Living bio-drug therapies using mesenchymal stem cells and exosomes for mechanically ventilated patients with acute respiratory distress syndrome: A systematic review and meta-analysis.

BACKGROUND: Mesenchymal stem cells (MSCs), as a living bio-drug, are being considered as a potential treatment for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS) due to their immunomodulatory and reparative properties. AIM: To synthesize the existing evidence on MSCs and their derivative exosomes for treating COVID-19-induced ARDS, with a focus on the key outcomes of safety and efficacy. METHODS: Four databases were systematically searched for randomized controlled trials assessing MSCs and their derived exosomes for COVID-19-induced ARDS treatment. Their safety and efficacy were evaluated based on the duration of mechanical ventilation, hospital and intensive care unit stay, 6-minute walk distance, mortality rates, and adverse events. Weighted mean differences and odds ratios with 95% confidence intervals (CIs) were calculated to estimate treatment outcomes: A network meta-analysis (NMA) evaluated mortality, adverse events, and the number of ventilation-free days. RESULTS: Sixteen randomized controlled trials involving 1027 ARDS patients were included, with 574 receiving MSCs or MSC-derived exosomes. MSC-based therapy did not significantly improve mechanical ventilation duration, ventilation-free days, hospital or intensive care unit stay, or 6-minute walk distance. Sensitivity analysis revealed a significant reduction in mechanical ventilation duration when excluding an outlier (weighted mean difference: -4.84 days; 95%CI: -8.21 to -1.47; I 2 = 20%). In contrast, no significant differences were observed in the other outcomes. Mortality and adverse events were comparable between the groups (odds ratio for mortality: 0.77; 95%CI: 0.56-1.06). An NMA of ventilation-free days, mortality, and adverse events revealed no significant difference among MSCs, exosomes, and controls. Exosomes ranked highest in terms of probability of benefit, although without statistical significance. CONCLUSION: MSC and exosome-based therapies were found to be safe and associated with a reduced duration of mechanical ventilation in patients with ARDS. NMA showed that exosome-based therapy matched the benefits of its parent cells, but with practical and logistical advantages.