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The Proceedings of the American Thoracic Society 3:276-280 (2006)
© 2006 The American Thoracic Society

Chronic Obstructive Pulmonary Disease

Linking Outcomes and Pathobiology of Disease Modification

Stephen I. Rennard

University of Nebraska Medical Center, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd St., Omaha, NE 68198-5300. E-mail: srennard{at}unmc.edu

ABSTRACT

Recent guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease characterized by airflow limitation and systemic consequences. Airflow limitation in COPD worsens over years as assessed by the forced expiratory volume in one second (FEV1). Regardless, while it is likely that cardiovascular and other systemic components also worsen as COPD progresses, there are no accepted or validated outcomes to measure such pathophysiologic changes as they relate to COPD disease progression. It is clear that health status in COPD is more closely related to levels of patients' physical functional capacity than it is to changes in FEV1. Furthermore, the relative contributions of pathoanatomic changes such as small airways fibrosis and pulmonary emphysema to declining airflow remain unknown. These features may even progress at different rates in the same individuals. Although stopping smoking is the only intervention shown to alter the relentless progression of COPD, the resultant slowing of FEV1 decline takes several years to evince and requires at least 1,000 subjects to demonstrate annual therapeutic benefits of as little as 20 ml. The FEV1 cannot distinguish between peribronchiolar fibrosis and emphysema and it is feasible that, as techniques are developed and validated, lung imaging methodologies may become important and sensitive outcomes measures of time- and age-dependent lung structural changes in COPD. The development of biomarkers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression.

Key Words: biomarkers • disease progression • imaging techniques • systemic disease

Chronic obstructive pulmonary disease (COPD) is defined in the most recent American Thoracic Society/European Respiratory Society Guidelines as "a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences" (1). The bold italics have been added to emphasize the differences from the Global Initiative for Obstructive Lung Disease (GOLD) Guidelines definition, 2001 (2). The 2004 definition is more optimistic as it emphasizes that COPD is preventable and treatable. It also recognizes the importance of smoking and adds a comment that COPD has important systemic features. Despite the appropriate optimism inherent in the current definition, COPD remains a progressive disease characterized by loss of lung function that occurs more rapidly than that associated with normal aging. In addition, the systemic features that characterize COPD are believed to worsen progressively. Therapies that could modify the course of the disease either by slowing or reversing the abnormalities characteristic of COPD would represent a major therapeutic advance.

Traditionally the most important measure of COPD has been the forced expiratory volume in one second (FEV1). This parameter quantifies expiratory airflow, the reduction of which is both the defining feature of COPD and the measure currently used for its staging. The classic view of COPD natural history, which derives from the studies of Fletcher and colleagues (3), relates the FEV1 to age. In this context, lung function increases as human individuals grow and reaches a maximum in young adulthood, after which it declines slowly (4, 5). Over 50 years of adult life span, the FEV1 will decline approximately one liter in normal individuals. Individuals who smoke lose lung function, on average, at about twice that normal rate (3, 4). As Fletcher and coworkers pointed out, approximately 15% of smokers will lose lung function at a sufficiently rapid rate, so that a diagnosis of COPD is made (3). Historically, this has occurred approximately in the sixth decade of life, at which time dyspnea on exertion is present and occurs with relatively modest exertion. A much larger percentage of smokers, however, will have abnormal lung function (6, 7).

In recent years, several observations have expanded this view of COPD natural history. First, approximately 20% of patients diagnosed with COPD, at least in the United States, may be lifelong nonsmokers (7). The risk factors contributing to disease in these individuals remain incompletely defined but include early life events that may compromise lung growth (8–10), exposures to occupational and environmental dusts and fumes (11–14), and genetic factors (15). Second, while approximately 15% of smokers have a diagnosis of COPD made, nonsmoking individuals with compromised lung function also experience increased mortality from cardiovascular disease (16, 17) and are likely to be compromised functionally. Such individuals may remain asymptomatic (i.e., free from symptoms of dyspnea) and, therefore, remain undiagnosed as having any lung disease, by limiting their level of activity. Third, assessments of health status in patients with COPD relate much more closely to levels of physical functional activity than they do to airflow as assessed by the FEV1 (18, 19). Fourth, alterations in airflow in patients with COPD can result from several distinct pathoanatomic processes (20, 21). Peribronchiolar fibrosis and narrowing of the small airways, for example, has been suggested to be the most important lesion in individuals with mild to moderate disease (22). In contrast, among individuals dying in respiratory failure, severe emphysema may be more important (23–25). It seems likely that these processes may progress with different natural histories even within an individual. Finally, COPD is characterized by a number of systemic manifestations, including skeletal muscle abnormalities (26, 27), osteoporosis (28), mental depression and, as noted above, increased risk for the development of cardiovascular disease (16, 17). The systemic effects may be more important in some patients than is the airflow limitation. The systemic diseases, moreover, also likely progress with their own unique natural histories. Taken together, these observations suggest that the natural history of COPD is far more complex than the progressive loss of lung function as assessed by the FEV1.

To date, only one therapeutic intervention, smoking cessation, has been demonstrated to alter the natural history of COPD, and alteration in the rate of decline in the FEV1 was used as the outcome parameter. The most definitive study addressing this question was the Lung Health Study (29). This trial enrolled nearly 6,000 subjects, one third of whom were treated with the usual care and two thirds of whom received a smoking cessation intervention: behavioral counseling combined with nicotine gum therapy. Over the first five years of the study, 22% of those in the intervention group achieved and remained abstinent, while approximately 50% never achieved abstinence. Among those who continued to smoke, lung function was lost at an accelerated rate consistent with that expected from the studies of Fletcher and colleagues (3). Among those who quit, in contrast, lung function improved initially, after which it declined at a rate expected for a nonsmoker. This difference in rate of decline over the last three years of the trial was significantly different between the groups. Although this study clearly shows benefits for smoking cessation, it is more difficult to show benefits of the intervention. An intention-to-treat analysis, which compares subjects treated with the intervention with those receiving usual care, took eleven years to achieve statistical significance (30).

The Lung Health Study demonstrated clearly the benefits of smoking cessation (29). There are a number of limitations, however, as well as issues raised by this study. First, subjects enrolled in the study generally had relatively mild disease. The benefits of smoking cessation later in the course of COPD remain unassessed. Interestingly, several studies of established patients with COPD have demonstrated persistent inflammation despite smoking cessation (31–33). Similarly, observational studies have suggested that accelerated lung function loss may occur with aging independent of smoking (34). It would be extremely interesting and potentially important to understand the effects of smoking cessation at other points in the natural history of COPD. The large number of subjects required in the Lung Health Study suggests such studies would be large and expensive, and this is related to the use of FEV1 as the outcome measure. The standard deviation of FEV1 measures within a subject is, under the best of circumstances, approximately 55 ml. Because the FEV1 changes relatively slowly over time, it is estimated that a minimum of 1,000 subjects followed for three years would be required to demonstrate an effect of 20 ml per year of any treatment (35). This sample size estimate is independent of the intervention. End points other than the FEV1, however, offer the opportunity of demonstrating benefits of smoking cessation in smaller numbers and over shorter time frames. The reduction in the risk of myocardial infarction, for example, can be observed within one year (36). Using endobronchial biopsy, it has been possible to demonstrate improvements in goblet cell metaplasia among normal smokers within three months after quitting with a sample size of 12 (37). These studies demonstrate the feasibility of using end points other than the FEV1 to assess smokers and, therefore, subjects who likely have COPD.

As noted above, several anatomic lesions contribute to the fixed airflow limitation that defines COPD (20, 21). These include peribronchiolar fibrosis and pulmonary emphysema. Peribronchiolar fibrosis, like all fibrotic processes, is characterized by the accumulation of fibroblasts/myofibroblasts and the dense extracellular connective tissue produced by these cells. Like other fibrotic tissues, the fibrosis in small airways is associated with tissue contraction (38). This results in narrowing of the small airways and limits airflow. Emphysema, in contrast, is characterized by destruction of the alveolar wall. This leads to loss of lung elastic recoil, which decreases both the driving pressure for expiratory airflow during exhalation and the intraluminal pressure that helps maintain airway patency during forced exhalations (20). In addition, loss of alveolar wall removes any tethering effects, which normally provide support to keep the airways open (39). Therapeutic interventions designed to either prevent or reverse these two lesions are being explored. Unfortunately, the FEV1, together with all its other limitations, cannot distinguish between these two processes.

Alternate clinical or diagnostic approaches that can distinguish airways disease from alveolar disease would, therefore, be extremely appealing. In this context, imaging methods hold great promise. Quantitative analysis of commuted tomography (CT) scans can provide a measure of the extent and/or severity of emphysema (40, 41). Recent analytical methods, moreover, offer the possibility of further defining subtypes of emphysema (42, 43). Imaging methods using hyperpolarized gas magnetic resonance imaging techniques cannot only image alveolar structures, but have the possibility of providing very subtle quantitative measures of alveolar size (44, 45). Magnetic resonance imaging, moreover, may be able to distinguish centrilobular emphysema by specifically quantifying small airway diameters (46). In addition, CT methods have been applied to the assessment of airways. Recent studies suggest that CT quantification of airway wall thickness and luminal size is feasible (47–49). The development and validation of these methods offer important novel end points for the assessment of COPD.

Advances in the understanding of the pathobiology of COPD, as noted above, create the opportunities to develop specifically targeted therapeutic interventions. For example, transforming growth factor (TGF)-ß, which is a pleiotropic cytokine believed to be involved in tissue repair responses (50, 51), is thought to play a major role in the pathogenesis of the peribronchiolar fibrosis characterizing COPD in some patients (52). There are several potential therapeutic strategies to mitigate the effects of TGF-ß. Biological agents such as antibodies that inhibit active TGF-ß have been developed and have activity in several animal models of fibrotic disease (53, 54). In addition, agents that interfere with TGF-ß signaling are also in development. In this context, the receptor for TGF-ß functions as a serine/threonine kinase that phosphorylates the signaling molecules Smad 2 and Smad 3. Inhibitors of this kinase activity have been developed and have the potential to block the development of fibrosis (55). Similarly, mice deficient in Smad 3 signaling are relatively resistant to the development of bleomycin-induced fibrosis (56).

Inhibition of repair responses in the alveoli and airways, however, may have adverse effects. Interestingly, Smad 3–deficient mice develop spontaneous pulmonary emphysema (57). This is consistent with the "American Hypothesis," which suggests that emphysema, at least in part, is a consequence of deficient repair (52). The development of a therapeutic agent that will block peribronchiolar fibrosis likely will require the reliable clinical assessment not only of the airways component to altered expiratory airflow, but also an independent accurate assessment of potential effects on alveolar wall structure.

Conversely, there are several approaches to alter the development of pulmonary emphysema. Blockade of the inflammatory processes thought to lead to alveolar wall destruction is one appealing strategy. The possibility that alveolar wall growth can be stimulated, at least in rats, after the development of emphysema has been suggested by the studies of Massaro and Massaro (58). These investigators demonstrated that retinoic acid is capable of inducing the formation of new alveolar wall after the development of elastase-induced emphysema in rats. Although limited studies with all-trans retinoic acid in human volunteers have not demonstrated a similar effect (59), these studies have led to an active area of research, and several alternate strategies are being pursued.

Therapeutic interventions designed to either slow the rate at which alveolar wall is lost in emphysema or to reverse the process, however, will require practical outcome measures. The FEV1 is likely to be relatively unsatisfactory for this purpose. Assessment of these therapeutic modalities, therefore, will require the development of novel approaches. Biomarkers, if validated adequately, may have great use for assessing such therapies.

A large number of biomarkers are being evaluated currently for the assessment of COPD (60–62). To be used as outcome measures in COPD, such biomarkers would have to be sensitive to change with therapeutic intervention and would have to predict clinical outcome reliably. To date, no available biomarkers are validated adequately by these criteria. Nevertheless, current understanding of the pathobiology of COPD suggests a number of biomarkers as potential candidates. These include most notably the inflammatory cells and their products that are believed to be the proximate causes of tissue destruction in patients with COPD. The assessment of these biomarkers is likely to have use in demonstrating proof-of-concept for novel therapeutic interventions. Markers may also have use in demonstrating biological effects of specific interventions and may add dose ranging. Their use as outcome measures, however, will require substantial additional validation using statistical, clinical, and biological criteria (63, 64).

In addition to novel outcomes that can assess both the structure and function of the lungs, the recognition that systemic effects are key features of COPD has created novel opportunities for outcome measures. In this context, the most common cause of death among patients with COPD is acute cardiac events (65). Reduction in lung function, independent of cigarette smoking, is a risk factor for death from myocardial events (16, 17) as are symptoms of cough and sputum (66). Consistent with this, biomarkers associated with cardiac risk are also associated with COPD and are related to its severity (67, 68). The underlying hypothesis that cardiac events are related to systemic inflammation, which, in turn, may be driven by inflammation in the lung, has been suggested. Consistent with this, a pilot study evaluating patients with COPD treated with inhaled glucocorticosteroids has suggested a reduction in systemic markers of inflammation (69). Similarly, a recent retrospective analysis of the EUROSCOP study data demonstrated significant reductions in cardiac events, including myocardial infarction and angina pectoris, in patients with COPD treated daily with 800 µg inhaled budesonide (70). This finding supports the concept that inflammation in the lung contributes to systemic disease, which can be a meaningful clinical outcome measure for COPD.

Other systemic features of COPD, which are often important clinical problems, are also important opportunities for the development of novel outcome measures for COPD. Understanding the pathobiological mechanism by which COPD leads to problems such as altered muscle strength, osteoporosis, and cardiac disease should expedite the development of novel therapeutic approaches. The assessment and application of such approaches will, conversely, likely require the validation of novel outcome measures.

CONCLUSIONS

Advances in the understanding of COPD are being made simultaneously in several distinct domains. First, it has become clear that the FEV1, while a crucial measure, is far from the only measure of altered lung function characterizing patients with COPD. The development of additional means to assess the lungs in patients with COPD, therefore, is essential to understanding COPD natural history.

FOOTNOTES

Conflict of Interest Statement: S.I.R. has participated as a speaker in scientific meetings and courses under the sponsorship of AstraZeneca and GlaxoSmithKline. He serves on Advisory Boards for Altana, Dey, and Inspire. He has conducted clinical trials for AstraZeneca, Centocor, GlaxoSmithKline, Pfizer, Roche, and Sanofi. He has served as a consultant for AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, and Roche. A patent is pending on the use of PDE4 inhibitors in repair; S.I.R. is a co-inventor of the patent owned by the University of Nebraska Medical Center.

(Received in original form December 19, 2005; accepted in final form January 6, 2006)

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