From FEV1 to Small Airways: A Methodological Review of Lung Function Assessment in Biologic-Treated Asthma

Abstract: Biologics have revolutionized the treatment of severe asthma, yet their clinical efficacy assessment has focused primarily on exacerbation reduction and symptom control, often overlooking the comprehensive evaluation of lung function improvement. Traditionally, forced expiratory volume in one second (FEV 1 ) has been the cornerstone metric for assessing airflow limitation. However, accumulating evidence highlights small airway dysfunction (SAD) as a critical driver of asthma symptoms, exacerbation risk, and heterogeneity in treatment response. This review explores the existing tools and metrics and their clinical relevance for assessing the impact of biologics on lung function, with a particular emphasis on small airway function in asthma patients. Methodologically, we appraise the physiological validity, repeatability, feasibility, responsiveness, and current regulatory readiness of small-airway endpoints for biologic trials and real-world effectiveness studies. We propose that these measures complement, rather than replace, FEV 1 within a multidimensional endpoint framework. We explore the application of techniques ranging from conventional spirometry (FEV 1 , FEF 2 5 – 7 5 , ie, forced expiratory flow at 25– 75% of forced vital capacity) to more advanced methods such as impulse oscillometry (IOS), body plethysmography, multiple-breath nitrogen washout (MBNW), and novel imaging modalities. Our analysis reveals the differences in the effects of various biologics (anti-IgE, anti-IL-5/5Rα, anti-IL-4Rα, anti-TSLP, etc.). on large and small airways. Furthermore, we also discuss the methodological frameworks, challenges, and future directions for integrating small airway function assessment into both clinical trial design and real-world effectiveness evaluations. Keywords: asthma, biologics, small airway dysfunction, lung function, FEV 1 , impulse oscillometry, methodology, efficacy evaluation