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.