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

Kaushal, S.; Khan, A.; Deatrick, K.; Ng, D. K.; Snyder, A.; Shah, A.; Caceres, L. V.; Bacallao, K.; Bembea, M.; Everett, A.; Zhu, J.; Kaczorowski, D.; Madathil, R.; Tabatabai, A.; Rosenthal, G.; Brooks, A.; Longsomboon, B.; Mishra, R.; Saha, P.; Desire, Y.; Saltzman, R.; Hankey, K. G.; Arias, S. A.; Ayoade, F.; Tovar, J. A.; Lamazares, R.; Gershengorn, H. B.; Magali, F. J.; Loebe, M.; Mullins, K.; Gunasekaran, M.; Karakeshishyan, V.; Jayaweera, D. T.; Atala, A.; Ghodsizad, A.; Hare, J. M.

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.