Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial

Abstract

Background COVID-19 is a multisystem disease that presents acute and persistent symptoms, the postacute sequelae (PASC). Long-term symptoms may be due to consequences from organ or tissue injury caused by SARS-CoV-2, associated clotting or inflammatory processes during acute COVID-19. Various strategies are being chosen by clinicians to prevent severe cases of COVID-19; however, a single treatment would not be efficient in treating such a complex disease. Mesenchymal stromal cells (MSCs) are known for their immunomodulatory properties and regeneration ability; therefore, they are a promising tool for treating disorders involving immune dysregulation and extensive tissue damage, as is the case with COVID-19. This study aimed to assess the safety and explore the long-term efficacy of three intravenous doses of UC-MSCs (umbilical cord MSCs) as an adjunctive therapy in the recovery and postacute sequelae reduction caused by COVID-19. To our knowledge, this is one of the few reports that presents the longest follow-up after MSC treatment in COVID-19 patients. Methods This was a phase I/II, prospective, single-center, randomized, double-blind, placebo-controlled clinical trial. Seventeen patients diagnosed with COVID-19 who require intensive care surveillance and invasive mechanical ventilation—critically ill patients—were included. The patient infusion was three doses of 5 × 105 cells/kg UC-MSCs, with a dosing interval of 48 h (n = 11) or placebo (n = 6). The evaluations consisted of a clinical assessment, viral load, laboratory testing, including blood count, serologic, biochemical, cell subpopulation, cytokines and CT scan. Results The results revealed that in the UC-MSC group, there was a reduction in the levels of ferritin, IL-6 and MCP1-CCL2 on the fourteen day. In the second month, a decrease in the levels of reactive C-protein, D-dimer and neutrophils and an increase in the numbers of TCD3, TCD4 and NK lymphocytes were observed. A decrease in extension of lung damage was observed at the fourth month. The improvement in all these parameters was maintained until the end of patient follow-up. Conclusions UC-MSCs infusion is safe and can play an important role as an adjunctive therapy, both in the early stages, preventing severe complications and in the chronic phase with postacute sequelae reduction in critically ill COVID-19 patients. Trial registration Brazilian Registry of Clinical Trials (ReBEC), UTN code-U1111-1254-9819. Registered 31 October 2020—Retrospectively registered, https://ensaiosclinicos.gov.br/rg/RBR-3fz9yr

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

“…Our systematic literature search yielded 712 unique citations. After title/abstract and full text screening, eight studies [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] met all criteria for inclusion in our review. Reasons for study exclusion at the full-text stage included wrong publication type (n=39), different outcome (n=20), uncontrolled design (n=9), did not study MSCs (n=6), language and wrong population studied (n=3) ( Figure 1 ).…”

“…The characteristics of the eight included studies are summarized in Table 1 . All eight studies were RCTs [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] . Study publication date ranged from August 18, 2020 [27] to March 21 st 2022 [33] .…”

“…All eight studies were RCTs [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] . Study publication date ranged from August 18, 2020 [27] to March 21 st 2022 [33] . Two of the studies were conducted in China,[ 27 , 30 ], one in the USA [28] , one in Indonesia [29] , one in Turkey [31] , one in Iran [32] , one in Brazil [33] , and one in France [34] .…”

“…Intervention characteristics are summarized in Table 2 . Seven of the eight studies used MSCs[ [27] , [28] , [29] , [30] , [31] , 33 , 34 ], and one of the studies used MSC-derived secretome [32] . All MSCs were derived from allogeneic human tissues, including umbilical cord tissue (n=7)[ [27] , [28] , [29] , [30] , [31] , 33 , 34 ], and menstrual blood (n=1) [32] .…”

“…Seven of the eight studies used MSCs[ [27] , [28] , [29] , [30] , [31] , 33 , 34 ], and one of the studies used MSC-derived secretome [32] . All MSCs were derived from allogeneic human tissues, including umbilical cord tissue (n=7)[ [27] , [28] , [29] , [30] , [31] , 33 , 34 ], and menstrual blood (n=1) [32] . The passage number in ex vivo culture of the MSCs varied widely between studies (passage 2 to passage 6) (see Table 2 ), with one of the studies [28] not reporting how many passages were performed before harvesting MSCs from ex vivo culture.…”