Systematic review and meta-analysis of mesenchymal stromal/stem cells as strategical means for the treatment of COVID-19

Abstract

Background: In coronavirus disease 2019 (COVID-19) patients, elevated levels of inflammatory cytokines from over stimulation of immune cells have become a concern due to the potential outburst of cytokine storm that damages the tissues and organs, especially the lungs. This leads to the manifestation of COVID-19 symptoms, such as pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and eventually death. Mesenchymal stromal/stem cells (MSCs) are currently one of hopeful approaches in treating COVID-19 considering its anti-inflammatory and immunomodulatory functions. On that account, the number of clinical trials concerning the use of MSCs for COVID-19 has been increasing. However, the number of systematic reviews and meta-analysis that specifically discuss its potential as treatment for the disease is still lacking. Therefore, this review will assess the safety and efficacy of MSC administration in COVID-19 patients. Objectives: To pool evidence on the safety and efficacy of MSCs in treating COVID-19 by observing MSC-related adverse effects as well as evaluating its effects in reducing inflammatory response and improving pulmonary function. Data Sources and Methods: Following literature search across six databases and one trial register, full-text retrieval, and screening against eligibility criteria, only eight studies were included for data extraction. All eight studies evaluated the use of umbilical cord-derived mesenchymal stromal/stem cell (UC-MSC), infused intravenously. Of these eight studies, six studies were included in meta-analysis on the incidence of mortality, adverse events (AEs), and serious adverse events (SAEs), and the levels of C-reactive protein (CRP) and interleukin (IL)-6. Meta-analysis on pulmonary function was not performed due to insufficient data. Results: MSC-treated group showed significantly lower risk of mortality than the control group ( p = 0.03). No statistical significance was observed on the incidence of AEs ( p = 0.78) and SAEs ( p = 0.44), and the levels of CRP ( p = 0.06) and IL-6 ( p = 0.09). Conclusion: MSCs were safe for use, with lower risk of mortality and no association with AEs. Regarding efficacy, descriptive analysis showed indications of improvement on the inflammatory reaction, lung clearance, and oxygenation status despite the lack of statistical significance in meta-analysis of CRP and IL-6. Nevertheless, more studies are needed for affirmation. Registration: This systematic review and meta-analysis was registered on the PROSPERO database (no. CRD42022307730).

Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery

“…We have summarized the RR and OR meta-analyses for different sub-groups and compared them with previous reports that presented RR/OR survival benefit of cell therapy for COVID-19 ( Table 6 ) ( 97 – 100 ). The first two previous meta-analyses in our table only used studies of IV MSC against controls, finding RR=0.54 for ten studies ( 97 ) and RR=0.50 for nine studies ( 98 ), respectively.…”

“…The fraction of the trials employing MSC was 72%, but 92% of the published outcomes are studies that relied on MSCs. The mechanisms of action by which ARDS and COVID-19 patients may benefit from MSC therapy have been exhaustively reviewed by the papers listed in Tables 2 , 3 ( 37 – 53 , 63 , 64 , 66 – 86 , 97 – 100 ), such as relying on multiple synergistic effector mechanisms, and promoting/triggering beneficial immunomodulatory and regenerative pathways, as well as angiogenesis and antiapoptosis ( 18 ). Hence, we will not repeat that discussion here, but only refer to the most crucial key observations in the discussion further below.…”

Mesenchymal Stem Cells in the Pathogenesis and Therapy of Autoimmune and Autoinflammatory Diseases

“…Based on satisfactory clinical results the authors concluded that MSCs could improve the outcomes of COVID-19 without any transfusion side effects. Up-to-date meta-analysis of MSC treatment of COVID-19 revealed that intravenous infusion of UC-MSC significantly decreased the risk of mortality in comparison to the control group (p = 0.03) [171]. No statistical significance was observed in the incidence of adverse events (p = 0.44).…”

“…Between 2020-2023, MSCs have been used as a potential therapy for treating patients with severe SARS-CoV-2-associated inflammation [171]. The first report from a pilot trial was obtained from China, where seven patients with COVID-19 pneumonia received MSC transplantation with assessment up to 14 days post-treatment [166].…”

“…No statistical significance was observed in the incidence of adverse events (p = 0.44). The ability of MSC in reducing inflammatory response was not determined because the levels of CRP or IL6 changed insignificantly (p = 0.06 and p = 0.09, respectively) [171].…”