Abstract
Over the past 20 y, a resurgence in vitamin D deficiency and nutritional rickets has been reported throughout the world, including the United States. Inadequate serum vitamin D concentrations have also been associated with complications from other health problems, including tuberculosis, cancer (prostate, breast, and colon), multiple sclerosis, and diabetes. These findings support the concept of vitamin D possessing important pleiotropic actions outside of calcium homeostasis and bone metabolism. In children, an association of nutritional rickets with respiratory compromise has long been recognized. Recent epidemiologic studies clearly demonstrate the link between vitamin D deficiency and the increased incidence of respiratory infections. Further research has also elucidated the contribution of vitamin D in the host defense response to infection. However, the mechanism(s) by which vitamin D levels contribute to pediatric infections and immune function has yet to be determined. This knowledge is particularly relevant and timely, because infants and children seem more susceptible to viral rather than bacterial infections in the face of vitamin D deficiency. The connection among vitamin D, infections, and immune function in the pediatric population indicates a possible role for vitamin D supplementation in potential interventions and adjuvant therapies.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- 1,25D:
-
1,25-dihydroxyvitamin D
- 25D:
-
25-hydroxy vitamin D
- AAP:
-
American Academy of Pediatrics
- ALRI:
-
acute lower respiratory tract infection
- CF:
-
cystic fibrosis
- DCs:
-
dendritic cells
- PTH:
-
parathyroid hormone
- TB:
-
tuberculosis
- VDR:
-
vitamin D receptor
References
White JH 2008 Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun 76: 3837–3843
Sichert-Hellert W, Wenz G, Kersting M 2006 Vitamin intakes from supplements and fortified food in German children and adolescents: results from the DONALD study. J Nutr 136: 1329–1333
Lehmann B, Knuschke P, Meurer M 2000 A novel pathway for hormonally active calcitriol. Horm Res 54: 312–315
Diaz L, Sanchez I, Avila E, Halhali A, Vilchis F, Larrea F 2000 Identification of a 25-hydroxyvitamin D3 1alpha-hydroxylase gene transcription product in cultures of human syncytiotrophoblast cells. J Clin Endocrinol Metab 85: 2543–2549
Mawer EB, Hayes ME, Still PE, Davies M, Lumb GA, Palit J, Holt PJ 1991 Evidence for nonrenal synthesis of 1,25-dihydroxyvitamin D in patients with inflammatory arthritis. J Bone Miner Res 6: 733–739
Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison M 2001 Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86: 888–894
Lin R, White JH 2004 The pleiotropic actions of vitamin D. Bioessays 26: 21–28
Vieth R 1999 Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 69: 842–856
Holick MF 2007 Vitamin D deficiency. N Engl J Med 357: 266–281
Misra M, Pacaud D, Petryk A, Collett-Solberg PF, Kappy M 2008 Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 122: 398–417
Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF 2007 Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila) 46: 42–44
Ziegler EE, Hollis BW, Nelson SE, Jeter JM 2006 Vitamin D deficiency in breastfed infants in Iowa. Pediatrics 118: 603–610
Rajakumar K, Fernstrom JD, Janosky JE, Greenspan SL 2005 Vitamin D insufficiency in preadolescent African-American children. Clin Pediatr (Phila) 44: 683–692
Sullivan SS, Rosen CJ, Halteman WA, Chen TC, Holick MF 2005 Adolescent girls in Maine are at risk for vitamin D insufficiency. J Am Diet Assoc 105: 971–974
Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ 2004 Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 158: 531–537
Looker AC, Dawson-Hughes B, Calvo MS, Gunter EW, Sahyoun NR 2002 Serum 25-hydroxyvitamin D status of adolescents and adults in two seasonal subpopulations from NHANES III. Bone 30: 771–777
Lawson M, Thomas M 1999 Vitamin D concentrations in Asian children aged 2 years living in England: population survey. BMJ 318: 28
Nicolaidou P, Hatzistamatiou Z, Papadopoulou A, Kaleyias J, Floropoulou E, Lagona E, Tsagris V, Costalos C, Antsaklis A 2006 Low vitamin D status in mother-newborn pairs in Greece. Calcif Tissue Int 78: 337–342
El-Hajj Fuleihan G, Nabulsi M, Choucair M, Salamoun M, Hajj Shahine C, Kizirian A, Tannous R 2001 Hypovitaminosis D in healthy schoolchildren. Pediatrics 107: E53
Du X, Greenfield H, Fraser DR, Ge K, Trube A, Wang Y 2001 Vitamin D deficiency and associated factors in adolescent girls in Beijing. Am J Clin Nutr 74: 494–500
Lehtonen-Veromaa M, Mottonen T, Irjala K, Karkkainen M, Lamberg-Allardt C, Hakola P, Viikari J 1999 Vitamin D intake is low and hypovitaminosis D common in healthy 9- to 15-year-old Finnish girls. Eur J Clin Nutr 53: 746–751
Ward LM, Gaboury I, Ladhani M, Zlotkin S 2007 Vitamin D-deficiency rickets among children in Canada. CMAJ 177: 161–166
Huh SY, Gordon CM 2008 Vitamin D deficiency in children and adolescents: epidemiology, impact and treatment. Rev Endocr Metab Disord 9: 161–170
Zipitis CS, Markides GA, Swann IL 2006 Vitamin D deficiency: prevention or treatment?. Arch Dis Child 91: 1011–1014
Bener A, Alsaied A, Al-Ali M, Al-Kubaisi A, Basha B, Abraham A, Guiter G, Mian M 2008 High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children. Acta Diabetol ( in press)
Zittermann A, Dembinski J, Stehle P 2004 Low vitamin D status is associated with low cord blood levels of the immunosuppressive cytokine interleukin-10. Pediatr Allergy Immunol 15: 242–246
Davies PD, Brown RC, Woodhead JS 1985 Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 40: 187–190
Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, Wright D, Latif M, Davidson RN 2000 Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355: 618–621
Bryce J, Boschi-Pinto C, Shibuya K, Black RE 2005 WHO estimates of the causes of death in children. Lancet 365: 1147–1152
Williams B, Williams AJ, Anderson ST 2008 Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 27: 941–942
Muhe L, Lulseged S, Mason KE, Simoes EA 1997 Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 349: 1801–1804
Najada AS, Habashneh MS, Khader M 2004 The frequency of nutritional rickets among hospitalized infants and its relation to respiratory diseases. J Trop Pediatr 50: 364–368
Wayse V, Yousafzai A, Mogale K, Filteau S 2004 Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr 58: 563–567
Karatekin G, Kaya A, Salihoglu O, Balci H, Nuhoglu A 2007 Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr, Nov 21 [Epub ahead of print]
Green D, Carson K, Leonard A, Davis JE, Rosenstein B, Zeitlin P, Mogayzel P Jr 2008 Current treatment recommendations for correcting vitamin D deficiency in pediatric patients with cystic fibrosis are inadequate. J Pediatr 153: 554–559
Yim S, Dhawan P, Ragunath C, Christakos S, Diamond G 2007 Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3). J Cyst Fibros 6: 403–410
Villamor E 2006 A potential role for vitamin D on HIV infection?. Nutr Rev 64: 226–233
Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos G, van 't Slot R, Wijmenga C, Goeman JJ, Kimpen JL, van Houwelingen HC, Kimman TG, Hoebee B 2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. J Infect Dis 196: 826–834
Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S 2007 Vitamin D status is not associated with the risk of hospitalization for acute bronchiolitis in early childhood. Eur J Clin Nutr 63: 297–299
Roth DE, Jones AB, Prosser C, Robinson JL, Vohra S 2008 Vitamin D receptor polymorphisms and the risk of acute lower respiratory tract infection in early childhood. J Infect Dis 197: 676–680
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E 2006 Epidemic influenza and vitamin D. Epidemiol Infect 134: 1129–1140
Pelletier AJ, Mansbach JM, Camargo CA Jr 2006 Direct medical costs of bronchiolitis hospitalizations in the United States. Pediatrics 118: 2418–2423
Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S, Helms PJ, Seaton A, Weiss ST 2007 Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 85: 853–859
Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, Kleinman K, Gillman MW 2007 Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 85: 788–795
Arkkola T, Uusitalo U, Kronberg-Kippila C, Mannisto S, Virtanen M, Kenward MG, Veijola R, Knip M, Ovaskainen ML, Virtanen SM 2008 Seven distinct dietary patterns identified among pregnant Finnish women—associations with nutrient intake and sociodemographic factors. Public Health Nutr 11: 176–182
Fronczak CM, Baron AE, Chase HP, Ross C, Brady HL, Hoffman M, Eisenbarth GS, Rewers M, Norris JM 2003 In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 26: 3237–3242
Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM 2001 Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358: 1500–1503
Brekke HK, Ludvigsson J 2007 Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes 8: 11–14
Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC, Canadian Collaborative Study Group 2005 Timing of birth and risk of multiple sclerosis: population based study. BMJ 330: 120
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A 2006 Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296: 2832–2838
Adams JS, Gacad MA, Singer FR, Sharma OP 1986 Production of 1,25-dihydroxyvitamin D3 by pulmonary alveolar macrophages from patients with sarcoidosis. Ann N Y Acad Sci 465: 587–594
Adams JS, Singer FR, Gacad MA, Sharma OP, Hayes MJ, Vouros P, Holick MF 1985 Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab 60: 960–966
Adams JS, Gacad MA 1985 Characterization of 1 alpha-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 161: 755–765
Barnes PF, Modlin RL, Bikle DD, Adams JS 1989 Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis. J Clin Invest 83: 1527–1532
Fagan DL, Prehn JL, Adams JS, Jordan SC 1991 The human myelomonocytic cell line U-937 as a model for studying alterations in steroid-induced monokine gene expression: marked enhancement of lipopolysaccharide-stimulated interleukin-1 beta messenger RNA levels by 1,25-dihydroxyvitamin D3. Mol Endocrinol 5: 179–186
Hewison M, Dabrowski M, Faulkner L, Hughson E, Vadher S, Rut A, Brickell PM, O'Riordan JL, Katz DR 1994 Transfection of vitamin D receptor cDNA into the monoblastoid cell line U937. The role of vitamin D3 in homotypic macrophage adhesion. J Immunol 153: 5709–5719
Hewison M, Dabrowski M, Vadher S, Faulkner L, Cockerill FJ, Brickell PM, O'Riordan JL, Katz DR 1996 Antisense inhibition of vitamin D receptor expression induces apoptosis in monoblastoid U937 cells. J Immunol 156: 4391–4400
Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R 2003 Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 170: 5382–5390
Jordan SC, Lemire JM, Sakai RS, Toyoda M, Adams JS 1990 Exogenous interleukin-2 does not reverse the immunoinhibitory effects of 1,25-dihydroxyvitamin D3 on human peripheral blood lymphocyte immunoglobulin production. Mol Immunol 27: 95–100
Lemire JM, Adams JS, Kermani-Arab V, Bakke AC, Sakai R, Jordan SC 1985 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro. J Immunol 134: 3032–3035
Lemire JM, Adams JS, Sakai R, Jordan SC 1984 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 74: 657–661
Prehn JL, Fagan DL, Jordan SC, Adams JS 1992 Potentiation of lipopolysaccharide-induced tumor necrosis factor-alpha expression by 1,25-dihydroxyvitamin D3. Blood 80: 2811–2816
D'Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di LP, Lang R, Sinigaglia F, Panina-Bordignon P 1998 Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Invest 101: 252–262
Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V 2000 Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 164: 4443–4451
Yang S, Smith C, Prahl JM, Luo X, DeLuca HF 1993 Vitamin D deficiency suppresses cell-mediated immunity in vivo. Arch Biochem Biophys 303: 98–106
Lathers DM, Clark JI, Achille NJ, Young MR 2004 Phase 1B study to improve immune responses in head and neck cancer patients using escalating doses of 25-hydroxyvitamin D3. Cancer Immunol Immunother 53: 422–430
Krutzik SR, Tan B, Li H, Ochoa MT, Liu PT, Sharfstein SE, Graeber TG, Sieling PA, Liu YJ, Rea TH, Bloom BR, Modlin RL 2005 TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11: 653–660
Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J, Stanford J 1986 Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57: 159–163
Crowle AJ, Ross EJ, May MH 1987 Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55: 2945–2950
Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL 2006 Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311: 1770–1773
Dowling GB 1957 The present status of vitamin D2 in the treatment of lupus vulgaris. Dermatologica 115: 491–495
Morcos MM, Gabr AA, Samuel S, Kamel M, el Baz M, el Beshry M, Michail RR 1998 Vitamin D administration to tuberculous children and its value. Boll Chim Farm 137: 157–164
Nursyam EW, Amin Z, Rumende CM 2006 The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 38: 3–5
Wagner CL, Greer FR 2008 Prevention of rickets and vitamin d deficiency in infants, children, and adolescents. Pediatrics 122: 1142–1152
Hollis BW, Pittard WB III 1984 Evaluation of the total fetomaternal vitamin D relationships at term: evidence for racial differences. J Clin Endocrinol Metab 59: 652–657
Canadian Paediatric Society 2007 Vitamin D supplementation: recommendations for Canadian mothers and infants. Paediatr Child Health 12: 583–598
Kovacs CS 2008 Vitamin D in pregnancy and lactation: maternal, fetal, and neonatal outcomes from human and animal studies. Am J Clin Nutr 88: 520S–528S
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by NIH/NIAID A147868 (to R.L.M.), NIH/NIAID A173539 (R.L.M.), RWJF 053510 (V.P.W.).
Rights and permissions
About this article
Cite this article
Walker, V., Modlin, R. The Vitamin D Connection to Pediatric Infections and Immune Function. Pediatr Res 65, 106–113 (2009). https://doi.org/10.1203/PDR.0b013e31819dba91
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e31819dba91
This article is cited by
-
Comparison of cord blood and 6‐month‐old vitamin D levels of healthy term infants supplemented with 400 IU/day dose of vitamin D
European Journal of Clinical Nutrition (2023)
-
Spatio-temporal analysis of socio-economic characteristics for pulmonary tuberculosis in Sichuan province of China, 2006–2015
BMC Infectious Diseases (2020)
-
Nutritional Rickets with Severe Complications in Syrian and Iraqi Refugee Children
Indian Pediatrics (2020)
-
Evolving Role of Vitamin D in Immune-Mediated Disease and Its Implications in Autoimmune Hepatitis
Digestive Diseases and Sciences (2019)
-
Vitamin D status and vitamin D receptor gene polymorphism in Saudi children with acute lower respiratory tract infection
Molecular Biology Reports (2019)