Efficacy and safety of mesenchymal stem cells therapy in COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background: The coronavirus disease 2019 (COVID-19) has become a serious public health issue. In COVID-19 patients, the elevated levels of inflammatory cytokines lead to the manifestation of COVID-19 symptoms, such as lung tissue edema, lung diffusion dysfunction, acute respiratory distress syndrome (ARDS), secondary infection, and ultimately mortality. Mesenchymal stem cells (MSCs) exhibit anti-inflammatory and immunomodulatory properties, thus providing a potential treatment option for COVID-19. The number of clinical trials of MSCs for COVID-19 has been rising. However, the treatment protocols and therapeutic effects of MSCs for COVID-19 patients are inconsistent. This meta-analysis was performed to systematically determine the safety and efficacy of MSC infusion in COVID-19 patients.

Methods: We conducted a comprehensive literature search from PubMed/Medline, Web of Science, EMBASE, and Cochrane Library up to 22 November 2023 to screen for eligible randomized controlled trials. Inclusion and exclusion criteria for searched literature were formulated according to the PICOS principle, followed by the use of literature quality assessment tools to assess the risk of bias. Finally, outcome measurements including therapeutic efficacy, clinical symptoms, and adverse events of each study were extracted for statistical analysis.

Results: A total of 14 randomized controlled trials were collected. The results of enrolled studies demonstrated that patients with COVID-19 pneumonia who received MSC inoculation showed a decreased mortality compared with counterparts who received conventional treatment (RR: 0.76; 95% CI [0.60, 0.96]; p = 0.02). Reciprocally, MSC inoculation improved the clinical symptoms in patients (RR: 1.28; 95% CI [1.06, 1.55]; p = 0.009). In terms of immune biomarkers, MSC treatment inhibited inflammation responses in COVID-19 patients, as was indicated by the decreased levels of CRP and IL-6. Importantly, our results showed that no significant differences in the incidence of adverse reactions or serious adverse events were monitored in patients after MSC inoculation.

Conclusion: This meta-analysis demonstrated that MSC inoculation is effective and safe in the treatment of patients with COVID-19 pneumonia. Without increasing the incidence of adverse events or serious adverse events, MSC treatment decreased patient mortality and inflammatory levels and improved the clinical symptoms in COVID-19 patients. However, large-cohort randomized controlled trials with expanded numbers of patients are required to further confirm our results.

Keywords: COVID-19; Efficacy; Mesenchymal stem cells; Meta-analysis; Safety.

Fig. 1

PRISMA 2020 flow diagram of the search strategy and study selection

Fig. 2

Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies

Fig. 3

Risk of bias summary: review authors' judgments about each risk of bias item for each included study

Fig. 4

Forest plot of primary indicator: pooled results of mortality

Fig. 5

Forest plot of primary indicator: pooled results of AEs

Fig. 6

Forest plot of primary indicator: pooled results of SAEs

Fig. 7

Forest plot of secondary indicators: clinical improvement rate

Fig. 8

Forest plot of secondary indicators: time subgroup of clinical improvement rate

Fig. 9

Forest plot of secondary indicators: days of hospital stays

Fig. 10

Forest plot of secondary indicators: changes in CRP in MSC and control groups

Fig. 11

Forest plot of secondary indicators: changes in IL-6 in MSC and control groups (fixed-effects model)

Fig. 12

Forest plot of primary indicator: pooled results of AEs after eliminating heterogeneous

Fig. 13

Funnel plot of publication bias: A Funnel plots on the mortality from eleven RCTs. B Funnel plots on the incidence of AEs from eight RCTs. C Funnel plots on the incidence of SAEs from six RCTs