Endothelial dysfunction contributes to severe COVID-19 in combination with dysregulated lymphocyte responses and cytokine networks

  1. Louisa Ruhl
  2. Isabell Pink
  3. Jenny F. Kühne
  4. Kerstin Beushausen
  5. Jana Keil
  6. Stella Christoph
  7. Andrea Sauer
  8. Lennart Boblitz
  9. Julius Schmidt
  10. Sascha David
  11. Hans-Martin Jäck
  12. Edith Roth
  13. Markus Cornberg
  14. Thomas F. Schulz
  15. Tobias Welte
  16. Marius M. Höper
  17. Christine S. Falk

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Abstract

The systemic processes involved in the manifestation of life-threatening COVID-19 and in disease recovery are still incompletely understood, despite investigations focusing on the dysregulation of immune responses after SARS-CoV-2 infection. To define hallmarks of severe COVID-19 in acute disease ( n  = 58) and in disease recovery in convalescent patients ( n  = 28) from Hannover Medical School, we used flow cytometry and proteomics data with unsupervised clustering analyses. In our observational study, we combined analyses of immune cells and cytokine/chemokine networks with endothelial activation and injury. ICU patients displayed an altered immune signature with prolonged lymphopenia but the expansion of granulocytes and plasmablasts along with activated and terminally differentiated T and NK cells and high levels of SARS-CoV-2-specific antibodies. The core signature of seven plasma proteins revealed a highly inflammatory microenvironment in addition to endothelial injury in severe COVID-19. Changes within this signature were associated with either disease progression or recovery. In summary, our data suggest that besides a strong inflammatory response, severe COVID-19 is driven by endothelial activation and barrier disruption, whereby recovery depends on the regeneration of the endothelial integrity.

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  1. Version published to 10.1038/s41392-021-00819-6
  2. ScreenIT

    SciScore for 10.1101/2021.07.08.21260169: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Study approval: The study was approved by the Hannover Medical School Ethics Committee.
    Consent: All patients or participants provided written informed consent before participation in the study (9001 BO K, 968-2011).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    SARS-CoV-2 S-and N-specific antibodies were detected using the SARS-CoV-2 Antigen Panel 1 IgG, IgM, IgA assay (Millipore HC19SERM1-85K-04, HC19SERA1-85K-04, HC19SERG1-85K-04) following manufacturer’s instructions.
    SARS-CoV-2 S-and N-specific antibodies
    suggested: None
    SARS-CoV-2 S-and N-specific
    suggested: None
    S-and
    suggested: None
    Antigen Panel 1 IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    Quantification of cells from EDTA blood via TruCount™ analysis: Absolute cell numbers were calculated from whole blood using BD Trucount™ Tubes (BD Biosciences), following manufacturer’s instructions.
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    Statistical analyses: Statistical analyses of the data were performed with GraphPad Prism v7.0/v9.0 software (GraphPad Software).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    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: We detected the following sentences addressing limitations in the study:
    The limitations of our study include the single-center setting with a rather small and heterogeneous patient cohort. Furthermore, samples were obtained at variable time points during disease. Further studies are needed to define therapeutic consequence of our observations. To the best of our knowledge, the present study shows for the first time that endothelial damage is another major driver of COVID-19 severity together with substantial immune dysregulation. Thus, severe and life-threatening conditions of COVID-19 patients are not only characterized by a highly activated immune phenotype and pro-inflammatory cascades but also by substantial endothelial injuries, which may explain multi-organ involvement in severe COVID-19.

    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.

    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 10.1101/2021.07.08.21260169v1 on medRxiv