The Role of Vitamin D in Allergic Diseases in Children

Miraglia del Giudice, Michele MD; Allegorico, Annalisa MD

doi: 10.1097/MCG.0000000000000679
Presentation

The role of vitamin D in calcium and phosphate homeostasis is well known; however, in addition to traditional functions, vitamin D modulates a variety of processes, and evidence shows that it has an important role in different allergic diseases such as asthma, atopic dermatitis, and food allergy. Vitamin D acts by binding to the vitamin D receptor, which is present in a variety of tissues; for this reason it is considered a hormone. One of the most important functions is to modulate the immune system response, both innate and adaptive, by suppressing Th2-type response and increasing natural killer cells. Recent studies show that higher serum levels of 25-hydroxyvitamin D were associated with a reduced risk for asthma exacerbations and hospitalization. Other experimental data suggest that vitamin D can potentially increase the therapeutic response to glucocorticoid and potentially be used as an add-on treatment in steroid-resistant asthmatic patients. However, vitamin D stimulates the production and regulation of skin antimicrobial peptides, such as cathelicidins, which have both direct antimicrobial activity and induced host cellular response by triggering cytokine release. Recent evidence suggests that low blood vitamin D level is a risk factor for food allergy; vitamin D deficiency predisposes to gastrointestinal infections, which may promote the development of food allergy. In conclusion, several data suggest that serum 25-hydroxyvitamin D levels are often insufficient in children with asthma, atopic dermatitis, and food allergy. Further clinical trials are needed to provide conclusive evidence and to identify the effects of vitamin D in allergic diseases.

Department of Women, Child and General and Special Surgery, Second University of Naples, Naples, Italy

The authors declare that they have nothing to disclose.

Address correspondence to: Michele Miraglia del Giudice, MD, Department of Women, Child and General and Special Surgery, Second University of Naples, Naples Via De Crecchio, Naples 4-80138, Italy (e-mail: michele.miraglia@unina2.it).

Article Outline

Vitamin D refers to a group of fat-soluble steroids, among which vitamin D3 (cholecalciferol) is the most important for humans. The most common function of vitamin D3 is the regulation of calcium and phosphate homeostasis. Recently, vitamin D3 was found to be associated with cardiovascular disease, malignancies, microbial infections, autoimmune disorders, and allergic diseases.1

Cholecalciferol can be ingested from the diet or synthesized in the skin by exposure to sunlight UVB radiation. Subsequently it is converted into 25-hydroxyvitamin D [25(OH)D] in the liver and thereafter by the kidneys into 1,25-dihydroxyvitamin D (1,25(OH)D), the biologically active form of vitamin D. Thereafter, this compound activates the vitamin D receptor (VDR), regulating the expression of genes involved in calcium metabolism, proliferation, differentiation, apoptosis, and immunity.2

VDR was found to be present in a variety of tissues, suggesting the importance of vitamin D in various cellular and tissue functions.3 One of the most important functions is to modulate the immune system response, both innate and adaptive.

Atopic diseases are a Th2-dominant condition, characterized by the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13, and the production of IgE by B cells.4 Vitamin D has shown the ability to inhibit Th2-type response by suppressing the production of both IL-4 and IL-13.5

Regulatory T cells (Tregs) play an important role in maintaining immune homoeostasis in response to allergen exposure by suppressing Th2-mediated inflammation, such as airway eosinophilia, mucous hypersecretion, and airway hyperresponsiveness.6,7 Vitamin D can induce antigen-specific IL-10-producing Tregs that express low levels of the CD4+CD25+ Treg-associated transcription factor FoxP3.8

Vitamin D and its receptor (VDR) are both essential for the development of natural killer cells and for IL-4 and interferon (IFN)-γ production.9 Natural killer cells produce several proinflammatory cytokines such as IFN-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor.10 Vitamin D can suppress the proinflammatory cytokine IL-17, which has a key role in nonatopic asthma.11 All these mechanisms could explain the growing evidence connecting vitamin D to allergic diseases like asthma, atopic dermatitis (AD), and food allergy.

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VITAMIN D AND ASTHMA

Several studies have found that low cord blood vitamin D levels are associated with increased risk for wheezing or recurrent lung symptoms in young children, but not with asthma.12–14

A recent systematic review15 found that several prospective studies measuring 25(OH)D in cord blood at birth or during pregnancy did not find any association between 25(OH)D levels and asthma in children from 4 to 8 years. However, higher serum levels of 25(OH)D were associated with a reduced risk for asthma exacerbations.15 In the Childhood Asthma Management Program study, the higher risks for severe asthma exacerbations leading to Emergency Department visits or hospitalizations were associated with vitamin D insufficiency (25OHD<30 ng/mL).16

Recent experimental data suggest that vitamin D can potentially increase the therapeutic response to glucocorticoid and potentially be used as an add-on treatment in steroid-resistant asthmatic patients.17 Xystrakis et al17 showed that typical impaired production of IL-10 by CD4+ regulatory T cells in steroid-resistant asthmatic patients could be reversed by the addition of dexamethasone and vitamin D. In the same study the use of vitamin D overcame the downregulation of glucocorticoid receptor expression on CD4+ T cells induced by dexamethasone. With regard to inhaled steroids, a study examining children with persistent asthma treated with inhaled steroids found a greater improvement in lung function over a period of 1 year in children with vitamin D sufficiency compared with those with vitamin D deficiency.18 In addition, children with severe therapy-resistant asthma have been shown to have significantly lower vitamin D levels compared with children with moderate asthma.19

Vitamin D supplementation may potentially decrease the severity of asthma through a variety of mechanisms including its effects on immune cells, prevention of predisposing infections,20 decreased inflammatory responses, improved lung function,21 and reduced airway remodeling.22

In our recent study we investigated the relationship between exhaled nitric oxide and vitamin D levels in 66 mild to moderate asthmatic children. Our data show a significant decrease in bronchial inflammation assessed on the basis of exhaled nitric oxide levels (P=0.0018) in children with vitamin D levels >30 ng/mL.23

Brehm et al16 associated high vitamin D levels with a reduced risk for hospitalization (odds ratio, 0.05) and use of anti-inflammatory medications (odds ratio, 0.18) in asthmatic children.

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VITAMIN D AND AD

AD is a common chronic inflammatory condition characterized clinically by pruritus, eczematous lesions, and a defective epidermal barrier.24

Vitamin D is implicated in the formation of the stratum corneum barrier as a result of protein synthesis (such as filaggrin) and through the regulation of keratinocyte proliferation and differentiation.

Vitamin D stimulates the production and regulation of skin antimicrobial peptides such as cathelicidins.25 Antimicrobial peptides show both a direct antimicrobial activity and an induced host cellular response by inducing cytokine release. Therefore, vitamin D deficiency might predispose patients with AD to skin superinfection from Staphylococcus aureus or its superantigens.26 Vitamin D deficiency is also associated with greater severe skin lesions on localized body areas not exposed to sunlight.27 UV light, administered in the controlled setting, is a widely recognized treatment for severe AD. The benefit of UV light exposure is attributed to improved vitamin D status.28

Several studies show that vitamin D deficiency is related to the severity of AD. Wang et al29 measured 25(OH)D levels in 498 children with AD and in 328 nonallergic controls. AD severity, assessed by SCORAD score, showed inverse associations with serum 25(OH)D levels. Peroni et al30 showed that serum levels of 25(OH)D were higher in patients affected by mild AD compared with those in children with moderate or severe AD. In contrast, Chiu et al31 found no statistically significant association between vitamin D levels and AD severity.

Vitamin D deficiency at birth is associated with higher risk of developing AD. In a birth cohort study of 239 newborns, low cord blood 25(OH)D levels were associated with higher risk for developing AD at ages of 1, 2, 3, and 5 years.32

In conclusion, systematic supplementation of vitamin D in children affected by AD cannot be recommended currently. Additional studies with adequate sample size, longer duration of treatment, standardization of AD severity assessment, and adequate correction for confounding factors such as sun/UVB exposure are currently needed.

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VITAMIN D AND FOOD ALLERGY

Recently it was proposed that low blood vitamin D level is a risk factor for food allergy.

Vassallo et al33 hypothesized that vitamin D deficiency predisposes to more severe and frequent infections from common gastrointestinal pathogens due to altered production of antimicrobial peptides. Gut infections promote dysbiosis and impair the intestinal barrier function. The increasing exposure to food antigens in genetically susceptible subjects may promote the development of food allergy. In vitro experimental data show that 1,25(OH)2D3 induces junction protein expression (ZO-1, claudin 1, claudin 2, and E-cadherin) and strengthens the tight junction complex, improving the maintenance of mucosal barrier function.34 In that regard, Chiu et al35 have proved that low cord blood vitamin D levels increase milk sensitization.

There was a higher prevalence of food allergies in children living in areas with low exposure to sunlight (such as Australia) and in children born in autumn or winter.36 Two recent large population-based studies have shown that low serum vitamin D levels are associated with increased risk for peanut sensitization and challenge-proven peanut or egg allergy.37

In conclusion, several data suggest that serum 25(OH)D levels are often insufficient in children with asthma AD and food allergy. A certain number of studies show that vitamin D supplementation may have a role in allergic illness but there are studies that do not confirm this hypothesis. Further clinical trials are needed to provide conclusive evidence and to identify the optimal dosage, length of treatment, and target serum 25(OH)D levels in allergic diseases.

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Keywords:

vitamin D; allergic disease; asthma; atopic dermatitis; food allergy

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