Markers of brain and endothelial Injury and inflammation are acutely and sex specifically regulated in SARS-CoV-2 infection

Objective: To investigate brain injury markers (BIM), endothelial injury markers (EIM) and cytokine/chemokine (CC) markers of systemic inflammation in coronavirus disease 2019 (COVID-19) and across sex. Methods: Plasma samples from 57 subjects at <48 hours of COVID 19 hospitalization, 14 subjects at 3 months of COVID 19 hospitalization and 20 matched controls were interrogated for the levels of six BIMs, including GFAP, S100B, Syndecan1, UCHLI, MAP2 and NSE, two EIMs, including sICAM1 and sVCAM1 and thirty eight CCs. Statistical and bioinformatics methods were used to measure differences in the marker profiles across (a) COVID 19 vs controls and (b) men vs women. Results: Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFa; were significantly (p<0.05) elevated in the COVID 19 cohort compared to controls. Two CCs: MDC and MIP1a; were significantly lower in the COVID-19 cohort. Bioinformatics analysis reveal a stronger positive association between BIM/CC/EIMs in the COVID-19 cohort. Analysis across sex revealed that several BIMs and CCs including NSE, IL10, IL15 and IL8 were significantly (p<0.05) higher in men compared to women. Men also expressed a more robust BIM/ EIM/CC association profile compared to women. At 3 months, BIMs and CCs were not significantly different in the COVID-19 cohort compared to controls. Conclusion: The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization suggest that brain injury is mediated by endotheliopathy and inflammation. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.