Background Mesenchymal stromal cells (MSCs) may reduce mortality in patients with COVID-19; however, early evidence is based on few studies with marked interstudy heterogeneity. The second iteration of our living systematic review and meta-analysis evaluates a framework needed for synthesizing evidence from high-quality studies to accelerate consideration for approval. Methods A systematic search of the literature was conducted on November 15, 2021, to identify all English-language, full-text, and controlled clinical studies examining MSCs to treat COVID-19 (PROSPERO: CRD42021225431). Findings Eleven studies were identified (403 patients with severe and/or critical COVID-19, including 207 given MSCs and 196 controls). All 11 studies reported mortality and were pooled through random-effects meta-analysis. MSCs decreased relative risk of death at study endpoint (RR: 0.50 [95% CI, 0.34-0.75]) and RR of death at 28 days after treatment (0.19 [95% CI], 0.05-0.78) compared to controls. MSCs also decreased length of hospital stay (mean difference (MD: −3.97 days [95% CI, −6.09 to −1.85], n = 5 studies) and increased oxygenation levels at study endpoint compared to controls (MD: 105.62 mmHg O2 [95% CI, 73.9-137.3,], n = 3 studies). Only 2 of 11 studies reported on all International Society for Cellular Therapy (ISCT) criteria for MSC characterization. Included randomized controlled trials were found to have some concerns (n = 2) to low (n = 4) risk of bias (RoB), while all non-randomized studies were found to have moderate (n = 5) RoB. Interpretation Our updated living systematic review concludes that MSCs can likely reduce mortality in patients with severe or critical COVID-19. A master protocol based on our Faster Approval framework appears necessary to facilitate the more accelerated accumulation of high-quality evidence that would reduce RoB, improve consistency in product characterization, and standardize outcome reporting.
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.
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