• Spyridon Fortis, Matthew Strand, Surya P Bhatt, Patrick Ten Eyck, Linder Wendt, Trisha Parekh, MeiLan K Han, John E Hokanson, Gregory Kinney, Jeffrey L Curtis, Russell P Bowler, Emily S Wan, Ken M Kunisaki, Chris H Wendt, Elizabeth Regan, Mark Dransfield, James D Crapo, Edwin K Silverman, and Alejandro P Comellas.
• University of Iowa Hospitals and Clinics, Division of Pulmonary, Critical Care and Occupation Medicine, Iowa City, Iowa, United States; spyridon-fortis@uiowa.edu.
• Am. J. Respir. Crit. Care Med. 2025 Feb 13.

RationaleThe 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.ObjectiveTo assess the association of respiratory exacerbations with lung function decline and mortality in people with normal spirometry and current or former cigarette smoking history.MethodsWe analyzed data from COPDGene participants with ≥10 pack-years cigarette smoking and normal spirometry at enrollment (Visit 1) defined as post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FEV1 ≥LLN. We examined whether respiratory exacerbations occurring between Visits 1 and the 5-year follow-up visit (Visit 2) were associated with FEV1 decline, and all-cause mortality.Measurements And Main ResultsAmong 2,939 participants with cigarette smoking history and normal lung function at Visit 1, each additional exacerbation between visit 1 and 2 was associated with a 2.96 ml/year FEV1 decline (95%CI 1.81 to 4.12; P<0.001) at Visit 2. Experiencing ≥1 severe exacerbation between Visits 1 and 2 was associated with 14.6 ml/year FEV1 decline relative to those with no severe exacerbations (95% CI 8.56 to 20.6; P<0.001). Individuals with ≥1 severe exacerbation between Visits 1 and 2 had increased mortality compared to 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).ConclusionsRespiratory exacerbations in people with cigarette smoking but normal spirometry were associated lung function decline. Experiencing a severe respiratory exacerbation was associated with increased mortality.

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