Mesenchymal Stem/Stromal Cells as a Therapeutic Intervention for COVID-19: A Living Systematic Review and Meta-Analysis

Abstract

Background: Since its emergence in December 2019, SARS-CoV-2, the coronavirus responsible for COVID-19, has spread across the globe, infected millions of people and caused several million deaths. One promising intervention to combat the ongoing COVID-19 pandemic is mesenchymal stem/stromal cells (MSCs). Many trials were registered at the onset of the pandemic to determine the safety and efficacy of MSCs in COVID-19 patients. However, currently published studies are underpowered to provide an estimate of safety and efficacy on their own. Thus, a living systematic review (SR) is needed to establish the benefits and drawbacks of MSCs for COVID-19 on a relevant timescale. Methods: Systematic literature searches were conducted on Feb 3rd, 2021 and November 15th, 2021 to identify all English-language, full-text, clinical studies examining MSCs to treat COVID-19. (PROSPERO:CRD42021225431). Findings/Conclusions: Our first search identified nine studies (4 controlled) examining the use of MSC derived products to treat COVID-19 patients. This first iteration of our SR revealed that MSCs were safe and reduced mortality in patients suffering from COVID-19. However, risk of bias (RoB) and poor adherence to ISCT cell product characterization guidelines limited the strength of our conclusions. In the second iteration of our living SR, we only included controlled studies to strengthen our conclusions. We identified eleven controlled studies (5 RCTs). MSCs continued to demonstrate safety and efficacy at reducing mortality at study endpoint (RR: 0.50 [0.34 to 0.75, 95% CI, p=0.0006, I2=0%]). However, we continued to encounter barriers which prevented us from drawing more definitive conclusions. A master protocol appears necessary to facilitate the accelerated accumulation of high-quality evidence where standardized outcome reporting and consistent product characterization allow for a more definitive and timely estimate regarding the safety and efficacy of this cell-based therapy for COVID-19.