The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial

Abstract

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Clinical efficacy and mechanism of mesenchymal stromal cells in treatment of COVID-19

“…According to the World Health Organization (WHO), the cumulative number of deaths due to COVID-19 has surpassed 5.5 million globally. Multiple studies have shown that MSC therapy can significantly reduce the incidence and mortality of critical illness (Table 3 ) [ 14 – 19 ]. For example, Shu et al [ 14 ] found the mortality in the MSC treatment group was zero.…”

“…Several published clinical trials indicate that MSCs can effectively control the expression of inflammatory cytokines in COVID-19 patients [ 14 – 16 , 18 , 19 ]. Several studies have reported that proinflammatory cytokines, such as interleukin (IL)-8, tumor necrosis factor (TNF)-α, CRP, IL-6, INF-γ, IL-2, IL-12, and IL-17A, decreased significantly after MSC infusion, while anti-inflammatory cytokines IL-4 and IL-10 increased significantly [ 14 , 15 , 18 ].…”

Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application

“…Phase I and II clinical studies have shown that MSCs transplantation is a safe and potentially effective method for the treatment of moderate to severe ARDS [63,64]. Besides, recent exploratory clinical studies showed that MSCs treatment was associated with improvements in mortality, dyspnea and chest imaging findings for severe and critically ill COVID-19 patients [65][66][67][68][69]. And phase I and II clinical trials have also shown that intravenous MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated [70,71].…”

A Retrospective Look at Recent COVID-19 Articles Published in Cell Transplantation: Research Leading to Further Understanding

“…Fortunately, MSC infusions had a relatively quick and lasting effect, by decreasing pro-inflammatory cytokines (TNFα) and inflammatory markers (i.e., CRP), and increasing anti-inflammatory cytokines (IL10) and growth factors (KGF). In their CT article, Adas et al 7 reported that a MSC treated patient group had a shorter ICU length of stay and fewer deaths. The Senegaglia et al .…”

“…MSC have been beneficial in animal models of ARDS and were used to treat patients suffering from influenza A (H7N9 infections) 9 , 12 , 14 . In critically ill COVID-19 patients who have failed to respond to all other treatments, MSC have been used almost as a last-ditch effort 7 , 11 , 12 . Fortunately, MSC infusions had a relatively quick and lasting effect, by decreasing pro-inflammatory cytokines (TNFα) and inflammatory markers (i.e., CRP), and increasing anti-inflammatory cytokines (IL10) and growth factors (KGF).…”