Abstract: Open Forum Infectious Diseases Major Article Vitamin K & D Deficiencies Are Independently Associated With COVID-19 Disease Severity Ankita P. Desai,1,2,3,a, Sahera Dirajlal-Fargo,1,2,3,a Jared C. Durieux,1 Heather Tribout,1 Danielle Labbato,1 and Grace A. McComsey1,2,3 1 University Hospitals Cleveland Medical Center; Cleveland, Ohio, USA, 2Rainbow Babies and Children’s Hospital, Cleveland, Ohio, USA, and 3Case Western Reserve University, Cleveland, Ohio, USA Since the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, there has been a substantial worldwide effort in understanding the pathogenesis of coronavirus disease 2019 (COVID-19), treatment modalities, and prevention. Those infected with this virus may have a wide range of symptoms from an asymptomatic or mild state to severe pneumonia, coagulopathy, and death [1]. The ability to predict severe disease and response to treatment remains elusive [2]. Several risk factors have been identified for disease severity, including advanced age, male sex, non-White race, obesity, vitamin and mineral deficiencies (specifically vitamin D, vitamin C, and selenium), diabetes, and hypertension. Received 23 June 2021; editorial decision 12 July 2021; accepted 28 July 2021. a Equal contribution Correspondence: Grace A. McComsey, MD, FIDSA, University Hospitals Cleveland Medical Center and Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106 (grace.mccomsey@uhhospitals.org). Open Forum Infectious Diseases®2021 © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/ licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com https://doi.org/10.1093/ofid/ofab408 Severe outcomes have been associated with multiorgan failure, which may correspond to the underlying inflammatory response postinfection. Host factors triggered by the virus can lead to an exaggerated inflammatory response or “cytokine storm,” leading to pulmonary damage through calcification of pulmonary interstitial arteriolar walls, hypercoagulation, and disseminated intravascular coagulation [3]. Vitamin K is the name given to a group of essential fat-soluble vitamins, phylloquinone (vitamin K1) and menaquinones (vitamin K2), which are co-factors for several proteins involved in coagulation homeostasis and calcium homeostasis. Phylloquinone and menaquinones share the same head group (2-methyl-napthoquinone) but have different compositions of the poly-isoprenoid side chain (at the 3-position). In the circulation, there is a differential distribution of vitamin K to lipoproteins, where the majority of short-chain vitamin K (phylloquinone) is associated with triacylglycerol-rich lipoproteins, and the longer menaquinones are more associated with low-density lipoproteins (LDLs). The associations with different lipoproteins allow different distribution in the body, where the long-chain menaquinones reach extrahepatic tissues that possess LDL receptors [4]. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial..