Treatment of COVID-19 Patients: Insights into the Use of Bone Marrow-Derived Mesenchymal Stem Cells
Authors: Andrade Heitor Duarte , Kondo Andrea Tiemi , Kerbauy Lucila , Paiva Raquel de Melo Alves , Oliveira Denise Cristine , Coa Larissa Leggieri , Alvarez Kelen Cristina Arcuri , Savioli Mariana Lorenzi , Loureiro Bruna Melo Coelho , Okamoto Oswaldo Keith , Hamerschlak Nelson , Kutner Jose Mauro , Godoy Juliana Aparecida Preto 
Published: November 2021

Abstract
Patients with SARS-CoV-2 may be affected by the acute respiratory distress syndrome (ARDS), which has been associated with high mortality rate. As no specific drugs are available for ARDS, mesenchymal stem cells (MSC) seems to be a promising cell therapy due to immunomodulatory effects on reducing and healing inflammation-induced lung and other tissue injuries. The goal of this Phase I clinical trial was to explore the safety and efficacy of bone marrow-derived MSC (BM-MSC) infusions in patients with COVID-19 ARDS. The inclusions criteria were age between 18 to 70 years and PaO2/FiO2≤200mmHg. The BM-MSC infusions were as follow: one to 3 infusions intravenous doses of BM-MSC of 1x10 6 cells/kg; each dose could be administered with an interval between 3 to 7 days. The primary endpoint was safety (adverse events) within 6 hours; cardiac arrest or death within 24 hours post-infusion. The secondary endpoint includes patient survival at 30 days after the first infusion.
Six patients were included in the trial and treated with at least one infusion of BM-MSC. The median age was 60,3 years (54 to 69), 5 were male. The median time between the worsening of respiratory distress and the BM-MSC infusion was 10 days (3 to 31 days). The median of PaO2/FiO2 before infusion was 151.86 (127.80-164.44) and median PaCO2 was 63,85 (39 to 117). One patient was treated with 3 MSC doses, two patients with 2 doses and 3 patients one dose. No serious adverse effects were observed within 24 hours post-infusion; only one death was observed following 30 days of cell administration. None of them showed adverse events during BM-MSC infusion. Only one patient showed signs of pulmonary infection one week after first BM-MSC infusion. This patient was at increased risk for infection due to prolonged intubation and a high dose of corticosteroid. Therefore, it was not possible to conclude its association with BM-MSC treatment.
Only two patients showed clinical improvement after BM-MSC infusion. Patient 1 had BM-MSC infusion 72 hours after worsening of respiratory parameters, and thorax CT suggested the hypothesis of cryptogenic organizing pneumonia, which led to decision of using methylprednisolone 125mg I.V. for 3 days and carry on with MSC infusion. We observed a decrease in CRP levels from 126 to 67 mg/dL on day 1 after the first infusion, and PaO2/FiO2 ratio improved from 155 to 297 mmHg on day 5. He received the second dose within 7 days interval and by day 11 of the first infusion a new thorax TC showed complete resolution of alveolar consolidation areas in both lungs (Figure 1A and 1B). Patient 2 had BM-MSC administration 11 days after respiratory worsening and also presented improvement of PaO2/FiO2 ratio (148 to 215 mmHg after 2 days of infusion) and had thorax CT images suggesting cryptogenic organizing pneumonia with administration of methylprednisolone 250mg I.V. Nevertheless, the second dose was not administered due to ventilator-associated pneumonia and urinary infection.
Four patients showed a non-sustained increase of PaO2/FiO2 ratio, with higher median PCO2 levels of 69,3 mmHg (range, 61,2 to 117) comparing to 39 and 47,3 mmHg of patients 1 and 2, respectively. PCO2 parameter could be a marker to indicate a worse response to MSC treatment, since it could point out chronic phases of COVID-19 disease. The patients died due to COVID-19 complications.
No difference in inflammatory markers, such as interleukin 6, C-protein reactive test, procalcitonin, ferritin was observed before and after treatment.
Inclusion criteria did not defined interval between respiratory worsening and first BM-MSC infusion. Four patients had chronic phase of COVID-19 without inflammatory markers and hypercapnia. It could be related to severity of pulmonary disease, such as reported in chronic obstructive pulmonary disease. Two patients were discharged after MSC treatment and they received methylprednisolone to treat cryptogenic organizing pneumonia. There are only a few clinical trials and observational studies evaluating the use of high-dose of glucocorticoid for severe COVID-19 pneumonia. Therefore, it is not possible to conclude that use of glucocorticoid has contributed to favorable outcomes.
In conclusion, BM-MSC showed to be a secure therapeutic option for severe COVID-19 pneumonia, possibly with superior benefit in acute phases and lower PCO2 levels. Further studies involving a large cohort or randomized controlled trials are warranted.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.