Sex-Specific Signatures of Circulating Protein and Cellular Host Responses Predicting COVID-19 Severity

Background/Objectives: Although COVID-19 is generally more severe in males, data on sex-specific differences in the predictive value of commonly used inflammatory biomarkers remain limited. The study aimed to evaluate the sex-specific prognostic performance of selected biomarkers during the Alpha variant wave. Methods: In single-center study, univariate and multivariable regressions analyses, along with receiver operating characteristic curve (ROC) analyses, were performed to assess the association of acute-phase proteins, cytokines, and white blood cell indices (at admission and 7 days later) and disease severity and mortality in patients with severe-to-critical COVID-19. Results: At admission, the combined assessment of ferritin and D-dimer predicted disease severity in both sexes; however, optimal cut-off values and diagnostic performance (specificity and sensitivity) differed between males and females. In males, neutrophil and lymphocyte counts provided additional clinically relevant predictive value. Seven days after admission, the combination of ferritin, D-dimer, and fibrinogen in males, and ferritin, as an independent predictor within a model including lactate dehydrogenase, in females demonstrated strong predictive performance for severe-to-critical COVID-19. At this time-point, lymphocyte count in males was also identified as an independent predictor of disease severity. Notably, C-reactive protein and neutrophil count correlated with mortality in males with severe-to-critical disease. Conclusions: Severe COVID-19 is predicted by distinct acute-phase proteins and shared, sex-specific biomarkers, but with distinct cut-offs and predictive accuracy. In males, white blood cell indices also serve as independent predictors. Furthermore, prognostic utility changes of these biomarkers over the course of the disease, suggesting sex-specific and time-dependent role in COVID-19 pathogenesis.