Small Airway Physiological Signatures of Response to Biologic Therapy in Severe Asthma

Abstract Severe asthma remains a major clinical challenge despite advances in biologic therapies. Small airway dysfunction (SAD) contributes substantially to persistent symptoms, exacerbation burden, and heterogeneous treatment responses. Despite emerging evidence, most available studies remain limited to single-center severe asthma biologic cohorts, underscoring the need for pooled international oscillometry datasets to develop more generalizable predictors of response variability. This systematic review synthesizes evidence on the role of small airway physiological biomarkers as predictors and monitoring tools for biologic therapy response in severe asthma. Literature published between 2016 and 2025 was systematically reviewed following PRISMA 2020 principles. Across included studies, impulse oscillometry (IOS) indices such as R5-R20 and AX, spirometric markers including FEF25-75%, and lung volume measures consistently demonstrated predictive and longitudinal utility. Patients with abnormal baseline SAD markers showed distinct response patterns to dupilumab, mepolizumab, and other biologics. Improvement in distal airway physiology was associated with better asthma control, fewer exacerbations, and corticosteroid sparing. These findings support the integration of small airway physiology into precision biologic selection and long-term monitoring. Furthermore, pooled international oscillometry data from existing severe asthma cohorts may enable the development of novel, translatable, and generalizable biomarkers for biologic response prediction.