Table 3.

Study type and patient characteristics

Author and reference no.	Country	Study type	Total, n IT; Ctrl	Age (y) IT; Ctrl	Comorbidities IT; Ctrl	Disease severity IT; Ctrl	Pharmacological treatment IT; Ctrl	Follow-up
Disease: COVID-19/IT: MSCs
Shi L, et al. [71, 72]	China	Randomized, double-blind, placebo-controlled, phase 2 clinical trial, with up to 1-y open-label follow-up period in moderate and severe disease	100 65; 35	IT: mean 60.72, SD 9.14; Ctrl: mean 59.94, SD 7.79	IT: HT 17 (26.15%), DM 12 (18.46%), CB 2 (3.08%) COPD 2 (3.08%); Ctrl: HT 10 (28.6%), DM 5 (14.3%), CB 3 (8.6%), COPD 0	IT: 14 (21.5%) pts not requiring supplemental oxygen, 50 (76.9%) pts requiring supplemental oxygen, 1 (1.5%) pt on NIV or high-flow oxygen; Ctrl: 10 (28.6%) pts not requiring supplemental oxygen, 25 (71.4%) pts requiring supplemental oxygen, 0 pts on NIV or high-flow oxygen Comparable proportions of total lung lesion volume and solid component lesion volume by high-resolution chest CT and image analysis No differences for time from symptom onset to study entry, laboratory data, levels of CRP, IL-6, and D-dimer	Comparable proportions of pts on treatment with antivirals, antibiotics, and glucocorticoids	28 D Open-label follow-up at 3, 6, 9, and 12 mo, when 56/65 pts in IT group and 30/35 pts in ctrl group were finally assessed
Lanzoni G, et al. [74]	USA	Randomized, double-blind, placebo-controlled, phase 1/2a clinical trial in ARDS, with randomization and stratification by ARDS severity	24 12; 12	IT: mean 58.58, SD 15.93; Ctrl: mean 58.83, SD 11.61	IT: DM 5 (41.7%), HT 7 (58.3%), obesity 11 (91.7%), cancer 0, heart disease 1 (8.3%); Ctrl: DM 6 (50%,) HT 9 (75%), obesity 5 (41.7%), cancer 1 (8.3%), heart disease 3(25%) Significantly higher BMI in the IT group	Bilateral infiltrates on frontal chest radiograph or bilateral ground glass opacities on a chest CT scan 3 pts (25%) in each group with mild-to-moderate ARDS: PaO2/FiO2 > 150 mm Hg 9 pts (75%) in each group with moderate-to-severe ARDS: PaO2/FiO2 < 150 mm Hg IMV: 4 pts in the IT group and 7 pts in the ctrl group High-flow oxygen therapy: 8 pts in the IT group and 5 in the ctrl group No significant differences in median viral load between groups at D 0 Significantly higher levels of IL-6 in the peripheral blood of pts in the ctrl group. Comparable levels of GM-CSF, IFNγ, IL-2, IL-5, IL-7, TNFα TNFβ, PDGF-BB, and RANTES	No significant differences in concomitant treatments with heparin, remdesivir, convalescent plasma, glucocorticoids, tocilizumab, hydroxychloroquine. Alteplase treatment only in 2 pts in the ctrl group	28 D from last infusion
Dilogo IH, et al. [75]	Indonesia	Randomized, double-blind, placebo-controlled, multicenter clinical trial in critical disease	40 20; 20	IT: < 40 4, 40–60 8, > 60 8; Ctrl: < 40 3, 40–60 7, > 60 10	IT: DM 8, HT 6, CHKD 2, CAD 2, congestive heart failure 1, tuberculosis 1, others 10; Ctrl: DM 12, HT 10, CHKD 5, CAD 3, congestive heart failure 1, tuberculosis 1, others 6	All pts intubated in the ICU	Concomitant medications in all pts: azithromycin 500 mg and oseltamivir 75 mg (according to local guidelines)	Period of stay in ICU until death or recovery
Monsel A, et al. [81]	France	Randomized, double-blind, placebo-controlled, multicenter clinical trial in ARDS	45 21; 24	IT: mean 64, SD 10.4; Ctrl: mean 63.2, SD 11.4	IT: obesity 33.3%, COPD 0, AF 13.3%, HT 73.3%, CAD 13.3%, stroke 13.3%; Ctrl: obesity 25%, COPD 6.7%, AF 0, HT 66.7%, CAD 13.3%, stroke 6.7%;	IT: (NIV and/or HFNO) 10 (47.6%), IMV 11 (52.4%), SpO2 94.6% (3.4%), PaO2/FiO2 156.2 (68.2) mmHg, LIS 3.0 (0.7), mean SOFA score 5.5 (SD 2.7); Ctrl: (NIV and/or HFNO) 4 (16.7%), IMV 20 (83.6%), SpO2 96.0% (3.0%), PaO2/FiO2 171.2 (72.9) mmHg, LIS 2.8 (0.5), mean SOFA score 5.9 (SD 2.7)	IT: 5 pts (23.8%) on vasopressor, 6 pts (28.6%) on neuromuscular blockade, 15 pts (71.4%) using glucocorticoids for 7 D; Ctrl: 14 pts (58.3%) on vasopressor, 16 pts (66.7%) on neuromuscular blockade, 19 pts (79.2%) using glucocorticoids for 7 D	28 D
Rebelatto CLK, et al. [82]	Brazil	Randomized, double-blind, placebo-controlled, single-center clinical trial in ARDS	17 11; 6	IT: mean 53, SD 15.3; Ctrl: mean 61.7, SD 9.7	IT: obesity 54.5%, HT 54.5%, DM 36.4%, CHKD 9.1%, COPD 0%, schizophrenia 9.1%; Ctrl: obesity 50%, HT 50%, DM 50%, CHKD 0%, COPD 16.7%, schizophrenia 0%	IT: IMV in the ICU 100%, 200 < PaO2/FiO2 ≤ 300 mmHg 36.4%, 100 < PaO2/FiO2 ≤ 200 mmHg 54.5%, PaO2/FiO2 ≤ 100 mmHg 9.1%, time from symptom onset to first infusion: 10.7 ± 3.9 D; Ctrl: IMV in the ICU 100%, 200 < PaO2/FiO2 ≤ 300 mmHg 83.3%, 100 < PaO2/FiO2 ≤ 200 mmHg 0%, PaO2/FiO2 ≤ 100 mmHg 16.6%, time from symptom onset to first infusion: 12.1 ± 2.2 D Total lymphocyte count and proportion of CD3 and CD4 T lymphocytes significantly lower in the IT group. No differences between groups for D-dimer, CRP, ferritin troponin, and creatinine	Concomitant treatment with anticoagulant and glucocorticoids in 100% of pts in both groups, antiviral drugs in 2 pts in the IT group, antibiotics when needed	4 mo
Zhu R, et al. [85]	China	Randomized, single-blind, placebo-controlled, 2-center clinical trial in common/mild, severe, and critical COVID-19	58 29; 29	IT: median 64, IQR 54.5–68; Ctrl: median 66, IQR 59.5–69.5	IT: CAD 10.3%, DM 13.8%, cerebrovascular disease 10.3%, HT 41.4%, chronic respiratory disease 3.4%, history of liver and kidney disease 6.9%; Ctrl: CAD 10.3%, DM 13.8%, cerebrovascular disease 6.9%, HT 37.9%, chronic respiratory disease 0%, history of liver and kidney disease 10.3%	IT: pts with common/mild disease 51.7%, severe disease 37.9%, critical disease 10.3%, requiring oxygen therapy 93.1%, on NIMV 10.3%, on IMV 0%; Ctrl: pts with common/mild disease 55.2%, severe disease 34.5%, critical disease 10.3%, requiring oxygen therapy 88.9%, on NIMV 6.9%, on IMV 0% No significant between-group differences in laboratory data Median D (IQR) from symptom onset to starting treatment 13 D (9.5–15.5) in the IT group and 11 D (8–14.5) in the ctrl group	Before enrollment IT: glucocorticoids in 70% of pts (median D 4, QR 3–6, median dose 40 mg/D, IQR 40–73.3), antibiotics in 62.1% of pts, antivirals (IFN alpha, ribavirin, or ganciclovir) in 44.8% of pts; Before enrollment ctrl: glucocorticoids in 65.5% of pts (median D 4, IQR 2–7, median dose 40 mg/D, IQR 40–80), antibiotics in 65.5% of pts, antivirals (IFN alpha, ribavirin, or ganciclovir) in 44.8% of pts Concomitant treatment IT: glucocorticoids in 55.2% of pts (median D 4, IQR 1–9, median dose 24.4 mg/D, IQR 3–41.7), antibiotics in 55.2% of pts, antivirals (IFN-alpha or ribavirin) in 41.4% of pts; Concomitant treatment ctrl: glucocorticoids in 58.6% of pts (median D 7, IQR 5–14, median dose 28.6 mg/D, IQR 13.3–46.4), antibiotics in 62.1% of pts, antivirals (IFN alpha or ribavirin) in 51.7% of pts	28 D
Shu L, et al. [76]	China	Randomized, open-label parallel-group, phase 1 clinical trial in severe disease, not responding to standard therapy for 7–10 D	41 12; 29	IT: mean 61.00, SD 17.87; Ctrl: mean 57.86, SD 15.79	IT: DM 3 (25%), HT 3 (33.33%); Ctrl: DM 5 (17.24%), HT 6 (20.69%)	IT: no supplemental oxygen 1 (8.33%), supplemental oxygen 7 (58.33%), HFNC or NIV 4 (33.33%), HMO or IMV 0; Ctrl: no supplemental oxygen 2 (6.90%), supplemental oxygen 21 (72.41%), HFNC or NIV 6 (20.69%), HMO or IMV 0 IT: median CT score 18.50 (IQR 16.25, 20.75), median no. lobes involved 4 (IQR 4, 5) Ctrl: median CT score 16.00 (IQR 15.00, 20.00), median no. of lobes involved 4 (IQR 3.5, 5)	In all pts concomitant standard treatment with antiviral agents (abidor/oseltamivir) and glucocorticoids (1–2 mg/Kg) Antibiotic agents in 10 pts in the IT group (83.33%) and in 26 pts in the ctrl group (89.65%)	28 D
Adas G, et al. [77]	Turkey	Randomized, open-label parallel-group phase 1 clinical trial in critically ill pts, with 10 pts with moderate disease evaluated as additional control group	30 10; 10 + 10	Mean 56 NR; NR + NR	NR	Critically ill pts in the IT and in the ctrl group were all intubated and followed up in the ICU Additional ctrl group of hospitalized pts with moderate COVID-19: no signs of severe pneumonia and no need for supplemental oxygen Inflammatory markers significantly increased in the two groups of critically ill pts versus group of patients with moderate disease. No significant between-group difference in the critically ill pts	IT as an add-on therapy to conventional therapy including antibiotics, antivirals, dexamethasone, hydroxychloroquine, and enoxaparin Additional ctrl group treated and followed up in the infectious disease clinic	Markers of systemic inflammation and cytokine storm evaluated on D 0, 1, 4, and 7. Clinical outcome monitored during the entire hospital stay
Leng Z, et al. [69]	China	Nonrandomized, open-label, parallel-group, phase I study in moderate, severe, and critical disease	10 7; 3	IT: mean 57; Ctrl: mean 65	IT: HT (1); Ctrl: NR	IT: 2 pts with moderate disease, 4 pts with severe disease, 1 pt with critical disease, mean SpO2 92% (SD 0.02), mean SOB 2.29 (scale 1–3, SD 0.95); Ctrl: all pts with severe disease, mean SpO2 92% (SD 0.01), mean SOB 2 (scale 1–3; SD 1)	IT initiated when worsening on antiviral drugs (lopinavir-ritonavir, with/without antipyretics) and supportive therapy	14 D
Meng F, et al. [70]	China	Nonrandomized, open-label, parallel group, phase I study in moderate and severe disease	18 9; 9	IT: mean 45.1; Ctrl: mean 49.6	IT: HT (2) DM (1) Liver disease (1); Ctrl: HT (1) Asthma (1)	Five pts in each group with moderate disease: fever, respiratory symptoms, confirmed pneumonia on CT imaging or x-ray Four pts in each group with severe disease: SOB or dyspnea after activity, and/or RR ≥ 30/min, and/or oxygen saturation ≤ 93% at rest and/or PaO2/FiO2 < 300	Glucocorticoids in all pts in the IT group and in 6/9 pts in the ctrl group Lopinavir-ritonavir in 8/9 pts in the IT group and all pts in the ctrl group	28 D
Xu X, et al. [78]	China	Nonrandomized, multicenter, open-label, parallel-group, exploratory clinical trial in severe and critical disease	44 26; 18	IT: mean 58.31, SD 12.49; Ctrl: mean 61.11, SD 11.03	NR	IT: 16 (61.5%) pts with severe disease and 10 (38.5%) critically ill pts; Ctrl: 10 (55.6%) pts with severe disease and 8 (44.4%) critically ill pts	No significant between-group differences in concomitant medications: symptomatic treatment, antiviral therapy, antibacterial treatment, glucocorticoids, gut microflora modulator, traditional Chinese medicine. In both groups, significantly more critically ill pts than pts with severe disease received extracorporeal blood system purification	30 D
Wei F, et al. [86]	China	Prospective, parallel-group two-center trial in moderate, severe, and critical COVID-19	25 12; 13	IT: median 67, IQR 56–70; Ctrl: median 68, IQR 65–78	IT: DM (1), hemorrhagic cerebral infarction (1); Ctrl: NR	IT: 5 pts with moderate disease, 6 pts with severe disease, 1 pt with critical disease, median PaO2/FiO2 321, IQR 170–455; Ctrl: no. of pts with moderate or severe disease NR, 2 pts with critical disease, median PaO2/FiO2 and IQR NR Oxygen support: in the IT group 10 pts on LFNC, 1 pt on HFNC, 1 pt on IMV; in the ctrl group NR Median time (IQR) from disease onset to IT infusion: 42 D (29–46). Median time (IQR) from admission to IT infusion: 18 D (9–27)	In both groups, pts treated with arbidol and lopinavir-ritonavir (12/12 in the IT group, NR for the ctrl group), plus methylprednisolone (4/12 pts in the IT group, NR for the ctrl group)	60 D for pts in the IT group; NR for the ctrl group
Grégoire C, et al. [88]	Belgium	Prospective, single-arm study in severe ARDS with retrospectively selected ctrl group of matched pts	32 8; 24 IT: males 7/8; Ctrl: males NR	IT: median 50, IQR 43–58; Ctrl: median 54, IQR 49.5–63	IT: NR; Ctrl: NR	IT: pts requiring HFNC (7) or IMV (1) within 24 h of ICU admission, median PaO2/FiO2 85.5 (IQR 77.9–93.4), WHO severity score of 6 (7 pts) and 8 (1 pt), median SOFA score 4 (IQR 3–5), elevated levels of CRP, ferritin, and D-dimer; Ctrl: pts requiring HFNC with 24 h of ICU admission and with comparable functional data, severity scores, and levels of CRP, ferritin, and D-dimer	All pts received dexamethasone (6 mg/D for 10 D) and prophylactic doses of heparin unless a therapeutic dose was indicated	60 D
Iglesias M, et al. [73]	Mexico	Prospective, single-arm study in severe ARDS not responding to standard medical management	5 5; 0	Mean 52.6	Obesity 3, Overweight 1, DM 2, HT 1, hypotiroidism 1, PAD 1, dyslipidemia 1, PF 1	Bilateral COVID-19 pneumonia by chest CT, complicated with severe ARDS, persistent PaO2/FiO2 < 100 (median 76, IQR 62–84), requiring IMV (4 pts) or BiPAP (1 pt, 15 L/min) Persistent fever, increase in D-dimer concentrations ≥ 50% from baseline and/or ferritin concentrations > 1000 ng/mL despite standard medical management in intensive care unit; SOFA score < 11 (mean 5.8 from 4 to 7)	No clinical improvement after 48 h of standard pharmacological treatment with antibiotics and enoxaparin in all pts, glucocorticoids in 2 pts, and tocilizumab in 1 pt plus supportive therapy in the ICU	21 D
Sánchez-Guijo F, et al. [79]	Spain	Prospective, single-arm, proof-of-concept study in patients requiring IMV despite treatment with antivirals and anti-inflammatory agents	13 13; 0 (12/13 males)	Mean 60.31 (median 60, IQR 11)	None 3, Hepatitis B virus 1, hypertension 6, COPD 2, DM 1, hyperthyroidism 1, hypothyroidism 1, Behçet Syndrome 1 Ex-smokers 5 BMI range 24.49–35.16 kg/m2	All pts under IMV in the ICU. Median time from hospital admission to IMV 4 D (IQR 3 D). Median duration of IMV before first IT dose 7 D (IQR 12 D) Mean SOFA score 4.08, from 2 to 11	Previous treatment with glucocorticoids, antibiotics, and low molecular weight heparin in all patients, tocilizumab and hydroxychloroquine with/without azithromycin, and lopinavir–ritonavir in 85% of pts, anakinra in 15% of pts after tocilizumab with further administration of siltuximab in one pt Glucocorticoids administered concomitantly with IT, together with standard supportive therapy for IMV	28 D
Guo Z, et al. [80] (2020)	China	Prospective, single-arm study in patients with severe or critical disease already receiving standard treatment	31 31; 0 25/31 (80%) males	Median (IQR): 70 (61–71)	HT 13 (41.9%), COPD 6 (19.4%), CAD 5 (16.1%), DM 5 (16.1%)	23 pts (74.2%) with severe disease requiring oxygen inhalation (19 pts, 61.3%) or NIMV (4 pts, 12.9%); 8 pts (25.8%) with critical disease requiring IMV. Median (IQR) PaO2/FiO2 242 mm Hg (200–294 mm Hg). Persistent fever and increased levels of CRP, IL-6, and D-dimer before IT infusion. Mean D (SD) between symptom onset and IT infusion 50.7 (12.6), median D (IQR) between hospital admission and IT infusion 10.0 (6.0–22.0). ICU admission for 16 pts (51.6%)	Standard treatment with antivirals (83.9%), arbidol (64.5%) interferon alpha-2b (29.0%), antibiotics (74.2%), glucocorticoids (19.4%), oseltamivir (9.7%), chloroquine (9.7%), and/or IV immunoglobulin therapy (25.8%)	NR
Sharma A, et al. [87]	India	Prospective, single-arm, single-center study in patients with moderate pneumonia, first stage	10 10 (8 males); 0	Mean 47.3, range 28–65	DM 6, HT 4, vitiligo 1, history of tuberculosis 1, none 3	Shortness of breath in 100% of pts, RR > 24/min, SaO2 ≤ 93% on room air, PaO2/FiO2 200–300 mm Hg Pts receiving supplemental oxygen if/when SpO2 < 95% on room air, n = NR	Concomitant standard treatment with one antiviral (lopinavir–ritonavir or favipiravir or remdesivir), methylprednisolone, low molecular weight heparin	6 mo
Disease: COVID-19/IT: MSC-derived products
Fathi-Kazerooni M, et al. [84]	Iran	Randomized, double-blind placebo-controlled clinical trial of MSC-derived secretome in severe disease	30 15; 15	IT: mean 46.43, SD 11.91; Ctrl: mean 53.67, SD 10.30	IT: DM 3 (21.5%) HT 4 (28.5%); Ctrl: DM 4 (26.6%) HT 5 (33.3%)	IT: RR > 30/min 15, resting SpO2 ≤ 90% 15 (< 80% 9), PaO2/FiO2 ≤ 300 mmHg 15, pulmonary infiltration > 50% in 24–48 h 15 (> 75% 7), O2 support: IMV 2, NIV 5, O2 Reserve Mask 7; Ctrl: RR > 30/min 15, resting SpO2 ≤ 90% 15 (< 80% 6), PaO2/FiO2 ≤ 300 mmHg 15, pulmonary infiltration > 50% in 24–48 h 15 (> 75% 6), O2 support: IMV 2, NIV 6, O2 Reserve Mask 7	Concomitant best standard of care as per institutional guidelines in both groups, with all pts already receiving remdesivir, glucocorticoids, and anticoagulants at study entry	28 D
Sengupta V, et al. [83]	USA	Prospective, single-center cohort study of MSC-derived exosomes in severe disease not responding to the institutional standard treatment	27 27; 0	Median 59 (range 29–84)	Pre-DM 3, DM 20, HT 12, hyperlipidemia 5, any condition 25	Mild ARDS (PaO2/FiO2 200 to < 300) 1, moderate ARDS (PaO2/FiO2 100 to ≤ 200) 11, severe ARDS (PaO2/FiO2 < 100) 13 O2 support: IMV 2, BiPAP 2, HFNC 5, NRBM 10, NC 4, room air 1	IT when fever and/or dyspnea for > 72 h and overall clinical deterioration as evidenced by down-trending PaO2/FiO2 on treatment with hydroxychloroquine and azithromycin	14 D post-treatment
Disease: influenza/IT: MSCs
Chen J, et al. [89]	China	Nonrandomized, open-label, parallel-group study in H7N9 influenza virus-induced ARDS	61 17; 44	IT: mean 62.8, SD 14.4; Ctrl: mean 61.6, SD 11.8	IT: HT 58.8%, CAD 0%, COPD 0%, DM 29.4%, liver disease 5.9%, renal failure complication 9%, shock complication 70.6% (P = 0.03 versus ctrl); Ctrl: HT 52.3%, CAD 18.2%, COPD 2.3%, DM 15.9%, liver disease 2.3%, renal failure complication 22.7%, shock complication 36.4%	All pts: PaO2/FiO2 < 200, requiring IMV and/or ECMO SOB and fatigue more frequently reported in the IT group than in the ctrl group IT: IMV 14 (82.4%), and/or ECMO 8 (47.1%); Ctrl: IMV 31 (70.5%), and/or ECMO 14 (31.8%) Inflammatory index PCT significantly more elevated in the ctrl group	IT concomitant treatment (% of pts): antivirals 100%, glucocorticoids 52.9%, antibiotics 82.4%, vasoactive drugs 70.6%, ALSS 76.5%, CRRT 70.6% (P = 0.016 versus ctrl); Ctrl concomitant treatment (% of pts): antivirals 100%, glucocorticoids 54.5%, antibiotics 81.8%, vasoactive drugs 43.2%, ALSS 40.9%, CRRT 36.4%	5 y Performed only in 4 survivors in the IT group

AF atrial fibrillation, AKI acute kidney injury, ALSS artificial support liver system, AML acute myeloid leukemia, APACHE Acute Physiology and Chronic Health Evaluation, ARDS acute respiratory distress syndrome, BiPAP bilevel positive airway pressure, BM-MSCs bone marrow derived mesenchymal stem cells, CAD coronary artery disease, CHKD chronic kidney disease, CB chronic bronchitis, CLL chronic lymphocytic leukemia, CMP cardiomyopathy, COPD chronic obstructive pulmonary disease, COVID coronavirus disease, CRP C-reactive protein, CRRT continuous renal replacement therapy, CT computed tomography, Ctrl control, D day(s), DM diabetes mellitus, ECMO extracorporeal membrane oxygenation, GM-CSF granulocyte–macrophage colony-stimulating factor, hr hour, HT hypertension, IFN interferon, IL interleukin, IMV invasive mechanical ventilation, IQR interquartile range, HFNC high-flow nasal cannula oxygen therapy, IQR interquartile range, IT investigational therapy, ITP idiopathic thrombocytopenic purpura, LFNC low-flow nasal cannula oxygen therapy, LIS lung injury score, MAP mean airway pressure, min minute(s), mo month(s), MSCs mesenchymal stem/stroma cells, NA not applicable, NC nasal cannula, NIMV noninvasive mechanical ventilation, NIV noninvasive ventilation, NK natural killer, NR not reported, NRBM non-rebreather mask, PAD peripheral artery disease, PaO2/FiO2 arterial oxygen partial pressure/fractional inspired oxygen, PCT procalcitonin, PDGF platelet-derived growth factor, PF pulmonary fibrosis, Pt patient, RANTES regulated on activation, normal T-cell expressed and secreted, RR respiratory rate, SaO2 arterial oxygen saturation, SD standard deviation, SOB shortness of breath, SOFA sequential organ failure assessment, SpO2 peripheral oxygen saturation (by pulse oximeter), SpO2/FiO2 pulse oximetry oxygen saturation/fractional inspired oxygen, TNF tumor necrosis factor, wks weeks, y year(s)