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

Table 1 Baseline characteristics of the included studies, n (%)

Ref.	Intervention	Control	F/U period	Sample size			Mean age (years)		Outcome measures
				Total	Intervention (males)	Control (males)	Intervention	Control
Shi et al[20], 2022, China	UC-MSCs	Placebo	12 months	100	65 (56.92)	35 (54.29)	60.72	59.94	Safety; mortality; 6-MWD; length of hospitalization
Zarrabi et al[21], 2023, Iran	Perinatal MSCs and MSCs-Exo	Standard therapy	28 days	43	MSCs group: 11 (90.9), MSCs + Exo: 8 (62.5)	24 (66.7)	MSCs group = 50, MSCs + Exo group = 47.75	49.4	Safety mortality
Lightner et al[22], 2023, United States	BM-MSCs-Exo (Exoflo)	Placebo	60 days	102	Exoflo-10: 34 (61.8), MSCs Exoflo-15: 34 (64.7)	34 (70.6)	MSCs group Exoflo-10 = 62.1, MSCs group Exoflo-15 = 56.8	58.5	Safety; mortality; ventilation-free days; length of hospitalization
Soetjahjo et al[23], 2023, Indonesia	UC-MSCs	Placebo	22 days	42	21 (47.6)	21 (57.1)	56.10	55.86	Safety mortality-duration of hospitalization; 6-MWD
Li et al[24], 2023, China	UC-MSCs	Placebo	24 months	100	65 (56.92)	35 (54.29)	60.72	59.94	6-MWD test, adverse events
Bowdish et al[25], 2023, United States	UC-MSCs	Placebo	12 months	222	112 (70.54)	110 (68.18)	61.8	59.6	Mortality, hospitalizations; adverse events: Mechanical ventilatory support
Pochon et al[26], 2023, France	UC-MSCs	Placebo	90 days	30	15 (87)	15 (47)	49.13	61	Survival at day 90, ventilation-free days for 28 days
Martínez-Muñoz et al[27], 2024, Spain	BM-MSCs	Placebo	12 months	20	10 (50)	10 (80)	59.5	65.5	Hospital length of stay
Sitbon et al[28], 2024, France	UC-MSCs	Placebo	12 months	45	21 (81)	24 (83.3)	64	63.2	Adverse events
Rebelatto et al[29], 2022, Brazil	UC-MSCs	Placebo	4 months	17	11 (72.7)	6 (66.6)	53	61.7	Mortality, safety
Gorman et al[30], 2023, United Kingdom	UC-MSCs	Placebo	24 months	59	30 (80)	29 (69)	58.4	58.4	Adverse events, mortality, duration of ventilation, and duration of hospital and ICU stay
Lanzoni et al[31], 2021, United States	UC-MSCs	Placebo	59 days	24	12 (41.7)	12 (66.7)	58.58	58.83	Safety, mortality
Shi et al[32], 2021, China	UC-MSCs	Placebo	3 months	100	65 (56.92)	35 (54.29)	60.72	59.94	Safety, mortality; 6-MWD; length of hospitalization
Abdullah et al[33], 2022, Indonesia	UC-MSC-secretome	Placebo	14 days	40	20 (27.5)	20 (27.5)	51.25	49.9	Mortality, safety
Monsel et al[34], 2022, France	UC-MSCs	Placebo	28 days	45	21 (81)	24 (83.3)	64	63.2	Mortality, safety
Adas et al[35], 2021, Turkey	UC-MSCs	Standard therapy	108 days	38	19 (63)	19 (63)	56	56	Mortality

F/U: Follow-up; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; 6-MWD: 6-minute walk distance; MSCs: Mesenchymal stem cells; MSCs-Exo: Mesenchymal stem cells-derived exosomes; BM-MSCs: Bone marrow-derived mesenchymal stem cells; Exo: Exosomes; ICU: Intensive care unit.

Table 2 Summary of outcomes analyzed by conventional pairwise meta-analysis and network meta-analysis, including pooled effect estimates with 95% confidence intervals and P values

Outcome	Analysis	Comparison(s)	Effect estimate (95%CI), P value	Notes
Duration of MV	CMA	MSCs vs control	WMD: -2.73 (-8.00 to 2.53), P = 0.31	Not significant; sensitivity analysis showed -4.84 days
MV-free days	CMA	MSCs vs control	WMD: -0.84 (-4.33 to 2.65), P = 0.64	No difference
	NMA	MSCs vs control	WMD: -0.59 (-5.23 to 4.04)
	NMA	Exosomes vs control	WMD: 2.78 (-6.69 to 12.26)
	NMA	MSCs vs exosomes	WMD: 3.38 (-7.17 to 13.93)
Length of hospital stay	CMA	MSCs vs control	WMD: 2.11 (-7.82 to 12.04), P = 0.68	No difference; heterogeneity reduced after sensitivity analysis
Length of ICU stay	CMA	MSCs vs control	WMD: 0.97 (-3.84 to 5.78), P = 0.69	No difference
6-MWD	CMA	MSCs vs control	WMD: 0.08 (-27.08 to 27.08), P = 1.00	No difference; heterogeneity reduced after sensitivity analysis
Mortality	CMA	MSCs/exosomes vs control	OR: 0.77 (0.56-1.06), P = 0.11	Trend toward reduction, not significant
	NMA	MSCs vs control	OR: 0.84 (0.58-1.22)
	NMA	Exosomes vs control	OR: 0.62 (0.30-1.28)
	NMA	Exosomes vs MSCs	OR: 0.74 (0.33-1.66)
Adverse events	CMA	MSCs/exosomes vs control	OR: 1.04 (0.75-1.44), P = 0.80	No difference
	NMA	MSCs vs control	OR: 1.02 (0.72-1.45)
	NMA	Exosomes vs control	OR: 1.34 (0.56-3.20)
	NMA	Exosomes vs MSCs	OR: 1.31 (0.52-3.34)

CI: Confidence interval; MV: Mechanical ventilation; CMA: Conventional meta-analysis; MSCs: Mesenchymal stem cells; WMD: Weighted mean difference; NMA: Network meta-analysis; ICU: Intensive care unit; 6-MWD: Six-minute walk distance; OR: Odds ratio.