Clinical Research in Chronic Obstructive Pulmonary Disease

Needs and Opportunities

NHLBI Workshop Summary

Published in Am J Respir Crit Care Med Vol 167. pp 1142-1149, 2003 Internet address: www.atsjournal.org

Thomas L. Croxton, Gail G. Weinmann, Robert M. Senior, Robert A. Wise, James D. Crapo, and A. Sonia Buist

Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Departments of Medicine and of Cell Biology and Physiology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri; Department of Medicine, The Johns Hopkins University, Baltimore, Maryland; Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado; and Department of Medicine, Oregon Health and Science University, Portland, Oregon

Chronic obstructive pulmonary disease (COPD) is a common condition, and one difficult to manage. Available treatments, other than smoking cessation, are only minimally effective, and the knowledge basis for clinical decision making is limited. To identify areas in which further clinical research may lead to significant improvements in the care of patients with COPD, the National Heart, Lung, and Blood Institute convened a Working Group, entitled "Clinical Research in COPD: Needs and Opportunities," on March 21-22, 2002. This group of experts identified important questions in the field and made the following recommendations: (1 ) establish a multicenter Clinical Research Network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD; (2 ) create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data; (3 ) develop standards for the classification and staging of COPD; (4 ) characterize the development and progression of COPD using measures and biomarkers that relate to current concepts of pathogenesis; and (5 ) evaluate indications for long-term oxygen therapy for patients with COPD.

Keywords: chronic obstructive pulmonary disease; lung diseases, obstructive; National Institutes of Health

Chronic obstructive pulmonary disease (COPD) causes more than 500,000 hospitalizations and more than 100,000 deaths in the United States each year (1, 2). In addition, millions of Americans are disabled as a result of this disease. Unfortunately, the treatment options available to patients with COPD and their physicians are limited, and no pharmacologic therapy slows the progressive loss of lung function that occurs. Smoking cessation slows the decline in FEV1, but the sustained quit rates attained by intensive smoking cessation in­terventions are low. Long-term oxygen therapy is the only other treatment that has been shown to improve survival, but oxygen appears to extend life by less than 2 years in patients with advanced disease (3).

Because of the health burden imposed by COPD and the urgent need for better management of this disease, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on March 21-22, 2002 to examine needs and opportunities for clinical research in COPD. This article summarizes background information considered by the Working Group, lists important questions that were raised, and reports specifc recommendations. Recommendations from a complementary Working Group, focused primarily on basic science issues related to COPD, were reported previously (4).

STATUS OF COPD IN THE UNITED STATES

What is COPD? Issues of Diagnosis and Awareness
COPD is usually defined in terms of physiology--a condition of airflow limitation that is due to both airway and airspace disease, is relatively stable , and is only partially alleviated by bronchodilator drugs (5). The airflow limitation typically progresses slowly over time. Other descriptions emphasize specific aspects of the COPD spectrum (e.g., chronic bronchitis or emphysema) or clinical presentation (e.g., chronic dyspnea, usually in a long-term smoker with productive cough). The phrase "abnormal inflammatory response of the lung to noxious particles or gases" found in the NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease definition of COPD may portend future emphasis on pathogenetic mechanisms in descriptions of COPD (6).

A profusion of terminology used with COPD causes confusion among patients, if not among physicians. Many patients diagnosed with smokers' lung, emphysema, bronchitis, chronic bronchitis, chronic obstructive bronchitis, or obstructive lung disease do not even realize that they have COPD. This multiplicity of names complicates epidemiologic studies of COPD: self report of physician diagnosis is a poor measure of COPD prevalence, and reports of impaired lung function from the National Health and Nutrition Examination Survey (NHANES) III carefully defined "obstructive" but included in the analysis those in whom the impairments may not have been "chronic" (e.g., viral infection), "pulmonary" (e.g., congestive heart failure), or "disease" (e.g., normal subjects with outlier laboratory values) (7). Although the risk of lung cancer is common knowledge, few smokers recognize "COPD" as a threat that is nearly as likely to kill them and far more likely to severely disable them.

Burden of Disease in the United States

Despite limitations of the epidemiologic data, it is abundantly clear that COPD is a tremendous public health problem whose risk factors, in particular genetic risk factors, are poorly understood. COPD typically occurs insidiously in individuals with a long history of cigarette smoking, which usually begins at about age 15. Who will and who will not develop COPD cannot usually be ascertained until middle age, and an additional 15 years may pass between the onset of detectable disease and physician diagnosis of COPD. Only about 15% of chronic smokers develop clinically significant COPD, and fewer than 15% of these are diagnosed with emphysema (5). Significant factors for disease risk within the population of smokers have not been identified. On the other hand, about 15% of cases are not attributable to cigarettes, and the causes of disease in this minority are poorly characterized (5). COPD afflicts more than 15 million Americans, results in more than 15 million physician office visits each year, and causes approximately 150 million days of disability per year (8-10). The total direct cost of medical care related to COPD is approximately $15 billion per year (11).

This dire situation is not expected to improve for years. COPD has risen to become the fourth leading cause of death in the United States (2). Fewer than half of those in this country with airflow limitation that can be detected by spirometry have been diagnosed with an obstructive lung disease, and the remainder are presumably unaware of their high risk for progressive loss of lung function (7). Only a fourth of willing participants in smoking cessation programs become sustained quitters, and the prevalence of current smoking is fairly constant at one fourth of American adults (12). Especially discouraging is the fact that a fourth of high school students smoke (13). Each day, as nearly 300 of their forebears die, 6,000 children try their first cigarette and 3,000 advance to daily smoking (14).

Medical and Surgical Management of COPD

The only intervention of proven value in early-stage COPD is smoking cessation. The Lung Health Study demonstrated that those randomized to a smoking cessation program had better pulmonary function 11 years later than those who received usual care, and the rate of decline in FEV1 in sustained quitters was similar to that seen in nonsmokers (15). Unfortunately, smoking interventions achieve long-term cessation in only a minority of participants. It is not yet known if the original intensive smoking cessation intervention will alter mortality in the Lung Health Study cohort (intent to treat analysis).

The only medical therapy shown to improve survival in COPD is long-term oxygen administration to individuals with advanced disease and low arterial oxygen levels. Controlled clinical trials performed more than 20 years ago demonstrated enhanced survival with oxygen supplementation in those with severe arterial hypoxemia (3, 16). This effect was greatest in those for whom oxygen was prescribed 24 hours per day. No comparable studies have satisfactorily assessed the value of oxygen therapy in those with less severe hypoxemia or with isolated nocturnal or exercise-related oxyhemoglobin desaturation, although supplemental oxygen is often used in these situations.Furthermore, possible effects of oxygen supplementation on quality of life, depression, and cognitive function have not been well studied.

Bronchodilators are commonly used in COPD to provide symp­tomatic relief, but they do not retard the progression of the disease as measured by decline in FEV1 (5). Anticholinergics, long-and short-acting beta-adrenergic agonists, or formulations combining these classes of drugs, appear to decrease dyspnea, increase FEV1, decrease the frequency of reported exacerbations, and improve quality of life (17, 18). Theophylline may be of benefit in some patients, even in the absence of measurable bronchodilation (19).

Regular use of inhaled corticosteroids may reduce symptoms, frequency of exacerbations, and numbers of outpatient physician visits in patients with moderate or severe COPD, but does not affect the rate of decline in postbronchodilator FEV1 (20, 21). Courses of systemic corticosteroids begun during an acute exacerbation appear to speed the recovery of lung function, reduce the length of hospitalization, and decrease the frequency of treatment failure (22, 23). However, chronic use of systemic corticosteroids does not improve the course of COPD, and may increase mortality (6, 24).

Antibiotics are often given for exacerbations of COPD, in part because of an association of bacterial infection with exacerba­tions in some cases (25). Clinical trials examining the effects of antibiotics have shown benefits, albeit inconsistently, with respect to peak expiratory flow rate and duration of exacerbation (26, 27). The benefit of antibiotics appears to be greatest in those with more severe exacerbations or more severe disease. It is noteworthy that most studies of antibiotics were performed 30-45 years ago and that the antibiotics most commonly used today for exacerbations have not been tested in clinical trials for COPD.

Because excess production of mucus is a prominent feature in many patients with COPD, there is longstanding interest in drugs that regulate mucous secretions. Experts disagree with regard to the clinical value of mucolytic agents in COPD. The ATS Statement of 1995 allowed, but did not encourage, the use of mucokinetic agents, and the recent Global Initiative for Chronic Obstructive Lung Disease guidelines judged the overall effects of these drugs to be small, and did not recommend their widespread use (5, 6). However, a recent Cochrane Review meta-analysis found significant effects of mucolytics in reducing exacerbations in stable chronic bronchitis and COPD (28). Because none of the available drugs is a particularly effective mucoregulatory agent, the real potential of this general therapeutic approach has yet to be tested.

Pulmonary rehabilitation is a multidisciplinary intervention that combines an exercise program with behavioral, psychosocial, and educational support. There is strong evidence that such programs increase exercise tolerance and decrease dyspnea, and there is weaker evidence for improvements in quality of life and use of health care resources (29, 30). No significant increase in survival has yet been demonstrated; longer-term results from short-term programs have shown inconsistent results.

Lung transplantation is a conceptually attractive treatment for COPD, but is accessible to few patients because of the small number of available donor organs and limited resources. Limited data indicate that transplantation improves pulmonary function, exercise capacity, and quality of life, but studies are inconsistent with regard to effects on survival (31-35). Lung volume reduction surgery for emphysema is reported to be beneficial in some patients (36). The ongoing National Emphysema Treatment Trial is designed to measure the efficacy of this procedure in individuals with severe emphysema and to identify characteristics of those patients most likely to benefit from it (37). Results are expected in 2003. New surgical approaches to treatment are being investigated in animal models of emphysema.

Potential for Novel Therapies

Given the modest benefits from current treatment modalities, substantial progress in COPD treatment may require the development of entirely new therapeutic approaches. Recent advances in understanding of pathophysiologic processes that may underlie this disease suggest six possible approaches. The first derives from the early discovery that deficiency of the protease inhibitor alpha1-antitrypsin is one cause of emphysema (38). Recent attention has focused on matrix metalloproteinases, which are released from a variety of lung and inflammatory cells and may play a key role in the pathogenesis of COPD (39). Notably, transgenic mice deficient in macrophage elastase were resistant to cigarette smoke-induced airspace enlargement (40). Hence, there is hope that inhibition of specific matrix metalloproteinases, inhibition of serine proteases that inactivate inhibitors of the matrix metal­loproteinases, or reduction of matrix metalloproteinase expression through transcriptional regulation might slow or prevent the development or progression of COPD. A theoretical concern with this approach is that interfering with some of these proteases may increase the risks of infection or cancer.

A second approach would be to counter the effects of elastic fiber degradation by enhancing the synthesis, rate of assembly, or stability of elastic fibers in the lung. Elastic fiber synthesis is a complex process, and little is known about it in the context of emphysema. The role(s) of the microfibrillar components of the fibers has received little attention. Moreover, the linkage of elastic fibers to cells via fibulin-5 appears to be crucial to preservation of the fibers, because transgenic mice deficient in fibulin-5 developed severely disorganized elastic fibers and emphysema (41, 42). The process of elastic fiber assembly may admit both vulnerabilities and opportunities for therapeutic manipulation.

A third approach would be to prevent that portion of matrix injury due to inflammatory cell products by inhibiting the recruitment of inflammatory cells to the lung. Failure of corticosteroids to alter the course of COPD does not disprove this concept, because corticosteroids are relatively ineffective against neutrophilic inflammation and have other actions that might override a beneficial antiinflammatory effect (43). Implementation of this approach may first require detailed characterization of the inflammatory process throughout the natural history of COPD, identification of factors that exaggerate the inflammatory process (such as latent adenoviral infection [44]), and development of selective drugs that target relevant inflammatory pathways or cells.

A fourth approach is enhancement of the antioxidant capabilities of the lung. Several observations indicate that oxidants may function as mediators of COPD pathogenesis: (1 ) substantial oxidative stress derives both from cigarette smoke and from neutrophils; (2 ) oxidants produce a multitude of relevant biological effects, including enhancement of neutrophilic inflammation, secretion of mucous, activation of matrix metalloproteinases, inactivation of alpha1-antitrypsin, and inhibition of glucocorticoid responses (45-47); (3 ) biomarkers of oxidative stress are increased in the breath of subjects with stable COPD, including those who have never smoked (48); and (4 ) observational studies suggest a beneficial effect of dietary antioxidants on pulmonary function (49). Prospective data are needed to determine if exogenous antioxidants can prevent COPD or slow its progression.

A fifth possible approach is based on the observations that (1 ) induction of apoptosis of pulmonary endothelial cells in experimental animals caused emphysema, and (2) increased numbers of apoptotic cells were observed in the alveolar septae of emphysematous human lungs (50, 51). If, as these data suggest, apoptotic death of alveolar cells plays a role in the pathogenesis of emphysema, pharmacologic inhibition of apoptosis might prevent loss of alveoli. Related possibilities for therapy may exist in other pathways involved in physiologic maintenance of lung structure or in lung growth during development. An example of the latter is the possible use of retinoids to stimulate alveolarization (52).

A sixth novel approach to COPD treatment would be to decrease the production of mucus by regulation of goblet and glandular mucous cells. Many possible targets for novel therapies exist, including chemical mediators of mucous secretion or mucous metaplastic transformation, growth factors for cellular hyperplasia, and signal transduction pathways involved in mucin gene expression.

Much remains to be learned about the disease process in COPD, and other novel approaches to COPD treatment may be forthcoming in the next few years. Vigorous evaluation of all possibilities is important, because experts in COPD do not expect any single agent or approach to be sufficient in itself for the prevention or treatment of COPD. Rather, it is thought that a combination of drugs will be required for adequate control of this complex disease.

IMPORTANT CLINICAL QUESTIONS IN COPD

While considering what is currently known, the Working Group identified a number of specific deficits in knowledge that limit improvements in the clinical management of COPD. These deficits range from basic understanding of the disease process to uncertainties in the use and evaluation of existing treatments to questions of how to better develop and test new therapies. This section describes 14 questions raised by the Working Group, which convey these important deficits of knowledge and which underlie the recommendations developed by the group.

1. What Changes Occur in the Lung Early in the Development of COPD?

Little is known about early changes, before the onset of significant airflow limitation, that occur in the lungs of smokers who will develop COPD. Research is needed to identify molecular, cellular, structural, and functional changes in the lungs of smokers, with and without COPD, across a wide range of ages. A companion need is for the identification and validation of biomarkers that correlate with disease activity and can be related to specific biochemical pathways.

2. Is Early Diagnosis of Value?

Spirometry offers a sensitive and inexpensive means of detecting COPD long before the stage at which most patients seek medical attention. However, few primary care physicians perform routine spirometry, even in those smokers over age 45 for whom it has been recommended (53). Hence, COPD is greatly underdiagnosed. Because no therapy other than smoking cessation is known to alter the course of mild or moderate COPD, the strongest rationale for early detection is the possibility that a patient's knowledge of disease (i.e., low FEV1) might enhance smoking cessation efforts. Existing studies of the influence of spirometric testing on quit rate are inconsistent (54, 55). Additional clinical trials, which take into account the covariance of FEV1 and nicotine dependence (56), are needed to determine if spirometric testing can augment smoking cessation interventions.

3. Can the Heterogeneous COPD Population Be Divided into More Homogenous Subgroups on the Basis of Clinical Features and Laboratory Measures?

COPD is a protean condition whose diverse presentations include centriacinar emphysema, panacinar emphysema, and chronic bronchitis without appreciable emphysema (5). Furthermore, a host of clinical and laboratory measurements are often abnormal in COPD, and some of these show both great variability among patients and weak correlation with other measures. Various biomarkers have been identified, and certain genotypes have been associated with the disease (43, 57). Although a rich array of parameters is available for stratification of patients with COPD, few of these (e.g., FEV1, methacholine responsiveness, radiographic indices of emphysema) are commonly used to predict outcome. Guidelines for the selection of therapies are generally based on unidimensional scales of severity (5, 6). An important challenge in COPD is the development of more powerful, multi­variate methods for predicting individual outcome and individual responsiveness to particular therapies on the basis of clinical and laboratory characteristics.

4. What Is the Natural History of COPD during its Later Stages?

Much of our knowledge of the natural history of COPD comes from cross-sectional studies of symptoms and spirometry in occupational cohorts performed more than a quarter century ago. Those studies provided little information about the late stages of COPD. Furthermore, they were performed outside the context of current medical management (e.g., long-term oxygen therapy), without modern measures of the disease (e.g., CT assessment of emphysema), and with little emphasis on exercise limitation as an important, quantifiable manifestation of severe disease. Improvements in clinical care for those with severe COPD would be aided by longitudinal studies of late stage disease that correlate advanced measures of the disease with outcome.

5. What Is the Pathogenetic Relationship between COPD and Lung Cancer?

Epidemiologic studies have demonstrated comorbidity of COPD and lung cancer in excess of that attributable to smoking, suggesting that these conditions may share genetic risk factors or involve common pathogenetic mechanisms (58). For example, inflammatory mediators, including oxidants and NO, that may be important in COPD can also induce DNA damage, inhibit DNA repair, and chemically activate carcinogens (59, 60). Identification of common molecular processes in COPD and lung cancer could have important implications for the prevention and management of both diseases. Human, animal, and in vitro studies are needed to investigate cellular and molecular mechanisms common to COPD and lung cancer. There is also rationale for unified clinical studies of COPD and lung cancer in the areas of genetic susceptibility and chemoprevention.

6. What Measures of Disease Status Are Useful Indices of Therapeutic Benefit?

Demonstration of airflow limitation (e.g., decreased FEV1) is essential for diagnosis and is the best known predictor of outcome in COPD. Hence, decline in postbronchodilator FEV1 over time has been used as the "gold standard" measure of disease progression in premorbid COPD. However, emerging evidence indicates that alternative measures, such as inspiratory capacity, may better reflect the ventilatory dysfunction in COPD (61, 62). Furthermore, reliance on FEV1 may cause studies to miss beneficial effects of therapies such as increased exercise capacity, quality of life, or cognitive function, or lessened dyspnea, cough, sputum production, depression, or frequency or severity of exacerbations (63). Alternative measures are needed that better reflect the clinical status of patients with COPD and allow detection of clinically important responses to therapies. It is noteworthy that, in a trial of alpha1-antitrypsin augmentation in patients deficient in this protein, progression of emphysema could apparently be detected in less time by measurement of lung density using computed tomography than by pulmonary function testing (64).

7. How Can Exacerbations Be Better Managed?

Acute exacerbations of COPD are the major battle front of the physician's war on this disease, and the arsenal is ineffective (65). Current treatment consists primarily of supportive measures in combination with drugs appropriated from the pharmacopoeias of asthma and pneumonia, which have limited effectiveness in COPD (65). Although such treatments are of some benefit, nearly half of patients with COPD hospitalized for severe exacerbations are dead within a year (66). Controlled studies are needed to rigorously evaluate the efficacy of current management approaches and to refine the indications for existing drugs. Methods of mechanical ventilation can likely be improved with better understanding of how patients with severe exacerbations of COPD respond physiologically to critical care interventions. New pharmacologic agents are needed, especially drugs that are capable of controlling the excess production and/or retention of mucus within the airways. In addition, greater emphasis is needed on the prevention of exacerbations, because this approach may do much to extend life and reduce the costs of care for patients with COPD.

8. Who Should Get Long-Term Oxygen Therapy and When?

Although oxygen supplementation relieves hypoxemia, it may increase oxidative stress, an insult thought to be involved in the pathogenesis of COPD (59). Hence, the value of oxygen treatment in COPD should be determined by clinical trials of sufficient duration to detect effects on mortality. Although there is clear value for long-term oxygen in those with resting PaO2 <= 55 mm Hg (3), there have not been adequate trials to assess the benefit of this treatment in other groups (67). Studies are needed in those with moderate hypoxemia, those with nocturnal oxyhemoglobin desaturation, and those who desaturate with ambulation. Possible effects of oxygen therapy on cognitive function and quality of life need to be assessed.

9. How Can Exercise Capacity Be Increased?

Exercise limitation is prevalent in COPD and is predictive of mortality among those with severe disease (68, 69). The physiologic basis of this limitation is multifactorial (70). Ventilatory impairment, sensation of dyspnea, cardiopulmonary interactions, skeletal and respiratory muscle dysfunction, and general systemic illness may all contribute in certain patients. A better understanding of the proximate causes of diminished exercise capacity is important for improvements in pulmonary rehabilitation programs and for the development of new therapeutic strategies that may enhance physical performance in those with COPD. Of particular interest are the origin and treatment of skeletal muscle dysfunction, a well-documented systemic manifestation of COPD that may be amenable to pharmacologic interventions (71).

10. How Can Nutritional Status Be Improved?

Weight loss is often observed in severe COPD, and low body mass index is an independent predictor of respiratory mortality among those with COPD (72). There is no satisfactory explanation for why some, but not all, individuals with severe COPD lose weight, and there is no accurate method for predicting who will or will not become cachectic. Understanding the mechanisms of COPD-associated cachexia would be helpful for the design of a rational therapy for this condition. Although it is thought that weight loss in COPD is mainly due to diminished food intake rather than increased metabolism, trials of caloric supplementation have generally been disappointing. A meta-analysis of selected studies demonstrated increases in weight, but no significant improvement in other measures of disease severity (73). Nutritional supplementation in combination with exercise and/or anabolic drugs has not been adequately tested.

11. Is Control of Sleep Disorders an Important Aspect of COPD Management?

Sleep disturbance is common in COPD, and may contribute to depression, cognitive dysfunction, and lessened quality of life in this disease (74). Effective treatments of sleep disturbance in individuals with COPD are needed that minimize the respiratory depressant effects of many hypnotic drugs (75). In addition, COPD can coexist with obstructive sleep apnea, compounding the ventilatory defect of each condition (76). Studies are needed to evaluate the use of oxygen or noninvasive ventilatory support in patients with this "overlap syndrome."

12. How Should Comorbid Conditions Be Managed?

Patients with COPD are at enhanced risk of associated comorbidities such as cardiovascular disease, lung cancer, and sleep-disordered breathing (58, 74). Despite this, little research has been done to determine the optimal means of managing COPD in combination with other conditions. For example, there is uncertainty as to whether COPD should be a relative contraindication for the use of beta-adrenergic blockers in patients with heart disease (77); and denials of lung cancer resection because of low FEV1 may unnecessarily discriminate against those with COPD (78). Studies are needed to improve management strategies for those with coexisting diseases.

13. What Can Be Done to Promote the Development and Testing of Novel Agents for the Treatment of COPD?

Several factors impede the development and testing of novel treatments for COPD. First, because the key pathogenetic pathways are not established, financial incentives for pharmaceutical companies favor trials of drugs already used for other diseases, rather than de novo development of targeted agents for COPD. Second, the unavailability of validated surrogate markers of COPD makes studies to establish proof of principle or appropriate dosage both complex and expensive. Third, the slow progression of COPD requires that efficacy trials be of long duration. Fourth, the heterogeneity of COPD requires large numbers of subjects for clinical trials of therapeutics. Efforts that may reduce these barriers to the development of novel agents include basic research on COPD pathogenesis; investigations of surrogate endpoints and indices for therapeutic stratification; exploration of alternative outcome measures; and greater cooperation among research institutions, funding agencies, health care providers, regulatory agencies, pharmaceutical companies, and health care payors in the conduct of clinical studies. For some drugs, there may be advantages to initial testing in patients with alpha1-antitrypsin deficiency because of the more rapid decline of FEV1 in this group than in usual COPD. The Alpha-1 Research Registry, now maintained by the Alpha One Foundation and the Medical University of South Carolina (Charleston, SC), contains demographic and clinical data on individuals with severe alpha1-antitrypsin deficiency, and can assist in the recruitment of this subpopulation of patients with emphysema for research studies.

14. What Is the Cost-Effectiveness of Strategies for COPD Prevention and Treatment?

Despite substantial expenditures on medical care for those with COPD, few studies have examined the cost-effectiveness of dif­ferent treatment modalities. It is likely that reductions in the frequency and severity of acute exacerbations of COPD would be especially cost-effective, because hospitalizations, primarily for exacerbations, account for approximately two thirds of the direct costs of COPD care (Figure 1) (79-81). Because those with advanced disease are more likely to be hospitalized, therapeutic advances that produce even modest improvements in the health of those with severe COPD may have a substantial economic impact. Greater emphasis should be placed on studies of the cost-effectiveness of COPD management approaches.

Figure 1. Allocation of expenditures for direct costs of COPD care. Total expenditure for home oxygen therapy is from Reference 79 and may include some costs not due to COPD. Estimates of expenditures for hospitalizations (inpatient plus emergency department), outpatient (clinic plus physician office), and drugs are based on data from References 80 (prevalence of COPD by hospitalizations) and 81 (costs per COPD patient for care related to COPD).

RECOMMENDATIONS FOR FUTURE RESEARCH

The Working Group identified five major goals for clinical research in COPD in the next several years. Each was rated as high priority by a substantial majority of the participants. Collectively, these five initiatives could provide a platform for addressing all of the important clinical questions in COPD identified in the previous section.

Establish a Multicenter Clinical Research Network to Perform Multiple, Short-term Clinical Trials of Treatments in Patients with Moderate-to-Severe COPD

Controlled trials are needed to assess the efficacy of and refine indications for various drugs currently used in COPD, including beta2-agonists, anticholinergics, antibiotics, inhaled corticosteroids, and mucus-altering drugs. In severe disease or exacerbations of disease, such clinical trials can be completed in a relatively short period of time (e.g., 1-2 years), but require access to a relatively large number of research subjects, personnel experienced in clinical research, and appropriate infrastructure for subject recruitment and data collection and analysis. An efficient framework for such trials is a multicenter, multistudy Clinical Research Network, established for the rapid design and implementation of sequential or simultaneous clinical trials. A COPD Clinical Research Network is needed to evaluate treatments currently used in individuals with COPD, with emphasis on the management of acute exacerbations. This network could also investigate subject stratification by phenotype, efficacy of novel agents, treatment of coexisting heart disease, alternative markers of therapeutic response (e.g., inspiratory capacity, quality of life), and interventions related to muscle dysfunction, while obtaining longitudinal data on disease progression in severe COPD.

Create a System for the Standardized Collection, Processing, and Distribution of Lung Tissue Specimens and Associated Clinical and Laboratory Data

A major need in COPD research is for correlation of gene and protein expression in the lung with tissue structure, pulmonary function, and disease status. The requisite tools are available, including a wealth of antibodies for immunohistochemistry and advanced methods of molecular histopathology that are capable of quantifying inflammatory cells, gene expression, protein content, cellular phenotype, and microbial and viral infections with exquisite sensitivity and high spatial resolution. Furthermore, lung tissues are available for study from lobes excised for suspected cancer or tissue removed in lung volume reduction surgery or lung transplantation. Nonetheless, histopathologic research in COPD is impeded by the considerable infrastructure and expense required to recruit and characterize lung tissue donors, procure tissue samples, and process the specimens.

To enable molecular studies of COPD causation and progression, the Working Group recommended that a Lung Tissue Resource be established that would prepare and distribute to researchers collections of tissue specimens obtained at surgery. This resource would make available systematic collections of anonymized specimens, linked to extensive clinical and laboratory data from the donor subjects. The program should collect clinical data; perform specified clinical tests (including pulmonary function testing and high resolution computed tomography); and harvest, process, and distribute lung tissues. The program would complement recent initiatives of the NHLBI in proteomics and genomics, adding important capabilities for studying expression of specific genes in particular cell types and correlation of these data with a detailed clinical and physiologic profile of the subject. Tissue specimens linked to extensive phenotypic data would not only be invaluable for research on disease pathogenesis, but would also be useful for studies of the mechanisms of enhanced lung cancer risk in COPD, for identification and validation of biomarkers, and for correlation of radiographic measures with pathology.

Because the extent of disease often varies substantially within a lobe, this program could also prepare tissue arrays from single individuals by systematic sampling from central to peripheral regions of a lobe. Such tissue arrays would be invaluable for correlating molecular biological properties with local pathologic indices, including tissue structure and inflammatory and microbiological measurements. In addition, the fact that portions of each lung specimen can be provided to many different investigators makes a centralized resource cost-efficient.

Develop Standards for the Classification and Staging of COPD

Unlike many other diseases, only rudimentary standards are available for describing the severity of COPD. A standardized method for classifying patients with COPD is needed to allow comparisons among different studies and to facilitate recognition of subpopulations that may differ in responsiveness to specific therapeutic approaches. The system of classification should include indicators of disease character, which might reflect differences in pathogenesis, and of disease severity. Although spirometry is critical for diagnosis of COPD, FEV1 may be of limited value in a classification scheme designed to illuminate differences in disease mechanism among individuals. Any system of patient classification in COPD will require periodic reassessment and revision.

Characterize the Development and Progression of COPD Using Measures and Biomarkers that Relate to Current Concepts of Pathogenesis

The epidemiology and natural history of COPD are primarily known in terms of FEV1 in male smokers, and there is little description of the disease with regard to inflammatory status, biomarkers, radiographic changes, genomics, proteomics, genetics of susceptibility, socioeconomic factors, quality of life, and therapeutic responsiveness. Improved understanding of COPD during the slow progression from preclinical to moderate disease would aid the development of strategies for primary and secondary prevention. A multicenter observational study that encompasses a wide range of ages is needed to provide a more comprehensive description of the disease. Although a longitudinal study has some advantages, a cross-sectional design is considered to be more practical. Such a study could also be used to validate biomarkers of COPD and to address hypotheses related to individual susceptibility to cigarette smoke.

Evaluate Indications for Long-Term Oxygen Therapy for Patients with COPD

There are discrepancies between scientific evidence, physician practices, and insurance reimbursement policies with regard to indications for long-term oxygen therapy. Although the life-prolonging potential of oxygen may be great, oxygen is already a significant portion of the total dollar cost of care for patients with COPD (Figure1). Hence, a strong evidentiary basis is needed for guidelines for oxygen prescription. A controlled clinical trial is especially needed to assess the benefit of long-term oxygen therapy in individuals with moderate hypoxemia (e.g., PaO2 between 55 and 65 mm Hg). Such a trial might also address the issue of oxygen supplementation for those who are normoxic at rest but desaturate with ambulation, or who are normoxic by day but show nocturnal oxyhemoglobin desaturation. Ancillary studies of noninvasive methods of mechanical ventilatory support or of sleep disturbance and its management might also be performed within the framework of a controlled trial of oxygen therapy.

Acknowledgment: Participants: A. Sonia Buist, M.D., Portland, OR, and James D. Crapo, M.D., Denver, CO, Co-Chairs; Robert M. Senior, M.D., St. Louis, MO, and Robert A. Wise, M.D., Baltimore, MD, Discussion Leaders; and Nicholas R. Anthonisen, M.D., Ph.D., Winnipeg, MB, Canada; Richard Casaburi, Ph.D., M.D., Torrance, CA; Gerard J. Criner, M.D., Philadelphia, PA; Thomas L. Croxton, Ph.D., M.D., Bethesda, MD; John V. Fahy, M.D., San Francisco, CA; James E. Fish, Ph.D., Philadelphia, PA; Jonathan Goldin, M.D., Ph.D., Los Angeles, CA; Edward P. Ingen­ito, M.D., Ph.D., Boston, MA; James P. Kiley, Ph.D., Bethesda, MD; Jenny Mao, M.D., Los Angeles, CA; Fernando J. Martinez, M.D., Ann Arbor, MI; Dennis E. Niewoehner, M.D., Minneapolis, MN; Denis E. O’Donnell, M.D., Kingston, ON, Canada; Hector G. Ortega, M.D., Sc.D., Bethesda, MD; Barbara Phillips, M.D., Lexington, KY; Sri Ram, Ph.D., Bethesda, MD; Cynthia S. Rand, Ph.D., Baltimore, MD; Andrew L. Ries, M.D., M.P.H., San Diego, CA; Gordon L. Snider, M.D., Boston, MA; Norbert F. Voelkel, M.D., Denver, CO; Gail G. Weinmann, M.D., Bethesda, MD; and Roger D. Yusen, M.D., M.P.H., St. Louis, MO.

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Correspondence and requests for reprints should be addressed to:
Thomas Croxton, Ph.D., M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10208
Bethesda, MD 20892-7952.
E-mail: croxtont@nhlbi.nih.gov