Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren
Mitsuyoshi Urashima, Takaaki Segawa, Minoru Okazaki, Mana Kurihara, Yasuyuki Wada, Hiroyuki Ida
The American Journal of Clinical Nutrition, doi:10.3945/ajcn.2009.29094
Background: To our knowledge, no rigorously designed clinical trials have evaluated the relation between vitamin D and physiciandiagnosed seasonal influenza. Objective: We investigated the effect of vitamin D supplements on the incidence of seasonal influenza A in schoolchildren. Design: From December 2008 through March 2009, we conducted a randomized, double-blind, placebo-controlled trial comparing vitamin D 3 supplements (1200 IU/d) with placebo in schoolchildren. The primary outcome was the incidence of influenza A, diagnosed with influenza antigen testing with a nasopharyngeal swab specimen. Results: Influenza A occurred in 18 of 167 (10.8%) children in the vitamin D 3 group compared with 31 of 167 (18.6%) children in the placebo group [relative risk (RR), 0.58; 95% CI: 0.34, 0.99; P = 0.04]. The reduction in influenza A was more prominent in children who had not been taking other vitamin D supplements (RR: 0.36; 95% CI: 0.17, 0.79; P = 0.006) and who started nursery school after age 3 y (RR: 0.36; 95% CI: 0.17, 0.78; P = 0.005). In children with a previous diagnosis of asthma, asthma attacks as a secondary outcome occurred in 2 children receiving vitamin D 3 compared with 12 children receiving placebo (RR: 0.17; 95% CI: 0.04, 0.73; P = 0.006).
Conclusion: This study suggests that vitamin D 3 supplementation during the winter may reduce the incidence of influenza A, especially in specific subgroups of schoolchildren. This trial was registered at https://center.umin.ac.jp as UMIN000001373.
and signs of influenza by reducing cytokine secretion. In this study, vitamin D reduced the incidence of influenza A, but not of influenza B. The cytokine secretion pattern can differ between influenza A and influenza B (18) . If vitamin D modulates cytokine secretion, preventive effects of vitamin D may be different between influenza A and influenza B. Because taking vitamin D 3 supplements for 1 y with a dose ranging from 200 to 2000 IU in schoolchildren has been shown to be safe (19) , we set the dose of vitamin D 3 at 1200 IU in this trial. No serious adverse events occurred. It reportedly takes '3 mo to reach a steady state of vitamin D concentrations by supplementation (20) . Thus, December might be theoretically
References
Aloia, Ng, Re: epidemic influenza and vitamin D, Epidemiol Infect
Aloia, Talwar, Pollack, Yeh, A randomized controlled trial of vitamin D3 supplementation in African American women, Arch Intern Med
Bahar-Shany, Ravid, Koren, Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D, J Cell Physiol
Black, Scragg, Relationship between serum 25-hydroxyvitamin D and pulmonary function in the Third National Health and Nutrition Examination Survey, Chest
Bosse, Lemire, Poon, Asthma and genes encoding components of the vitamin D pathway, Respir Res
Brehm, Celedo ´n, Soto-Quiros, Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica, Am J Respir Crit Care Med
Camargo Ca, Rifas-Shiman, Litonjua, Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age, Am J Clin Nutr
Cannell, Zasloff, Garland, Scragg, Giovannucci, On the epidemiology of influenza, Virol J
Chong, Thangavel, Tang, Enhanced expression of murine beta-defensins (MBD-1, -2,-3, and -4) in upper and lower airway mucosa of influenza virus infected mice, Virology
Cohen, Varsano, Kahan, Sarrell, Uziel, Effectiveness of an herbal preparation containing echinacea, propolis, and vitamin C in preventing respiratory tract infections in children: a randomized, double-blind, placebo-controlled, multicenter study, Arch Pediatr Adolesc Med
Damera, Fogle, Lim, Vitamin D inhibits growth of human airway smooth muscle cells through growth factor-induced phosphorylation of retinoblastoma protein and checkpoint kinase 1, Br J Pharmacol
Devereux, Macdonald, Hawrylowicz, Vitamin D and asthma: time for intervention?, Am J Respir Crit Care Med
Doss, White, Tecle, Interactions of alpha-, beta-, and theta-defensins with influenza A virus and surfactant protein D, J Immunol
Gentile, Patel, Ollila, Diminished IL-10 production in subjects with allergy after infection with influenza A virus, J Allergy Clin Immunol
Ginde, Mansbach, Camargo, Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey, Arch Intern Med
Gordon, Ortega, Kuan, Prevalence and seasonality of influenza-like illness in children, Nicaragua, 2005-2007, Emerg Infect Dis
Hansdottir, Monick, Lovan, Powers, Gerke et al., Vitamin D decreases respiratory syncytial virus induction of NF-kappaB-linked chemokines and cytokines in airway epithelium while maintaining the antiviral state, J Immunol
Jeffery, Burke, Mura, 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
Leikina, Delanoe-Ayari, Melikov, Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins, Nat Immunol
Leyer, Li, Mubasher, Reifer, Ouwehand, Probiotic effects on cold and influenza-like symptom incidence and duration in children, Pediatrics
Li-Ng, Aloia, Pollack, A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections, Epidemiol Infect
Maalouf, Nabulsi, Vieth, Short-and long-term safety of weekly high-dose vitamin D3 supplementation in school children, J Clin Endocrinol Metab
Sato, Hosoya, Wright, Differences in serum cytokine levels between influenza virus A and B infections in children, Cytokine
Shun-Shin, Thompson, Heneghan, Perera, Harnden et al., Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials, BMJ
Stubbs, Idiculla, Slusser, Menard, Quarles, Cholecalciferol supplementation alters calcitriol-responsive monocyte proteins and decreases inflammatory cytokines in ESRD, J Am Soc Nephrol
Vieth, Chan, Macfarlane, Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level, Am J Clin Nutr
Wang, Dabbas, Laperriere, Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-beta defensin 2 innate immune pathway defective in Crohn's disease, J Biol Chem
Yamshchikov, Desai, Blumberg, Ziegler, Tangpricha, Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials, Endocr Pract
{ 'indexed': {'date-parts': [[2024, 5, 14]], 'date-time': '2024-05-14T18:42:09Z', 'timestamp': 1715712129646},
'reference-count': 28,
'publisher': 'Elsevier BV',
'issue': '5',
'license': [ { 'start': { 'date-parts': [[2010, 5, 1]],
'date-time': '2010-05-01T00:00:00Z',
'timestamp': 1272672000000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/'},
{ 'start': { 'date-parts': [[2023, 2, 21]],
'date-time': '2023-02-21T00:00:00Z',
'timestamp': 1676937600000},
'content-version': 'vor',
'delay-in-days': 4679,
'URL': 'http://www.elsevier.com/open-access/userlicense/1.0/'}],
'content-domain': {'domain': ['elsevier.com', 'sciencedirect.com'], 'crossmark-restriction': True},
'published-print': {'date-parts': [[2010, 5]]},
'DOI': '10.3945/ajcn.2009.29094',
'type': 'journal-article',
'created': {'date-parts': [[2010, 3, 11]], 'date-time': '2010-03-11T03:51:00Z', 'timestamp': 1268279460000},
'page': '1255-1260',
'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy',
'source': 'Crossref',
'is-referenced-by-count': 649,
'title': 'Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren',
'prefix': '10.1016',
'volume': '91',
'author': [ {'given': 'Mitsuyoshi', 'family': 'Urashima', 'sequence': 'first', 'affiliation': []},
{'given': 'Takaaki', 'family': 'Segawa', 'sequence': 'additional', 'affiliation': []},
{'given': 'Minoru', 'family': 'Okazaki', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mana', 'family': 'Kurihara', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yasuyuki', 'family': 'Wada', 'sequence': 'additional', 'affiliation': []},
{'given': 'Hiroyuki', 'family': 'Ida', 'sequence': 'additional', 'affiliation': []}],
'member': '78',
'reference': [ { 'key': '10.3945/ajcn.2009.29094_bib1',
'doi-asserted-by': 'crossref',
'first-page': '29',
'DOI': '10.1186/1743-422X-5-29',
'article-title': 'On the epidemiology of influenza.',
'volume': '5',
'author': 'Cannell',
'year': '2008',
'journal-title': 'Virol J'},
{ 'key': '10.3945/ajcn.2009.29094_bib2',
'doi-asserted-by': 'crossref',
'first-page': '1618',
'DOI': '10.1001/archinte.165.14.1618',
'article-title': 'A randomized controlled trial of vitamin D3 supplementation in African '
'American women.',
'volume': '165',
'author': 'Aloia',
'year': '2005',
'journal-title': 'Arch Intern Med'},
{ 'key': '10.3945/ajcn.2009.29094_bib3',
'doi-asserted-by': 'crossref',
'first-page': '1095',
'DOI': '10.1017/S0950268807008308',
'article-title': 'Re: epidemic influenza and vitamin D.',
'volume': '135',
'author': 'Aloia',
'year': '2007',
'journal-title': 'Epidemiol Infect'},
{ 'key': '10.3945/ajcn.2009.29094_bib4',
'doi-asserted-by': 'crossref',
'first-page': '1396',
'DOI': '10.1017/S0950268809002404',
'article-title': 'A randomized controlled trial of vitamin D3 supplementation for the '
'prevention of symptomatic upper respiratory tract infections.',
'volume': '137',
'author': 'Li-Ng',
'year': '2009',
'journal-title': 'Epidemiol Infect'},
{ 'key': '10.3945/ajcn.2009.29094_bib5',
'doi-asserted-by': 'crossref',
'first-page': '384',
'DOI': '10.1001/archinternmed.2008.560',
'article-title': 'Association between serum 25-hydroxyvitamin D level and upper '
'respiratory tract infection in the Third National Health and Nutrition '
'Examination Survey.',
'volume': '169',
'author': 'Ginde',
'year': '2009',
'journal-title': 'Arch Intern Med'},
{ 'key': '10.3945/ajcn.2009.29094_bib6',
'doi-asserted-by': 'crossref',
'first-page': '438',
'DOI': '10.4158/EP09101.ORR',
'article-title': 'Vitamin D for treatment and prevention of infectious diseases: a '
'systematic review of randomized controlled trials.',
'volume': '15',
'author': 'Yamshchikov',
'year': '2009',
'journal-title': 'Endocr Pract'},
{ 'key': '10.3945/ajcn.2009.29094_bib7',
'doi-asserted-by': 'crossref',
'first-page': 'b3620',
'DOI': '10.1136/bmj.b3172',
'article-title': 'Neuraminidase inhibitors for treatment and prophylaxis of influenza in '
'children: systematic review and meta-analysis of randomised controlled '
'trials.',
'volume': '339',
'author': 'Shun-Shin',
'year': '2009',
'journal-title': 'BMJ'},
{ 'key': '10.3945/ajcn.2009.29094_bib8',
'doi-asserted-by': 'crossref',
'first-page': 'e172',
'DOI': '10.1542/peds.2008-2666',
'article-title': 'Probiotic effects on cold and influenza-like symptom incidence and '
'duration in children.',
'volume': '124',
'author': 'Leyer',
'year': '2009',
'journal-title': 'Pediatrics'},
{ 'key': '10.3945/ajcn.2009.29094_bib9',
'doi-asserted-by': 'crossref',
'first-page': '217',
'DOI': '10.1001/archpedi.158.3.217',
'article-title': 'Effectiveness of an herbal preparation containing echinacea, propolis, '
'and vitamin C in preventing respiratory tract infections in children: a '
'randomized, double-blind, placebo-controlled, multicenter study.',
'volume': '158',
'author': 'Cohen',
'year': '2004',
'journal-title': 'Arch Pediatr Adolesc Med'},
{ 'key': '10.3945/ajcn.2009.29094_bib10',
'doi-asserted-by': 'crossref',
'unstructured': 'Wang TT, Dabbas B, Laperriere D, et al. Direct and indirect induction by '
'1,25-dihydroxyvitamin D3 of the NOD2/CARD15-beta defensin 2 innate '
'immune pathway defective in Crohn’s disease. J Biol Chem (Epub ahead of '
'print 30 November 2009).',
'DOI': '10.1074/jbc.C109.071225'},
{ 'key': '10.3945/ajcn.2009.29094_bib11',
'doi-asserted-by': 'crossref',
'first-page': '995',
'DOI': '10.1038/ni1248',
'article-title': 'Carbohydrate-binding molecules inhibit viral fusion and entry by '
'crosslinking membrane glycoproteins.',
'volume': '6',
'author': 'Leikina',
'year': '2005',
'journal-title': 'Nat Immunol'},
{ 'key': '10.3945/ajcn.2009.29094_bib12',
'doi-asserted-by': 'crossref',
'first-page': '7878',
'DOI': '10.4049/jimmunol.0804049',
'article-title': 'Interactions of alpha-, beta-, and theta-defensins with influenza A '
'virus and surfactant protein D.',
'volume': '182',
'author': 'Doss',
'year': '2009',
'journal-title': 'J Immunol'},
{ 'key': '10.3945/ajcn.2009.29094_bib13',
'doi-asserted-by': 'crossref',
'first-page': '136',
'DOI': '10.1016/j.virol.2008.07.024',
'article-title': 'Enhanced expression of murine beta-defensins (MBD-1, -2,- 3, and -4) in '
'upper and lower airway mucosa of influenza virus infected mice.',
'volume': '380',
'author': 'Chong',
'year': '2008',
'journal-title': 'Virology'},
{ 'key': '10.3945/ajcn.2009.29094_bib14',
'doi-asserted-by': 'crossref',
'first-page': '729',
'DOI': '10.1002/jcp.22004',
'article-title': 'Upregulation of MMP-9 production by TNFalpha in keratinocytes and its '
'attenuation by vitamin D.',
'volume': '222',
'author': 'Bahar-Shany',
'year': '2010',
'journal-title': 'J Cell Physiol'},
{ 'key': '10.3945/ajcn.2009.29094_bib15',
'doi-asserted-by': 'crossref',
'first-page': '965',
'DOI': '10.4049/jimmunol.0902840',
'article-title': 'Vitamin D decreases respiratory syncytial virus induction of '
'NF-kappaB-linked chemokines and cytokines in airway epithelium while '
'maintaining the antiviral state.',
'volume': '184',
'author': 'Hansdottir',
'year': '2010',
'journal-title': 'J Immunol'},
{ 'key': '10.3945/ajcn.2009.29094_bib16',
'doi-asserted-by': 'crossref',
'first-page': '353',
'DOI': '10.1681/ASN.2009040451',
'article-title': 'Cholecalciferol supplementation alters calcitriol-responsive monocyte '
'proteins and decreases inflammatory cytokines in ESRD.',
'volume': '21',
'author': 'Stubbs',
'year': '2010',
'journal-title': 'J Am Soc Nephrol'},
{ 'key': '10.3945/ajcn.2009.29094_bib17',
'doi-asserted-by': 'crossref',
'first-page': '5458',
'DOI': '10.4049/jimmunol.0803217',
'article-title': '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.',
'volume': '183',
'author': 'Jeffery',
'year': '2009',
'journal-title': 'J Immunol'},
{ 'key': '10.3945/ajcn.2009.29094_bib18',
'doi-asserted-by': 'crossref',
'first-page': '65',
'DOI': '10.1016/j.cyto.2009.05.003',
'article-title': 'Differences in serum cytokine levels between influenza virus A and B '
'infections in children.',
'volume': '47',
'author': 'Sato',
'year': '2009',
'journal-title': 'Cytokine'},
{ 'key': '10.3945/ajcn.2009.29094_bib19',
'doi-asserted-by': 'crossref',
'first-page': '2693',
'DOI': '10.1210/jc.2007-2530',
'article-title': 'Short- and long-term safety of weekly high-dose vitamin D3 '
'supplementation in school children.',
'volume': '93',
'author': 'Maalouf',
'year': '2008',
'journal-title': 'J Clin Endocrinol Metab'},
{ 'key': '10.3945/ajcn.2009.29094_bib20',
'doi-asserted-by': 'crossref',
'first-page': '288',
'DOI': '10.1093/ajcn/73.2.288',
'article-title': 'Efficacy and safety of vitamin D3 intake exceeding the lowest observed '
'adverse effect level.',
'volume': '73',
'author': 'Vieth',
'year': '2001',
'journal-title': 'Am J Clin Nutr'},
{ 'key': '10.3945/ajcn.2009.29094_bib21',
'doi-asserted-by': 'crossref',
'first-page': '408',
'DOI': '10.3201/eid1503.080238',
'article-title': 'Prevalence and seasonality of influenza-like illness in children, '
'Nicaragua, 2005-2007.',
'volume': '15',
'author': 'Gordon',
'year': '2009',
'journal-title': 'Emerg Infect Dis'},
{ 'key': '10.3945/ajcn.2009.29094_bib22',
'doi-asserted-by': 'crossref',
'first-page': '1045',
'DOI': '10.1016/S0091-6749(99)70177-6',
'article-title': 'Diminished IL-10 production in subjects with allergy after infection '
'with influenza A virus.',
'volume': '103',
'author': 'Gentile',
'year': '1999',
'journal-title': 'J Allergy Clin Immunol'},
{ 'key': '10.3945/ajcn.2009.29094_bib23',
'doi-asserted-by': 'crossref',
'first-page': '98',
'DOI': '10.1186/1465-9921-10-98',
'article-title': 'Asthma and genes encoding components of the vitamin D pathway.',
'volume': '10',
'author': 'Bossé',
'year': '2009',
'journal-title': 'Respir Res'},
{ 'key': '10.3945/ajcn.2009.29094_bib24',
'doi-asserted-by': 'crossref',
'first-page': '3792',
'DOI': '10.1378/chest.128.6.3792',
'article-title': 'Relationship between serum 25-hydroxyvitamin D and pulmonary function '
'in the Third National Health and Nutrition Examination Survey.',
'volume': '128',
'author': 'Black',
'year': '2005',
'journal-title': 'Chest'},
{ 'key': '10.3945/ajcn.2009.29094_bib25',
'doi-asserted-by': 'crossref',
'first-page': '788',
'DOI': '10.1093/ajcn/85.3.788',
'article-title': 'Maternal intake of vitamin D during pregnancy and risk of recurrent '
'wheeze in children at 3 y of age.',
'volume': '85',
'author': 'Camargo',
'year': '2007',
'journal-title': 'Am J Clin Nutr'},
{ 'key': '10.3945/ajcn.2009.29094_bib26',
'doi-asserted-by': 'crossref',
'first-page': '765',
'DOI': '10.1164/rccm.200808-1361OC',
'article-title': 'Serum vitamin D levels and markers of severity of childhood asthma in '
'Costa Rica.',
'volume': '179',
'author': 'Brehm',
'year': '2009',
'journal-title': 'Am J Respir Crit Care Med'},
{ 'key': '10.3945/ajcn.2009.29094_bib27',
'doi-asserted-by': 'crossref',
'first-page': '1429',
'DOI': '10.1111/j.1476-5381.2009.00428.x',
'article-title': 'Vitamin D inhibits growth of human airway smooth muscle cells through '
'growth factor-induced phosphorylation of retinoblastoma protein and '
'checkpoint kinase 1.',
'volume': '158',
'author': 'Damera',
'year': '2009',
'journal-title': 'Br J Pharmacol'},
{ 'key': '10.3945/ajcn.2009.29094_bib28',
'doi-asserted-by': 'crossref',
'first-page': '739',
'DOI': '10.1164/rccm.200901-0145ED',
'article-title': 'Vitamin D and asthma: time for intervention?',
'volume': '179',
'author': 'Devereux',
'year': '2009',
'journal-title': 'Am J Respir Crit Care Med'}],
'container-title': 'The American Journal of Clinical Nutrition',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S0002916523018324?httpAccept=text/xml',
'content-type': 'text/xml',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://api.elsevier.com/content/article/PII:S0002916523018324?httpAccept=text/plain',
'content-type': 'text/plain',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'http://academic.oup.com/ajcn/article-pdf/91/5/1255/23864600/1255.pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 3, 25]],
'date-time': '2024-03-25T01:26:04Z',
'timestamp': 1711329964000},
'score': 1,
'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S0002916523018324'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2010, 5]]},
'references-count': 28,
'journal-issue': {'issue': '5', 'published-print': {'date-parts': [[2010, 5]]}},
'alternative-id': ['S0002916523018324'],
'URL': 'http://dx.doi.org/10.3945/ajcn.2009.29094',
'relation': {},
'ISSN': ['0002-9165'],
'subject': [],
'container-title-short': 'The American Journal of Clinical Nutrition',
'published': {'date-parts': [[2010, 5]]},
'assertion': [ {'value': 'Elsevier', 'name': 'publisher', 'label': 'This article is maintained by'},
{ 'value': 'Randomized trial of vitamin D supplementation to prevent seasonal influenza A '
'in schoolchildren',
'name': 'articletitle',
'label': 'Article Title'},
{ 'value': 'The American Journal of Clinical Nutrition',
'name': 'journaltitle',
'label': 'Journal Title'},
{ 'value': 'https://doi.org/10.3945/ajcn.2009.29094',
'name': 'articlelink',
'label': 'CrossRef DOI link to publisher maintained version'},
{'value': 'article', 'name': 'content_type', 'label': 'Content Type'},
{ 'value': 'Copyright © 2010 American Society for Nutrition. Published by Elsevier Inc. All '
'rights reserved.',
'name': 'copyright',
'label': 'Copyright'}]}
