Análisis del papel de la vitamina D en la defensa inmunitaria contra la COVID-19 en los adultos mayores
Palabras clave:
envejecimiento, COVID-19, inflamación, vitamina D, infecciones por coronavirus, sistema inmunológico
Resumen
La enfermedad por coronavirus 2019 (COVID-19) fue anunciada como una pandemia mundial por la Organización Mundial de la Salud el 11 de febrero de 2020. A partir de ese momento han surgido desafíos con respecto a cómo apoyar de manera óptima el sistema inmunitario en la población en general, y especialmente en los adultos mayores. Existen muchas evidencias de que la gravedad de las infecciones por SARS-CoV-2 varía ampliamente con la edad, siendo generalmente más severa en los ancianos. Una respuesta inmunitaria óptima depende de una dieta y nutrición adecuadas para contrarrestar adecuadamente la infección. Varios estudios han demostrado la importancia de la vitamina D como un factor clave en la regulación de las respuestas inmunitarias. En esta revisión, analizamos el papel de la vitamina D en la respuesta inmunitaria durante la infección por SARS-CoV-2 con especial énfasis en los adultos mayores.
Citas
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2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181(2):271-80.e8. doi: 10.1016/j.cell.2020.02.052
3. Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. COVID-19 (Novel Coronavirus 2019) - recent trends. Eur Rev Med Pharmacol Sci. 2020; 24(4):2006-11. doi: 10.26355/eurrev_202002_20378
4. Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 2020; 92(5):491-4. doi: 10.1002/jmv.25709
5. Huang X, Wei F, Hu L, Wen L, Chen K. Epidemiology and clinical characteristics of COVID-19. Arch Iran Med. 2020; 23(4):268-71. doi: 10.34172/aim.2020.09
6. Weir EK, Thenappan T, Bhargava M, Chen Y. Does vitamin D deficiency increase the severity of COVID-19? Clin Med (Lond). 2020; 20(4):e107-e108. doi: 10.7861/clinmed.2020-0301
7. DeLuca HF. Chapter one - Vitamin D: Historical overview. En: Litwack G. edited. Vitamins & Hormones. Elsevier; 2016. Series Vitamin D Hormone; Vol.100. p.1-20. doi: 10.1016/bs.vh.2015.11.001
8. Pike JW, Christakos S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol Metab Clin North Am. 2017; 46(4):815-43. doi: 10.1016/j.ecl.2017.07.001
9. Norman AW. The history of the discovery of vitamin D and its daughter steroid hormone. Ann Nutr Metab. 2012; 61(3):199-206. doi: 10.1159/000343104
10. Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan Ch, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011; 31(17):3653-69. doi: 10.1128/MCB.05020-11
11. Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, hormone, and immunomodulator. Nutrients. 2018; 10(11):1656. doi: 10.3390/nu10111656
12. Zhu X, Zhu Y, Li C, Yu J, Ren DD, Qiu S, et al. 1,25 Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by suppressing miR-125b. Int Immunopharmacol. 2019; 67:106-18. doi: 10.1016/j.intimp.2018.12.015
13. 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):236. doi: 10.3390/nu12010236
14. Lang PO, Aspinall R. Vitamin D status and the host resistance to infections: What it is currently (Not) understood. Clin Ther. 2017; 39(5):930-45. doi: 10.1016/j.clinthera.2017.04.004
15. Rondanelli M, Miccono A, Lamburghini S, Avanzato I, Riva A, Allegrini P, et al. Self-care for common colds: The pivotal role of vitamin D, vitamin C, zinc, and echinacea in three main immune interactive clusters (Physical barriers, innate and adaptive immunity) involved during an episode of common colds-practical advice on dosages and on the time to take these nutrients/botanicals in order to prevent or treat common colds. Evid Based Complement Alternat Med. 2018 Apr 29; 2018: ID 5813095. doi: 10.1155/2018/5813095
16. Schröder-Heurich B, von Hardenberg S, Brodowski L, Kipke B, Meyer NV, Borns K, et al. Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells. FASEB J. 2019; 33(8):9142-53. doi: 10.1096/fj.201802750RR
17. Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients. 2020; 12(2):575. doi: 10.3390/nu12020575
18. Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R, Balloch A, et al. Anti-Inflammatory effects of vitamin D on human immune cells in the context of bacterial infection. Nutrients. 2016; 8(12):806. doi: 10.3390/nu8120806
19. Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. 2014; 5:244. doi: 10.3389/fphys.2014.00244
20. Nagaoka I, Suzuki K, Niyonsaba F, Tamura H, Hirata M. Modulation of neutrophil apoptosis by antimicrobial peptides. ISRN Microbiol. 2012; 2012:ID 345791. doi: 10.5402/2012/345791
21. Barlow PG, Beaumont PE, Cosseau C, Mackellar A, Wilkinson TS, Hancock REW, et al. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am J Respir Cell Mol Biol. 2010; 43(6):692-702. doi: 10.1165/rcmb.2009-0250OC
22. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One. 2011; 6(10):e25333. doi: 10.1371/journal.pone.0025333
23. Schögler A, Muster RJ, Kieninger E, Casaulta C, Tapparel C, Jung A, et al. Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. Eur Respir J. 2016; 47(2):520-30. doi: 10.1183/13993003.00665-2015
24. Telcian AG, Zdrenghea MT, Edwards MR, Laza-Stanca V, Mallia P, Johnston SL, et al. Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. Antiviral Res. 2017; 137:93-101. doi: 10.1016/j.antiviral.2016.11.004
25. Campbell GR, Spector SA. Vitamin D inhibits human immunodeficiency virus type 1 and mycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog. 2012; 8(5):e1002689. doi: 10.1371/journal.ppat.1002689
26. Branchett WJ, Lloyd CM. Regulatory cytokine function in the respiratory tract. Mucosal Immunol. 2019; 12(3):589-600. doi: 10.1038/s41385-019-0158-0
27. Bi ChS, Li X, Qu HL, Sun LJ, An Y, Hong YL, et al. Calcitriol inhibits osteoclastogenesis in an inflammatory environment by changing the proportion and function of T helper cell subsets (Th2/Th17). Cell Prolif. 2020; 53(6):e12827. doi: 10.1111/cpr.12827
28. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011; 241(1):260-8. doi: 10.1111/j.1600-065X.2011.01018.x
29. Bishop E, Ismailova A, Dimeloe SK, Hewison M, White JH. Vitamin D and immune regulation: antibacterial, antiviral, anti-inflammatory. JBMR Plus. 2020; 5(1):e10405. doi: 10.1002/jbm4.10405
30. Liu ChY, Zhang ZH, Yang HF, Xu H, Cheng FF, Xu JZ. Effect of vitamin D3 on maturation and antigen-presenting function of dendritic cells treated with mycobacterium tuberculosis. Asian Pac J Trop Med. 2016; 9(1):54-7. doi: 10.1016/j.apjtm.2015.12.011
31. Barragan M, Good M, Kolls JK. Regulation of dendritic cell function by vitamin D. Nutrients. 2015; 7(9):8127-51. doi: 10.3390/nu7095383
32. Fülöp T, Dupuis G, Witkowski JM, Larbi A. The role of immunosenescence in the development of age-related diseases. Rev Invest Clin. 2016; 68(2):84-91
33. Thomas R, Wang W, Su DM. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing. 2020; 17:2. doi: 10.1186/s12979-020-0173-8
34. Gallagher JCh. Vitamin D and aging. Endocrinol Metab Clin North Am. 2013; 42(2):319-32. doi: 10.1016/j.ecl.2013.02.004
35. Ferri E, Casati M, Cesari M, Vitale G, Arosio B. Vitamin D in physiological and pathological aging: Lesson from centenarians. Rev Endocr Metab Disord. 2019; 20(3):273-282. doi: 10.1007/s11154-019-09522-y
36. Aslam MM, John P, Bhatti A, Jahangir S, Kamboh MI. Vitamin D as a principal factor in mediating rheumatoid arthritis-derived immune response. Biomed Res Int. 2019; 2019:3494937. doi: 10.1155/2019/3494937
37. Ebadi M, Montano-Loza AJ. Perspective: improving vitamin D status in the management of COVID-19. Eur J Clin Nutr. 2020; 74(6):856-9. doi: 10.1038/s41430-020-0661-0
38. Honardoost M, Ghavideldarestani M, Khamseh ME. Role of vitamin D in pathogenesis and severity of COVID-19 infection. Arch Physiol Biochem. 2020:1-7. doi: 10.1080/13813455.2020.1792505
39. 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
40. Zemb P, Bergman P, Camargo CA Jr, Cavalier E, Cormier C, Courbebaisse M, et al. Vitamin D deficiency and the COVID-19 pandemic. J Glob Antimicrob Resist. 2020; 22:133-4. doi: 10.1016/j.jgar.2020.05.006
41. Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 2016; 13(7):404-17. doi: 10.1038/nrcardio.2016.73
42. Wu WX, He DR. Low vitamin D levels are associated with the development of deep venous thromboembolic events in patients with ischemic stroke. Clin Appl Thromb Hemost. 2018; 24(9_suppl):69S-75S. doi: 10.1177/1076029618786574
43. Mohammad S, Mishra A, Ashraf MZ. Emerging role of vitamin D and its associated molecules in pathways related to pathogenesis of thrombosis. Biomolecules. 2019; 9(11):649. doi: 10.3390/biom9110649
44. Gruber-Bzura BM. Vitamin D and influenza-prevention or therapy?. Int J Mol Sci. 2018; 19(8):2419. doi: 10.3390/ijms19082419
45. Grant WB, Bhattoa HP, Boucher BJ. Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. J Steroid Biochem Mol Biol. 2017; 173:5-12. doi: 10.1016/j.jsbmb.2017.01.003
46. Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013; 8(6):e65835. doi: 10.1371/journal.pone.0065835
47. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017; 356:i6583. doi: 10.1136/bmj.i6583
48. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019; 380(1):33-44. doi: 10.1056/NEJMoa1809944
49. Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford ChR, 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
50. Perin A, Zanatta E, Pigatto E, Carniello S, Cozzi F. Hypovitaminosis D in an hospitalized old population of Western Friuli. Reumatismo. 2012; 64(3):166-71. doi: 10.4081/reumatismo.2012.166
51. Manios Y, Moschonis G, Lambrinou CP, Tsoutsoulopoulou K, Binou P, Karachaliou A, et al. A systematic review of vitamin D status in southern european countries. Eur J Nutr. 2018; 57(6):2001-36. doi: 10.1007/s00394-017-1564-2
52. Boccardi V, Lapenna M, Gaggi L, Garaffa FM, Croce MF, Baroni M, et al. Hypovitaminosis D: A disease marker in hospitalized very old persons at risk of malnutrition. Nutrients. 2019; 11(1):128. doi: 10.3390/nu11010128
53. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, 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. doi: 10.1016/j.jsbmb.2020.105751
54. Annweiler C, Hanotte B, Grandin de l'Eprevier C, Sabatier JM, Lafaie L, Célarier T. Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol. 2020; 204:105771. doi: 10.1016/j.jsbmb.2020.105771
2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020; 181(2):271-80.e8. doi: 10.1016/j.cell.2020.02.052
3. Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. COVID-19 (Novel Coronavirus 2019) - recent trends. Eur Rev Med Pharmacol Sci. 2020; 24(4):2006-11. doi: 10.26355/eurrev_202002_20378
4. Liu J, Zheng X, Tong Q, Li W, Wang B, Sutter K, et al. Overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses SARS-CoV, MERS-CoV, and 2019-nCoV. J Med Virol. 2020; 92(5):491-4. doi: 10.1002/jmv.25709
5. Huang X, Wei F, Hu L, Wen L, Chen K. Epidemiology and clinical characteristics of COVID-19. Arch Iran Med. 2020; 23(4):268-71. doi: 10.34172/aim.2020.09
6. Weir EK, Thenappan T, Bhargava M, Chen Y. Does vitamin D deficiency increase the severity of COVID-19? Clin Med (Lond). 2020; 20(4):e107-e108. doi: 10.7861/clinmed.2020-0301
7. DeLuca HF. Chapter one - Vitamin D: Historical overview. En: Litwack G. edited. Vitamins & Hormones. Elsevier; 2016. Series Vitamin D Hormone; Vol.100. p.1-20. doi: 10.1016/bs.vh.2015.11.001
8. Pike JW, Christakos S. Biology and mechanisms of action of the vitamin D hormone. Endocrinol Metab Clin North Am. 2017; 46(4):815-43. doi: 10.1016/j.ecl.2017.07.001
9. Norman AW. The history of the discovery of vitamin D and its daughter steroid hormone. Ann Nutr Metab. 2012; 61(3):199-206. doi: 10.1159/000343104
10. Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan Ch, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011; 31(17):3653-69. doi: 10.1128/MCB.05020-11
11. Sassi F, Tamone C, D'Amelio P. Vitamin D: Nutrient, hormone, and immunomodulator. Nutrients. 2018; 10(11):1656. doi: 10.3390/nu10111656
12. Zhu X, Zhu Y, Li C, Yu J, Ren DD, Qiu S, et al. 1,25 Dihydroxyvitamin D regulates macrophage polarization and ameliorates experimental inflammatory bowel disease by suppressing miR-125b. Int Immunopharmacol. 2019; 67:106-18. doi: 10.1016/j.intimp.2018.12.015
13. 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):236. doi: 10.3390/nu12010236
14. Lang PO, Aspinall R. Vitamin D status and the host resistance to infections: What it is currently (Not) understood. Clin Ther. 2017; 39(5):930-45. doi: 10.1016/j.clinthera.2017.04.004
15. Rondanelli M, Miccono A, Lamburghini S, Avanzato I, Riva A, Allegrini P, et al. Self-care for common colds: The pivotal role of vitamin D, vitamin C, zinc, and echinacea in three main immune interactive clusters (Physical barriers, innate and adaptive immunity) involved during an episode of common colds-practical advice on dosages and on the time to take these nutrients/botanicals in order to prevent or treat common colds. Evid Based Complement Alternat Med. 2018 Apr 29; 2018: ID 5813095. doi: 10.1155/2018/5813095
16. Schröder-Heurich B, von Hardenberg S, Brodowski L, Kipke B, Meyer NV, Borns K, et al. Vitamin D improves endothelial barrier integrity and counteracts inflammatory effects on endothelial progenitor cells. FASEB J. 2019; 33(8):9142-53. doi: 10.1096/fj.201802750RR
17. Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients. 2020; 12(2):575. doi: 10.3390/nu12020575
18. Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R, Balloch A, et al. Anti-Inflammatory effects of vitamin D on human immune cells in the context of bacterial infection. Nutrients. 2016; 8(12):806. doi: 10.3390/nu8120806
19. Wöbke TK, Sorg BL, Steinhilber D. Vitamin D in inflammatory diseases. Front Physiol. 2014; 5:244. doi: 10.3389/fphys.2014.00244
20. Nagaoka I, Suzuki K, Niyonsaba F, Tamura H, Hirata M. Modulation of neutrophil apoptosis by antimicrobial peptides. ISRN Microbiol. 2012; 2012:ID 345791. doi: 10.5402/2012/345791
21. Barlow PG, Beaumont PE, Cosseau C, Mackellar A, Wilkinson TS, Hancock REW, et al. The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium. Am J Respir Cell Mol Biol. 2010; 43(6):692-702. doi: 10.1165/rcmb.2009-0250OC
22. Barlow PG, Svoboda P, Mackellar A, Nash AA, York IA, Pohl J, et al. Antiviral activity and increased host defense against influenza infection elicited by the human cathelicidin LL-37. PLoS One. 2011; 6(10):e25333. doi: 10.1371/journal.pone.0025333
23. Schögler A, Muster RJ, Kieninger E, Casaulta C, Tapparel C, Jung A, et al. Vitamin D represses rhinovirus replication in cystic fibrosis cells by inducing LL-37. Eur Respir J. 2016; 47(2):520-30. doi: 10.1183/13993003.00665-2015
24. Telcian AG, Zdrenghea MT, Edwards MR, Laza-Stanca V, Mallia P, Johnston SL, et al. Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. Antiviral Res. 2017; 137:93-101. doi: 10.1016/j.antiviral.2016.11.004
25. Campbell GR, Spector SA. Vitamin D inhibits human immunodeficiency virus type 1 and mycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog. 2012; 8(5):e1002689. doi: 10.1371/journal.ppat.1002689
26. Branchett WJ, Lloyd CM. Regulatory cytokine function in the respiratory tract. Mucosal Immunol. 2019; 12(3):589-600. doi: 10.1038/s41385-019-0158-0
27. Bi ChS, Li X, Qu HL, Sun LJ, An Y, Hong YL, et al. Calcitriol inhibits osteoclastogenesis in an inflammatory environment by changing the proportion and function of T helper cell subsets (Th2/Th17). Cell Prolif. 2020; 53(6):e12827. doi: 10.1111/cpr.12827
28. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011; 241(1):260-8. doi: 10.1111/j.1600-065X.2011.01018.x
29. Bishop E, Ismailova A, Dimeloe SK, Hewison M, White JH. Vitamin D and immune regulation: antibacterial, antiviral, anti-inflammatory. JBMR Plus. 2020; 5(1):e10405. doi: 10.1002/jbm4.10405
30. Liu ChY, Zhang ZH, Yang HF, Xu H, Cheng FF, Xu JZ. Effect of vitamin D3 on maturation and antigen-presenting function of dendritic cells treated with mycobacterium tuberculosis. Asian Pac J Trop Med. 2016; 9(1):54-7. doi: 10.1016/j.apjtm.2015.12.011
31. Barragan M, Good M, Kolls JK. Regulation of dendritic cell function by vitamin D. Nutrients. 2015; 7(9):8127-51. doi: 10.3390/nu7095383
32. Fülöp T, Dupuis G, Witkowski JM, Larbi A. The role of immunosenescence in the development of age-related diseases. Rev Invest Clin. 2016; 68(2):84-91
33. Thomas R, Wang W, Su DM. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing. 2020; 17:2. doi: 10.1186/s12979-020-0173-8
34. Gallagher JCh. Vitamin D and aging. Endocrinol Metab Clin North Am. 2013; 42(2):319-32. doi: 10.1016/j.ecl.2013.02.004
35. Ferri E, Casati M, Cesari M, Vitale G, Arosio B. Vitamin D in physiological and pathological aging: Lesson from centenarians. Rev Endocr Metab Disord. 2019; 20(3):273-282. doi: 10.1007/s11154-019-09522-y
36. Aslam MM, John P, Bhatti A, Jahangir S, Kamboh MI. Vitamin D as a principal factor in mediating rheumatoid arthritis-derived immune response. Biomed Res Int. 2019; 2019:3494937. doi: 10.1155/2019/3494937
37. Ebadi M, Montano-Loza AJ. Perspective: improving vitamin D status in the management of COVID-19. Eur J Clin Nutr. 2020; 74(6):856-9. doi: 10.1038/s41430-020-0661-0
38. Honardoost M, Ghavideldarestani M, Khamseh ME. Role of vitamin D in pathogenesis and severity of COVID-19 infection. Arch Physiol Biochem. 2020:1-7. doi: 10.1080/13813455.2020.1792505
39. 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
40. Zemb P, Bergman P, Camargo CA Jr, Cavalier E, Cormier C, Courbebaisse M, et al. Vitamin D deficiency and the COVID-19 pandemic. J Glob Antimicrob Resist. 2020; 22:133-4. doi: 10.1016/j.jgar.2020.05.006
41. Pilz S, Verheyen N, Grübler MR, Tomaschitz A, März W. Vitamin D and cardiovascular disease prevention. Nat Rev Cardiol. 2016; 13(7):404-17. doi: 10.1038/nrcardio.2016.73
42. Wu WX, He DR. Low vitamin D levels are associated with the development of deep venous thromboembolic events in patients with ischemic stroke. Clin Appl Thromb Hemost. 2018; 24(9_suppl):69S-75S. doi: 10.1177/1076029618786574
43. Mohammad S, Mishra A, Ashraf MZ. Emerging role of vitamin D and its associated molecules in pathways related to pathogenesis of thrombosis. Biomolecules. 2019; 9(11):649. doi: 10.3390/biom9110649
44. Gruber-Bzura BM. Vitamin D and influenza-prevention or therapy?. Int J Mol Sci. 2018; 19(8):2419. doi: 10.3390/ijms19082419
45. Grant WB, Bhattoa HP, Boucher BJ. Seasonal variations of U.S. mortality rates: Roles of solar ultraviolet-B doses, vitamin D, gene exp ression, and infections. J Steroid Biochem Mol Biol. 2017; 173:5-12. doi: 10.1016/j.jsbmb.2017.01.003
46. Bergman P, Lindh AU, Björkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013; 8(6):e65835. doi: 10.1371/journal.pone.0065835
47. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017; 356:i6583. doi: 10.1136/bmj.i6583
48. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019; 380(1):33-44. doi: 10.1056/NEJMoa1809944
49. Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford ChR, 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
50. Perin A, Zanatta E, Pigatto E, Carniello S, Cozzi F. Hypovitaminosis D in an hospitalized old population of Western Friuli. Reumatismo. 2012; 64(3):166-71. doi: 10.4081/reumatismo.2012.166
51. Manios Y, Moschonis G, Lambrinou CP, Tsoutsoulopoulou K, Binou P, Karachaliou A, et al. A systematic review of vitamin D status in southern european countries. Eur J Nutr. 2018; 57(6):2001-36. doi: 10.1007/s00394-017-1564-2
52. Boccardi V, Lapenna M, Gaggi L, Garaffa FM, Croce MF, Baroni M, et al. Hypovitaminosis D: A disease marker in hospitalized very old persons at risk of malnutrition. Nutrients. 2019; 11(1):128. doi: 10.3390/nu11010128
53. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, 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. doi: 10.1016/j.jsbmb.2020.105751
54. Annweiler C, Hanotte B, Grandin de l'Eprevier C, Sabatier JM, Lafaie L, Célarier T. Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol. 2020; 204:105771. doi: 10.1016/j.jsbmb.2020.105771
