Buick B, Kinney C, Lowry RC, McDevitt DG. The efficacy of orally administered theophylline, inhaled salbutamol, and a combination of the two as chronic therapy in the management of chronic bronchitis with reversible air-flow obstruction. Am Rev Respir Dis 1985; 131:747-51.
45. The COMBIVENT Inhalation Solution Study Group. Routine nebulized ipratropium and albuterol together are better than either alone in COPD. Chest 1997; 112:1514-21.
46. Gross N, Tashkin D, Miller R, Oren J, Coleman W, Linberg S. Inhalation by nebulization of albuterol-ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration 1998; 65:354-62.
47. van Noord JA, de Munck DR, Bantje TA, Hop WC, Akveld ML, Bommer AM. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 2000; 15:878-85.
48. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life for clinical trials in chronic lung disease.Thorax 1987; 42:773-8.
49. Easton PA, Jadue C, Dhingra S, Anthonisen NR. A comparison of the bronchodilating effects of a beta-2 adrenergic agent (albuterol) and an anticholinergic agent (ipratropium bromide), given by aerosol alone or in sequence. N Engl J Med 1986; 315:735-9.
50. Friedman M, Serby CW, Menjoge SS, Wilson JD, Hilleman DE, Witek TJ Jr. Pharmacoeconomic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 1999; 115:635-41.
51. Tashkin DP, Bleecker E, Braun S, Campbell S, DeGraff AC Jr, Hudgel DW, et al. Results of a multicenter study of nebulized inhalant bronchodilator solutions. Am J Med 1996; 100:62S-9.
52. Callahan CM, Dittus RS, Katz BP. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 1991; 114:216-23.
53. Senderovitz T, Vestbo J, Frandsen J, Maltbaek N, Norgaard M, Nielsen C, et al. Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease. The Danish Society of Respiratory Medicine. Respir Med 1999; 93:715-8.
54. Postma DS, Peters I, Steenhuis EJ, Sluiter HJ. Moderately severe chronic airflow obstruction. Can corticosteroids slow down obstruction? Eur Respir J 1988; 1:22-6.
55. Postma DS, Steenhuis EJ, van der Weele LT, Sluiter HJ. Severe chronic airflow obstruction: can corticosteroids slow down progression? Eur J Respir Dis 1985; 67:56-64.
56. Decramer M, de Bock V, Dom R. Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:1958-64.
57. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994; 150:11-6.
58. Decramer M, Stas KJ. Corticosteroid-induced myopathy involving respiratory muscles in patients with chronic obstructive pulmonary disease or asthma. Am Rev Respir Dis 1992; 146:800-2.
59. Confalonieri M, Mainardi E, Della Porta R, Bernorio S, Gandola L, Beghe B, et al. Inhaled corticosteroids reduce neutrophilic bronchial inflammation in patients with chronic obstructive pulmonary disease.Thorax 1998; 53:583-5.
60. Wilcke JT, Dirksen A. The effect of inhaled glucocortico- steroids in emphysema due to alpha1-antitrypsin deficiency. Respir Med 1997; 91:275-9.
61. Rutgers SR, Koeter GH, van der Mark TW, Postma DS. Short-term treatment with budesonide does not improve hyperresponsiveness to adenosine 5'-monophosphate in COPD. Am J Respir Crit Care Med 1998; 157:880-6.
62. Weiner P, Weiner M, Azgad Y, Zamir D. Inhaled budesonide therapy for patients with stable COPD. Chest 1995; 108:1568-71.
63. Chan CH, Cohen M, Pang J. The effects of inhaled corticosteroids on chronic airflow limitation. Asian Pac J Allergy Immunol 1993; 11:97-101.
64. Wesseling GJ, Quaedvlieg M, Wouters EF. Inhaled budesonide in chronic bronchitis. Effects on respiratory impedance. Eur Respir J 1991; 4:1101-5.
65. Engel T, Heinig JH, Madsen O, Hansen M, Weeke ER. A trial of inhaled budesonide on airway responsiveness in smokers with chronic bronchitis. Eur Respir J 1989; 2:935-9.
66. Boothman-Burrell D, Delany SG, Flannery EM, Hancox RJ, Taylor DR. The efficacy of inhaled corticosteroids in the management of non asthmatic chronic airflow obstruction. N Z Med J 1997; 110:370-3.
67. Shim CS, Williams MH Jr. Aerosol beclomethasone in patients with steroid-responsive chronic obstructive pulmonary disease. Am J Med 1985; 78:655-8.
68. Nishimura K, Koyama H, Ikeda A, Tsukino M, Hajiro T, Mishima M, et al. The effect of high-dose inhaled beclomethasone dipropionate in patients with stable COPD. Chest 1999; 115:31-7.
69. Weir DC, Gove RI, Robertson AS, Burge PS. Response to corticosteroids in chronic airflow obstruction: relationship to emphysema and airways collapse. Eur Respir J 1991; 4:1185-90.
70. Watson A, Lim TK, Joyce H, Pride NB. Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction. Chest 1992; 101:350-5.
71. Auffarth B, Postma DS, de Monchy JG, van der Mark TW, Boorsma M, Koeter GH. Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease.Thorax 1991; 46:372-7.
72. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou J. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. International COPD Study Group [published erratum appears in Lancet 1998; 351:1968]. Lancet 1998; 351:773-80.
73. The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000; 343:1902-9.
74. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 1997. Available from: URL: http://www.nhlbi.nih.gov
75. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 1994; 331:778-84.
76. Edwards KM, Dupont WD, Westrich MK, Plummer WD Jr, Palmer PS, Wright PF. A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 1994; 169:68-76.
77. Hak E, van Essen GA, Buskens E, Stalman W, de Melker RA. Is immunising all patients with chronic lung disease in the community against influenza cost effective? Evidence from a general practice based clinical prospective cohort study in Utrecht, the Netherlands. J Epidemiol Community Health 1998; 52:120-5.
78. Simberkoff MS, Cross AP, Al-Ibrahim M, Baltch AL, Geiseler PJ, Nadler J, et al. Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 315:1318-27.
79. Williams JH, Jr., Moser KM. Pneumococcal vaccine and patients with chronic lung disease. Ann Intern Med 1986; 104:106-9.
80. Davis AL, Aranda CP, Schiffman G, Christianson LC. Pneumococcal infection and immunologic response to pneumococcal vaccine in chronic obstructive pulmonary disease. A pilot study. Chest 1987; 92:204-12.
81. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis: influence of penicillin and tetracylcline administered daily, or intermittently for exacerbations. BMJ 1961; 2:979-85.
82. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis: influence of daily penicillin and tetracycline on exacerbations and their cost. A report to the research committee of the British Tuberculosis Assoication by their Chronic Bronchitis Subcommittee. BMJ 1960; 1:297-303.
83. Fletcher CM, Ball JD, Carstairs LW, Couch AHC, Crofton JM, Edge JR, et al. Value of chemoprophylaxis and chemotherapy in early chronic bronchitis. A report to the Medical Research Council by their Working Party on trials of chemotherapy in early chronic bronchitis. BMJ 1966; 1:1317-22.
84. Johnston RN, McNeill RS, Smith DH, Dempster MB, Nairn JR, Purvis MS, et al. Five-year winter chemoprophylaxis for chronic bronchitis. BMJ 1969; 4:265-9.
85. Isada CM, Stoller JK. Chronic bronchitis: the role of antibiotics. In: Niederman MS, Sarosi GA, Glassroth J, eds. Respiratory infections: a scientific basis for management. London: WB Saunders; 1994. p. 621-33.
86. Siafakas NM, Bouros D. Management of acute exacerbation of chronic obstructive pulmonary disease. In: Postma DS, Siafakas NM, eds. Management of chronic obstructive pulmonary disease. Sheffield: ERS Monograph; 1998. p. 264-77.
87. Allegra L, Cordaro CI, Grassi C. Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial. Respiration 1996; 63:174-80.
88. Guyatt GH, Townsend M, Kazim F, Newhouse MT. A controlled trial of ambroxol in chronic bronchitis. Chest 1987; 92:618-20.
89. Petty TL. The National Mucolytic Study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 1990; 97:75-83.
90. Poole PJ, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2000; 2: Available from: URL: www.update-software.com or www.updatusa.com
91. Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J 1995; 8:1398-420.
92. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 1987; 136:225-44.
93. Hansen NC, Skriver A, Brorsen-Riis L, Balslov S, Evald T, Maltbaek N, et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med 1994; 88:531-5.
94. British Thoracic Society Research Committee. Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction.Thorax 1985; 40:832-5.
95. Boman G, Backer U, Larsson S, Melander B, Wahlander L. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis 1983; 64:405-15.
96. Rasmussen JB, Glennow C. Reduction in days of illness after long-term treatment with N- acetylcysteine controlled-release tablets in patients with chronic bronchitis. Eur Respir J 1988; 1:351-5.
97. Collet JP, Shapiro P, Ernst P, Renzi T, Ducruet T, Robinson A. Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group. Prevention of acute respiratory infection by an immunostimulant . Am J Respir Crit Care Med 1997; 156:1719-24.
98. Anthonisen NR. OM-8BV for COPD [editorial; comment]. Am J Respir Crit Care Med 1997; 156:1713-4.
99. Irwin RS, Boulet LP, Cloutier MM, Fuller R, Gold PM, Hoffstein V, et al. Managing cough as a defense mechanism and as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 114:133-81S.
100. Barbera JA, Roger N, Roca J, Rovira I, Higenbottam TW, Rodriguez-Roisin R. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet 1996; 347:436-40.
101. Jones AT, Evans TW. NO: COPD and beyond.Thorax 1997; 52 Suppl 3:S16-21.
102. Watanabe S, Kanner RE, Cutillo AG, Menlove RL, Bachand RT Jr, Szalkowski MB, et al. Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease. Am Rev Respir Dis 1989; 140:1269-73.
103. Bardsley PA, Howard P, DeBacker W, Vermeire P, Mairesse M, Ledent C, et al. Two years treatment with almitrine bismesylate in patients with hypoxic chronic obstructive airways disease. Eur Respir J 1991; 4:308-10.
104. Winkelmann BR, Kullmer TH, Kneissl DG, Trenk D, Kronenberger H. Low-dose almitrine bismesylate in the treatment of hypoxemia due to chronic obstructive pulmonary disease. Chest 1994; 105:1383-91.
105. Eiser N, Denman WT, West C, Luce P. Oral diamorphine: lack of effect on dyspnoea and exercise tolerance in the "pink puffer" syndrome. Eur Respir J 1991; 4:926-31.
106. Young IH, Daviskas E, Keena VA. Effect of low dose nebulised morphine on exercise endurance in patients with chronic lung disease.Thorax 1989; 44:387-90.
107. Woodcock AA, Gross ER, Gellert A, Shah S, Johnson M, Geddes DM. Effects of dihydrocodeine, alcohol, and caffeine on breathlessness and exercise tolerance in patients with chronic obstructive lung disease and normal blood gases. N Engl J Med 1981; 305:1611-6.
108. Rice KL, Kronenberg RS, Hedemark LL, Niewoehner DE. Effects of chronic administration of codeine and promethazine on breathlessness and exercise tolerance in patients with chronic airflow obstruction. Br J Dis Chest 1987; 81:287-92.
109. Poole PJ, Veale AG, Black PN. The effect of sustained-release morphine on breathlessness and quality of life in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1877-80.
110. American Thoracic Society. Pulmonary rehabilitation-1999. Am J Respir Crit Care Med 1999; 159:1666-82.
111. Fishman AP. Pulmonary rehabilitation research. Am J Respir Crit Care Med 1994; 149:825-33.
112. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel, American College of Chest Physicians and American Association of Cardiovascular and Pulmonary Rehabilitation. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines. Chest 1997; 112:1363-96.
113. Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. Lancet 1996; 348:1115-9.
114. Goldstein RS, Gort EH, Stubbing D, Avendano MA, Guyatt GH. Randomised controlled trial of respiratory rehabilitation. Lancet 1994; 344:1394-7.
115. Wijkstra PJ, Van Altena R, Kraan J, Otten V, Postma DS, Koeter GH. Quality of life in patients with chronic obstructive pulmonary disease improves after rehabilitation at home. Eur Respir J 1994; 7:269-73.
116. O'Donnell DE, McGuire M, Samis L, Webb KA. The impact of exercise reconditioning on breathlessness in severe chronic airflow limitation. Am J Respir Crit Care Med 1995; 152:2005-13.
117. Lake FR, Henderson K, Briffa T, Openshaw J, Musk AW. Upper-limb and lower-limb exercise training in patients with chronic airflow obstruction. Chest 1990; 97:1077-82.
118. Ries AL, Ellis B, Hawkins RW. Upper extremity exercise training in chronic obstructive pulmonary disease. Chest 1988; 93:688-92.
119. Martinez FJ, Vogel PD, Dupont DN, Stanopoulos I, Gray A, Beamis JF. Supported arm exercise vs. unsupported arm exercise in the rehabilitation of patients with severe chronic airflow obstruction. Chest 1993; 103:1397-402.
120. Wijkstra PJ, Ten Vergert EM, van Altena R, Otten V, Kraan J, Postma DS, et al. Long term benefits of rehabilitation at home on quality of life and exercise tolerance in patients with chronic obstructive pulmonary disease.Thorax 1995; 50:824-8.
121. Berry MJ, Rejeski WJ, Adair NE, Zaccaro D. Exercise rehabilitation and chronic obstructive pulmonary disease stage. Am J Respir Crit Care Med 1999; 160:1248-53.
122. Foglio K, Bianchi L, Bruletti G, Battista L, Pagani M, Ambrosino N. Long-term effectiveness of pulmonary rehabilitation in patients with chronic airway obstruction. Eur Respir J 1999; 13:125-32.
123. Young P, Dewse M, Fergusson W, Kolbe J. Improvements in outcomes for chronic obstructive pulmonary disease (COPD) attributable to a hospital-based respiratory rehabilitation programme. Aust N Z J Med 1999; 29:59-65.
124. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, et al. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial [published erratum appears in Lancet 2000; 355:1280]. Lancet 2000; 355:362-8.
125. McGavin CR, Gupta SP, Lloyd EL, McHardy GJ. Physical rehabilitation for the chronic bronchitic: results of a controlled trial of exercises in the home.Thorax 1977; 32:307-11.
126. Wedzicha JA, Bestall JC, Garrod R, Garnham R, Paul EA, Jones PW. Randomized controlled trial of pulmonary rehabilitation in severe chronic obstructive pulmonary disease patients, stratified with the MRC dyspnoea scale. Eur Respir J 1998; 12:363-9.
127. Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of disability in patients with chronic airways obstruction.Thorax 1992; 47:1019-24.
128. Mahler DA. Pulmonary rehabilitation. Chest 1998; 113:263-8S.
129. American College of Sports Medicine position stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness in healthy adults. Med Sci Sports Exerc 1990; 22:265-74.
130. Smith K, Cook D, Guyatt GH, Madhavan J, Oxman AD. Respiratory muscle training in chronic airflow limitation: a meta-analysis. Am Rev Respir Dis 1992; 145:533-9.
131. Belman MJ, Botnick WC, Nathan SD, Chon KH. Ventilatory load characteristics during ventilatory muscle training. Am J Respir Crit Care Med 1994; 149:925-9.
132. Bernard S, Whittom F, Leblanc P, Jobin J, Belleau R, Berube C, et al. Aerobic and strength training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:896-901.
133. Schols AM, Soeters PB, Dingemans AM, Mostert R, Frantzen PJ, Wouters EF. Prevalence and characteristics of nutritional depletion in patients with stable COPD eligible for pulmonary rehabilitation. Am Rev Respir Dis 1993; 147:1151-6.
134. Engelen MP, Schols AM, Baken WC, Wesseling GJ, Wouters EF. Nutritional depletion in relation to respiratory and peripheral skeletal muscle function in out-patients with COPD. Eur Respir J 1994; 7:1793-7.
135. Wilson DO, Rogers RM, Wright EC, Anthonisen NR. Body weight in chronic obstructive pulmonary disease. The National Institutes of Health Intermittent Positive-Pressure Breathing Trial. Am Rev Respir Dis 1989; 139:1435-8.
136. Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1791-7.
137. Gray-Donald K, Gibbons L, Shapiro SH, Macklem PT, Martin JG. Nutritional status and mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:961-6.
138. Gorecka D, Gorzelak K, Sliwinski P, Tobiasz M, Zielinski J. Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia.Thorax 1997; 52:674-9.
139. Efthimiou J, Fleming J, Gomes C, Spiro SG. The effect of supplementary oral nutrition in poorly nourished patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1988; 137:1075-82.
140. Rogers RM, Donahoe M, Costantino J. Physiologic effects of oral supplemental feeding in malnourished patients with chronic obstructive pulmonary disease. A randomized control study. Am Rev Respir Dis 1992; 146:1511-7.
141. Whittaker JS, Ryan CF, Buckley PA, Road JD. The effects of refeeding on peripheral and respiratory muscle function in malnourished chronic obstructive pulmonary disease patients. Am Rev Respir Dis 1990; 142:283-8.
142. Jones PW, Quirk FH, Baveystock CM. The St. George's Respiratory Questionnaire. Respir Med 1991; 85 Suppl B:25-31, discussion 3-7.
143. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473-83.
144. Goldstein RS, Gort EH, Guyatt GH, Feeny D. Economic analysis of respiratory rehabilitation. Chest 1997; 112:370-9.
145. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77-121.
146. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 1980; 93:391-8.
147. Tarpy SP, Celli BR. Long-term oxygen therapy. N Engl J Med 1995; 333:710-4.
148. Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; 1:681-6.
149. Weitzenblum E, Sautegeau A, Ehrhart M, Mammosser M, Pelletier A. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1985; 131:493-8.
150. Zielinski J, Tobiasz M, Hawrylkiewicz I, Sliwinski P, Palasiewicz G. Effects of long-term oxygen therapy on pulmonary hemodynamics in COPD patients: a 6-year prospective study. Chest 1998; 113:65-70.
151. Petty TL. Supportive therapy in COPD. Chest 1998; 113:256-62S.
152. Petty TL, O'Donohue WJ Jr. Further recommendations for prescribing, reimbursement, technology development, and research in long-term oxygen therapy. Summary of the Fourth Oxygen Consensus Conference, Washington, DC, October 15-16, 1993. Am J Respir Crit Care Med 1994; 150:875-7.
153. Pelletier-Fleury N, Lanoe JL, Fleury B, Fardeau M. The cost of treating COPD patients with long-term oxygen therapy in a French population. Chest 1996; 110:411-6.
154. Heaney LG, McAllister D, MacMahon J. Cost minimisation analysis of provision of oxygen at home: are the drug tariff guidelines cost effective? BMJ 1999; 319:19-23.
155. Gong H Jr. Air travel and oxygen therapy in cardiopulmonary patients. Chest 1992; 101:1104-13.
156. Berg BW, Dillard TA, Rajagopal KR, Mehm WJ. Oxygen supplementation during air travel in patients with chronic obstructive lung disease. Chest 1992; 101:638-41.
157. Gong H Jr, Tashkin DP, Lee EY, Simmons MS. Hypoxia-altitude simulation test. Evaluation of patients with chronic airway obstruction. Am Rev Respir Dis 1984; 130:980-6.
158. Christensen CC, Ryg M, Refvem OK, Skjonsberg OH. Development of severe hypoxaemia in chronic obstructive pulmonary disease patients at 2,438 m (8,000 ft) altitude. Eur Respir J 2000; 15:635-9.
159. Muir JF. Pulmonary rehabilitation in chronic respiratory insufficiency. 5. Home mechanical ventilation.Thorax 1993; 48:1264-73.
160. Simonds AK. Negative pressure ventilation in acute hypercapnic chronic obstructive pulmonary disease [editorial; comment].Thorax 1996; 51:1069-70.
161. Corrado A, Gorini M, Villella G, De Paola E. Negative pressure ventilation in the treatment of acute respiratory failure: an old noninvasive technique reconsidered. Eur Respir J 1996; 9:1531-44.
162. Shapiro SH, Ernst P, Gray-Donald K, Martin JG, Wood-Dauphinee S, Beaupre A, et al. Effect of negative pressure ventilation in severe chronic obstructive pulmonary disease. Lancet 1992; 340:1425-9.
163. Hillberg RE, Johnson DC. Noninvasive ventilation. N Engl J Med 1997; 337:1746-52.
164. Strumpf DA, Millman RP, Carlisle CC, Grattan LM, Ryan SM, Erickson AD, et al. Nocturnal positive-pressure ventilation via nasal mask in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1991; 144:1234-9.
165. Meecham Jones DJ, Paul EA, Jones PW, Wedzicha JA. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 1995; 152:538-44.
166. Clini E, Sturani C, Porta R, Scarduelli C, Galavotti V, Vitacca M, et al. Outcome of COPD patients performing nocturnal non-invasive mechanical ventilation. Respir Med 1998; 92:1215-22.
167. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation - a consensus conference report. Chest 1999; 116:521-34.
168. Mehran RJ, Deslauriers J. Indications for surgery and patient work-up for bullectomy. Chest Surg Clin N Am 1995; 5:717-34.
169. Hughes JA, MacArthur AM, Hutchison DC, Hugh-Jones P. Long term changes in lung function after surgical treatment of bullous emphysema in smokers and ex-smokers.Thorax 1984; 39:140-2.
170. Laros CD, Gelissen HJ, Bergstein PG, Van den Bosch JM, Vanderschueren RG, Westermann CJ, et al. Bullectomy for giant bullae in emphysema. J Thorac Cardiovasc Surg 1986; 91:63-70.
171. Cooper JD, Trulock EP, Triantafillou AN, Patterson GA, Pohl MS, Deloney PA, et al. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106-16,; discussion 16-9.
172. Criner G, Cordova FC, Leyenson V, Roy B, Travaline J, Sudarshan S, et al. Effect of lung volume reduction surgery on diaphragm strength. Am J Respir Crit Care Med 1998; 157:1578-85.
173. Martinez FJ, de Oca MM, Whyte RI, Stetz J, Gay SE, Celli BR. Lung-volume reduction improves dyspnea, dynamic hyperinflation, and respiratory muscle function. Am J Respir Crit Care Med 1997; 155:1984-90.
174. Fessler HE, Permutt S. Lung volume reduction surgery and airflow limitation. Am J Respir Crit Care Med 1998; 157:715-22.
175. Cooper JD, Patterson GA, Sundaresan RS, Trulock EP, Yusen RD, Pohl MS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319-29.
176. Russi EW, Stammberger U, Weder W. Lung volume reduction surgery for emphysema. Eur Respir J 1997; 10:208-18.
177. Gelb AF, McKenna RJ Jr, Brenner M, Schein MJ, Zamel N, Fischel R. Lung function 4 years after lung volume reduction surgery for emphysema. Chest 1999; 116:1608-15.
178. Brenner M, McKenna RJ Jr, Gelb AF, Fischel RJ, Wilson AF. Rate of FEV1 change following lung volume reduction surgery. Chest 1998; 113:652-9.
179. Elpern EH, Behner KG, Klontz B, Warren WH, Szidon JP, Kesten S. Lung volume reduction surgery: an analysis of hospital costs. Chest 1998; 113:896-9.
180. Albert RK, Lewis S, Wood D, Benditt JO. Economic aspects of lung volume reduction surgery. Chest 1996; 110:1068-71.
181. Geddes D, Davies M, Koyama H, Hansell D, Pastorino U, Pepper J, et al. Effect of lung-volume-reduction surgery in patients with severe emphysema. N Engl J Med 2000; 343:239-45.
182. Benditt JO, Albert RK. Surgical options for patients with advanced emphysema. Clin Chest Med 1997; 18:577-93.
183. Rationale and design of the National Emphysema Treatment Trial (NETT): A prospective randomized trial of lung volume reduction surgery. J Thorac Cardiovasc Surg 1999; 118:518-28.
184. Trulock EP. Lung transplantation. Am J Respir Crit Care Med 1997; 155:789-818.
185. Theodore J, Lewiston N. Lung transplantation comes of age [editorial; comment]. N Engl J Med 1990; 322:772-4.
186. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The registry of the International Society for Heart and Lung Transplantation: fifteenth official report - 1998. J Heart Lung Transplant 1998; 17:656-68.
187. Annual report of the US scientific registry for transplant recipients and the Organ Procurement and Transplantation Network. Transplant data: 1988-1994. Washington, DC: Division of Transplantation, Health Resources and Services Administration, US Department of Health and Human Services; 1995.
188. Hosenpud JD, Bennett LE, Keck BM, Edwards EB, Novick RJ. Effect of diagnosis on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998; 351:24-7.
189. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation 1998; 66:951-6.
190. Ramsey SD, Patrick DL, Albert RK, Larson EB, Wood DE, Raghu G. The cost effectiveness of lung transplantation. A pilot study. University of Washington Medical Center Lung Transplant Study Group. Chest 1995; 108:1594-601.
191. Al MJ, Koopmanschap MA, van Enckevort PJ, Geertsma A, van der Bij W, de Boer WJ, et al. Cost effectiveness of lung transplantation in the Netherlands: a scenario analysis. Chest 1998; 113:124-30.
192. van Enckevort PJ, Koopmanschap MA, Tenvergert EM, Geertsma A, van der Bij W, de Boer WJ, et al. Lifetime costs of lung transplantation: estimation of incremental costs. Health Econ 1997; 6:479-89.
193. van Enckevort PJ, TenVergert EM, Bonsel GJ, Geertsma A, van der Bij W, de Boer WJ, et al. Technology assessment of the Dutch Lung Transplantation Program. Int J Technol Assess Health Care 1998; 14:344-56.

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 about one-third of severe exacerbations cannot be identified (Evidence B).
• Inhaled bronchodilators (particularly inhaled ß2-agonists and/or anticholinergics), theophylline, and systemic, preferably oral, glucocorticosteroids are effective 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, and/or fever) may benefit from antibiotic treatment (Evidence B).
• Noninvasive intermittent 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).

INTRODUCTION

COPD is often associated with acute exacerbations of symptoms1-4. In patients with Stage I: Mild COPD to Stage II: Moderate COPD, an exacerbation is associated with increased breathlessness, often accompanied by increased cough and sputum production, and may require medical attention outside of the hospital5. The need for medical intervention intensifies as the airflow limitation worsens. Exacerbations in Stage III: Severe COPD are associated with acute respiratory failure, representing a significant burden on the health care system. Hospital mortality of patients admitted for an acute exacerbation of COPD is approximately 10%, and the long-term outcome is poor. Mortality reaches 40% in one year6-9, and is even higher (up to 59%) for patients older than 65 years9. These figures vary from country to country depending on the health care system and the availability of intensive care unit (ICU) beds.

The most common causes of an exacerbation (Figure 5-4-1) are infection of the tracheobronchial tree10-14 and air pollution15, but the cause of about one-third of severe exacerbations cannot be identified6,16. The role of bacterial infections, once believed to be the main cause of COPD exacerbations, is controversial10-14,17-20. Conditions that may mimic an acute exacerbation include pneumonia, congestive heart failure, pneumothorax, pleural effusion, pulmonary embolism, and arrhythmia.

DIAGNOSIS AND ASSESSMENT OF SEVERITY

Medical History

Increased breathlessness, the main symptom of an exacerbation, is often accompanied by wheezing and chest tightness, increased cough and sputum, change of the color and/or tenacity of sputum, and fever. Exacerbations may also be accompanied by a number of nonspecific complaints, such as malaise, insomnia, sleepiness, fatigue, depression, and confusion. A decrease in exercise tolerance, fever, and/or new radiological anomalies suggestive of pulmonary disease may herald a COPD exacerbation. An increase in sputum volume and purulence points to a bacterial cause, as does prior history of chronic sputum production4,14.

Assessment of Severity

Assessment of the severity of an acute exacerbation is based on the patient's medical history before the exacerbation, symptoms, physical examination, lung function tests, arterial blood gas measurements, and other laboratory tests (Figure 5-4-2). Specific information is required on the frequency and severity of attacks of breathlessness and cough, sputum volume and color, and limitation of daily activities. When available, prior tests of lung function and arterial blood gases are extremely useful for comparison with those made during the acute episode, as an acute change in these tests is more important than their absolute values. Thus, where possible, physicians should instruct their patients to bring the summary of their last evaluation when they come to the hospital with an exacerbation. In patients with very severe COPD, the most important sign of a severe exacerbation is a change in the alertness of the patient and this signals a need for immediate evaluation in the hospital.

Lung function tests. Even simple lung function tests can be difficult for a sick patient to perform properly. In general, a PEF < 100 L/min or an FEV1 < 1.00 L indicates a severe exacerbation21-23, except in patients with chronically severe airflow limitation. For instance, an FEV1 of 0.75 L, or a PaO2/FiO2 (FiO2 = fractional concentration of oxygen in dry inspired gas) of 33 kPa (24.5 mm Hg) may be well tolerated by a subject with severe COPD who copes with these values in stable conditions, whereas they may reflect a severe exacerbation for a subject with slightly higher values, e.g., an FEV1 of 0.90 L or a PaO2/FiO2 of 38 kPa (28.2 mm Hg) in stable conditions24.

Arterial blood gases. In the hospital, measurement of arterial blood gases is essential to assess the severity of an exacerbation. A PaO2 < 8.0 kPa (60 mm Hg) and/or SaO2 < 90% when breathing room air indicate respiratory failure. In addition, a PaO2 < 6.7 kPa (50 mm Hg), PaCO2 > 9.3 kPa (70 mm Hg), and pH < 7.30 point toward a life-threatening episode that needs ICU management25.

Chest X-ray and ECG. Chest radiographs (posterior/anterior plus lateral) are useful in identifying alternative diagnoses that can mimic the symptoms of an exacerbation. Although the history and physical signs can be confusing, especially when pulmonary hyperinflation masks coexisting cardiac signs, most problems are resolved by the chest X-ray and ECG. An ECG aids in the diagnosis of right heart hypertrophy, arrhythmias, and ischemic episodes. Pulmonary embolism can be very difficult to distinguish from an acute exacerbation, especially in severe COPD, because right ventricular hypertrophy and large pulmonary arteries lead to confusing ECG and radiographic results. Spiral CT scanning and angiography, and perhaps specific D-dimer assays, are the best tools presently available for the diagnosis of pulmonary embolism in patients with COPD, but ventilation-perfusion scanning is of no value. A low systolic blood pressure and an inability to increase the PaO2 above 8.0 kPa (60 mm Hg) despite high-flow oxygen also suggest pulmonary embolism. If there are strong indications that pulmonary embolism has occurred, it is best to treat for this along with the exacerbation.

Other laboratory tests. The whole blood count may identify polycythemia (hematocrit > 55%) or bleeding. White blood cell counts are usually not very informative. The presence of purulent sputum during an exacerbation of symptoms is sufficient indication for starting empirical antibiotic treatment. Streptococcus pneumoniae, Hemophiles influenzae, and Moraxella catarrhalis are the most common bacterial pathogens involved in COPD exacerbations. If an infectious exacerbation does not respond to the initial antibiotic treatment, a sputum culture and an antibiogram should be performed. Biochemical tests can reveal whether the cause of the exacerbation is an electrolyte disturbance(s) (hyponatremia, hypokalemia, etc.), a diabetic crisis, or poor nutrition (low proteins), and may suggest a metabolic acid-base disorder.

HOME MANAGEMENT

There is increasing interest in home care for end-stage COPD patients, although economic studies of home-care services have yielded mixed results. One study found that quality of life improved and hospital days per admission fell after a home-care program was instituted26, but a randomized controlled trial found that substituting home care for inpatient hospital care produced no better health outcomes while increasing costs27,28. A major outstanding issue is when to treat an exacerbation at home and when to hospitalize the patient.

The algorithm reported in Figure 5-4-3 may assist in the management of an acute exacerbation at home; a stepwise therapeutic approach is recommended29-32.

Home management of COPD exacerbations involves increasing the dose and/or frequency of existing bronchodilator therapy(Evidence A). If not already used, an anticholinergic can be added until the symptoms improve. In more severe cases, high-dose nebulizer therapy can be given on an as-needed basis for several days and if a suitable nebulizer is available. However, long-term use of nebulizer therapy after an acute episode is not routinely recommended.

Glucocorticosteroids

Systemic glucocorticosteroids are beneficial in the management of acute exacerbations of COPD. They shorten recovery time and help to restore lung function more quickly33-35 (Evidence A). They should be considered in addition to bronchodilators if the patient's baseline FEV1 is < 50% predicted. A dose of 40 mg prednisolone per day for 10 days is recommended (Evidence D).

Antibiotics

Antibiotics are only effective when patients with worsening dyspnea and cough also have increased sputum volume and purulence4(Evidence B). The choice of agents should reflect local patterns of antibiotic sensitivity among S. pneumoniae, H. influenzae, and M. catarrhalis.

HOSPITAL MANAGEMENT

The risk of dying from an acute exacerbation of COPD is closely related to the development of respiratory acidosis, the presence of significant co-morbidities, and the need for ventilatory support6. Patients lacking these features are not at high risk of dying, but those with severe underlying COPD often require hospitalization in any case. Attempts at managing such patients entirely in the community have met with only limited success28, but returning them to their homes with increased social support and a supervised medical care package after initial emergency room assessment has been much more successful36. Several randomized controlled trials have confirmed that this is a safe alternative to hospitalization, although it probably only applies to about 25% of COPD admissions. Savings on inpatient expenditures37 offset the additional costs of maintaining a community-based COPD nursing team. However, detailed cost-benefit analyses of these approaches are awaited.

Hospital assessment/admission should be considered for all patients who fit the criteria shown in Figure 5-4-4. Some patients need immediate admission to an intensive care unit (ICU). Admission of patients with severe COPD exacerbations to intermediate or special respiratory care units may be appropriate if personnel, skills, and equipment exist to identify and manage acute respiratory failure successfully.

Emergency Department or Hospital

The first actions when a patient reaches the emergency department are to provide controlled oxygen therapy and to determine whether the exacerbation is life threatening. If so, the patient should be admitted to the ICU immediately. Otherwise, the patient may be managed in the emergency department or hospital as detailed in Figure 5-4-6.

Controlled oxygen therapy. Oxygen therapy is the cornerstone of hospital treatment of COPD exacerbations. Adequate levels of oxygenation (PaO2 > 8.0 kPa, 60 mm Hg, or SaO2 > 90%) are easy to achieve in uncomplicated exacerbations, but CO2 retention can occur insidiously with little change in symptoms. Once oxygen is started, arterial blood gases should be checked 30 minutes later to ensure satisfactory oxygenation without CO2retention or acidosis. Venturi masks are more accurate sources of controlled oxygen than are nasal prongs but are more likely to be removed by the patient.

Bronchodilator therapy. Short-acting inhaled ß2-agonists are usually the preferred bronchodilators for treatment of acute exacerbations of COPD30,31,38 (Evidence A). If a prompt response to these drugs does not occur, the addition of an anticholinergic is recommended, even though evidence concerning the effectiveness of this combination is rather controversial39,40. Despite its widespread clinical use, aminophylline’s role in the treatment of exacerbations of COPD remains controversial. Most studies of aminophylline have demonstrated minor improvements in lung volumes but also worsening of gas exchange and hypoxemia41,42. In more severe exacerbations, addition of an oral or intravenous methylxanthine to the treatement can be considered. However, close monitoring of serum theophylline is recommended to avoid the side effects of these drugs41,43-45.

Glucocorticosteroids. Oral or intravenous glucocorticosteroids are recommended as an addition to bronchodilator therapy (plus eventually antibiotics and oxygen therapy) in the hospital management of acute exacerbations of COPD33-35 (Evidence A). The exact dose that should be recommended is not known, but high doses are associated with a significant risk of side effects. Thirty to 40 mg of oral prednisolone daily for 10 to 14 days is a reasonable compromise between efficacy and safety (Evidence D). Prolonged treatment does not result in greater efficacy and increases the risk of side effects.
Antibiotics. Antibiotics are only effective when patients with worsening dyspnea and cough also have increased sputum volume and purulence4. The choice of agents should reflect local patterns of antibiotic sensitivity among S. pneumoniae, H. influenzae, and M. catarrhalis.

Ventilatory support. The primary objectives of mechanical support in patients with acute exacerbations in Stage III: Severe COPD are to decrease mortality and morbidity and to relieve symptoms. Ventilatory support includes both noninvasive mechanical ventilation using either negative or positive pressure devices, and invasive (conventional) mechanical ventilation by oro/naso-tracheal tube or tracheostomy.

Noninvasive mechanical ventilation. Noninvasive intermittent positive pressure ventilation (NIPPV) has been studied in many uncontrolled and five randomized controlled trials in acute respiratory failure46. The studies show consistently positive results with success rates of 80-85%47. Taken together they provide evidence that NIPPV increases pH, reduces PaCO2, reduces the severity of breathlessness in the first 4 hours of treatment, and decreases the length of hospital stay (Evidence A). More importantly, mortality - or its surrogate, intubation rate - is reduced by this intervention48-51. However, NIPPV is not appropriate for all patients, as summarized in Figure 5-4-747.

Invasive (conventional) mechanical ventilation. During exacerbations of COPD the events occurring within the lungs include bronchoconstriction, airway inflammation, increased mucous secretions, and loss of elastic recoil, all of which prevent the respiratory system from reaching its passive functional residual capacity at the end of expiration, enhancing dynamic hyperinflation52. As a result of these processes, an elastic threshold load, referred to as intrinsic or auto-positive end-expiratory pressure (PEEPi), is imposed on the inspiratory muscles at the beginning of inspiration and increases the work of breathing. For these reasons, patients who show impending acute respiratory failure and those with life-threatening acid-base status abnormalities and/or altered mental status despite aggressive pharmacologic therapy are likely to be the best candidates for invasive (conventional) mechanical ventilation. The indications for initiating mechanical ventilation during exacerbations of COPD are shown in Figure 5-4-8, the first being the commonest and most important reason. Figure 5-4-9 details the factors determining benefit from invasive ventilation. The three ventilatory modes most widely used are assisted-control ventilation, and pressure support ventilation alone or in combination with intermittent mandatory ventilation53.

The use of invasive ventilation in end-stage COPD patients is influenced by the likely reversibility of the precipitation event, the patient’s wishes, and the availability of intensive care facilities. Major hazards include the risk of ventilator-acquired pneumonia (especially when multi-resistant organisms are prevalent), barotrauma, and failure to wean to spontaneous ventilation. Contrary to some opinions, mortality among COPD patients with respiratory failure is no greater than mortality among patients ventilated for non-COPD causes.

A review of a large number of North American COPD patients ventilated for respiratory failure indicated an in-hospital mortality of 17-30%54. Further attrition over the next 12 months was particularly high among those patients who had poor lung function before ventilation (FEV1 < 30% predicted), had a non-respiratory comorbidity, or were housebound. Patients who did not have a previously diagnosed underlying disease, had respiratory failure due to a potentially reversible cause (such as an infection), or were relatively mobile and not using long-term oxygen did surprisingly well with ventilatory support. When possible, a clear statement of the patient's own treatment wishes - an advance directive or "living will" - makes these difficult decisions much easier to resolve.

Weaning or discontinuation from mechanical ventilation can be particularly difficult and hazardous in patients with COPD. The most influential determinant of mechanical ventilatory dependency in these patients is the balance between the respiratory load and the capacity of the respiratory muscles to cope with this load55. By contrast, pulmonary gas exchange by itself is not a major difficulty in patients with COPD56-58. Weaning patients from the ventilator can be a very difficult and prolonged process and the best method remains a matter of debate59,68. Whether pressure support or a T-piece trial is used, weaning is shortened when a clinical protocol is adopted (Evidence A). Non-invasive ventilation has been applied to facilitate the weaning process in COPD patients with acute or chronic respiratory failure54. Compared with invasive pressure support ventilation, noninvasive intermittent positive pressure ventilation (NIPPV) during weaning shortened weaning time, reduced the stay in the intensive care unit, decreased the incidence of nosocomial pneumonia, and improved 60-day survival rates. Similar findings have been reported when NIPPV is used after extubation for hypercapnic respiratory failure61 (Evidence C).

Other measures. Further treatments that can be used in the hospital include: fluid administration (accurate monitoring of fluid balance is essential); nutrition (supplementary when the patient is too dyspneic to eat); low molecular heparin in immobilized, polycythemic, or dehydrated patients with or without a history of thromboembolic disease; and sputum clearance (by stimulating coughing and low-volume forced expirations as in home management). Manual or mechanical chest percussion and postural drainage may be beneficial in patients producing > 25 ml sputum per day or with lobar atelectasis.

Hospital Discharge and Follow-Up

Insufficient clinical data exist to establish the optimal duration of hospitalization in individual patients developing an exacerbation of COPD1,62,63. Consensus and limited data support the discharge criteria listed in Figure 5-4-10. Figure 5-4-11 provides items to include in a follow-up assessment 4 to 6 weeks after discharge from the hospital. Thereafter, follow-up is the same as for stable COPD, including supervising smoking cessation, monitoring the effectiveness of each drug treatment, and monitoring changes in spirometric parameters38.

If hypoxemia developed during the exacerbation, arterial blood gases should be rechecked at discharge and at the follow-up visit. If the patient remains hypoxemic, long-term oxygen therapy should be instituted. Decisions about suitability for continuous domiciliary oxygen based on the severity of the acute hypoxemia during an exacerbation are frequently misleading.

The opportunities for prevention of future exacerbations should be reviewed before discharge, with particular attention to future influenza vaccination plans, knowledge about current therapy including inhaler technique641, 65, and how to recognize symptoms of exacerbations. Pharmacotherapy known to reduce the number of exacerbations should be considered. Social problems should be discussed and principal caregivers identified if the patient has a significant persisting disability.

REFERENCES

1. Regueiro CR, Hamel MB, Davis RB, Desbiens N, Connors AF Jr, Phillips RS. A comparison of generalist and pulmonologist care for patients hospitalized with severe chronic obstructive pulmonary disease: resource intensity, hospital costs, and survival. SUPPORT investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment. Am J Med 1998; 105:366-72.
2. Gibson PG, Wlodarczyk JH, Wilson AJ, Sprogis A. Severe exacerbation of chronic obstructive airways disease: health resource use in general practice and hospital. J Qual Clin Pract 1998; 18:125-33.
3. Warren PM, Flenley DC, Millar JS, Avery A. Respiratory failure revisited: acute exacerbations of chronic bronchitis between 1961-68 and 1970-76. Lancet 1980; 1:467-70.
4. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106:196-204.
5. Thompson AB, Mueller MB, Heires AJ, Bohling TL, Daughton D, Yancey SW, et al. Aerosolized beclomethasone in chronic bronchitis. Improved pulmonary function and diminished airway inflammation. Am Rev Respir Dis 1992; 146:389-95.
6. Connors AF Jr, Dawson NV, Thomas C, Harrell FE Jr, Desbiens N, Fulkerson WJ, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments) [published erratum appears in Am J Respir Crit Care Med 1997; 155:386]. Am J Respir Crit Care Med 1996; 154:959-67.
7. Kong GK, Belman MJ, Weingarten S. Reducing length of stay for patients hospitalized with exacerbation of COPD by using a practice guideline. Chest 1997; 111:89-94.
8. Fuso L, Incalzi RA, Pistelli R, Muzzolon R, Valente S, Pagliari G, et al. Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease. Am J Med 1995; 98:272-7.
9. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA 1995; 274:1852-7.
10. Macfarlane JT, Colville A, Guion A, Macfarlane RM, Rose DH. Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the community. Lancet 1993; 341:511-4.
11. Smith CB, Kanner RE, Golden CA, Klauber MR, Renzetti AD Jr. Effect of viral infections on pulmonary function in patients with chronic obstructive pulmonary diseases. J Infect Dis 1980; 141:271-80.
12. Soler N, Torres A, Ewig S, Gonzalez J, Celis R, El-Ebiary M, et al. Bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (COPD) requiring mechanical ventilation. Am J Respir Crit Care 1998; 157:1498-505.
13. Wilson R. The role of infection in COPD. Chest 1998; 113:242-8S.
14. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest 2000; 117:1638-45.
15. Anderson HR, Spix C, Medina S, Schouten JP, Castellsague J, Rossi G, et al. Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project. Eur Respir J 1997; 10:1064-71.
16. Chodosh S, McCarty J, Farkas S, Drehobl M, Tosiello R, Shan M, et al. Randomized, double-blind study of ciprofloxacin and cefuroxime axetil for treatment of acute bacterial exacerbations of chronic bronchitis. The Bronchitis Study Group. Clin Infect Dis 1998; 27:722-9.
17. Walsh EE, Falsey AR, Hennessey PA. Respiratory syncytial and other virus infections in persons with chronic cardiopulmonary disease. Am J Respir Crit Care 1999; 160:791-5.
18. Mogulkoc N, Karakurt S, Isalska B, Bayindir U, Celikel T, Korten V, et al. Acute purulent exacerbation of chronic obstructive pulmonary disease and Chlamydia pneumoniae infection. Am J Respir Crit Care Med 1999; 160:349-53.
19. Murphy TF, Sethi S, Klingman KL, Brueggemann AB, Doern GV. Simultaneous respiratory tract colonization by multiple strains of nontypeable Haemophilus influenzae in chronic obstructive pulmonary disease: implications for antibiotic therapy. J Infect Dis 1999; 180:404-9.
20. Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA, Maldonado JA, Gallego M. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest 1999; 116:40-6.
21. Emerman CL, Effron D, Lukens TW. Spirometric criteria for hospital admission of patients with acute exacerbation of COPD. Chest 1991; 99:595-9.
22. Emerman CL, Lukens TW, Effron D. Physician estimation of FEV1 in acute exacerbation of COPD. Chest 1994; 105:1709-12.
23. Emerman CL, Cydulka RK. Use of peak expiratory flow rate in emergency department evaluation of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 1996; 27:159-63.
24. Barbera JA, Roca J, Ferrer A, Felez MA, Diaz O, Roger N, et al. Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease. Eur Respir J 1997; 10:1285-91.
25. Emerman CL, Connors AF, Lukens TW, Effron D, May ME. Relationship between arterial blood gases and spirometry in acute exacerbations of chronic obstructive pulmonary disease. Ann Emerg Med 1989; 18:523-7.
26. Miles-Tapping C. Home care for chronic obstructive pulmonary disease: impact of the Iqaluit program. Arctic Med Res 1994; 53:163-75.
27. Shepperd S, Harwood D, Gray A, Vessey M, Morgan P. Randomised controlled trial comparing hospital at home care with inpatient hospital care. II: cost minimisation analysis. BMJ 1998; 316:1791-6.
28. Shepperd S, Harwood D, Jenkinson C, Gray A, Vessey M, Morgan P. Randomised controlled trial comparing hospital at home care with inpatient hospital care. I: three month follow up of health outcomes. BMJ 1998; 316:1786-91.
29. Celli BR. Current thoughts regarding treatment of chronic obstructive pulmonary disease. Med Clin North Am 1996; 80:589-609.
30. Siafakas NM, Vermeire P, Pride NB, Paoletti P, Gibson J, Howard P, et al. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J 1995; 8:1398-420.
31. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995; 152:S77-121.
32. Sachs FL. Chronic bronchitis. Clin Chest Med 1981; 2:79-89.
33. Thompson WH, Nielson CP, Carvalho P, Charan NB, Crowley JJ. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996; 154:407-12.
34. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354:456-60.
35. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med, 1999; 340:1941-7.
36. Gravil JH, Al-Rawas OA, Cotton MM, Flanigan U, Irwin A, Stevenson RD. Home treatment of exacerbations of chronic obstructive pulmonary disease by an acute respiratory assessment service. Lancet 1998; 351:1853-5.
37. Soderstrom L, Tousignant P, Kaufman T. The health and cost effects of substituting home care for inpatient acute care: a review of the evidence. CMAJ 1999; 160:1151-5.
38. The COPD Guidelines Group of the Standards of Care Committee of the BTS. BTS guidelines for the management of chronic obstructive pulmonary disease. Thorax 1997; 52 Suppl 5:S1-28.
39. Moayyedi P, Congleton J, Page RL, Pearson SB, Muers MF. Comparison of nebulised salbutamol and ipratropium bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease. Thorax 1995; 50:834-7.
40. Fernandez A, Munoz J, de la Calle B, Alia I, Ezpeleta A, de la Cal MA, et al. Comparison of one versus two bronchodilators in ventilated COPD patients. Intensive Care Med 1994; 20:199-202.
41. Barbera JA, Reyes A, Roca J, Montserrat JM, Wagner PD, Rodriguez-Roisin R. Effect of intravenously administered aminophylline on ventilation/perfusion inequality during recovery from exacerbations of chronic obstructive pulmonary disease. Am Rev Respir Dis 1992; 145:1328-33.
42. Mahon JL, Laupacis A, Hodder RV, McKim DA, Paterson NA, Wood TE, et al. Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice. Chest 1999; 115:38-48.
43. Lloberes P, Ramis L, Montserrat JM, Serra J, Campistol J, Picado C, et al. Effect of three different bronchodilators during an exacerbation of chronic obstructive pulmonary disease. Eur Respir J 1988; 1:536-9.
44. Murciano D, Aubier M, Lecocguic Y, Pariente R. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 1984; 311:349-53.
45. Emerman CL, Connors AF, Lukens TW, May ME, Effron D. Theophylline concentrations in patients with acute exacerbation of COPD. Am J Emerg Med 1990; 8:289-92.
46. Meyer TJ, Hill NS. Noninvasive positive pressure ventilation to treat respiratory failure. Ann Intern Med 1994; 120:760-70.
47. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation--a consensus conference report. Chest 1999; 116:521-34.
48. Bott J, Carroll MP, Conway JH, Keilty SE, Ward EM, Brown AM, et al. Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease. Lancet 1993; 341:1555-7.
49. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995; 333:817-22.
50. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 1995; 151:1799-806.
51. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet 2000; 355:1931-5.
52. Rossi A, Gottfried SB, Higgs BD, Zocchi L, Grassino A, Milic-Emili J. Respiratory mechanics in mechanically ventilated patients with respiratory failure. J Appl Physiol 1985; 58:1849-58.
53. Esteban A, Anzueto A, Alia I, Gordo F, Apezteguia C, Palizas F, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med 2000; 161:1450-8.
54. Keenan SP, Kernerman PD, Cook DJ, Martin CM, McCormack D, Sibbald WJ. Effect of noninvasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: a meta-analysis. Crit Care Med 1997; 25:1685-92.
55. Purro A, Appendini L, De Gaetano A, Gudjonsdottir M, Donner CF, Rossi A. Physiologic determinants of ventilator dependence in long-term mechanically ventilated patients. Am J Respir Crit Care Med 2000; 161:1115-23.
56. Torres A, Reyes A, Roca J, Wagner PD, Rodriguez-Roisin R. Ventilation-perfusion mismatching in chronic obstructive pulmonary disease during ventilator weaning. Am Rev Respir Dis 1989; 140:1246-50.
57. Beydon L, Cinotti L, Rekik N, Radermacher P, Adnot S, Meignan M, et al. Changes in the distribution of ventilation and perfusion associated with separation from mechanical ventilation in patients with obstructive pulmonary disease. Anesthesiology 1991; 75:730-8.
58. Nava S, Ambrosino N, Clini E, Prato M, Orlando G, Vitacca M, et al. Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial. Ann Intern Med 1998; 128:721-8.
59. Esteban A, Frutos F, Tobin MJ, Allia I, Solsona JF, Valverdu I, et al., for the Spanish Lung Failure Collaborative Group. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med 1995;332:345-50.
60. Brochard L, Rauss A, Benito S, Conti G, Mancebo J, Rekik N, et al. Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 1994; 150:896-903
61. Hilbert G, Gruson D, Portel L, Gbikpi-Benissan G, Cardinaud JP. Noninvasive pressure support ventilation in COPD patients with postextubation hypercapnic respiratory insufficiency. Eur Respir J 1998; 11:1349-53.
62. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 159:158-64.
63. Mushlin AI, Black ER, Connolly CA, Buonaccorso KM, Eberly SW. The necessary length of hospital stay for chronic pulmonary disease. JAMA 1991; 266:80-3.
64. Stoller JK, Lange PA. Inpatient management of chronic obstructive pulmonary disease. Respir Care Clin N Am 1998; 4:425-38.
65. Peach H, Pathy MS. Follow-up study of disability among elderly patients discharged from hospital with exacerbations of chronic bronchitis. Thorax 1981; 36:585-9.

    Top

    
    

A better understanding of the molecular and cellular pathogenic mechanisms of COPD should lead to many new directions for both basic and clinical investigations. Improved methods of 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 and future program goals are provided to stimulate the efforts of investigators around the world. There are many additional avenues to explore.

• Until there is a better understanding of the causal mechanisms of COPD, an absolutely rigid definition of COPD, and its relationship to other obstructive airways diseases, will remain controversial. The defining characteristics of COPD should be better identified.
• The stages and natural history of COPD vary from one patient to another. The clinical utility of the four-stage classification of severity used in the GOLD Report needs to be evaluated.
• Surrogate markers of inflammation, possibly derived from the analysis of 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.
• Information is needed about the cellular and molecular mechanisms involved in inflammation in stable COPD and 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.
• 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.
• 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.
• Data are needed on the use, cost, and relative distribution of medical and non-medical 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 workers 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.
• 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.
• Since 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 is effective in directing management decisions in COPD outcomes are required.
• 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 increasing 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 homes.
• The specific components of effective education for COPD patients need to be determined. It is not known, for example, whether COPD patients 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.
• 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 are 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.
• Collecting and evaluating data to classify COPD exacerbations by severity would stimulate standardization of this outcome measure that is so frequently used in clinical trials. Further exploration of the ethical principles of life support and greater insight into the behavioral influences that inhibit discussion of such intangible issues are needed, along with studies to define the needs of end-stage COPD patients.
• 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 COPD patients.

Bronchodilators: Bronchodilators are the mainstay of symptomatic therapy and new short-acting and long-acting bronchodilators are anticipated. With the recognition that there are different subtypes of muscarinic receptors, there has been a search for more selective antagonists. Tiotropium bromide, a new drug in advanced clinical trials, is a quaternary ammonium compound like ipratropium bromide, but with the unique property of kinetic selectivity and very long duration of action. Selective phosphodiesterase type IV inhibitors might combine bronchodilator and anti-inflammatory activity.

Mediator antagonists: Attention has largely focused on mediators involved in recruitment and activation of neutrophils, and reactive oxygen species. In this category are the LTB4 antagonists, lipoxygenase inhibitors, chemokine inhibitors, and TNF- inhibitors.

Antioxidants: Oxidative stress is increased in patients with COPD, particularly during exacerbations. Oxidants are present in cigarette smoke and are produced endogenously by activated inflammatory cells, including neutrophils and alveolar macrophages, suggesting that antioxidants may be of use in therapy for COPD.

Anti-inflammatory drugs: The limited value of glucocorticosteroids in reducing inflammation in COPD suggests that novel types of nonsteroidal anti-inflammatory treatment may be needed. There are several new approaches to anti-inflammatory treatment in COPD including, for example, phosphodiesterase inhibitors, transcription factor NF-kB inhibitors, and adhesion molecule blockers.

Proteinase inhibitors: There is compelling evidence that an imbalance between proteinases that digest elastin (and other structural proteins) and antiproteinases that protect against this digestion exists in COPD. Considerable progress has been made in identifying the enzymes involved in elastolytic activity in emphysema and in characterizing the endogenous antiproteinases that counteract this activity, including neutrophil elastase inhibitors, cathepsin G and proteinase 3 inhibitors, and matrix metalloproteinase inhibitors. Other serine proteinase inhibitors (serpins), such as elafin, may also be important in counteracting elastolytic activity in the lung.

Mucoregulators: It may be important to develop drugs that inhibit the hypersecretion of mucus, without suppressing the normal secretion of mucus or impairing mucociliary clearance. There are several types of mucoregulatory drugs in development including tachykinin antagonists, sensory neuropeptide inhibitors, mediator and enzyme inhibitors, mucin gene suppressors, mucolytic agents, macrolide antibiotics, and purinoceptor blockers.

Alveolar repair: A major mechanism of airway obstruction in COPD is loss of elastic recoil due to proteolytic destruction of the lung parenchyma. Thus, it seems unlikely that this obstruction can be reversed by drug therapy, although it might be possible to reduce the rate of progression by preventing the inflammatory and enzymatic disease processes. It is even possible that drugs might be developed to stimulate regrowth of alveoli. Retinoic acid increases the number of alveoli in rats and, remarkably, reverses the histological and physiological changes induced by elastase treatment. The molecular mechanisms involved and whether this can be extrapolated to humans are not yet known. Several retinoic acid receptor subtype agonists have now been developed that may have a greater selectivity for this effect. Hepatocyte growth factor (HGF) has a major effect on the growth of alveoli in the fetal lung, and it is possible that in the future drugs might be developed that switch on responsiveness to HGF in adult lung or mimic the action of HGF.

Route of delivery: Many inhalers that deliver bronchodilators have been optimized to deliver drugs to the respiratory tract in asthma. Methods to quickly and safely deliver medications to target sites of inflammation and tissue destruction in COPD need to be evaluated.