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Background Methods Acknowledgments Correspondence Critical COVID-19 disease explained by type I interferon autoantibodies found in patients within the Military Health System. Maria Leondaridis1, Debra Yee1, Marana Tso2, Elana Shaw3, Lindsey B. Rosen3, Emily Samuels2, Paul Bastard4,5,6, Jean-Laurent Casanova4,5,6, Steven M. Holland3, Helen C. Su3, Stephanie Richard7,8, Katrin Mende7,8,9, Tahaniyat Lalani7,8,10, David Lindholm9, Catherine M. Berjohn11, Ryan C. Maves11, Rhonda E. Colombo7,8,12, Christopher J Colombo12, Derek T. Larson13, Evan C. Ewers13, Anuradha Ganesan7,8,14, Nikhil Huprikar14, Rupal M. Mody15, Milissa U. Jones16, Mark P Simons7, David Tribble7, Eric D. Laing2, Brian Agan7,8, Simon Pollett7,8, Timothy H Burgess7, Andrew L. Snow1 & the EPICC Study Group. This work was supported by awards from the Defense Health Program (HU00012020067) and the National Institute of Allergy and Infectious Disease (HU00011920111). The protocol was executed by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed by the Uniformed Services University of the Health Sciences (USUHS) through a cooperative agreement by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF). This project has been funded in part by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, under an interagency agreement (Y1-AI-5072). The authors declare no conflicts of interest. Results Results Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10-20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto- Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potent, RITM0037391, Neutralizing auto-antibodies (auto-Abs) that target type I interferons (IFN), a group of cytokines that induce innate immune responses upon viral infection, are found within approximately 10-20% of patients with critical COVID-19. We sought to determine if neutralizing type I IFN auto- Abs contribute to severe COVID-19 in patients within the Military Health System (MHS). The Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential (EPICC) cohort collected demographic data, clinical data and sera from SARS-CoV-2 infected patients enrolled across 10 U.S. military treatment facilities. We screened sera collected <21 days post-symptom onset from 249 COVID-19 inpatients and 312 COVID-19 outpatients for IFN auto-Ab positivity and neutralizing activity using Luminex and intracellular flow cytometry, respectively. Similar to previous reports, we detected neutralizing auto-Abs against IFN-? and/or IFN-? in a significantly higher frequency of inpatients (10 total, 4%) versus outpatients (1, 0.32%) (p=0.009). Remarkably, IFN auto- Abs persisted 6-12 months post-infection in most inpatients, including several with a history of autoimmune disease. Among inpatients, multivariate logistic regression analyses demonstrated that type I IFN auto-Abs were associated with a greater risk of severe and critical COVID-19 (adjusted odds ratio (aOR) = 3.99 and 4.69, respectively) after adjusting for age, sex and comorbidity burden. Our results confirm a robust association between critical COVID-19 and the presence of type I IFN auto-Abs, which may predispose to other severe respiratory viral infections that cause substantial morbidity and mortality in the MHS.