Post-Bronchodilator FEF25-75 and COPD Exacerbations: The Role of Airflow Obstruction Severity in the KOCOSS Cohort.

BACKGROUND: FEF25-75 is a spirometric index of mid-expiratory flow that is strongly related to conventional airflow obstruction. We evaluated its association with 3-year COPD exacerbations and whether this association was independent of airflow obstruction severity. METHODS: We analyzed 830 KOCOSS participants (≥40 years; post-BD FEV1/FVC <0.7; ≥10 pack-years) with post-bronchodilator FEF25-75 and complete 3-year exacerbation outcomes. Participants were categorized into quartiles of post-bronchodilator FEF25-75 % predicted: Q1, ≥37%; Q2, 26-36%; Q3, 18-25%; and Q4, ≤17%. Logistic regression assessed the risk of at least one moderate-to-severe exacerbation, and negative binomial regression assessed cumulative exacerbation counts. Sequential models adjusted for clinical factors, FVC % predicted, and FEV1 % predicted. RESULTS: The proportion of participants experiencing at least one moderate-to-severe exacerbation increased from 54.0% in Q1 to 81.1% in Q4 (P<0.001), and the mean cumulative exacerbation count increased from 2.0 to 5.8. In the clinical model, Q4 was associated with a higher risk of exacerbation (OR 2.67, 95% CI 1.66-4.30) and a higher cumulative exacerbation rate (IRR 2.32, 95% CI 1.68-3.19) compared with Q1. These associations persisted after adjustment for FVC, but were no longer significant after adjustment for FEV1 (OR 1.00, 95% CI 0.47-2.11; IRR 1.24, 95% CI 0.75-2.04). CONCLUSIONS: Lower post-bronchodilator FEF25-75 identifies COPD patients with a higher long-term exacerbation burden; however, this association is predominantly attributable to FEV1-defined airflow obstruction severity. FEF25-75 should therefore be interpreted primarily as a marker of overall physiological impairment rather than an independent, small-airway-specific predictor of exacerbations.