Sex difference in the cytokine profile among patients hospitalized for COVID-19 and during their recovery: predominance of females in adhesion molecules and males in oxidative stress (preprint)

ABSTRACT

Background Male sex is associated with greater severity and mortality from coronavirus disease 2019 (COVID-19), although infections are equally distributed between men and women. The present study aims to investigate sex differences in the hyperinflammatory immune response to SARS-CoV-2 infection and consequent thrombosis using linked cytokine profile and blood laboratory data.Methods This observational cohort study involved 99 COVID-19 patients (69 male and 30 female adults), hospitalized between March 2021 and April 2022. Their clinical and laboratory data were collected to examine sex difference in oxidative stress, neutrophil extracellular traps (NETs) formation and plasma cytokines at hospital admission and up to 5 months of their recovery.Results Dihydrotestosterone (DHT) levels were transiently reduced, while sex hormone binding globulin levels were continuously decreased in male post-COVID-19 patients after its rise at diagnosis. Regarding inflammatory cytokines, interleukin-6 (IL-6) and interferon-gamma are generally increased at diagnosis, while IL-6 is decreasing in post-COVID-19 patients. Tumor necrosis factor-alpha had 5-fold increase in females at diagnosis. Chemokines IL-8 and monocyte chemoattractant protein-1 and coagulation markers intercellular adhesion molecule-1 and E-selectin were consistently upregulated in female COVID-19 and post-COVID-19 patients, in contrast to vascular cell adhesion molecule-1 and P-selectin. DHT increased reactive oxygen species in neutrophils of male patients, while estrogen decreased in females. Markers for NETs formation, such as circulating DNA and myeloperoxidase, were significantly increased in the plasma of patients. Sex hormones are mostly negatively correlated with leukocytes, while in positive correlation with coagulation markers.Conclusions Markers of chemotaxis, endothelial dysfunction and inflammation are still detectable and partially sex dependent in COVID-19 patients after 5 months of hospital admission. These distributions of sex steroid hormones splitted endothelial adhesion molecules, coagulation and inflammation factors, while they generalized chemokines.