Acessibilidade / Reportar erro

Reasons to avoid vitamin D deficiency during COVID-19 pandemic

ABSTRACT

The effects of vitamin D on the musculoskeletal system are well established. Its deficiency causes osteomalacia, secondary hyperparathyroidism, and an increased risk for fractures and falls. However, clinical and experimental evidence points to extra-skeletal actions of vitamin D, including on immune and respiratory systems. Thus, during this COVID-19 pandemic, a possible deleterious role of vitamin D deficiency has been questioned. This paper aims to present a brief review of the literature and discuss, based on evidence, the role of vitamin D in the lung function and in the prevention of respiratory infections. Relevant articles were searched in the databases MEDLINE/PubMed and SciELO/LILACS. The mechanisms of vitamin D action in the immune system response will be discussed. Clinical data from systematic reviews and meta-analyses show benefits in the prevention of respiratory infections and improvement of pulmonary function when vitamin D-deficient patients are supplemented. At the time of writing this paper, no published data on vitamin D supplementation for patients with COVID-19 have been found. Vitamin D supplementation is recommended during this period of social isolation to avoid any deficiency, especially in the context of bone outcomes, aiming to achieve normal values of 25(OH)D. The prevention of respiratory infections and improvement of pulmonary function are additional benefits observed when vitamin D deficiency is treated. Thus far, any protective effect of vitamin D specifically against severe COVID-19 remains unclear. We also emphasize avoiding bolus or extremely high doses of vitamin D, which can increase the risk of intoxication without evidence of benefits.

Keywords
Coronavirus; vitamin D; respiratory infections; immune system

INTRODUCTION

In December 2019, an outbreak of pneumonia of unknown origin was initially reported in Wuhan, Hubei Province, China. SARS-CoV-2 (previously 2019-nCoV), a single-stranded RNA virus, was identified as the agent. Six other kinds of coronaviruses are known to cause human disease, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2012, respectively. SARS-CoV-2 is highly similar to a bat coronavirus, indicating that bats can be the natural reservoir host of various SARS-related coronaviruses and could also be the original host of SARS-CoV-2. Coronavirus disease 2019 (COVID-19) was declared a global pandemic on March 11, 2020 (11. Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med. 2020;14(2):126-35.

2. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.
-33. Wu D, Wu T, Liu Q, Yang Z. The SARS-CoV-2 outbreak: What we know. Int J Infect Dis. 2020;94:44-8.).

According to the COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University, on June 22, 2020, a total of 9 million cases and 469,122 deaths were reported around the world (44. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.).

The median incubation period is 5.1 days, and 97.5% of the infected subjects will develop symptoms within 11.5 days of infection. Fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), expectoration (28.2%), and dyspnea (21.9%) are the most common symptoms reported (22. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.). There is a wide range of clinical manifestations in patients with SARS-CoV-2, from mild, to moderate, to severe and fulminant disease. In those patients who develop pneumonia, ground-glass opacity and multiple mottling are described on thorax computed tomography (22. Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.). In 10% to 20% of severe patients, the respiratory injury will develop into acute respiratory distress syndrome (ARDS) with high morbidity and mortality. Risk factors for developing severe to critical cases include advanced age and underlying comorbidities such as hypertension, diabetes, and cardiovascular disease (11. Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med. 2020;14(2):126-35.).

Regarding the pathogenic mechanism that produces pneumonia, the available data suggest that the COVID infection is capable of producing an excessive immune reaction in the host (“cytokine storm”) and extensive tissue damage, especially in the lungs (55. Di Gennaro F, Pizzol D, Marotta C, Antunes M, Racalbuto V, Veronese N, et al. Coronavirus diseases (COVID-19) current status and future perspectives: A narrative review. Int J Environ Res Public Health. 2020;17(8):2690.).

In general, innate immune responses (Toll-like receptors, type I interferons, macrophages, and dendritic cells) represent the initial host defense against invading pathogens. This inhibits virus replication, promotes virus clearance, induces tissue repair, and triggers a prolonged adaptive immune response (T-cells produce proinflammatory cytokines via the NF‐kB and MAPK signaling pathway) against the viruses. In most cases, pulmonary and systemic inflammatory responses associated with CoVs are triggered by the innate immune system when it recognizes the viruses (66. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424-32.,77. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7(6):4240-70.).

The main factor of this storm in COVID-19 seems to be interleukin 6 (IL-6), which is produced by activated leukocytes (88. Aziz M, Fatima R, Assaly R. Elevated Interleukin‐6 and Severe COVID‐19: A Meta‐Analysis. J Med Virol. 2020;10.1002/jmv.25948.
https://doi.org/10.1002/jmv.25948...
). Giamarellos-Bourboulis and cols. described a pattern of immune profile in severe cases characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation (99. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3.). Huang and cols. showed that intensive unit care patients had higher plasma levels of IL-2, IL-7, IL-10, GSCF, IP10, MCP1, MIP1A, and TNF-α (1010. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.).

Vitamin D has been investigated for its immunomodulatory action related especially to respiratory infections. The discussion proves to be quite timely in the face of the coronavirus pandemic.

VITAMIN D

Although it is called a vitamin, vitamin D is conceptually a pre-hormone that, together with parathyroid hormone (PTH), acts as an important regulator of calcium homeostasis and bone metabolism. It can be obtained from food sources, but endogenous skin synthesis triggered by ultraviolet radiation type B is the main source. The vitamin D produced in the skin or ingested as a nutrient or supplement is transported into the liver, where it is converted into 25-hydroxyvitamin D [25(OH)D], or calcidiol, which is the main form of circulating vitamin D and also used for serum dosage, though still not active. In the kidney, 25(OH)D is converted to its biologically active form, 1,25(OH)2D3, or calcitriol through the enzyme 1α-hydroxylase. The main actions of 1,25(OH)2D3 are mediated by the nuclear transcription factor, called the vitamin D receptor (VDR), located in the nucleus of the cells (1111. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.) (Figure 1). The classic actions of vitamin D are related to bone metabolism, where it modulates PTH synthesis, promotes calcium absorption by the intestine, and in the kidneys, the 1,25(OH)2D stimulates calcium reabsorption of glomerular filtrate, and these actions are related to better bone mass and muscle function (1111. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.). In addition, vitamin D receptors and the enzyme 1α-hydroxylase have been found in cells of the immune system such as neutrophils, macrophages and dendritic cells, which reinforces the hypothesis of vitamin D effects beyond the musculoskeletal system (1212. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221(4616):1181-3.).

Figure 1
Proposed mechanism whereby 1,25(OH)2D3 -VDR signaling acts on the respiratory system (adapted according to references 7, 13, 14, and 29. Abbreviations: DBP = vitamin D binding protein; Ang-2 = angiopoietin-2; MLCK = Ang-2-Tie-2-kinase cascade – MLC = myosin light chain; RAS = renin-angiotensin system; DC = dendritic cell; BC = B-cell (B cell: B lymphocyte, cyto T cell, cytotoxic T cell); VDR = vitamin D receptor; T cell = T lymphocyte; TH = helper T cell; Treg = regulatory T cell; IL = interleukin; TNF = tumor necrosis factor; INF = interferon; AMPs = antimicrobial peptides cathelicidin (LL-37) and human beta-defensins (hBDs), and MMP-9 = matrix metalloproteinase 9; ARTI = acute respiratory tract infection; COPD = chronic obstructive pulmonary disease.

Furthermore, an experimental research demonstrated that calcitriol modulates the expression of the angiotensin-converting enzyme 2, which is the host receptor for SARS-CoV-2 entry into cells. VDR-null mice presented more severe acute lung injury in a LSP-induced sepsis model, compared with wild-type counterparts. Likewise, calcitriol acts in the regulation of phosphorylation of myosin light chains, the main indicator of vascular permeability. Thus, as a result of the modulation of these systems, by which they act on vascular permeability, as well as the blocking of cell apoptosis in the lung, together, they might prevent the worsening of pulmonary disorders (1313. Kong J, Zhu X, Shi Y, Liu T, Chen Y, Bhan I, et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013;27(12):2116-25.).

Concerning the non-skeletal actions of vitamin D, many systematic reviews and meta-analyses showed that its administration is associated with reductions in upper respiratory infections, exacerbation of asthma, and mortality, and these data will be discussed below (Table 1).

Table 1
Recent systematic reviews and meta-analysis from observational and randomized controlled studies evaluating vitamin D effects in immune system and respiratory infections

VITAMIN D AND THE IMMUNE RESPONSE AGAINST RESPIRATORY INFECTIONS: EXPERIMENTAL DATA

VDR and vitamin D enzymes are present in virtually all cells of the innate and adaptive pathways of the immune system. These cells produce locally, and the expression of CYP27B1 is regulated by a network of immunoregulatory 1,25(OH)2D3 rather than calcium homeostatic inputs (1414. Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40(4):1109-51.).

In vitro and experimental studies show that vitamin D enhances cellular innate immunity partly through the induction of antimicrobial peptides, including human cathelicidin LL-37, by 1,25(OH)2D3, and beta-defensins (77. Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7(6):4240-70.). Cathelicidins exhibit direct antimicrobial activities against a spectrum of microbes, including viruses. Vitamin D is also involved in cellular immunity, partially reducing the cytokine storm induced by the innate immune system. 1,25(OH)2D3 suppresses responses mediated by the T helper cell type 1 (Th1) by repressing the production of inflammatory cytokines IL-2 and interferon-gamma (INFγ). Additionally, 1,25(OH)2D3 promotes cytokine production by T helper type 2 (Th2) cells, which helps enhance the indirect suppression of Th1 cells by complementing this with actions mediated by a multitude of cell types (1515. Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M, et al. Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS One. 2009;4(6):e5810.

16. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020;12(4):988.
-1717. Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-6.) (Figure 1).

Immune and structural cells in the lung can express the 1α-hydroxylase enzyme CYP27B1, suggesting that localized synthesis of active vitamin D from circulating precursors could be an important mechanism for vitamin D to exert effects at sites of inflammation. Liu and cols. demonstrated that after an allergic stimulus, levels of cathelicidins, 1,25(OH)2D3, and 25(OH)D increased in bronchoalveolar lavage fluid (1818. Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy. 2012;42(3):383-91.).

VITAMIN D AND THE IMMUNE RESPONSE AGAINST RESPIRATORY INFECTIONS: CLINICAL DATA

In the past, tuberculosis patients were sent to sanatoriums, where treatment included exposure to sunlight, which was thought to directly kill Mycobacterium tuberculosis. Curiously, in 1849, Williams described the use of cod liver oil in the treatment of tuberculosis, before the discovery of vitamin D (1919. Cod-Liver Oil in Phthisis. Prov Med Surg J. 1849;13(7):196.). In general, infections are known to contribute to death in nursing home patients or those with a critical illness.

Recently, Ilie and cols. observed a negative correlation between mean 25(OH)D levels of the population from 20 European countries and COVID-19 mortality, as the number of people infected. Elderly people are the most vulnerable group for COVID-19 infection, as well as the group that has the most deficient vitamin D levels (2020. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32(7):1195-8.).

The Third National Health and Nutrition Examination Survey evaluated 18,883 participants older than 12 years in the US. After adjustments to the season of the year, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease, the authors found that serum 25(OH)D levels had an independent, inverse association with a recent upper respiratory tract infection. Although 25(OH)D levels less than 30 ng/mL and these infections were more common in the winter season, 25(OH)D levels and respiratory infections were still inversely associated across all seasons (2121. Ginde AA, Mansbach JM, Camargo CA. Association between Serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009;169(4):384-90.).

In a blinded prospective cohort study, Sabetta and cols. evaluated monthly concentrations of 25(OH)D over the fall and winter 2009-2010 in 198 healthy adults. Concentrations of 38 ng/mL or more were associated with a significant two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill. Although this was an observational study, it is possible to speculate on whether reaching these levels with cholecalciferol administration would reduce the risk of acute respiratory infection (2222. Sabetta JR, Depetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5(6):e11088.).

No prospective studies have been published evaluating the benefits of vitamin D administration in COVID 19 patients so far. However, in HIV patients, vitamin D administration induced a potential reduction in secondary microbial infections such as tuberculosis, as well as an increase in CD4+ T-lymphocyte count and a decreased in biomarkers associated with chronic inflammation (2323. Alvarez N, Aguilar-Jimenez W, Rugeles MT. The potential protective role of vitamin D supplementation on HIV-1 infection. Front Immunol. 2019;10:2291.).

In a randomized placebo-controlled double-blind trial, 86 participants received 1,000 IU of oral vitamin D3 or placebo for 90 days. Vitamin D supplementation significantly increased airway surface liquid antimicrobial activity and serum concentration of 25(OH)D. Interestingly, in a subgroup analysis, Vargas Buonfiglio and cols. found that smokers did not have an increase in their baseline antimicrobial activity in response to vitamin D (2424. Vargas Buonfiglio LG, Cano M, Pezzulo AA, Vanegas Calderon OG, Zabner J, Gerke AK, et al. Effect of vitamin D3 on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial. BMJ Open Respir Res. 2017;4(1):e000211.). In a post-hoc analysis from another large randomized, double-blind, placebo-controlled trial, vitamin D supplementation improved lung function demonstrated through the forced expiratory volume in 1 s (FEV1), but only among ever-smokers, and especially in those with vitamin D deficiency and with asthma and COPD (2525. Sluyter JD, Camargo CA, Waayer D, Lawes CMM, Toop L, Khaw KT, et al. Effect of monthly, high-dose, long-term vitamin D on lung function: A randomized controlled trial. Nutrients. 2017;9(12):1353.).

In a longitudinal study, a cohort of healthy Mexican participants older than 55 years (n = 23) was followed for 12 months and evaluated every three months. Their 25(OH)D levels remained below 30 ng/mL throughout all seasons. Inflammatory markers such as IL-1β, IL-6, IL-10, IL-18, MCP-1, and TNF-α significantly varied with the season independently of 25(OH)D concentrations, considering age, sex, and individual as random effects, with the highest levels occurring during autumn and/or winter, and the lowest levels occurring in the spring. In this study, TNF-α levels were dependent on 25(OH)D concentrations, being higher in individuals with vitamin D deficiency (2626. Elizondo-Montemayor L, Castillo EC, Rodríguez-López C, Villarreal-Calderón JR, Gómez-Carmona M, Tenorio-Martínez S, et al. Seasonal Variation in Vitamin D in Association with Age, Inflammatory Cytokines, Anthropometric Parameters, and Lifestyle Factors in Older Adults. Mediators Inflamm. 2017;2017:5719461.).

Jolliffe and cols. published a systematic review of clinical studies (3939. Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S, et al. Long-Term Bioavailability After a Single Oral or Intramuscular Administration of 600,000 IU of Ergocalciferol or Cholecalciferol: Implications for Treatment and Prophylaxis. J Clin Endocrinol Metab. 2013;98(7):2709-15. studies: 4 cross-sectional studies, 8 case-control studies, 13 cohort studies, and 14 clinical trials) evaluating the association between vitamin D deficiency and susceptibility to acute respiratory infection in humans. The observational studies reported statistically significant associations between low vitamin D status and increased risk of both upper and lower respiratory tract infections (2727. Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J Steroid Biochem Mol Biol. 2013;136:321-9.).

Table 1 summarizes the most recent meta-analyses evaluating observational and intervention data of vitamin D in the immune system and respiratory infections.

Rejnmark and cols. (2828. Rejnmark L, Bislev LS, Cashman KD, Eiríksdottir G, Gaksch M, Grübler M, et al. Non-skeletal health effects of Vitamin D supplementation: A systematic review on findings from meta-Analyses summarizing trial data. PLoS One. 2017;12(7):e0180512.) published a systematic review of meta-analyses and randomized controlled trials (RCTs) focusing on the effects of vitamin D supplementation on the risk of respiratory tract infections. They observed that these studies were included relatively small samples and were of short duration. The beneficial effects of vitamin D supplementation were reported in some of the RCTs. In conclusion, the pooled overall findings suggest a beneficial effect of vitamin D on respiratory tract infections, despite it not being possible to discriminate the etiology of the infections, according to the authors. The studies included in this meta-analysis, however, were quite heterogeneous, including participants from newborns to elderly and with a wide range of infectious diseases, raising questions about the accuracy of these conclusions.

A more recent meta-analysis by Martineau and cols. (2525. Sluyter JD, Camargo CA, Waayer D, Lawes CMM, Toop L, Khaw KT, et al. Effect of monthly, high-dose, long-term vitamin D on lung function: A randomized controlled trial. Nutrients. 2017;9(12):1353. RCTs, 11,321 participants, aged from 0 to 95 years) showed that vitamin D supplementation reduced the risk of acute respiratory infections among all participants by 12% (aOR 0.88, 95%CI 0.81-0.96), and subgroup analysis revealed that protective effects were seen only in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95%CI 0.72-0.91). These protective effects of vitamin D were stronger in individuals taking daily or weekly doses together with a baseline 25(OH)D < 10 ng/mL (aOR 0.30, 95%CI 0.17-0.53) than in those with a baseline 25(OH)D ≥ 10 ng/mL (Table 1). Nonetheless, the authors warned that the causes of the infections in the study were diverse, and radiological confirmation was carried out in the minority of events (2929. Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44.).

Autier and cols. published recently a systematic review of meta-analyses and randomized trials on non-skeletal effects of vitamin D supplementation, which included 28 meta-analyses with participants of all ages who used cholecalciferol or ergocalciferol administered as oral or injectable preparations. The authors concluded that vitamin D supplementation is associated with a reduction in cancer mortality, especially in middle-aged and older people (doses of 800-1,200 IU per day of vitamin D), mainly when they are in the hospital or are institutionalized. However, the main finding highlighted by this study is that vitamin D supplementation might help to prevent common upper respiratory tract infections and asthma exacerbations, mostly in people with low 25(OH)D concentrations. The authors hypothesized that vitamin D supplementation could promote immunomodulatory effects that reinforce resistance to acute infections, which could reduce the mortality in debilitated individuals (3030. Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5(12):986-1004.). On the other hand, this systematic review found no evidence that vitamin D supplementation affects biomarkers of systemic inflammation, and the authors suggested that low 25(OH)D could be a consequence of systemic inflammation rather than a cause (3030. Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5(12):986-1004.).

Nevertheless, vitamin D plays a role in regulating human lung fibroblast functions in wound repair and tissue remodeling (3131. Baek MS, Yoon DS, Park JS, Yoon BW, Oh BS, Park J, et al. Vitamin D inhibits expression and activity of matrix metalloproteinase in human lung fibroblasts (HFL-1) cells. Tuberc Respir Dis (Seoul). 2014;77(2):73-80.). In a post hoc analysis, vitamin D supplementation also improved spirometric parameters of lung function in postmenopausal women without regular practice of physical activity, compared with those not supplemented (3232. Nolasco R, Moreira LDF, Bocalini DS, Fronza FCAO, Marin RV, Lazaretti-Castro M. Effects of vitamin D supplementation on pulmonary function in postmenopausal women following an aquatic exercise program. Arch Endocrinol Metab. 2017;61(1):28-35.). Additionally, meta-analyses of trials in children, adults, and pregnant women showed that vitamin D supplementation can reduce the risk of exacerbations in patients with mild and moderate asthma who require corticosteroid treatment (3333. Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev. 2016;(9):CD011511.,3434. Vahdaninia M, Mackenzie H, Helps S, Dean T. Prenatal Intake of Vitamins and Allergic Outcomes in the Offspring: A Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract. 2017;5(3):771-8.e5.).

It is important to highlight that vitamin D deficiency is common mainly among the elderly, who are at risk for severe COVID 19 infection, especially during the period of lockdown, social distancing, and wintertime (1111. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.,3535. Rhodes JM, Subramanian S, Laird E, Kenny RA. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment Pharmacol Ther. 2020;51(12):1434-7.). Likewise, other patients who belong to the groups at risk for this infection are associated with low levels of vitamin D (Table 1). Lack of physical activity outdoors also favors less sun exposure (3636. Carter SJ, Baranauskas MN, Fly AD. Considerations for obesity, vitamin D, and physical activity amid the COVID‐19 pandemic. Obesity (Silver Spring). 2020;28(7):1176-7.). So far, there is no evidence that vitamin D protects specifically against SARS-CoV-2 infection, but it prevents respiratory infections and regulates the cytokine inflammatory response, possibly reducing the risk of subsequent ARDS (2929. Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44.,3737. Zabetakis I, Lordan R, Norton C, Tsoupras A. Covid-19: The inflammation link and the role of nutrition in potential mitigation. Nutrients. 2020;12(5):1466.).

The reasonable recommendation is to maintain levels of 25(OH)D above 30 ng/mL in the risk groups, including individuals over 60 years old (3838. Moreira CA, Ferreira CES, Madeira M, Silva BCC, Maeda SS, Batista MC, et al. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab [Internet]. 2020. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en.
http://www.scielo.br/scielo.php?script=s...
).

THE LACK OF EVIDENCE FOR THE RECOMMENDATION OF BOLUS OR HIGH DOSES VITAMIN D

Due to the worldwide repercussions of the coronavirus pandemic, there is an unbridled search for therapies to treat or minimize the effects of the COVID infection. In this context, some recommendations extrapolate data from other observations, suggesting the use of very high doses of vitamin D against infections (1616. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020;12(4):988.).

Regarding the routes, oral or intramuscular, of vitamin D administration, in a prospective intervention study, was observed in elderly that oral 600,000 UI single dose of cholecalciferol or ergocalciferol showed to be more effective in increasing serum 25(OH)D than the equivalent intramuscular dose and is more rapidly metabolized. Although the authors had appointed greater efficacy of cholecalciferol than of ergocalciferol in improving vitamin D status regardless of the route of administration (3939. Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S, et al. Long-Term Bioavailability After a Single Oral or Intramuscular Administration of 600,000 IU of Ergocalciferol or Cholecalciferol: Implications for Treatment and Prophylaxis. J Clin Endocrinol Metab. 2013;98(7):2709-15.), clinical data suggest that daily or weekly doses offer better results than bolus (2929. Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44.) in the protection against acute pulmonary infections (Table 1). In addition, supplementation with extremely high doses of vitamin D could be harmful, especially to elderly individuals, and can potentially lead to falls and fractures (3838. Moreira CA, Ferreira CES, Madeira M, Silva BCC, Maeda SS, Batista MC, et al. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab [Internet]. 2020. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en.
http://www.scielo.br/scielo.php?script=s...
,4040. Marcinowska-Suchowierska E, Kupisz-Urbanska M, Lukaszkiewicz J, Pludowski P, Jones G. Vitamin D Toxicity – a clinical perspective. Front Endocrinol (Lausanne). 2018;9:550.).

Hypervitaminosis D increases intestinal calcium uptake, renal tubular reabsorption, and bone resorption, leading to hypercalcemia and related symptoms such as nausea, vomiting, weakness, anorexia, polydipsia, polyuria, dehydration, acute renal failure, apathy, confusion, and, in the long term, kidney stones. The recent consensus of the Brazilian Society of Clinical Pathology/Laboratory Medicine and the Brazilian Society of Endocrinology and Metabolism considers increased risk for intoxication when the values of 25(OH)D are above 100 ng/mL (1111. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.,3838. Moreira CA, Ferreira CES, Madeira M, Silva BCC, Maeda SS, Batista MC, et al. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab [Internet]. 2020. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en.
http://www.scielo.br/scielo.php?script=s...
).

The usual recommended dose for correction of vitamin D deficiency [25(OH)D < 20 ng/mL] is 50,000 IU/week or 7,000 IU/day for 6-8 weeks. For maintenance, the dose varies from 400 to 2,000 IU/day, depending on the age and clinical condition of the individual (1111. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.,3838. Moreira CA, Ferreira CES, Madeira M, Silva BCC, Maeda SS, Batista MC, et al. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab [Internet]. 2020. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en.
http://www.scielo.br/scielo.php?script=s...
) (Table 2).

Table 2
Recommended maintenance doses per day of cholecalciferol according to age

In conclusion, experimental and clinical data demonstrate that vitamin D has a physiological role in lung function and the innate and adaptive immune response against microorganisms. Cells from the respiratory tract can produce active vitamin D (calcitriol) and have its receptor in their nucleus. Vitamin D deficiency could increase the risk of acute respiratory infections and seems to impair the efficiency of gas exchanges, increasing the risk of asthma and COPD exacerbation. Current evidence has shown that individuals with low levels of 25(OH)D could experience additional benefits in terms of prevention of respiratory infections and improvement of pulmonary function after vitamin D replacement.

Due to vitamin D's peculiar metabolism, its deficiency is strongly related to low solar exposition, a very common situation during winter and spring, and especially in some populations such as the elderly, obese, and those with chronic diseases, conditions also associated with the most severe COVID-19 presentation.

Although the protective effect of vitamin D against severe COVID-19 remains speculative, there are reasons to strongly recommend vitamin D supplementation to avoid severe deficiency, especially during this pandemic, in conditions of social isolation and wintertime. Furthermore, vitamin D supplementation is usually indicated for the general population due to the clear benefits to the musculoskeletal system.

The recommended doses of vitamin D vary from 400 to 2,000 IU/day, according to different stages of life and clinical conditions. These doses are sufficient to prevent severe deficiency and are very safe, without the risk of intoxication. Therefore, they can be indicated without the need for blood measurements at this moment.

Acknowledgment:

we thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) for supporting the Brazilian postgraduation system and for carrying out this study.

REFERENCES

  • 1
    Zhou M, Zhang X, Qu J. Coronavirus disease 2019 (COVID-19): a clinical update. Front Med. 2020;14(2):126-35.
  • 2
    Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.
  • 3
    Wu D, Wu T, Liu Q, Yang Z. The SARS-CoV-2 outbreak: What we know. Int J Infect Dis. 2020;94:44-8.
  • 4
    Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020;92(6):577-83.
  • 5
    Di Gennaro F, Pizzol D, Marotta C, Antunes M, Racalbuto V, Veronese N, et al. Coronavirus diseases (COVID-19) current status and future perspectives: A narrative review. Int J Environ Res Public Health. 2020;17(8):2690.
  • 6
    Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424-32.
  • 7
    Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients. 2015;7(6):4240-70.
  • 8
    Aziz M, Fatima R, Assaly R. Elevated Interleukin‐6 and Severe COVID‐19: A Meta‐Analysis. J Med Virol. 2020;10.1002/jmv.25948.
    » https://doi.org/10.1002/jmv.25948
  • 9
    Giamarellos-Bourboulis EJ, Netea MG, Rovina N, Akinosoglou K, Antoniadou A, Antonakos N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3.
  • 10
    Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
  • 11
    Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, et al. Recomendações da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) para o diagnóstico e tratamento da hipovitaminose D. Arq Bras Endocrinol Metabol. 2014;58(5):411-33.
  • 12
    Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221(4616):1181-3.
  • 13
    Kong J, Zhu X, Shi Y, Liu T, Chen Y, Bhan I, et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013;27(12):2116-25.
  • 14
    Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40(4):1109-51.
  • 15
    Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M, et al. Convergence of IL-1beta and VDR activation pathways in human TLR2/1-induced antimicrobial responses. PLoS One. 2009;4(6):e5810.
  • 16
    Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths. Nutrients. 2020;12(4):988.
  • 17
    Aranow C. Vitamin D and the immune system. J Investig Med. 2011;59(6):881-6.
  • 18
    Liu MC, Xiao HQ, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy. 2012;42(3):383-91.
  • 19
    Cod-Liver Oil in Phthisis. Prov Med Surg J. 1849;13(7):196.
  • 20
    Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32(7):1195-8.
  • 21
    Ginde AA, Mansbach JM, Camargo CA. Association between Serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009;169(4):384-90.
  • 22
    Sabetta JR, Depetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5(6):e11088.
  • 23
    Alvarez N, Aguilar-Jimenez W, Rugeles MT. The potential protective role of vitamin D supplementation on HIV-1 infection. Front Immunol. 2019;10:2291.
  • 24
    Vargas Buonfiglio LG, Cano M, Pezzulo AA, Vanegas Calderon OG, Zabner J, Gerke AK, et al. Effect of vitamin D3 on the antimicrobial activity of human airway surface liquid: preliminary results of a randomised placebo-controlled double-blind trial. BMJ Open Respir Res. 2017;4(1):e000211.
  • 25
    Sluyter JD, Camargo CA, Waayer D, Lawes CMM, Toop L, Khaw KT, et al. Effect of monthly, high-dose, long-term vitamin D on lung function: A randomized controlled trial. Nutrients. 2017;9(12):1353.
  • 26
    Elizondo-Montemayor L, Castillo EC, Rodríguez-López C, Villarreal-Calderón JR, Gómez-Carmona M, Tenorio-Martínez S, et al. Seasonal Variation in Vitamin D in Association with Age, Inflammatory Cytokines, Anthropometric Parameters, and Lifestyle Factors in Older Adults. Mediators Inflamm. 2017;2017:5719461.
  • 27
    Jolliffe DA, Griffiths CJ, Martineau AR. Vitamin D in the prevention of acute respiratory infection: Systematic review of clinical studies. J Steroid Biochem Mol Biol. 2013;136:321-9.
  • 28
    Rejnmark L, Bislev LS, Cashman KD, Eiríksdottir G, Gaksch M, Grübler M, et al. Non-skeletal health effects of Vitamin D supplementation: A systematic review on findings from meta-Analyses summarizing trial data. PLoS One. 2017;12(7):e0180512.
  • 29
    Martineau AR, Jolliffe DA, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, et al. Vitamin D supplementation to prevent acute respiratory infections: Individual participant data meta-analysis. Health Technol Assess. 2019;23(2):1-44.
  • 30
    Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5(12):986-1004.
  • 31
    Baek MS, Yoon DS, Park JS, Yoon BW, Oh BS, Park J, et al. Vitamin D inhibits expression and activity of matrix metalloproteinase in human lung fibroblasts (HFL-1) cells. Tuberc Respir Dis (Seoul). 2014;77(2):73-80.
  • 32
    Nolasco R, Moreira LDF, Bocalini DS, Fronza FCAO, Marin RV, Lazaretti-Castro M. Effects of vitamin D supplementation on pulmonary function in postmenopausal women following an aquatic exercise program. Arch Endocrinol Metab. 2017;61(1):28-35.
  • 33
    Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev. 2016;(9):CD011511.
  • 34
    Vahdaninia M, Mackenzie H, Helps S, Dean T. Prenatal Intake of Vitamins and Allergic Outcomes in the Offspring: A Systematic Review and Meta-Analysis. J Allergy Clin Immunol Pract. 2017;5(3):771-8.e5.
  • 35
    Rhodes JM, Subramanian S, Laird E, Kenny RA. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment Pharmacol Ther. 2020;51(12):1434-7.
  • 36
    Carter SJ, Baranauskas MN, Fly AD. Considerations for obesity, vitamin D, and physical activity amid the COVID‐19 pandemic. Obesity (Silver Spring). 2020;28(7):1176-7.
  • 37
    Zabetakis I, Lordan R, Norton C, Tsoupras A. Covid-19: The inflammation link and the role of nutrition in potential mitigation. Nutrients. 2020;12(5):1466.
  • 38
    Moreira CA, Ferreira CES, Madeira M, Silva BCC, Maeda SS, Batista MC, et al. Reference values of 25-hydroxyvitamin D revisited: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Society of Clinical Pathology/Laboratory Medicine (SBPC). Arch Endocrinol Metab [Internet]. 2020. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en.
    » http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2359-39972020005003202&lng=en&nrm=iso&tlng=en
  • 39
    Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S, et al. Long-Term Bioavailability After a Single Oral or Intramuscular Administration of 600,000 IU of Ergocalciferol or Cholecalciferol: Implications for Treatment and Prophylaxis. J Clin Endocrinol Metab. 2013;98(7):2709-15.
  • 40
    Marcinowska-Suchowierska E, Kupisz-Urbanska M, Lukaszkiewicz J, Pludowski P, Jones G. Vitamin D Toxicity – a clinical perspective. Front Endocrinol (Lausanne). 2018;9:550.
  • 41
    Li B, Wang M, Zhou L, Wen Q, Zou J. Association between serum vitamin D and chronic rhinosinusitis: a meta-analysis. Braz J Otorhinolaryngol [Internet]. 2019. Available from: https://pubmed.ncbi.nlm.nih.gov/31653607/
    » https://pubmed.ncbi.nlm.nih.gov/31653607/
  • 42
    Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency and community-acquired pneumonia: A meta-analysis of observational studies. Medicine (Baltimore). 2019;98(38):e17252.
  • 43
    Pham H, Rahman A, Majidi A, Waterhouse M, Neale RE. Acute respiratory tract infection and 25-hydroxyvitamin D concentration: A systematic review and meta-analysis. Int J Environ Res Public Health. 2019;16(17):3020.
  • 44
    Cariolou M, Cupp MA, Evangelou E, Tzoulaki I, Berlanga-Taylor AJ. Importance of Vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: A systematic review and meta-analysis. BMJ Open BMJ Open. 2019;9(5):e027666.
  • 45
    Gou X, Pan L, Tang F, Gao H, Xiao D. The association between Vitamin D status and tuberculosis in children: A meta-analysis. Medicine (Baltimore). 2018;97(35):e12179.
  • 46
    Huang SJ, Wang XH, Liu ZD, Cao WL, Han Y, Ma AG, et al. Vitamin D deficiency and the risk of tuberculosis: A meta-analysis. Drug Des Devel Ther. 2017;11:91-102.
  • 47
    Jat KR. Vitamin D deficiency and lower respiratory tract infections in children: a systematic review and meta-analysis of observational studies. Trop Doct. 2017;47(1):77-84.
  • 48
    Feng H, Xun P, Pike K, Wills AK, Chawes BL, Bisgaard H, et al. In utero exposure to 25-hydroxyvitamin D and risk of childhood asthma, wheeze, and respiratory tract infections: A meta-analysis of birth cohort studies. J Allergy Clin Immunol. 2017;139(5):1508-17.
  • 49
    Zhang J, Chen C, Yang J. Effectiveness of vitamin D supplementation on the outcome of pulmonary tuberculosis treatment in adults: A meta-analysis of randomized controlled trials. Chin Med J (Engl). 2019;132(24):2950-9.
  • 50
    Wu HX, Xiong XF, Zhu M, Wei J, Zhuo KQ, Cheng DY. Effects of vitamin D supplementation on the outcomes of patients with pulmonary tuberculosis: A systematic review and meta-analysis. BMC Pulm Med. 2018;18(1):108.
  • 51
    Yakoob MY, Salam RA, Khan FR, Bhutta ZA. Vitamin D supplementation for preventing infections in children under five years of age. Cochrane Database Syst Rev. 2016;11(11):CD008824.
  • 52
    Vuichard Gysin D, Dao D, Gysin CM, Lytvyn L, Loeb M. Effect of vitamin D3 supplementation on respiratory tract infections in healthy individuals: A systematic review and meta-Analysis of randomized controlled trials. PLoS One. 2016;11(9):e0162996.

Publication Dates

  • Publication in this collection
    28 Aug 2020
  • Date of issue
    Sep-Oct 2020

History

  • Received
    17 May 2020
  • Accepted
    30 July 2020
Sociedade Brasileira de Endocrinologia e Metabologia Rua Botucatu, 572 - Conjuntos 81/83, 04023-061 São Paulo SP Brasil, Tel: (55 11) 5575-0311 - São Paulo - SP - Brazil
E-mail: aem.editorial.office@endocrino.org.br