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

Background/Objectives: While COVID-19 is typically more severe in males, there is limited data on sex-specific differences in the predictive value of common inflammatory biomarkers. To address this gap, their predictive capacity was evaluated in a single-center study of male and female patients during the Alpha variant wave. Methods: Univariate, multivariable, and receiver operating characteristic (ROC) analyses were used to evaluate the association of acute-phase proteins, cytokines, and white blood cell counts (measured on admission and day seven) with COVID-19 severity and mortality in severely/critically ill COVID-19 subjects. Results: On admission, the combination of ferritin and D-dimer effectively predicted disease severity in both sexes, though cut-off values and diagnostic accuracy (specificity and sensitivity) varied by sex. In males, neutrophil and lymphocyte counts provided additional clinically relevant predictive value. Seven days post-admission the combination of ferritin, D-dimer and fibrinogen in males and ferritin (as independent predictor comprising model with lactate dehydrogenase) in females emerged as efficient predictors of severe/critical COVID-19. On this evaluation-point, lymphocytes in males and neutrophil-to-lymphocyte ratio in females were also identified as independent predictors of severe/critical COVID-19. Notably, on this evaluation-point C-reactive protein and neutrophil count independently predicted mortality in males with severe/critical disease. Conclusion: Different acute-phase proteins (or the same proteins with distinct cut-off values and predictive characteristics) and white blood cell indices should be considered as independent predictors of severe/critical COVID-19 in males and females and ii) the prognostic capacity of many of them evolves during disease progression, indicating their sex-specific, time-dependent pathogenetic role in COVID-19.