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Vitamin D: a potentially important secosteroid for coping with COVID-19

Abstract

COVID-19 is a disease that has caused a high number of deaths in the world, and despite being controlled, it requires attention and the search for new quick and economical therapeutic strategies. In this sense, vitamin D stands out, an immunomodulator that has shown beneficial effects in decreasing the risk and severity of acute respiratory tract infections, including COVID-19. Therefore, this review presents a number of experimental, observational and clinical studies on the importance of vitamin D against viral infections with an emphasis on COVID-19, highlighting the relationship between vitamin D, Renin-Angiotensin System and cytokine storms with decreased inflammatory lesions in patients with COVID-19. In addition, aspects of pathophysiology, metabolism, risk factors, sources and recommendations of vitamin D are described. We conclude that vitamin D plays a protective role against inflammatory lesions and can decrease the risk of infections and the severity of COVID-19. Therefore, it is essential to maintain adequate levels of vitamin D to avoid complications related to its deficiency.

Key words
COVID-19; fat-soluble vitamin; Renin-Angiotensin System; SARS-CoV-2

INTRODUCTION

In the past five decades, several infectious diseases, including herpes and legionnaires in 1970, AIDS, Ebola, Zika, Severe Acute Respiratory Syndrome (SARS), and, recently, COVID-19, continue to threaten humans (Huremović 2019HUREMOVIĆ D. 2019. Psychiatry of Pandemics. A Mental Health Response to Infection Outbreak. In: Huremović D (Ed), Brief History of Pandemics (Pandemics Throughout History), Manhasset: Springer, New York, USA, p. 7-36., Jones 2020JONES DS. 2020. History in a Crisis - Lessons for Covid-19. The N Engl J Med 382: 1681-1683.). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), popularly known as COVID-19, started in Wuhan province in China in December 2019 and is a disease caused by the SARS-CoV-2 virus, a new member of the Coronaviridae family (Lu et al. 2020LU R ET AL. 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395: 565-574.). However, only on March 11, 2020, did the World Health Organization (WHO) declared COVID-19 a global pandemic (WHO 2020WHO – WORLD HEALTH ORGANIZATION. 2020. WHO Director-General’s opening remarks at the media briefing on COVID-19 - 11 March 2020. https://www.who.int/director-general/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. (accessed March 20, 2020).
https://www.who.int/director-general/spe...
). This is the third-largest epidemic of coronavirus (CoV) infections. Previous CoV epidemics include Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), started in China in 2002 (Zhong et al. 2003ZHONG NS ET AL. 2003. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet 362: 1353-1358.), and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), first reported in 2012 in the Middle East (Assiri et al. 2013ASSIRI A ET AL. 2013. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med 369: 407-416.).

The spread of the new SARS-CoV-2 virus and COVID-19 disease continues at an accelerated pace. According to WHO data, 521,920,560 cases and 6,274,323 deaths were confirmed (WHO 2022WHO – WORLD HEALTH ORGANIZATION. 2022. WHO Coronavirus Disease (COVID-19) Dashboard. https://covid19.who.int/. (accessed May 20, 2022).
https://covid19.who.int/...
). Given these numbers, saving lives, and reducing the world pandemic are of extreme importance for the general population.

The characteristics of this disease include fever, dry cough, dyspnea, myalgia, and fatigue. A small number of patients also experience sputum, headaches, hemoptysis, and diarrhea. In addition, patients commonly have leukopenia and lymphopenia (Huang et al. 2020aHUANG C ET AL. 2020a. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395: 497-506.). These symptoms can gradually progress to severe manifestations, such as lethal Acute Respiratory Distress Syndrome (ARDS).

Therefore, alternative solutions to prevent progression, and severity of this disease are important. The focus on the use of existing drugs in an attempt to obtain a faster therapeutic option may be an alternative to mitigate the harmful effects of COVID-19. Different drugs have been reported, including: Lopinavir-Ritonavir (Cao et al. 2020CAO B ET AL. 2020. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 382: 1787-1799.), Remdesivir (Wang et al. 2020bWANG Y ET AL. 2020b. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lacent 395: 1569-1578.), Hydroxychloroquine (Horby et al. 2020aHORBY P ET AL. 2020a. Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med 383: 2030-2040.), Tocilizumab (Guaraldi et al. 2020GUARALDI G ET AL. 2020. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lacent 2: 474-484.), Arbidol (Zhu et al. 2020ZHU Z, LU Z, XU T, CHEN C, YANG G, ZHA T, LU J & XUE Y. 2020. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect 81: 21-23.), Ivermectin (Caly et al. 2020CALY L, DRUCE JD, CATTON MG, JANS DA & WAGSTAFF KM. 2020. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res 178: 104787.) e Dexamethasone (Horby et al. 2020bHORBY P ET AL. 2020b. Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. N Engl J Med 383: 2030-2040.). However, contraindications have been reported and the use of these drugs is not a definitive therapy.

In addition to these attempts, vitamin D supplementation in patients with COVID-19 was associated with lower disease severe and improved clinical status of hospitalized patients (Annweiler et al. 2020ANNWEILER G, CORVAISIER M, GAUTIER J, DUBÉE V, LEGRAND E, SACCO G & ANNWEILER C. 2020. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 12: E3377., Castillo et al. 2020CASTILLO MS, COSTA LME, BARRIOS JMV, DÍAZ JFA, MIRANDA JL, BOUILLON R & DOMEZ JMQ. 2020. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol 203: 105751.). However, little is known about the definitive role of vitamin D in preventing COVID-19 infection and fatality. In this sense, this article proposes a review of the general aspects of vitamin D, highlighting its possible role against the COVID-19.

Vitamin D: fundamental concepts, pathophysiology, and importance for the organism

Vitamin D is a fat-soluble secosteroid that exists in two main forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). These structures differ chemically only in the side chain, where vitamin D2 has a double bond between carbon atoms C-22 and C-23, in addition to a methyl group (CH3) on carbon C-24, unlike vitamin D3 (Figure 1). Vitamin D3 is produced in the skin from the cholesterol derivative 7-Dehydrocholesterol (7-DHC) during exposure to sunlight (UVB radiation 285-315 nm) (Lehmann et al. 2001LEHMANN B, GENEHR T, KNUSCHKE P, PIETZSCH J & MEURER M. 2001. UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J Invest Dermatol 117: 1179-1185.), whereas the vitamin D2 isomer is produced by UVB radiation in plants and fungi from ergosterol (Boland et al. 2003BOLAND R, SKLIAR M, CURINO A & MILANESI L. 2003. Vitamin D compounds in plants. Plant Science 164: 357-369.).

Figure 1
Metabolism of vitamin D2 and vitamin D3.

Humans obtain vitamin D from three sources: from UVB radiation, from the diet, or through supplementation (Holick 2007HOLICK MF. 2007. Vitamin D deficiency. N Engl J Med 357: 266-281.). The D2 and D3 forms of vitamin D are inactive in a biological environment and their active forms are formed from a sequence of enzymatic hydroxylation reactions. Initially, vitamin D (D2 and D3) is transported in the blood mainly by a vitamin D binding glycoprotein (DBP) until it reaches the liver, where the enzyme CYP2R1 promotes a hydroxylation at C-25 carbon atoms, giving rise to the pre-hormones 25-hydroxyvitamin D2 (25(OH)D2) and 25-hydroxyvitamin D3 [25(OH)D3 (calcidiol)], respectively. Subsequently, when these prehormones reach the kidney, they undergo a second hydroxylation at C-1 carbon atoms through the enzyme CYP27B1, leading to the biologically active hormones 1α,25-dihydroxyvitamin D2 (1,25(OH)2D2) and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3 (calcitriol)], respectively (Figure 1) (Bikle & Christakos 2020BIKLE D & CHRISTAKOS S. 2020. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nat Rev Endocrinol 16: 234-252.). It is important to highlight that in the blood of normal individuals, about 85% of circulating vitamin D metabolites are bound to DBP. Albumin binds about 15% of these metabolites and does so with much lower affinity. Approximately 0.4% of total 1,25(OH)2D3 and 0.03% of total 25OHD3 are free in serum from normal individuals (Bikle & Schwartz 2019BIKLE DD & SCHWARTZ J. 2019. Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front Endocrinol (Lausanne) 10: 317-329.).

Free vitamin D diffuses through the plasma membrane and binds to the vitamin D receptor (VDR) in the cell nucleus, where the complex formed between vitamin D and VDR interacts with the vitamin D response elements in the genome. Vitamin D, through its active metabolites, affects the transcription of several genes, including the genes responsible for cell proliferation, differentiation, and apoptosis (Pike et al. 2016PIKE JW, MEYER MB, BENKUSK NA, LEE SM, JOHN AC, ONAL M & SHAMSUZZAMAN S. 2016. Genomic Determinants of Vitamin D-Regulated Gene Expression. Vitam Horm 100: 21-44.).

The active compounds of vitamin D, mainly calcitriol, are best known for their effects on calcium and phosphate absorption, activation of osteoclasts, and, therefore, on bone calcification and muscle strength (Bikle 2012BIKLE DD. 2012. Vitamin D and Bone. Curr Osteoporos Rep 10: 151-159.). However, vitamin D receptors are widely expressed and the tissues with the highest VDR content are the intestine, kidney, parathyroid gland, and bone, all associated with the maintenance of calcium homeostasis (Wang et al. 2012WANG Y, ZHU J & DELUCA HF. 2012. Where is the vitamin D receptor? Arch Biochem Biophys 523: 123-133.). Vitamin D receptors are also expressed by immune cells, where inactive forms of vitamin D are metabolized to their active forms, indicating a regulatory role for vitamin D in the innate immune system (immediate “nonspecific” response to pathogens) and adaptive (response specific to the antigen that follows the innate immune response) (Di Rosa et al. 2011DI ROSA M, MALAGUARNERA M, NICOLETTI F & MALAGUARNERA L. 2011. Vitamin D3: a helpful immuno-modulator. Immunology 134: 123-139.).

Vitamin D is a known regulator of innate immunity modulating the function of monocytes/macrophages and dendritic cells in response to infections. Therefore, vitamin D leads to the expression of several genes, mainly including the microbial proteins cathelicidin (CAMP) and β-defensin 2 (DEFB4) (Gombart et al. 2005GOMBART AF, BORREGAARD N & KOEFFLER HP. 2005. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 19: 1067-1077., Wang et al. 2005WANG TT ET AL. 2005. Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol 19: 2685-2695.). It increases the chemotaxis and the phagocytic capabilities of innate immune cells. (Gauzzi et al. 2005GAUZZI MC, PURIFICATO C, DONATO K, JIN Y, WANG L, DANIEL KC, MAGHAZACHI AA, BELARDELLI F, ADORINI L & GESSANI S. 2005. Suppressive Effect of 1α,25-Dihydroxyvitamin D3 on Type I IFN-Mediated Monocyte Differentiation into Dendritic Cells: Impairment of Functional Activities and Chemotaxis. J Immunol 174: 270-276., Xu et al. 1993XU H, SORURI A, GIESELER RK & PETERS JH. 1993. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class-II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 38: 535-540.). Additionally, vitamin D promotes an anti-inflammatory response by inhibiting the maturation of dendritic cells, negatively regulating antigen-presenting molecules (MHC-class II), co-stimulatory molecules (CD1a, CD14, CD40, CD80 and CD86) and pro-inflammatory cytokines (IL-12 and IL-23, IL-6 TNFα), while increasing the production of anti-inflammatory cytokine (IL-10 and TGFβ) and regulatory T cells (Treg) (Almerighi et al. 2009ALMERIGHI C, SINISTRO A, CAVAZZA A, CIAPRINI C, ROCCHI G & BERGAMINI A. 2009. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 45: 190-197., Pedersen et al. 2009PEDERSEN AW, HOLMSTRØM K, JENSEN SS, FUCHS D, RASMUSSEN S, KVISTBORG P, CLAESSON MH & ZOCCA MB. 2009. Phenotypic and functional markers for 1alpha,25-dihydroxyvitamin D(3)-modified regulatory dendritic cells. Clin Exp Immunol 157: 48-59., Quraishi et al. 2015QURAISHI AS, DE PASCALE G, NEEDLEMAN JS, NAKAZAWA H, KANEKI M, BAJWA EK, CAMARGO CA & BHAN I. 2015. Effect of cholecalciferol supplementation on vitamin D status and cathelicidin levels in sepsis: A randomized, placebo-controlled trial. Crit Care Med 43: 1928-1937., Unger et al. 2009UNGER WW, LABAN S, KLEIJWEGT FS, VAN DER SLIK AR & ROEP BO. 2009. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur J Immunol 39: 3147-3159.). Vitamin D also acts on the adaptive immune system by modulating the function of CD4 + T cell and B cell in response to infections. Thus, vitamin D reduces the proliferation of auxiliary T cells of the Th1/Th17 type, inhibiting the production of inflammatory cytokines including IL-2, IFNγ, IL-17 and IL-22, in addition to increasing the anti-inflammatory cytokines associated with Th2 cells (IL-5, IL-10, IL-4, IL-13) (Alroy et al. 1995ALROY I, TOWERS TL & FREEDMAN LP. 1995. Transcriptional repression of the interleukin-2 gene by vitamin D3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 15: 5789-5799., Jeffery et al. 2009JEFFERY LE, BURKE F, MURA M, ZHENG Y, QURESHI OS, HEWISON M, WALKER LSK, LAMMAS DA, RAZA K & SANSOM DM. 2009. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183: 5458-5467., Joshi et al. 2011JOSHI S ET AL. 2011. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 31: 3653-3669., Lemire et al. 1985LEMIRE JM, ADAMS JS, KERMANI-ARAB V, BAKKE AC, SAKAI R & JORDAN SC. 1985. 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 134: 3032-3035.). Vitamin D also acts on B cells, causing apoptosis, differentiation of impaired plasma cells, inhibition of the formation of memory B cells and increased production of IL-10 (Terrier et al. 2012TERRIER B ET AL. 2012. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther 17(14): R221.). Figure 2 summarizes the main effects of vitamin D on the innate and adaptive immune system. Additional details can be found in the works of Chirumbolo et al. (2017)CHIRUMBOLO S, BJØRKLUND G, SBOARINA A & ANTONIO VELLA A. 2017. The Role of Vitamin D in the Immune System as a Pro-survival Molecule. Clin Ther 39: 894-916., Chun et al. (2014)CHUN RF, LIU PT, MODLIN RL, ADAMS JS & HEWISON M. 2014. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol 5: 151., Sassi et al. (2018)SASSI F, TAMONE C & D’AMELIO P. 2018. Vitamin D: Nutrient, Hormone, and Immunomodulator. Nutrients 10: 1656. and Jiménez-Sousa et al. (2018)JIMÉNEZ-SOUSA MÁ, MARTÍNEZ I, MEDRANO LM, FERNÁNDEZ-RODRÍGUEZ A & RESINO S. 2018. Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease. Front Immunol 9: 458..

Figure 2
Summary of the main effects of vitamin D on the innate and adaptive system. Adapted from Jiménez-Sousa et al. (2018)JIMÉNEZ-SOUSA MÁ, MARTÍNEZ I, MEDRANO LM, FERNÁNDEZ-RODRÍGUEZ A & RESINO S. 2018. Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease. Front Immunol 9: 458..

The discovery of the expression of nuclear vitamin D receptors and metabolic vitamin D enzymes in immune cells provides a scientific explanation for the potential role of vitamin D in maintaining immune homeostasis and preventing the development of autoimmune processes (Vanherwegen et al. 2017VANHERWEGEN AS, GYSEMANS C & MATHIEU C. 2017. Vitamin D endocrinology on the cross-road between immunity and metabolism. Mol Cell Endocrinol 453: 52-67.). Although vitamin D has been recognized mainly for bone metabolism, growing evidence indicates its proper function for almost all tissues in the body, including the brain, heart, lung, muscle, immune system, and skin (Mostafa & Hegazy 2015MOSTAFA WZ & HEGAZY RA. 2015. Vitamin D and the skin: Focus on a complex relationship: A review. J Adv Res 6: 793-804.). Therefore, vitamin D hormones have important functions, including immunomodulating, anti-inflammatory, and anti-infectious roles, performing important role in the immune system that are highly relevant to response to different pathogens.

Risks associated with vitamin D deficiency

The most accurate way to quantify vitamin D in the body is through biochemical tests that measure the levels of prehormones 25(HO)D2 and 25(HO)D3 produced by liver hydroxylation of vitamin D from the skin or intestine by ingestion of oral food or supplementation. The clinical advantages of these metabolic forms as markers of vitamin D status can be attributed to these metabolites being in higher concentration than all other vitamin D metabolites, their levels remaining stable for almost two weeks and, in addition, it is believed that vitamin D toxicity is a function of these pre-hormones (Rajasree et al. 2001RAJASREE S, RAJPAL K, KARTHA CC, SARMA PS, KUTTY VR, IYER CS & GIRIJA G. 2001. Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. Eur J Epidemiol 17: 567-571.).

It is important to note that there are at least three biological limitations impeding the achievement of a robust result in for determining vitamin D; these are represented by the hydrophobic nature of the compound with the tight binding to its carrier (vitamin D binding protein (DBP)), the different forms circulating in blood, and the issue of standardization. Furthermore, endogenous lipids may affect binding and chromatographic separation, as they co-extract from plasma and serum (Romagnoli et al. 2013ROMAGNOLI E, PEPE J, PIEMONTE S, CIPRIANI C & MINISOLA S. 2013. Value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol 169: 59-69.). Despite these limitations, the measurement of vitamin D levels is mainly carried out using two methodologies: i) competitive immunoassays, such as competitive protein-binding assays or radioimmunoassay (RIA), which do not differentiate between the 25(OH)D2 prehormones and 25(OH)D3; and ii) tests using high-performance liquid chromatography (HPLC) and direct detection with liquid chromatography coupled with mass spectrometry (LC/MS) which are highly sensitive and allow independent quantification of 25(OH)D2 and 25(OH)D3 (Holick 2009HOLICK MF. 2009. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 19: 73-78., Hollis 2010HOLLIS BW. 2010. Assessment and interpretation of circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in the clinical environment. Endocrinol Metab Clin North Am 39: 271-286.).

Different studies classify vitamin D levels, which are usually expressed in nanograms per milliliter (ng/mL) or nanomole per liter (nmol/L). Although there are some variations in these quantities and their classifications in different studies in the literature (Chang & Lee 2019CHANG SW & LEE HC. 2019. Vitamin D and Health - the Missing Vitamin in Humans. Pediatr Neonatol 60: 237-344., Holick & Chen 2008HOLICK MF & CHEN TC. 2008. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87: 1080-1086., Holick et al. 2011HOLICK MF, BINKLEY NC, BISCHOFF-FERRARI HA, GORDON CM, HANLEY DA, HEANEY RP, MURAD MH & WEAVER CM. 2011. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96: 1911-1930., Lips et al. 2019LIPS P, CASHMAN KD, LAMBERG-ALLARDT C, BISCHOFF-FERRARI HA, OBERMAYER-PIETSCH B, BIANCHI ML, JAN STEPAN J, FULEIHAN GE & BOUILLON R. 2019. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol 180: 23-54., Norman & Bouillon 2010NORMAN AW & BOUILLON R. 2010. Vitamin D nutritional policy needs a vision for the future. Exp Biol Med (Maywood) 235: 1034-1045.), the classification found in Table I is the most common (Alshahrani & Aljohani 2013ALSHAHRANI F & ALJOHANI N. 2013. Vitamin D: deficiency, sufficiency and toxicity. Nutrients 5: 3605-3616.). Thus, we consider that a value less than 20 ng/mL of 25[OH]D corresponds to vitamin D deficiency.

Table I
Classification of vitamin D levels in the body.

Several risk factors contribute to vitamin D deficiency, including lack of adequate sun exposure (UVB) (Van der Mei et al. 2007VAN DER MEI IA, PONSONBY AL, DWYER T, BLIZZARD L, TAYLOR BV, KILPATRICK T, BUTZKUEVEN H & MCMICHAEL AJ. 2007. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol 254: 581-590.), dark skin (Clemens et al. 1982CLEMENS TL, ADAMS JS, HENDERSON SL & HOLICK MF. 1982. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1: 74-76.), smoking (Brot et al. 1999BROT C, JORGENSEN NR & SORENSEN OH. 1999. The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr 53: 920-926.), living with air pollution (Agarwal et al. 2002AGARWAL KS, MUGHAL MZ, UPADHYAY P, BERRY JL, MAWER EB & PULIYEL JM. 2002. The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India. Arch Dis Child 87: 111-113.), winter, living in higher latitudes (Huotari & Herzig 2008HUOTARI A & HERZIG KH. 2008. Vitamin D and living in northern latitudes - an endemic risk area for vitamin D deficiency. Int J Circumpolar Health 67: 164-178.), and malabsorption syndromes (Dedeoglu et al. 2014DEDEOGLU M, GARIP Y & BODUR H. 2014. Osteomalacia in Crohn’s disease. Arch Osteoporos 9: 177.). Also, some pharmaceutical drugs activate the pregnane X receptor (PXR), reducing serum concentrations of vitamin D in the prehormonal form (Pascussi et al. 2005PASCUSSI JM ET AL. 2005. Possible involvement of pregnane X receptor– enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 115: 177-186., Gröber 2020GRÖBER U. 2020. Common drugs as vitamin D disruptors. J Transl Sci 6: 1-4.).

Since vitamin D has receptors in most types of tissue cells, regulating various biological pathways, vitamin D deficiency is associated with an increased risk of chronic diseases, including autoimmune diseases (Dankers et al. 2017DANKERS W, COLIN EM, VAN HAMBURG JP & LUBBERTS E. 2017. Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential. Front Immunol 7: 697.), various types of cancers (Weinstein et al. 2015WEINSTEIN SJ ET AL. 2015. Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer 136: 654-664.), cardiovascular diseases (Wang et al. 2008WANG TJ, PENCINA MJ, BOOTH SL, JACQUES PF, INGELSSON E, LANIER K, BENJAMIN EJ, D’AGOSTINO RB, WOLF M & VASAN RS. 2008. Vitamin D deficiency and risk of cardiovascular disease. Circulation 117: 503-511.), infectious diseases (Gois et al. 2017GOIS PHF, FERREIRA D, OLENSKI S & SEGURO AC. 2017. Vitamin D and Infectious Diseases: Simple Bystander or Contributing Factor? Nutrients 9: 651.), dementia and Alzheimer’s (Chai et al. 2019CHAI B, GAO F, WU R, DONG T, GU C, LIN Q & ZHANG Y. 2019. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol 19: 284.), schizophrenia (Yüksel et al. 2014YÜKSEL RN, ALTUNSOY N, TIKIR B, KÜLÜK MC, UNAL K, GOKA S, AYDEMIR C & GOKA E. 2014. Correlation between total vitamin D levels and psychotic psychopathology in patients with schizophrenia: therapeutic implications for add-on vitamin D augmentation. Ther Adv Psychopharmacol 4: 268-275.), myopia (Yazar et al. 2014YAZAR S ET AL. 2014. Myopia is associated with lower vitamin D status in young adults. Invest Ophthalmol Vis Sci 55: 4552-4559.), osteoporosis (Shahnazari et al. 2019SHAHNAZARI B, MOGHIMI J, FOROUTAN M, MIRMOHAMMADKHANI M & GHORBANI A. 2019. Comparison of the effect of vitamin D on osteoporosis and osteoporotic patients with healthy individuals referred to the Bone Density Measurement Center. Biomol Concepts 10: 44-50.), rickets (Thacher et al. 2006THACHER TD, FISCHER PR, STRAND MA & PETTIFOR JM. 2006. Nutritional rickets around the world: causes and future directions. Ann Trop Paediatr 26: 1-16.) and type 2 diabetes (Mattila et al. 2007MATTILA C, KNEKT P, MÄNNISTÖ S, RISSANEN H, LAAKSONEN MA, MONTONEN J & REUNANEN A. 2007. Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care 30: 2569-2570.).

It is important to mention that vitamin D deficiency (<20 ng/mL) is a public health problem that affects more than one billion people worldwide, with 50% of the population having vitamin D insufficiency (<30 ng/mL) (Holick 2010HOLICK MF. 2010. The vitamin D deficiency pandemic: a forgotten hormone important for health. Public Health Rev 32: 267-283.). Therefore, maintaining adequate levels of vitamin D in the body, either through exposure to solar radiation, a balanced diet, or through supplementation is essential to maintain the proper functioning of the body.

Sources of vitamin D and daily needs

The daily requirement for vitamin D is estimated between 5 and 20 micrograms, depending on age and physiological status. Ultraviolet radiation (UVB) is the main source of vitamin D, providing about 80% in the form of vitamin D3 (cholecalciferol) in healthy individuals up to 65 years of age. The rest is obtained from the diet or supplementation (Biesalski 2020BIESALSKI HK. 2020. Vitamin D deficiency and co-morbidities in COVID-19 patients - A fatal relationship? NFS J 20: 10-21.). However, with increasing age, the production of vitamin D in the skin, and the serum concentrations of 1α,25-dihydroxyvitamin D decrease considerably (McLaughlin & Holick 1985MCLAUGHLIN J & HOLICK MF. 1985. Aging decreases the capacity of human skin to produce Vitamin D3. J Clin Invest 76: 1536-1538.).

Several government agencies have established recommendations on the daily requirement for vitamin D based on different target populations. A detailed list involving recommendations in different countries was published by Bouillon (2017)BOUILLON R. 2017. Comparative analysis of nutritional guidelines for vitamin D. Nat Rev Endocrinol 13: 466-479.. An update of these recommendations was made available by Roth et al. (2018)ROTH DE ET AL. 2018. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad Sci 1430: 44-79. involving the main organizations. Table II summarizes the recommendations for vitamin D intake by age group.

Table II
Recommendations for vitamin D intake by age group. Adapted from Roth et al. (2018)ROTH DE ET AL. 2018. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad Sci 1430: 44-79..

It is not easy to get daily necessities from diet alone, as few foods contain vitamin D. Foods like salmon and other oily fish, cod liver oil, egg yolk, milk, and sun-dried mushrooms are the main natural sources of vitamin D (Schmid & Walther 2013SCHMID A & WALTHER B. 2013. Natural Vitamin D Content in Animal Products. American Society for Nutrition. Adv Nutr 4: 453-462.). The concentration in these foods is low and generally does not meet the daily requirement. However, the enrichment or fortification of staple foods with vitamin D, including mainly dairy products and flour products, can significantly increase their concentration (Pilz et al. 2018PILZ S ET AL. 2018. Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper. Front Endocrinol 9: 373.). Figure 3 shows the main sources of vitamin D and their quantities in international units (IU).

Figure 3
Main sources of vitamin D. Adapted from Holick (2007)HOLICK MF. 2007. Vitamin D deficiency. N Engl J Med 357: 266-281. and Schmid & Walther (2013)SCHMID A & WALTHER B. 2013. Natural Vitamin D Content in Animal Products. American Society for Nutrition. Adv Nutr 4: 453-462..

Evidence that vitamin D may be associated with a lower risk and severity of viral infections

In addition to the benefits of vitamin D for homeostasis, several in vitro and in vivo studies, including clinical trials of vitamin D supplementation, have extensively shown the characteristics of vitamin D against different respiratory viruses, such as respiratory syncytial virus (RSV) (Halasa et al. 2015HALASA N, WILLIAMS J, FAOURI S, SHEHABI A, VERMUND SH, WANG L, FONNESBECK C & KHURI-BULOS N. 2015. Natural history and epidemiology of respiratory syncytial virus infection in the Middle East: Hospital surveillance for children under age two in Jordan. Vaccine 33: 6479-6487.), human metapneumovirus (hMPV) (Hurwitz et al. 2017HURWITZ JL, JONES BG, PENKERT RR, GANSEBOM S, SUN Y, TANG L, BRAMLEY AM, JAIN S, MCCULLERS JA & ARNOLD SR. 2017. Retinol-binding protein and vitamin D levels are associated with severe outcomes in children hospitalized with lower respiratory tract infection and respiratory syncytial virus or human metapneumovirus detection. J Pediatr 187: 323-327.), human rhinovirus (HRV) (Schögler et al. 2015SCHÖGLER A ET AL. 2015. Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. Eur Respir J 47: 520-530.), influenza A (Urashima et al. 2010URASHIMA M, SEGAWA T, OKAZAKI M, KURIHARA M, WADA Y & IDA H. 2010. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 91: 1255-1260.), influenza H9N2 (Gui et al. 2017GUI B, CHEN Q, HU C, ZHU C & HE G. 2017. Effects of calcitriol (1,25-dihydroxy-vitamin D3) on the inflammatory response induced by H9N2 influenza virus infection in human lung A549 epithelial cells and in mice. Virol J 14: 10.), influenza H5N1 (Huang et al. 2020bHUANG F ET AL. 2020b. Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury. PLoS Pathog 16: e1008341.), and COVID-19 (Annweiler et al. 2020ANNWEILER G, CORVAISIER M, GAUTIER J, DUBÉE V, LEGRAND E, SACCO G & ANNWEILER C. 2020. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 12: E3377., Castillo et al. 2020CASTILLO MS, COSTA LME, BARRIOS JMV, DÍAZ JFA, MIRANDA JL, BOUILLON R & DOMEZ JMQ. 2020. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol 203: 105751.), in addition hepatitis C (Gal-Tanamy et al. 2011GAL-TANAMY M, BACHMETOV L, RAVID A, KOREN R, ERMAN A, TUR-KASPA R & ZEMEL R. 2011. Vitamin D: an innate antiviral agent suppressing hepatitis C vírus in human hepatocytes. Hepatology 54: 1570-1579.), rotavirus (Zhao et al. 2019ZHAO Y ET AL. 2019. Vitamin D Alleviates Rotavirus Infection through a Microrna-155-5p Mediated Regulation of the TBK1/IRF3 Signaling Pathway In Vivo and In Vitro. Int J Mol Sci 20: 3562.), human immunodeficiency virus (HIV) and M. tuberculosis (Campbell & Spector 2012CAMPBELL GR & SPECTOR SA. 2012. Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog 8: e1002689.), herpesvirus (Kumar et al. 2018KUMAR A, SINGH MP, KUMAR RS & RATHO RK. 2018. 25-Hydroxyvitamin D3 and 1,25-Dihydroxyvitamin D3 as an Antiviral and Immunomodulator Against Herpes Simplex Virus-1 Infection in HeLa Cells. Viral Immunol 31: 589-593.) and dengue virus (Martinez-Moreno et al. 2020MARTINEZ-MORENO J, HERNANDEZ JC & URCUQUI-INCHIMA S. 2020. Effect of high doses of vitamin D supplementation on dengue virus replication, Toll-like receptor expression, and cytokine profiles on dendritic cells. Mol Cell Biochem 464: 169-180.).

Although vitamin D has beneficial effects on various viral infections, Lee (2020)LEE C. 2020. Controversial Effects of vitamin D and related genes on viral infections, pathogenesis, and treatment outcomes. Nutrients 12: 962. highlights, in his extensive review about the role of vitamin D in the progression of viral diseases, that there are some inconsistent and, in some cases, contradictory results. In the case of acute respiratory tract infections, some studies have suggested that vitamin D supplementation does not prevent respiratory tract infection and can be harmful, especially for those who are not vitamin D deficient and/or those receiving bolus doses (Lehouck et al. 2012LEHOUCK A, MATHIEU C, CARREMANS C, BAEKE F, VERHAEGEN J, ELDERE JV, DECALLONNE B, BOUILLON R, DECRAMER M & JANSSENS W. 2012. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 156: 105-114., Manaseki-Holland et al. 2012MANASEKI-HOLLAND S, MAROOF Z, BRUCE J, MUGHAL MZ, MASHER MI, BHUTTA ZA, WALRAVEN G & CHANDRAMOHAN D. 2012. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. The Lancet 379: 1419-1427., Remmelts et al. 2013REMMELTS HHF, SPOORENBERG SMC, OOSTERHEERT JJ, BOS WJW, DE GROOT MCH & VAN DE GARDE EMW. 2013. The role of vitamin D supplementation in the risk of developing pneumonia: three independent case-control studies. Thorax 68: 990-996.).

On the other hand, population-based studies show positive associations between circulating vitamin D concentrations and lung function (Craveiro et al. 2018CRAVEIRO V, CABRAL M, ARAÚJO J, FALCÃO H, GUIMARÃES JT & RAMOS E. 2018. Association of sérum 25-hydroxyvitamin D concentration with pulmonary function in Young adults. Nutrients 10: 1728.). In addition, a recent meta-analysis concluded that serum vitamin D levels are inversely associated with the risk and severity of acute respiratory infections, indicating that hypovitaminosis D is a risk factor for respiratory infections (Pham et al. 2019PHAM H, RAHMAN A, MAJIDI A, WATERHOUSE M & NEALE RE. 2019. Acute Respiratory Tract Infection and 25-Hydroxyvitamin D Concentration: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health 16: 3020.). Another meta-analysis included randomized, double-blind, placebo-controlled clinical trials in which patients were supplemented with vitamin D3 or D2, and the effectiveness of the incidence of acute respiratory infections was verified. The study gathered 25 clinical trials with a total of 11,321 patients from 0 to 95 years of age. It was concluded that the administration of vitamin D daily or weekly was able to reduce the risk of acute respiratory infections among all patients. In addition, the authors concluded that the protective effects of vitamin D have better effects in patients who had precisely baseline levels of vitamin D <10 ng/mL (Martineau et al. 2017MARTINEAU AR ET AL. 2017. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 356: i6583.).

Vitamin D can reduce the risk of respiratory infections in three main ways: physical barrier, natural cellular immunity and adaptive immunity (Rondanelli et al. 2018RONDANELLI M, MICCONO A, LAMBURGHINI S, AVANZATO I, RIVA A, ALLEGRINI P, FALIVA MA, PERONI G, MARA M & PERNA S. 2018. Self-care for common colds: the pivotal role of vitamin D, vitamin C, zinc, and Echinacea in three main immune interactive clusters (physical barriers, innate and adaptive immunity) involved during na episode of common colds-Practical advice on dosages and on the time to take these nutrients/botanicals in order to prevent or treat common colds. Evid Based Complement Alternat Med 2018: 5813095.). In this way, studies have shown that immunomodulatory properties, which include negative regulation of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines, are the main route to mitigate the risk and severity of acute respiratory tract infections (Kong et al. 2013KONG J, ZHU X, SHI Y, LIU T, CHEN Y, BHAN I, ZHAO Q, RAVI THADHANI R & LI YC. 2013. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol 27: 2116-2125., Tsujino et al. 2019TSUJINO I, USHIKOSHI-NAKAYAMA R, YAMAZAKJ T, MATSUMOTO N & ICHIRO SAITO I. 2019. Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia. J Clin Biochem Nutr 65: 245-251.).

The active vitamin D-generating enzyme, 1α-hydroxylase (CYP27B1), is expressed by the airway epithelium, alveolar macrophages, dendritic cells, and lymphocytes, indicating that active vitamin D can be produced locally within the lungs. The effects of vitamin D in the lungs include increased secretion of the antimicrobial peptide cathelicidin, decreased production of chemokines (pro-inflammatory cytokines), inhibition of dendritic cell activation, and alteration of T cell activation (Hansdottir & Monick 2011HANSDOTTIR S & MONICK MM. 2011. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm 86: 217-237.). These cellular effects are important for the host’s responses to infections. The secretion of cathelicidins is one of the most important pathophysiological events, as these peptides have a direct antimicrobial effect against gram-positive and gram-negative bacteria, fungi, non-enveloped and enveloped viruses, such as the coronavirus (Herr et al. 2007HERR C, SHAYKHIEV R & BALS R. 2007. The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther 7: 1449-1461.).

Vitamin D can also reduce viral transmission and decrease lung damage by modulating the Renin-Angiotensin System (Yuan et al. 2007YUAN W, PAN W, KONG J, ZHENG W, SZETO FL, WONG KE, COHEN R, KLOPOT A, ZHANG Z & LI YC. 2007. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 282: 29821-29830.). In this sense, recent studies involving the administration of calcitriol in rats have shown that the clinical characteristics and the pathological changes of the lung tissues were notably lighter than the controls. It was noted that calcitriol in rats with lung injury decreased the concentration of angiotensin-converting enzyme (ACE) and the ACE/ACE2 ratio, in addition to increasing the concentration of angiotensin-converting enzyme II (ACE2) (Lin et al. 2016LIN M, GAO P, ZHAO T, HE L, LI M, LI Y, SHUI H & WU X. 2016. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep 43: 397-406., Yang et al. 2016YANG J, XU J & ZHANG H. 2016. Effect of Vitamin D on ACE2 and Vitamin D Receptor Expression in Rats with LPS-Induced Acute Lung Injury. Chin J Integr Med 25: 1284-1289.). An important study reported by Xu et al. (2017)XU J, YANG J, CHEN J, LUO Q, ZHANG Q & ZHANG H. 2017. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system. Mol Med Rep 16: 7432-7438. demonstrated that, in animal models with an acute respiratory syndrome, pretreatment with vitamin D reduced the transmission of the virus to the lungs by modulating the activity of the Renin-Angiotensin System and expression of ACE2. In that study, rats supplemented with vitamin D exhibited milder symptoms of the acute respiratory syndrome and moderate lung changes compared to controls. Cui et al. (2019)CUI C, XU P, LI G, QIAO Y, HAN W, GENG C, LIAO D, YANG M, CHEN D & JIANG P. 2019. Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: Role of renin-angiotensin system. Redox Biol 26: 101295. reported that calcitriol suppressed the angiotensin II receptor type 1 (AT1) and ACE and reduced the formation of angiotensin II in spontaneously hypertensive rats. According to these authors, ACE2 protects against acute lung injury and calcitriol has marked impacts on the ACE2/Ang-(1-7)/MAS axis with enhanced expression of ACE2.

Additionally, low serum vitamin D levels have been associated with acute respiratory tract infections (Ginde et al. 2009GINDE AA, MANSBACH JM & CAMARGO CA. 2009. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 169: 384-390., Kuwabara et al. 2020KUWABARA A, TSUGAWA N, AO M, OHTA J & TANAKA K. 2020. Vitamin D deficiency as the risk of respiratory tract infections in the institutionalized elderly: A prospective 1-year cohort study. Clin Nutr ESPEN 40 309-313.). Other trials have shown that treatment with high doses of vitamin D (250,000 to 500,000 IU) is safe in adult patients on mechanical ventilation and in critical condition. This treatment was associated with a shorter hospital stay, improved blood capacity to carry oxygen, and increased hemoglobin levels (Han et al. 2016HAN JE ET AL. 2016. High dose vitamin D administration in ventilated intensive care unit patients: a pilot double blind randomized controlled Trial. J Clin Transl Endocrinol 4: 59-65., Smith et al. 2018SMITH EM, JONES JL, HAN JE, ALVAREZ JA, SLOAN JH, KONRAD RJ, ZUGHAIER SM, MARTIN GS, ZIEGLER TR & TANGPRICHA V. 2018. High-dose vitamin D3 administration is associated with increases in hemoglobin concentrations in mechanically ventilated critically Ill adults: a pilot double-blind, randomized, placebo-controlled trial. JPEN J Parenter Enter Nutr 42: 87-94.).

Structure of SARS-CoV-2 and its relationship to the Renin-Angiotensin System

Phylogenetic analyses of the coronavirus genomes revealed that SARS-CoV-2 belongs to the family Coronaviridae and is a member of the genus betacoronavirus. It is a single-stranded RNA virus, positive polarity, enveloped, and basically consisting of four structural proteins that perform different functions. The name coronavirus derives from the crown of tips, seen in electron microscopy images, consisting of a glycoprotein called spike, which has two domains. The S1 domain or receptor-binding domain (RBD) is responsible for recognizing the virus at the transmembrane ACE2 receptor, while the S2 domain is responsible for fusing the virus with cell membranes (Lu et al. 2020LU R ET AL. 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 395: 565-574.) (Figure 4). It is important to mention that SARS-CoV-2 enters the cell only when this virus binds to the transmembrane ACE2. The presence of soluble ACE2 can prevent the virus from binding to the transmembrane ACE2, preventing its entry into the cell and can also activate antibodies against this virus (Kruse 2020KRUSE RL. 2020. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res 9: 72.).

Figure 4
General structure of SARS-CoV-2 and its interaction with ACE2. The structure of the complex formed between the spike protein and its RBD domain with the ACE2 receptor was obtained from the protein database (PDB 2020PDB – PROTEIN DATA BANK. https://www.rcsb.org/structure/6CS2. (accessed september 23, 2020).
https://www.rcsb.org/structure/6CS2...
), determined by Kirchdoerfer et al. (2018)KIRCHDOERFER RN, WANG N, PALLESEN J, WRAPP D, TURNER HL, COTTRELL CA, CORBETT KS, GRAHAM BS, MCLELLAN JS & WARD AB. 2018. Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis. Sci Rep 8: 15701..

Angiotensin-converting enzyme 2 (ACE2) is part of the renin-angiotensin-aldosterone system, which is a regulatory system for body fluid homeostasis and inflammatory responses (Ocaranza et al. 2019OCARANZA MP, RIQUELME JA, GARCÍA L, JALIL JE, CHIONG M, SANTOS RAS & LAVANDERO S. 2019. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 17: 116-129.). Briefly, the functioning of this system begins with the secretion of renin by renal juxtaglomerular cells. Renin converts angiotensinogen to angiotensin I (ang I), which is inactive, and by the action of the angiotensin-converting enzyme (ACE) is converted to angiotensin II (ang II). Angiotensin I can be converted to angiotensin 1-9 [(ang-(1-9)] via the enzyme ACE2. In turn, angiotensin 1-9 can be converted to angiotensin 1-7 [(ang-(1-7)] by the action of ACE enzymes and neutral endopeptidase (NEP). Also, angiotensin I can be converted directly into angiotensin 1-7 using the enzymes NEP and prolyl endopeptidase (PEP). Besides, angiotensin II can also be converted to angiotensin 1-7 by the action of ACE2 (Figure 5). When angiotensin II binds to its AT1-type receptor, in addition to vasoconstriction, a series of inflammatory effects occur, damaging tissues, including kidney, heart, and lung damage. On the other hand, when angiotensin 1-7 binds to its MAS receptor, it triggers opposite effects, such as vasodilation, anti-inflammatory, antifibrogenic, cardioprotective, nephroprotective, and protection against lung injuries (Gheblawi 2020GHEBLAWI M. 2020. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circ Res 126: 1457-1475., Kai & Kai 2020KAI H & KAI M. 2020. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 43: 648-654., Silva & Flynn 2012SILVA ACS & FLYNN JT. 2012. The renin-angiotensin-aldosterone system in 2011: role in hypertension and chronic kidney disease. Pediatr Nephrol 27: 1835-1845., Verdecchia et al. 2020VERDECCHIA P, CAVALLINI C, SPANEVELLO A & FABIO ANGELI F. 2020. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 76: 14-20.).

Figure 5
General overview of the renin-angiotensin system.

Once the virus binds to transmembrane ACE2, there is a decrease in the expression of this enzyme, including soluble ACE2, which is derived from transmembrane ACE2. Therefore, there is less conversion of angiotensin II to angiotensin 1-7, increasing lesions in various tissues/organs, and leading to greater severity of COVID-19 (Vaduganathan et al. 2020VADUGANATHAN M, VARDENY O, MICHEL T, MCMURRAY JJV, PFEFFER AM & SOLOMON SD. 2020. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 382: 1653-1659.). In addition, as ACE2 is expressed in various tissues, including the epithelial cells of the lungs, intestines, kidneys, and blood vessels, therefore, these tissues/organs are vulnerable to infection by the new SARS-CoV-2 (Sungnak et al. 2020SUNGNAK W ET AL. 2020. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 26: 681-687., Zou et al. 2020ZOU X, CHEN K, ZOU J, HAN P, HAO J & HAN Z. 2020. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 14: 185-192.). Thus, the new coronavirus can be considered a systemic virus, leading to multiple organ dysfunction and not just a cause of respiratory diseases.

A potential adjuvant is vitamin D, since supplementation of hospitalized patients with COVID-19 has been associated and less disease severity (Annweiler et al. 2020ANNWEILER G, CORVAISIER M, GAUTIER J, DUBÉE V, LEGRAND E, SACCO G & ANNWEILER C. 2020. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 12: E3377., Castillo et al. 2020CASTILLO MS, COSTA LME, BARRIOS JMV, DÍAZ JFA, MIRANDA JL, BOUILLON R & DOMEZ JMQ. 2020. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol 203: 105751.).

Possible action of vitamin D against SARS-CoV-2 and COVID-19

In general, when the SARS-CoV-2 virus is inhaled, it binds to the transmembrane ACE2 through its spike protein, forming a complex that is the target of transmembrane serine protease 2 (TMPRSS2). TMPRSS2 is responsible for activating the spike protein, resulting in the fusion of the virus with the cell membrane for entry of the viral RNA into the host cell, initiating its processes of replication, injury, and contamination of other cells (Hoffmann et al. 2020HOFFMANN M ET AL. 2020. SARS-CoV-2 Cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271-280., Rabi et al. 2020RABI FA, AL ZOUBI MS, KASASBEH GA, SALAMEH DM & AL-NASSER AD. 2020. SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far. Pathogens 9: 231.).

In the early stages of viral infection, the protective immune response is responsible for eliminating the virus and, in most cases, patients recover without further complications. However, as the disease progresses and reaches the pulmonary alveoli, causing alveolar damage due to the release of proinflammatory cytokines, immune system cells are recruited to these sites, creating a fluid with a high content of serum proteins and leukocytes. At this stage, gas exchange is compromised, as well as all dependent processes. At this stage of inflammation, a dysfunctional immune response occurs that triggers the release of several cytokines, a process known as a “cytokine storm” (Tang et al. 2020TANG Y, LIU J, ZHANG D, XU Z, JI J & WEN C. 2020. Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies. Front Immunol 10(11): 1708.).

Several studies have shown that the severity of COVID-19 is determined by the presence of pneumonia, severe acute respiratory distress syndrome, myocarditis, microvascular thrombosis, and/or cytokine storms. All involving underlying inflammation due to increased generation of pro-inflammatory cytokines (Wang et al. 2020aWANG D ET AL. 2020a. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavírus-infected pneumonia in Wuhan, China. JAMA 323: 1061-1069.). In view of these lesions, the main defense against uncontrolled inflammation and viral infection, in general, is provided by the action of regulatory T lymphocytes (Tregs), but in patients with COVID-19, a common feature is a lymphopenia, making patients still most vulnerable (Chen & Wherry 2020CHEN Z & WHERRY EJ. 2020. T cell responses in patients with COVID-19. Nat Rev Immunol 20: 529-536., Yang et al. 2020YANG L, LIU S, LIU J, ZHIXIN Z, XIAOCHUN W, BO H, YOUHAI C & YI Z. 2020. COVID-19: immunopathogenesis and Immunotherapeutics. Sig Transduct Target Ther 5: 7-25.). In addition, during the cytokine storm, patients infected with COVID-19 showed high concentrations of interleukin (IL)-1, IL-1B, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), interferon-γ inducible protein 10 (IP-10), macrophage inflammatory protein 1-α (MIP-1α), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and IFN-γ (Conti et al. 2020CONTI P, RONCONI G, CARAFFA A, GALLENGA CE, ROSS R, FRYDAS I & KRITAS SK. 2020. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 34: 327-331., Huang et al. 2020aHUANG C ET AL. 2020a. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395: 497-506.).

A potentially important alternative pathway that can mitigate the severity of COVID-19 is vitamin D supplementation since studies have shown that vitamin D supplementation can increase Treg levels (Fisher et al. 2019FISHER SA, RAHIMZADEH M, BRIERLEY C, GRATION B, DOREE C, KIMBER CE, CAJIDE AP, LAMIKANRA AA & ROBERTS DJ. 2019. The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A systematic review. PLoS ONE 14: e0222313., Prietl et al. 2014PRIETL B, TREIBER G, MADER JK, HOELLER E, WOLF M, PILZ S, GRANINGER WB, OBERMAYER-PIETSCH BM & PIEBER TR. 2014. High-dose cholecalciferol supplementation significantly increases peripheral CD4+ Tregs in healthy adults without negatively affecting the frequency of other immune cells. Eur J Nutrition 53: 751-759.) and also mitigate the cytokine storm in patients with the respiratory syndrome (Khoo et al. 2011KHOO AL, CHAI LY, KOENEN HJ, SWEEP FCG, JOOSTEN I, NETEA MG & VAN DER VEN AJAM. 2011. Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol 164: 72-79.). Recently, vitamin D has been shown to regulate the response of auxiliary CD4+ T lymphocytes to suppress the gene expression of pro-inflammatory cytokines, such as IFN-γ and IL-17, and in addition to inducing anti-inflammatory cytokines, such as IL-10, suppresses Th1 type cytokines and Th3 type cytokines, such as IL17A, IL17F, IL22 and IL26. (R. McGregor et al. unpublished data) Additionally, vitamin D decreases the generation of TNFα and nuclear factor-κB (NFκB) (Peterson & Heffernan 2008PETERSON CA & HEFFERNAN ME. 2008. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm (Lond) 5: 10., Talmor et al. 2008TALMOR Y, BERNHEIM J, KLEIN O, GREEN J & RASHID G. 2008. Calcitriol blunts pro-atherosclerotic parameters through NFkappaB and p38 in vitro. Eur J Clin Invest 38: 548-554.), in addition to inhibiting the action of the inflammatory cytokine IL-2 (Provvedini et al. 1983PROVVEDINI DM, TSOUKAS CD, DEFTOS LJ & MANOLAGAS SC. 1983. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221: 1181-1183., Tsoukas et al. 1984TSOUKAS CD, PROVVEDINI DM & MANOLAGAS SC. 1984. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science 224: 1438-1440.). Thus, vitamin D can mitigate the deleterious effects of the cytokine storm in patients with COVID-19.

It is also important to highlight that the Renin-Angiotensin System (RAS) is involved in the pathogenesis of COVID-19 and that vitamin D can play an important role against inflammatory lesions caused by hyperactivation of the Renin-Angiotensin System. Under normal RAS conditions, ACE2 is highly expressed in the lungs, in order to balance the higher levels of angiotensin II produced by ACE. Coronavirus studies have shown that viral replication can down-regulate ACE2 (Dijkman et al. 2012DIJKMAN R, JEBBINK MF, DEIJS M, MILEWSKA A, PYRC K, BUELOW E, VAN DER BIJL A & VAN DER HOEK L. 2012. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol 93: 1924-1929.). A gradual depletion of ACE2 during the progression of SARS-CoV-2 infection can unbalance RAS and lead to its activation. It is important to note that RAS activation in pulmonary fibrosis can be induced by chronic vitamin D deficiency (Shi et al. 2017SHI Y, LIU T, YAO L, XING Y, ZHAO X, FU J & XUE X. 2017. Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system. Sci Rep 7: 1-10.).

Low levels of vitamin D cause increased plasma renin activity, higher concentrations of angiotensin II and higher RAS activity, increasing inflammation, and damage to various organs (Forman et al. 2010FORMAN JP, WILLIAMS JS & FISHER ND. 2010. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 55: 1283-1288.). On the other hand, it has been shown that vitamin D suppresses renin activity, reduces the expression of ACE, reduces the production of angiotensin II, in addition to increasing the production of soluble ACE2, reducing inflammatory lesions (Lin et al. 2016LIN M, GAO P, ZHAO T, HE L, LI M, LI Y, SHUI H & WU X. 2016. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep 43: 397-406., Xu et al. 2017XU J, YANG J, CHEN J, LUO Q, ZHANG Q & ZHANG H. 2017. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system. Mol Med Rep 16: 7432-7438.). Therefore, vitamin D acts by negatively regulating RAS, modulating the expression of its components: renin, ACE, and ACE2. Vitamin D suppresses the transcription of the renin gene, blocking the activity of the cyclic AMP response element in the promoter of the renin gene and in the cascade ACE/Ang II/AT1 (Kong et al. 2013KONG J, ZHU X, SHI Y, LIU T, CHEN Y, BHAN I, ZHAO Q, RAVI THADHANI R & LI YC. 2013. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol 27: 2116-2125., Yuan et al. 2007YUAN W, PAN W, KONG J, ZHENG W, SZETO FL, WONG KE, COHEN R, KLOPOT A, ZHANG Z & LI YC. 2007. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 282: 29821-29830.), in addition to inducing activity of the axis ACE2/Ang-(1-7)/MAS (Xu et al. 2017XU J, YANG J, CHEN J, LUO Q, ZHANG Q & ZHANG H. 2017. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system. Mol Med Rep 16: 7432-7438.). This leads, for example, to a decrease in pro-inflammatory cytokines and an increase in antiviral and antibacterial peptides, such as defensin β2 and cathelicidin (Mahdavi 2020MAHDAVI AM. 2020. A brief review of interplay between vitamin D and angiotensinconverting enzyme 2: Implications for a potential treatment for COVID-19. Rev Med Virol 30: e2119.). A graphical overview of these events can be seen in Figure 6. Therefore, a adjuvant therapeutic approach to address COVID-19 and induced ARDS is to target the unbalanced negative regulation of RAS and ACE2 with vitamin D in SARS-CoV-2 infection.

Figure 6
Possible action of vitamin D on RAS and COVID-19. Adapted from Mahdavi (2020)MAHDAVI AM. 2020. A brief review of interplay between vitamin D and angiotensinconverting enzyme 2: Implications for a potential treatment for COVID-19. Rev Med Virol 30: e2119..

Aygun (2020)AYGUN H. 2020. Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn-Schmiedeberg’s Arch Pharmacol 393: 1157-1160. gathered important evidence that guides a possible role of vitamin D in coping with COVID-19 (Figure 7).

Figure 7
Possible role of vitamin D in face of COVID-19.

Evidence that vitamin D helps to combat COVID-19

A series of studies reported below indicate that vitamin D deficiency may be associated with greater severity of COVID-19 and that supplementation with vitamin D may mitigate the severity of this disease.

A study conducted at the Medical University of Chicago, from March 3 to April 10, 2020, sought to analyze whether deficiency and vitamin D treatment were associated with a positive test for COVID-19. That study included 489 patients with an average age of 49.2 ± 18.4 years and with vitamin D levels measured within 1 year before being tested for COVID-19. The relative risk of a positive test for COVID-19 was 1.77 times higher for patients with probable vitamin D deficiency (<20 ng/mL) compared to non-deficient patients (>20 ng/mL) of vitamin D (Meltzer et al. 2020MELTZER DO, BEST TJ, ZHANG H, VOKES T, ARORA V & SOLWAY J. 2020. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Network Open 3: e2019722.).

In the study by F.H. Lau et al. (unpublished data), the medical records of patients with COVID-19 between March 27 to April 21, 2020, were reviewed retrospectively. 20 patients with identified serum vitamin D levels were included in the study, 13 of whom were admitted to the ICU. The prevalence of vitamin D insufficiency in patients in the ICU was 84.6%, against 57.1% in patients not admitted to the ICU. In addition, 100% of ICU patients under 75 years of age had insufficient vitamin D; 62.5% had coagulopathy and 92.3% were lymphocytopenic.

A Swiss retrospective study conducted by D’Avolio et al. (2020)D’AVOLIO A, AVATANEO V, MANCA A, CUSATO J, DE NICOLÒ A, LUCCHINI R, FRANCO KELLER F & CANTÙ M. 2020. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients 12: 1359., between March 1 and April 14, 2020, assessed serum vitamin D levels in 107 patients with the acute respiratory syndrome and aged 63 to 81 years. Among these patients, those who tested positive for COVID-19 (27 patients) had low average levels of vitamin D (11.1 ng/mL), while patients who tested negative for COVID-19 (80 patients) had average vitamin D levels of 24.6 ng/mL.

Abrishami et al. (2020)ABRISHAMI A, DALILI N, TORBATI PM, ASGARI R, ARAB-AHMADI M, BEHNAM B & SANEI-TAHERI M. 2020. Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study. Eur J Nutr 30: 1-9. evaluated the possible existence of an interaction between serum 25(OH)D concentrations and the extent of pulmonary involvement and clinical evolution in patients with COVID-19. Demographic and clinical data, serum levels of 25(OH)D and chest computed tomography were evaluated in 73 individuals with confirmed diagnosis of COVID-19. The average age of patients was 55.18 ± 14.98 years, where 46.4% were male. It was found that the mean serum concentration of 25(OH)D was lower in patients who died (13.83 ± 12.53 ng/mL) compared to patients who were discharged (38.41 ± 18.51 ng/mL). In addition, higher levels of 25(OH)D were associated with less extent of lung involvement and less risk of death.

Ferrari & Locatelli (2020)FERRARI D & LOCATELLI M. 2020. No significant association between vitamin D and COVID-19. A retrospective study from a northern Italian hospital. Int J Vitam Nutr Res 2: 1-4. retrospectively analyzed vitamin D levels in 347 patients admitted to a hospital in northern Italy with suspected COVID-19, with 128 positive and 219 negative for COVID-19. The average age of patients was 62.28 ± 17.40 years, where 57.7% were male. It was found that there was no significant difference in the average levels of vitamin D in the two groups: 21.8 ± 16.1 ng/mL and 22.8 ± 14.0 ng/mL for the positive and negative groups, respectively. Since most patients had vitamin D insufficiency (<30 ng/mL), it was concluded that vitamin D supplementation, restoring normal levels, could be beneficial in reducing the risk of infection.

In a population-based Israeli study conducted between February 1 to April 30, 2020, the association of plasma vitamin D level with the likelihood of coronavirus infection and hospitalization for COVID-19 was assessed. The study included 14,832 people, of whom 7,807 were tested positive for COVID-19. It was concluded that plasma levels of vitamin D below ideal (30 ng/mL) may be a potential risk factor for COVID-19 infection, particularly for the high risks of hospitalization (Merzon et al. 2020MERZON E, TWOROWSKI D, GOROHOVSKI A, VINKER S, COHEN AG, GREEN I & MORGENSTERN MF. 2020. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. FEBS J 287: 3693-3702.). However, in a similar study conducted in the United Kingdom, no evidence was found to support a potential link between vitamin D concentrations and the risk of COVID-19 infection (Hastie et al. 2020HASTIE CE ET AL. 2020. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 14: 561-565.). But, this latest study is limited by the use of historical vitamin D measurements from 2006 to 2010 and may not reflect vitamin D concentrations in the current pandemic. In addition, two ecological studies have reported inverse correlations between estimates of vitamin D level with COVID-19 incidence and mortality in a total of 21 countries in Europe (Ilie et al. 2019ILIE PC, STEFANESCU S & SMITH L. 2019. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 6: 1-4., Laird et al. 2020LAIRD E, RHODES J & KENNY RA. 2020. Vitamin D and Inflammation: Potential Implications for Severity of Covid-19. Ir Med J 113: 81-88.). Besides that, several recent reports have found an inverse correlation between vitamin D levels and COVID-19 severity and mortality (A. Daneshkhah et al. unpublished data, Darling et al. 2021DARLING AL, AHMADI KR, WARD KA, HARVEY NC, COUTO ALVES A, DUNN-WATERS DK, LANHAM-NEW A, COOPER C & BLACKBOURN DJ. 2021. Vitamin D status, body mass index, ethnicity and COVID-19: Initial analysis of the first-reported UK Biobank COVID-19 positive cases (n 4643) compared with negative controls (n 1474). Proc Nutr Soc 80: E17., Jolliffe et al. 2021JOLLIFFE D ET AL. 2021. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol 9: 276-292., Kara et al. 2020KARA M, EKIZ T, RICCI V, KARA Ö, CHANG KV & ÖZÇAKAR L. 2020. ‘Scientific Strabismus’ or two related pandemics: coronavirus disease and vitamin D deficiency. Br J Nutr 124: 736-741.).

A systematic review and meta-analysis, described by Pereira et al. (2020)PEREIRA M, DANTAS DA, GALVÃO ALM, DE ALMEIDA OT & DA MOTA SJ. 2020. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr 4: 1-9., analyzed the association between vitamin D deficiency and COVID-19 severity, through an analysis of the prevalence of vitamin D deficiency and insufficiency in people with the disease. Inclusion criteria were observational studies measuring serum vitamin D in adults and the elderly with COVID-19, with 27 studies selected. It was concluded that vitamin D deficiency was not associated with an increased chance of COVID-19 infection, but in severe cases of the disease, vitamin D levels were 64% lower compared to mild cases. In addition, an insufficiency of vitamin D concentration increased COVID-19 hospitalization and mortality.

No large well-designed randomized controlled trial (RCT) has tested the effect of vitamin D supplements on COVID-19 outcomes yet. However, in hospital-based quasi-experimental study described by Annweiler et al. (2020)ANNWEILER G, CORVAISIER M, GAUTIER J, DUBÉE V, LEGRAND E, SACCO G & ANNWEILER C. 2020. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 12: E3377. 77 patients diagnosed with COVID-19 were divided into three groups: group 1 (29 patients, supplemented with vitamin D3 in the previous year); group 2 (16 patients, supplemented with vitamin D3 a few hours after the diagnosis of COVID-19) and group 3 (32 patients, not supplemented). In group 1, 93.1% of COVID-19 participants survived on the 14th day, compared with 81.2% of survivors in group 2 and 68.7% of survivors in group 3. It was concluded that vitamin D supplementation associated with COVID-19 decreased severity and increased survival in the elderly.

A pilot study was conducted to assess the clinical effectiveness of treating patients hospitalized for COVID-19 with calcifediol (25-hydroxyvitamin D3) in early stages of the disease. 76 patients were included in the study, 26 without treatment with calcifediol and 50 received treatment with calcifediol. Among the 26 patients not treated with calcifediol, 13 required admission to the ICU (50%), while of the 50 patients treated with calcifediol only 1 requested admission to the ICU, while the other patients remained in conventional admission. Of the patients treated with calcifediol, none died and all were discharged without complications, while of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged. It was concluded that the administration of calcifediol can improve the clinical outcome of individuals who require hospitalization for COVID-19 (Castillo et al. 2020CASTILLO MS, COSTA LME, BARRIOS JMV, DÍAZ JFA, MIRANDA JL, BOUILLON R & DOMEZ JMQ. 2020. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. J Steroid Biochem Mol Biol 203: 105751.).

It is important to highlight that, at the present moment, 45 clinical studies are underway in different regions of the world on the relationship between vitamin D and COVID-19. Such studies were recorded in the ClinicalTrials.gov (2020)CLINICALTRIALS.GOV. 2020. https://clinicaltrials.gov/ct2/home. (accessed December 1, 2020).
https://clinicaltrials.gov/ct2/home...
database, where different aspects of vitamin D in coping with COVID-19 are being analyzed.

Despite these advances, Martineau & Forouhi (2020)MARTINEAU AR & FOROUHI NG. 2020. Vitamin D for COVID-19: a case to answer? The Lancet 8: 735-736. highlight that vitamin D supplementation can be challenge in critically ill patients with COVID-19 for two reasons. The first is that patients tend to come to the hospital in the hyperinflammatory stage of the disease. Therefore, it may be too late for them to benefit from any antiviral effects induced by vitamin D supplementation. The other reason is that it may be difficult to show anti-inflammatory effects of vitamin D superior to dexamethasone, a glucocorticoid that has potent anti-inflammatory effects against severe cases of COVID-19.

Recommendations

Vitamin D deficiency and insufficiency are recognized as a public health problem, affecting many people around the world. In the current COVID-19 pandemic, social isolation measures have led people to adopt a new lifestyle, spending most of their time indoors with limited access to sunlight, which is the main natural source of vitamin D. Thus, due to the importance of vitamin D to the body and its role in helping viral diseases, especially in respiratory infections and possibly in the current COVID-19, it is essential to maintain adequate levels of vitamin D to avoid complications related to its deficiency.

Thus, safe exposure to sunlight is one of the first steps to increase vitamin D levels through dermal synthesis. In pandemic times, this can be done without leaving the house, in the garden, or on the balcony, with short and daily exposures. In order for the dermal synthesis to be efficient, the radiation must directly affect the skin (Webb & Engelsen 2006WEBB AR & ENGELSEN O. 2006. Calculated ultraviolet exposure levels for a healthy vitamin D status. Photochem Photobiol 82(6): 1697-1703., Webb 2006WEBB AR. 2006. Who, what, where and when-influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol 92: 17-25.). A nutritionally balanced diet is also important, including foods rich in vitamin D (Figure 3).

Adequate supplementation is an important option for rapidly increasing vitamin D levels and possibly mitigating the risk of infection and the severity of COVID-19 in the general population, especially in individuals positive for SARS-CoV-2 and professionals in the front line, who live in hospital environments with a high risk of infection. In this sense Grant et al. (2020)GRANT WB, LAHORE H, MCDONNELL SL, BAGGERLY CA, FRENCH CB, ALIANO JL & BHATTOA HP. 2020. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 12: e988. emphasize that hospitals are potentially infectious environments and recommend that during the COVID-19 epidemic, everyone in the hospital environment, including patients and staff, should take vitamin D supplements to increase its concentrations [40-50 ng/mL (100-125 nmol/L)] as an important step in preventing infection and spread. Recently, a pragmatic protocol performed in an Italian hospital on patients with COVID-19, suggested that patients with a vitamin D deficit <20 ng/mL should receive 50,000 IU/weekly, while patients with a deficit between 20 to <30 ng/mL should take 25,000 IU/weekly (Caccialanza et al. 2020CACCIALANZA R ET AL. 2020. Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol. Nutrition 74: 110835.).

It is important to mention that magnesium supplementation is recommended when taking vitamin D supplements. Magnesium helps to activate vitamin D since all enzymes that metabolize vitamin D seem to require magnesium, which acts as a cofactor in enzymatic reactions in the liver and kidneys. The recommended daily allowance of magnesium for adults is 310 to 420 mg/d (Uwitonze & Razzaque 2018UWITONZE AM & RAZZAQUE MS. 2018. Role of Magnesium in Vitamin D Activation and Function. J Am Osteopath Assoc 118: 181-189.).

Lanham-New et al. (2020)LANHAM-NEW SA ET AL. 2020. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutr Prev Health 3: 1-5. report that the UK Scientific Advisory Committee (SACN), the US Institute of Medicine (IOM), and the European Union’s European Food Safety Authority (EFSA) recommend that intake of vitamin D (total sum of food and supplements) should be limited to 4000 IU/day (100 µg/day) for adults. The authors also emphasize that there is a broad international consensus that the general public should avoid high-dose supplementation. Likewise, Hedlund et al. (2020)HEDLUND R, DIAMOND TK & UVERSKY VN. 2020. The latitude hypothesis, vitamin D, and SARS-Co-V2. J Biomol Struct Dyn 39(16): 1-3. suggest that vitamin D supplementation (400-4000 IU) is a safe intervention with great potential to reduce morbidity during the flu season and in the current COVID-9 pandemic. In addition, a meta-analysis study concluded that the effectiveness of vitamin D supplements in preventing acute respiratory tract infections was best demonstrated with the ingestion of low doses, to the detriment of the administration of large doses (Martineau et al. 2017MARTINEAU AR ET AL. 2017. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 356: i6583.). However, a clinical study reported that taking vitamin D supplementation from 4,000 to 10,000 IU/day for 6 weeks increases the baseline serum vitamin D concentration by 2 to 3 times, respectively, without adverse health effects (Charoenngam et al. 2020CHAROENNGAM N, SHIRVANI A, KALAJIAN TA, SONG A & HOLICK MF. 2020. The Effect of Various Doses of Oral Vitamin D3 Supplementation on Gut Microbiota in Healthy Adults: A Randomized, Double-blinded, Dose-response Study. Anticancer Res 40: 551-556.). Similarly, clinical studies of vitamin D supplementation in high doses, including 4,000-10,000 IU/day and 5,000-10,000 IU/day (McCullough et al. 2019MCCULLOUGH PJ, LEHRER DS & AMEND J. 2019. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol 189: 228-239.) have shown no adverse effects. However, these last two studies were carried out in patients who did not have infection with the new coronavirus.

Liu et al. (2020)LIU G, HONG T & YANG J. 2020. A Single Large Dose of Vitamin D Could be Used as a Means of Coronavirus Disease 2019 Prevention and Treatment. Drug Des Dev Ther 2020: 3429-3434. speculate that in patients with vitamin D deficiency or insufficiency, a single dose of 300,000 IU of vitamin D may play a role in the prevention and treatment of COVID-19. According to the authors, four weeks after administration, the serum concentration of 25(OH)D can be increased to about 60 ng/mL, and all patients have normal blood calcium levels.

However, while more data related to the effectiveness of vitamin D on COVID-19 is available, Trovas & Tournis (2020)TROVAS G & TOURNIS S. 2020. Vitamin D and COVID-19. Hormones 14: 1-2. recommend that the general population should take a daily supplement containing 800 to 1000 IU, which can confer a benefit and certainly cause no harm.

CONCLUSIONS

In this review we gathered an extensive set of information about vitamin D, highlighting its possible role against COVID-19. Several studies indicate that there is solid evidence that vitamin D acts in the regulation of the immune system and that hypovitaminosis D has an inverse relationship with acute respiratory infections and its greater severity. Besides, most of the studies indicate that the serum deficiency (<20 ng/mL) and insufficiency (<30 ng/mL) of vitamin D are associated with an increased risk of acute respiratory tract infections, including COVID-19 and supplementation for those with deficiency/insufficiency can improve the clinical picture of these diseases.

Vitamin D can reduce cytokine storm syndrome in patients with severe COVID-19 infection; induces the production of cathelicidin and defensins, which reduces the survival and replication of the virus; increases the level of soluble ACE2, reducing the virus from entering the cells; prevents the accumulation of angiotensin II and decrease its pro-inflammatory activity, suppressing the release of renin. Therefore, vitamin D can reduce the risk of injury to various tissues/organs, as well as the mortality and severity of patients with COVID-19.

In this sense, prophylaxis with vitamin D can reasonably serve as a highly accessible, natural, and economical adjuvant therapy to improve the immune response of patients, decrease the risk of infection by SARS-CoV-2 and improve the inflammatory lesions associated with COVID-19. Therefore, vitamin D prophylaxis can mitigate dependence on the use of antivirals, reduce hospitalizations and health costs, in addition to significantly improving quality of life, since hypovitaminosis D is associated with several pathologies. However, there is still no consensus on the adequate dose of vitamin D that can mitigate the severity of this disease. This may be associated with the heterogeneity of the affected populations and the risk factors that lead to greater vitamin D deficiency.

Although vitamin D’s role on COVID-19 is not yet fully understood and clinical studies are scarce, we believe that vitamin D supplementation, without overdosing, as part of standard nutrition can be effective in providing clinical benefit. In addition, it is essential to maintain adequate levels of vitamin D in the general population.

ACKNOWLEDGMENTS

The authors would like to thank the CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) development agencies (434012/2018-1) to PRONEM/ FACEPE (Programa de Apoio a Núcleos Emergentes/ Fundação de Amparo a Ciência e Tecnologia do Estado de Pernambuco) (APQ-0476-1.06/14) for the financial support and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for the scholarship granted.

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Publication Dates

  • Publication in this collection
    19 Aug 2022
  • Date of issue
    2022

History

  • Received
    30 Sept 2020
  • Accepted
    28 Jan 2021
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