Vitamin D deficiency associates inversely with COVID-19 risks; might avoidance of vitamin D inadequacy reduce those risks?
Main Article Content
Abstract
The risks of COVID-19, whether of becoming infected, needing intensive care or dying, consistently relate inversely to vitamin D status [serum 25(OH)D concentration], but low 25(OH)D is not just due to COVID-19 since they are seen in relation to pre-pandemic 25(OH)D values, both in individual cohorts and across many populations. Furthermore, many recognised risk factors for increased COVID-19 severity themselves reduce vitamin D status [e.g., obesity, dark skin, indoor lifestyles, low socio-economic status and increasing age], which complicates data analyses. Vitamin D has many mechanistic effects likely to provide adjunctive benefits protecting against COVID-19 severity. For example, vitamin D reduces the risks of microbial infection by promoting innate immunity and reduces tissue damage in severe infections by modulating the severity of adaptive immune responses. The protective mechanistic effects of correcting vitamin D inadequacy discussed support the view that increasing vitamin D status should reduce COVID-19 risks. However, many trials of cholecalciferol treatment have failed to do so, probably because it takes many weeks to raise serum 25(OH)D levels adequately whilst the increasing clinical use of the 25(OH)D metabolite [calcifediol] in COVID-19 treatment, which raises serum 25(OH)D concentrations rapidly, has led to reports of clinical benefits in COVID-19 illness.
Keywords:
Vitamin D deficiency, COVID-19
Article Details
How to Cite
BOUCHER, Barbara J.
Vitamin D deficiency associates inversely with COVID-19 risks; might avoidance of vitamin D inadequacy reduce those risks?.
Medical Research Archives, [S.l.], v. 12, n. 4, may 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5382>. Date accessed: 03 july 2024.
doi: https://doi.org/10.18103/mra.v12i4.5382.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Seyed-Alinaghi S, Shahidi R, Mojdeganlou H, Akhtaran FK, Maroufi SF, Maroufi SP, et al. The effect of macronutrient and micronutrient supplements on COVID-19: an umbrella review. J Health Popul Nutr. 2024.;43(1):16. doi: 10.1186/s41043-024-00504-8. ;
2. Mercola J, Grant WB, Wagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients. 2020;31;12(11):33 61. doi: 10.3390/nu12113361.
3. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-78. doi: 10.1016.
4. Dror AA, Morozov N, Daoud A, Namir Y, Yakir O, Shachar Y et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022; 17(2):e0263069. doi: 10.1371/journal.pone.0263069
5. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020;15(9):e0239252. Doi : 10.1371/journal..
6. Ahmad AS, Juber NF, Al-Naseri H, Heumann C, Ali R, Oliver T. Association between Average Vitamin D Levels and COVID-19 Mortality in 19 European Countries-A Population-Based Study. Nutrients. 2023;15(22):4818. doi: 10.3390/nu 15224818.
7. Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, et al. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol. 2019;180(4):23-54. doi: 10.1530/EJE-18-0736.
8. Adami S, Romagnoli E, Carnevale V, Scillitani A, Giusti A, Rossini M, et al. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Linee guida su prevenzione e trattamento dell'ipovitamino si D con colecalciferolo. SIOMMMS [Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. Reumatismo. 2011;63( 3):129-147. Italian. doi: 10.4081/reumatismo.
9. Villasis-Keever MA, López-Alarcón MG, Miranda-Novales G, Zurita-Cruz JN, Barrada-Vázquez AS, González-Ibarra J, et al. Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial. Arch Med Res. 2022;53(4):423-430. doi: 10.1016/j.arcmed 2022.04.003.
10. Ismailova A, White JH. Vitamin D, infections and immunity. Rev Endocr Metab Disord. 2022;23(2):265-277. doi: 10.1007/s11 154-021-09679-5.
11. Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70(7):617-24. doi: 10.1136/thoraxjnl-2014-206680.
12. Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023;186(2):279-286.e8. doi : 10.1016/j.cell.2022.12.018.
13.Malek Mahdavi A. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19. Rev Med Virol. 2020;30(5):e2119. doi: 10.1002/rmv.2119.
14. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2): 229-238. doi: 10.1172/JCI15219..
15. Martín Giménez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ, et al. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci. 2020;254:117808. doi: 10.1016/j.lfs.2020.117808..
16. Quesada-Gomez JM, Entrenas-Castillo M, Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J Steroid Biochem Mol Biol. 2020; 202:105719. doi: 10.1016/j.jsbmb.2020.105719.
17. Bishop E, Ismailova A, Dimeloe S, Hewison M, White JH. Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory. JBMR Plus. 2020;5(1):e10405. doi: 10.1002/jbm4.10405.
18. Chung C, Silwal P, Kim I, Modlin RL, Jo EK. Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection. Immune Netw. 2020;20(2):e12. doi: 10.4110/in.2020.20.e12.
19. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-177 3. doi: 10.1126/science.1123933..
20. Clark GJ, Angel N, Kato M, López JA, MacDonald K, Vuckovic S, et al. The role of dendritic cells in the innate immune system. Microbes Infect. 2000;2(3):257-272. doi: 10.1 016/s1286-4579(00)00302-6.
21. Wu N, Joyal-Desmarais K, Ribeiro PAB, Vieira AM, Stojanovic J, Sanuade C, et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir Med. 2023;11(5):439-452. doi: 10.1016 /S2213-2600(23)00015-2.
22. Gray R, Boyle I, DeLuca HF. Vitamin D metabolism: the role of kidney tissue. Science. 1971;172(3989):1232-1234. doi: 10.1126/scie nce.172.3989.1232.
23. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86(2):888-894. doi: 10.1210/jce m.86.2.7220..
24. White JH. Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection. Arch Biochem Biophys. 2012;523(1): 58-63. doi: 10.1016/j.abb.2011.11.006
25. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, et al. Soc Open Sci. 2020;7(12):201912. doi: 10.1098/rsos.201912.
26. Elkhwanky MS, Kummu O, Piltonen TT, Laru J, Morin-Papunen L, Mutikainen M, et al. Obesity Represses CYP2R1, the Vitamin D 25-Hydroxylase, in the Liver and Extrahepatic Tissues. JBMR Plus. 2020;4(11):e10397. doi: 10.1002/jbm4.10397.
27.Boucher BJ. The problems of vitamin d insufficiency in older people. Aging Dis. 2012;3(4):313-329. Epub 2012 Jun 6.
28. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(7):1911-1930. doi: 10.1210/jc.2011-0385.
29. O'Neill CM, Kazantzidis A, Ryan MJ, Barber N, Sempos CT, Durazo-Arvizu RA, et al. Seasonal Changes in Vitamin D-Effective UVB Availability in Europe and Associations with Population Serum 25-Hydroxyvitamin D. Nutrients. 2016; 8(9):533. doi: 10.3390/nu809 0533.
30. Shetty AJ, Banerjee M, Prasad TN, Bhadada SK, Pal R. Do vitamin D levels or supplementation play A role in COVID-19 outcomes?-a narrative review. Ann Palliat Med. 2024;13(1):162-177. doi: 10.21037/apm-23-113
31. Hsia CCW, Ravikumar P, Ye J. Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction. Bone. 2017; 100:10 0-109. doi: 10.1016/j.bone.2017.03.047.
32. Poursistany H, Azar ST, Azar MT, Raeisi S. The current and emerging Klotho-enhancement strategies. Biochem Biophys Res Commun. 2024;693:149357. doi: 10.1016 /j.bbrc.2023.149357..
33. Gayan-Ramirez G, Janssens W. Vitamin D Actions: The Lung Is a Major Target for Vitamin D, FGF23, and Klotho. JBMR Plus. 2021;5(12):e10569. doi: 10.1002/jbm4.10569.
34. Charoenngam N, Shirvani A, Holick MF. Vitamin D and Its Potential Benefit for the COVID-19 Pandemic. Endocr Pract. 2021;27(5 ):484-493. doi: 10.1016/j.eprac.2021.03.006.
35. Carlberg C. Genomic signaling of vitamin D. Steroids. 2023; 198: 109271. doi: 10.1016/j. steroids.2023.109271.
36. Cheng Q, Li YC, Boucher BJ, Leung PS. A novel role for vitamin D: modulation of expression and function of the local renin-angiotensin system in mouse pancreatic islets. Diabetologia. 2011; 54(8):2077-2081. doi: 10 .1007/s00125-011-2100-1.
37. Cheng S, So WY, Zhang D, Cheng Q, Boucher BJ, Leung PS. Calcitriol Reduces Hepatic Triglyceride Accumulation and Glucose Output Through Ca2+/CaMKKβ/ AMPK Activation Under Insulin-Resistant Conditions in Type 2 Diabetes Mellitus. Curr Mol Med. 2016;16(8):747-758. doi: 10.2174/1 566524016666160920111407.
38. Pinheiro MM, Fabbri A, Infante M. Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i). Immunotherapy. 2021; 13(9):753-765. doi: 10.2217/imt-2020-0349.
39. Sharif-Askari FS, Hafezi S, Sharif-Askari NS, Alsayed HAH, Mdkhana B, Selvakumar B, et al. Vitamin D modulates systemic inflammation in patients with severe COVID-19. Life Sci. 2022; 307:120909. doi: 10.1016/j. lfs.2022.120909.
40. Zsichla L, Müller V. Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors. Viruses. 2023;15(1):17 5. doi: 10.3390/v15010175.
41. Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017 Jun;18(2):153-165. doi: 10.1007/ s11154-017-9424-1. PMID: 28516265.
42. Sauneuf B, Brunet J, Lucidarme O, du Cheyron D. Prevalence and risk factors of vitamin D deficiency in critically ill patients. Inflamm Allergy Drug Targets. 2013;12(4):223 -229. doi: 10.2174/18715281113129990045..
43. Vijay GS, Ghonge S, Vajjala SM, Palal D. Prevalence of Vitamin D Deficiency in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study. Cureus. 2023;15(5):e38952. doi: 10.77 59/cureus.38952.
44. Jolliffe DA, Holt H, Greenig M, Talaei M, Perdek N, Pfeffer P, et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT). BMJ. 2022;378 :e071230. doi: 10.1136/bmj-2022-071230.
45. Ozonoff A, Schaenman J, Jayavelu ND, Milliren CE, Calfee CS, Cairns CB, et al; IMPACC study group members. Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study. EBioMedicine. 2022;83: 104208. doi: 10.1016/j.ebiom.2022.104208. Erratum in: EBioMedicine. 2023;98: 104860
46. Hyppönen E, Boucher BJ. Avoidance of vitamin D deficiency in pregnancy in the United Kingdom: the case for a unified approach in National policy. Br J Nutr. 2010; 104(3):309-314. doi: 10.1017/S0007114510002436..
47.Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, et al. The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr. 2017;105(6):1512-1520. doi: 10.394 5/ajcn.116.151415.
48. Laaksi IT, Ruohola JP, Ylikomi TJ, Auvinen A, Haataja RI, Pihlajamäki HK, et al. Vitamin D fortification as public health policy: significant improvement in vitamin D status in young Finnish men. Eur J Clin Nutr. 2006;60(8):1035-1038. doi: 10.1038/sj.ejcn.1602414.
49. Aguiar M, Andronis L, Pallan M, Högler W, Frew E. The economic case for prevention of population vitamin D deficiency: a modelling study using data from England and Wales. Eur J Clin Nutr. 2020;74(5):825-833. doi: 10.1038 /s41430-019-0486-x.
50. Pérez-Escamilla R. Periconceptional folic acid and neural tube defects: public health issues. Bull Pan Am Health Organ. 1995;29(3): 250-63. PMID: 8520610.
51. Boucher BJ. Discrepancies between current guidance from NICE on the treatment of vitamin D deficiency and the recommended daily amounts [RDAs] for its prevention in the UK. Expert Rev Endocrinol Metab. 2022;17(3): 201-203. doi: 10.1080/17446651.2022.2067143.
52.https://www.thetimes.co.uk/article/vitamin-d-are-you-sure-youre-getting-enough-0hmqjxdjq accessed Feb 28th 2024
53. personal observation:- 2021-2023
54. Dowdy JC, Sayre RM, Holick MF. Holick’s rule and vitamin D from sunlight. J Steroid Biochem Mol Biol. 2020;121(1-2):328-330. doi: 10.1016/j.jsbmb.2010.04.002.
55. Chaplin G, Jablonski NG. Vitamin D and the evolution of human depigmentation. Am J Phys Anthropol. 2009 Aug;139(4):451-61. doi: 10.1002/ajpa.21079. PMID: 19425101.
56. https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adultsac. Accessed March 2nd 2024
57. Scragg R. Emerging Evidence of Thresholds for Beneficial Effects from Vitamin D Supplementation. Nutrients. 2018;10(5):56. doi: 10.3390/nu10050561.
58. Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, et al. D2d Research Group. Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care. 2020;43 (12):2916-2922. doi: 10.2337/dc20-1765.
59. Pittas AG, Kawahara T, Jorde R, Dawson Hughes B, Vickery EM, Angellotti E, et al. Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials. Ann Intern Med. 2023;176(3):355-363. doi: 10.7326/M22-3018.
60. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Land). 2021;21(1):e48-e51. doi: 10.7861/clinmed.2020-0858.
61. Pludowski P, Grant WB, Karras SN, Zittermann A, Pilz S. Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population. Nutrients. 2024;16(3):391 . doi: 10.3390/nu16030391.
62. Hosseini B, El Abd A, Ducharme FM. Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis. Nutrients. 2022;14 (10):2134. doi: 10.3390/nu14102134
63. Mazess RB, Bischoff-Ferrari HA, Dawson-Hughes B. Vitamin D: Bolus Is Bogus-A Narrative Review. JBMR Plus. 2021 Oct 30;5(12):e10567. doi: 10.1002/jbm4.10567.
64. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, Subramanian S, Thickett D. Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19. Clin Med (Lond). 2021 Mar;21(2):e 144-e149. doi: 10.7861/clinmed.2021-0035.
65. Singh A, Rastogi A, Puri GD, Ganesh V, Naik NB, Kajal K, et al. Therapeutic high- dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double blind, placebo-controlled study (SHADE-S). J Public Health (Ox. 2024; fdae007. doi: 10.1 093/pubmed/fdae007.
66. Annweiler C, Beaudenon M, Gautier J, Gonsard J, Boucher S, Chapelet G, et al. COVIT-TRIAL study group. High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial. PLoS Med. 2022 May 31;19(5) :e1003999. doi: 10.1371/journal .pmed.1003999.
67. Quesada-Gomez JM, Lopez-Miranda J, Entrenas-Castillo M, Casado-Diaz A, Nogues Y Solans X, et al. Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol. Nutrients. 2022;14(13):2716. doi: 10.3390/nu 14132716.
68. Rust P, Ekmekcioglu C. The Role of Diet and Specific Nutrients during the COVID-19 Pandemic: What Have We Learned over the Last Three Years? Int J Environ Res Public Health. 2023 Apr 4;20(7):5400. doi: 10.3390/ijerph20075400.
69. Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements and risk of coronavIrus disease 2019 (COVID-19) infection: a prospective study in UK Biobank. Am J Clin Nutr. 2021;113(5):1275-1281. doi:10.1093/ajcn/nqaa381
70. Mingiano C, Picchioni T, Cavati G, Pirrotta F, Calabrese M, Nuti R, et al. Vitamin D Deficiency in COVID-19 Patients and Role of Calcifediol Supplementation. Nutrients. 2023;15(15):3392. doi: 10.3390/nu15153392
71. Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers. PLoS One. 2014;9(11):e111265. doi: 10.1371/journ al.pone.0111265.
72. Jodar E, Campusano C, de Jongh RT, Holick MF. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. Eur J Nutr. 2023;62(4):1579-1597. doi: 10.1007/s00394-023-03103-1.
73. Sartini M, Del Puente F, Oliva M, Carbone A, Bobbio N, Schinca E. et al. Preventative vitamin D supplementation and risks for COVID-19 infection: a systematic review and meta- analysis. Nutrients.2024;16:679, doi.or g/10.3390/nu16050679
2. Mercola J, Grant WB, Wagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity. Nutrients. 2020;31;12(11):33 61. doi: 10.3390/nu12113361.
3. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73-78. doi: 10.1016.
4. Dror AA, Morozov N, Daoud A, Namir Y, Yakir O, Shachar Y et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022; 17(2):e0263069. doi: 10.1371/journal.pone.0263069
5. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One. 2020;15(9):e0239252. Doi : 10.1371/journal..
6. Ahmad AS, Juber NF, Al-Naseri H, Heumann C, Ali R, Oliver T. Association between Average Vitamin D Levels and COVID-19 Mortality in 19 European Countries-A Population-Based Study. Nutrients. 2023;15(22):4818. doi: 10.3390/nu 15224818.
7. Lips P, Cashman KD, Lamberg-Allardt C, Bischoff-Ferrari HA, Obermayer-Pietsch B, et al. Current vitamin D status in European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement of the European Calcified Tissue Society. Eur J Endocrinol. 2019;180(4):23-54. doi: 10.1530/EJE-18-0736.
8. Adami S, Romagnoli E, Carnevale V, Scillitani A, Giusti A, Rossini M, et al. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Linee guida su prevenzione e trattamento dell'ipovitamino si D con colecalciferolo. SIOMMMS [Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. Reumatismo. 2011;63( 3):129-147. Italian. doi: 10.4081/reumatismo.
9. Villasis-Keever MA, López-Alarcón MG, Miranda-Novales G, Zurita-Cruz JN, Barrada-Vázquez AS, González-Ibarra J, et al. Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial. Arch Med Res. 2022;53(4):423-430. doi: 10.1016/j.arcmed 2022.04.003.
10. Ismailova A, White JH. Vitamin D, infections and immunity. Rev Endocr Metab Disord. 2022;23(2):265-277. doi: 10.1007/s11 154-021-09679-5.
11. Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70(7):617-24. doi: 10.1136/thoraxjnl-2014-206680.
12. Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023;186(2):279-286.e8. doi : 10.1016/j.cell.2022.12.018.
13.Malek Mahdavi A. A brief review of interplay between vitamin D and angiotensin-converting enzyme 2: Implications for a potential treatment for COVID-19. Rev Med Virol. 2020;30(5):e2119. doi: 10.1002/rmv.2119.
14. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110(2): 229-238. doi: 10.1172/JCI15219..
15. Martín Giménez VM, Inserra F, Tajer CD, Mariani J, Ferder L, Reiter RJ, et al. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci. 2020;254:117808. doi: 10.1016/j.lfs.2020.117808..
16. Quesada-Gomez JM, Entrenas-Castillo M, Bouillon R. Vitamin D receptor stimulation to reduce acute respiratory distress syndrome (ARDS) in patients with coronavirus SARS-CoV-2 infections: Revised Ms SBMB 2020_166. J Steroid Biochem Mol Biol. 2020; 202:105719. doi: 10.1016/j.jsbmb.2020.105719.
17. Bishop E, Ismailova A, Dimeloe S, Hewison M, White JH. Vitamin D and Immune Regulation: Antibacterial, Antiviral, Anti-Inflammatory. JBMR Plus. 2020;5(1):e10405. doi: 10.1002/jbm4.10405.
18. Chung C, Silwal P, Kim I, Modlin RL, Jo EK. Vitamin D-Cathelicidin Axis: at the Crossroads between Protective Immunity and Pathological Inflammation during Infection. Immune Netw. 2020;20(2):e12. doi: 10.4110/in.2020.20.e12.
19. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770-177 3. doi: 10.1126/science.1123933..
20. Clark GJ, Angel N, Kato M, López JA, MacDonald K, Vuckovic S, et al. The role of dendritic cells in the innate immune system. Microbes Infect. 2000;2(3):257-272. doi: 10.1 016/s1286-4579(00)00302-6.
21. Wu N, Joyal-Desmarais K, Ribeiro PAB, Vieira AM, Stojanovic J, Sanuade C, et al. Long-term effectiveness of COVID-19 vaccines against infections, hospitalisations, and mortality in adults: findings from a rapid living systematic evidence synthesis and meta-analysis up to December, 2022. Lancet Respir Med. 2023;11(5):439-452. doi: 10.1016 /S2213-2600(23)00015-2.
22. Gray R, Boyle I, DeLuca HF. Vitamin D metabolism: the role of kidney tissue. Science. 1971;172(3989):1232-1234. doi: 10.1126/scie nce.172.3989.1232.
23. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab. 2001;86(2):888-894. doi: 10.1210/jce m.86.2.7220..
24. White JH. Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection. Arch Biochem Biophys. 2012;523(1): 58-63. doi: 10.1016/j.abb.2011.11.006
25. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, et al. Soc Open Sci. 2020;7(12):201912. doi: 10.1098/rsos.201912.
26. Elkhwanky MS, Kummu O, Piltonen TT, Laru J, Morin-Papunen L, Mutikainen M, et al. Obesity Represses CYP2R1, the Vitamin D 25-Hydroxylase, in the Liver and Extrahepatic Tissues. JBMR Plus. 2020;4(11):e10397. doi: 10.1002/jbm4.10397.
27.Boucher BJ. The problems of vitamin d insufficiency in older people. Aging Dis. 2012;3(4):313-329. Epub 2012 Jun 6.
28. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96(7):1911-1930. doi: 10.1210/jc.2011-0385.
29. O'Neill CM, Kazantzidis A, Ryan MJ, Barber N, Sempos CT, Durazo-Arvizu RA, et al. Seasonal Changes in Vitamin D-Effective UVB Availability in Europe and Associations with Population Serum 25-Hydroxyvitamin D. Nutrients. 2016; 8(9):533. doi: 10.3390/nu809 0533.
30. Shetty AJ, Banerjee M, Prasad TN, Bhadada SK, Pal R. Do vitamin D levels or supplementation play A role in COVID-19 outcomes?-a narrative review. Ann Palliat Med. 2024;13(1):162-177. doi: 10.21037/apm-23-113
31. Hsia CCW, Ravikumar P, Ye J. Acute lung injury complicating acute kidney injury: A model of endogenous αKlotho deficiency and distant organ dysfunction. Bone. 2017; 100:10 0-109. doi: 10.1016/j.bone.2017.03.047.
32. Poursistany H, Azar ST, Azar MT, Raeisi S. The current and emerging Klotho-enhancement strategies. Biochem Biophys Res Commun. 2024;693:149357. doi: 10.1016 /j.bbrc.2023.149357..
33. Gayan-Ramirez G, Janssens W. Vitamin D Actions: The Lung Is a Major Target for Vitamin D, FGF23, and Klotho. JBMR Plus. 2021;5(12):e10569. doi: 10.1002/jbm4.10569.
34. Charoenngam N, Shirvani A, Holick MF. Vitamin D and Its Potential Benefit for the COVID-19 Pandemic. Endocr Pract. 2021;27(5 ):484-493. doi: 10.1016/j.eprac.2021.03.006.
35. Carlberg C. Genomic signaling of vitamin D. Steroids. 2023; 198: 109271. doi: 10.1016/j. steroids.2023.109271.
36. Cheng Q, Li YC, Boucher BJ, Leung PS. A novel role for vitamin D: modulation of expression and function of the local renin-angiotensin system in mouse pancreatic islets. Diabetologia. 2011; 54(8):2077-2081. doi: 10 .1007/s00125-011-2100-1.
37. Cheng S, So WY, Zhang D, Cheng Q, Boucher BJ, Leung PS. Calcitriol Reduces Hepatic Triglyceride Accumulation and Glucose Output Through Ca2+/CaMKKβ/ AMPK Activation Under Insulin-Resistant Conditions in Type 2 Diabetes Mellitus. Curr Mol Med. 2016;16(8):747-758. doi: 10.2174/1 566524016666160920111407.
38. Pinheiro MM, Fabbri A, Infante M. Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i). Immunotherapy. 2021; 13(9):753-765. doi: 10.2217/imt-2020-0349.
39. Sharif-Askari FS, Hafezi S, Sharif-Askari NS, Alsayed HAH, Mdkhana B, Selvakumar B, et al. Vitamin D modulates systemic inflammation in patients with severe COVID-19. Life Sci. 2022; 307:120909. doi: 10.1016/j. lfs.2022.120909.
40. Zsichla L, Müller V. Risk Factors of Severe COVID-19: A Review of Host, Viral and Environmental Factors. Viruses. 2023;15(1):17 5. doi: 10.3390/v15010175.
41. Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017 Jun;18(2):153-165. doi: 10.1007/ s11154-017-9424-1. PMID: 28516265.
42. Sauneuf B, Brunet J, Lucidarme O, du Cheyron D. Prevalence and risk factors of vitamin D deficiency in critically ill patients. Inflamm Allergy Drug Targets. 2013;12(4):223 -229. doi: 10.2174/18715281113129990045..
43. Vijay GS, Ghonge S, Vajjala SM, Palal D. Prevalence of Vitamin D Deficiency in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study. Cureus. 2023;15(5):e38952. doi: 10.77 59/cureus.38952.
44. Jolliffe DA, Holt H, Greenig M, Talaei M, Perdek N, Pfeffer P, et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT). BMJ. 2022;378 :e071230. doi: 10.1136/bmj-2022-071230.
45. Ozonoff A, Schaenman J, Jayavelu ND, Milliren CE, Calfee CS, Cairns CB, et al; IMPACC study group members. Phenotypes of disease severity in a cohort of hospitalized COVID-19 patients: Results from the IMPACC study. EBioMedicine. 2022;83: 104208. doi: 10.1016/j.ebiom.2022.104208. Erratum in: EBioMedicine. 2023;98: 104860
46. Hyppönen E, Boucher BJ. Avoidance of vitamin D deficiency in pregnancy in the United Kingdom: the case for a unified approach in National policy. Br J Nutr. 2010; 104(3):309-314. doi: 10.1017/S0007114510002436..
47.Jääskeläinen T, Itkonen ST, Lundqvist A, Erkkola M, Koskela T, Lakkala K, et al. The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr. 2017;105(6):1512-1520. doi: 10.394 5/ajcn.116.151415.
48. Laaksi IT, Ruohola JP, Ylikomi TJ, Auvinen A, Haataja RI, Pihlajamäki HK, et al. Vitamin D fortification as public health policy: significant improvement in vitamin D status in young Finnish men. Eur J Clin Nutr. 2006;60(8):1035-1038. doi: 10.1038/sj.ejcn.1602414.
49. Aguiar M, Andronis L, Pallan M, Högler W, Frew E. The economic case for prevention of population vitamin D deficiency: a modelling study using data from England and Wales. Eur J Clin Nutr. 2020;74(5):825-833. doi: 10.1038 /s41430-019-0486-x.
50. Pérez-Escamilla R. Periconceptional folic acid and neural tube defects: public health issues. Bull Pan Am Health Organ. 1995;29(3): 250-63. PMID: 8520610.
51. Boucher BJ. Discrepancies between current guidance from NICE on the treatment of vitamin D deficiency and the recommended daily amounts [RDAs] for its prevention in the UK. Expert Rev Endocrinol Metab. 2022;17(3): 201-203. doi: 10.1080/17446651.2022.2067143.
52.https://www.thetimes.co.uk/article/vitamin-d-are-you-sure-youre-getting-enough-0hmqjxdjq accessed Feb 28th 2024
53. personal observation:- 2021-2023
54. Dowdy JC, Sayre RM, Holick MF. Holick’s rule and vitamin D from sunlight. J Steroid Biochem Mol Biol. 2020;121(1-2):328-330. doi: 10.1016/j.jsbmb.2010.04.002.
55. Chaplin G, Jablonski NG. Vitamin D and the evolution of human depigmentation. Am J Phys Anthropol. 2009 Aug;139(4):451-61. doi: 10.1002/ajpa.21079. PMID: 19425101.
56. https://cks.nice.org.uk/topics/vitamin-d-deficiency-in-adultsac. Accessed March 2nd 2024
57. Scragg R. Emerging Evidence of Thresholds for Beneficial Effects from Vitamin D Supplementation. Nutrients. 2018;10(5):56. doi: 10.3390/nu10050561.
58. Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, et al. D2d Research Group. Intratrial Exposure to Vitamin D and New-Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study. Diabetes Care. 2020;43 (12):2916-2922. doi: 10.2337/dc20-1765.
59. Pittas AG, Kawahara T, Jorde R, Dawson Hughes B, Vickery EM, Angellotti E, et al. Vitamin D and Risk for Type 2 Diabetes in People With Prediabetes : A Systematic Review and Meta-analysis of Individual Participant Data From 3 Randomized Clinical Trials. Ann Intern Med. 2023;176(3):355-363. doi: 10.7326/M22-3018.
60. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Land). 2021;21(1):e48-e51. doi: 10.7861/clinmed.2020-0858.
61. Pludowski P, Grant WB, Karras SN, Zittermann A, Pilz S. Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population. Nutrients. 2024;16(3):391 . doi: 10.3390/nu16030391.
62. Hosseini B, El Abd A, Ducharme FM. Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis. Nutrients. 2022;14 (10):2134. doi: 10.3390/nu14102134
63. Mazess RB, Bischoff-Ferrari HA, Dawson-Hughes B. Vitamin D: Bolus Is Bogus-A Narrative Review. JBMR Plus. 2021 Oct 30;5(12):e10567. doi: 10.1002/jbm4.10567.
64. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, Subramanian S, Thickett D. Perspective: Vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: implications for COVID-19. Clin Med (Lond). 2021 Mar;21(2):e 144-e149. doi: 10.7861/clinmed.2021-0035.
65. Singh A, Rastogi A, Puri GD, Ganesh V, Naik NB, Kajal K, et al. Therapeutic high- dose vitamin D for vitamin D-deficient severe COVID-19 disease: randomized, double blind, placebo-controlled study (SHADE-S). J Public Health (Ox. 2024; fdae007. doi: 10.1 093/pubmed/fdae007.
66. Annweiler C, Beaudenon M, Gautier J, Gonsard J, Boucher S, Chapelet G, et al. COVIT-TRIAL study group. High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial. PLoS Med. 2022 May 31;19(5) :e1003999. doi: 10.1371/journal .pmed.1003999.
67. Quesada-Gomez JM, Lopez-Miranda J, Entrenas-Castillo M, Casado-Diaz A, Nogues Y Solans X, et al. Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol. Nutrients. 2022;14(13):2716. doi: 10.3390/nu 14132716.
68. Rust P, Ekmekcioglu C. The Role of Diet and Specific Nutrients during the COVID-19 Pandemic: What Have We Learned over the Last Three Years? Int J Environ Res Public Health. 2023 Apr 4;20(7):5400. doi: 10.3390/ijerph20075400.
69. Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements and risk of coronavIrus disease 2019 (COVID-19) infection: a prospective study in UK Biobank. Am J Clin Nutr. 2021;113(5):1275-1281. doi:10.1093/ajcn/nqaa381
70. Mingiano C, Picchioni T, Cavati G, Pirrotta F, Calabrese M, Nuti R, et al. Vitamin D Deficiency in COVID-19 Patients and Role of Calcifediol Supplementation. Nutrients. 2023;15(15):3392. doi: 10.3390/nu15153392
71. Ekwaru JP, Zwicker JD, Holick MF, Giovannucci E, Veugelers PJ. The importance of body weight for the dose response relationship of oral vitamin D supplementation and serum 25-hydroxyvitamin D in healthy volunteers. PLoS One. 2014;9(11):e111265. doi: 10.1371/journ al.pone.0111265.
72. Jodar E, Campusano C, de Jongh RT, Holick MF. Calcifediol: a review of its pharmacological characteristics and clinical use in correcting vitamin D deficiency. Eur J Nutr. 2023;62(4):1579-1597. doi: 10.1007/s00394-023-03103-1.
73. Sartini M, Del Puente F, Oliva M, Carbone A, Bobbio N, Schinca E. et al. Preventative vitamin D supplementation and risks for COVID-19 infection: a systematic review and meta- analysis. Nutrients.2024;16:679, doi.or g/10.3390/nu16050679