Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

  1. Lina Ma
  2. Sanjaya K. Sahu
  3. Marlene Cano
  4. Vasanthan Kuppuswamy
  5. Jamal Bajwa
  6. Ja’Nia McPhatter
  7. Alexander Pine
  8. Matthew Meizlish
  9. George Goshua
  10. C-Hong Chang
  11. Hanming Zhang
  12. Christina Price
  13. Parveen Bahel
  14. Henry Rinder
  15. Tingting Lei
  16. Aaron Day
  17. Daniel Reynolds
  18. Xiaobo Wu
  19. Rebecca Schriefer
  20. Adriana M. Rauseo
  21. Charles W. Goss
  22. Jane A. O’Halloran
  23. Rachel M. Presti
  24. Alfred H. Kim
  25. Andrew E. Gelman
  26. Charles Dela Cruz
  27. Alfred I. Lee
  28. Phillip Mudd
  29. Hyung J. Chun
  30. John P. Atkinson
  31. Hrishikesh S. Kulkarni

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Abstract

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

SUMMMARY

Complement has been implicated in COVID-19. However, whether this is distinctive of COVID-19 remains unanswered. Ma et al report increased complement activation in COVID-19 compared to influenza and non-COVID respiratory failure, and demonstrate alternative pathway activation as a key marker of multiorgan failure and death.

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  1. ScreenIT

    SciScore for 10.1101/2021.02.22.432177: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study Approval: The Institutional Review Board approved this study at both Washington University School of Medicine (ID#201707160, 201801209, 201808171, 201710220, 201808115, and 201910011, 201904191, 202004091, 202003085) and the Yale School of Medicine independently (IRB 2000027792 and 1401013259).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical analysis was performed using IBM SPSS Statistics for Macintosh, Version 27.0 (IBM Corp, Armonk, NY), and GraphPad Prism 9 (GraphPad Software, La Jolla, CA) was employed for generating figures.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)
    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:
    Our findings have several limitations. First, the samples were not simultaneously collected among the COVID-19, influenza, and non-COVID acute respiratory failure groups. However, they were collected in a similar time frame leading up to the SARS-CoV-2 pandemic, and subsequently processed using the same protocol, to minimize any differences in the findings. Second, we did not have levels of SARS-CoV-2 RNA to evaluate how complement activation correlates with viral load in COVID-19. A prior report would suggest that markers of complement activation do not correlate with concurrently measured viral load (Holter et al., 2020). This is possible, given that the patients enrolled in our study are likely presenting in the “hyperinflammatory phase” of the illness, when viral loads may be lower than the initial phase of infection (van Kampen et al., 2021). Third, decision-making in our ICU changed over a period of time; initially, there was a tendency for early intubation. Hence, we also included hospitalization and ICU admission in our data points; and provided data on mortality where applicable, derived from our electronic medical records. Fourth, for certain outcomes, our sample size was such that there were differences in the levels of the markers between the two groups, but they did not always meet statistical significance (e.g., mortality signal in sC5b-9); one explanation is that our study was not specifically powered for that outcome, and additionally, there may be other facto...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04369469Active, not recruitingEfficacy and Safety Study of IV Ravulizumab in Patients With…

    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.

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  2. Version published to 10.1101/2021.02.22.432177 on bioRxiv