Effects of Vitamin D in the Prophylaxis and Treatment of COVID-19: A Systematic Review
Main Article Content
Abstract
Despite the possible effects of Vitamin D (VD) in decreasing the risk of infections and mortality in some viral diseases, the role of therapeutic VD supplementation in individuals infected with COVID is still obscure. This article reviews the possible effects of VD on COVID-19 severity. MEDLINE–PubMed, EMBASE, and Cochran were searched following PRISMA guidelines. Some studies have reported that VD does not seem to augment the immunogenicity of seasonal vaccines, nor does it significantly reduce the incidence or duration of upper respiratory tract infection, although others have. The reason for not getting a positive or significant difference may be due to inadequate VD treatment levels, and VD may not be that important in immunized individuals with adaptive immunity. VD deficiency is most prevalent in the elderly, obese, men, ethnic minorities with darker skin, people with diabetes, hypertension, and in nursing homes or institutionalized. These are individuals that are at increased risk of severe consequences of COVID-19 such as acute respiratory distress syndrome with the need for mechanical ventilation and death. Perhaps supplementation of VD to adequate VD levels will improve the inflammatory reaction and modulate a faster patient recovery with decreased morbidity and mortality.
Keywords:
COVID-19, SARS-CoV-2, Vitamin D, cholecalciferol
Article Details
How to Cite
BARBALHO, sandra Maria et al.
Effects of Vitamin D in the Prophylaxis and Treatment of COVID-19: A Systematic Review.
Medical Research Archives, [S.l.], v. 10, n. 6, june 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2906>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i6.2906.
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. Huang F, Zhang C, Liu Q, et al. Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury. PLoS Pathog. 2020;16(3):e1008341.
2. Patel A, Jernigan DB. Initial Public Health Response and Interim Clinical Guidance for the 2019 Novel Coronavirus Outbreak - United States, December 31, 2019-February 4, 2020. MMWR Morbidity and mortality weekly report. 2020;69(5):140-146.
3. Saponaro F, Franzini M, Okoye C, et al. Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19? Frontiers in immunology. 2021;12:745713.
4. Choteau M, Scohy A, Messe S, et al. Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection. Scientific reports. 2022;12(1):2077.
5. Li H, Zheng S, Liu F, Liu W, Zhao R. Fighting against COVID-19: Innovative strategies for clinical pharmacists. Res Social Adm Pharm. 2020.
6. Zayet S, N'Dri Juliette KO, Royer PY, Toko L, Gendrin V, Klopfenstein T. Coronavirus disease 2019: new things to know! J Med Virol. 2020.
7. Kakodkar P, Kaka N, Baig MN. A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19). Cureus. 2020;12(4):e7560.
8. Paybast S, Emami A, Koosha M, Baghalha F. Novel Coronavirus Disease (COVID-19) and Central Nervous System Complications: What Neurologist Need to Know. Acta Neurol Taiwan. 2020;29(1):24-31.
9. Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med. 2020;26(4):506-510.
10. Arabi SM, Ranjbar G, Bahrami LS, Vafa M, Norouzy A. The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis. Nutrition journal. 2020;19(1):11.
11. di Michele F, Talamo A, Niolu C, Siracusano A. Vitamin D and N-Acetyl cysteine supplementation in treatment resistant depressive disorder patients: a general review. Current pharmaceutical design. 2020.
12. Lee C. Controversial Effects of Vitamin D and Related Genes on Viral Infections, Pathogenesis, and Treatment Outcomes. Nutrients. 2020;12(4).
13. Vanherwegen AS, Gysemans C, Mathieu C. Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity. Endocrinol Metab Clin North Am. 2017;46(4):1061-1094.
14. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200.
15. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients. 2020;12(1).
16. Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients. 2020;12(7):2097.
17. Murai IH, Fernandes AL, Antonangelo L, Gualano B, Pereira RMR. Effect of a Single High-Dose Vitamin D3 on the Length of Hospital Stay of Severely 25-Hydroxyvitamin D-Deficient Patients with COVID-19. Clinics (Sao Paulo, Brazil). 2021;76:e3549.
18. Kong J, Zhu X, Shi Y, et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013;27(12):2116-2125.
19. Laird E, McNulty H, Ward M, et al. Vitamin D deficiency is associated with inflammation in older Irish adults. The Journal of clinical endocrinology and metabolism. 2014;99(5):1807-1815.
20. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-422.
21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, w264.
22. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical research ed). 2021;372:n71.
23. Higgins JP, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.
24. Dzieciatkowski T, Szarpak L, Filipiak KJ, Jaguszewski M, Ladny JR, Smereka J. COVID-19 challenge for modern medicine. Cardiol J. 2020.
25. Giwa AL, Desai A, Duca A. Novel 2019 coronavirus SARS-CoV-2 (COVID-19): an overview for emergency clinicians. Pediatr Emerg Med Pract. 2020;17(5):1-24.
26. Moore HB, Barrett CD, Moore EE, et al. Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)? J Trauma Acute Care Surg. 2020.
27. Ye Q, Wang B, Mao J. Cytokine Storm in COVID-19 and Treatment. J Infect. 2020.
28. Li J, Fan JG. Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease. J Clin Transl Hepatol. 2020;8(1):13-17.
29. Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res. 2015;35(4):252-264.
30. Chaudhry F, Lavandero S, Xie X, et al. Manipulation of ACE2 expression in COVID-19. 2020;7(2):e001424.
31. Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgraduate Medical Journal. 2022;98(1156):87.
32. Elamir YM, Amir H, Lim S, et al. A randomized pilot study using calcitriol in hospitalized COVID-19 patients. Bone. 2022;154:116175.
33. Cannata-Andía JB, Díaz-Sottolano A, Fernández P, et al. A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D-a randomised multicentre international clinical trial. BMC Med. 2022;20(1):83.
34. Karonova TL, Chernikova AT, Golovatyuk KA, et al. Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers. Nutrients. 2022;14(3).
35. Sabico S, Enani MA, Sheshah E, et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients. 2021;13(7).
36. Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. Jama. 2021;325(11):1053-1060.
37. Fernandes AL, Murai IH, Reis BZ, et al. Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19. The American journal of clinical nutrition. 2022;115(3):790-798.
38. Lakkireddy M, Gadiga SG, Malathi RD, et al. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Sci Rep. 2021;11(1):10641.
39. Sánchez-Zuno GA, González-Estevez G, Matuz-Flores MG, et al. Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation. J Clin Med. 2021;10(11).
40. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020;203:105751.
41. Maghbooli Z, Sahraian MA, Jamalimoghadamsiahkali S, et al. Treatment With 25-Hydroxyvitamin D(3) (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial. Endocr Pract. 2021;27(12):1242-1251.
42. Bae JH, Choe HJ, Holick MF, Lim S. Association of vitamin D status with COVID-19 and its severity : Vitamin D and COVID-19: a narrative review. Rev Endocr Metab Disord. 2022:1-21.
43. Dror AA, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022;17(2):e0263069.
44. Maghbooli Z, Sahraian MA, Ebrahimi M, et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One. 2020;15(9):e0239799.
45. Jolliffe DA, Camargo CA, Jr., Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. medRxiv. 2020.
46. Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Scientific Reports. 2020;10(1):20191.
47. Ginde AA, Mansbach JM, Camargo CA, Jr. 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):384-390.
48. 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;136:321-329.
49. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Bmj. 2017;356:i6583.
50. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj. 2008;336(7650):924-926.
51. Bergman P, Norlin AC, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2(6).
52. Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency andcommunity-acquired pneumonia: A meta-analysis of observational studies. Medicine (Baltimore). 2019;98(38):e17252.
53. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536-1538.
54. Gröber U, Kisters K. Influence of drugs on vitamin D and calcium metabolism. Dermatoendocrinol. 2012;4(2):158-166.
55. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020;11(7):995-998.
56. Laird E, Rhodes J, Kenny R. Vitamin D and Inflammation: Potential Implications for Severity of Covid-19.
57. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA network open. 2020;3(9):e2019722.
58. Katz J, Yue S, Xue W. Increased risk for COVID-19 in patients with vitamin D deficiency. Nutrition (Burbank, Los Angeles County, Calif). 2020;84:111106.
59. Angelidi AM, Belanger MJ, Lorinsky MK, et al. Vitamin D Status is Associated With In-hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients. Paper presented at: Mayo Clinic Proceedings.
60. Pearce SH, Cheetham TD. Diagnosis and management of vitamin D deficiency. Bmj. 2010;340:b5664.
61. Kabbani N, Olds JL. Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk. Mol Pharmacol. 2020;97(5):351-353.
62. Baig AM. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther. 2020;26(5):499-501.
63. Bianconi V, Mannarino MR, Figorilli F, et al. Prevalence of vitamin D deficiency and its prognostic impact in hospitalized patients with COVID-19.
2. Patel A, Jernigan DB. Initial Public Health Response and Interim Clinical Guidance for the 2019 Novel Coronavirus Outbreak - United States, December 31, 2019-February 4, 2020. MMWR Morbidity and mortality weekly report. 2020;69(5):140-146.
3. Saponaro F, Franzini M, Okoye C, et al. Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19? Frontiers in immunology. 2021;12:745713.
4. Choteau M, Scohy A, Messe S, et al. Development of SARS-CoV2 humoral response including neutralizing antibodies is not sufficient to protect patients against fatal infection. Scientific reports. 2022;12(1):2077.
5. Li H, Zheng S, Liu F, Liu W, Zhao R. Fighting against COVID-19: Innovative strategies for clinical pharmacists. Res Social Adm Pharm. 2020.
6. Zayet S, N'Dri Juliette KO, Royer PY, Toko L, Gendrin V, Klopfenstein T. Coronavirus disease 2019: new things to know! J Med Virol. 2020.
7. Kakodkar P, Kaka N, Baig MN. A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19). Cureus. 2020;12(4):e7560.
8. Paybast S, Emami A, Koosha M, Baghalha F. Novel Coronavirus Disease (COVID-19) and Central Nervous System Complications: What Neurologist Need to Know. Acta Neurol Taiwan. 2020;29(1):24-31.
9. Wu JT, Leung K, Bushman M, et al. Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China. Nat Med. 2020;26(4):506-510.
10. Arabi SM, Ranjbar G, Bahrami LS, Vafa M, Norouzy A. The effect of vitamin D supplementation on hemoglobin concentration: a systematic review and meta-analysis. Nutrition journal. 2020;19(1):11.
11. di Michele F, Talamo A, Niolu C, Siracusano A. Vitamin D and N-Acetyl cysteine supplementation in treatment resistant depressive disorder patients: a general review. Current pharmaceutical design. 2020.
12. Lee C. Controversial Effects of Vitamin D and Related Genes on Viral Infections, Pathogenesis, and Treatment Outcomes. Nutrients. 2020;12(4).
13. Vanherwegen AS, Gysemans C, Mathieu C. Regulation of Immune Function by Vitamin D and Its Use in Diseases of Immunity. Endocrinol Metab Clin North Am. 2017;46(4):1061-1094.
14. Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200.
15. Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System-Working in Harmony to Reduce the Risk of Infection. Nutrients. 2020;12(1).
16. Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients. 2020;12(7):2097.
17. Murai IH, Fernandes AL, Antonangelo L, Gualano B, Pereira RMR. Effect of a Single High-Dose Vitamin D3 on the Length of Hospital Stay of Severely 25-Hydroxyvitamin D-Deficient Patients with COVID-19. Clinics (Sao Paulo, Brazil). 2021;76:e3549.
18. Kong J, Zhu X, Shi Y, et al. VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin system. Mol Endocrinol. 2013;27(12):2116-2125.
19. Laird E, McNulty H, Ward M, et al. Vitamin D deficiency is associated with inflammation in older Irish adults. The Journal of clinical endocrinology and metabolism. 2014;99(5):1807-1815.
20. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-422.
21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, w264.
22. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical research ed). 2021;372:n71.
23. Higgins JP, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019.
24. Dzieciatkowski T, Szarpak L, Filipiak KJ, Jaguszewski M, Ladny JR, Smereka J. COVID-19 challenge for modern medicine. Cardiol J. 2020.
25. Giwa AL, Desai A, Duca A. Novel 2019 coronavirus SARS-CoV-2 (COVID-19): an overview for emergency clinicians. Pediatr Emerg Med Pract. 2020;17(5):1-24.
26. Moore HB, Barrett CD, Moore EE, et al. Is There a Role for Tissue Plasminogen Activator (tPA) as a Novel Treatment for Refractory COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS)? J Trauma Acute Care Surg. 2020.
27. Ye Q, Wang B, Mao J. Cytokine Storm in COVID-19 and Treatment. J Infect. 2020.
28. Li J, Fan JG. Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease. J Clin Transl Hepatol. 2020;8(1):13-17.
29. Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res. 2015;35(4):252-264.
30. Chaudhry F, Lavandero S, Xie X, et al. Manipulation of ACE2 expression in COVID-19. 2020;7(2):e001424.
31. Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgraduate Medical Journal. 2022;98(1156):87.
32. Elamir YM, Amir H, Lim S, et al. A randomized pilot study using calcitriol in hospitalized COVID-19 patients. Bone. 2022;154:116175.
33. Cannata-Andía JB, Díaz-Sottolano A, Fernández P, et al. A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D-a randomised multicentre international clinical trial. BMC Med. 2022;20(1):83.
34. Karonova TL, Chernikova AT, Golovatyuk KA, et al. Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers. Nutrients. 2022;14(3).
35. Sabico S, Enani MA, Sheshah E, et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients. 2021;13(7).
36. Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. Jama. 2021;325(11):1053-1060.
37. Fernandes AL, Murai IH, Reis BZ, et al. Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19. The American journal of clinical nutrition. 2022;115(3):790-798.
38. Lakkireddy M, Gadiga SG, Malathi RD, et al. Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Sci Rep. 2021;11(1):10641.
39. Sánchez-Zuno GA, González-Estevez G, Matuz-Flores MG, et al. Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation. J Clin Med. 2021;10(11).
40. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020;203:105751.
41. Maghbooli Z, Sahraian MA, Jamalimoghadamsiahkali S, et al. Treatment With 25-Hydroxyvitamin D(3) (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial. Endocr Pract. 2021;27(12):1242-1251.
42. Bae JH, Choe HJ, Holick MF, Lim S. Association of vitamin D status with COVID-19 and its severity : Vitamin D and COVID-19: a narrative review. Rev Endocr Metab Disord. 2022:1-21.
43. Dror AA, Morozov N, Daoud A, et al. Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness. PLoS One. 2022;17(2):e0263069.
44. Maghbooli Z, Sahraian MA, Ebrahimi M, et al. Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PLoS One. 2020;15(9):e0239799.
45. Jolliffe DA, Camargo CA, Jr., Sluyter JD, et al. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. medRxiv. 2020.
46. Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Scientific Reports. 2020;10(1):20191.
47. Ginde AA, Mansbach JM, Camargo CA, Jr. 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):384-390.
48. 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;136:321-329.
49. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. Bmj. 2017;356:i6583.
50. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj. 2008;336(7650):924-926.
51. Bergman P, Norlin AC, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study. BMJ Open. 2012;2(6).
52. Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency andcommunity-acquired pneumonia: A meta-analysis of observational studies. Medicine (Baltimore). 2019;98(38):e17252.
53. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536-1538.
54. Gröber U, Kisters K. Influence of drugs on vitamin D and calcium metabolism. Dermatoendocrinol. 2012;4(2):158-166.
55. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms. ACS Chem Neurosci. 2020;11(7):995-998.
56. Laird E, Rhodes J, Kenny R. Vitamin D and Inflammation: Potential Implications for Severity of Covid-19.
57. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA network open. 2020;3(9):e2019722.
58. Katz J, Yue S, Xue W. Increased risk for COVID-19 in patients with vitamin D deficiency. Nutrition (Burbank, Los Angeles County, Calif). 2020;84:111106.
59. Angelidi AM, Belanger MJ, Lorinsky MK, et al. Vitamin D Status is Associated With In-hospital Mortality and Mechanical Ventilation: A Cohort of COVID-19 Hospitalized Patients. Paper presented at: Mayo Clinic Proceedings.
60. Pearce SH, Cheetham TD. Diagnosis and management of vitamin D deficiency. Bmj. 2010;340:b5664.
61. Kabbani N, Olds JL. Does COVID19 Infect the Brain? If So, Smokers Might Be at a Higher Risk. Mol Pharmacol. 2020;97(5):351-353.
62. Baig AM. Neurological manifestations in COVID-19 caused by SARS-CoV-2. CNS Neurosci Ther. 2020;26(5):499-501.
63. Bianconi V, Mannarino MR, Figorilli F, et al. Prevalence of vitamin D deficiency and its prognostic impact in hospitalized patients with COVID-19.