Lung Function-Based Assessment of Small Airway Dysfunction in Chronic Respiratory Diseases

Small airway dysfunction (SAD) is increasingly recognized as an early and clinically important component of chronic respiratory diseases. Because pathological changes in the peripheral airways may remain clinically silent until disease is advanced, sensitive methods to detect and characterize SAD are required to improve phenotyping and support mechanism-based therapeutic development. This narrative review summarized key SAD mechanisms, including epithelial injury and dysregulated repair, mucus retention, inflammation-driven mucosal edema, smooth muscle dysfunction, and matrix remodeling, that contribute to small-airway narrowing and ventilation heterogeneity. We synthesized lung function approaches used to quantify SAD and relate measurement outputs to functional abnormalities, including ventilation heterogeneity, small-airway narrowing, airway closure, and gas trapping. We reviewed commonly used clinical and research assessments, including spirometry, forced oscillation techniques (FOTs), impulse oscillometry (IOS), multiple-breath washout (MBW), fractional exhaled nitric oxide (FeNO), and static lung volume measurements. We also highlighted the practical advantages, key limitations, and interpretive pitfalls of each modality and proposed a pragmatic framework for integrating these physiological tests into clinical evaluation and phenotypic identification of SAD. Finally, we identified priorities for standardization and future studies to determine how lung function-based SAD endpoints can guide treatment decisions and serve as outcome measures in clinical trials.