Discussion
Multiorgan failure, CRS, ARDS, extensive lung damage
SYSTEMIC INFLAMMATORY RESPONSE, SARS-COV-2 INFECTION, ADVERSE EVENTS, CYTOKINE RELEASE SYNDROME, MULTIORGAN FAILURE, ARDS, PATHOGENESIS
In this study, we administered allogenic MSCs to COVID-19 patients who were in the progressive phase of ARDS. We observed that systemic administration of MSC and local administration of MSC-EVs in COVID-19 patients is safe, with minimal adverse events. Furthermore, MSCs had significant effects on inflammatory markers compared to the control group.Evaluating laboratory outcomes of COVID-19 patients after administering MSCs was one of the goals of this study. The unpredictable clinical course of SARS-CoV-2 infection presents a challenging issue in managing COVID-19 [Assessing the laboratory markers of coagulation was another goal of this study. Multiorgan failure due to cytokine storm is usually reported in severe cases of COVID-19 patients, particularly in patients with ARDS [In this study, we also evaluated the impact of MSCs on inflammatory markers. We observed that MSCs significantly decreased the concentration of inflammatory markers in COVID-19 patients. Cytokine release syndrome (CRS), which is a rigorous systemic inflammatory response, may be responsible for severe COVID-19 pathogenesis and extensive lung damage [The decrement of inflammatory cytokines was more pronounced in the case of IL-6, which was reduced by both MSCs and MSCs plus EV administration. However, routine treatment according to national guidelines for COVID-19 did not change IL-6 values in the control group. This finding is particularly valuable considering that IL-6 is a key mediator of cytokine storm and strongly correlates with complicated COVID-19 patients with adverse clinical outcomes [Our study suggested that the administration of MSCs is safe in COVID-19 patients. We observed lower rates of mortality in intervention groups compared to the control group, although this difference was not significant. Previous studies have also demonstrated no adverse events of MSCs in COVID-19 patients [In summary, stem cell therapy, particularly the use of MSCs has emerged as a promising treatment option for severe COVID-19 cases. Several clinical studies have been conducted so far in this regard. Clinical studies have demonstrated that MSC therapy is generally safe and well-tolerated in severe COVID-19 patients, associated with no significant adverse events [This study has certain remarkable advantages. It has one of the largest sample sizes in the national population, providing a suitable view of MSCs administration in Iranian COVID-19 patients. In addition, we assessed basic laboratory parameters and reported their improvement in the MSC treated COVID-19 patients. Another positive aspect of this study is the administration of MSC-EVs through a nebulizing device, which can be an accessible method for COVID-19 patients. However, the current study has some limitations. Many COVID-19 patients with ARDS had been treated with corticosteroids and antiviral drugs before MSCs transfusion, according to the national guideline for treating COVID-19 induced ARDS. This is a confounding variable in assessing the inflammatory markers. Besides, the levels of routine laboratory outcomes in many patients had some abnormality due to the severe condition and we couldn’t assess the exact impact of MSC or MSC-EV on laboratory outcomes. Our medical records did not include any other critical laboratory parameters to include in the study and also, we cannot assess advance laboratory parameters, such as flow cytometric analysis of lymphocytes due to high costs. Furthermore, given the pandemic situation, we could not register their complete laboratory data and this issue was one of the pitfalls of this study. We started the MSC-based at the critical stage of COVID-19 and earlier infusion of MSCs might be associated with better outcomes. Besides, lower sample size of the intervention group was challenging for subgroup analysis. These issues should be addressed in the future studies. In addition, many other molecules and signaling pathways that are essential in the pathogenesis of COVID-19 were not evaluated in this study.