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

Abstract

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.

Immune Profiles to Distinguish Hospitalized Versus Ambulatory Covid-19 Cases in Older Patients

“…The COVID-19-associated hospitalization rates are also higher among males than females (5.1 vs. 4.1 per 100,000) (61). Indeed, markers of brain and endothelial injury and inflammation were shown to be sex specifically regulated in SARS-CoV-2 infection (63). Nonetheless, scant information is available regarding the differences/similarities in cytokine levels between males and females, even though sex differences are likely to impact immune responses to SARS-CoV-2, as seen against other viruses, for examples, sex hormone-regulated pDC responses and sex differences in cytokine and chemokine production and neutrophil recruitment during influenza virus infection (64).…”

“…We evaluated here a comprehensive profile of SARS-CoV-2-specific antibodies (total Ig, isotypes/subtypes, Fab-and Fc-mediated functions) and a panel of 48 cytokines and chemokines in serum samples from a cohort of SARS-CoV-2-infected patients with demographic risk factors for severe COVID-19: 81% were male, 79% were >50 years old (median of 63), and 85% belonged to US minority groups (black and/or Hispanic). Comparison of hospitalized vs. ambulatory patients within this cohort revealed two features that differed between severe vs. mild COVID-19 cases: a discordant Ab response to the S2 subunit of the viral spike protein in the mild cases and an elevated response of specific cytokines and chemokines, notably IL-27, in the severe cases.…”