Vitamin D modulation of innate immune responses to respiratory viral infections
Corresponding Author
Mihnea T. Zdrenghea
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
These authors contributed equally to this paper.Correspondence
M. T. Zdrenghea, Iuliu Hatieganu University of Medicine and Pharmacy, Babeş Str. 8, 400124 Cluj-Napoca, Romania.
Email: [email protected]
Search for more papers by this authorHeidi Makrinioti
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorCristina Bagacean
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Laboratory of Immunology and Immunotherapy, University Hospital Brest, France
Search for more papers by this authorAndy Bush
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital and Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorSebastian L. Johnston
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorLuminita A. Stanciu
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorCorresponding Author
Mihnea T. Zdrenghea
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
These authors contributed equally to this paper.Correspondence
M. T. Zdrenghea, Iuliu Hatieganu University of Medicine and Pharmacy, Babeş Str. 8, 400124 Cluj-Napoca, Romania.
Email: [email protected]
Search for more papers by this authorHeidi Makrinioti
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorCristina Bagacean
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Laboratory of Immunology and Immunotherapy, University Hospital Brest, France
Search for more papers by this authorAndy Bush
Department of Paediatric Respiratory Medicine, Royal Brompton Hospital and Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorSebastian L. Johnston
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorLuminita A. Stanciu
Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj and Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania
Airways Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, UK
These authors contributed equally to this paper.Search for more papers by this authorSummary
Vitamin D, in addition to its classical functions in bone homeostasis, has a modulatory and regulatory role in multiple processes, including host defense, inflammation, immunity, and epithelial repair. Patients with respiratory disease are frequently deficient in vitamin D, implying that supplementation might provide significant benefit to these patients. Respiratory viral infections are common and are the main trigger of acute exacerbations and hospitalization in children and adults with asthma and other airways diseases. Respiratory monocytes/macrophages and epithelial cells constitutively express the vitamin D receptor. Vitamin D, acting through this receptor, may be important in protection against respiratory infections. Whether the in vitro findings can be translated into a substantial in vivo benefit still remains uncertain. Here we review the in vitro data on the role of vitamin D in antiviral innate immunity, the data concerning the deficient levels of vitamin D in lung diseases, and the in vivo role of supplementation as protection against respiratory viral infections in healthy individuals and in patients with chronic respiratory diseases. Finally, we suggest ways of improving the effectiveness of vitamin D as an adjuvant in the prevention and treatment of acute respiratory infections.
REFERENCES
- 1Kain K. Some clinical trials are driven by fashion, not science. BMJ. 2015; 350: h288. doi: 10.1136/bmj.h288
- 2Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014; 348: g2035. doi: 10.1136/bmj.g2035
- 3Jolliffe 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. doi: 10.1016/j.jsbmb.2012.11.017
- 4Allan GM, Arroll B. Prevention and treatment of the common cold: making sense of the evidence. CMAJ. 2014; 186: 190–199. doi: 10.1503/cmaj.121442
- 5Bryson KJ, Nash AA, Norval M. Does vitamin D protect against respiratory viral infections? Epidemiol Infect. 2014; 142: 1789–1801. doi: 10.1017/S0950268814000193
- 6Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006; 311: 1770–1773.
- 7Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011; 96: 53–58. doi: 10.1210/jc.2010-2704
- 8Rosen CJ, Abrams SA, Aloia JF, et al. IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab. 2012; 97: 1146–1152. doi: 10.1210/jc.2011-2218
- 9Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96: 1911–1930. doi: 10.1210/jc.2011-0385
- 10Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M. Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014; 144(Pt A): 132–137. doi: 10.1016/j.jsbmb.2013.09.012
- 11Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of 25-hydroxyvitamin D3-1 alpha-hydroxylase and production of 1 alpha,25-dihydroxyvitamin D3 by human dendritic cells. Blood. 2003; 102: 3314–3316. doi: 10.1182/blood-2002-11-3521
- 12Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW. Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J Immunol 2008; 181: 7090-7099. DOI: 181/10/7090 [pii]
- 13Adams JS, Liu PT, Chun R, Modlin RL, Hewison M. Vitamin D in defense of the human immune response. Ann N Y Acad Sci. 2007; 1117: 94–105.
- 14Prosser DE, Jones G. Enzymes involved in the activation and inactivation of vitamin D. Trends Biochem Sci. 2004; 29: 664–673.
- 15Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999; 69: 842–856.
- 16Wagner D, Dias AG, Schnabl K, Van der Kwast T, Vieth R. Determination of 1,25-dihydroxyvitamin D concentrations in human colon tissues and matched serum samples. Anticancer Res. 2012; 32: 259–263.
- 17Matilainen JM, Malinen M, Turunen MM, Carlberg C, Vaisanen S. The number of vitamin D receptor binding sites defines the different vitamin D responsiveness of the CYP24 gene in malignant and normal mammary cells. J Biol Chem. 2010; 285: 24174–24183. doi: 10.1074/jbc.M110.124073
- 18Haussler MR, Jurutka PW, Mizwicki M, Norman AW. Vitamin D receptor (VDR)-mediated actions of 1alpha,25(OH)(2)vitamin D(3): genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011; 25: 543–559. doi: 10.1016/j.beem.2011.05.010
- 19Campbell MJ. Vitamin D and the RNA transcriptome: more than mRNA regulation. Front Physiol. 2014; 5: 181. doi: 10.3389/fphys.2014.00181
- 20Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC. Vitamin D receptor inhibits nuclear factor kappa B activation by interacting with IkappaB kinase beta protein. J Biol Chem. 2013; 288: 19450–19458. doi: 10.1074/jbc.M113.467670
- 21Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr. 1995; 125: 1704S–1708S.
- 22Zhang Y, Leung DY, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol. 2012; 188: 2127–2135. doi: 10.4049/jimmunol.1102412
- 23Jeffery LE, Burke F, Mura M, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009; 183: 5458–5467. doi: 10.4049/jimmunol.0803217
- 24Fawaz L, Mrad MF, Kazan JM, Sayegh S, Akika R, Khoury SJ. Comparative effect of 25(OH)D3 and 1,25(OH)2D3 on Th17 cell differentiation. Clin Immunol. 2016; 166-167: 59–71. doi: 10.1016/j.clim.2016.02.011
- 25Schedel M, Jia Y, Michel S, et al. 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. Nat Commun. 2016; 7: 10213. doi: 10.1038/ncomms10213
- 26Bock G, Prietl B, Mader JK, et al. The effect of vitamin D supplementation on peripheral regulatory T cells and beta cell function in healthy humans: a randomized controlled trial. Diabetes Metab Res Rev. 2011; 27: 942–945. doi: 10.1002/dmrr.1276
- 27Allen AC, Kelly S, Basdeo SA, et al. A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers. Mult Scler. 2012; 18: 1797–1800. doi: 10.1177/1352458512442992
- 28Konijeti GG, Arora P, Boylan MR, et al. Vitamin D supplementation modulates T cell-mediated immunity in humans: results from a randomized control trial. J Clin Endocrinol Metab. 2016; 101: 533–538. doi: 10.1210/jc.2015-3599
- 29Hewison M. Vitamin D and immune function: autocrine, paracrine or endocrine? Scand J Clin Lab Invest Suppl. 2012; 243: 92–102. doi: 10.3109/00365513.2012.682862
- 30Hansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm. 2011; 86: 217–237. doi: 10.1016/B978-0-12-386960-9.00009-5
- 31Kho AT, Sharma S, Qiu W, et al. Vitamin D related genes in lung development and asthma pathogenesis. BMC Med Genomics. 2013; 6: 47. doi: 10.1186/1755-8794-6-47
- 32Lowry MB, Guo C, Borregaard N, Gombart AF. Regulation of the human cathelicidin antimicrobial peptide gene by 1alpha,25-dihydroxyvitamin D3 in primary immune cells. J Steroid Biochem Mol Biol. 2014; 143: 183–191. doi: 10.1016/j.jsbmb.2014.02.004
- 33Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol. 2013; 94: 40–49. doi: 10.1099/vir.0.045013-0
- 34Currie SM, Findlay EG, McHugh BJ, et al. The human cathelicidin LL-37 has antiviral activity against respiratory syncytial virus. PLoS One. 2013; 8: e73659. doi: 10.1371/journal.pone.0073659
- 35Mansbach JM, Piedra PA, Borregaard N, et al. Serum cathelicidin level is associated with viral etiology and severity of bronchiolitis. J Allergy Clin Immunol. 2012; 130: 1007–1008 e1001. doi: 10.1016/j.jaci.2012.07.044
- 36Proud D, Sanders SP, Wiehler S. Human rhinovirus infection induces airway epithelial cell production of human beta-defensin 2 both in vitro and in vivo. J Immunol. 2004; 172: 4637–4645.
- 37Kota S, Sabbah A, Chang TH, et al. Role of human beta-defensin-2 during tumor necrosis factor-alpha/NF-kappaB-mediated innate antiviral response against human respiratory syncytial virus. J Biol Chem. 2008; 283: 22417–22429. doi: 10.1074/jbc.M710415200
- 38Hansdottir S, Monick MM, Lovan N, Powers L, Gerke A, Hunninghake GW. Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010; 184: 965–974. doi: 10.4049/jimmunol.0902840
- 39Khare D, Godbole NM, Pawar SD, et al. Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells. Eur J Nutr. 2013; 52: 1405–1415. doi: 10.1007/s00394-012-0449-7
- 40Brockman-Schneider RA, Pickles RJ, Gern JE. Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS One. 2014; 9: e86755. doi: 10.1371/journal.pone.0086755
- 41Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1alpha,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. J Allergy Clin Immunol. 2013; 132: 297–304 e293. doi: 10.1016/j.jaci.2013.03.037
- 42Monlezun DJ, Bittner EA, Christopher KB, Camargo CA, Quraishi SA. Vitamin D status and acute respiratory infection: cross sectional results from the United States National Health and Nutrition Examination Survey, 2001-2006. Nutrients. 2015; 7: 1933–1944. doi: 10.3390/nu7031933
- 43Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res. 2009; 65: 106R–113R. doi: 10.1203/PDR.0b013e31819dba91
- 44Camargo CA Jr, Ingham T, Wickens K, et al. Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing, and asthma. Pediatrics. 2011; 127: e180–e187. doi: 10.1542/peds.2010-0442
- 45Belderbos ME, Houben ML, Wilbrink B, et al. Cord blood vitamin D deficiency is associated with respiratory syncytial virus bronchiolitis. Pediatrics. 2011; 127: e1513–e1520. doi: 10.1542/peds.2010-3054
- 46Morales E, Romieu I, Guerra S, et al. Maternal vitamin D status in pregnancy and risk of lower respiratory tract infections, wheezing, and asthma in offspring. Epidemiology. 2012; 23: 64–71. doi: 10.1097/EDE.0b013e31823a44d3
- 47Magnus MC, Stene LC, Haberg SE, et al. Prospective study of maternal mid-pregnancy 25-hydroxyvitamin D level and early childhood respiratory disorders. Paediatr Perinat Epidemiol. 2013; 27: 532–541. doi: 10.1111/ppe.12080
- 48Science M, Maguire JL, Russell ML, Smieja M, Walter SD, Loeb M. Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. Clin Infect Dis. 2013; 57: 392–397. doi: 10.1093/cid/cit289
- 49Sabetta 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: e11088. doi: 10.1371/journal.pone.0011088
- 50Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr. 2011; 106: 1433–1440. doi: 10.1017/S0007114511001991
- 51He CS, Handzlik M, Fraser WD, et al. Influence of vitamin D status on respiratory infection incidence and immune function during 4 months of winter training in endurance sport athletes. Exerc Immunol Rev. 2013; 19: 86–101.
- 52Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995; 310: 1225–1229.
- 53Chi A, Wildfire J, McLoughlin R, et al. Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma study. Clin Exp Allergy. 2011; 41: 842–850. doi: 10.1111/j.1365-2222.2011.03712.x
- 54Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012; 26(Suppl 1): 75–90. doi: 10.1111/j.1365-3016.2012.01283.x
- 55Foong RE, Bosco A, Jones AC, et al. In utero vitamin D deficiency increases airway smooth muscle mass and impairs lung function. Am J Respir Cell Mol Biol. 2015. doi: 10.1165/rcmb.2014-0356OC
- 56Vasiliou JE, Lui S, Walker SA, et al. Vitamin D deficiency induces Th2 skewing and eosinophilia in neonatal allergic airways disease. Allergy. 2014; 69: 1380–1389. doi: 10.1111/All.12465
- 57Pike KC, Inskip HM, Robinson S, et al. Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes. Thorax. 2012; 67: 950–956. doi: 10.1136/thoraxjnl-2012-201888
- 58Hansen S, Maslova E, Strom M, et al. The long-term programming effect of maternal 25-hydroxyvitamin D in pregnancy on allergic airway disease and lung function in offspring after 20 to 25 years of follow-up. J Allergy Clin Immunol. 2015. doi: 10.1016/j.jaci.2014.12.1924
- 59Brehm JM, Celedon JC, Soto-Quiros ME, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009; 179: 765–771. doi: 10.1164/rccm.200808-1361OC
- 60Brehm JM, Schuemann B, Fuhlbrigge AL, et al. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. J Allergy Clin Immunol. 2010; 126: 52–58 e55. doi: 10.1016/j.jaci.2010.03.043
- 61Gupta A, Sjoukes A, Richards D, et al. Relationship between serum vitamin D, disease severity, and airway remodeling in children with asthma. Am J Respir Crit Care Med. 2011; 184: 1342–1349. doi: 10.1164/rccm.201107-1239OC
- 62Brehm JM, Acosta-Perez E, Klei L, et al. Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children. Am J Respir Crit Care Med. 2012; 186: 140–146. doi: 10.1164/rccm.201203-0431OC
- 63McNally JD, Sampson M, Matheson LA, Hutton B, Little J. Vitamin D receptor (VDR) polymorphisms and severe RSV bronchiolitis: a systematic review and meta-analysis. Pediatr Pulmonol. 2014; 49: 790–799. doi: 10.1002/Ppul.22877
- 64Ginde 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: 384–390. doi: 10.1001/archinternmed.2008.560
- 65Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 2010; 181: 699–704. doi: 10.1164/rccm.200911-1710OC
- 66Korn S, Hubner M, Jung M, Blettner M, Buhl R. Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respir Res. 2013; 14: 25. doi: 10.1186/1465-9921-14-25
- 67Salas NM, Luo L, Harkins MS. Vitamin D deficiency and adult asthma exacerbations. J Asthma. 2014; 51: 950–955. doi: 10.3109/02770903.2014.930883
- 68Confino-Cohen R, Brufman I, Goldberg A, Feldman BS. Vitamin D, asthma prevalence and asthma exacerbations: a large adult population-based study. Allergy. 2014; 69: 1673–1680. doi: 10.1111/all.12508
- 69Columbo M, Panettieri RA Jr, Rohr AS. Asthma in the elderly: a study of the role of vitamin D. Allergy Asthma Clin Immunol. 2014; 10: 48. doi: 10.1186/1710-1492-10-48
- 70Tsai CL, Delclos GL, Huang JS, Hanania NA, Camargo CA Jr. Age-related differences in asthma outcomes in the United States, 1988-2006. Ann Allergy Asthma Immunol. 2013; 110: 240–246 e241. doi: 10.1016/j.anai.2013.01.002
- 71Zittermann A, Ernst JB, Gummert JF, Borgermann J. Vitamin D supplementation, body weight and human serum 25-hydroxyvitamin D response: a systematic review. Eur J Nutr. 2014; 53. doi: 10.1007/s00394-013-0634-3
- 72Zittermann A, Pilz S, Hoffmann H, Marz W. Vitamin D and airway infections: a European perspective. Eur J Med Res. 2016; 21: 14. doi: 10.1186/s40001-016-0208-y
- 73Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011; 96: E447–E452. doi: 10.1210/jc.2010-2230
- 74Bischoff-Ferrari HA, Dawson-Hughes B, Stocklin E, et al. Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Miner Res. 2012; 27: 160–169. doi: 10.1002/jbmr.551
- 75Houghton LA, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006; 84: 694–697.
- 76Biancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013; 98: 973–979. doi: 10.1210/jc.2012-2114
- 77Bacchetta J, Zaritsky JJ, Sea JL, et al. Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol. 2014; 25: 564–572. doi: 10.1681/ASN.2013040355
- 78Bhan I, Camargo CA Jr, Wenger J, et al. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol. 2011; 127: 1302–1304 e1301. doi: 10.1016/j.jaci.2010.12.1097
- 79Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J. 2008; 5: 29. doi: 10.1186/1743-422X-5-29
- 80Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009; 19: 73-78. DOI: S1047-2797(08)00002-1 [pii]. doi: 10.1016/j.annepidem.2007.12.001
- 81Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrinol. 2012; 4: 95–100. doi: 10.4161/derm.19833
- 82Hollis BW, Wagner CL. Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013; 98: 4619–4628. doi: 10.1210/jc.2013-2653
- 83Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012; 308: 1333–1339. doi: 10.1001/jama.2012.12505
- 84Martineau AR, Hanifa Y, Witt KD, et al. Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). Thorax. 2015. doi: 10.1136/thoraxjnl-2015-206996
10.1136/thoraxjnl-2015-206996 Google Scholar
- 85Weiss ST, Litonjua AA. Vitamin D dosing for infectious and immune disorders. Thorax. 2015. doi: 10.1136/thoraxjnl-2015-207334
- 86Bergman P, Lindh AU, Bjorkhem-Bergman L, Lindh JD. Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials. PLoS One. 2013; 8: e65835. doi: 10.1371/journal.pone.0065835
- 87Kearns MD, Binongo JN, Watson D, et al. The effect of a single, large bolus of vitamin D in healthy adults over the winter and following year: a randomized, double-blind, placebo-controlled trial. Eur J Clin Nutr. 2015; 69: 193–197. doi: 10.1038/ejcn.2014.209
- 88Kimball S, Vieth R, Dosch HM, et al. Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J Clin Endocrinol Metab. 2011; 96: 2826–2834. doi: 10.1210/jc.2011-0325
- 89Grant CC, Kaur S, Waymouth E, et al. Reduced primary care respiratory infection visits following pregnancy and infancy vitamin D supplementation: a randomised controlled trial. Acta Paediatr. 2015; 104: 396–404. doi: 10.1111/apa.12819
- 90Fried DA, Rhyu J, Odato K, Blunt H, Karagas MR, Gilbert-Diamond D. Maternal and cord blood vitamin D status and childhood infection and allergic disease: a systematic review. Nutr Rev. 2016; 74: 387–410. doi: 10.1093/nutrit/nuv108
- 91Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010; 91: 1255–1260. doi: 10.3945/ajcn.2009.29094
- 92Camargo CA Jr, Ganmaa D, Frazier AL, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012; 130: e561–e567. doi: 10.1542/peds.2011-3029
- 93Xiao L, Xing C, Yang Z, et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: a systematic review of randomised controlled trials. Br J Nutr. 2015; 114: 1026–1034. doi: 10.1017/S000711451500207X
- 94Majak P, Olszowiec-Chlebna M, Smejda K, Stelmach I. Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infection. J Allergy Clin Immunol. 2011; 127: 1294–1296. doi: 10.1016/j.jaci.2010.12.016
- 95Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet. 2012; 379: 1419–1427. doi: 10.1016/S0140-6736(11)61650-4
- 96Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009; 137: 1396–1404. doi: 10.1017/S0950268809002404
- 97Yusupov E, Li-Ng M, Pollack S, Yeh JK, Mikhail M, Aloia JF. Vitamin D and serum cytokines in a randomized clinical trial. Int J Endocrinol. 2010; 2010. doi: 10.1155/2010/305054
- 98Jorde R, Witham M, Janssens W, et al. Vitamin D supplementation did not prevent influenza-like illness as diagnosed retrospectively by questionnaires in subjects participating in randomized clinical trials. Scand J Infect Dis. 2012; 44: 126–132. doi: 10.3109/00365548.2011.621446
- 99Bergman 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. doi: 10.1136/bmjopen-2012-001663
- 100Goodall EC, Granados AC, Luinstra K, et al. Vitamin D3 and gargling for the prevention of upper respiratory tract infections: a randomized controlled trial. BMC Infect Dis. 2014; 14: 273. doi: 10.1186/1471-2334-14-273
- 101Simpson S, van der Mei I, Stewart N, Blizzard L, Tettey P, Taylor B. Weekly cholecalciferol supplementation results in significant reductions in infection risk among the vitamin D deficient: results from the CIPRIS pilot RCT. BMC Nutrition. 2015; 1: 1–10. doi: 10.1186/2055-0928-1-7
- 102Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA. 2014; 311: 2083–2091. doi: 10.1001/jama.2014.5052
- 103Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax. 2015; 70: 451–457. doi: 10.1136/thoraxjnl-2014-206449
- 104Chandy DD, Kare J, Singh SN, et al. Effect of vitamin D supplementation, directly or via breast milk for term infants, on serum 25 hydroxyvitamin D and related biochemistry, and propensity to infection: a randomised placebo-controlled trial. Br J Nutr. 2016; 116: 52–58. doi: 10.1017/S0007114516001756
- 105Stanciu LA, Shute J, Promwong C, Holgate ST, Djukanovic R. Increased levels of IL-4 in CD8+ T cells in atopic asthma. J Allergy Clin Immunol. 1997; 100: 373–378.
- 106Stanciu LA, Roberts K, Lau LC, Coyle AJ, Johnston SL. Induction of type 2 activity in adult human CD8(+) T cells by repeated stimulation and IL-4. Int Immunol. 2001; 13: 341–348.
- 107Stanciu LA, Roberts K, Papadopoulos NG, et al. IL-4 increases type 2, but not type 1, cytokine production in CD8+ T cells from mild atopic asthmatics. Respir Res. 2005; 6: 67
- 108Edfeldt K, Liu PT, Chun R, et al. T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci U S A. 2010; 107: 22593–22598. doi: 10.1073/pnas.1011624108
- 109Kalra P, Das V, Agarwal A, et al. Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant. Br J Nutr. 2012; 108: 1052–1058. doi: 10.1017/S0007114511006246
- 110Goldring ST, Griffiths CJ, Martineau AR, et al. Prenatal vitamin D supplementation and child respiratory health: a randomised controlled trial. PLoS One. 2013; 8: e66627. doi: 10.1371/journal.pone.0066627
- 111Litonjua AA, Carey VJ, Laranjo N, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA. 2016; 315: 362–370. doi: 10.1001/jama.2015.18589
- 112Chawes BL, Bonnelykke K, Stokholm J, et al. Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. JAMA. 2016; 315: 353–361. doi: 10.1001/jama.2015.18318
- 113Busse WW, Lemanske RF Jr, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 2010; 376: 826–834. doi: 10.1016/S0140-6736(10)61380-3
- 114Depner M, Fuchs O, Genuneit J, et al. Clinical and epidemiologic phenotypes of childhood asthma. Am J Respir Crit Care Med. 2014; 189: 129–138. doi: 10.1164/rccm.201307-1198OC
- 115Gold DR, Litonjua AA, Carey VJ, et al. Lung VITAL: rationale, design, and baseline characteristics of an ancillary study evaluating the effects of vitamin D and/or marine omega-3 fatty acid supplements on acute exacerbations of chronic respiratory disease, asthma control, pneumonia and lung function in adults. Contemp Clin Trials. 2016; 47: 185–195. doi: 10.1016/j.cct.2016.01.003