Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown. Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up. Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV1 decline based on reported exacerbations or acute respiratory events. Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2–44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23–151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV1 decline. Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Rationale: Depression is prevalent in patients with chronic obstructive pulmonary disease (COPD); however, its etiology and relationship to the clinical features of COPD are not well understood. Objectives: Using data from a large cohort, we explored prevalence and determinants of depression in subjects with COPD. Methods: The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study is an observational 3-year multicenter study that enrolled smokers with and without COPD and nonsmoker controls. At baseline, several patient-reported outcomes were measured including the Center for Epidemiologic Studies of Depression Scale. For the purposes of this analysis, depression was defined as a score of 16 and higher on this scale, which reflects a high load of depressive symptoms and has a good correspondence with a clinical diagnosis of major depression. Measurements and Main Results: The study cohort consisted of 2,118 subjects with COPD; 335 smokers without COPD (smokers); and 243 nonsmokers without COPD (nonsmokers). A total of 26%, 12%, and 7% of COPD, smokers, and nonsmokers, respectively, suffered from depression. In subjects with COPD, higher depression prevalence was seen in females, current smokers, and those with severe disease (Global Initiative for Obstructive Lung Disease [GOLD]-defined). Multivariate modeling of depression determinants in subjects with COPD revealed that increased fatigue, higher St. George's Respiratory Questionnaire for COPD patients score, younger age, female sex, history of cardiovascular disease, and current smoking status were all significantly associated with depression; physiologic and biologic measures were weak or nonsignificant descriptors. Conclusions: Depression is more prevalent in subjects with COPD compared with smokers and nonsmokers without COPD. Clinical and biologic measures were less important determinants of depression in COPD than disease symptoms and quality-of-life. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).