Citation: Gotelli, E.; Soldano, S.; Hysa, E.; Paolino, S.; Campitiello, R.; Pizzorni, C.; Sulli, A.; Smith, V.; Cutolo, M. Vitamin D and COVID-19: Narrative Review after 3 Years of Pandemic. Nutrients 2022, 14, 4907. https://doi.org/10.3390/ nu14224907 Academic Editors: Bruce W. Hollis and Carlos Camargo Received: 21 October 2022 Accepted: 17 November 2022 Published: 20 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Review Vitamin D and COVID-19: Narrative Review after 3 Years of Pandemic Emanuele Gotelli 1 , Stefano Soldano 1 , Elvis Hysa 1 , Sabrina Paolino 1 , Rosanna Campitiello 1 , Carmen Pizzorni 1 , Alberto Sulli 1 , Vanessa Smith 2,3,4 and Maurizio Cutolo 1, * 1 Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology, Department of Internal Medicine and Specialties, University of Genova, IRCCS San Martino Polyclinic Hospital, 16132 Genova, Italy 2 Department of Internal Medicine, Ghent University Hospital, 9000 Ghent, Belgium 3 Department of Rheumatology, Ghent University Hospital, 9000 Ghent, Belgium 4 Unit for Molecular Immunology and Inflammation, Vlaams Instituut voor Biotechnologie (VIB), Inflammation Research Center (IRC), 9000 Ghent, Belgium * Correspondence: mcutolo@unige.it Abstract: Active vitamin D [1,25(OH) 2 D 3 —calcitriol] is a secosteroid hormone whose receptor is expressed on all cells of the immune system. Vitamin D has a global anti-inflammatory effect and its role in the management of a SARS-CoV-2 infection has been investigated since the beginning of the COVID-19 pandemic. In this narrative review, the laboratory and clinical results of a vitamin D supplementation have been collected from both open-label and blinded randomized clinical trials. The results are generally in favor of the utility of maintaining the serum concentrations of calcifediol [25(OH)D 3 ] at around 40 ng/mL and of the absolute usefulness of its supplementation in subjects with deficient serum levels. However, two very recent large-scale studies (one open-label, one placebo-controlled) have called into question the contribution of vitamin D to clinical practice in the era of COVID-19 vaccinations. The precise role of a vitamin D supplementation in the anti-COVID-19 armamentarium requires further investigations in light of the breakthrough which has been achieved with mass vaccinations. Keywords: vitamin D; neuroendocrine immunology; intracrinology; COVID-19; inflammation 1. Introduction Active vitamin D [1,25(OH) 2 D 3 —calcitriol] is a fat-soluble hormone that exerts multi- ple biological properties (endocrine, paracrine and intracrine) in the human body [1]. The paracrine and intracrine functions of vitamin D have aroused great interest, in particular for the almost ubiquitous expression of the vitamin D receptor (VDR) by the cells of the immune system, supporting a role in the regulation of the acute and chronic inflammatory response [2]. In particular, the link between vitamin D and inflammation in course of respiratory infections has been studied for more than a century, starting from the clinical pieces of evidence of the antimicrobial activity exerted by vitamin D against Mycobacterium tuberculo- sis [3]. Recently, a robust meta-analysis of more than 1500 researches on this topic identified a vitamin D supplementation as a protective factor against acute airways infections, thanks to its immunomodulatory properties [4]. Vitamin D does not act directly against the most common respiratory viruses (i.e., influenza virus, rhinovirus and respiratory syncytial virus), but it globally reduces the expression and secretion of pro-inflammatory chemokines and cytokines [5,6]. Following the spread of the COVID-19 pandemic between the end of 2019 and the beginning of 2020, several investigations have been carried out regarding the correlation Nutrients 2022, 14, 4907. https://doi.org/10.3390/nu14224907 https://www.mdpi.com/journal/nutrients