Innate immune deficiencies are associated with severity and poor prognosis in patients with COVID-19

  1. Marine Peyneau
  2. Vanessa Granger
  3. Paul-Henri Wicky
  4. Dounia Khelifi-Touhami
  5. Jean-François Timsit
  6. François-Xavier Lescure
  7. Yazdan Yazdanpanah
  8. Alexy Tran-Dinh
  9. Philippe Montravers
  10. Renato C. Monteiro
  11. Sylvie Chollet-Martin
  12. Margarita Hurtado-Nedelec
  13. Luc de Chaisemartin

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Abstract

COVID-19 can cause acute respiratory distress syndrome, leading to death in many individuals. Evidence of a deleterious role of the innate immune system is accumulating, but the precise mechanisms involved remain unclear. In this study, we investigated the links between circulating innate phagocytes and severity in COVID-19 patients. We performed in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, anti-microbial functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Neutrophils and monocytes had a strikingly disturbed phenotype, and elevated concentrations of activation markers (calprotectin, myeloperoxidase, and neutrophil extracellular traps) were measured in plasma. Critical patients had increased CD13 low immature neutrophils, LOX-1 + and CCR5 + immunosuppressive neutrophils, and HLA-DR low downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity. Moreover, neutrophils and monocytes of critical patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.

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  1. Version published to 10.1038/s41598-021-04705-7
  2. ScreenIT

    SciScore for 10.1101/2021.03.29.21254560: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study was approved by National Ethics committee CEEI/IRB under the number 20-715.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All samples were acquired on a FACS Lyrics cytometer (BD Biosciences), and analysis of data was done on FlowJo 10.0 (this applies to all flow cytometry experiments of this study).
    BD Biosciences
    suggested: (BD Biosciences, RRID:SCR_013311)
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistical analyses were performed with GraphPad Prism versions 8.0 (GraphPad Software Inc.)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    , Statview 5.0 (SAS Institute Inc.) and hierarchical clustering with Genesis 1.8.1 (Gratz University of Technology).
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)
    Genesis
    suggested: (Genesis, RRID:SCR_015775)

    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:
    There are some limitations to this study. First, this study was performed in the middle of the first wave of the COVID-19 pandemic in France, when many treatments were tested in parallel on critical patients, increasing variability between patients and reducing our ability to detect small effects. In the same line of thought, immunomodulatory treatments were used either on almost all patients (e.g. corticosteroids) or in a small number of patients for each molecules (e.g. tocilizumab), which precludes from in-depth multivariate statistical analysis that could control for their use. Finally, it was not possible for logistic reasons to realize a longitudinal sampling of the patients, which prevent us to reconstitute the precise trajectory of immune responses. Despite these limitations, we were able to see some strongly significant associations that we are in the process of confirming on a larger cohort from the second and third wave of infections. The fact that neutrophil activation parameters were associated with poor prognosis in both patient groups is a strong incentive for neutrophil-targeting clinical trials, some of which are already ongoing. For example, N-acetylcysteine has been proposed as an antioxidant treatment but a first phase III clinical trial was negative (58). The use of intratracheal DNAse (dornase alfa) to dismantle NETs has been tried in small cohorts and at least one clinical trial is ongoing. Finally, use of a potent elastase inhibitor, sivelestat has bee...

    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

    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 10.1101/2021.03.29.21254560v1 on medRxiv