Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DR hi CD11c hi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR lo monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.

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atients with COVID-19 exhibit a broad spectrum of disease progression, with 81% showing mild, moderate or no symptoms; 14% showing severe symptoms; and 5% experiencing critical disease with high mortality risk 1 . The risk of developing severe or critical disease has been associated with advanced age 1,2 , comorbidities 1,2 , hyperactivation of the immune system 3,4 , sex 1,2 and other factors. However, an understanding of these risk factors at the molecular and cellular levels is in its infancy.In this study, we investigated the immune response in patients with COVID-19 by single-cell RNA sequencing (scRNA-seq) of nasopharyngeal and bronchial samples to identify molecular correlates of disease severity. Two recent studies applied scRNA-seq to bronchioalveolar lavage fluid samples from patients with COVID-19 and provide an extensive characterization of the inflammatory immune phenotype in the lower respiratory tract 5,6 . However, SARS-CoV-2 and other coronaviruses infect and replicate in both COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis