Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis.

The objective of this study was to assess whether mesenchymal stem cells (MSCs) therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang, and CNKI was performed from December 1, 2019 to December 25, 2022. The primary outcome was all-cause mortality. Trial sequential analysis (TSA) was conducted in this meta analysis. Besides, subgroup analysis and meta-regression was performed using a random-effects model to find the potential sources of heterogeneity. Seventeen randomized controlled trials (RCTs) involving a total of 1073 patients with COVID-19 were included in this study. Compared with the control group, patients in the MSCs groups were associated with significantly reduced all-cause mortality (MSCs 18.4% vs. control 25.5%; risk ratio [RR] 0.73; 95% confidence interval [CI] 0.59-0.90; p = 0.004; I² = 0%). For all secondary outcomes, there wasn't significant improvement in the experimental group versus the control group regarding symptom remission rate (53.2%, 201/378 vs. 46.5%, 164/353; RR 1.15; 95% CI 1.00-1.32; p = 0.05; I² = 43%), but the pooled analysis revealed significant differences between the groups in length of hospital stay (MD: -3.82, 95% CI: -5.87 to -1.77; p = 0.0003, I2 = 0%), requirement of invasive mechanical ventilation (RR 0.52; 95% CI 0.33-0.82; p = 0.005; I  = 0%) and post-CRP level (MD: -31.61; 95% CI -46.74 to -16.49; p < 0.0001). Moreover, regarding the incidence of adverse events (AEs) (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and serious adverse events (sAEs) (RR 0.87; 95% CI 0.40-1.92; p = 0.73; I² = 39%), no significant differences were observed between MSCs and control groups. The TSA analysis showed that the result of all-cause mortality might be false-positive result. Based on the pooled results in this study, compared with standard treatment, MSCs therapy may reduce all-cause mortality of patients with COVID-19 with no increase risk of AEs and sAEs, but may not improve symptom remission rate. Further more high-quality and large-sample RCTs should be performed to confirm these findings.