Background: New anti-IL-5 antibodies, mepolizumab and benralizumab, have recently been approved for severe asthma, sharing the same inclusion criteria. Objective: To contribute on biomarkers research leading to the personalized choice, we investigated L-selectin, Krebs von den Lungen (KL-6), and lymphocyte subsets as bioindicators of airway hyper-responsiveness and remodeling. Materials and Methods: A cohort of 28 patients affected by severe eosinophilic asthma were treated with anti-IL-5 drugs. According to clinical parameters, patients were subdivided into early and partial responders. Lymphocytes subsets were analyzed through flow cytometry, while KL-6 and sL-selectin were analyzed on serum samples. Clinical, functional, and immunological data at baseline (T0), after 1 month (T1), and 6 months of therapy were collected in a database. Results: All treated patients showed an increase in the percentage of forced expiratory volume in the first second (FEV1) and FEV1/forced vital capacity ratio and a decrease of peripheral eosinophils for both drugs after 1 month of treatment. Mepolizumab-treated patients also showed decreased CD8+ and NKT-like cell percentages and a significant increase in sL-selectin concentrations between T0 and T1. Stratifying the cohort of our patients in early and partial responders at T0, they showed a reduction of peripheral eosinophils, sL-selectin and KL-6, while no differences were found at T0 between early and partial responders patients treated with benralizumab. Conclusions: This real-life study provides new insights for the personalized approach to severe asthma therapy. Although preliminary, the results indicate that besides eosinophils, KL-6 and sL-selectin are useful as biomarkers of early response that can also involve in the pathogenesis of severe asthma.

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