Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19

  1. Davide Scozzi
  2. Marlene Cano
  3. Lina Ma
  4. Dequan Zhou
  5. Ji Hong Zhu
  6. Jane A O’Halloran
  7. Charles Goss
  8. Adriana M. Rauseo
  9. Zhiyi Liu
  10. Valentina Peritore
  11. Monica Rocco
  12. Alberto Ricci
  13. Rachele Amodeo
  14. Laura Aimati
  15. Mohsen Ibrahim
  16. Ramsey Hachem
  17. Daniel Kreisel
  18. Philip A. Mudd
  19. Hrishikesh S. Kulkarni
  20. Andrew E. Gelman

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Abstract

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.

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  1. ScreenIT

    SciScore for 10.1101/2020.07.30.227553: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementStudy Approval The study was approved by the Washington University School of Medicine Institutional Review Board (ID#202004091 and #202003085).Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variableAmong these subjects, 55.6% (54/97) were male, 77.3% (75/97) were AfricanAmerican, 46.4% (45/97) were obese (BMI ≥ 30), and 46.3% (45/97) had a positive smoking history.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All the statistical analyses were calculated, and all figures were prepared using Graphpad Prism 8.4.2 (GraphPad Software Inc., La Jolla, CA).
    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:

    Our study has several limitations. First, we were unable to concurrently enroll a COVID19 negative group with severe respiratory disease. Our center, as many others experienced a decline in hospital presentations for illnesses other than COVID-19 during this time making a concurrent, adequately matched control group not possible. Additionally, as our samples were drawn as a part of a prospective study of subjects with known SARS-CoV-2 positivity, any other adequately matched control group would not be entirely comparable, as it was not concurrently drawn. Importantly, we do not aim to propose that MT-DNA levels are different in those with COVID-19 compared to those with acute lung injury due to other etiologies. Multiple emerging studies suggest that biomarkers may be no different in subjects with COVID-19-induced lung injury versus those due to other etiologies (Sinha et al., 2020b). However, the strength of our study lies in an assay that can potentially identify subjects presenting with COVID-19 who are likely to develop adverse outcomes during the course of their hospitalization, which becomes increasingly important when resources are constrained as has been unfortunately common during this pandemic (Barrett et al., 2020; Litton et al., 2020; Moghadas et al., 2020). Second, this study does not assess how MT-DNA correlates with viral load in COVID-19, which is especially important in the context of deciding when to intervene with targeted therapeutics (Catanzaro et al., 2020; Du and Yuan, 2020; Maggi et al., 2020). Therefore, further studies will be necessary to evaluate whether it may be a predictor of response to treatment (Sinha et al., 2020a). Third, decision-making in the ICU changed over the course of our enrollment. For example, there was a tendency towards intubating earlier in the course of the critical illness in the initial months of the COVID-19 pandemic. However, we identified MT-DNA as a predictor of severity utilizing mortality as a primary endpoint, and then ICU admission and the requirement for intubation as independent, secondary endpoints. In summary, we demonstrate that MT-DNA measured early in the disease course can predict survival status, the requirement for intensive level care, and the need for endotracheal intubation. We also show that MT-DNA levels are associated with exploratory biomarkers implicated in the pathogenesis of COVID-19-related morbidity and mortality. Further studies will be needed to discern the contribution of MT DAMPs such as MT-DNA to COVID-19 pathogenesis, as well as to understand whether MTDNA and other inflammatory mediators, such as activated complement, act synergistically to promote cellular injury.

    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.

    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.

  2. ScreenIT

    SciScore for 10.1101/2020.07.30.227553: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Study Approval: The study was approved by the Washington University School of Medicine Institutional Review Board (ID#202004091 and #202003085).
    Consent: Written informed consent was obtained from all subjects.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All the statistical analyses were calculated, and all figures were prepared using Graphpad Prism 8.4.2 (
    Graphpad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad Software Inc.,
    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 study has several limitations. First, we were unable to concurrently enroll a COVID-19 negative group with severe respiratory disease. Our center, as many others experienced a decline in hospital presentations for illnesses other than COVID-19 during this time making a concurrent, adequately matched control group not possible. Additionally, as our samples were drawn as a part of a prospective study of subjects with known SARS-CoV-2 positivity, any other adequately matched control group would not be entirely comparable, as it was not concurrently drawn. Importantly, we do not aim to propose that MT-DNA levels are different in those with COVID-19 compared to those with acute lung injury due to other etiologies. Multiple emerging studies suggest that biomarkers may be no different in subjects with COVID-19-induced lung injury versus those due to other etiologies (Sinha et al., 2020b). However, the strength of our study lies in an assay that can potentially identify subjects presenting with COVID-19 who are likely to develop adverse outcomes during the course of their hospitalization, which becomes increasingly important when resources are constrained as has been unfortunately common during this pandemic (Barrett et al., 2020; Litton et al., 2020; Moghadas et al., 2020). Second, this study does not assess how MT-DNA correlates with viral load in COVID-19, which is especially important in the context of deciding when to intervene with targeted therapeutics (Catanzaro et al., 2...

    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 10.1101/2020.07.30.227553 on bioRxiv