Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy

  1. Jan Remsik
  2. Jessica A. Wilcox
  3. N. Esther Babady
  4. Tracy A. McMillen
  5. Behroze A. Vachha
  6. Neil A. Halpern
  7. Vikram Dhawan
  8. Marc Rosenblum
  9. Christine A. Iacobuzio-Donahue
  10. Edward K. Avila
  11. Bianca Santomasso
  12. Adrienne Boire

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Abstract

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction. Here we show that a particularly vulnerable population with neurologic manifestations of COVID-19 harbor an influx of inflammatory cytokines within the cerebrospinal fluid in the absence of viral neuro-invasion. The majority of these inflammatory mediators are driven by type 2 interferon and are known to induce neuronal injury in other disease models. Levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks following convalescence from the acute respiratory infection. These prolonged neurologic sequelae following a systemic cytokine release syndrome lead to long-term neurocognitive dysfunction with a wide range of phenotypes.

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  1. ScreenIT

    SciScore for 10.1101/2020.09.15.20195511: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethical approval for COVID-19-relared research was obtained from MSKCC Institutional Review Board (IRB) under protocol #20-006.
    Consent: All participants provided written informed consent for sample and clinical data collection and subsequent analyses.
    RandomizationSamples were then dispensed in randomized fashion into 96-well PCR plate and stored at −80°C until further analysis.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    All patients tested positive for the presence of COVID-19 viral RNA in nasopharyngeal swab and/or anti-COVID-19 antibodies in serum or plasma as described below, using CDC and FDA approved methods.
    anti-COVID-19
    suggested: None
    Primary anti-ACE-2 antibody (AF933, R&D) was used as recommended by the manufacturer, followed by the incubation with HRP-conjugated anti-goat secondary antibody (Immpress HRP Anti-Goat IgG, MP-7405, Vector Laboratories) and subsequently DAB EqV (SK-4103, Vector Laboratories).
    anti-ACE-2
    suggested: None
    anti-goat
    suggested: (Vector Laboratories Cat# MP-7405, RRID:AB_2336526)
    Anti-Goat IgG
    suggested: (Vector Laboratories Cat# MP-7405, RRID:AB_2336526)
    Software and Algorithms
    SentencesResources
    Detection of anti-SARS-CoV-2 immunoglobulins: Clinical IgG test against SARS-CoV-2 was performed using FDA EUA kit from Abbott (6R86-20).
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Pathway analysis was performed with Reactome (www.reactome.org) and IPA (Qiagen).
    Reactome
    suggested: (Reactome, RRID:SCR_003485)
    Statistical analyses were conducted in Prism (v8, GraphPad).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    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.

    About SciScore

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  2. Version published to 10.1101/2020.09.15.20195511v1 on medRxiv