Not Just Th 2: Eosinophil‐Associated Proteomic Networks Reveal Fundamental Differences Between COPD and Asthma

INTRODUCTION: While eosinophils are established pathogenic drivers and therapeutic targets in asthma, their role in chronic obstructive pulmonary disease (COPD) remains conflicting. This study aimed to investigate the bidirectional associations of eosinophils with COPD and asthma, and to elucidate the potential distinct underlying mechanisms. METHODS: In 302,370 UK Biobank participants, multivariable-adjusted Cox proportional hazards models assessed associations between blood eosinophil counts and incident COPD, asthma, and asthma COPD overlap (ACO). Bidirectional two-sample Mendelian randomization (MR) tested causality. Among 32,121 participants with available baseline Olink proteomic data, proteomic profiling characterized eosinophil-associated plasma protein signatures and their associations with disease risk. RESULTS: During approximately 13.5 years of follow-up, elevated blood eosinophils were associated with increased risks of COPD, asthma, and ACO. Unlike asthma, pre-existing COPD did not predict subsequent eosinophil elevation. MR indicated a unidirectional effect of eosinophils on COPD but bidirectional causality for asthma. Proteomics revealed a broader protein interaction network in COPD (378 proteins) than in asthma (70 proteins). Exploratory mediation analyses, assuming an eosinophil-to-protein direction, estimated that the eosinophil-associated proteomic signature statistically accounted for 87.8% of the association with COPD (p = 0.076) and 59.1% of the association with asthma (p < 0.001). Among these proteins, COPD-associated mediators were linked to a broad and intricately woven inflammatory network, in contrast to the more streamlined network that is mainly confined to Type 2 inflammation seen in asthma. CONCLUSION: Although elevated eosinophil levels are associated with increased COPD risk, their pathogenic role-embedded within a complex inflammatory network-differs fundamentally from the Th2-centric inflammatory pathway characteristic of asthma. This observational study suggests that eosinophilic COPD is not simply a surrogate for asthma-like Type 2 inflammation.