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Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu
Several common themes emerged in the discussions in Session 1, setting the stage for the remainder of the conference.
Dr. MacNee's presentation on pathogenesis emphasized the importance of inflammation in current thinking on chronic obstructive pulmonary disease (COPD) pathogenesis. However, whether the inflammation that characterizes COPD and that is present to greater degrees in more severe disease is a cause of the disease or an effect remains undetermined. Dr. MacNee averred that a rigorous test of that question would be available only from adequate trials of therapies that inhibited the inflammation.
The interaction between cigarette smoking and inflammation and the persistence of inflammation among ex-smokers with COPD was discussed. Most studies comparing smoking patients with COPD with ex-smokers have not controlled for time since the last cigarette and greater understanding is needed relating to the acute effects of smoking. Nevertheless, all studies have demonstrated persistent inflammation in ex-smoking patients with COPD. The mechanisms that may account for persistent inflammation include an autoimmune response, which would be consistent with the prominent accumulation of lymphocytes in many patients. Infection could also play a role, particularly in driving the development of lymphoid follicles in the lung.
The suggestion was made that infection was likely to be variably present among patients and could, therefore, contribute to COPD heterogeneity. Because lung inflammation is thought to contribute to systemic effects, heterogeneity of the inflammatory response could also lead to heterogeneity in these manifestations of COPD. The discussion of heterogeneity of COPD was extended to the several histologic lesions that can variably contribute to airflow limitation. The peribronchiolar fibrosis seen in COPD differs from that seen in emphysema and likely reflects different pathogenic mechanisms. Emphysema, moreover, has distinct histologic patterns. Delineating the pathogenic relationship between panlobular and centrilobular disease, for example, will be important to fully understand pathogenesis.
Dr. Gross's discussion of current treatments of COPD made the point that the tools used to test treatments for approval by regulatory bodies and that support their recommendation in guidelines depend on measurements that are validated for measuring group effects in populations of subjects. This contrasts with clinical practice, where individual patient response is key. The most important test, named the SF-1 by Dr. Gross, is "How are you doing?" It is not really the same as formalized instruments designed to measure individual symptoms or overall disease-related health status ("quality of life"), which are aggregate tests. In addition, effects in patients can reflect external events. For example, depression was noted across treatment groups in the wake of the September 11, 2001 terrorist attacks.
Whether "responder analyses" would be more appropriate to gauge therapeutic effect was discussed. Other options, such as biological measurements of samples obtained from sputum or by bronchoscopy, may be able to demonstrate therapeutic effects faster than clinical outcomes. The possibility that tests that could distinguish small-airway disease from other causes of airflow limitation could thus address the heterogeneity issue. Dr. Gross recalled the many studies that attempted to address this issue without success, but thought the question could be readdressed with novel methods. Finally, the issue of whether a combination end point combining a variety of measurements could be used as a clinical outcome was suggested; Dr. Gross suggested it might be difficult to validate to the degree required by regulatory agencies.
Dr. Donohue's presentation addressed the current use of combination therapy in COPD. In the discussion that followed, the use of symptom-based outcomes and the concept of responders as predictors of clinical outcome were further addressed. The lack of approval of such measurements by the U.S. Food and Drug Administration was believed to engender a lack of enthusiasm for this approach. However, it was pointed out that in the approach to rheumatoid arthritis such measurements are not only widely used, but that any study that did not include such determinations would be regarded as seriously limited or worse. As several of the available therapeutic agents demonstrate a beneficial response in a large percentage of subjects, with correspondingly low numbers needed to treat, this approach was thought to be feasible. Moreover, patients with COPD will have a variety of complaints that may be their primary concern. Many may be bothered by dyspnea. For others cough may be more important. Response to the SF-1, therefore, becomes an appealing clinical end point, particularly for treatments such as combinations that may have several benefits. The practicality of using such an approach was addressed briefly.
Dr. Toews concluded the session with a review of the basic principles of quantifying pharmacologic activity with particular attention to how this relates to combinations. One of the key issues that arose in the earlier discussions was the very modest effect on outcomes observed in response to most current treatments, which complicates dose ranging and assessment of pharmacodynamic effects. Dr. Toews suggested that the answer might be not so much to find outcomes that are more sensitive to change, but rather to find treatments that have bigger effects. He also suggested that the basic pharmacologic principles used to develop combination treatments for chronic disorders should be the same as those for acute conditions, though their application may be difficult.
The issue of how to apply pharmacologic principles to gauge potency and efficacy in chronic disorders was discussed without resolution. The possibility that treatments may have variable effects at different points in the natural history of disease was also raised. For example, the progressive evolution of a lymphocytic reaction in the airways or the development of mucus-secreting cells suggests that agents that target those cells could be very effective at one point in the disease but not at others. The ability to target basic biological processes, however, offers an option to direct therapies to more manageable end points. The concept that the anatomic lesions of COPD could be reversible, moreover, suggested that Dr. Toews' "big effects" might be possible, even within modest time frames. Such approaches, however, were believed to require a change in thinking about the disease, which has traditionally been regarded as mostly irreversible.
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(Received in original form June 15, 2005; )
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