Multidimensional Inflammatory Biomarker Profiling in COPD: A Latent Inflammatory Construct Associated with Disease Severity and Exacerbation Burden

Background/Objectives: Systemic inflammation is a widely recognised feature of chronic obstructive pulmonary disease (COPD). The combined contribution of acute-phase reactants and pro-inflammatory cytokines to disease severity and exacerbation risk remains incompletely understood. This study evaluated the associations of TNF-α, IL-8, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen with clinical outcomes in COPD and investigated whether a latent systemic inflammation construct provides additional information on exacerbation burden beyond individual biomarkers. Methods: We conducted a cross-sectional observational study in Romania, including 96 patients with clinically stable COPD. TNF-α and IL-8 were measured by ELISA, whereas CRP, ESR, and fibrinogen were determined using standard laboratory methods. Spirometry and patient-reported outcomes were assessed, and exacerbation history over the preceding 12 months was recorded retrospectively via patient interviews and verified against medical records when available. Negative binomial regression, Cox proportional hazards modelling, and generalised structural equation modelling (GSEM) were used to examine associations between inflammatory biomarkers and clinical outcomes. Results: All five inflammatory biomarkers increased across GOLD grades and correlated inversely with spirometric indices, with ESR showing the strongest correlations. Higher biomarker concentrations were associated with worse CAT, mMRC, and SGRQ-C scores (all p < 0.001). Individual biomarkers were associated with exacerbation frequency in unadjusted analyses but lost significance after adjustment for disease severity and comorbidities. In contrast, the latent systemic inflammation construct remained independently associated with annual exacerbation rate (IRR = 1.407, 95% CI: 1.145–1.668, p < 0.001). Neither the individual biomarkers nor the eosinophilic phenotype showed a clinically meaningful association with time to first exacerbation. Conclusions: A latent systemic inflammation construct integrating multiple biomarkers remained independently associated with exacerbation burden after additional adjustment for GOLD spirometric grade, although the association was attenuated (IRR = 1.186 vs. 1.407 in the primary model) and should be interpreted as exploratory given the differing covariate adjustment sets. These findings support further investigation of integrated inflammatory profiling in COPD, particularly in prospective multicentre studies.