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

Abstract

Background: Covid-19 has contributed to high mortality and morbidity among hospitalized patients. One of the main pathophysiological processes of the disease is an exuberant immune response leading to respiratory failure. MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies have shown promise in modulating responses in inflammatory diseases and trend in decreasing mortality in ARDS. Controlled clinical trials with limited sample size assessing the effectiveness of MSC in patients hospitalized for COVID-19 suggest safety and potential to improve outcomes. We performed a meta-analysis of published trials assessing the clinical effectiveness and adverse events of MSC cell therapy in individuals hospitalized for COVID-19.Methods: Systematic searches were performed in multiple databases through April 8 th , 2021. Reports in all languages were included. Randomized clinical trials, comparative observational studies, and case series/case reports that evaluated safety and/or efficacy of MSC cell therapy in hospitalized patients with COVID-19.Independent reviewers selected studies and extracted data. Random effects model was used to pool outcomes from RCTs and comparative observational studies. Outcome measures included all-cause mortality, serious adverse events (SAEs), mild adverse events (AEs), pulmonary function, laboratory and imaging findings. Findings: A total of 413 patients were identified from 25 studies, which included 8 controlled trials (3 RCTs), 5 comparative observational studies, n=300) and 17 case-series/case reports (n=113). The patients age was 60.5 years (mean) and 33.7% were women. When compared with the control group receiving institutionally defined standard of care, MSC cell therapy was associated with reduction in all-cause mortality (RR=0.31, 95% CI: 0.12 to 0.75, I 2 =0.0%; 3 RCTs and 5 comparative observational studies, 300 patients), and reduction in SAEs (IRR=0.36, 95% CI: 0.14 to 0.90, I 2 =0.0%; 3 RCTs and 2 comparative studies, n=219). There was no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC cell therapy. Interpretation: Together these findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function in patients hospitalized for COVID-19 compared to conventional care. Large scale double-blinded, well-powered randomized controlled trials should be conducted to further explore these results. Funding: None to declare. Declaration of Interest: W. Q., J. M. H., J. K., C. R. reported roles as principal investigators of MSC trials. J. M. H. reported having a patent for cardiac cell-based therapy, holds equity in Vestion, Inc., and maintains a professional relationship with Vestion, Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board; J. M. H. is also the Chief Scientific Officer, a compensated consultant and advisory board member, for Longeveron and holds equity in Longeveron; J. M. H. is the coinventor of intellectual property licensed to Longeveron. J. M. H. declared inventor or patent holder and research funding from Longeveron, Heart Genomics; advisory role and research funding with Vestion; research funding from NHLBI. J. K. declare Intellectual property rights with IDF, hCT-MSC for treatment of ASD, HIE, which were licensed to CryoCell Int’l by Duke University; NMDP Scientific Advisor; Celularity SAB; research funding from the Marcus Foundation, NIH, HRSA; leadership position with Istari—CMO (spouse). G. B. consults for SciNeuro and Vida Ventures, had consulted for AbbVie, E-Scape, and Eisai, and receives funding from NIH and Cure Alzheimer’s Fund. He serves as a Co-Editor-in-Chief for Molecular Neurodegeneration. The other authors indicated no potential conflicts of interest. K.M. is a consultant in RESTEM.