Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma

<bold>Background:</bold> IL5 promotes eosinophilia, a key therapeutic target in severe asthma (SA). The effect of IL5 blocking biologics on homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. <bold>Objective:</bold> To determine the effect of mepolizumab and benralizumab treatment on eosinophil subsets in SA. <bold>Methods:</bold> Cross-sectional observational study of SA (eosinophilic [EA] n=32, non-eosinophilic [NEA] n=23, mepolizumab-treated n=25), with longitudinal follow-up of 30 EA participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n=20) or benralizumab (n=10). Blood hEOs and iEOs assessed by flow cytometry measure of surface CD62L protein. The study was preregistered on ANZCTR: ACTRN12621000113853. <bold>Results:</bold> Mepolizumab treatment was associated with decreased iEO proportion in the cross-sectional and longitudinal studies. Depletion of iEOs was similar with mepolizumab and benralizumab, however hEO number was significantly greater in mepolizumab versus benralizumab at follow-up. Higher iEO proportion correlated with poorer asthma control in EA but not NEA. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in some mepolizumab-treated SA participants, which was associated with improved clinical outcomes (better asthma control, spirometry, exacerbation rate). <bold>Conclusion:</bold> Mepolizumab depletes iEOs in SA but preserves a residual population of circulatory hEOs, while benralizumab depletes both iEOs and hEOs. Increased iEOs are associated with poorer asthma control in EA. Monitoring eosinophil phenotype and viability may be useful to predict biologic treatment response in SA.