BACKGROUND: The combination of pre-treatment peripheral blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) levels for optimizing the therapeutic response of T2-biologics in patients with severe eosinophilic asthma (SEA) remains unclear. OBJECTIVE: We aimed to compare the longitudinal clinical outcome changes across subgroups stratified by the combination of high and low levels of BEC and FeNO. METHODS: Overall, 278 patients with SEA (anti-IL-5/IL-5Rα users: n=82
anti-IL-4Rα users: n=196) were stratified based on pre-treatment BEC and FeNO levels and followed up for 6-12 months. Group differences in exacerbation rate, lung function, asthma control test (ACT), BEC, FeNO, and clinical remission over time were compared. RESULTS: Approximately 75% and 63% of patients presented with concurrent high BEC (≥300 cells/μL) and high FeNO (≥25 ppb) in the anti-IL-5/IL-5Rα and anti-IL-4Rα groups, respectively. Among anti-IL-5/IL-5Rα users, no significant differences were observed among BEC-FeNO groups regarding exacerbation rates or clinical remission. Patients with concurrent high BEC and FeNO levels demonstrated more pronounced reductions in both markers and greater FEV1 and ACT score improvements compared to those with high FeNO but low BEC. In the anti-IL-4Rα group, patients with low BEC and FeNO, and those with high BEC but low FeNO, exhibited a significantly lower likelihood of achieving clinical remission (OR [95% CI]: 0.08 [0.00-0.46] and 0.11 [0.01-0.63], respectively) and a slower rate of FEV1 improvement (all P for slope <
0.05) compared to those with concurrent high BEC and FeNO. CONCLUSION: Concurrently elevated BEC and FeNO levels ensure optimal therapeutic response in SEA patients treated with T2-biologics.