Intravenous Mesenchymal Stem Cells in Extracorporeal Oxygenation Patients with Severe COVID-19 Acute Respiratory Distress Syndrome

Abstract

Background: There is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking. Methods: We conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance. Findings: MSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame. Interpretation: Together these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

Safety and efficacy of mesenchymal stem cells in severe/critical patients with COVID-19: A systematic review and meta-analysis

“…Finally, 13 studies reported in 14 articles were included for the study quality assessment and data analysis. 5 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 The study selection process and reasons for excluding studies are presented in Figure 1 .

Figure 1 PRISMA flow diagram for article selection.

…”

“… 37 For the dose, seven studies administered 1-3 × 10 6 cells per kg of body weight, 5 , 32 , 35 , 36 , 38 , 39 , 41 four studies administered 3-12 × 10 7 cells per infusion, 29 , 30 , 33 , 40 and two studies did not report the stem cell dose. 34 , 37 Among the 210 patients in the experimental group, 59 patients received a single dose, 5 , 32 , 36 , 39 , 41 35 patients received two doses, 35 , 37 , 40 and 116 patients received three doses of therapy. 29 , 30 , 33 , 34 , 35 , 38 All included studies applied intravenous (IV) as the route of delivery.…”

“…Among the 13 included studies, eight studies used umbilical cord-derived derived MSCs, 5 , 29 , 32 , 33 , 36 , 38 , 39 , 40 , 41 two studies used healthy bone-marrow-derived MSCs, 34 , 35 one study used menstrual blood-derived MSCs, 30 and one study used non-hematopoietic enriched stem cells. 37 For the dose, seven studies administered 1-3 × 10 6 cells per kg of body weight, 5 , 32 , 35 , 36 , 38 , 39 , 41 four studies administered 3-12 × 10 7 cells per infusion, 29 , 30 , 33 , 40 and two studies did not report the stem cell dose.…”

“… 34 , 37 Among the 210 patients in the experimental group, 59 patients received a single dose, 5 , 32 , 36 , 39 , 41 35 patients received two doses, 35 , 37 , 40 and 116 patients received three doses of therapy. 29 , 30 , 33 , 34 , 35 , 38 All included studies applied intravenous (IV) as the route of delivery. However, not all studies reported the details of standard care.…”

Venovenous ECMO application as bridge to recovery or lung transplantation; ongoing challenge as we look at a pre‐ and post‐COVID‐19 era

“…With over 4,000,000 deaths worldwide and over 600,000 deaths in the USA out‐of‐box thinking is needed 4 . At our program in Miami COVID‐19 patients who have been on VV ECMO for more than 10 days or could not be weaned off VV ECMO after 4 weeks were offered work up for adult stem cell therapy and lung transplantation starting 2020 5 . Two COVID‐19 patients on VV ECMO were bridged to lung transplantation with a 50% 6 months survival including one case undergoing bilateral pneumonectomy on VV ECMO.…”