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

  1. Sunjay Kaushal
  2. Aisha Khan
  3. Kristopher Deatrick
  4. Derek K. Ng
  5. Abigail Snyder
  6. Aakash Shah
  7. Lina V. Caceres
  8. Ketty Bacallao
  9. Melania Bembea
  10. Allen Everett
  11. Jie Zhu
  12. David Kaczorowski
  13. Ronson Madathil
  14. Ali Tabatabai
  15. Geoffrey Rosenthal
  16. Adriana Brooks
  17. Bangon Longsomboon
  18. Rachana Mishra
  19. Progyaparamita Saha
  20. Yvenie Desire
  21. Russell Saltzman
  22. Kim G.Hankey
  23. Sixto A. Arias
  24. Folusakin Ayoade
  25. Jairo A. Tovar
  26. Rejane Lamazares
  27. Hayley B. Gershengorn
  28. Magali J. Fontaine
  29. Matt Klein
  30. Kristin Mullins
  31. Muthukumar Gunasekaran
  32. Matthias Loebe
  33. Vela Karakeshishyan
  34. Dushyantha T. Jayaweera
  35. Anthony Atala
  36. Ali Ghodsizad
  37. Joshua M. Hare
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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.

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