Obesity and COVID-19 severity independently shape adipokine dysregulation and immune cell remodeling.

BACKGROUND: Obesity is a major risk factor for severe COVID-19, yet the immunological mechanisms by which it modifies disease progression remain incompletely characterized. We aimed to dissect the independent and interactive contributions of obesity and COVID-19 severity on circulating adipokines, cytokines, and immune cell populations. METHODS: Sixty patients with confirmed SARS-CoV-2 infection were stratified by disease severity (Mild/Moderate, n = 8; Severe, n = 30; Critical, n = 22) and obesity status (persons without obesity [PwoO], n = 30; persons with obesity [PwO], n = 30; BMI threshold 30 kg/m²). Serum TNF-α, resistin, IL-1β, IL-8, and NETs-ISG15 complexes were measured alongside circulating Th1, Th2, Th17, CD8 Treg, CD8 Tcm, intermediate monocytes, and low-density granulocytes (LDGs). Statistical analysis used Aligned Rank Transform ANOVA (ART-ANOVA), followed by Kruskal-Wallis and Dunn's post-hoc test with Holm adjustment within each obesity stratum. RESULTS: ART-ANOVA identified three distinct immunological patterns. First, TNF-α and resistin were significantly elevated by obesity as independent main effects (p = 0.012 and p = 0.026), with resistin additionally driven by severity (p = 0.0001). Second, IL-1β, IL-8, and NETs-ISG15 complexes were governed by disease severity (p = 0.0003, p = 0.0003, p = 0.002); IL-1β showed a symmetric Severe-to-Critical elevation across obesity strata, whereas IL-8 and NETs-ISG15 were selectively amplified in PwO at the critical stage (Severe vs. Critical: IL-8 p = 0.0002; NETs-ISG15 p = 0.015). Third, CD8 Treg cells and LDGs showed the largest severity-driven effects (both p < 0.0001), with symmetric depletion and expansion across obesity strata, identifying them as severity biomarkers independent of metabolic background. Th17 cells were suppressed by obesity (p = 0.001) and severity (p = 0.021). CD8 Tcm exhibited a unique obesity × severity interaction (p = 0.009), with a paradoxical expansion in critical PwO patients, absent in PwoO. CONCLUSION: Obesity and COVID-19 severity exert distinct, non-interacting effects on the immune landscape, with three exceptions: TNF-α and IL-8/NETs-ISG15 show obesity-conditional amplification of severity, and CD8 Tcm undergoes an obesity-specific expansion at the critical stage. These findings provide a mechanistic framework for obesity-modified immune responses in COVID-19 and identify candidate biomarkers for severity stratification.