Three Spirometry-Based At-Risk Phenotypes Predict Incident Airflow Limitation: A Population-Based Study.

BACKGROUND AND OBJECTIVE: Incident airflow limitation is frequently diagnosed at advanced stages. Identifying individuals at risk through primary care spirometry may enable earlier intervention, yet validated, pragmatic frameworks remain lacking. METHODS: We applied a framework of three mutually exclusive spirometric at-risk phenotypes, termed Three-Phenotype Spirometry-Based Identification (hereafter TriSpi), to 6123 participants from two population-based cohorts: KORA (n = 1973, 3-year Follow-up, derivation) and SHIP (n = 4150, 5-year Follow-up, validation). TriSpi+ individuals were defined as meeting criteria for one of the three phenotypes: Early airflow limitation (EAL, FEV1/FVC > 0.7 and < 10th percentile or < 0.7 and > 5th percentile), small airway dysfunction (SAD) defined using FEF50- or FEF75-based thresholds; and preserved-ratio impaired-spirometry (PRISm). Associations with incident airflow limitation were tested using Firth's regression. RESULTS: EAL, PRISm, and SAD (defined using either FEF50 or FEF75-based thresholds) were significantly associated with incident airflow limitation across cohorts and follow-ups. TriSpi+ individuals accounted for 26%-36% of the population, identifying 74%-93% of future cases, while TriSpi+ was associated with a 10-25-fold increase in risk. Negative predictive values exceeded 95% across definitions, and the number needed to screen among TriSpi+ individuals ranged from 7 to 13. EAL showed the strongest individual association (OR up to 53.2), while SAD was more common in younger adults. CONCLUSION: Combining definitions for EAL, PRISm, and SAD enables robust prediction of incident airflow limitation. TriSpi may serve as a scalable, pragmatic approach for early risk stratification in primary care, in absence of post-BD spirometry.