Mesenchymal stem/stromal cell–based therapies for COVID-19: First iteration of a living systematic review and meta-analysis

Abstract

Background : Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. Methods and Findings : All English language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients) and four were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random effects meta-analysis. MSCs decreased the risk of death at study endpoint compared to controls (RR: 0.18, 0.04-0.74; p=0.02; I 2 =0%) although follow-up differed. Among secondary outcomes, IL-6 levels were most commonly reported and were decreased compared to controls (SMD: -0.69, -1.15 to -0.22, p=0.004; I 2 =0%) (n=3 studies). Other outcomes were not reported consistently and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low (2 of 9 studies RoB analysis revealed a low to moderate risk of bias in controlled studies and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. Conclusion : Use of MSCs to treat COVID-19 appears promising, however, few studies were identified and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.

Characteristics of Living Systematic Review for COVID-19

“… 16–21 , 23–44 , 46–51 , 53–57 , 59–69 , 73–79 The impact factor published in SCI journals ranged from 1.04 to 39.89, with an average of 11.72 and a standard deviation of 11.30. The impact factor of 64.1% studies was >5, 16–20 , 23 , 26 , 27 , 30 , 32 , 33 , 36 , 37 , 39–44 , 46 , 47 , 49–51 , 54–57 , 60–64 , 67–69 , 73–76 , 79 the impact factor of 17.2% studies was >15. 16 , 17 , 23 , 42 , 43 , 51 , 62–64 , 74 , 76 LSRs were published in journals with high impact factor, which indicated COVID-19 related studies have attracted much attention from readers ( Table 1 ).…”

“…The topic most studied (40.6%) was the treatment of COVID-19. 20 , 22 , 25 , 32 , 37 , 39 , 43 , 46 , 47 , 49 , 51 , 55 , 56 , 58 , 62–64 , 67–74 , 79 The population most studied (76.6%) was general COVID-19 patients, 18–23 , 26 , 27 , 29 , 31–34 , 36 , 37 , 39 , 42–44 , 46 , 47 , 49–65 , 67–76 , 79 but there were fewer (6.3%) studies concerning pregnant women 16 , 17 , 30 , 78 and children 28 , 30 , 77 , 78 with COVID-19, even no study concerning the elderly with COVID-19. ( Table 1 , Supplementary Material Table 1 )…”

“… 20 , 71 , 74 In the meantime, three similar LSRs on the topic of cell therapy for COVID-19 also occurred. 47 , 58 , 63 Potential reasons for the replication might be that some authors considered publishing the study without registration could be quicker, especially under the requirement of numerous SRs applications for registration under the COVID-19 pandemic. 80 Although registration might delay publication of LSRs, to improve the quality of LSRs and reduce replicated publications, it was still recommended that LSRs should be registered prior to commencement.…”

Immunomodulation of Mesenchymal Stem Cells in Acute Lung Injury: From Preclinical Animal Models to Treatment of Severe COVID-19

“…Nevertheless, current preliminary clinical results of MSC-based therapy show some favorable outcomes for severe and critically severe patients with COVID-19. A meta-analysis by Kirkham et al demonstrated that the risk of death at the study endpoint is lower in patients receiving MSC therapy (risk ratio, 0.18), although follow-up differed [ 60 ]. Promising results regarding MSC therapy in COVID-19 included: (1) patients were well-tolerated without significant and severe adverse effects; (2) improvements were observed in clinical symptoms and pulmonary functions, such as oxygenation and PaO 2 /FiO 2 ratio; (3) downregulating cytokine storm by MSCs can be noted by decreasing circulating levels of proinflammatory cytokines and laboratory parameters (C-reactive protein, procalcitonin, ferritin, and D-dimer), increasing lymphocyte count, and resolving inflammatory lung lesions; (4) MSC-treated patients had a faster recovery time, a shorter hospital stay, and a lower mortality rate.…”

Safety and efficacy of mesenchymal stem cells in severe/critical patients with COVID-19: A systematic review and meta-analysis

“… 20 A recent living systematic review conducted by Kirkham et al stated that treating COVID-19 using MSCs appear promising. 21 However, there is a lack of systematic evidence on the efficacy and safety of MSCs in treating severe/critical patients with COVID-19. The present study aims to systematically review the literature to better understand the efficacy and safety of MSCs in treating severe/critical patients with COVID-19.…”