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

Purpose: 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). Methods: An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang and CNKI was performed from December 1st, 2019 to December 25th, 2022. We included studies recruiting patients with COVID-19 and treated with MSCs. Data were independently extracted by two reviewers and synthesized with a random-effect analysis model. The primary outcome was all-cause mortality. Secondary outcomes included symptom remission rate, time to symptom remission, length of hospital stay (LOS), requirement of oxygen therapy, requirement of non-invasive ventilation (NIV), requirement of invasive mechanical ventilation (IMV), days of MV, peripheral arterial haemoglobin oxygen saturation (SpaO ), biomarkers of inflammatory dysregulation and pulmonary imaging changes. Safety outcomes included the incidence of all adverse events (AEs) and serious adverse events (sAEs). 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. Results: Sixteen randomized controlled trials (RCTs) involving a total of 1053 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 18.1% vs control 24.9%; risk ratio [RR] 0.74; 95% confidence interval [CI] 0.60-0.92; p = 0.007; I² = 1%). For all secondary outcomes, there wasn’t significant improvement in the experimental group versus the control group regarding symptom remission rate (52.7%, 194/368 vs 46.6%, 160/343; RR 1.13; 95% CI 0.99-1.30; p = 0.07, I² = 43%), but the pooled analysis revealed significant differences between the groups in LOS (MD: -3.91, 95% CI: -5.97 to -1.84; P = 0.0002; I = 0%), requirement of IMV ( RR 0.52; 95%CI 0.33-0.82; p = 0.005; I = 0%) and post-CRP level (MD: -31.38; 95% CI -47.23 to -15.54; p=0.0001). Moreover, regarding the incidence of AEs (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and 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. Conclusions: Based on the pooled results in this study, MSCs therapy may reduce all-cause mortality 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.