Small Airways Disease Adversely Impacts the Response to Biologic Therapies in Severe Asthma

Introduction: Small airways disease (SAD) is increasingly recognized as a relevant trait in severe asthma, but its influence on outcomes with biologic therapies remains uncertain. We assessed the prevalence of SAD and its association with real-world treatment response in a severe asthma cohort. We hypothesized that baseline SAD, particularly when identified by oscillometry, would be associated with non-response to biologic therapy over 12 months. Methods: This single-center, retrospective cohort included adult severe asthma outpatients initiating biologic therapy. At enrolment, participants underwent clinical and biomarker evaluation, complete lung function testing (spirometry/plethysmography), and the Forced Oscillation Technique. SAD was defined by the coexistence of ≥ 1 oscillometry abnormality and ≥ 1 spirometry/plethysmography abnormality. "Non-responders" were defined as patients experiencing ≥ 2 exacerbations during 12-month follow-up. Multivariable logistic regression was used to identify independent predictors of response, adjusting for biologic therapy and key confounders (including BMI). Results: The analytic sample comprised 156 patients (aged 55 ± 18 years, 91 females) treated with omalizumab (n = 60), benralizumab (n = 23), mepolizumab (n = 32), or dupilumab (n = 41). After 12 months, 24/156 patients (15%) were classified as non-responders. At baseline, SAD was present in 69/156 patients (44%) and was more prevalent in non-responders than in responders (75% vs. 40%, p < 0.01). Non-responders showed worse spirometric indices (FEV1% and FEV1/VC) and more abnormal oscillometry (lower X5exp and higher ΔXrs, R5exp, and R5-R19). In multivariable models adjusted for biologic and key confounders, baseline oscillometry abnormalities were independently associated with a reduced odds of response (adjusted OR 0.08, 95% CI 0.02-0.37; p = 0.001). Conclusions: In a real-world severe asthma cohort, baseline SAD, particularly when identified by oscillometry, was associated with subsequent non-response to biologic therapy, suggesting potential value for risk stratification.