Respiratory Exacerbations and Lung Function Decline in People with Smoking History and Normal Spirometry.

Rationale: The impact of respiratory exacerbation on chronic obstructive pulmonary disease (COPD) is well established. The effects of respiratory exacerbations in people with cigarette smoking but normal spirometry are unknown. Objectives: To assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history. Methods: We analyzed data from COPDGene study participants with ⩾10 pack-years of cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator FEV1/FVC greater than or equal to the lower limit of normal and FEV1 greater than or equal to the lower limit of normal. We examined whether respiratory exacerbations occurring between Visit 1 and the 5-year follow-up visit (Visit 2) were associated with FEV1 decline and all-cause mortality. Measurements and Main Results: Among 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between Visits 1 and 2 was associated with a 2.96 ml/yr FEV1 decline (95% confidence interval [CI], 1.81 to 4.12; P < 0.001) at Visit 2. Experiencing one or more severe exacerbations between Visits 1 and 2 was associated with 14.6 ml/yr FEV1 decline relative to those with no severe exacerbations (95% CI, 8.56 to 20.6; P < 0.001). Individuals with one or more severe exacerbations between Visits 1 and 2 had increased mortality compared with those with no severe exacerbations (17.1% vs. 9.8%; adjusted hazard ratio, 1.97; 95% CI, 1.40 to 2.77; P < 0.001). Conclusions: Respiratory exacerbations in people with cigarette smoking but normal spirometry were associated with lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.