“GOLD E” VERSUS “FREQUENT EXACERBATOR” CLASSIFICATIONS IN COPD: A PROTEO-METABOLOMIC PERSPECTIVE. [COMUNICACIÓN PREMIADA]

COPD treatment is often guided by the GOLD E phenotype (≥1 hospitalization or >1 exacerbation/prior year) versus GOLD AB. Alternatively, frequent exacerbators (FE) are defined as ≥3 exacerbations/year, regardless of hospitalization. Their biological basis requires exploration by omics approaches. Plasma from 136 COPD patients (103 FE, 33 NFE; 58 GOLD E, 78 GOLD AB) and 34 controls were analyzed using LC-MS/MS proteomics (with partial depletion of high-abundance proteins) and untargeted metabolomics. Differentially abundant proteins (DAPs) and metabolites (DAMs) were identified by comparisons with controls and between phenotypes. Functional annotation was performed. Predictive models were trained on a single-center cohort (n = 58) and then externally validated in a multicenter Spanish cohort (n = 80). Compared with controls, GOLD E showed 47 DAMs (14 xenobiotics) and 92 DAPs, while FE showed 54 DAMs (18 xenobiotics) and 69 DAPs. GOLD AB and NFE revealed 44 and 60 DAPs, respectively. Direct COPD comparisons detected no differences between GOLD E and AB, but 45 DAMs (17 xenobiotics) between FE and NFE. When control-based differences were incorporated, there were 16 DAMs and 2 DAPs (HRG, FCR3B), and 60 DAMs, respectively. Their best models were biomics without xenobiotics (83% accuracy; 30% coverage) and metabolomics with xenobiotics (75% accuracy; 87.5% coverage). Proteomics highlighted COPD hemostasis and immunity, while metabolomics suggested alterations in catabolism and nitric oxide metabolism, among others. Omics-derived biomarkers may aid in the profiling of exacerbators. GOLD E and FE share molecular features, but FE exhibits greater biological homogeneity. Metabolomics outperformed proteomics in classification.