Epigenetic liquid biopsies reveal endothelial turnover and erythropoiesis in asymptomatic COVID-19

Understanding the full spectrum of tissues affected by SARS-CoV-2 is crucial for deciphering the heterogeneous clinical course of COVID-19. We analyzed DNA methylation and histone modifications in circulating chromatin to assess cell type–specific turnover in patients ranging from asymptomatic to severe cases, in relation to clinical outcomes. Severe COVID-19 was marked by a massive el-evation of circulating cell-free DNA (cfDNA) from lung epithelium, cardiomyocytes, vascular endothelium, and erythroblasts, indicat-ing increased cell death or turnover. The immune response was reflected by elevated B-cell and monocyte/macrophage cfDNA and an interferon response before cfDNA release. Strikingly, monocyte/ macrophage cfDNA (but not monocyte counts), as well as lung epithelial and endothelial cfDNA, predicted clinical deterioration and duration of hospitalization. Asymptomatic patients had elevated immune cfDNA but no evidence of pulmonary or cardiac damage. Surprisingly, these patients showed elevated endothelial and erythroblast cfDNA, suggesting subclinical vascular and erythrocyte turnover are universal features of COVID-19, indepen-dent of disease severity. Epigenetic liquid biopsies provide a noninvasive means of monitoring COVID-19 patients and reveal subclinical vascular damage and red blood cell turnover.