Residual exacerbation phenotypes during anti-IL-5/IL-5R (IL-5 receptor) therapy in severe eosinophilic asthma

Background: Although anti-interleukin (IL) 5/IL-5 receptor therapies effectively reduce the exacerbation burden in severe eosinophilic asthma, some patients continue to experience residual exacerbations despite biologic treatment. The inflammatory characteristics of these exacerbations remain insufficiently defined. Objective: The objective was to evaluate the clinical and inflammatory phenotypes of asthma exacerbations that occur during mepolizumab or benralizumab therapy in patients with severe eosinophilic asthma. Methods: This retrospective real-world study included patients with severe eosinophilic asthma who experienced exacerbations despite anti-IL-5/IL-5 receptor therapy. Exacerbations were classified as eosinophilic, neutrophilic, paucigranulocytic, or mixed granulocytic according to peripheral blood eosinophil and neutrophil counts. Clinical characteristics, inflammatory phenotypes, pulmonary function parameters, eosinophil levels, and annual exacerbation frequencies were evaluated. Results: Forty-two patients who experienced 63 exacerbations during biologic therapy were included. The median age was 48.5 years, and 66.7% of the patients were women. The annual exacerbation frequency significantly decreased after biologic treatment initiation in both treatment groups. Among the patients who completed the first treatment year, 66.7% of the patients treated with benralizumab and 55.1% of the patients treated with mepolizumab remained exacerbation-free. No significant differences were observed between biologic agents with regard to infectious exacerbation frequency or inflammatory exacerbation phenotypes. Paucigranulocytic exacerbations represented the most common phenotype in both treatment groups, whereas mixed granulocytic exacerbations were rare. Pulmonary function parameters and eosinophil levels during exacerbations were comparable between the biologic agents. Conclusion: Residual exacerbations that occurred during anti-IL-5/IL-5 receptor therapy demonstrated heterogeneous inflammatory phenotypes rather than a uniformly eosinophilic pattern. The predominance of paucigranulocytic exacerbations suggests that mechanisms beyond persistent eosinophilic inflammation may contribute to residual exacerbations during biologic therapy in severe eosinophilic asthma.