The role of short-term grass pollen exposure in food skin-prick test reactivity, food allergy, and eczema flares in children.

BACKGROUND: While the relationship between pollen and respiratory allergies is well-documented, the role of short-term pollen exposure in food allergy and eczema flares has not previously been explored. We aimed to investigate these associations in a population-based sample of children. METHODS: We investigated 1- (n = 1108) and 6-year-old (n = 675) children in the grass pollen season from the HealthNuts cohort. Grass pollen concentrations were considered on the day of testing (lag 0), up to three days before (lag 1-lag 3) and cumulatively (lag 0-3). Associations between grass pollen and food skin-prick test reactivity (SPT ≥ 2 mm at age 1 year and ≥ 3 mm at age 6 years), eczema flares, challenge-confirmed food allergy, reaction threshold to oral food challenges (OFC), and serum food-specific IgE levels were analyzed using either logistic or quantile regression models. Atopy and family history of allergic disease were considered as potent effect modifiers. RESULTS: Grass pollen at lag 0-3 (every 20 grains/m3 increase) was associated with an up to 1.2-fold increased odds of food SPT reactivity and eczema flares in 6-year-olds. In 1-year-olds, the associations were only observed for peanut in those with a family history of food allergy. Increasing grass pollen concentrations were associated with a lower reaction threshold to OFC and higher serum IgE levels in peanut-allergic 1-year-olds only. CONCLUSION: Increasing grass pollen concentration was associated with increased risk of food SPT reactivity and eczema flares in children. The associations in peanut-allergic infants may be related to immune activation and/or peanut and grass pollen cross-reactivity leading to a lower reaction threshold.

A pragmatic approach to infant feeding for food allergy prevention.

Early introduction of allergenic foods into an infant's diet is currently the most promising strategy to prevent food allergy, with infant guidelines around the world shifting from promoting avoidance to actively encourage the introduction of allergenic foods in the infant diet. Infant feeding guidelines vary according to regional public health priorities, and knowledge gaps remain, resulting in ongoing challenges for clinicians and families to translate guidelines into practical strategies for the introduction of complementary foods for food allergy prevention. Evidence from Australia demonstrates high community support and uptake of revised guidelines with most parents introducing allergenic foods in the first year of life, although this has not had the expected impact on substantially reducing food allergy prevalence. To uptake of guidelines from other countries is less clear, and several barriers have been noted in infant feeding RCTs, which may warrant intervention strategies. Further research is needed to understand additional strategies for food allergy prevention, particularly in infants who develop food allergy prior to when they are developmentally ready to commence solids. Several RCTs are underway investigating preventative strategies that target the window before allergen ingestion, such as vitamin D supplementation, emollient use, and immunizations that prime the immune response away from a Th2-driven allergic phenotype. Further research is also needed to understand the role of the environment and the host environment in the development of tolerance to foods.

Children With Food Allergy Are at Risk of Lower Lung Function on High-Pollen Days.

BACKGROUND: Grass pollen exposure is a risk factor for childhood asthma hospital attendances. However, its short-term influence on lung function, especially among those with other allergic conditions, has been less well-studied. OBJECTIVE: To investigate this association in a population-based sample of children. METHODS: Within the HealthNuts cohort, 641 children performed spirometry during the grass pollen season. Grass pollen concentration was considered on the day of testing (lag 0), up to 3 days before (lag 1-lag 3), and cumulatively (lag 0-3). We used linear regression to assess the relevant associations and examined potential interactions with current asthma, hay fever or eczema, and food allergy. RESULTS: Associations were observed only in children with allergic disease (P value for interaction ≤ 0.1). In children with food allergy, grass pollen concentration was associated with a lower ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) and lower mid-forced expiratory flows (FEF25%-75%) at all lags (eg, at lag 2, FEV1/FVC z-score = -0.50 [95% CI -0.80 to -0.20] and FEF25%--75% z-score = -0.40 [-0.60 to -0.04] per 20 grains/m3 pollen increase), and increased bronchodilator responsiveness (BDR) at lag 2 and lag 3 (eg, at lag 2, BDR = (31 [95% CI -0.005 to 62] mL). In children with current asthma, increasing grass pollen concentration was associated with lower FEF25%-75% and increased BDR, whereas children with current hay fever or eczema had increased BDR only. CONCLUSIONS: A proactive approach needs to be enforced to manage susceptible children, especially those with food allergy, before high-grass pollen days.

Associations between grass pollen exposures in utero and in early life with food allergy in 12-month-old infants.

Birth during pollen seasons may influence food allergy risk but no study has assessed pollen exposure. Using the HealthNuts population-based cohort of 5276 infants, we assessed grass pollen exposures, in utero and up to the first 6 months of life, on hen's egg, sesame and peanut allergy outcomes at 12 months. Cumulative pollen exposure in the first 7 days of life increased risk of peanut sensitization aMOR (adjusted multinomial odds ratio) = 1.21 (95% CI: 1.01-1.44). Exposure between first 4-6 months of life increased risk of hen's egg aMOR = 1.02 (95% CI: 1.004-1.04) and sensitization to all foods aMOR = 1.02 (95% CI: 1.003-1.04). Grass pollen exposure was associated with food challenge diagnosed food allergy, but only among infants with a maternal history of food allergy. Exposure to grass pollen in the intrauterine period and infancy may be important but more studies are needed to replicate these findings.

The maternal gut microbiome during pregnancy and offspring allergy and asthma.

Environmental exposures during pregnancy that alter both the maternal gut microbiome and the infant's risk of allergic disease and asthma include a traditional farm environment and consumption of unpasteurized cow's milk, antibiotic use, dietary fiber, and psychosocial stress. Multiple mechanisms acting in concert may underpin these associations and prime the infant to acquire immune competence and homeostasis following exposure to the extrauterine environment. Cellular and metabolic products of the maternal gut microbiome can promote the expression of microbial pattern recognition receptors, as well as thymic and bone marrow hematopoiesis relevant to regulatory immunity. At birth, transmission of maternally derived bacteria likely leverages this in utero programming to accelerate postnatal transition from a TH2- to TH1- and TH17-dominant immune phenotype and maturation of regulatory immune mechanisms, which in turn reduce the child's risk of allergic disease and asthma. Although our understanding of these phenomena is rapidly evolving, the field is relatively nascent, and we are yet to translate existing knowledge into interventions that substantially reduce disease risk in humans. Here, we review evidence that the maternal gut microbiome impacts the offspring's risk of allergic disease and asthma, discuss challenges and future directions for the field, and propose the hypothesis that maternal carriage of Prevotella copri during pregnancy decreases the offspring's risk of allergic disease via production of succinate, which in turn promotes bone marrow myelopoiesis of dendritic cell precursors in the fetus.

Is short-term exposure to grass pollen adversely associated with lung function and airway inflammation in the community?

BACKGROUND: The association between grass pollen exposure and early markers of asthma exacerbations such as lung function changes and increase in airway inflammation is limited. We investigated the associations between short-term grass pollen exposure and lung function and airway inflammation in a community-based sample, and whether any such associations were modified by current asthma, current hay fever, pollen sensitization, age, and other environmental factors. METHODS: Cross-sectional and short-term analyses of data from the Melbourne Atopy Cohort Study (MACS) participants (n = 936). Lung function was assessed using spirometry. Airway inflammation was assessed by fractional exhaled nitric oxide (FeNO) and exhaled breath condensate pH and nitrogen oxides (NOx). Daily pollen counts were collected using a volumetric spore trap. The associations were examined by linear regression. RESULTS: Higher ambient levels of grass pollen 2 days before (lag 2) were associated with lower mid-forced expiratory flow (FEF25%-75% ) and FEV1 /FVC ratio (Coef. [95% CI] = -119 [-226, -11] mL/s and -1.0 [-3.0, -0.03] %, respectively) and also 3 days before (lag 3). Increased levels of grass pollen a day before (lag 1) were associated with increased FeNO (4.35 [-0.1, 8.7] ppb) and also at lag 2. Adverse associations between pollen and multiple outcomes were greater in adults with current asthma, hay fever, and pollen sensitization. CONCLUSION: Grass pollen exposure was associated with eosinophilic airway inflammation 1-2 days after exposure and airway obstruction 2-3 days after exposure. Adults and individuals with asthma, hay fever, and pollen sensitization may be at higher risk.

Decreased maternal serum acetate and impaired fetal thymic and regulatory T cell development in preeclampsia.

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.

Important risk factors for the development of food allergy and potential options for prevention.

Introduction: Food allergy currently affects up to 10% of infants. Identification and implementation of effective food allergy prevention strategies is thus imperative. Areas covered: We focus on five food allergy risk factors/prevention strategies which have been or are currently being tested in randomized controlled trials: (1) timely introduction of allergenic foods into the infant diet; (2) maternal diet and consumption of allergenic foods during pregnancy and breastfeeding; (3) infant skin barrier and the role of moisturizers in early life; (4) infant Vitamin D levels and the role of Vitamin D supplementation; and (5) microbial exposure in early life. Expert commentary: Earlier introduction of allergenic foods, particularly peanut, in the infant diet has been shown to reduce food allergy. Novel intervention strategies, including infant vitamin D supplementation, maternal diet modifications, and moisturizing infants to improve skin barrier, are currently being tested in large-scale clinical trials. As results of these trials become available, we hope strategies that are both efficacious and cost-effective will be revealed and their implementation in the population, along with the timely introduction of allergenic foods, will reduce the burden of food allergy in future generations.

Impact of Lactobacillus reuteri colonization on gut microbiota, inflammation, and crying time in infant colic.

Infant colic is a distressing condition of unknown etiology. An aberrant gastrointestinal microbiota has been associated, and Lactobacillus reuteri supplementation has been shown to reduce crying and/or fussing time ('crying time') in some infants with colic. The relationship between L. reuteri gut colonization and crying time has not been examined. We investigated the relationship between L. reuteri colonization and fecal microbiota (microbial diversity and Escherichia coli), intestinal inflammation, and crying time in infants with colic, using a subset of 65 infants from the Baby Biotics trial, which randomized healthy term infants aged <13 weeks with infant colic to receive probiotic L. reuteri DSM 17938 (1 × 108 colony forming units) or placebo daily for 28 days. We observed an overall reduction in median crying time, regardless of L. reuteri colonization status (n = 14 colonized). There were no differences in E. coli colonization rates or densities, microbial diversity or intestinal inflammation by L. reuteri colonization status. We found that L. reuteri density positively correlated with crying time, and E. coli density negatively correlated with microbial diversity. As density of L. reuteri was associated with increased crying time, L. reuteri supplementation may not be an appropriate treatment for all infants with colic.

Polymorphisms affecting vitamin D-binding protein modify the relationship between serum vitamin D (25[OH]D3) and food allergy.

BACKGROUND: There is evolving evidence that vitamin D insufficiency may contribute to food allergy, but findings vary between populations. Lower vitamin D-binding protein (DBP) levels increase the biological availability of serum vitamin D. Genetic polymorphisms explain almost 80% of the variation in binding protein levels. OBJECTIVE: We sought to investigate whether polymorphisms that lower the DBP could compensate for adverse effects of low serum vitamin D on food allergy risk. METHODS: From a population-based cohort study (n = 5276) we investigated the association between serum 25-hydroxyvitamin D3 (25[OH]D3) levels and food allergy at age 1 year (338 challenge-proven food-allergic and 269 control participants) and age 2 years (55 participants with persistent and 50 participants with resolved food allergy). 25(OH)D3 levels were measured using liquid chromatography-tandem mass spectrometry and adjusted for season of blood draw. Analyses were stratified by genotype at rs7041 as a proxy marker of DBP levels (low, the GT/TT genotype; high, the GG genotype). RESULTS: Low serum 25(OH)D3 level (≤50 nM/L) at age 1 years was associated with food allergy, particularly among infants with the GG genotype (odds ratio [OR], 6.0; 95% CI, 0.9-38.9) but not in those with GT/TT genotypes (OR, 0.7; 95% CI, 0.2-2.0; P interaction = .014). Maternal antenatal vitamin D supplementation was associated with less food allergy, particularly in infants with the GT/TT genotype (OR, 0.10; 95% CI, 0.03-0.41). Persistent vitamin D insufficiency increased the likelihood of persistent food allergy (OR, 12.6; 95% CI, 1.5-106.6), particularly in those with the GG genotype. CONCLUSIONS: Polymorphisms associated with lower DBP level attenuated the association between low serum 25(OH)D3 level and food allergy, consistent with greater vitamin D bioavailability in those with a lower DBP level. This increases the biological plausibility of a role for vitamin D in the development of food allergy.

VITALITY trial: protocol for a randomised controlled trial to establish the role of postnatal vitamin D supplementation in infant immune health.

INTRODUCTION: Postnatal vitamin D supplementation may be associated with a reduction in IgE-mediated food allergy, lower respiratory tract infections and improved bone health. Countries in the Northern hemisphere recommend universal infant vitamin D supplementation to optimise early vitamin D levels, despite the absence of large trials proving safety or efficacy for any disease outcome. With the aim of determining the clinical and cost-effectiveness of daily vitamin D supplementation in breastfed infants from age 6-8 weeks to 12 months of age, we have started a double-blind, randomised, placebo-controlled trial of daily 400 IU vitamin D supplementation during the first year of life, VITALITY. METHODS ND ANALYSIS: Infants (n=3012) who are fully breastfed and not receiving vitamin D supplementation will be recruited at the time of their first immunisation, from council-led immunisation clinics throughout metropolitan Melbourne, Australia. The primary outcome is challenge-proven food allergy at 12 months of age. Secondary outcomes are food sensitisation (positive skin prick test), number of lower respiratory infections (through hospital linkage), moderately-severe and persistent eczema (by history and examination) and vitamin D deficiency (serum vitamin D <50 nmol/L) at age 12 months. The trial is underway and the first 130 participants have been recruited. ETHICS AND DISSEMINATION: The VITALITY study is approved by the Royal Children's Hospital (RCH) Human Research Ethics Committee (#34168). Outcomes will be disseminated through publication and will be presented at scientific conferences. TRIAL REGISTRATION NUMBERS: ANZCTR12614000334606 and NCT02112734; pre-results.

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease.

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-γ (PPARγ) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and ß-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPARγ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-(Δ12,14)-prostaglandin J2 (15-deoxy-PGJ2)] or ß-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPARγ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized (days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than ß-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than ß-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPARγ-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to ß-adrenoceptor agonists is limited.

Is Low Vitamin D Status A Risk Factor For Food Allergy? Current Evidence And Future Directions.

Studies from several countries have reported an association between latitudes further from the equator and proxy markers of food allergy prevalence. As latitudes further from the equator are associated with lower sun exposure and vitamin D status (VDS), it has been proposed that low VDS may be a risk factor for food allergy. A range of basic science evidence supports the biological plausibility of this hypothesis; and recent work has identified a cross sectional association between low VDS and challenge proven food allergy in infants. Overall, however, the evidence regarding the relationship between VDS and food allergy remains controversial and the limited longitudinal data are discouraging. In this review we consider the evidence for and against low VDS as a risk factor for food allergy and discuss the possibility that other factors (including genetic variables) may contribute to the inconsistent nature of the available observational evidence. We then discuss whether genetic and/or environmental factors may modify the potential influence of VDS on food allergy risk. Finally, we argue that given the rising burden of food allergy, the balance of available evidence regarding the potential relevance of VDS to this phenomenon, and the inherent limitations of the existing observational data, there is a compelling case for conducting randomised clinical trials of vitamin D supplementation for the prevention of food allergy during early life.

Environmental and genetic determinants of vitamin D insufficiency in 12-month-old infants.

We aimed to investigate the relationship between genetic and environmental exposure and vitamin D status at age one, stratified by ethnicity. This study included 563 12-month-old infants in the HealthNuts population-based study. DNA from participants' blood samples was genotyped using Sequenom MassARRAY MALDI-TOF system on 28 single nucleotide polymorphisms (SNPs) in six genes. Using logistic regression, we examined associations between environmental exposure and SNPs in vitamin D pathway and filaggrin genes and vitamin D insufficiency (VDI). VDI, defined as serum 25-hydroxyvitamin D3(25(OH)D3) level ≤50nmol/L, was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infants were stratified by ethnicity determined by parent's country of birth. Infants formula fed at 12 months were associated with reduced odds of VDI compared to infants with no current formula use at 12 months. This association differed by ethnicity (Pinteraction=0.01). The odds ratio (OR) of VDI was 0.29 for Caucasian infants (95% CI, 0.18-0.47) and 0.04 for Asian infants (95% CI, 0.006-0.23). Maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being VDI (OR, 2.39; 95% CI, 1.11-5.18 and OR, 2.5; 95% CI, 1.20-5.24 respectively). Presence of a minor allele for any GC SNP (rs17467825, rs1155563, rs2282679, rs3755967, rs4588, rs7041) was associated with increased odds of VDI. Caucasian infants homozygous (AA) for rs4588 had an OR of 2.49 of being associated with VDI (95% CI, 1.19-5.18). In a country without routine infant vitamin D supplementation or food chain fortification, formula use is strongly associated with a reduced risk of VDI regardless of ethnicity. There was borderline significance for an association between filaggrin mutations and VDI. However, polymorphisms in vitamin D pathway related genes were associated with increased likelihood of being VDI in infancy.

Perinatal maternal administration of Lactobacillus paracasei NCC 2461 prevents allergic inflammation in a mouse model of birch pollen allergy.

BACKGROUND: The hygiene hypothesis implies that microbial agents including probiotic bacteria may modulate foetal/neonatal immune programming and hence offer effective strategies for primary allergy prevention; however their mechanisms of action are poorly understood. We investigated whether oral administration of Lactobacillus paracasei NCC 2461 to mothers during gestation/lactation can protect against airway inflammation in offspring in a mouse model of birch pollen allergy, and examined the immune mechanisms involved. METHODS: BALB/c mice were treated daily with L. paracasei in drinking water or drinking water alone in the last week of gestation and during lactation. Their offspring were sensitized with recombinant Bet v 1, followed by aerosol challenge with birch pollen extract. RESULTS: Maternal exposure to L. paracasei prevented the development of airway inflammation in offspring, as demonstrated by attenuation of eosinophil influx in the lungs; reduction of IL-5 levels in bronchoalveolar lavage, and in lung and mediastinal lymph node cell cultures; and reduced peribronchial inflammatory infiltrate and mucus hypersecretion. While allergen-specific IgE and IgG antibody levels remained unchanged by the treatment, IL-4 and IL-5 production in spleen cell cultures were significantly reduced upon allergen stimulation in offspring of L. paracasei treated mice. Offspring of L. paracasei supplemented mothers had significantly reduced Bet v 1-specific as well as Concanavalin A-induced responses in spleen and mesenteric lymph node cell cultures, suggesting the modulation of both antigen-specific and mitogen-induced immune responses in offspring. These effects were associated with increased Foxp3 mRNA expression in the lungs and increased TGF-beta in serum. CONCLUSION: Our data show that in a mouse model of birch pollen allergy, perinatal administration of L. paracasei NCC 2461 to pregnant/lactating mothers protects against the development of airway inflammation in offspring by activating regulatory pathways, likely through TLR2/4 signalling.