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.
After the discovery that vitamin D deficiency is the cause of nutritional rickets, the emphasis on vitamin D status in children was relegated to a discussion primarily focused on prevention and treatment of the disease. A few early clinicians, however, astutely recognized the increased incidence of respiratory infections among infants and children with rickets. Most presumed, however, that the increased incidence of respiratory infections in these children reflected compromised lung compliance from the rib deformities associated with severe rickets and an overall poor nutritional status. Now epidemiologic studies have identified a link between inadequate vitamin D concentrations and infectious disease. Furthermore, the contribution of vitamin D in host defense against infection has been elucidated. The goal of this study is to provide an overview on the current knowledge available regarding the role of vitamin D in immunologic function and the manifestations of infectious diseases in the pediatric population.
Delineating Vitamin D Sufficiency, Insufficiency, and Deficiency
By definition, vitamin D is not a true vitamin because adequate exposure to sunlight either negates or significantly diminishes the need for dietary supplementation. Instead, this imprecise descriptor refers to a group of steroid molecules also encompassing both vitamin D2 (derived from plants that use ergosterol rather than cholesterol) and vitamin D3 molecules (derived from cholesterol). The human body thus procures vitamin D through two independent pathways: the photochemical action of solar UVB light (∼295 to 320 nm) in the skin and some limited dietary sources (1).
Given that vitamin D2 is produced by plants, dietary sources (naturally occurring and/or obtained via oral supplementation) are the only means for acquiring it. Vitamin D3, on the other hand, is predominantly procured via the sunlight driven cutaneous reaction described earlier or from dietary sources. For adults, consumption of fatty fish and/or oral supplementation supplies the most abundant amounts of vitamin D3. In contrast, the major dietary sources of vitamin D in the pediatric population are provided by fortified foods such as cereal, cheese, and milk, none of which are uniformly consumed in large quantities by all age groups. The average adult diet typically provides <10–20% of an individual's vitamin D stores with a child's diet likely to provide even less vitamin D (2).
In the body, 25-hydroxy vitamin D (25D) is the major circulating vitamin D metabolite. It is generated predominantly through hepatic 25-hydroxylation via many potential catalysts, including CYP2R1 and CYP27A1. The conversion to hormonal 1,25-dihydroxyvitamin D (1,25D) requires the enzyme CYP27B1. The kidneys have long been considered the major site for 1α-hydroxylation of 25D to 1,25D. Unlike the loosely regulated hepatic hydroxylation of 25D, the renal 1α-hydroxylation falls under tight control of parathyroid hormone (PTH) and is primarily involved in calcium regulation and signaling. In sites other than the renal tubule, such as keratinocytes (3), the trophoblastic layer of the placenta (4), IFN-γ stimulated macrophages (5), and granulomata (6), this type of fastidious regulation is either absent or operates very inefficiently. Compared with adults, strict control of renal 1α-hydroxylation and the normal feedback suppression by 1,25D is also less precise in infants.
Once converted, 1,25D serves as the active form of vitamin D and binds to the vitamin D receptor (VDR), a nuclear receptor and ligand-activated transcription factor (7). VDR is expressed in most tissues and regulates cellular differentiation and function in many cell types. For example, VDR expression is found in monocytes as well as stimulated macrophages, dendritic cells, natural killer cells, T cells, and B cells of the immune system. Activation of the VDR leads to production of downstream gene products. In immune cells, VDR activation elicits potent antiproliferative, prodifferentiative, and immunomodulatory effects.
Initially, research focused on the role of vitamin D in bone metabolism and calcium homeostasis. Regulation of intestinal calcium transport is still the most significant effect of 1,25D acting through its binding to the VDR. More recently, however, it has become clear that vitamin D has pleiotropic effects. This includes some VDR transcription-independent actions and vitamin D playing a key role in immune system regulation. Activation of the VDR by 1,25D alters cytokine secretion patterns, suppresses effector T-cell activation, and induces regulatory T cells. In dendritic cells, it has also been demonstrated to affect maturation, differentiation, and migration. 1,25D can enhance the phagocytic activity of macrophages and increase the activity of natural killer cells. Therefore, tissue- and cell-specific differences in the regulation of 25D are highly relevant to the roles of 25D and 1,25D as immunomodulators.
The effects observed with vitamin D are dependent on the availability of the substrate. Designations for sufficient, toxic, insufficient, and deficient states are defined by the serum concentrations of 25D. Normal 25D concentrations associated with a vitamin D sufficient individual are usually >30 to 32 ng/mL (75–80 nM). Hypervitaminosis D is arbitrarily defined as 25D concentrations >100 ng/mL (250 nmol/L). However, people living and/or working in sun-enriched environments, such as lifeguards and sunbathers, reached 25D concentrations exceeding this value without evidence of deleterious consequences beyond the well-characterized solar damage from ultra violet radiation (UVR) (8). Symptoms of vitamin D intoxication typically do not manifest until circulating 25D concentrations rise above 150 ng/mL (375 nM). The most common adverse effect is hypercalcemia, which can lead to the formation of kidney or bladder stones and cause renal failure.
Vitamin D deficiency is typically defined as circulating 25D concentrations <20 ng/mL (50 nM) (7,9). In this state, the subsequently low ionized calcium (iCa) concentration stimulates PTH secretion, which eventually leads to increased 1,25D synthesis. The elevated PTH concentrations also lead to a decrease in bone mineralization and osteomalacia. In the immature bones of children, the term rickets describes the osteomalacia and the abnormal organization of the cartilaginous growth plate along with the accompanying impairment of cartilage mineralization (10). PTH and 25D concentrations are inversely related until the 25D concentration is >30–40 ng/mL (75–100 nM), after which PTH concentrations fall precipitously.
Individuals with 25D concentrations >20 ng/mL (50 nM) have been originally classified in the vitamin D sufficient category. With more information emphasizing the important roles vitamin D plays outside of calcium homeostasis and bone metabolism, 25D concentrations that span the range between the loosely defined parameters of vitamin D sufficiency and deficiency are now associated with manifestations of disease. In both the adult and the pediatric population, use of the term vitamin D insufficiency is increasingly recommended for ranges that fall between 20 ng/mL (50 nM) and 30 to 32 ng/mL (75–80 nM) to account for these observations.
During the winter solstice period (outside the latitudinal lines, Tropic of Cancer and Tropic of Capricorn), surface solar UVB irradiation is inadequate to trigger sufficient production of vitamin D3. The seasonal variations in temperate climates, related to distance in latitude from the equator and decreased sun exposure, greatly exacerbate the problem of vitamin D insufficiency/deficiency. The melanin content in the epidermis of an individual also affects absorption of UVB with darker pigmented individuals absorbing less UVB due to melanin acting as a natural sunscreen. Any mechanism that prevents UVB absorption (clothing, increased pollution, longer periods spent indoors, etc.) works in a similar fashion to prevent cutaneous production of vitamin D3. Using the aforementioned definitions, estimates suggest that 1 billion people around the world may be vitamin D insufficient/deficient.
In characterizing the global health status of children, recognition of vitamin D insufficiency has increased significantly, particularly over the past 20 y. In the United States, relatively high rates of vitamin D deficiency not necessarily associated with rickets have been reported in healthy infants (11,12), children (13,14), and adolescents (15,16). A high prevalence of vitamin D deficiency has also been reported in infants, children, and adolescents from other countries, including the United Kingdom (17), Greece (18), Lebanon (19), China (20), Finland (21), and Canada (22). Besides the resurgence of rickets, vitamin D insufficiency in children is implicated as a risk factor for the development of chronic diseases later in life, including asthma, diabetes, heart disease, and cancer (23). A separate study from the United Kingdom, also found that the cost of preventing vitamin D deficiency in a high-risk population of Asian children theoretically favored this approach compared with the financial burden of treating the general health problems associated with chronic vitamin D deficiency (24). Despite the small cohort, the study provides an impetus for considering more aggressive prevention and treatment of widespread vitamin D deficiency.
Vitamin D Insufficiency/Deficiency and Infectious Diseases
Vitamin D insufficiency and deficiency have been associated with various disease states. Below “normal” vitamin D concentrations in adults have been strongly associated with tuberculosis, influenza, autoimmune diseases, cancer (prostate, colon, and breast), and myocardial infarction. Expanded studies in infants and children are also exploring the effects of vitamin D insufficiency and type 1 diabetes mellitus (25) as well as investigating the risk of developing of allergies and atopic diseases (26). Still, a significant gap exists in our understanding of the consequences of vitamin D insufficiency/deficiency in the pediatric population.
The prototypical example of a connection between vitamin D insufficiency and susceptibility to infectious disease is tuberculosis (TB). Published studies over the past 20 y ago have strongly connected the association of decreased serum 25D concentrations and increased severity and/or susceptibility to TB infection. Davies et al. (27) demonstrated significantly lower 25D3 concentrations among patients with culture positive TB versus their matched controls. More recently, a case-control study of the Gujarati Indian population in London found that 25D3 deficiency was more commonly observed in patients with active TB (67%) versus their uninfected household co-inhabitants (26%) who served as the control group (28).
In children, infections remain a major cause of morbidity and mortality around the world (29). Several recent epidemiology studies have observed the association between inadequate vitamin D concentrations and hospitalization and/or respiratory infection among children. Williams et al. (30) determined the vitamin D status of 64 children infected with TB. Eighty-six percent of their patients had inadequate vitamin D stores. Although TB is the prototypical association of vitamin D deficiency and infectious disease, other infectious diseases have also been linked to inadequate vitamin D stores in children.
Muhe et al. (31) examined the risk for developing pneumonia among Ethiopian children with nutritional rickets. This case-control study found a strong positive correlation between vitamin D deficiency and respiratory compromise. More recently, Najada et al. (32) studied a cohort of hospitalized infants with respiratory diseases and found a higher incidence of nutritional rickets. Wayse et al. (33) also investigated acute lower respiratory tract infections (ALRIs) in nonrachitic children admitted to a private hospital in India. Their study led to recognition of a link between subclinical vitamin D deficiency, nonexclusive breastfeeding, and increased risk for severe ALRIs. Karatekin et al. (34) followed up with a report from Turkey on ALRIs and nonrachitic vitamin D deficiency in newborns. They found that serum 25D concentrations in the newborns with ALRIs were lower than the healthy control group. The risk for developing an ALRI also increased significantly with 25D concentrations <10 ng/mL (25 nM). In their study population, infants with ALRIs spent an average of 8 d in the NICU, again implying the financial and social impact of vitamin D insufficiency/deficiency.
The incidence of viral infections, particularly in the pediatric population, typically peaks in the winter months when cutaneous vitamin D synthesis is naturally impaired. In contrast to data available from adult subjects, infections observed in children with inadequate vitamin D stores are more frequently reported as viral in origin. Several of the previously cited studies have pointed to adequate vitamin D concentrations playing a potential role in protecting against upper and lower respiratory tract infections. One of the key points in these studies is the suggestion that susceptibility to infection occurs before many of the overt manifestations of nutritional rickets might appear. More specifically, the risk for acquiring an infection necessitating hospitalization is also reflective of a vitamin D insufficient state, rather than a secondary manifestation of the more severe vitamin D deficiency typically documented in cases of nutritional rickets. For most populations, inadequate concentrations of vitamin D seem to clinically impact the health of children more severely and often before the manifestations of rickets and osteomalacia.
Cystic fibrosis (CF) is another disease encountered in the pediatric population characterized by recurrent infections and inadequate serum concentrations of vitamin D (35). Patients with CF usually experience problems with malabsorption and are typically placed on oral supplementation of fat-soluble vitamins, including vitamin D. Severe pulmonary infections often require repeated hospitalizations. Treatment for these infections has led to the increasingly problematic issue of antibiotic resistance by the causative pathogens. One promising area of research for improving the efficacy of antibiotic therapy is the use of antimicrobial peptides (AMPs) as therapeutic adjuvants. Cathelicidin is an AMP with multifunctional roles in host defense whose expression is up-regulated by 1,25D. Yim et al. (36) recently investigated the production of cathelicidin in primary cultures of normal and CF bronchial epithelial cells. They were able to demonstrate 1,25D-stimulated induction of cathelicidin in this cell type. They also provided evidence for 1,25D-treated bronchial epithelial cells exhibiting increased antibacterial activity against common CF airway pathogens such as Pseudomonas aeruginosa and Bordetella bronchiseptica. On the basis of these results, they speculate on the targeted use of inhaled 1,25D to augment the expression of cathelicidin on the mucosal surface of bronchial epithelia.
HIV is an example of an infection where the clinical and genetic evidence is aggregating together to suggest that vitamin D may play a role in susceptibility to and control of the infection. To our knowledge, no studies to date have found a correlation between vitamin D status and risk for death from HIV. In one study, however, HIV-positive patients supplemented with vitamin D demonstrated a positive impact on their CD4+ T-cell counts (37). Further research into the connection between vitamin D and HIV is ongoing and includes studies on the role of vitamin D signaling and the VDR in HIV infection.
Research into VDR gene polymorphisms also supports the association between vitamin D and other infectious diseases. Janssen et al. (38) reported a significant association between genetic susceptibility to respiratory syncytial virus (RSV) bronchiolitis and several single nucleotide polymorphisms (SNPs) of genes related to innate immune function, including the VDR. Roth et al. (39) previously published a report which demonstrated no association between ALRI and vitamin D concentrations in Canadian hospitalized children. Most of the children in their study, however, were relatively vitamin D replete. They then undertook a secondary analysis of the subject population used for that study. They identified two SNPs using the TaqI and FokI restriction endonucleases as these had been previously associated with pulmonary TB in several adult populations. The designation of a lowercase t (TaqI) or f (FokI) indicated the presence of a restriction site. Among their study population, children with the ff genotype were at a high risk for developing an ALRI (predominantly RSV bronchiolitis) (40). Their finding remained statistically significant even after attempting to account for potential confounders such as ethnicity.
Vitamin D-related pathways have been studied in terms of their involvement in the host immune response to viral respiratory infections, such as influenza (41). In several pediatric studies, an association with the ff genotype of the VDR increased the risk of acquiring an acute lower respiratory tract infection (predominantly viral bronchiolitis). The ff genotype seems to encode a less active VDR and diminish the ability of immune cells to use vitamin D for its immunomodulatory effects or to generate antimicrobial activity. With estimates of costs exceeding $500 million dollars per year (42), bronchiolitis places a tremendous financial burden on the healthcare system in the United States. A relatively simple intervention such as vitamin D supplementation that might decrease the incidence of this disease would be a highly sought after option for treatment provided by healthcare providers and requested by parents and public health officials.
Effects of Vitamin D on Immune Function
The effects of vitamin D on immune function can be thought of in relation to diseases characterized by autoimmune dysfunction, such as asthma, type 1 diabetes mellitus, and multiple sclerosis. Inadequate intake of vitamin D and low serum concentrations of 25D in pregnancy have been associated with higher risk of wheezing illnesses in children (43). A study from Boston, MA, suggested that increasing maternal vitamin D intake while pregnant could potentially decrease the risk of recurrent wheeze during early childhood in the offspring of the mother's compliant with the recommendations (44).
In type 1 diabetes, studies of vitamin D supplementation during pregnancy and early childhood demonstrated a potential to reduce the risk of developing the disease (45–47). A population-based birth cohort study of 10,366 Finnish children followed for three decades found that children who regularly ingested 2,000 IU of vitamin D during the first year of life were 80% less likely to develop type 1 diabetes mellitus (47). Some other studies have reported contrasting findings. A Swedish birth cohort study of 11,081 children found that maternal supplementation with >200 IU of vitamin D during pregnancy reduced islet autoimmunity at 1 y of age, but this effect was not sustained when children were examined at 2½ y of age. Supplementation with a daily dose of 400 IU during infancy was not associated with islet autoimmunity (48). Discrepancies between study designs may partially explain the discrepancy between findings.
Vitamin D deficiency as an infant has been implicated as one risk factor for the development of multiple sclerosis. The season of birth, used as a surrogate marker of vitamin D concentrations during pregnancy, was associated with familial cases of multiple sclerosis in a population based study conducted throughout several different countries (49). Using serum samples stored in the US Department of Defense Serum Repository, another group of investigators conducted a prospective, nested case-control study and found interesting differences between the ethnically diverse populations represented in the repository. Among white adults, those in the highest quintile of measured vitamin 25D before diagnosis had less of a risk for developing multiple sclerosis than those in the lowest quintile (odds ratio, 0.59) (50). The inverse relationship between vitamin D and risk of a multiple sclerosis diagnosis was strongest when the 25D concentrations were measured in subjects before their reaching 20 y of age. These findings, however, were not duplicated in the samples from African-American and Latino sera contained in the repository.
The effects of vitamin D on the immune system extend beyond manifestations of autoimmune diseases with several studies extensively investigating and summarizing the role of 1,25D on the innate (51–59) and adaptive (59–62) immune responses. In general, 1,25D acts not only to promote the innate immune response to microbial pathogens but to also quell what might be an overzealous adaptive immune response to pathogens that prove difficult for the macrophage to handle effectively. Although 1,25D has direct effects on the adaptive immune system, it also affects the ability of the innate immune system to instruct the adaptive immune response. In this instance, 1,25D is a potent suppressor of IL-12 production (63) and dendritic cell (DC) differentiation (64). It is important to note that all the in vitro studies demonstrating an effect for 1,25D on innate immunity added exogenous 1,25D to cell cultures either at levels above the physiologic serum range or in addition to the 1,25D present in the serum supplemented media. Furthermore, the serum 1,25D levels, as mentioned, are tightly regulated by parathyroid feedback, even in the face of 25D insufficiency. These findings raised questions as to whether there was a role for vitamin D at physiologic concentrations in host immune responses.
The association of 25D insufficiency with various disease states combined with the in vitro studies, prompted researchers to investigate direct effects of 25D on innate immunity. Hewison et al. (58) found that 25D at physiologic levels (100 nM) suppressed CD40L-induced IL-12 production in day-7 GM-CSF/IL-4–derived DCs. Similarly, there is little data on the effects of altering the 25D status in vivo on the immune status of the host. Yang et al. (65) showed that profound reduction in the serum 25D in mice resulted in significant blunting of the cell-mediated immune response to cutaneous DNFB challenge. Administration of 25D to humans with head and neck squamous cell carcinoma increased plasma IL-12 and IFN-γ levels, and improved T-cell blastogenesis (66). One possible resolution of these conflicting data are that the cell-surface makers of a GM-CSF/IL-4–derived DC do not represent a physiologic DC that can be detected in human tissue (67), so this remains an area for new investigation.
In the 1980s, important studies from Rook et al. (68) and Crowle et al. (69) demonstrated the ability of 1,25D to induce antimicrobial activity in Mycobacterium tuberculosis–infected macrophages. These studies were carried out before the in situ conversion of 25D to 1,25D in extrarenal tissues was widely recognized and appreciated. As such, the investigators were appropriately cautious to raise concerns regarding their methodology in that they used concentrations of 1,25D far greater than normal serum levels. They questioned whether or not their findings were replicable in the presence of the presumed physiologic serum concentrations of 1,25D available to macrophages. Recent studies in our laboratory (70) addressed these questions and concerns by providing new insight into the involvement of vitamin D in the toll-like receptor triggering of an antimicrobial response to infection (Fig. 1). Using microarray studies, we found that signaling through human macrophage TLR 2/1 heterodimers stimulated with bacterial lipopepties induced expression of both CYP27B1 and the VDR. The exciting aspect of the findings demonstrated that in TRL 2/1-stimulated human macrophages cultured in the presence of human serum, downstream VDR-driven responses were strongly dependent on serum 25D concentrations. VDR-driven responses were either greatly diminished or absent in serum from vitamin D deficient individuals. This response could be “rescued,” with 25D supplementation in vitro to a physiologically equivalent serum concentration thereby providing a rationale for considering vitamin D supplementation as prevention and/or as a therapeutic adjuvant.
Vitamin D Supplementation
As mentioned previously, naturally occurring dietary sources of vitamin D are limited. Foods enriched with vitamin D include fatty fish (e.g. sockeye salmon, raw Atlantic herring, pickled herring, and canned pink salmon with bones in oil), fish oils (e.g. cod liver), and sun-dried shitake mushrooms (9,10). None of these comprise a typical adolescent's, child's, or infant's diet. Fortified foods such as infant formulas, cow's milk, orange juice, breakfast cereals, cheese, and butter are more likely to be consumed by children but contain significantly less and often fluctuating amounts of vitamin D. Furthermore, fortification of dairy products in the United States is not mandatory as required in Canada. Fortification of foods is fraught with problems related to lax regulations on compliance with fortification requirements as well as decreasing consumption of vitamin-D fortified foods and beverages.
Sun-avoidant behavior due to concerns for skin cancer leaves many dependent on inadequate diets for intake of vitamin D. Besides the difficulty in obtaining a sufficient quantity of vitamin D via dietary sources to compensate for the lack of cutaneous D3 synthesis, availability of vitamin D in foods consumed are often further diminished by the methods used in preparation and cooking. Generally, oral supplementation with multivitamins has become a widely accepted means of addressing nutritional deficiencies and inadequacies. With oral supplements, most commercially available multivitamins contain vitamin D2. In terms of potency, plant-derived vitamin D2 is considered less potent than vitamin D3. Poly-Vi-Sol, however, is one pediatric multivitamin that contains vitamin D3. The amount of vitamin D available via oral supplements lacks uniformity or standardized regulation. These discrepancies in food fortification and contradictory recommendations for use of oral supplements directly conflict with the studies supporting the use of vitamin D supplementation in treatment of diseases other than nutritional rickets.
In 1827, the introduction of routine oral cod liver oil administration successfully remedied the manifestations of nutritional rickets. Several decades later, vitamin D3 was identified as the active ingredient in cod liver oil. As early as the 19th century, sanatoria were also popular because of their beneficial effects on patients suffering from a variety of ailments, including cutaneous TB. In 1903, the Nobel Prize in Medicine was awarded to Niels Ryberg Finsen for his use of UV treatment to specifically treat cutaneous TB. However, the past 20 y has seen a resurgence in vitamin D deficiency and rickets. More concerning are the studies linking vitamin D insufficiency/deficiency to a host of other health problems, including asthma, cancer, diabetes, respiratory infections, and multiple sclerosis.
Quite a long history exists documenting the use of vitamin D to treat mycobacterial infections with apparent success. In 1946, Dowling (71) reported the treatment of patients with lupus vulgaris (a form of cutaneous TB) with oral vitamin D2. Eighteen of 32 patients seemed to be cured and nine others improved. Morcos et al. (72) treated 24 newly diagnosed cases of TB in children with standard chemotherapy with and without vitamin D. They noted clinical and radiologic improvement in the group who received treatment plus the vitamin D adjuvant therapy. Nursyam et al. (73) administered vitamin D or placebo to 67 patients with TB after the sixth week of standard TB treatment. Of 60 total patients, the group treated with vitamin D had higher sputum conversion and radiologic improvement (100%) compared with the placebo group (76.7%). This difference was statistically significant (p = 0.002). In vitro study results published from our laboratory indicate that the inactive 25D can be converted to the active 1,25D form on monocyte activation (70). This could be a possible mechanism by which supplementation of patients with inactive vitamin D leads to a positive therapeutic outcome.
In 1997, the Institute of Medicine recommended 200 IU of vitamin D per day for children. The American Academy of Pediatrics (AAP) also adopted this recommendation in their 2003 consensus statement. These recommendations were approved and disseminated despite historical evidence demonstrating one tablespoon of cod liver oil daily for prevention of rickets (a tablespoon of cod liver oil contains ∼400 IU of vitamin D). Administering a daily dose of 200 IU of vitamin D to children also contradicted the FDA recommendations of 400 IU per day for infants, children, and adolescents. Recognizing the continued increase in cases of rickets in the United States, the AAP revised their consensus statement in October 2008 (74). The current recommendations outlined several major issues related to vitamin D insufficiency in the United States.
The consensus committee stressed that, despite rickets being a completely preventable disease, exclusively breastfed and/or darkly pigmented infants remain at high risk for vitamin D deficiency and rickets. Additionally, vitamin D insufficiency among pregnant women places newborns at a greater risk for vitamin D deficiency because fetal and newborn concentrations of vitamin D are dependent on and correlated with maternal serum 25D concentrations (75). In mother-infant pairs, cord blood concentrations of 25D (reflective of the neonate) are typically significantly less than the 25D concentrations measured in the mother. Neonates born to marginally sufficient women, therefore, are still at risk for vitamin D deficiency and those born to vitamin D insufficient women are almost certainly deficient themselves.
To exacerbate the problem for the newborn, the vitamin D content of human milk also correlates with a mother's serum 25D concentration (74). Because of the multiple factors affecting a person's vitamin D status, providing supplementation with a daily dose of 400 IU does not guarantee that a mother's measured 25D serum concentration will rise to a value sufficient for an exclusively breastfeeding infant. Infant formulas in the United States have required minimum (40 IU/100 kcal) and maximum (100 IU/100 kcal) vitamin D concentrations. Based on a typical 20 kcal/oz formula, this is the equivalent of 258 IU/L to 666 IU/L. Fortunately, all US formulas contain at least 400 IU/L of vitamin D3. In the case of exclusively formula-fed infants, who are expected to consume at least a liter of formula each day, commercially available formula products would provide a minimum of 400 IU/d of vitamin D3. However, the increasing recognition of vitamin D insufficiency among women of childbearing age combined with the increase in exclusive and partial breastfeeding may prevent many infants from receiving an adequate amount of vitamin D from their diets. Studies demonstrating increased cases of rickets, ALRIs, and hospitalizations in vitamin D insufficient children seem to bear out these concerns.
Despite vitamin D deficiency rickets being a disease of infants and children, there are also cases of nutritional rickets being reported among adolescents (15). As mentioned previously, the typical adolescent diet lacks an abundant supply of vitamin D fortified foods and drinks. Based on the myriad of concerns, the AAP now recommends 400 IU daily of vitamin D with supplementation to begin in the first few days after birth and continue through childhood and adolescence. The consensus committee also suggests further studies to examine supplementation with higher doses (1000–4000 IU) similar to some recommendations for adults and, in countries like Canada, pregnant women (76,77).
The ideal amount of vitamin D intake needed to prevent the adverse health conditions associated with vitamin D insufficiency/deficiency remains unclear. Disagreements on cutoff values for vitamin D sufficiency in the pediatric population likewise complicate interpretation of the recommendations. Furthermore, recommendations for increased sunlight exposure to promote adequate cutaneous vitamin D3 synthesis will need to be balanced with concerns for the risks associated with the increased time spent in the sun exposed to UV radiation. Based on currently available research, however, support for supplementation greater than what prevents the most adverse outcomes (i.e. severe rickets) is strongly advocated.
Over the past 20 y, clinicians around the world have alerted us to the resurgence of vitamin D-associated rickets. Even in the United States, several vulnerable populations have been identified, including premature infants, medically fragile children, and exclusively breastfed dark-skinned infants (23). A tremendous amount of historical evidence and epidemiologic data support the association between inadequate vitamin D concentrations and infections.
Investigators have demonstrated how appropriate serum concentrations of vitamin D facilitate the ability of immune cells to defend against bacterial and viral infections. Ongoing research in this area has provided new ways of understanding the immune system and how the pleiotropic actions of vitamin D serve an important immunoregulatory role in proper immune function. With the increasing evidence of vitamin D insufficiency's detrimental effects beyond the classically defined cause of rickets, the full story behind the role of vitamin D insufficiency/deficiency in pediatric infection and immune function awaits full elucidation.
25-hydroxy vitamin D
American Academy of Pediatrics
acute lower respiratory tract infection
vitamin D receptor
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
Supported by NIH/NIAID A147868 (to R.L.M.), NIH/NIAID A173539 (R.L.M.), RWJF 053510 (V.P.W.).
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
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)
BMC Pregnancy and Childbirth (2021)
Spatio-temporal analysis of socio-economic characteristics for pulmonary tuberculosis in Sichuan province of China, 2006–2015
BMC Infectious Diseases (2020)
Sunlight exposure, consumption of vitamin D-rich foods and vulvovaginal candidiasis in an African population: a prevalence case–control study
European Journal of Clinical Nutrition (2020)
Indian Pediatrics (2020)