Rethinking Blood Eosinophils for Assessing ICS Response in COPD: A Post-Hoc Analysis from FLAME

Background The varied treatment response to inhaled corticosteroids (ICS) in COPD, and the increased risk of pneumonia necessitate a personalised ICS approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. This post-hoc analysis evaluates the ability of different BEC measurements to predict ICS treatment response. BEC measured either on or off ICS treatment, and BEC change during ICS treatment were investigated. Methods FLAME, a 52-week, double-blind RCT compared LABA/LAMA versus LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing pre and post run-in period BEC to represent BEC on and off ICS, respectively. In this post-hoc analysis, we revisited outcome data, exploring how the three BEC biomarkers interacted with treatment response to the ICS containing regimen. Results Our study confirms that LABA/LAMA combination is superior, or at least non-inferior, to LABA/ICS in curbing exacerbations for most FLAME participants. Lower BEC off and BEC on ICS and lack of significant BEC suppression during ICS treatment corresponded to superior response to LABA/LAMA in terms of exacerbation rate, time-to-first exacerbation, and time-to-first pneumonia. In a subgroup, including 9% of participants, BEC changed significantly during ICS treatment, and higher BEC on ICS did not predict ICS treatment response. For these patients BEC off ICS and BEC change proved more predictive. Conclusion This exploratory analysis advocates preferentially using BEC off ICS or BEC change during ICS treatment for guiding ICS treatment decisions. BEC measured on ICS is less predictive of treatment response. What is already known on this topic Blood eosinophil count (BEC) is used to guide the administration of inhaled corticosteroids (ICS) for COPD, but they may be suppressed in response to systemic or inhaled corticosteroids. What this study adds This post-hoc analysis suggests that BEC change during treatment with ICS and this change is associated with treatment response to ICS containing regimens. More specifically, BEC suppression is associated with favourable response to ICS, while unchanged or increased BEC is associated with inferior ICS treatment effect and increased risk of pneumonia. In 9% of participants, BEC changes significantly (≥200 cells/μL) during ICS treatment, and in these patients, BEC on ICS is not reliable in predicting treatment response to ICS, as it appears that some ICS responders may actually have low BEC on ICS and vice versa. How this study might affect research, practice or policy These findings highlight the potential utility of BEC change during ICS treatment as a predictive biomarker of treatment response to ICS and question the use of BEC on ICS to guide withdrawal of ICS, but need prospective validation. ### Competing Interest Statement The authors declare no conflicts of interest directly related to this work. SB, PS and J-UJ report no conflicts of interest. AGM reports honoraria for presenting from GSK, not related to this work. DS reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Theravance, and Verona and personal fees from Cipla, Genentech and Peptinnovate, not related to this work. JV reports honoraria for consulting and/or presenting from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis and Teva, not related to this work. ### Clinical Trial NCT01782326 ### Funding Statement AGM, DS and JV were supported by the National Institute for Health and Care Research Manchester Biomedical Research Centre (NIHR Manchester BRC, NIHR203308). AGM was supported by an NIHR Clinical Lectureship in Respiratory Medicine. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The FLAME trial was approved by the ethics committee at each trial center, and all the patients provided written informed consent. For conducting this post-hoc analysis, we only accessed fully anonymised data and such analyses by independent researchers were covered by the original ethics application. Therefore, no further ethics application was necessary. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the FLAME trial are available upon request through the clinical study data request platform (clinicalstudydatarequest.com. Applications are reviewed for merit by an independent review board before access is granted.