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.
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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.

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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.

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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.

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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.

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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

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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.
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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.
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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