Mesenchymal stromal cells may improve outcomes in severe COVID-19 related ARDS by normalizing SARS-CoV2-related lymphopenia

<bold>Background:</bold> SARS-CoV2 virus resulted in severe acute respiratory distress syndrome (ARDS) which was the main cause of morbidity and mortality. Mesenchymal stromal cells (MSCs) exert beneficial immunomodulatory effects in preclinical models of ARDS. <bold>Objective:</bold> To determine safety and efficacy of freshly cultured umbilical cord (UC)-MSCs for treatment of severe ARDS in COVID-19 patients. <bold>Methods:</bold> CIRCA-19 was a multi-site, placebo-controlled, randomized (2:1) clinical trial with a primary outcome of number of days free of oxygen by noninvasive ventilation, high flow nasal cannula or mechanical ventilation within 28 days. <bold>Results:</bold> 22 patients were enrolled: 14 received 90×10⁶ UC-MSCs over 3 consecutive days (cumulative dose: 270×10⁶ MSCs) and 8 received placebo. Although not adequately powered for statistical analysis, MSCs resulted in an ~40% reduction in median oxygen-free days and median ICU-free days at 28-days compared to the placebo group, with a decrease in mortality at day 28 (14% vs. 25%, respectively) and 1 year (21% vs. 40%, respectively). Biomarker analyses suggested a reduction in IL-6 and IL-8 with MSCs, associated with an increase in IFN gamma. Importantly, at baseline both groups demonstrated lymphopenia, which was selectively and significantly reversed by MSC treatment (p<0.01). <bold>Conclusion:</bold> Freshly cultured UC-derived MSCs resulted in a non-statistically significant improvement in oxygen free-days, ICU-free days and survival, associated with a significant increase in lymphocyte count. These findings suggest that normalization of lymphopenia may play a key role in the beneficial immunomodulatory effects of MSCs in severe COVID-19 ARDS.