BackgroundEosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.MethodsWe performed a cross‐sectional observational study of severe asthma (eosinophilic n = 32, non‐eosinophilic n = 23, mepolizumab‐treated n = 25), with longitudinal follow‐up of 30 eosinophilic participants at two timepoints (4–24 weeks, >24 weeks) post‐commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.ResultsiEO proportion was significantly lower in mepolizumab‐treated participants in both the cross‐sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow‐up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non‐eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab‐treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab‐treated participants, which was associated with significantly better asthma control and spirometry.ConclusionsMepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab‐treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.

中文翻译：

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美泊利单抗在严重哮喘中消耗炎症但保留稳态嗜酸性粒细胞


背景嗜酸性粒细胞是严重哮喘的关键治疗靶点，受 IL5 （美泊利单抗） 和 IL5 受体 （贝那利珠单抗） 阻断抑制。IL5 通路生物制剂对最近描述的稳态 （hEOs） 和炎症 （iEOs） 嗜酸性粒细胞亚群的影响尚不清楚。我们旨在确定美泊利单抗和贝那利珠单抗治疗对嗜酸性粒细胞亚群和表型的相对影响，并探讨嗜酸性粒细胞亚群与严重哮喘特征和治疗反应的临床关联。方法我们对严重哮喘 （嗜酸性粒细胞性 n = 32，非嗜酸性粒细胞性 n = 23，美泊利单抗治疗 n = 25） 进行了横断面观察研究，并在美泊利单抗 （n = 20） 或贝那利珠单抗 （n = 10） 开始后的两个时间点 （4-24 周，>24 周） 对 30 名嗜酸性粒细胞参与者进行了纵向随访。通过流式细胞术评估表面 CD62L 蛋白来测量血液 hEOs 和 iEOs。结果在横断面和纵向研究中，美泊利单抗治疗参与者的 iEO 比例均显著降低。美泊利单抗和贝那利珠单抗在相似程度上耗尽了 iEOs，但在随访时，美泊利单抗参与者中仍有大量 hEOs。较大的 iEO 比例与嗜酸性粒细胞性哮喘但非嗜酸性粒细胞性哮喘的哮喘控制较差相关。较高的残余 iEO 比例与美泊利单抗治疗个体的哮喘控制较差相关。在大约一半接受美泊利单抗治疗的参与者中观察到血嗜酸性粒细胞活力降低，这与哮喘控制和肺活量测定的显著改善有关。结论美泊利单抗在严重哮喘中消耗 iEO 并降低循环嗜酸性粒细胞活力，但保留循环 hEOs 的残余种群。 相比之下，贝那利珠单抗耗尽了 iEOs 和 hEOs。较高的 iEO 丰度和嗜酸性粒细胞活力与美泊利单抗治疗后较差的临床结果相关。监测循环嗜酸性粒细胞表型和活力可能有助于预测严重哮喘的生物治疗反应。