Table 1 Clinical and study characteristics.
From: Stem cell-based therapy for COVID-19 and ARDS: a systematic review
Author | Disease | Cell type and administration | Number of patients | Inclusion criteria | Evaluated parameters | Main outcomes | Adverse effects | Study design/evidence level |
|---|---|---|---|---|---|---|---|---|
Shi L.et al.19. | COVID-19 | UC-MSC IV | 100 | - Severe COVID-19 - CT confirmed pneumonia and any of the following: (1) Noninvasive ventilation, shock, or other organ failures (2) RR ≥30 times/min; (3) O2 of 93% (4) PaO2/FiO2 ≤300 mmHg; (5) CXR/CT evidence of progression >50% in 24–48 h | Clinical outcomes Biomarker response inflammatory factors Leukocytes count | ↓ Pro-inflammatory factors improvement on CT | Pneumothorax Not related | Phase 2 clinical trial: multicenter, double-blind, randomized, controlled. 1 A: high |
Matthay MA. et al.27. | ARDS | BM-MSCs IV | 60 | (1) Endotracheally intubated (2) ↓ PaO2/FiO2 (3) Positive pressure ventilation (4) Bilateral infiltrates on CXR (5) No clinical evidence of left-heart failure or volume overload | Hospital indexes SOFA score Angiopoietin-2 Respiratory parameters Inflammatory factors Alveolar epithelial injury | ↓ Angiopoietin-2 The results had no statistical relevance | Cardiopulmonary arrest Not related | Phase 2 clinical trial: multicenter, double-blind, randomized, controlled. 1 A: high |
Zheng G. et al.31. | ARDS | AD-MSCs IV | 12 | ARDS diagnostic criteria according to the New Berlin definition | PaO2/FIO2 Hospital indexes Inflammatory factor biomarker responses | ↑ PaO2/FIO2 | Diarrhea and rash in chest area related | Clinical trial: single-center, randomized, double-blind, controlled. 1B: moderate |
Lanzoni G. et al.14. | COVID-19 | UC-MSC IV | 24 | (1) Hospitalized patient ≥18 years (2) SpO2 ≤94% (3) PaO2/FiO2 <300 mmHg (4) Bilateral infiltrates CXR or bilateral ground-glass opacities on a CT | Survival Inflammatory factors | ↓ Pro-inflammatory factors ↑Survival/↓Mortality Improvement on hospital discharge ↓Biomarker responses | Bradycardia Related Acute respiratory failure not related | Phase 1 clinical trial: a single-center, double-blinded, randomized, controlled. 1B: moderate |
Bellingan G. et al.33. | ARDS | BM-MAPC IV | 30 | (1) PaO2/FiO2 above or below 150 mmHg (2) Need for vasopressors (3) 96-h of moderate-to-severe ARDS onset | Clinical outcomes PaO2/FIO2 Hospital indexes Biomarker responses | ↑ PaO2/FIO2 ↑Survival/↓Mortality Clinical improvement Improvement on hospital discharge Discontinuation of oxygen support ↓Biomarker responses | Single CTCAE grade 1 Related | Phase 1 clinical trial: multicenter, open-label, randomized, controlled. 1B: moderate |
Meng F. et al.17. | COVID-19 | UC-MSC IV | 18 | (1) Patients aged 18–70 years old. (2) Confirmed COVID-19 (3) Pneumonia evidenced by CXR or CT | inflammatory factor biomarker responses PaO2 | ↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT | Transient facial flushing Fever Related Hypoxemia Not related | Phase 1 clinical trial: a single-center, open-label, non- randomized, controlled. 2B: low |
Shu L. et al.18. | COVID-19 | UC-MSC IV | 41 | - PCR COVID-19 - CT indicators of pneumonia and any of the following: (1) respiratory distress, RR ≥30 times/min; (2) O2 saturation ≤93%; (3) PaO2/FiO2 ≤300 mmHg | Biomarker responses Inflammatory factors Leukocytes count | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ O2 saturation Improvement on CT Clinical improvement | None | Clinical trial: single-center open-label, randomized, controlled. 2B: low |
Feng Y.et al.21. | COVID-19 | UC-MSC IV | 16 | Severe COVID-19 using the Clinical classification by the National Health Commission of China | Biomarker responses Inflammatory factors Leukocytes count EKG CT | ↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement ↑ PaO2/FIO2 | Bacterial pneumonia Septic shock Not related | Pilot trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low |
Wilson J. et al.26. | ARDS | BM-MSCs IV | 9 | (1) Positive pressure ventilation ↓ PaO2/FiO2 (2) Bilateral infiltrates on CXR (3) No clinical evidence of left atrial hypertension (4) Criteria 1–3 must be present within a 24 h period and at the time of enrollment | Lung injury score (LIS) Angiopoietin-2 Alveolar epithelial injury Inflammatory factors SOFA score Biomarker responses | LIS improved ↓ SOFA The results had no statistical relevance | Respiratory arrest Sepsis Embolic infarcts Not related | Phase 1 clinical trial: multicenter, open-label, non- randomized, noncontrolled 2B: low |
Sánchez-Guijo F. et al.32. | COVID-19 | AD-MSCs IV | 13 | - PCR COVID-19 - Pneumonia diagnosed by CXR or CT requiring mechanical ventilation in the ICU and any of the following: (1) RR 30 times/min (2) finger O2 saturation 93% (3) PaO2/FiO2 <300 mmHg (4) CXR/CT evidence of progression >50% in 24–48 h (5) SOFA score >3 points (6) WHO OSCI level 6 (7) No evidence of multiorgan failure Compassionate use | Safety EKG CXR Biomarker responses Inflammatory factors Leukocytes count Clinical outcomes Hospital indexes | ↓ Pro-inflammatory factors ↑ Lymphocyte count Improvement on CT/CXR Clinical improvement Discontinuation of oxygen support | Massive gastrointestinal bleeding Hypotension Tachycardia Pneumonia Fungal infection by Candida spp. Not related | Clinical trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low |
Leng Z. et al.34. | COVID-19 | ACE2-MSCs IV | 10 | No improvement under the standard treatments | Biomarker responses Inflammatory factors Clinical outcomes Leukocytes count CT RR | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ O2 saturation Improvement on CT Clinical improvement | None | Pilot trial: a single-center, open-label, non- randomized, controlled. 2B: low |
Tang L. et al.36. | COVID-19 | Menstrual blood-derived SC IV | 2 | Not applicable | Hospital indexes Biomarker responses Inflammatory factors CT | ↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement Improvement on CT | None | Pilot trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low |
Hashemian S. et al.38. | COVID-19 | P-MSCs IV | 11 | (1) Patients with 18–70 years (2) Evidence of pneumonia in CXR or CT and/or COVID-19 positive by RT-PCR (3) ARDS diagnosed (4) SpO2/FiO2 ≤315 (5) SOFA score between 2 and 13 (6) Required mechanical ventilation and/or supplemental O2 | Clinical outcomes Leukocytes count SOFA PaO2/FIO2 RR | ↓ Pro-inflammatory factors Improvement on CT/CXR Clinical improvement ↓Biomarker responses | Transient shivering Related Cardiac arrest Not related | Phase 1 clinical trial: multicenter, open-label, non- randomized, noncontrolled 2B: low |
Iglesias M. et al.16. | COVID-19 | UC-MSC IV | 5 | (1) Severe ARDS -Berlin definition (2) PCR COVID-19 (3) No clinical improvement after standard management (4) Persistent fever (5) D-dimer by at least 50% up from the baseline value and/or ferritin concentrations >1000 ng/mL (6) CT with ground-glass opacity and bilateral pneumonia (7) SOFA <11 Compassionate use | Biomarker responses Inflammatory factors Leukocytes count CT RR, HR PaO2/FIO2 | ↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT ↑Survival/↓Mortality Discontinuation of oxygen support | Hypoxemia Hypotension and/or hypertension Muscle spasms Related Acute Kidney Injury Cardiomyopathy and Liver Failure Bacterial Pneumonia Bleeding Lower-extremity arterial thrombosis Epistaxis and hematuria Not related | Pilot trial: single-center, open-label, non- randomized, noncontrolled. 2 C: low |
Singh S. et al.22. | COVID-19 | CDC IV | 6 | (1) RT-PCR COVID-19; (2) severe COVID-19, requiring supplemental oxygen and/or shock requiring inotropes; (3) not enrolled in another clinical trial; Compassionate use | Inflammatory factors Leukocytes count Biomarker responses | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↑Survival/↓Mortality Clinical improvement Discontinuation of oxygen support Improvement on hospital discharge | None | Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low |
Chen X. et al.23. | COVID-19 | BM-MSCs IV | 25 | (1) Diagnosis of severe COVID-19; (2) age ≥18 years; (3) Receiving MSCs therapy | Clinical outcomes CT Leukocytes count Inflammatory factors Biomarker responses | Clinical improvement Improvement on CT ↑Survival/↓Mortality LAC, cTnT, and CK-MB elevated | Liver dysfunction Heart failure Allergic rash Related | Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low Retrospective |
Helene H. et al.28. | COVID-19 | BM-MSCs IV | 23 | (1) Confirmed COVID-19 (2) Horovitz index <100 on admission. | Biomarker responses Inflammatory factors Leukocytes count | ↓ Pro-inflammatory factors ↓ Neutrophil count ↑ Lymphocyte count ↑ PaO2/FIO2 ↑Survival/↓Mortality Improvement on hospital discharge Discontinuation of oxygen support | None | Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low |
Sengupta V. et al.29. | COVID-19 | BM-MSCs IV | 24 | (1) RT-PCR COVID-19; (2) Fever and/or dyspnea for more than 72 h (3) ↓ PaO2/FiO2 ratio Compassionate use | PaO2/FIO2 Oxygen support requirements Inflammatory factors CXR; EKG Cultures | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↓ Neutrophil count ↑Survival/↓Mortality ↑ PaO2/FIO2 Clinical improvement Improvement on hospital discharge Discontinuation of oxygen support | Hypoxic respiratory failure Pulmonary embolism Acute renal failure Expiration Not related | Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low |
Zhinian G. et al.11. | COVID-19 | UC-MSC IV | 31 | Severe COVID-19 pneumonia | Inflammatory factors PaO2/FIO2 Leukocytes count MSCs regulation Biomarker responses | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ PaO2/FIO2 | None | Clinical trial: a single-center, open-label noncontrolled, non- randomized. 2 C: low |
Zhang Y. 1et al.12. | COVID-19 | UC-MSC IV | 1 | Not applicable | Clinical outcomes Lung function Leukocytes count Inflammatory factors Biomarker responses | ↓ Pro-inflammatory factors ↑ O2 saturation Improvement on CT Clinical improvement Improvement on hospital discharge | None | Case Report 4 C: very low |
Chang Y. et al.13 | ARDS | UC-MSC IT | 1 | Compassionate use | PaO2/FIO2 CT Mental status Lung compliance | ↑ PaO2/FIO2 Clinical improvement Discontinuation of oxygen support His mental status, lung compliance, P/F ratio improved | Repeated pulmonary infections Septic shock empyema Not related | Case Report 4 C: very low |
Liang B. et al.15. | COVID-19 | UC-MSC IV | 1 | Not applicable | Leukocytes count Biomarker responses Inflammatory factors | ↓ Pro-inflammatory factors ↑ Lymphocyte count ↓Biomarker responses ↓ Neutrophil count | None | Case Report 4 C: very low |
Peng H. et al.20. | COVID-19 | UC-MSC IV | 1 | No improvement under the standard treatments | Clinical outcomes Biomarker responses Inflammatory factors CT PaO2 | ↓ Pro-inflammatory factors ↓ Neutrophil count ↑ Lymphocyte count Clinical improvement Discontinuation of oxygen support Improvement on CT | None | Case Report 4 C: very low |
Simonson O. et al.24. | ARDS | BM-MSCs IV | 2 | Two patients with severe ARDS treated on a compassionate use | Physical capacity HRQoL Lung function DECT | Improvement on CT Discontinuation of oxygen support Clinical improvement | None | Cohort: 5-year follow-up. 4 C: very low |
Simonson O. et al.25. | ARDS | BM-MSCs IV | 2 | Refractory ARDS | BALF Inflammatory factors CXR and CT Clinical outcomes Respiratory measurements Biomarker responses | ↓ Pro-inflammatory factors Discontinuation of oxygen support Improvement on CT Clinical improvement | Nosocomial pneumonia Not related | Case Series 4 C: very low |
Jungebluth P. et al.30. | ARDS | PBMCs IT | 1 | Refractory ARDS | Gene expression Bronchoscopy Clinical outcomes Inflammatory factors | ↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT Clinical improvement Discontinuation of oxygen support | Disseminated fungal infection Intra-abdominal sepsis Not related | Case Report 4 C: very low |
Lu J. et al.35. | COVID-19 | Menstrual blood-derived SC IV | 1 | No improvement under the standard treatments | CT Inflammatory factors | ↓ Pro-inflammatory factors Improvement on CT | None | Case Report 4 C: very low |
Wu J. et al.37. | COVID-19 | IMRCs IV | 1 | No improvement under the standard treatments Compassionate use | Clinical outcomes CT Inflammatory factors Blood pressure, O2 saturation Leukocytes count | ↓ Pro-inflammatory factors Clinical improvement | None | Case Report 4 C: very low |
Tao J. et al.63. | COVID-19 | UC-MSC IV | 1 | No improvement under the standard treatments Compassionate use | Blood gas analysis Clinical outcomes Biomarker responses | ↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement ↓Biomarker responses ↑ PaO2/FIO2 | Lung transplant rejection | Case Report 4 C: very low |
