Abstract: Original Manuscript SCIENCE PROGRESS Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19 Science Progress 2022, Vol. 105(1) 1–12 © The Author(s) 2022 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/00368504221074574 journals.sagepub.com/home/sci José Luis Izquierdo1,2 , Joan B Soriano3,4,5, Yolanda González6, Sara Lumbreras6,7, Julio Ancochea3,4,5 , Christian Echeverry6 and José Miguel Rodríguez1,8 1 Department of Medicine and Medical Specialties, Universidad de Alcalá, Madrid, Spain 2 Respiratory Medicine, Hospital Universitario de Guadalajara, Guadalajara, Spain 3 Respiratory Medicine, Hospital Universitario de La Princesa, Madrid, Spain 4 Universidad Autónoma de Madrid, Madrid, Spain 5 Respiratory Diseases Networking Biomedical Research Centre (CIBERES), Institute of Health Carlos III (ISCIII), Madrid, Spain 6 SAVANA 7 Universidad Pontificia Comillas-IIT, Madrid, Spain 8 Respiratory Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain Abstract Infection by SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) can be associated with serious and life-threatening conditions, including acute respiratory distress syndrome (ARDS). Severity and mortality have been related to a cytokine storm, an imbalance of oxidative stress, and a pro-thrombotic state. We conducted an observational retrospective cohort study from a community-based large population of hospitalized COVID-19 PCR + patients admitted from March 01, 2020, to January 24, 2021, with integrated primary to tertiary care information in Castilla la Mancha, Spain. We Corresponding author: Sara Lumbreras, Institute for Research in Technology, Universidad Pontificia Comillas-IIT, C/ Santa Cruz de Marcenado, 26. 28015, Madrid, Spain. Email: slumbreras@comillas.edu Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 Science Progress 105(1) explored the potential benefits of the antioxidant, anti-inflammatory and anti-thrombotic drug Nacetylcysteine (NAC) administered orally in high doses (600 mg every 8 h), added to standard of care in COVID-19 patients by using the free text information contained in their electronic health records (EHRs). Out of 19,208 patients with a diagnosis of COVID-19 hospitalized, we studied 2071 (10.8%) users of oral NAC at high doses. COVID-19 patients treated with NAC were older, predominantly male, and with more comorbidities such as hypertension, dyslipidemia, diabetes, and COPD when compared with those not on NAC (all p < 0.05). Despite greater baseline risk, use of NAC in COVID-19 patients was associated with significantly lower mortality (OR 0.56; 95%CI 0.47– 0.67), a finding that remained significant in a multivariate analysis adjusting by baseline characteristics and concomitant use of corticosteroids. There were no significant differences with the use of NAC on the mean duration of hospitalization, admission to the intensive care unit or use of invasive mechanical ventilation. The observed association signaling to better relevant outcomes in COVID-19 patients..