Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial

Abstract

One of the main causes of acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19) is cytokine storm, although the exact cause is still unknown. Umbilical cord mesenchymal stromal cells (UC-MSCs) influence proinflammatory T-helper 2 (Th₂ ) cells to shift to an anti-inflammatory agent. To investigate efficacy of UC-MSC administration as adjuvant therapy in critically ill patients with COVID-19, we conducted a double-blind, multicentered, randomized controlled trial at four COVID-19 referral hospitals in Jakarta, Indonesia. This study included 40 randomly allocated critically ill patients with COVID-19; 20 patients received an intravenous infusion of 1 × 10⁶ /kg body weight UC-MSCs in 100 ml saline (0.9%) solution (SS) and 20 patients received 100 ml 0.9% SS as the control group. All patients received standard therapy. The primary outcome was measured by survival rate and/or length of ventilator usage. The secondary outcome was measured by clinical and laboratory improvement, with serious adverse events. Our study showed the survival rate in the UC-MSCs group was 2.5 times higher than that in the control group (P = .047), which is 10 patients and 4 patients in the UC-MSCs and control groups, respectively. In patients with comorbidities, UC-MSC administration increased the survival rate by 4.5 times compared with controls. The length of stay in the intensive care unit and ventilator usage were not statistically significant, and no adverse events were reported. The application of infusion UC-MSCs significantly decreased interleukin 6 in the recovered patients (P = .023). Therefore, application of intravenous UC-MSCs as adjuvant treatment for critically ill patients with COVID-19 increases the survival rate by modulating the immune system toward an anti-inflammatory state.

Keywords: COVID-19; adjuvants; cord stem cell transplantation; cytokine release syndrome; immunology; mesenchymal stromal cells.

FIGURE 1

Timeline of the study. Standard of care consists of therapy given in accordance to the guidelines, namely, azithromycin 500 mg and oseltamivir 75 mg, which is given tailored to the patient's need and the attending's discretion and clinical judgment. BW, body weight; NS, normal saline; UC‐MSCs, umbilical cord mesenchymal stromal cells

FIGURE 2

Kaplan‐Meier diagram of the time from intervention (administration of umbilical cord MSCs or placebo) to death or improvement. MSC, mesenchymal stromal cell

FIGURE 3

Trend of IL‐6 (A), IL‐10 (B), LIF (C), VEGF (D), and ferritin (E) in the MSCs group vs the control group with the interval of 7 days. D‐0: Day 0 (before application), D‐7: Day 7 (7 days following the application); IL, interleukin; LIF, Leukemia Inhibitory Factor; MSC, mesenchymal stromal cell; VEGF, vascular endothelial growth factor