Efficacy and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

  1. Wenchun Qu
  2. Zhen Wang
  3. Erica Engelberg-Cook
  4. Dan Yan
  5. Abu Bakar Siddik
  6. Guojun Bu
  7. Julie G Allickson
  8. Eva Kubrova
  9. Arnold I Caplan
  10. Joshua M Hare
  11. Camillo Ricordi
  12. Carl J Pepine
  13. Joanne Kurtzberg
  14. Jorge M Pascual
  15. Jorge M Mallea
  16. Ricardo L Rodriguez
  17. Tarek Nayfeh
  18. Samer Saadi
  19. Ravindra V Durvasula
  20. Elaine M Richards
  21. Keith March
  22. Fred P Sanfilippo

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Abstract

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I  2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I  2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

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  1. Version published to 10.1093/stcltm/szac032
  2. ScreenIT

    SciScore for 10.1101/2021.10.05.21264559: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    RandomizationEligibility criteria: We included all published randomized clinical trials, comparative observational studies and case series/case reports that evaluated the safety and/or effectiveness of stem cells administered to patients hospitalized with COVID-19 or SARS-CoV-2 infection.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Databases included EBM Reviews – Cochrane Central Register of Controlled Trials, EBM Reviews – Cochrane Database of Systematic Reviews, Ovid MEDLINE
    Cochrane Central Register of Controlled Trials
    suggested: (Cochrane Central Register of Controlled Trials, RRID:SCR_006576)
    Cochrane Database of Systematic Reviews
    suggested: None
    Risk of bias: We used the Cochrane Collaboration’s Risk of Bias 2 tool to assess risk of bias for RCTs39, the Newcastle-Ottawa tool for comparative observational studies,40 and the risk of bias tool developed by Murad et.al for case series/case report.
    Cochrane Collaboration’s
    suggested: None
    7 (StataCorp LLC, College Station, TX).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    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:
    Limitations: Although this analysis found a reduction in mortality associated with MSC cell therapy, it is important to note that the conclusion was derived by comparing MSC cell therapy to the institutionally defined standard of care in the early phase of the COVID-19 pandemic. More recently, refinements of therapeutic approaches and vaccinations have considerably reduced mortality. The benefit of MSC cell therapy may be reduced or absent in patients not responding to these more contemporary treatments.

    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 10.1101/2021.10.05.21264559v1 on medRxiv