Brain injury, endothelial injury and inflammatory markers are elevated and express sex-specific alterations after COVID-19

Abstract

Objective Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. Methods Plasma samples from 57 subjects at < 48 h of COVID-19 hospitalization, and 20 matched controls were interrogated for the levels of six BIMs—including GFAP, S100B, Syndecan-1, UCHLI, MAP2 and NSE, two EIMs—including sICAM1 and sVCAM1. Additionally, several cytokines/chemokines were analyzed by multiplex. 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 TNFα were significantly (p < 0.05) elevated in the COVID-19 cohort compared to controls. 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. Conclusion The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

Response to: SARS-CoV-2 and type I interferon signaling in brain endothelial cells: Blurring the lines between friend or foe

“…The findings by Savarraj et al. nicely complement our data, since here, plasma was analyzed in rather acute COVID-19 cases ( Savarraj et al., 2021 ). However, this is in contrast to the patient CNS material that was used in our study, which was investigated postmortem after sometimes long disease durations.…”

“…Some of the references mentioned by Vavougios et al. had not been published when we submitted to Stem Cell Reports ( Constant et al., 2021 ; Kim et al., 2021 ; Savarraj et al., 2021 ; Wenzel et al., 2021 ; Zhang et al., 2021 ) and were therefore not cited. Some published studies were not included because of space constraints, in part resulting from specific requests during the revision, and were deprioritized; others because they did not fit the focus of our paper.…”

Plasma biomarkers of brain injury in COVID-19 patients with neurological symptoms

“…The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to have a neuroinvasive potential [ 1 , 2 ]. Possible mechanisms for central nervous system (CNS) involvement have been proposed as direct effect of the virus or indirect effects of systemic infammation due to immune activation or hypoxia [ [3] , [4] , [5] ]. Accumulating data have described various neurological manifestations in coronavirus disease 2019 (COVID-19) [ 3 , [6] , [7] , [8] ].…”

Sex differences in global metabolomic profiles of COVID-19 patients

“…Sex differences in the immune response may explain sex-dependent responses to COVID-19 [ 14 – 20 ]. Levels of several pro-inflammatory chemokines and cytokines are higher in affected males [ 16 ].…”