Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial

Abstract

Background Acute respiratory distress syndrome (ARDS) is the devastating complication of the new COVID-19 pandemic, directly correlated with releasing large amounts of inflammatory cytokines. Due to their immunoregulatory features, mesenchymal stromal cells (MSCs) provide a promising approach against this disease. In this regard, this study was designed as a single-center, open-label, phase 1 clinical trial with a control group to examine the safety and explore the possible potency of three injections of umbilical cord-derived MSCs (UC-MSCs) in mild–moderate COVID-19-induced ARDS patients. Methods Twenty confirmed COVID-19 patients with mild-to-moderate ARDS degree entered the study and were divided into two groups: control group (standard care) and intervention group (standard care + UC-MSCs). The patients received three intravenous infusions of UC-MSCs (1 × $${10}^{6}$$ 10 6 cells/kg BW per injection) every other day. Respiratory markers, CRP levels and specific serum cytokines were assessed four times (days of 0, 5, 10 and 17) during the 17-day follow-up period. Results During the study, there were no serious adverse effects after cell transplantations. Besides, significant improvement in SPO2/FIO2 ratio and serum CRP levels was observed. On the other hand, a significant decrease (P < 0.05) in serum cytokine levels of IL-6, IFN-g, TNF-α, IL-17 A and a significant increase in serum cytokine levels of TGF-B, IL-1B and IL-10 were observed. Also, no significant changes were observed in CT scan images of patients during the study period. Conclusion Our obtained results demonstrated that multiple intravenous transplantations of allogenic UC-MSCs in non-severe COVID-19-induced ARDS patients are a safe procedure. In addition, this intervention is a hopeful approach to decline cytokine storm and recover respiratory functions. Indeed, more clinical trials with larger sample sizes are required to confirm these results. Trial registration This clinical trial was registered with the Iranian Registry of Clinical Trials (ID: IRCT20160809029275N1 at 2020.05.30).

The safety and efficacy of mesenchymal stromal cells in ARDS: a meta-analysis of randomized controlled trials

“…Six included studies reported the effect of MSC on oxygenation. Though three included studies implied that MSC may increase PaO 2 /FiO 2 ratio [ 16 , 37 , 39 ], the other three studies suggested that MSC did not have much impact on PaO 2 /FiO 2 ratio at any timepoints [ 17 , 19 , 34 ]. On ventilation-free days to 28 days in ARDS, five studies didn’t detect any significant difference between MSC and controls [ 16 , 17 , 19 , 34 , 38 ].…”

“…In terms of ICU-free days, although five studies discovered no significant difference between the two groups [ 16 , 19 , 34 , 38 , 40 ], one study revealed that MSC may reduce ICU-free days in ARDS [ 17 ]. Meanwhile, the effects of MSC on serum IL-6 in ARDS were also controversial, as while three studies suggested no significant difference detected [ 16 , 17 , 40 ], four others implied that MSC may downregulate serum IL-6 [ 18 , 19 , 35 , 39 ]. Additionally, three included studies reported no significant impact of MSC on serum IL-8 in ARDS [ 16 , 17 , 35 ].…”

Effect and safety of mesenchymal stem cells for patients with COVID‐19: Systematic review and meta‐analysis with trial sequential analysis

“…S3A). 22,24,26,27,46,47 However, there were no significant differences between CRP level before and after in control group (MD: 5.66; 95% CI −1.64 to 12.97; p = 0.13; I² = 35%) (Figure S3B). 22,24,26,27,46,47 The present metaanalysis also revealed that compared with standard treatment, MSC therapy could significantly decrease the post-CRP level (MD: −31.61;…”

“…Among all the included studies, eight of them were multicenter studies, [26][27][28][30][31][32]43,45 10 studies were double-blind RCTs with placebo, 23,24,[28][29][30][31][43][44][45][46] one study was single-blind RCT with placebo 26 and four studies were designed as open-label trials. 22,25,27,32 The inclusion criteria were different from each other, six studies included patients with critical COVID-19, 23,28,31,32,43,47 seven studies included severe patients, 22,24,25,29,30,42,46 only one study included not severe patients, 44 and the remaining studies had no limitations on the patient's severity of disease. 26,27,45 Except for 58.8% of studies used human umbilical cord-derived MSCs (hUC-MSCs), 22,23,25,26,[28][29]...…”

Therapeutic Benefits of Mesenchymal Stem Cells in Acute Respiratory Distress Syndrome: Potential Mechanisms and Challenges

“… 25 , 66 In these 2 years, MSCs have been administered intravenously for the treatment of patients with COVID-19-associated ARDS, with excellent results in terms of clinical tolerance and benefits on the prognosis. 83 , 84 For the treatment of ventilator-associated lung injury, MSCs also have certain therapeutic effects. These results are mainly focused on bronchopulmonary dysplasia that develops in premature newborns in clinical trials.…”