Multiomic chromatin accessibility and gene expression in peripheral blood predicts future decompensation in hospitalized adults with COVID-19

To elucidate host response elements that define impending decompensation during SARS-CoV-2 infection, we enrolled subjects hospitalized with COVID-19 who were matched for disease severity and comorbidities at the time of admission and initial sampling. We then performed combined single-cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) from the time of admission and compared subjects who improved from their initial low-level oxygen requirement (no change from initial WHO Ordinal category 4/5) to those who later clinically decompensated and required invasive mechanical ventilation or died (WHO Ordinal score 7/8). Chromatin accessibility and transcriptomic immune profiles were markedly altered at admission in patients who will go on to develop critical illness. The greatest immunologic signals were seen in CD4+ T cells, inflammatory T cells, dendritic cells, and NK cell subsets, where an aggregate multiomic signature score calculated at admission offered strong prediction of future clinical deterioration (area under the receiver operating characteristic curve (auROC) 0.91). Epigenetic and transcriptional changes in PBMCs reveal unique, early, and conserved aspects of the immune response before typical clinical signals of decompensation are apparent and thus provide novel biomarkers that can predict future disease severity. Overall design: COVID-19 subjects were matched for disease severity and comorbidities at the time of admission and initial sampling. Combined single-cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) on peripheral blood mononuclear cells (PBMCs) from the time of admission were performed and compared subjects who improved from their initial low-level oxygen requirement to those who later clinically decompensated and required invasive mechanical ventilation or died.