While the acute phase of the COVID-19 pandemic has passed, understanding its pathophysiology remains critical for managing long-term sequelae and future viral threats. Oxidative stress is a proposed key driver of COVID-19 severity, but its relationship with the dynamic inflammatory cascade and its value as a standalone biomarker requires further validation.

Case-control study was conducted to quantify systemic oxidative stress burden in 109 hospitalized COVID-19 patients (56 severe, 53 mild-moderate) and 112 healthy controls. Serum total oxidant status (TOS) and total antioxidant status (TAS) were measured, and the oxidative stress index (OSI) was calculated and correlated to the inflammatory mediators (IL-6, IL-8, IL-10, IP-10, CRP, SAA).

COVID-19 patients exhibited a profound redox imbalance, characterized by elevated TOS and OSI, and depleted TAS compared to controls (p <0.05). This imbalance was exacerbated in severe disease, where TOS and OSI were significantly increased. The OSI demonstrated superior diagnostic performance for disease severity (AUC = 0.90; 95% CI: 0.86–0.95) compared to TOS (AUC = 0.89) and TAS (AUC = 0.78). Crucially, both TOS and OSI showed strong positive correlations with inflammatory cytokines and acute-phase proteins (IL-6, IL-10, IP-10, CRP, SAA; all p <0.001). After adjusting for age, time from symptom onset, and comorbidity burden (Charlson Comorbidity Index), multivariate analysis confirmed that high OSI was independently associated with disease severity (adjusted OR: 4.8; 95% CI: 1.9–12.1).

The OSI is a robust, integrative biomarker that strongly reflects COVID-19 severity and is closely linked to the hyperinflammatory state. The OSI is strongly correlated with increased inflammatory cytokines and acute-phase proteins in acute COVID-19.