Hyperglycemia, Reduced Hematopoietic Stem Cells, and Outcome of COVID-19

Admission hyperglycemia has emerged worldwide as a predictor of poor COVID-19 outcome. Hyperglycemia leads to a defect in circulating hematopoietic stem/progenitor cells (HSPCs) which, in turn, predicts diabetic complications. Here, we explored whether reduced HSPCs mediated at least part of the prognostic effect of hyperglycemia on COVID-19 outcome. We found that patients with COVID-19 (n=100) hospitalized in a non-intensive setting displayed dramatically (50-60%) reduced levels of HSPCs measured by flow cytometry as CD34⁺, CD34⁺CD45^dim or CD34⁺CD133⁺ cells, compared with controls (n=595). This finding was highly significant (all p<10^-10) after multivariable adjustment, or manual 1:1 patient match, or propensity score matching. Admission hyperglycemia (≥7.0 mmol/l) was present in 45% of patients, was associated with a significant further ~30% HSPCs reduction and predicted a 2.6-fold increased risk of the primary outcome of adverse COVID-19 course (admittance to the intensive care unit or death). Low HSPCs were also associated with advanced age, higher peak C-reactive protein and neutrophil/lymphocyte ratio. Independently from confounders, one standard deviation lower CD34⁺ HSPCs was associated with a >3-fold higher risk of adverse outcome. Upon formal analysis, reduction of HSPCs was a significant mediator of the admission hyperglycemia on COVID-19 outcome, being responsible for 28% of its prognostic effect.