The proposal "COPD Exacerbations: Pharmacogenetic Approaches to Therapy" presents the commitment of an established group of clinical investigators at Harvard Medical School with a long-standing interest in COPD to participate as a Clinical Center in the proposed COPD Clinical Research Network and to work with other Clinical Centers to create and implement protocols directed at improving the care of patients with COPD. The applicants propose to recruit patients with COPD from patients admitted to hospitals for treatment of COPD, established pulmonary practices in major teaching hospitals, and an associated large health care provider network. Strategies for recruitment include the use of several large clinical databases that have identified patients with COPD. The scientific focus of the proposal is on the prevention and treatment of exacerbations. Exacerbations of COPD, defined as an increase in shortness of breath and an increase in the amount and/or purulence of sputum, are a major determinant of patient quality of life and account for substantial health care expenditures. The applicants propose 2 protocols for consideration by the network; one is directed at treatment of acute exacerbations with inhaled corticosteroids and the second at prevention of exacerbations by use of a leukotriene inhibitor. The first protocol offers the potential advantage of a therapy that has fewer complications than current standard therapy with oral or intravenous corticosteroids. Patients will be randomized to either inhaled or oral steroids for therapy of exacerbation. The primary outcome will be time to next exacerbation. The second examines the role of a class of medications, leukotriene inhibitors, that has been demonstrated to be beneficial in asthma but have not been systematically evaluated in patients with COPD. Patients will be randomized to receive zileuton or placebo for 12 months. Frequency of exacerbations will be the primary outcome. Both protocols have associated pharmacogenetic studies designed to identify subsets of patients likely to respond to the particular class of medications. These analyses are intended to provide a strategy for more specific targeting of therapy within the heterogeneous population of patients with COPD, estimated at approximately 18 million people in the U.S.