Intravenous Mesenchymal Stromal Cells for Severe and Critical COVID-19: Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials

Background Severe and critical COVID-19 are characterized by immune dysregulation, systemic inflammation, endothelial injury, and high short-term mortality. While antiviral therapy and corticosteroids have improved outcomes, therapeutic options that directly modulate the hyperinflammatory state remain limited. Intravenous mesenchymal stromal cells (MSCs) have emerged as a regenerative medicine strategy intended to attenuate inflammation and improve clinical outcomes. Objective To evaluate randomized placebo-controlled clinical trial evidence for intravenous MSC therapy in adults with severe and critical COVID-19, with emphasis on short-term mortality and systemic inflammatory biomarker outcomes. Methods A systematic review was conducted to identify randomized placebo-controlled clinical trials evaluating intravenous MSC therapy in severe or critical COVID-19. The primary endpoint was short-term all-cause mortality. Secondary outcomes included clinical severity measures and systemic inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6). When trials did not provide numeric endpoint values in tables, values were extracted from published figures as estimated mean and dispersion measures. Outcomes were synthesized under a random effects framework. Results Four randomized placebo-controlled trials met criteria for quantitative synthesis. Across trials, MSC therapy demonstrated a favorable direction of effect for short-term mortality compared with placebo. MSC therapy was consistently associated with greater reductions in CRP and IL-6 compared with placebo control arms. No clear signal of increased serious treatment-related adverse events was identified. Conclusion Randomized placebo-controlled clinical trial evidence suggests intravenous MSC therapy may reduce systemic inflammation and favorably influence short-term outcomes in severe and critical COVID-19. Larger randomized trials with standardized outcome reporting are needed to further define efficacy, durability, and optimal patient selection.