Opinion Paper The snapshot of metabolic health in evaluating micronutrient status, the risk of infection and clinical outcome of COVID-19 Dimitris Tsoukalas a, b, *, 1 , Evangelia Sarandi b, c, **, 1 , Spyridoula Georgaki b, 1 a European Institute of Nutritional Medicine, 00198 Rome, Italy b Metabolomic Medicine, Health Clinic for Autoimmune and Chronic Diseases, 10674 Athens, Greece c Laboratory of Toxicology and Forensic Sciences, Medical School, University of Crete, 71003 Heraklion, Greece article info Article history: Received 14 June 2021 Accepted 14 June 2021 Keywords: COVID-19 Metabolomics Metabolic health Micronutrient deficiencies Insulin resistance Infection susceptibility Post-COVID summary COVID-19 has re-established the significance of analyzing the organism through a metabolic perspective to uncover the dynamic interconnections within the biological systems. The role of micronutrient status and metabolic health emerge as pivotal in COVID-19 pathogenesis and the immune system's response. Metabolic disruption, proceeding from modifiable factors, has been proposed as a significant risk factor accounting for infection susceptibility, disease severity and risk for post-COVID complications. Metab- olomics, the comprehensive study and quantification of intermediates and products of metabolism, is a rapidly evolving field and a novel tool in biomarker discovery. In this article, we propose that leveraging insulin resistance biomarkers along with biomarkers of micronutrient deficiencies, will allow for a diagnostic window and provide functional therapeutic targets. Specifically, metabolomics can be applied as: a. At-home test to assess the risk of infection and propose nutritional support, b. A screening tool for high-risk COVID-19 patients to develop serious illness during hospital admission and prioritize medical support, c(i). A tool to match nutritional support with specific nutrient requirements for mildly ill pa- tients to reduce the risk for hospitalization, and c(ii). for critically ill patients to reduce recovery time and risk of post-COVID complications, d. At-home test to monitor metabolic health and reduce post-COVID symptomatology. Metabolic rewiring offers potential virtues towards disease prevention, dissection of high-risk patients, taking actionable therapeutic measures, as well as shielding against post-COVID syndrome. © 2021 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). 1. Introduction In March 2020, the World Health Organization declared the outspread acute respiratory syndrome coronavirus 2 (SARS-COV-2/ COVID-19) a global pandemic. At the time of writing, the viral infection accounts for 2.8 million deaths and 132 million infected cases [1]. Although the underlying disease mechanisms have not yet fully unraveled, it seems that common inflammatory cascades, also known as ‘cytokine storm,’ are responsible for the spectrum of clinical manifestations; from asymptomatic cases, loss of smell or/ and taste senses, to mild upper respiratory tract infections and acute respiratory distress syndrome (ARDS), characterized by se- vere organ failure and eventually, death [2,3]. Among the most prominent recruited molecules, IL-1, IL-6, tumor necrosis factor (TNF- a), and interferon (IFN) levels rise abruptly, leading to un- controlled inflammatory responses and, eventually, tissue damage due to aberrant cellular interactions [4]. Several factors have been acknowledged to affect whether patients will develop severe COVID-19 phenotype, which, as defined by the Centers for Disease Control and Prevention (CDC), includes hospitalization, admission to the intensive care unit, intubation or mechanical ventilation, or death [5]. Clinical data on COVID-19 have demonstrated that individuals of older age (over 65), immunocompromised, presenting with comorbidities, including cancer, lung and heart disease, as well as patients with metabolic complications, such as type 2 diabetes * Corresponding author. European Institute of Nutritional Medicine, 00198 Rome, Italy. ** Corresponding author. Metabolomic Medicine, Health Clinic for Autoimmune and Chronic Diseases, 10674 Athens, Greece. E-mail addresses: dtsoukalas@einum.org (D. Tsoukalas), esarandi6@hotmail. com (E. Sarandi), research@metabolomicmedicine.com (S. Georgaki). 1 All authors have equally contributed. Contents lists available at ScienceDirect Clinical Nutrition ESPEN journal homepage: http://www.clinicalnutritionespen.com https://doi.org/10.1016/j.clnesp.2021.06.011 2405-4577/© 2021 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC BY- NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical Nutrition ESPEN 44 (2021) 173e187