Severe COVID-19 Is Marked By A Dysregulated Myeloid Cell Compartment Jonas Schulte-Schrepping1,2, Nico Reusch1,2, Daniela Paclik3, Kevin Baßler1,2, Stephan Schlickeiser3, Bowen Zhang4, Benjamin Krämer5, Tobias Krammer6, Sophia Brumhard7, Lorenzo Bonaguro1,2, Elena De Domenico1, Daniel Wendisch7, Anna C. Aschenbrenner2,8, Yang Li4,9, Jacob Nattermann5,10, Birgit Sawitzki3, Antoine-Emmanuel Saliba6, Leif Erik Sander7,11, Joachim L. Schultze2,9, Deutsche COVID-19 OMICS Initiative (DeCOI) 1 Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany 2 Genomics & Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Germany 3 Institute of Medical Immunology, Charité, Universitätsmedizin Berlin, Berlin, Germany 4 Centre for Individualised Infection Medicine (CiiM) & TWINCORE, joint ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany 5 Department of Internal Medicine I, University Hospital Bonn, Bonn Germany 6 Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany 7 Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany 8 Radboud UMC, Nijmegen, The Netherlands 9 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands 10 German Center for Infection Research (DZIF) 11 German Center for Lung Research (DZL) Coronavirus Disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progresses 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, remains 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 vs. severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRhiCD11chi inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors indicative of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DRlo 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.