key: cord-0842035-p9hqw4zb authors: Turrubiates-Hernández, Francisco Javier; Sánchez-Zuno, Gabriela Athziri; González-Estevez, Guillermo; Hernández-Bello, Jorge; Macedo-Ojeda, Gabriela; Muñoz-Valle, José Francisco title: Potential immunomodulatory effects of vitamin D in the prevention of severe coronavirus disease 2019: An ally for Latin America (Review) date: 2021-02-01 journal: Int J Mol Med DOI: 10.3892/ijmm.2021.4865 sha: ec45cfd144372ce03df7667515c277e95a3afe56 doc_id: 842035 cord_uid: p9hqw4zb Currently, the world is under a pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19). This disease is characterized by a respiratory syndrome that can progress to an acute respiratory distress syndrome. To date, limited effective therapies are available for the prevention or treatment of COVID-19; therefore, it is necessary to propose novel treatment options with immunomodulatory effects. Vitamin D serves functions in bone health and has been recently reported to exert protective effects against respiratory infections. Observational studies have demonstrated an association between vitamin D deficiency and a poor prognosis of COVID-19; this is alarming as vitamin D deficiency is a global health problem. In Latin America, the prevalence of vitamin D deficiency is unknown, and currently, this region is in the top 10 according to the number of confirmed COVID-19 cases. Supplementation with vitamin D may be a useful adjunctive treatment for the prevention of COVID-19 complications. The present review provides an overview of the current knowledge of the potential immunomodulatory effects of vitamin D in the prevention of COVID-19 and sets out vitamin D recommendations for the Latin American population. coronaviruses (coVs) belong to one of the four genera of the Coronaviridae family characterized by a positive-sense single-stranded RNA genome of ~30 kb (1) . Previously, coVs were considered serious pathogens in animals with low influence on human health (1) (2) (3) . However, at the beginning of the 21st century, the outbreak of the severe acute respiratory syndrome (SARS)-coV emerged, followed by the Middle East respiratory syndrome (MERS)-coV a decade later, confirming the animal-to-human and human-to-human transmission of coVs (1, 4, 5) . currently, the world is under a pandemic of the third wave of CoV, initially identified as 2019-novel coV that emerged in december 2019 in Wuhan, Hubei Province, China (6); following phylogeny analysis and taxonomy, and based on the established naming practice for viruses in this genus, the Coronaviridae Study Group of the International committee on Taxonomy Viruses termed the novel virus SARS-coV-2 (7) . Subsequently, on February 11, 2020, the World Health Organization (WHO) reported that the disease caused by SARS-coV-2 would be named coronavirus disease 2019 (cOVId-19) (8) . This disease is characterized by a respiratory syndrome that can progress to severe interstitial pneumonia and acute respiratory distress syndrome (ARdS) (9) (10) (11) . The causative agent of cOVId-19, SARS-coV-2, is transmitted mainly between individuals through contact, respiratory droplets and aerosols, allowing the virus to spread rapidly (8, 12) . The transmission rate of SARS-coV-2 has been reported to be higher compared with that of SARS-coV (R 0 =5.7 vs. ~3.0) (13, 14) . The mechanism of infection of SARS-coV-2 involves the spike protein of SARS-coV-2 binding to the angiotensin-converting enzyme 2 (AcE2) in the host lung epithelial cells to enter the cell and initiate infection (15, 16) . AcE2 expression levels are high in the intestine, heart, and kidneys; therefore, this virus compromises various organs (17) . The outbreak and rapid spread of SARS-coV-2 are a health threat with unprecedented consequences worldwide. On August 3, 2020, the Johns Hopkins university dashboard reported 18,282,208 confirmed cases and 693,694 deaths worldwide due to cOVId-19 (18) . On the same date, five Latin American countries (brazil, Mexico, Peru, chile and colombia) were among the top 10 countries with the highest number of confirmed cases, and three countries in this region (brazil, Mexico and Peru) were in the top 10 countries with the highest number of deaths (18) . To date, various factors have been identified as predisposing for an aggressive phenotype of cOVId-19, including the male sex, age >65 years, smoking and comorbidities such as diabetes, hypertension and cardiovascular disease (19) . The majority of these comorbidities are associated with a sedentary lifestyle and an unhealthy diet that is commonly characterized by a high intake of saturated fats, salt, sugars, refined grains and processed meats (20, 21) . A healthy diet is characterized by appropriate consumption of macronutrients and micronutrients, and is necessary for growth, development and adequate physiological functioning (21) . Nutrition is also essential for the function of the immune system; this relationship is currently being studied. Particularly, it has been reported that the Mediterranean diet, as well as nutrients and active food components can modulate the immune response through the inhibition of pro-inflammatory mediators, production of anti-inflammatory functions and participation in the communication between the innate and adaptive immune system (22) . For example, the Mediterranean diet (23) , vitamin d (24) , and polyunsaturated fatty acids (PUFAs) (25) have demonstrated promising effects on chronic inflammation and autoimmune diseases, whereas vitamin E (26) , zinc (27) and probiotics (28) exhibit effects in reducing infections. Immunonutrition is defined as the provision of nutrients in amounts greater than those typically recommended in a diet that modulates the immune system activity; immunonutrients include amino acids, PUFAs, short-chain fatty acids, vitamins and trace elements (29, 30) . In particular, vitamin d is a crucial immunonutrient that can be obtained through the diet; however, it is produced mostly (80%) endogenously by induction of ultraviolet-b (UV-b) rays in the skin (31) . Although the primary function of vitamin d appears to be calcium homeostasis, this vitamin also serves immunomodulatory functions and may have protective effects against respiratory infections (32) . Vitamin D deficiency is considered a public health problem worldwide; it is estimated that one billion individuals are deficient in vitamin D, and that insufficiency affects ~50% of the population (33) . Various factors influence vitamin D deficiency, such as age, geographic latitude and skin pigmentation (34) . In Latin American countries, vitamin D insufficiency has been suggested to be a potential public health problem; however, no representative data are available from this region, and the magnitude of the problem cannot be established (35) . based on the aforementioned information, the restoration of adequate serum levels of vitamin d through supplementation has demonstrated a protective effect against respiratory infections (32) . In addition, considering the lack of effective therapies for the prevention and treatment of cOVId-19, it is essential to propose novel therapeutic options. Therefore, the present review aims to overview the potential immunomodulatory effects of vitamin d in the prevention of cOVId-19 and to establish guideline recommendations for vitamin d supplementation for the Latin American population. Until late december 2019, only six coV species had been identified with implications for human health, of which four (229e, OC43, nL63, and HKu1) can cause mild symptoms such as the common cold (6) . currently, SARS-coV-2, in addition to the other two remaining coV strains (SARS-coV and MERS-coV), can cause fatal outcomes (6) . The genome of SARS-coV-2 shares 79% similarity with that of SARS-coV (36). The coV genome encodes four main proteins: Spike, membrane, nucleocapsid and envelope (1, 9) . The spike protein of the virus is responsible for the viral entry to the host cells by recognizing and binding to the AcE2 receptor, which is highly expressed in various types of cells, including type II alveolar and myocardial cells, as well as the proximal tubule cells of the kidney (17, 37, 38) . The virus spike protein binding with the AcE2 receptor is proteolytically processed by the transmembrane serine protease 2, which causes the cleavage of AcE2 and the activation of the virus spike protein to facilitate its entry to the target cell (16, 39) . Once inside the cell, the viral RNA genome is released into the cytoplasm to begin its replication process (40) . ARdS is one of the features of the severe cOVId-19 as the virus can negatively regulate the expression of AcE2, causing the upregulation of angiotensin II (Ang II), which interacts with the Ang II type 1 receptor (AT1R) to modulate the nuclear factor-κb (NF-κb) signaling pathway, as well as macrophage activation that leads to the excessive production of pro-inflammatory cytokines (41) . This exacerbated cytokine production is commonly referred to as a cytokine storm, which, in addition to contributing to ARdS, triggers a pathogenic inflammatory immune response that leads to multiple organ failure and death in severe cOVId-19 (41) (42) (43) . On march 11, 2020, the WHO classified COVID-19 as a pandemic due to the alarming worldwide spread of the virus and governments' inaction to prevent infection (8) . A number of Latin American countries are currently among the countries with the highest number of confirmed cases and deaths associated with cOVId-19 (18) . Vulnerability to cOVId-19 in Latin America is caused by various factors such as precarious health systems, housing conditions, high rates of non-communicable diseases, income inequality, and poverty levels (44, 45) . Although some countries in this region have already started vaccinating their population (costa Rica, Argentina, Mexico, and chile) (46) , accessibility and individual factors (socioeconomic, education, religious and cultural) may affect vaccine coverage (47) . clinical trials have been conducted to identify a treatment for cOVId-19; however, limited effective therapies are available for the prevention or treatment of this disease (48) (49) (50) (51) (52) . Furthermore, despite the current availability of vaccines, their distribution may not be equitable since during the 2009 H1n1 swine flu pandemic, countries with the highest economic position left the poorer countries with limited supplies (53, 54) . In addition, although health services in Latin America have notably improved since 1950, there are still deficiencies and inequity in health care (55) . Therefore, it is important to propose host-directed therapeutic alternatives of easy access such as immunonutrients that may modulate the immune response to minimize the mortality rate of SARS-coV-2 infection until a universal and effective solution is identified (56) . One of the immunonutrients that has received the most interest is vitamin D; the sufficiency in serum levels of this vitamin in individuals may lead to a less severe course of cOVId-19 and a faster recovery compared with that in individuals with vitamin D deficiency by helping prevent the cytokine storm, as well as ARdS, which is one of the leading causes of mortality among patients infected with SARS-coV-2 (57). Vitamin d is a fat-soluble vitamin present in two main isoforms; vitamin d 2 (ergocalciferol) which is mainly present in mushrooms, and vitamin d 3 (cholecalciferol), which is abundant in fish, egg yolk and liver (58) . Chylomicrons support intestinal absorption of both vitamin d isoforms; however, vitamin d 3 is more easily absorbed compared with vitamin d 2 (33, 58) . However, achieving the recommended vitamin D dose from food sources may be impossible for a large part of the population (31, 58) . As aforementioned, the major source of vitamin d for physiological functions is through synthesis in the epidermis from a cholesterol precursor (7-dehydrocholesterol) following exposure to UV-b radiation (290-320 nm) from the sun (31, 59) . This process induces to the formation of pre-vitamin d 3 , which isomerizes to vitamin d 3 in a thermo-sensitive process (60) . dietary or skin-synthesized vitamin d 3 binds to the vitamin d-binding protein (dbP), which transports it to the liver, where it is metabolized mainly by the enzyme vitamin d-25-hydroxylase to form calcidiol, also termed 25-hydroxyvitamin D [25(OH)D] (59) . subsequently, 25(OH)D is transformed in the kidneys by cytochrome P450 family 27 subfamily b member 1 (cYP27b1, also termed 25-hydroxyvitamin d-1α-hydroxylase) to obtain 1,25-dihydroxyvitamin D [1,25(OH) 2 D], also termed calcitriol, which is the main active form of vitamin d responsible for its physiological functions (59, 60) . In the regulation of calcitriol production, parathyroid hormone (PTH) has the ability to stimulate renal calcitriol production by activating cYP27b1, whereas fibroblast growth factor 23 (FGF-23) and calcitriol itself inhibit cYP27b1 (60,61). Similarly, high serum calcium and calcitriol concentrations inhibit cYP27b1 indirectly by suppressing PTH, and high serum phosphate concentration suppresses renal calcitriol production through the stimulation of FGF-23 (61). excess 1,25(OH) 2 d is excreted through the bile or urine as calcitroic acid ( Fig. 1) (31, 62) . calcitriol exerts its genomic functions through the vitamin d receptor (VdR), which acts as a transcription factor that forms a complex with the retinoid-X receptor (RXR); this complex recruits transcriptional coactivators or corepressors to regulate gene transcription by binding to vitamin d response elements (VdREs) in the dNA (59, 60) . In addition to the endocrine function of calcitriol in regulating calcium levels for bone remodeling, extrarenal hydroxylation occurs to form calcitriol, exerting paracrine and autocrine effects (61,63). Extrarenal hydroxylation by cYP27b1 occurs in the prostate, brain, placenta, lungs and immune cells (63) . In particular, VdR activation by locally produced calcitriol has been reported to mediate the immune response (62) (63) (64) , as discussed in the following sections. Among the most common viruses that affect human health through respiratory tract infections are influenza viruses, classified into four types. Influenza type A is the most common in seasonal epidemics and pandemics, and is the primary cause of a severe illness that is associated with high mortality rates in high-risk populations (adults >65 years, individuals with chronic diseases or immunosuppression, pregnant women, individuals with obesity and infants ≤6 months) (65) . The influenza viruses exhibit typical winter infection peaks in temperate zones (66) , which correspond to November to April and May to October in the northern and southern hemisphere, respectively (65) . by contrast, in tropical zones, the seasonality of influenza infections appears to be poorly defined, although it is assumed that it can occur throughout the year (65, 67) . In 1981, Hope-simpson (68) was the first to describe the association between influenza infection peaks and temperate latitudes in the winter. He proposed the existence of a seasonal stimulus associated with the seasonality of epidemic influenza, and that the decrease in solar radiation during winter influenced the presence of the seasonal stimulus. The study also suggested that, in the tropical regions, although UV-b radiation is less seasonal, influenza outbreaks are more severe during the rainy seasons. Thus, Hope-simpson described that latitude determined the time of epidemics in the annual cycle, since solar radiation may act positively or negatively on the virus, the host or their interaction (68) . After >20 years, cannell et al (69) proposed that vitamin d was a likely candidate to be the seasonal stimulus described by Hope-simpson. Since vitamin d 3 is obtained by sun exposure, the serum levels of 25(OH)D are lower in people who live in temperate latitudes, and because vitamin d has modulating effects on the immune system (69) . based on the aforementioned theories, it has been reported that the levels of UV-b radiation in countries outside the 40˚ n and 40˚ s latitude range are insufficient to produce vitamin d in the skin during winter (70). The average concentration of 25(OH)D in european countries during winter has been reported to be 11.6 ng/ml (29 nmol/l) (71), 14.3 ng/ml (35.75 nmol/l) (72) and 13.3 ng/ml (33.25 nmol/l) (73) . Similarly, in the northern and central regions of the United States of America, the concentration of 25(OH)D during winter is ~21 ng/ml (52.5 nmol/l), whereas in the summer, it is ~28 ng/ml (70 nmol/l) (74) . canada has reported that between december and January (winter), there is a peak in the prevalence of 25(OH)D insufficiency/deficiency in its population (75) . Although the influence of solar radiation on vitamin D deficiency is evident, several additional factors impact its deficiency, which will be discussed in subsequent sections. These factors can also affect the tropical zone population, such as that in Latin America, although the intensity of the sun rays in this region is greater (70). Other factors associated with the seasonality of respiratory infections include the congregation indoors during winter, which increases the probability of contagion, as well as the cold and dry conditions that contribute to the influenza transmission (69, 76, 77) . A recent meta-analysis of 14 observational studies has reported that a low serum concentration of 25(OH)D is a risk factor for acute respiratory tract infection (OR=1.83; 95% cI, 1.42-2.37; P-value for heterogeneity, <0.001) (78) . Similarly, in a sub-analysis of four studies, a low serum concentration of 25(OH)D was associated with high mortality from acute respiratory tract infection (OR=3.00; 95% cI, 1.89-4.78; P-value for heterogeneity, 0.029). Notably, the funnel plot in the aforementioned study identified evidence of publication bias (78) . by contrast, a meta-analysis of 25 randomized controlled trials has reported that vitamin d supplementation is associated with a lower risk of acute respiratory tract infections (OR=0.88; 95% cI, 0.81-0.96; P=0.003; P-value for heterogeneity, <0.001) (32). coVs cause respiratory infections ranging from the common cold to severe conditions such as pneumonia and ARdS (1,6,10). Therefore, the immunoregulatory effects of vitamin d are being discussed due to its potential beneficial effects for clinical outcomes in SARS-coV-2 infection. In the international platforms for the registration of clinical trials, a number of studies evaluating the effects of vitamin d supplementation on cOVId-19 have been registered, although the majority of these studies have not yet reported any results. despite this temporal limitation, numerous studies support the association between vitamin d and the clinical outcomes of cOVId-19. Among the observational studies published in the first semester of 2020, significant associations were reported between latitudes and mortality from cOVId-19, as well as between 25(OH)D deficiency and sArs-CoV-2 infection (57, (79) (80) (81) (82) (83) (84) . These studies are summarized in Table I . Studies from the second half of 2020 that include observational, quasi-experimental studies and clinical trials have also reported valuable information on the association between vitamin d and cOVId-19. A number of these studies are described below. Merzon et al (85) through an ecological study (secondary data analysis from population databases). The mean serum of 25(OH)D concentration was lower in the positive compared with the negative cOVId-19 cases (P=0.026). In addition, an association was demonstrated between 25(OH)D <30 ng/ml (<75 nmol/l) and the risk of infection by SARS-coV-2. Therefore, it was concluded that suboptimal plasma levels of 25(OH)D may be a potential risk factor for cOVId-19. Another study identified that the GT rs7041 genotype of the DBP gene may confer susceptibility to cOVId-19, whereas the TT rs7041 genotype may exert a protective effect (86) . The authors of the aforementioned study considered that polymorphisms in the DBP gene may alter the affinity of DbP for vitamin D metabolites, which may affect cOVId-19 prevalence and mortality. In a retrospective study, carpagnano et al (87) reported that patients with 25(OH)D concentration <10 ng/ml (25 nmol/l) had a 50% probability of mortality, whereas the risk for those with a concentration ≥10 ng/ml was only 5% (P=0.019). Therefore, the authors concluded that vitamin d deficiency may be a risk factor for mortality in patients with cOVId-19 (87) . Similar results were obtained in other studies, which reported that vitamin D deficiency significantly increased the risk of mortality from cOVId-19 (88, 89) . by contrast, Ling et al (90) reported no significant association between serum concentrations of 25(OH)D and COVID-19 mortality. However, multivariate analysis revealed that treatment with high-dose vitamin d 3 booster therapy reduced the risk of mortality (90) . Therefore, Ling et al (90) consider that vitamin d 3 , due to its low cost, may be a potential therapeutic option for cOVId-19 worldwide. A cross-sectional study reported vitamin d deficiency (<12 ng/ml; <30 nmol/l) in 15.6% of the samples from individuals with symptoms suggestive of cOVId-19, and the presence of antibodies to the SARS-coV-2 virus was higher in subjects with vitamin D deficiency compared with that in individuals with higher levels of 25(OH)D (P= 0.003) (91) . In addition, vitamin D deficiency was identified as an independent factor for seropositivity to SARS-coV-2 in subjects with cOVId-19 symptoms (91). Therefore, Faniyi et al (91) conclude that supplementation with vitamin d may be an adequate therapeutic strategy for preventing or alleviating cOVId-19. In a case-control study by Ye et al (92) , it was reported that patients with cOVId-19 presented with lower levels of 25(OH)D compared with those in healthy control subjects (P<0.05). A subsequent sub-group analysis comparing mild and severe COVID-19 cases identified a significant association between vitamin D deficiency and COVID-19 severity (92). A prospective cohort study comparing asymptomatic individuals (group A) vs. patients with severe cOVId-19 (group b) reported a lower concentration of 25(OH)D in group b (P= 0.0001). The incidence of vitamin D deficiency (<20 ng/ml; <50 nmol/l) and mortality were higher in group b compared with those in group A (93) . In a sub-analysis, patients with 25(OH)D concentration <20 ng/ml (50 nmol/l) presented with significantly higher serum concentrations of IL-6 (P=0.0300) and ferritin (P=0.0003) compared with those in patients with a concentration ≥20 ng/ml; thus, the authors concluded that vitamin D deficiency may increase the inflammatory status and the possibility of a severe cOVId-19 phenotype (93) . by contrast, another prospective cohort study (94) reported no associations between vitamin d deficiency and clinical features of patients with COVID-19; however, the authors suggested that this result may be due to the evaluated population mainly comprising comorbid elderly patients. In a quasi-experimental study by Annweiler et al (95) , 66 elderly patients (mean age, 87.7±9.0 years) with cOVId-19 residing in a nursing home were evaluated. The intervention group included patients who received an oral bolus of 80,000 IU (2,000 µg) vitamin d 3 as part of the routine maintenance treatment; the control group did not receive vitamin d 3 supplementation. The results demonstrated that vitamin d 3 had a protective effect on mortality, as the survival analysis revealed a shorter survival time among residents who did not receive vitamin d supplementation (P=0.002). Similar results were reported in another quasi-experimental study by Annweiler et al (96) . Additionally, it was suggested that long-term regular vitamin d supplementation may protect against infections such as SARS-coV-2 more effectively compared with oral bolus administered after cOVId-19 diagnosis (96) . An open-label clinical trial evaluated whether calcifediol treatment may reduce the need for admission of patients with cOVId-19 to the intensive care unit (IcU) (97) . The intervention group received calcifediol and standard treatment (azithromycin and hydroxychloroquine); the control group only received the standard treatment. The patients were followed-up until they were admitted to the IcU, discharged or succumbed to the disease. The probability of admission to the IcU was significantly lower in the intervention group (2%) compared with that in the control group (50%) (P<0.001) (97) . Therefore, Entrenas castillo et al (97) concluded that calcifediol may improve the clinical outcome of subjects with cOVId-19. Rastogi et al (98) conducted a clinical trial to evaluate the effects of high-dose vitamin d 3 on SARS-coV-2 viral clearance. Patients with mild symptoms or asymptomatic individuals positive for SARS-coV-2 infection and with vitamin d deficiency were randomly assigned to the intervention group to receive 60,000 IU (1,500 µg) of vitamin d 3 daily, or the control group, who received a placebo. The intervention was performed daily for 7 days. Patients who reached a concentration >50 ng/ml of 25(OH)D received only one additional dose of 60,000 IU, whereas those who did not reach the desired 25(OH)D levels received the same daily dose until day 14. The patients were evaluated periodically until day 21 or virus negativity. In the intervention group, ~63% of the subjects had a negative result for SARS-coV-2, whereas only 20.8% of those in the control group had this outcome (P=0.018). In addition, the intervention group presented with a more pronounced decrease in fibrinogen levels compared with that in the control group (P=0.001). No episodes of hypercalcemia were observed in the evaluated population (98) . Therefore, Rastogi et al (98) considered that vitamin d may reduce the transmission rates of SARS-coV-2 infection. A recent meta-analysis has reported that insufficient vitamin d levels increase the rates of hospitalization and mortality among patients with cOVId-19 (99) . Severe cases have a higher probability of vitamin D deficiency (Or=1.64; 95% cI, 1.30-2.09; I 2 =35.7%). Thus, vitamin d intervention as an adjunctive treatment may be crucial in severe cases of COVID-19 with low 25(OH)D levels. similarly, supplementation in therapeutic doses may be useful for the prevention of SARS-coV-2 infection, according to d'Avolio et al (81) , Meltzer et al (82) , Merzon et al (85) and Faniyi et al (91) , since the active metabolite of vitamin d exerts biological activities in the innate immune system, in particular, through the maintenance of the integrity of physical barriers and the promotion of antimicrobial peptides (64) . In addition, another meta-analysis has reported an association between low 25(OH)D levels and the risk of SARS-coV-2 infection (OR=1.43; 95% CI, 1.00-2.05) (100) . However, these results should be interpreted with caution due to the heterogeneity of the included studies (I 2 =64.9%; P=0.036) and the risk of publication bias. Finally, according to the meta-analysis by Martineau et al (32) , vitamin D supplementation did not significantly affect any types of adverse events. However, the individual recommendatios of vitamin d 3 for preventive or adjuvant treatment should be evaluated by a physician. Similarly, a consensus is considered necessary to propose public health policies for supplementation with this vitamin in risk groups. As aforementioned, vitamin D in its active form [1,25(OH) 2 d or calcitriol] binds to the VDr and rXr to regulate gene transcription. The classic functions of vitamin d are the regulation of calcium absorption, homeostasis, bone metabolism, cell growth and division (61). In addition, VdR is expressed in immune cells such as macrophages, dendritic cells (dcs), b and T lymphocytes, and neutrophils, suggesting that vitamin d may be an important regulator of the immune system (101, 102) . Physical barriers. Physical barriers are the first line of defense against infection. currently, the prevention and treatment of diseases focus on the preservation and restoration of the proper functioning of epithelial cells (103) . In the pulmonary epithelium, the severity of acute lung injury is associated with its barrier dysfunction (104) . To maintain the integrity of the alveolar wall, which forms a physical barrier against the external environment, the integrity of tight junctions (TJs) and adherens junctions (AJs) between the alveolar epithelial cells is essential (105) . Epithelial TJs create a barrier that regulates the paracellular permeability of small molecules (106) . The composition of TJs includes occludin, claudins and zonula occludens (zO) proteins (105) . AJs mainly comprise transmembrane proteins such as E-cadherin, as well as intracellular components (β-catenin and α-catenin), which regulate the adhesion of cells to their neighbors (105, 106) . A recent study has reported that in VdR -/mice, the mRNA levels of claudins 2, 4, 10, 12, 15, and 18, as well as the protein levels of claudins 2, 4, 12, and 18 were significantly decreased compared with those in wild-type (WT) mice (107) . In addition, another study reported a significant decrease in mrnA and protein levels of zO-1 and occludin in VDr -/compared with WT mice (108) . In both studies, VdR -/mice exhibited significant increases in the levels of inflammatory mediators compared with those in WT mice; therefore, these results suggest that VdR may serve a crucial role in maintaining lung permeability ( Fig. 2A) (107,108) . Innate immunity. The innate immune response is responsible for the early recognition of invading pathogens to prevent infection (109) . This action is mainly carried out by pathogen-recognition receptors, among which the Toll-like receptors (TLRs) are prominent (110) . In monocytes, the heterodimer TLR2/1 interaction with pathogens induces antimicrobial peptides such as β-defensins and human cathelicidin (LL-37), as well as the activation of autophagy and phagolysosomal fusion (109, 110) . These antimicrobial peptides neutralize infection by disturbing the pathogen membrane homeostasis and promoting autophagy (109, 111) . cathelicidin and autophagy complement each other to enhance pathogen clearance (110) . TLR activation induces the expression of cYP27b1 and VdR in monocytes; subsequently, locally produced 1,25(OH) 2 d exerts its function through VdRs to upregulate the expression of β-defensins and LL-37 (112) . This mechanism can also occur in epithelial cells of the intestine and the lungs, as well as in keratinocytes (111, 113, 114) . by contrast, it has been reported that the induction of cathelicidin in lung epithelial cells is independent of TLRs (111) . Previous studies have demonstrated that the antimicrobial activity of the innate immune response is partially dependent on vitamin d levels ( Fig. 2b) (115) (116) (117) . calcitriol can also alter the functioning of antigen-presenting cells, which are responsible for the initiation of the adaptive immune response. In particular, it has been described that 1,25(OH) 2 d can preserve an immature phenotype of dcs by reducing the expression of mHC class II molecules, as well as co-stimulatory molecules (cd80, cd86), which also results in a decline of IL-12 secretion (Fig. 2c) (118-121) . Adaptive immunity. Vitamin d also exerts immunomodulatory effects on the adaptive immune response. calcitriol has been reported to suppress the activity of type 1 T-helper (Th1) cells, achieving the repression of pro-inflammatory cytokine production, including IL-2 and IFNγ (111) . The repression of IL-2 production is mediated by the 1,25(OH) 2 d-VdR-RXR complex, which blocks the formation of the nuclear factor of activated T-cells (NFAT) and activator protein 1 complex (122). The 1,25(OH) 2 d-VdR-RXR complex binds to the IL-2 promoter to interrupt the function of NFAT (111) . by contrast, it has been reported that 1,25(OH) 2 d-VdR-RXR binds to the IFNγ promoter to interfere with its activation (123) . In addition, calcitriol affects the regulation of IL-17 in Th17 cells (124) . Although its mechanism is not yet fully understood, it has been suggested that 1,25(OH) 2 d inhibits the master regulator of Th17 cells. Additionally, the 1,25(OH) 2 d-VdR-RXR complex competes with NFAT for the IL-17A promoter; once the complex is bound, it recruits histone deacetylases to limit the transcription of this cytokine (124) (125) (126) . calcitriol has also been demonstrated to inhibit NF-κb via upregulation of Iκb expression or by interfering with the binding of NF-κb to dNA (Fig. 2d) (127) (128) (129) . by contrast, vitamin d favors the differentiation of Th2 cells and the subsequent production of anti-inflammatory cytokines IL-4, IL-5 and IL-13 (130, 131) . 1,25(OH) 2 d upregulates GATA-binding protein 3 (GATA3), which is recognized as the master regulator of Th2 cells (130, 132) . This upregulation is mediated by the activation of STAT6, which acts upstream of GATA3 transcription (109,130,133 ). In addition, vitamin d increases the differentiation of regulatory T cells (Tregs) through the upregulation of the transcription factor FOXP3 and cTLA-4 expression; Treg differentiation contributes to the production of anti-inflammatory cytokines, such as IL-10 ( Fig. 2d) (125, (134) (135) (136) . Renin-angiotensin system. The renin-angiotensin system (RAS) comprises renin, angiotensinogen (ANG), Ang I, Ang-converting enzyme (AcE) and Ang II (41, 137) . This system acts as a cascade where renin degrades ANG to produce Ang I; subsequently, the AcE transforms Ang I to II (138) . Ang II regulates blood pressure and electrolyte balance (137) . As aforementioned, the maintained interaction of Ang II with AT1r contributes to the production of pro-inflammatory cytokines by activating NF-κb and macrophages (41) . The crucial role of AcE2 in this cascade is its ability to maintain a balance, since AcE2 degrades Ang II to produce Ang (1-7) with vasodilator, antiproliferative, antithrombotic and anti-inflammatory effects (139). However, in sArs-CoV-2 infection, a negative regulation of AcE2 has been demonstrated, which leads to the subsequent cytokine storm and, therefore, severe cOVId-19 (41,139) . 1,25(OH) 2 d has been reported to be an essential regulator of RAS since it suppresses the activity of renin; although the underlying mechanism is currently unclear, it has been suggested that 1,25(OH) 2 d suppresses renin expression by blocking the binding of the cAMP response element-binding protein with its response elements in the renin gene promoter (Fig. 2E) (140-142) . Vitamin D insufficiency affects ~50% of the world's population. The high prevalence of this vitamin insufficiency is considered a public health problem (33), since hypovitaminosis D has been identified as an independent risk factor for all-cause mortality in the general population (143) . Vitamin d is commonly referred to as the 'sunshine vitamin', as most of the endogenous vitamin d is synthesized during exposure to solar UV-b rays, which causes the formation of vitamin d 3 in the skin (33, 70) . Therefore, its deficiency is generally attributed to latitude or insufficient solar radiation; however, several additional factors contribute to low serum levels of 25(OH)D, which is a reliable marker of vitamin d status (144) . These additional factors that predispose individuals to vitamin d deficiency impact tropical countries despite sufficient solar radiation intensity (70). For example, skin pigmentation and the use of sunscreens affect the synthesis of vitamin d 3 in the skin (145) (146) (147) , low vitamin d intake and obesity decrease the bioavailability of 25(OH)D (58, 148) , whereas liver failure and nephrotic syndrome alter its synthesis and excretion, respectively (149) (150) (151) . Similarly, certain factors impact the catabolism and synthesis of 1,25(OH)D (152-156). These and other factors are described in detail in Table II (157-162 ). As aforementioned, in addition to latitude, various factors influence vitamin d levels in the human body (62) . Therefore, the Latin American population, the vast majority of which resides in the tropical zone, is not exempt from vitamin D deficiency (70). Vitamin D insufficiency in this region may be a public health problem; however, despite studies that report 25(OH)D deficiencies in the Latin American population, it is impossible to establish the magnitude of the problem due to the lack of nationally representative data (35) . Table III summarizes the most recent reports on the status of 25(OH)D in the population of Latin American countries that are among the top 10 countries by confirmed cases and deaths from cOVId-19 globally (18, (163) (164) (165) (166) (167) . Although the definition of serum 25(OH)D status varies among the studies, the majority of these reports align with the recommendations of the Institute of Medicine (IOM) (168) and the Endocrine society (169) : Vitamin D deficiency is defined as serum levels of 25(OH)D <20 ng/ml (<50 nmol/l), and vitamin D insufficiency is defined as serum levels between 21 ng/ml (52.5 nmol/l) and 29 ng/ml (72.5 nmol/l). Of note, the IOm suggests that 25(OH)D levels >20 ng/ml (>50 nmol/l) are sufficient to meet the needs of ~98% of the population; however, this recommendation mainly considers the maintenance of bone health (168). Various factors cause a high prevalence of vitamin D deficiency. However, although latitude and season are key factors, certain countries with long winters report lower rates of deficiency compared with those in countries in the tropical zone; this may be due to food fortification, high consumption of fatty fish and supplementation (170) . Therefore, although the recommendations for restoring the levels of vitamin d include the consumption of foods rich in vitamin d and increased sun exposure, considering the difficulty of generalized access to foods such as fish, clothing habits and the avoidance of sunlight, supplementation may represent an effective strategy (58) . Furthermore, the recommendation of vitamin d supplementation may not only help prevent low concentrations of 25(OH)D and improve bone health, but may also be useful for the prevention of complications following infection with SARS-coV-2 (57) . Regarding the recommendations for vitamin d intake, these may vary between populations. The IOM recommends daily consumption of 600 IU (15 µg) for children >1 year and adults ≤70 years (168) . similarly, the european Food safety Authority recommends a daily intake of 600 IU (15 µg), with a maximum intake of 4,000 IU/day (100 µg) in healthy adults (171, 172) . The uK scientific Advisory Committee on Nutrition recommends vitamin d intake of 400 IU/day (10 µg) for everyone in the general population >4 years (173) , whereas the European Food Safety Agency has reported that vitamin D doses of ≤10,000 Iu/day (≤250 µg) are safe if there are no comorbidities (171, 172) . Other reports indicate that doses ≤6,000 Iu/day (≤150 µg) are necessary to achieve serum 25(OH)D concentrations >40 ng/ml (100 nmol/l). Doses of ≤15,000 Iu/day (≤375 µg) have also been reported to be safe and effective for rapidly increasing 25(OH)D concentrations (174) . The brazilian society of Endocrinology and Metabology (175) and the Ministry of Health of the Government of Chile (176) adhere to the recommendations indicated by the IOM. In colombia, the colombian consensus on Vitamin d recommends an intake of ≤2,000 Iu/day (≤50 µg) in cases of insufficiency, and ≤6,000 Iu/day (≤150 µg) in deficiency (177) . The suggested daily intake in Mexico is only 224 IU (5.6 µg), as there are currently no studies demonstrating the need to supplement vitamin d in the Mexican population (178) . Supplementation with vitamin d may be necessary for individuals with deficiency to achieve a sufficient concentration of 25(OH)D, which is >30 ng/ml (75 nmol/l), even with consumption of fortified foods, since it is difficult to maintain this concentration with food alone (179) . An international consensus for the recommended daily intake for vitamin d would be useful; however, considering that vitamin D deficiency is an undoubted global problem, that there is a lack of clinical trials that accurately indicate the appropriate dose of vitamin d supplementation. due to the need to establish accessible strategies for the prevention of complications from cOVId-19, the authors of the present review agree with the current proposal of Grant et al (180) , who suggested that individuals with low levels of 25(OH)D should be supplemented for a month with 10,000 IU/day (250 µg) of vitamin d 3 for the rapid restoration of the desired concentrations between 40 and 60 ng/ml (100 and 150 nmol/l). For maintenance, this should be followed by daily supplementation of 5,000 IU (125 µg). notably, that baseline monitoring of 25(OH)D concentrations should be considered. In addition, avoiding high doses of calcium and assessing the consumption of magnesium and vitamin K 2 should be considered for the prevention of long-term adverse effects of high doses of vitamin d (180, 181) . The lack of effective therapies and the uncertainty of universal access to possible vaccines for cOVId-19 demand alternatives with potential immunomodulatory effects such as vitamin d supplementation, which may contribute to the prevention of respiratory infections and their complications. However, it is necessary to await the results of the undergoing clinical trials and to continue with the execution of further studies to determine the effects of vitamin d supplementation on cOVId-19 and establish the ideal dosage. Observational studies appear to demonstrate an association between low vitamin d concentrations and susceptibility to SARS-coV-2 infection. However, it is also vital to carry out national and international studies to determine the prevalence of vitamin d deficiency in Latin America. The authors of the present study call on the corresponding authorities to assess the fortification with vitamin d of foods for daily consumption, since supplementation may represent a difficulty for individuals with a low income. Not applicable. This research was funded by the National council of Science and Technology (cONAcYT ciencia básica; grant no. A1-S-8774) and Universidad de Guadalajara through the 'Fortalecimiento de la Investigación y el Posgrado 2020' fund. Not applicable. FJTH, and JFmV conceived, drafted, and finalized the manuscript. JFmV, GAsz, GGe, JHb, and GmO critically reviewed the manuscript for important intellectual content. All authors read and approved the final manuscript. Not applicable. Not applicable. The emergence of SARS, MERS and novel SARS-2 coronaviruses in the 21st century Porcine epidemic diarrhea virus: An emerging and re-emerging epizootic swine virus Progress and challenges toward the development of vaccines against avian infectious bronchitis Aetiology: Koch's postulates fulfilled for sArs virus Osterhaus ADme and Fouchier RAM: Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia A novel coronavirus from patients with pneumonia in china coronaviridae Study Group of the International committee on Taxonomy of Viruses: The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-ncoV and naming it SARS-coV-2 World Health Organization: Timeline of WHO's response to cOVId-19 SARS and MERS: Are they closely related? Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, china: A descriptive study clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province Aerosol transmission of SARS-coV-2? Evidence, prevention and control High contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 Structure, function, and antigenicity of the SARS-coV-2 spike glycoprotein SARS-coV-2 cell entry depends on AcE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor single-cell RNA-seq data analysis on the receptor AcE2 expression reveals the potential risk of different human organs vulnerable to 2019-ncoV infection Johns Hopkins university coronavirus Resource center: cOVId-19 dashboard by the center for Systems Science and engineering (Csse) at Johns Hopkins university (JHu) Risk factors of critical & mortal cOVId-19 cases: A systematic literature review and meta-analysis Common risk factors for major noncommunicable disease, a systematic overview of reviews and commentary: The implied potential for targeted risk reduction Ther Adv chronic dis: Oct Defining a healthy diet: evidence for the role of contemporary dietary patterns in health and disease Nutritional modulation of immune function: Analysis of evidence, mechanisms, and clinical relevance The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: A systematic review of human prospective studies efficacy and safety of vitamin D supplementation in patients with systemic lupus erythematosus: A meta-analysis of randomized controlled trials Fish oil derived omega 3 fatty acids suppress adipose NLRP3 inflammasome signaling in human obesity Immune boosting role of vitamin E against pulmonary tuberculosis Effects of zinc supplementation in the prevention of respiratory tract infections and diarrheal disease in colombian children: A 12-month randomised controlled trial Prospective study of probiotic supplementation results in immune stimulation and improvement of upper respiratory infection rate Immunonutrition in critical illness: What is the role? Immunonutrition: Role in wound healing and tissue regeneration Keppel mH, Grübler mr, märz W and Pandis m: Vitamin d testing and treatment: A narrative review of current evidence Vitamin d supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data Vitamin d: The 'sunshine' vitamin Global prevalence and disease burden of vitamin d deficiency: A roadmap for action in low-and middle-income countries Less than adequate vitamin d status and intake in Latin America and the caribbean: A problem of unknown magnitude Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus AcE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia Ad: SARS-coV-2 and coronavirus disease 2019: What we know so far COVID-19 pathophysiology: A review Protective role of AcE2 and its downregulation in SARS-coV-2 infection leading to macrophage activation syndrome: Therapeutic implications Molecular immune pathogenesis and diagnosis of cOVId-19 COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons burki T: cOVId-19 in Latin America Spread of SARS-coV-2 through Latin America and the caribbean region: A look from its economic conditions, climate and air pollution indicators World Health Organization: Our World in Data: Coronavirus (cOVId-19) Vaccinations barriers to vaccination in Latin America: A systematic literature review no benefit of hydroxychloroquine in cOVId-19: Results of systematic review and meta-analysis of randomized controlled trials Novartis: Novartis provides update on cAN-cOVId trial in hospitalized patients with cOVId-19 pneumonia and cytokine release syndrome (cRS), 2020. 51. sanofi: sanofi provides update on Kevzara ® (sarilumab) Phase 3 trial in severe and critically Astrazeneca: update on CALAVI phase II trials for calquence in patients hospitalised with respiratory symptoms of cOVId-19 Iserson KV: sArs-CoV-2 (COVID-19) vaccine development and production: An ethical way forward The equitable distribution of cOVId-19 therapeutics and vaccines epidemiology in Latin America and the caribbean: current situation and challenges Azhar eI, memish zA and maeurer m: reducing mortality from 2019-nCoV: Host-directed therapies should be an option editorial: Low population mortality from cOVId-19 in countries south of latitude 35 degrees North supports vitamin d as a factor determining severity Vitamin d in foods and as supplements Exploring vitamin d metabolism and function in cancer Vitamin d: Metabolism, molecular mechanism of action, and pleiotropic effects Holick mF: Vitamin D deficiency The immunological implication of the new vitamin d metabolism Immunologic effects of vitamin d on human health and disease environmental predictors of seasonal influenza epidemics across temperate and tropical climates Untergruppe ʻbewertung blutassoziierter Krankheitserregerʼ: Influenza virus The role of season in the epidemiology of influenza 70. mendes mm, Hart KH, botelho Pb and Lanham-new sA: Vitamin d status in the tropics: Is sunlight exposure the main determinant? Vitamin D and living in northern latitudes-an endemic risk area for vitamin D deficiency Vitamin D deficiency during winter months among an adult, predominantly urban, population in Northern Poland Widespread vitamin D deficiency among adults from northern Poland (54°N) after months of low and high natural UVb radiation Temporal relationship between vitamin d status and parathyroid hormone in the United States Influenza virus transmission is dependent on relative humidity and temperature Roles of humidity and temperature in shaping influenza seasonality Acute respiratory tract infection and 25-hydroxyvitamin d concentration: A systematic review and meta-analysis The role of vitamin d in the prevention of coronavirus disease 2019 infection and mortality Vitamin D concentrations and COVID-19 infection in uK biobank 25-Hydroxyvitamin D concentrations are lower in patients with positive PcR for SARS-coV-2 Association of vitamin d deficiency and treatment with cOVId-19 incidence Whittemore Pb: cOVId-19 fatalities, latitude, sunlight, and vitamin d Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with cOVId-19 are associated with greater disease severity Low plasma 25(OH) vitamin D level is associated with increased risk of cOVId-19 infection: An Israeli population-based study The role of DbP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to cOVId-19 Possible association of vitamin d status with lung involvement and outcome in patients with cOVId-19: A retrospective study Gryspeerdt s and martens GA: serum 25(OH)D level on hospital admission associated with cOVId-19 stage and mortality High-dose cholecalciferol booster therapy is associated with a reduced risk of mortality in patients with cOVId-19: A cross-sectional multi-centre observational study Vitamin d status and seroconversion for COVID-19 in uK healthcare workers does serum vitamin d level affect cOVId-19 infection and its severity?-A case-control study Analysis of vitamin d level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital Vitamin d and survival in cOVId-19 patients: A quasi-experimental study Vitamin d supplementation associated to better survival in hospitalized frail elderly cOVId-19 patients: The GERIA-cOVId Quasi-experimental study 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 Short term, high-dose vitamin d supplementation for cOVId-19 disease: A randomised Vitamin d deficiency aggravates cOVId-19: Systematic review and meta-analysis Low vitamin d status is associated with coronavirus disease 2019 outcomes: A systematic review and meta-analysis 102. cantorna MT, Snyder L, Lin Yd and Yang L: Vitamin d and 1,25(OH)2D regulation of T cells Vitamin D, vitamin D receptor, and tissue barriers. Tissue barriers 1: e23118 Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome Acute respiratory distress syndrome Interplay between tight junctions & adherens junctions Vitamin D receptor deletion leads to the destruction of tight and adherens junctions in lungs Vitamin d/VdR signaling attenuates lipopolysaccharide-induced acute lung injury by maintaining the integrity of the pulmonary epithelial barrier Vitamin d: Nutrient, hormone, and immunomodulator Hewison m: Antibacterial effects of vitamin D Mechanisms underlying the regulation of innate and adaptive immunity by vitamin d Vitamin d-cathelicidin axis: At the crossroads between protective immunity and pathological inflammation during infection Vitamin d-induced up-regulation of human keratinocyte cathelicidin anti-microbial peptide expression involves retinoid X receptor α Interleukin 13 exposure enhances vitamin d-mediated expression of the human cathelicidin antimicrobial peptide 18/LL-37 in bronchial epithelial cells Vitamin d status contributes to the antimicrobial activity of macrophages against mycobacterium leprae Vitamin d is required for IFN-gamma-mediated antimicrobial activity of human macrophages IFN-gamma-and TNF-independent vitamin d-inducible human suppression of mycobacteria: The role of cathelicidin LL-37 Vitamin d3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells Pruenster m, rot A and Nagy L: 1,25-dihydroxyvitamin d3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype Aranow c: Vitamin d and the immune system Pieber Tr and Amrein K: Vitamin D and immune function Transcriptional repression of the interleukin-2 gene by vitamin d3: direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor Vitamin d3: A transcriptional modulator of the interferon-gamma gene Lineage-specific effects of 1,25-dihydroxyvitamin d(3) on the development of effector cd4 T cells Vitamin d in autoimmunity: molecular mechanisms and therapeutic potential calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response Vitamin d decreases NFkappab activity by increasing Ikappabalpha levels 25-dihydroxyvitamin D3 decreases dNA binding of nuclear factor-kappab in human fibroblasts Predominance of Th2 polarization by vitamin d through a STAT6-dependent mechanism The impact of vitamin D levels on inflammatory status: A systematic review of immune cell studies GATA3 and the T-cell lineage: Essential functions before and after T-helper-2-cell differentiation Vitamin d: Modulator of the immune system ) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A 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 The active form of vitamin d transcriptionally represses Smad7 signaling and activates extracellular signal-regulated kinase (erK) to inhibit the differentiation of a inflammatory T helper cell subset and suppress experimental autoimmune encephalomyelitis Vitamin d regulation of the renin-angiotensin system 139. mahmudpour m, roozbeh J, Keshavarz m, Farrokhi s and nabipour I: COVID-19 cytokine storm: The anger of inflammation Vitamin D can prevent COVID-19 infection-induced multiple organ damage The effects of vitamin d on the renin-angiotensin system 1,25-dihydroxyvitamin d3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter 25-hydroxyvitamin d levels and the risk of mortality in the general population 25-Hydroxyvitamin D as a biomarker of vitamin d status and its modeling to inform strategies for prevention of vitamin d deficiency within the population Does chronic sunscreen use reduce vitamin D production to insufficient levels? The effect of sunscreen on vitamin d: A review The protective role of melanin against UV damage in human skin Vitamin D deficiency: Consequence or cause of obesity? medicina (Kaunas) 55: 541 Vitamin D deficiency in chronic liver disease Vitamin d metabolites and calcium metabolism in patients with nephrotic syndrome and normal renal function Association of glucocorticoid use and low 25-hydroxyvitamin d levels: Results from the national health and nutrition examination survey (nHAnes Vitamin D supplementation for bone health in adults with epilepsy: A systematic review blumberg b, schuetz eG and Thummel Ke: steroid and xenobiotic receptor and vitamin d receptor crosstalk mediates cYP24 expression and drug-induced osteomalacia Vitamin D and kidney disease Chang Ys and Hong YA: serum 1,25-dihydroxyvitamin d better ref lects renal parameters than 25-hydoxyvitamin d in patients with glomerular diseases Genetic regulation of vitamin D levels Common genetic determinants of vitamin D insufficiency: A genome-wide association study Vitamin D: Light side and best time of sunshine in Riyadh Vitamin d and aging Vitamin D deficiency in patients with intestinal malabsorption syndromes-think in and outside the gut Jm: drug-vitamin d interactions: A systematic review of the literature Obesity and 25(OH)D serum concentration are more important than vitamin d intake for changes in nutritional status indicators: A population-based longitudinal study in a state capital city in Southern brazil Vitamin d deficiency in mexicans have a high prevalence: A cross-sectional analysis of the patients from the centro Médico Nacional 20 de Noviembre PURA study investigators: Association between serum 25-hydroxy vitamin d levels and blood pressure among adolescents in two resource-limited settings in Peru Passive commuting and higher sedentary time is associated with vitamin D deficiency in adult and older women: results from chilean national health survey Vitamin d nutritional status in the adult population in Colombia-an analytical cross-sectional study The 2011 report on dietary reference intakes for calcium and vitamin d from the institute of medicine: What clinicians need to know Evaluation, treatment, and prevention of vitamin d deficiency: An endocrine society clinical practice guideline Is vitamin D deficiency a major global public health problem? Vitamin D supplementation EFSA Panel on dietetic Products Nutrition and Allergies (nDA): scientific opinion on the tolerable upper intake level of vitamin d scientific Advisory Committee on nutrition: Vitamin D and Health Perspective: Improving vitamin d status in the management of cOVId-19 Recomendações da Sociedade brasileira de Endocrinologia e Metabologia (SbEM) para o diagnóstico e tratamento da hipovitaminose d Ministerio de Salud del Gobierno de chile: Estudio para revisión y actualización de las guías alimentarias para la población chilena Vitamina d. consenso colombiano de expertos Deficiencia de vitamina D en la edad pediátrica. una oportunidad de prevención Vitamin d supplementation guidelines Aliano JL and bhattoa HP: evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths Goddek s: Vitamin D3 and K2 and their potential contribution to reducing the cOVId-19 mortality rate The authors declare that they have no competing interests.