We conducted a pilot trial of intravenous infusion of UC-MSCs in 16 severe and critically severe COVID-19 patients, confirming its safety and feasibility, with a significant increase in oxygenation index and relatively low mortality. The improvement of chest imaging, recovery of lymphocyte count and decrease of cytokine level were also observed in our trial, making UC-MSCs transplantation a promising treating strategy.
Safety of MSC transplantation has been identified in previous clinical trials treating ARDS[6, 7]. In the recent studies about MSC transplantation in COVID-19 patients, there was no MSC related adverse event either. In our study, there was no acute infusion-related or allergic reactions were observed, and no delayed hypersensitivity or secondary infections. As MSCs trend to accumulate in pulmonary circulation after infusion, the pulmonary embolism risk increased rapidly. In our study, none of the patients developed a thromboembolic event.
Multiple clinical trials using stem cell therapy to treat the COVID-19 have been registered at www.clinicaltrials.gov. Two published studies showed that ACE2− MSC and exosomes derived from bone marrow MSC could improve the clinical outcome of COVID-19 patients[4, 8]. In accordance with our findings, the use of exosomes derived from bone marrow MSC could increase the oxygenation index of severe COVID-19 patients which may reduce the need for invasive ventilator and shorten hospital stay.
The outcome of COVID-19 patients admitted to the ICU is poor. In a recent series of 1581 Italian patients in Lombardy Region with COVID-19 ARDS admitted to ICU, the mortality was 26% and only 16% had been discharged. In another series of patients in Milan, Italy, the mortality was 23% and 31% had been discharged. In Vancouver, Canada, the mortality in ICU patients was 15.4%. In our study, the mortality was about 6.25% which was relatively lower.
It is noteworthy that adults with COVID-19 often present with a profound decrease in lymphocyte count including CD4+ and CD8+ T-cell subsets at the early stage of this disease[12–14]. Qin et al also reported that severe cases of COVID-19 were likely to have lower lymphocyte count compared with non-severe patients. More recently, CD8+ T-cells have been reported to be significantly decreased in peripheral blood in patients with COVID-19. More importantly, CD8+ T-cells ≤ 75 cells/µL was a reliable predictor for mortality of patients with COVID-19. In our study, patients in group A had higher lymphocyte count than group B. Although patients enrolled in Leishenshan Hospital were not able to take the lymphocyte subsets test, the patients survived had CD8+ T-cells all over 75 cells/µL, while the non-survival patient only had 18 cells/µL CD8+ T-cells at baseline. After the transplantation of UC-MSC, the lymphocyte count including CD4+ T-cell subsets, CD8+ T-cell subsets, and NK cells were increased, which suggested the immunomodulation effect of UC-MSC may play an important role in the COVID-19 treatment.
In a subset of COVID-19 patients who progress to pneumonia, respiratory failure and death by the end of the first week showed extreme rise in inflammatory cytokines including IL2, IL7, IL10, and TNF-α. High levels of expression of IL-1β, IFN-γ, IP-10 have been detected in patients with COVID-19 . The serum levels of IL-2R and IL-6 in patients with COVID-19 are positively correlated with the severity of the disease. In our study, cytokines include IL-2, Interleukin-4, IL-6, IL-10, IFN-γ, and TNF-α were tested. As we accepted the results 7 days before enrollment, the baseline cytokines were relatively low, which might not in accordance with the real clinical situation. MSC could inhibit the secretion of pro-inflammatory cytokines, such as, IL-1, TNF-α, IL-6, Interleukin-12, and IFN-γ, thereby reducing the occurrence of cytokine storms[19, 20]. Meanwhile, MSC can secrete Interleukin-10, hepatocyte growth factor, keratinocyte growth factor and vascular endothelial growth factor to alleviate ARDS, regenerate and repair damaged lung tissues, and resist fibrosis. After the transplantation of UC-MSCs, the cytokine level varied in the normal range, which might prove the anti-inflammatory effect of UC-MSCs.
Our study has several limitations. First, the trial was lack of randomization, blinding, and comparison, with small sample size, which made it difficult to evaluate the efficacy of UC-MSC. Second, there was no specific statistics on the total length of hospital stay. During this pandemic in China, the COVID-19 patients were being treated in different designated hospitals in different disease period for treatment and quarantine. The hospital information systems were separate in different hospitals, made the total length of hospital stay beyond compute. Third, the lost rate of follow up and plan deviation, especially the missing of laboratory tests, were relatively higher than usual, due to the quarantine policy and psychological distress after the disease, made it difficult to do statistical analysis. Further high-quality randomization clinical trials are needed to provide more specific evidence.