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

  1. Jude Savarraj
  2. Eun S. Park
  3. Gabriela D. Colpo
  4. Sarah N. Hinds
  5. Diego Morales
  6. Hilda Ahnstedt
  7. Atzhiry S. Paz
  8. Andres Assing
  9. Fudong Liu
  10. Shivanki Juneja
  11. Eunhee Kim
  12. Sung-min Cho
  13. Aaron M. Gusdon
  14. Pramod Dash
  15. Louise D. McCullough
  16. H. Alex Choi

Reviewed by

Read the full article

Listed in

Log in to save this article

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.

Article activity feed

  1. Version published to 10.1186/s12974-021-02323-8
  2. ScreenIT

    SciScore for 10.1101/2021.05.25.21257353: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Inclusion criteria were laboratory-confirmed SARS-CoV-2 infection by real-time polymerase chain reaction, written informed consent from the patient or surrogate and age ≥ 18 years of age.
    Sex as a biological variableExclusion criteria were inability to complete long-term follow-up, severe functional disabilities before hospital admission for COVID-19 (defined by pre-admission modified Rankin Score(mRS)25 >1), history of pulmonary complications (including resection and transplant), pre-existing systemic diseases which would impact long term outcomes (including stroke, myocardial infarction, pulmonary disease requiring home oxygen, chronic renal failure necessitating hemodialysis and malignancy), documented neurologic and psychiatric disorders, prisoners and pregnant women.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The R package circlize26 was used to construct the chord diagrams.
    circlize26
    suggested: None

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: Our study has a few limitations. First, we included samples only the first available time-point after hospitalization. Typically, the measurements from the first-available time point is a reflection of the patient’s status during the earlier course of disease progress. However, this time-point is also the most accurate as in our hospital; all COVID-19 patients were administered dexamethasone, which could have a confounding effect on the measurements. Second, we have not related the observed BIMs with any long-term clinical outcomes. Third, we are underpowered to detect the effect of any co-morbidities on the neuronal injury.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.05.25.21257353v1 on medRxiv