Rethinking Blood Eosinophils for Assessing Inhaled Corticosteroids Response in COPD: A Post Hoc Analysis From the FLAME Trial

Background: The varied treatment response to inhaled corticosteroids (ICS) in patients with COPD and the associated increased risk of pneumonia necessitate a personalized ICS therapeutic approach. This is informed by blood eosinophil count (BEC), which predicts ICS treatment response. However, BEC appears to change in response to ICS treatment. Research Question: Does (1) BEC measured on ICS treatmen (2) BEC measured off ICS treatment, or (3) the change in BEC during ICS treatment best predict treatment response to ICS in COPD? Study Design and Methods: Fluticasone Salmeterol on COPD Exacerbations Trial (FLAME), a 52-week, double-blind randomized controlled trial compared long-acting beta-2 agonist (LABA)/long-acting muscarinic antagonist (LAMA) with LABA/ICS. Corticosteroids were prohibited during a 4-week run-in period. We chose patients previously on ICS, thereby allowing BEC before and after the run-in period 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 noninferior, to LABA/ICS in curbing exacerbations for most FLAME participants. However, higher BEC off ICS, higher BEC on ICS, and significant BEC suppression during ICS treatment corresponded to superior response to LABA/ICS 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 (≥ 200 cells/μL), and higher BEC on ICS did not predict ICS treatment response. For these patients, BEC off ICS and BEC change proved more predictive. Excess pneumonia risk associated with ICS appeared to be confined to patients who do not benefit from this treatment. BEC was not predictive of treatment effects on lung function and health status. Interpretation: 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. Clinical Trial Registration: ClinicalTrials.gov; No.: NCT01782326; URL: www.clinicaltrials.gov