Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Human milk oligosaccharide profiles and allergic disease up to 18 years.

BACKGROUND: Human milk oligosaccharides (HMO) are a diverse range of sugars secreted in breast milk that have direct and indirect effects on immunity. The profiles of HMOs produced differ between mothers. OBJECTIVE: We sought to determine the relationship between maternal HMO profiles and offspring allergic diseases up to age 18 years. METHODS: Colostrum and early lactation milk samples were collected from 285 mothers enrolled in a high-allergy-risk birth cohort, the Melbourne Atopy Cohort Study. Nineteen HMOs were measured. Profiles/patterns of maternal HMOs were determined using LCA. Details of allergic disease outcomes including sensitization, wheeze, asthma, and eczema were collected at multiple follow-ups up to age 18 years. Adjusted logistic regression analyses and generalized estimating equations were used to determine the relationship between HMO profiles and allergy. RESULTS: The levels of several HMOs were highly correlated with each other. LCA determined 7 distinct maternal milk profiles with memberships of 10% and 20%. Compared with offspring exposed to the neutral Lewis HMO profile, exposure to acidic Lewis HMOs was associated with a higher risk of allergic disease and asthma over childhood (odds ratio asthma at 18 years, 5.82; 95% CI, 1.59-21.23), whereas exposure to the acidic-predominant profile was associated with a reduced risk of food sensitization (OR at 12 years, 0.08; 95% CI, 0.01-0.67). CONCLUSIONS: In this high-allergy-risk birth cohort, some profiles of HMOs were associated with increased and some with decreased allergic disease risks over childhood. Further studies are needed to confirm these findings and realize the potential for intervention.

The influence of sensitisation to pollens and moulds on seasonal variations in asthma attacks.

No large study has described the seasonal variation in asthma attacks in population-based asthmatics in whom sensitisation to allergen has been measured. 2,637 young adults with asthma living in 15 countries reported the months in which they usually had attacks of asthma and had skin-prick tests performed. Differences in seasonal patterns by sensitisation status were assessed using generalised estimating equations. Most young adults with asthma reported periods of the year when their asthma attacks were more common (range: 47% in Sweden to 86% in Spain). Seasonal variation in asthma was not modified by sensitisation to house dust mite or cat allergens. Asthmatics sensitised to grass, birch and Alternaria allergens had different seasonal patterns to those not sensitised to each allergen, with some geographical variation. In southern Europe, those sensitised to grass allergens were more likely to report attacks occurred in spring or summer than in winter (OR March/April 2.60, 95% CI 1.70-3.97; OR May/June 4.43, 95% CI 2.34-8.39) and smaller later peaks were observed in northern Europe (OR May/June 1.25, 95% CI 0.60-2.64; OR July/August 1.66, 95% CI 0.89-3.10). Asthmatics reporting hay fever but who were not sensitised to grass showed no seasonal variations. Seasonal variations in asthma attacks in young adults are common and are different depending on sensitisation to outdoor, but not indoor, allergens.

Is vitamin D supplementation responsible for the allergy pandemic?

PURPOSE OF REVIEW: A link between vitamin D supplementation and allergy was already suspected soon after it became possible to chemically synthesise vitamin D2 by means of ultraviolet radiation. During the past decade, the assumed allergenic effect was confirmed by clinical and epidemiological studies although the most recent discussion has centred more on vitamin D insufficiency. The purpose of this review is to summarise studies published during the past year while attempting to reconcile some apparent inconsistencies. RECENT FINDINGS: Two new concepts are presented here - epigenetic programming of the fetal vitamin D system by low maternal vitamin D supply (Barker's paradox) and ubiquitous vitamin D exposure of the newborn (Rose's paradox). Taken together a misdirected epigenetic programming offers an explanation why also vitamin D insufficiency in pregnancy may be associated with increased allergy rates in the offspring.At least eight studies examined the association of early 25-hydroxy-vitamin D levels and atopic diseases in 2011, whereas no new study addressed the question of vitamin D supplementation in the newborn period. One study tested the whole range of 25-hydroxy-vitamin D levels in cord blood describing a U-shaped association with 2.4-fold odds ratio of low and 4-fold odds ratio of high levels to develop allergen-specific immunoglobulin E. SUMMARY: Randomised clinical trials with vitamin D supplements are therefore highly required. Several key points are presented for designing vitamin D trials.

Assessment of allergen sensitization in a general population-based survey (European Community Respiratory Health Survey I).

PURPOSE: Exposed to a common environment, the IgE-mediated immune response differs, for instance, among sensitized subjects, some of them reacting toward one allergen (monosensitized) whereas others are sensitized to a wide array of allergens (polysensitized). However, a better phenotypic characterization is needed for epidemiologic studies. Using the data collected during the ECRHS I (European Community Respiratory Health Survey), several assessments of skin prick tests and serum-specific IgE to identify mono- and polysensitized patients were compared. METHODS: Subjects took part in the ECRHS-I. The CAP-System was used for serum allergen-specific IgE, and allergen-coated Phazet was used for prick tests. Four allergens (Dermatophagoides pteronyssinus, cat, timothy grass, and Cladosporium) were measured using IgE and nine (the same ones plus olive pollen, birch, Alternaria, Parietaria, and ragweed) were skin tested. One to two local allergens were also tested, depending on countries. RESULTS: Prevalence of sensitization in 11,355 subjects (34.0 [27.9-40.1] years, 49.9% men) ranged from 32.3% (four specific IgE, 19.3% mono- and 13.0% polysensitized) to 41.8% (four specific IgE combined to nine prick tests, 19.6% mono- and 22.2% polysensitized). Concordance between four specific IgE and four prick tests was weak (weighted κ 0.65 [0.64-0.66]). Concordance between seven and nine prick tests was high (weighted κ 0.99 [0.98-1.00]). Local allergens induced small changes in the prevalence of sensitization, and reclassified some subjects from mono- to polysensitized. CONCLUSIONS: Skin tests or serum-specific IgE may be chosen to identify allergenic sensitivity, mono- and polysensitized subjects without being strictly interchangeable.

Introduction of oral vitamin D supplementation and the rise of the allergy pandemic.

The history of the allergy pandemic is well documented, enabling us to put the vitamin D hypothesis into its historical context. The purpose of this study is to compare the prevalence of rickets, vitamin D supply, and allergy prevalence at 50-year intervals by means of a retrospective analysis of the literature since 1880. English cities in 1880 were characterized by an extremely high rickets prevalence, the beginning of commercial cod liver oil production, and the near absence of any allergic diseases. By 1930 hay fever prevalence had risen to about 3% in English-speaking countries where cod liver oil was preferentially used for the treatment of rickets. In 1980 vitamin D was used nation-wide in all industrialized countries as supplement to industrial baby food, thus eradicating nearly all cases of rickets. At the same time the allergy prevalence reached an all-time high, affecting about 30% of the population. Time trends are therefore compatible with the vitamin D hypothesis although direct conclusions cannot be drawn. It is interesting, however, to note that there are at least two earlier research papers linking synthesized vitamin D intake and allergy (Reed 1930 and Selye 1962) published prior to the modern vitamin D hypothesis first proposed in 1999.

Allergic rhinitis and onset of bronchial hyperresponsiveness: a population-based study.

RATIONALE: Patients with allergic rhinitis have more frequent bronchial hyperresponsiveness (BHR) in cross-sectional studies. OBJECTIVES: To estimate the changes in BHR in nonasthmatic subjects with and without allergic rhinitis during a 9-year period. METHODS: BHR onset was studied in 3,719 subjects without BHR at baseline, who participated in the follow-up of the European Community Respiratory Health Survey. MEASUREMENTS AND MAIN RESULTS: BHR was defined as a >or=20% decrease in FEV(1) for a maximum dose of 1 mg of methacholine. Allergic rhinitis was defined as having a history of nasal allergy and positive specific IgE (>or=0.35 IU/ml) to pollen, cat, mites, or Cladosporium. The cumulative incidence of BHR was 9.7% in subjects with allergic rhinitis and 7.0% in subjects with atopy but no rhinitis, compared with 5.5% in subjects without allergic rhinitis and atopy (respective odds ratios [OR] and their 95% confidence intervals [95% CI] for BHR onset, 2.44 [1.73-3.45]; and 1.35 [0.86-2.11], after adjustment for potential confounders including sex, smoking, body mass index and FEV(1)). Subjects with rhinitis sensitized exclusively to cat or to mites were particularly at increased risk of developing BHR (ORs [95% CI], 7.90 [3.48-17.93] and 2.84 [1.36-5.93], respectively). Conversely, in subjects with BHR at baseline (n = 372), 35.3% of those with allergic rhinitis, compared with 51.8% of those without rhinitis had no more BHR at follow-up (OR [95% CI], 0.51 [0.33-0.78]). BHR "remission" was more frequent in patients with rhinitis treated by nasal steroids than in those not treated (OR [95% CI], 0.33 [0.14-0.75]). CONCLUSIONS: Allergic rhinitis was associated with increased onset of BHR, and less chance for remission except in those treated for rhinitis.

The vitamin D slant on allergy.

Oral vitamin D supplementation has been introduced into modern medicine to prevent rickets without the knowledge that this may have profound immunological consequences. The main vitamin D metabolite calcitriol suppresses dendritic cell maturation and consecutive Th(1) cell development, which has independently described as a key mechanism of allergy development. Animal studies and epidemiological surveys now provide a first link of early vitamin D supplementation and later allergy where several vitamin D regulated genes seem to be involved. A randomized clinical trial of vitamin D supplementation could be a further step to follow up the vitamin hypothesis.

Another explanation for the low allergy rate in the rural Alpine foothills.

A low allergy rate in coal and wood heated homes has been described in the small villages in the Alpine foothills and subsequently found to be associated with the farming environment. This was interpreted within the framework of the hygiene hypothesis but there are also alternative explanations. Lower air pollution could be one reason, which is, however, unlikely since the differences between the Bavarian countryside and the Munich municipal area were only weak. There could be genetic differences between the urban and rural population by previous isolation or by self-selection. The potential drop-out of allergy genes, however, will also not explain the absent increase of allergies in two generations. More likely, other lifestyle factors are important. Dietary habits are different in farmers and a less frequent vitamin D supplementation of newborns (otherwise expected to be allergy promoting) has been shown recently. The underlying cause for the "non-allergic farm child" remains speculative until the transfer of any farm-associated factor is leading to a similar risk reduction in the general population.

Variants in the vitamin D receptor gene and asthma.

BACKGROUND: Early lifetime exposure to dietary or supplementary vitamin D has been predicted to be a risk factor for later allergy. Twin studies suggest that response to vitamin D exposure might be influenced by genetic factors. As these effects are primarily mediated through the vitamin D receptor (VDR), single base variants in this gene may be risk factors for asthma or allergy. RESULTS: 951 individuals from 224 pedigrees with at least 2 asthmatic children were analyzed for 13 SNPs in the VDR. There was no preferential transmission to children with asthma. In their unaffected sibs, however, one allele in the 5' region was 0.5-fold undertransmitted (p = 0.049), while two other alleles in the 3' terminal region were 2-fold over-transmitted (p = 0.013 and 0.018). An association was also seen with bronchial hyperreactivity against methacholine and with specific immunoglobulin E serum levels. CONCLUSION: The transmission disequilibrium in unaffected sibs of otherwise multiple-affected families seem to be a powerful statistical test. A preferential transmission of vitamin D receptor variants to children with asthma could not be confirmed but raises the possibility of a protective effect for unaffected children.

Infant vitamin d supplementation and allergic conditions in adulthood: northern Finland birth cohort 1966.

Allergen-induced secretion of Th2-type cytokines and IgE production have recently been reported to be increased in mice treated with 1,25(OH)(2)D, the active form of vitamin D. Our objective was to investigate whether vitamin D supplementation in infancy is associated with the risk of atopy, allergic rhinitis, and asthma. The Northern Finland Birth Cohort consists of all individuals in the two most northern provinces of Finland who were due to be born in 1966. Data on vitamin D supplementation during the first year of life was obtained in 1967. Current asthma and allergic rhinitis were reported at age 31 years (n = 7,648), and atopy determined by skin-prick test in a sub-sample still living in northern Finland or the Helsinki area (n = 5,007). The prevalence of atopy and allergic rhinitis at age 31 years was higher in participants who had received vitamin D supplementation regularly during the first year compared to others (OR 1.46, 95%CI 1.4-2.0, and OR 1.66, 95%CI 1.1-1.6, respectively). A similar association was observed for asthma (OR 1.35, 95%CI 0.99-1.8). These associations persisted after adjustment for a wide range of behavioral and social factors (adjusted: OR 1.33 for all, P = 0.01 for atopy, P = 0.001 for allergic rhinitis, and P = 0.08 for asthma). We observed an association between vitamin D supplementation in infancy and an increased risk of atopy and allergic rhinitis later in life. Further study is required to determine whether these observations reflect long-term effects on immune regulation or differences in unmeasured determinants of vitamin D supplementation.