SRP329309 PRJNA748731 GSE180578 People critically ill with COVID-19 exhibit peripheral immune profiles predictive of mortality and reflective of SARS-CoV-2 lung viral burden There remains an urgent need to delinate immune cell states that contribute to mortality in critially ill COVID-19 patients. To better understand determinants of mortality, we performed high dimensional profiling of blood and respiratory samples from critially ill COVID-19 patients. Single-cell RNAseq based characterization of peripheral immune states reveal distinct expression profiles that were predictive of COVID-19 mortality. Temporal analysis revealed a that persistently elevated levels of inflammatory monocyte signatures and persistent interferon signaling preceeded concerted upregulation of inflammatory cytokines. Interrogation of lower respiratory tract saples revelaed that infected myeliod cells upregulated CXCL10, and elevated levels of CXCL10 in plasma were associated with a high risk of death. Overall, our data suggest a pivotal role for myeloid cell states in severe COVID-19 and may faciliate discovery of new diagnostics and therapeutics. Overall design: We analyzed a total of 86 samples by scRNAseq, including peripheral blood from 10 healthy donors, 5 non-COVID acute respiratory distress syndrome patients (ARDS), and 24 COVID-19 patients. Two samples were typically paired per channel of 10X 5-prime scRNAseq sample using TotalSeq-C antibodies. All COVID-19 and ARDS patients were undergoing treatment in the intensive care units (ICUs) at the University of Pittsburgh Medical Center. Samples were obtained from non-COVID ARDS and COVID-19 at up to 3 timepoints (day 1, day 5 and day 10 post-enrollment in the ICU). On day 1, we obtained 26 COVID-19 PBMC samples and 5 non-COVID ARDS samples; on day 5, we obtained 4 non-COVID ARDS and 20 COVID-19 samples; on day 10 we obtained 2 non-COVID ARDS and 19 COVID_19 samples. In addition to peripheral blood samples, we also obtained 6 endotracheal aspirate samples from COVID-19 patients. GSE180578 pubmed 34873589 parent_bioproject PRJEB40771