Safety and efficacy of mesenchymal stem cells in severe/critical patients with COVID-19: A systematic review and meta-analysis

BACKGROUND: The present study aims to better understand the efficacy and safety of mesenchymal stromal cells (MSCs) in treating severe/critical patients with COVID-19. METHODS: PubMed, the Cochrane Library, and the Chinese electronic database CNKI were searched from inception up to Dec 19, 2021. Original comparative studies for MSC treatment + standard treatment for severe/critical patients with COVID-19, with placebo or standard treatment as the control group, were included. The primary outcomes were in-hospital mortality and adverse events (AEs). A meta-analysis was performed to compare the mortality rates between the two groups. Then, a subgroup analysis was performed according to the category of the disease (severe or critical) and MSC dose. Afterwards, a descriptive analysis was performed for AEs and secondary outcomes. The funnel plot and Egger's test were used for the publication bias assessment. FINDINGS: Compared to placebo or standard care, MSCs provide significant benefit in the treatment of patients with severe/critical COVID-19, in terms of in-hospital mortality rate (odds ratio: 0.52, 95% CI 0.32-0.84), with very low heterogeneity (P=0.998 [Q test], I(2)=0.0%) and less AEs. No significant difference was found in mortality rate due to the different disease categories or MSC doses. Furthermore, no publication bias was found. INTERPRETATION: The present study demonstrates that MSCs are highly likely to reduce mortality and are safe to use for patients with severe or critical COVID-19, regardless of whether 1-3 doses are applied. However, due to the small sample size of the included studies, further high-quality, large-scale trials are needed to confirm this statement in the future. FUNDING: The National Key Research and Development Program of China (No. 2020YFC0860900), the Science and Technology Project of Wuhan (No. 2020020602012112), the Tianjin Science and Technology Research Program (18PTSYJC00070 and 16PTWYHZ00030), Haihe Laboratory of Cell Ecosystem Innovation Fund (HH22KYZX0046), and the Tianjin Free Trade Zone Innovation Development Project (ZMCY-03-2021002-01) funded the study. We are also grateful for the support from the 3551 Talent Plan of China Optics Valley.