Biochemical and cytokine profiles in COVID-19 patients from northeastern Brazil: IL-18BPa as a predictive marker and IL-37 associated with disease severity.

COVID-19 severity is largely determined by dysregulated host inflammatory responses, yet biomarkers that reflect this immunological imbalance and support clinical risk stratification remain insufficiently defined. The IL-1 cytokine family has emerged as a relevant component of antiviral and hyperinflammatory responses, particularly through the IL-18/IL-37/IL-18 binding protein a (IL-18BPa) axis, which integrates pro-inflammatory signaling and immune regulation. However, the clinical relevance of this axis in COVID-19 severity remains poorly characterized. In this cross-sectional study, we evaluated IL-37, total IL-18, free IL-18, and IL-18BPa in patients with mild COVID-19, severe ICU-admitted COVID-19, and healthy controls from Northeastern Brazil. Cytokines were quantified by ELISA, free IL-18 was estimated using the law of mass action, and biochemical markers were assessed. Statistical analyses included group comparisons, correlation analyses, and ROC curve evaluation. COVID-19 patients showed reduced IL-37 levels compared with healthy controls, while severe cases presented higher IL-37 concentrations than mild cases, suggesting a compensatory but insufficient regulatory response during disease progression. Conversely, total IL-18, free IL-18, and IL-18BPa were markedly increased in severe COVID-19. In severe patients, total and free IL-18 positively correlated with triglycerides, AST, ALT, and cholesterol, linking IL-18 bioactivity to metabolic and hepatic alterations associated with systemic inflammation. ROC analysis identified IL-18BPa as the strongest discriminator of severe disease (AUC = 0.9987; sensitivity 100%; specificity 96.97%), followed by total and free IL-18 (AUC > 0.94). These findings highlight IL-18BPa as a promising biomarker of COVID-19 severity and support the clinical relevance of this regulatory axis in hyperinflammatory disease.