Bridging Systemic–Airway Discordance: Sputum Stratification and Effectiveness of Anti-IL-4R

Background Systemic biomarkers such as peripheral blood eosinophils (PBE) and fractional exhaled nitric oxide (FeNO) are widely used to infer airway type 2 (T2) inflammation in asthma, yet discordance with local airway inflammation is common in clinical practice. Objectives To characterize sputum inflammatory profiles in severe asthma using a three-group stratification by PBE and sputum eosinophils, and to explore whether sputum soluble mediators relate to clinical remission after anti–IL-4Rα therapy. Methods We retrospectively analyzed 67 adults with asthma regularly followed at Niigata University Hospital. Sputum cell differentials and supernatant mediators (ECP, tryptase, YKL-40, IL-6, IL-18) were assessed alongside clinical indices. Patients were stratified into three groups by PBE (300/µL) and sputum eosinophils (3%). In those receiving biologics, we compared baseline characteristics between anti-IL-5/5R and anti-IL-4Rα and examined predictors of 12-month clinical remission under anti-IL-4Rα. Results Median sputum eosinophil and neutrophil percentage were 11.8% and 53.5%, respectively. ECP correlated positively with PBE, FeNO, IgE, and sputum eosinophils and inversely with percent of predicted forced expiratory volume in one second (%FEV ₁ ) and sputum neutrophils, whereas YKL-40 and IL-6 correlated positively with sputum neutrophils and inversely with T2 indices. The optimal PBE threshold for sputum eosinophils ≥ 3% was 266/µL (sensitivity 84.8%, specificity 93.8%). Among biologic users, anti-IL-5/5R recipients had higher sputum eosinophils than anti-IL-4Rα recipients. Notably, within the anti-IL-4Rα subgroup, baseline sputum IL-6 was higher in those who achieved clinical remission at 12 months, while FeNO tended to be higher. Conclusions Sputum-based phenotyping uncovered systemic–airway discordance and identified a paradoxical yet actionable signal: higher baseline sputum IL-6 associated with clinical remission under anti–IL-4Rα. If externally validated, IL-6—alongside FeNO and sputum cell counts—may inform biologic triage toward durable remission in severe asthma. Clinical trial number: not applicable.