Delineating sex-specific circulating host response signatures associated with COVID-19 severity and mortality.

Male SARS-CoV-2-infected patients have higher hospitalization rates, ICU admissions, and mortality compared to females, yet with unclear underlying mechanisms. We investigated the influence of biological sex on COVID-19 severity and patient outcomes. We profiled 41 circulating host response markers and identified differentially regulated proteins based on disease severity using covariates such as sex, age, BMI, diabetes, and corticosteroid administration. IL-8, D-dimer, S100B, IL-6, Angpt2, MMP8, TNFR1, uPAR, uPA, Osteopontin, IL-13, TNF-α, Pentraxin-3, P-selectin, Fractalkine, and SP-D levels were elevated in critically ill COVID-19 males compared to severe cases. In contrast, IL-8, D-dimer, IL-6, Angpt2, Tie2, uPAR, and SP-D were higher in females with critical-COVID-19 than in severe cases. Notably, D-dimer, IL-6, Pentraxin-3, and S100B were associated with male mortality, yet none of the measured plasma proteins associated with female mortality. Our study delineated distinct sex-specific plasma protein signatures linked to the severity and mortality of COVID-19 patients.