Table 6.
Secondary outcome: efficacy.
| References | Mortality in stem cell (death/n) | Mortality in control (death/n) | Morbidity in stem cell (afflicted/n) | Morbidity in control (afflicted/n) | Pulmonary and imaging changes | Systemic changes and symptoms | Inflammatory markers |
|---|---|---|---|---|---|---|---|
| Meng et al. (18) | 0/9 | 0/9 | 1/9 | 4/9 | CT images showed lung lesions entirely faded away within 2 weeks after MSC infusion, while lung lesions still existed in one severe patient in the control group at discharge | Clinical symptoms at discharge; respectively, for MSC and control group: (Fever: 5/9; 2/9), (Fatigue: 4/9; 5/9), (Cough: 4/9; 8/9) and (breath shortness: 1/9; 5/9). The period of admission to discharge was same in MSC and control group (20.00 vs. 23.00 days, P = 0.306) | There was a reduced trend in IFN-γ, TNF-α, MCP-1, IP-10, IL-22, IL-1RA, IL 18, IL-8, MIP-1 levels within 14 days in MSC group |
| Häberle et al. (19) | 1/5 | 10/18 | 4/5 | 14/18 | The MSC group had a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 + 0.2 vs. 2.8 + 0.3). At discharge, the MSC group showed a significantly lower Murray score than the control group (0.3 + 0.1 vs. 1.3 + 1.1) | ICU stay in control was less than the MSC group but not significant (P = 0.07) (due to the higher incidence of deceased patients within the control group and a higher percentage of ECMO use in the MSC group). The incidence of kidney injury and hepatic failure in the MSC group did not differ from the incidence in the control group of patients | The values for CRP and IL-6 did not differ significantly between the groups during ICU treatment. A significant reduction in leukocytes and neutrophils was found at discharge in the MSC group compared to the control group, showing a reduction of inflammation. A significant increase in lymphocytes at discharge was observed in the MSC group, suggesting that the acquired immune system is activated |
| Leng et al. (20) | 0/7 | 1/3 | 4/7 | 3/3 | 2–4 days after MSC infusion, the O2 saturations rose to ≥95% at rest, without or with oxygen uptake (5 l/min) | 2–4 days after MSC infusion, all the symptoms disappeared in all the patients | Reduction of pro-inflammatory TNF and increasing of anti-inflammatory IL-10 in serum was significant (p <0.05). The serum levels of IP-10 and growth factor VEGF were both increased but not significantly |
| Nesrin et al. (21) | 4/8 | 2/3 | 4/8 | 3/3 | In four patients, chest X-rays approved clinical improvement, and the need for O2 support was decreased, and they were discharged. Other four MSC patients remained in critical condition and died, although there was a significant improvement in their prognostic markers | The significant improvement in the efficacy outcome was not correlated with the clinical progress in four of eight MSC patients who passed away. Among the patients who survived until the end of the study (4 in case and 1 in control), all four patients in the case were discharged from ICU, and one patient in control still was in ICU | Compared to the baseline, there was a significant reduction in CRP (p = 0.036), Hb (p = 0.03), and fibrinogen (p = 0.012) values on post-treatment day 5. While there was an elevation in lymphocyte count between baseline and post-treatment, the change did not reach statistical significance (p = 0.06). There was no statistically significant change in ferritin, SaO2, RR, NC, troponin, and PC (p > 0.05) between baseline and post-treatment day 5 |
| Xu et al. (22) | 2/26 | 6/18 | 3/26 | 6/18 | Dyspnea and SpO2 showed a significant improvement after MSC infusions. Chest imaging findings were improved in the MSC group in the first month after infusion | The average time taken to improve for the MSC group was 5.8 days shorter, significantly less than the control group (P = 0.049), showing that MSC infusion could shorten the time required for treatment. There was no significant | no significant differences observed in inflammatory markers including CRP (P = 0.486), IL-6 (P = 0.375) serum level before and after MSC transplantation |
| difference in either the length of hospital stay, the number of days in ICU, the occurrence of shock or multiple organ failure between the two groups (P > 0.05 for all) | |||||||
| Giacomo et al. (23) | 2/12 | 7/12 | 2/12 | 8/12 | NM | MSC infusion was associated with significantly improved patient survival (91 vs. 42%, P = 0.015), SAE-free survival (P = 0.008), and recovery time (P = 0.03) | In a comparison between groups at day 6, significant differences were observed in the concentration of IFN-γ, GM-CSF, IL-5, IL-6, IL-7, TNF-α, TNF-β, PDGF-BB, and RANTES (P <0.05); median values of these molecules were lower in the MSC group |
| Lei et al. (24) | 0/65 | 0/35 | 37/65 | 21/35 | In the evaluation of the solid component lesions, the total lung lesion proportion of the whole lung volume showed a significant decrease in the MSC group against the placebo group (P = 0.043) | 6-min walking distance was longer in the MSC group than in the placebo group but not significant (P = 0.057). Other parameters including DLco and VCmax, the six-category scale, status of oxygen therapy, and mMRC dyspnea score were similar between the two groups | there was no significant difference in the subsets of peripheral lymphocyte counts (CD4+ T cells, CD8+ T cells, B cells, NK cells) and plasma biomarkers between the two groups |
| Shu et al. (25) | 0/12 | 3/29 | 0/12 | 4/29 | Chest CT scans approved that in the number of lobes involved, the CT scores, consolidation, and GGO in the MSC group were significantly better than those in the control group (P <0.05) | On day 14, 11 patients (91.67%) of the MSC group experienced obvious clinical symptom improvements, usually manifesting as obvious absorption on imaging and significant remission of dyspnea; however, only 15 patients (51.72%) of the control group felt symptom relief | CRP and IL-6 levels were significantly reduced from day 3 of MSC infusion, and the lymphocyte count gave back to normal levels in less time |
| Gina Marcela Torres et al. (26) | 4/20 | 6/24 | 5/20 | 8/24 | NM | The hospital stay period in the stem cell group was less than the control group (mean of 27.4 vs. 41.6 days). The interval from the intervention day until the discharge, the stem cell group had a maximum of 43 days compared with the control group with 125 days | In the stem cell group, the creatinine, WBC, neutrophil, and platelet count, did not show significant differences during the interval of study, but CRP and lymphocyte count were extremely low after the infusion |
| Dynasty (27) | 0/20 | 0/10 | 0/20 | 0/10 | NM | NM | NM |
CRP, C-reactive protein; CT, computed tomography; DLco, diffusion lung capacity for carbon monoxide; ECMO, extracorporeal membrane oxygenation; GGO, ground-glass opacity; GM-CSF, granulocyte-monocyte colony-stimulating factor; Hb, hemoglobin; ICU, intensive care unit; IFN, interferon; IL, interleukin; IL-1RA, interleukin 1 receptor type 1; IP-10, interferon-inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MIP-1, macrophage inflammatory protein 1-alpha; mMRS, modified Medical Research Council Dyspnea Scale; MSC, mesenchymal stem cell; NK cell, natural killer cell; NM, not mentioned; PC, platelet count; PDGF, platelet-derived growth factor two B subunits; RANTES, regulated on activation, normal T expressed and secreted (CCL5); SAE, severe adverse event; SpO2, oxygen saturation; TNF, tumor necrosis factor; VC, vital capacity; VEGF, vascular endothelial growth factor; WBC, white blood cell.