Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series

Abstract

Background Acute respiratory distress syndrome (ARDS) is a fatal complication of coronavirus disease 2019 (COVID-19). There are a few reports of allogeneic human mesenchymal stem cells (MSCs) as a potential treatment for ARDS. In this phase 1 clinical trial, we present the safety, feasibility, and tolerability of the multiple infusions of high dose MSCs, which originated from the placenta and umbilical cord, in critically ill COVID-19-induced ARDS patients. Methods A total of 11 patients diagnosed with COVID-19-induced ARDS who were admitted to the intensive care units (ICUs) of two hospitals enrolled in this study. The patients were critically ill with severe hypoxemia and required mechanical ventilation. The patients received three intravenous infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases). Findings There were eight men and three women who were 42 to 66 years of age. Of these, six (55%) patients had comorbidities of diabetes, hypertension, chronic lymphocytic leukemia (CLL), and cardiomyopathy (CMP). There were no serious adverse events reported 24–48 h after the cell infusions. We observed reduced dyspnea and increased SpO2 within 48–96 h after the first infusion in seven patients. Of these seven patients, five were discharged from the ICU within 2–7 days (average: 4 days), one patient who had signs of acute renal and hepatic failure was discharged from the ICU on day 18, and the last patient suddenly developed cardiac arrest on day 7 of the cell infusion. Significant reductions in serum levels of tumor necrosis factor-alpha (TNF-α; P < 0.01), IL-8 (P < 0.05), and C-reactive protein (CRP) (P < 0.01) were seen in all six survivors. IL-6 levels decreased in five (P = 0.06) patients and interferon gamma (IFN-γ) levels decreased in four (P = 0.14) patients. Four patients who had signs of multi-organ failure or sepsis died in 5–19 days (average: 10 days) after the first MSC infusion. A low percentage of lymphocytes (< 10%) and leukocytosis were associated with poor outcome (P = 0.02). All six survivors were well with no complaints of dyspnea on day 60 post-infusion. Radiological parameters of the lung computed tomography (CT) scans showed remarkable signs of recovery. Interpretation We suggest that multiple infusions of high dose allogeneic prenatal MSCs are safe and can rapidly improve respiratory distress and reduce inflammatory biomarkers in some critically ill COVID-19-induced ARDS cases. Patients that develop sepsis or multi-organ failure may not be good candidates for stem cell therapy. Large randomized multicenter clinical trials are needed to discern the exact therapeutic potentials of MSC in COVID-19-induced ARDS.

Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Treatment of Viral Diseases

“…Since MSCs may efficiently suppress detrimental immune response and are able to provide additional oxygen supply to injured lungs, several clinical trials have investigated the therapeutic potential of MSCs in the treatment of SARS-CoV-2-induced lung inflammation [35][36][37][38].…”

“…HIV and herpes viruses could incorporate their genetic information into the DNA of MSCs, and, therefore, MSCs could serve as reservoirs for these pathogens [42][43][44]. HIV infection impairs proliferation and attenuates the immunosuppressive properties of MSCs Hashemian and colleagues conducted a phase 1 clinical trial to evaluate the safety, tolerability and efficacy of the multiple infusions of placenta-derived MSCs (PL-MSCs) and UC-MSCs in the treatment of critically ill patients with COVID-19 [36]. A total of 11 patients with SARS-CoV-2 with life-threatening hypoxemia and ARDS who required artificial respiratory support intravenously received PL-MSCs or UC-MSCs (200 × 10 6 cells/infusion; total of three infusions) [36].…”

“…HIV infection impairs proliferation and attenuates the immunosuppressive properties of MSCs Hashemian and colleagues conducted a phase 1 clinical trial to evaluate the safety, tolerability and efficacy of the multiple infusions of placenta-derived MSCs (PL-MSCs) and UC-MSCs in the treatment of critically ill patients with COVID-19 [36]. A total of 11 patients with SARS-CoV-2 with life-threatening hypoxemia and ARDS who required artificial respiratory support intravenously received PL-MSCs or UC-MSCs (200 × 10 6 cells/infusion; total of three infusions) [36]. Significantly reduced dyspnea, improved oxygenation, downregulated serum levels of inflammatory cytokines (TNF-α, IL-8 and IL-6) and CRP were observed in six MSC-treated patients [36].…”

“…A total of 11 patients with SARS-CoV-2 with life-threatening hypoxemia and ARDS who required artificial respiratory support intravenously received PL-MSCs or UC-MSCs (200 × 10 6 cells/infusion; total of three infusions) [36]. Significantly reduced dyspnea, improved oxygenation, downregulated serum levels of inflammatory cytokines (TNF-α, IL-8 and IL-6) and CRP were observed in six MSC-treated patients [36]. Five MSC-treated patients were discharged from the intensive care unit (ICU) 2-7 days after MSCs infusion, while one patient was discharged from the ICU on day 18.…”

“…Five MSC-treated patients were discharged from the intensive care unit (ICU) 2-7 days after MSCs infusion, while one patient was discharged from the ICU on day 18. Four MSC-treated patients who had signs of multiorgan failure died within 5-19 days after the first MSCs injection, and one patient developed cardiac arrest on day 7 of the MSC infusion [36]. Although results obtained in this study indicated that multiple infusions of MSCs may rapidly improve respiratory function and reduce systemic inflammation in patients with COVID-19, the fact that beneficial effects were not observed in 45% (5/11) of MSC-treated patients suggested the need of a new, larger clinical trial, which should delineate the efficacy of MSC-based therapy in patients suffering from severe COVID-19-related lung injury [36].…”