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Abstract

After the modern vitamin D hypothesis firstly suggested in 1999 for the allergy pandemic, numerous conditions have been thought to be associated with vitamin D deficiency such as allergy, autoimmunity and neoplasm. Consistently, previous observational studies have linked lower vitamin D status to increased markers of atopy and allergic diseases e.g. atopic dermatitis, anaphylaxis and food allergy. Vitamin D is a “hormone” having important immunomodulatory and immunoregulatory properties. In vitamin D deficient conditions, disrupted mucosal and skin complex integrity and intercurrent infections may act synergistically with allergenic exposure to amplify sensitization risk. There has been emerging data to show that vitamin D can enhance the anti-inflammatory effects of glucocorticoids and potentially be used as adjuvant therapy in steroid-resistant severe asthma. And recent in vivo data suggest that vitamin D supplementation reduce the severity of eczema and allergic rhinitis as well as urticaria symptoms. However, there is presently inadequate evidence to support daily vitamin D supplementation in the prevention and/or treatment of allergic diseases in infants, children and adolescents.
MOJ Immunology
Vitamin D and Allergy
Submit Manuscript | http://medcraveonline.com
Volume 3 Issue 2 - 2016
Department of Pediatrics, Research and Training Hospital of
Sakarya University, Turkey
*Corresponding author: Öner Özdemir, Division of Allergy
and Immunology, Department of Pediatrics, Research and
Training Hospital of Sakarya University, Faculty of Medicine,



Received:| Published: April 12, 2016
Mini Review

Abstract
After the modern vitamin D hypothesis firstly suggested in 1999 for the allergy
pandemic, numerous conditions have been thought to be associated with
vitamin D deficiency such as allergy, autoimmunity and neoplasm. Consistently,
previous observational studies have linked lower vitamin D status to increased
markers of atopy and allergic diseases e.g. atopic dermatitis, anaphylaxis and
food allergy. Vitamin D is a “hormone” having important immunomodulatory
and immunoregulatory properties. In vitamin D deficient conditions, disrupted
mucosal and skin complex integrity and intercurrent infections may act
synergistically with allergenic exposure to amplify sensitization risk. There has
been emerging data to show that vitamin D can enhance the anti-inflammatory
effects of glucocorticoids and potentially be used as adjuvant therapy in
steroid-resistant severe asthma. And recent in vivo data suggest that vitamin D
supplementation reduce the severity of eczema and allergic rhinitis as well as
urticaria symptoms. However, there is presently inadequate evidence to support
daily vitamin D supplementation in the prevention and/or treatment of allergic
diseases in infants, children and adolescents.
Keywords: 
Introduction
        
1999 for the allergy pandemic, numerous conditions have been
         
atherosclerosis, autoimmunity and neoplasm [1]. Consistently,
previous observational studies have related lower vitamin D
         
diseases e.g. increased airway hyperresponsiveness, asthma,
       
Furthermore, recent research on vitamin D suggests that higher
serum vitamin D levels might improve some disorder outcomes


Vitamin D is a “hormone” having immunomodulatory and
 
disrupted skin/mucosal complex integrity and coincidental
infections might serve synergistically with allergen exposure
to amplify sensitization risk at critical periods of immune
development before tolerance is developed [6].
Vitamin D Deciency
The serum 25-hydroxyvitamin D concentration is accepted
as the marker of vitamin D status. In the general population, the
Institute of Medicine considers that a vitamin D level >20ng/ml
     
assume that an optimal vitamin D status is better described by
       
is more common reported worldwide than considered to be.
  
  
        
   

older children, female, African and Mexican Americans, drank
    

Low vitamin D levels have also been demonstrated in various
allergic diseases such as in asthma, eczema, allergic rhinitis, food
allergy, anaphylaxis and urticaria. Whether low vitamin D levels
are primary or secondary to allergic disease is not clear [2-6].
For instance: since more severe asthmatic patients spend less
time outdoors, this situation is an apparent cause of vitamin D

Vitamin D Supplementation
Primary sun wavelengths converting vitamin D are UV-B. When
someone makes vitamin D in the skin it remains 2-3 times longer
in the human body. However, there is no known evidence showing
any difference in disorder outcomes between the effect of oral
supplements and sun exposure. Sun exposure is an ineffective
mechanism of boosting vitamin D of the human body [9]. Food
sources of vitamin D might be required for boosting vitamin
D status in human under some circumstances e.g. cod liver oil
preparations including vitamin A and D [2]. There is emerging
   
effects of glucocorticoids and potentially be used as adjuvant
therapy in steroid-resistant severe asthma patients. And recent in
vivo data suggest that vitamin D intake can also reduce asthma
exacerbations, severity of atopic dermatitis, allergic rhinitis as
well as chronic urticaria symptoms [10,11].

  
Vitamin D and Allergy 2/4
Copyright:
©2016 Özdemir
Citation:
  2D3 and
affect expression of over 200 genes, up regulations nearly two-
thirds and down regulating one-third of those genes. Therefore,
VDRs found in different alleles having different effects [12,13]. A
mutated VDR in hereditary vitamin D-resistant rickets prevents
       
VDR ApaI an allele is associated with better childhood asthma
control and improvement in ability for daily activities [15]. Overall,
    
allergic disease development.
Pre-, Peri-, and Post-natal Vitamin D Status and Risk for
Allergy
In various studies, low maternal and cord vitamin D levels
were previously reported to be associated with increased risk
of atopic dermatitis in infancy and wheeze and/or asthma at 3,
 
begin in early childhood and are among the most common chronic
childhood disorder. The incidence has increased during the last
half of 20th century in developed and underdeveloped societies.

in these societies, possibly caused by a more sedentary indoor
lifestyle and decreased intake of vitamin D containing foods.
Vitamin D possesses a range of immunomodulatory properties,
         
during pregnancy may affect fetal immune system programming
and contribute to the development of asthma and allergic diseases

Supposed Immunologic Mechanisms of Vitamin D
Affecting Development of Allergy
       
and receptor agonists have immunomodulatory and
immunoregulatory activities [16]. The immunologic effects of
VDR agonists are shown in vitro studies and they are able to
function thru VDRs, which are widespread in the human body:
I. Innate immunity
 
b. Up-regulate antimicrobial proteins, maintains
epithelial and mucosal barrier integrity
c. Reduce dendritic cell maturation and migration
 
II. Th1- / Th2- cell functions
Vitamin D is well-known to inhibit Th1 cytokine release.


 
vivo environments
B. Stimulate Th2 cytokine secretion by peripheral blood
mononuclear cells [20].
C. Suppress Th2 responses by human cord blood
mononuclear cells [21].
        
having enhanced Treg phenotype [21].
       
polarization [22].
       
      

   
and IL-10 cytokines [23].
III. Lymphocytes
         

b. Decrease T -cell proliferation
c. Increase IL-2 production, steroid responsiveness and

IV. Mast cells: Inhibit maturation and promote apoptosis [25].
 
VI. Airway epithelium and smooth muscle
 
 


Allergy Development The results of investigations about maternal
vitamin D level effect during pregnancy on allergy development

D supplementation, rate of wheezing development was found to
  

        
difference for allergy development at 3 years of age [30]. Another
study performed in UK study demonstrated that high maternal

associated higher risk of eczema in children at 9 months of age
         
         


          
10-years of age. But there was a positive association with the
prevalence of eczema [33]. A recent meta-analysis supposes these
above mentioned results as inconclusive of randomized trials of
prenatal vitamin D for asthma prevention in offspring, curbing the
enthusiasm [5].
       
Development Low cord blood 25-OH-D3 was found as a risk
     
and multi-trigger wheezing, wheezing and risk of troublesome
lung symptoms development have been reported to be reversely
correlated in three different studies [35,36]. However, recent two
different birth cohort studies showed that cord blood vitamin D

Postnatal Serum Low Vitamin D Status in Allergy/ Allergic
Disease Development Recent studies have linked vitamin D
          
       
Vitamin D and Allergy 3/4
Copyright:
©2016 Özdemir
Citation:
        

     
normal / high Vitamin D status
On the contrary, some evidence suggests that vitamin D use /
supplementation itself might increase the risk of allergic disease
[2]. As mentioned above, high prenatal vitamin D status has
been mostly linked to decreased risk of atopic diseases in early
childhood, but whether such relations persist until adulthood
has not been explored yet. In a prospective birth cohort with 965
       
  
30. This cohort study did not provide support for a protective
effect of a high maternal vitamin D concentration on outcomes
of allergic airway disease and lung function at 20 to 25 years of
age. In contrast, a high maternal vitamin D concentration might be
associated with an increased risk of allergic diseases in offspring
   
cod liver oil was shown to be able to increase risk of asthma,

showed that children who received vitamin D supplements during
infancy had a higher risk of developing asthma, atopy and allergic
   
higher intake of vitamin D in 1st year of life was associated an

       
allergy and allergic disease

controlled trials of allergy-related research reported nowadays.
Most studies performed in this area are retrospective and
          
supplementation. Many studies did not differ between vitamin


patients demonstrate relations/associations but not causality
     
between vitamin D levels and allergy-related outcomes are shown
to vary by race and other genetic as well as environmental factors

Conclusion
There is presently inadequate evidence to support daily vitamin
D supplementation in the prevention and/or treatment of allergic

are still unanswered questions such as what dose of supplemental
vitamin D is optimal for prevention or control of allergy? How

status have any effect on the intestinal microbiota modifying the
immune system?
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
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2.    
  

3. 


      
Vitamin D levels, lung function, and steroid response in adult asthma.

5. 
trials of prenatal vitamin D for asthma prevention in offspring curbing

6.         
hypothesized link between sunshine, vitamin D, and food allergy in

 Geriatr

 Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML 


9.       
beds and cod liver oil as vitamin D sources. J Photochem Photobiol B

10. Hughes AM, Lucas RM, Ponsonby AL, Chapman C, Coulthard A, et al.

D in childhood asthma and hay fever: an Australian multicenter study.

11.           
Therapeutic effects of vitamin D in asthma and allergy. Mini Rev Med
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12. ö
Association of vitamin D receptor gene polymorphisms with severe
atopic dermatitis in adults. Br J D
13. 
Association of vitamin D receptor gene polymorphisms with asthma
risk: systematic review and updated meta-analysis of case-control

 
mutated vitamin D receptor in hereditary vitamin D-resistant rickets


15.     
      
better childhood asthma control and improvement in ability for daily

16.          

           

 Hartmann B, Heine G, Babina M, Steinmeyer A, Zü
Targeting the vitamin D receptor inhibits the B cell-dependent

19.      
         

20.    
  
   

Vitamin D and Allergy 4/4
Copyright:
©2016 Özdemir
Citation:
21. Pichler J, Gerstmayr M, Szépfalusi Z, Urbanek R, Peterlik M, et al.
          

22.            
Reversing the defective induction of IL-10-secreting regulatory T


23.            

             
allergic disorders and immune mechanisms. Allergy Asthma Proc

25.             
VDR-dependent regulation of mast cell maturation mediated by
1,25-dihydroxyvitamin D3. 
26.      
  Vitamin D     
nonatopic asthma. J Alle
     ohnson M,     et al.


 
Maternal vitamin D intake during pregnancy and early childhood

29.    
  
              

30. Chawes BL, Bøó 
        
on risk of persistent wheeze in the offspring: A Randomized Clinical

31.     
Maternal vitamin D status during pregnancy and child outcomes. 

32.             
     
with asthma in children. 
33.        

    

           
25-hydroxyvitamin D3 and allergic disease during infancy. Pediatrics

35. 
Cord serum 25-hydroxyvitamin D correlates with early childhood

36. Chawes BL, Bønnelykke K, Jensen PF, Schoos A-MM, Heickendorff L, et
        
asthma, allergy and eczema: The COPSAC2000 Birth Cohort

    
Cord blood vitamin D concentrations are unrelated to atopy and
wheeze in 2 diverse birth cohort studies. J Allergy Clin Immunol

 

39.          


 ø
The long-term programming effect of maternal 25-hydroxyvitamin D
in pregnancy on allergic airway disease and lung function in offspring
after 20 to 25 years of follow-up. 

 Hyppö
vitamin d supplementation and allergic conditions in adulthood:

 
life supplementation of vitamins A and D, in water-soluble form or
in peanut oil, and allergic diseases during childhood. J Allergy Clin
Immunol 
 
intake during infancy promote the development of atopic allergy?

 


   
Association between vitamin D levels and allergy-related outcomes
vary by race and other factors. J Allergy Clin Immunol 

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Background: Allergy-related studies that include biological measurements of vitamin D preceding well-measured outcomes are needed. Objective: We sought to examine the associations between early-life vitamin D levels and the development of allergy-related outcomes in the racially diverse Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study birth cohort. Methods: 25-Hydroxyvitamin D (25[OH]D) levels were measured in stored blood samples from pregnancy, cord blood, and age 2 years. Logistic regression models were used to calculate odds ratios (ORs) with 95% CIs for a 5 ng/mL increase in 25(OH)D levels for the following outcomes at age 2 years: eczema, skin prick tests (SPTs), increased allergen-specific IgE level (≥0.35 IU/mL), and doctor's diagnosis of asthma (3-6 years). Results: Prenatal 25(OH)D levels were inversely associated with eczema (OR, 0.85; 95% CI, 0.75-0.96). The association was stronger in white children (white children: OR, 0.79; 95% CI, 0.57-1.09; black children: OR, 0.96; 95% CI, 0.82-1.12), although this was not statistically significant. Cord blood 25(OH)D levels were inversely associated with having 1 or more positive SPT responses and aeroallergen sensitization. Both associations were statistically significant in white children (positive SPT response: OR, 0.50; 95% CI, 0.32-0.80; ≥1 aeroallergen sensitization: OR, 0.50; 95% CI, 0.28-0.92) in contrast with black children (positive SPT response: OR, 0.88; 95% CI, 0.68-1.14; ≥1 aeroallergen sensitization: OR, 0.85; 95% CI, 0.65-1.11). 25(OH)D levels measured concurrently with outcome assessment were inversely associated with aeroallergen sensitization (OR, 0.79; 95% CI, 0.66-0.96) only among black children (white children: OR, 1.21; 95% CI, 0.87-1.69). Conclusions: Prenatal and cord blood 25(OH)D levels were associated with some allergy-related outcomes, with a general pattern indicating that children with higher 25(OH)D levels tend to have fewer allergy-related outcomes.
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Importance Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown.Objective To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring.Design, Setting, and Participants A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014.Interventions Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care.Main Outcomes and Measures Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed.Results Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group . Vitamin D3 supplementation was not associated with the risk of persistent wheeze (hazard ratio [HR], 0.76 [95% CI, 0.52-1.12], P = .16), but the number of episodes of troublesome lung symptoms was reduced (mean episodes [95% CI]: 5.9 [5.2-6.6] for the vitamin D3 group vs 7.2 [6.4-8.1] for the control group; incidence risk ratio [IRR], 0.83 [95% CI, 0.71-0.97], P = .02), and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points, including asthma (32 children [12%] in the vitamin D3 group vs 47 children [14%] in the control group; odds ratio, 0.82 [95% CI, 0.50-1.36], P = .45), and respiratory tract infections (upper, mean [95% CI]: 5.2 [4.8-5.5] in the vitamin D3 group vs 5.3 [4.9-5.6] in the control group, IRR, 0.99 [95% CI, 0.90-1.09], P = .84; lower: 94 children [32%] in the vitamin D3 group vs 95 children [33%] in the control group, HR, 0.96 [95% CI, 0.72-1.27], P = .76). Intrauterine death was observed in 1 fetus (0%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group.Conclusions and Relevance The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect.Trial Registration clinicaltrials.gov Identifier: NCT00856947
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In recent years, low vitamin D status has been proposed as a putative risk factor for allergic diseases. A growing body of literature reports low vitamin D levels in atopic patients and supports an association between vitamin D deficiency and risk of adverse asthma and allergies outcomes. Therefore, it has been speculated that vitamin D supplementation may either prevent or reduce the risk of allergic diseases. Birth cohort studies addressing the role of vitamin D intake during pregnancy have shown conflicting results regarding allergy outcomes in offspring. Currently, only a few studies have tried to supplement vitamin D in asthmatic patients, often as an add-on therapy to standard asthma controller medications, and results are not all consistent. There is emerging data to show that vitamin D can enhance the antiinflammatory effects of glucocorticoids and potentially be used as adjuvant therapy in steroid-resistant asthma. Recent in vivo data suggest that vitamin D supplementation may also reduce the severity of atopic dermatitis. This review examines the existing relevant literature focusing on vitamin D supplementation in the treatment of allergic diseases.
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Vitamin D (VD) deficiency has re-emerged, after more than hundred years, as a public health problem worldwide. Asthma and allergic disorders constitute another major public health problem with studies having recorded increasing prevalences worldwide since the decade of the 60s. Most of the available experimental and epidemiologic evidence point towards a causal association between low levels of VD and the development of asthma and allergic disorders, and imply a role of VD deficiency on the currently high prevalences of asthma and allergic diseases. The proposed, but still largely hypothetical, underlying mechanism is that VD affects the programming of the fetus and it also has a central modulating role in immune functions involved in asthma and allergic disorders. However, the evidence is not yet clear, since there are studies which support that VD supplementation during pregnancy may promote the development of asthma and allergic disorders. More researches, and especially randomized clinical trials, are required in order to draw safe conclusions and define the role of VD in the prevention or even therapy of asthma and allergic disorders.