Systemic-airway eosinophil discordance and sputum mediator profiling in severe asthma treated with biologics: a retrospective cohort study.

BACKGROUND: Biologic therapies have expanded treatment options for severe asthma; however, systemic biomarkers do not always reflect airway inflammation. Induced sputum may provide complementary information for inflammatory phenotyping and for exploring predictors of treatment response. OBJECTIVES: To characterize sputum inflammatory profiles in severe asthma using a three-group stratification by peripheral blood eosinophils (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 adult asthma patients with paired blood and induced sputum assessments. Patients were stratified using commonly applied thresholds for type 2–related systemic eosinophilia and eosinophilic airway inflammation (PBE ≥ 300/µL and sputum eosinophils ≥ 3%). Among biologic-treated patients, we compared baseline characteristics between anti–IL-5/IL-5R and anti–IL-4Rα users and explored predictors of 12-month clinical remission in the anti–IL-4Rα cohort. RESULTS: Median sputum eosinophil and neutrophil percentage were 11.8% and 53.5%, respectively. Eosinophil cationic protein (ECP) correlated positively with PBE, FeNO, IgE, and sputum eosinophils and inversely with percent of predicted forced expiratory volume in one second (%FEV1) and sputum neutrophils, whereas human chitinase-3-like-1 (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 at baseline. 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: In this exploratory cohort, sputum-based phenotyping uncovered systemic–airway discordance and identified an unexpected yet potentially actionable signal: higher baseline sputum IL-6 was associated with 12-month clinical remission under anti–IL-4Rα. If externally validated, IL-6—alongside FeNO and sputum cell counts—may help inform biologic selection to achieve 12-month clinical remission in severe asthma.