Thanh Dang

Increasing the accuracy of peanut allergy diagnosis by using Ara h 2

BACKGROUND Measurement of whole peanut-specific IgE (sIgE) is often used to confirm sensitization but does not reliably predict allergy. Ara h 2 is the dominant peanut allergen detected in 90% to 100% of patients with peanut allergy and could help improve diagnosis. OBJECTIVES We sought to determine whether Ara h 2 testing might improve the accuracy of diagnosing peanut allergy and therefore circumvent the need for an oral food challenge (OFC). METHODS Infants from the population-based HealthNuts study underwent skin prick tests to determine peanut sensitization and subsequently underwent a peanut OFC to confirm allergy status. In a stratified random sample of 200 infants (100 with peanut allergy and 100 with peanut tolerance), whole peanut sIgE and Ara h 2 sIgE levels were quantified by using fluorescence enzyme immunoassay. RESULTS By using the previously published 95% positive predictive value of 15 kU(A)/L for whole peanut sIgE, a corresponding specificity of 98% (95% CI, 93% to 100%) was found in this study cohort. At the equivalent specificity of 98%, the sensitivity of Ara h 2 sIgE is 60% (95% CI, 50% to 70%), correctly identifying 60% of subjects with true peanut allergy compared with only 26% correctly identified by using whole peanut sIgE. We report that when using a combined approach of plasma sIgE testing for whole peanut followed by Ara h 2 for the diagnosis of peanut allergy, the number of OFCs required is reduced by almost two thirds. CONCLUSION Ara h 2 plasma sIgE test levels provide higher diagnostic accuracy than whole peanut plasma sIgE levels and could be considered a new diagnostic tool to distinguish peanut allergy from peanut tolerance, which might reduce the need for an OFC.

Vitamin D insufficiency is associated with challenge-proven food allergy in infants

BACKGROUND Epidemiological evidence has shown that pediatric food allergy is more prevalent in regions further from the equator, suggesting that vitamin D insufficiency may play a role in this disease. OBJECTIVE To investigate the role of vitamin D status in infantile food allergy. METHODS A population sample of 5276 one-year-old infants underwent skin prick testing to peanut, egg, sesame, and cows milk or shrimp. All those with a detectable wheal and a random sample of participants with negative skin prick test results attended a hospital-based food challenge clinic. Blood samples were available for 577 infants (344 with challenge-proven food allergy, 74 sensitized but tolerant to food challenge, 159 negative on skin prick test and food challenge). Serum 25-hydroxyvitamin D levels were measured by using liquid chromatography tandem mass spectrometry. Associations between serum 25-hydroxyvitamin D and food allergy were examined by using multiple logistic regression, adjusting for potential risk and confounding factors. RESULTS Infants of Australian-born parents, but not of parents born overseas, with vitamin D insufficiency (≤50 nmol/L) were more likely to be peanut (adjusted odds ratio [aOR], 11.51; 95% CI, 2.01-65.79; P=.006) and/or egg (aOR, 3.79; 95% CI, 1.19-12.08; P=.025) allergic than were those with adequate vitamin D levels independent of eczema status. Among those with Australian-born parents, infants with vitamin D insufficiency were more likely to have multiple food allergies (≥2) rather than a single food allergy (aOR, 10.48; 95% CI, 1.60-68.61 vs aOR, 1.82; 95% CI, 0.38-8.77, respectively). CONCLUSIONS These results provide the first direct evidence that vitamin D sufficiency may be an important protective factor for food allergy in the first year of life.

Natural history of peanut allergy and predictors of resolution in the first 4 years of life: A population-based assessment.

BACKGROUND There are no prospectively collected data available on the natural history of peanut allergy in early childhood. Previous studies of predictors of tolerance development have been biased by failure to challenge high-risk children when IgE antibody levels are high, therefore potentially introducing bias to persistent allergy. OBJECTIVES We sought to describe the natural history of peanut allergy between 1 and 4 years of age and develop thresholds for skin prick test (SPT) results and specific IgE (sIgE) levels measured at age 1 and 4 years that have 95% positive predictive value (PPV) or negative predictive value for the persistence or resolution of peanut allergy. METHODS One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the population-based, longitudinal HealthNuts Study (n = 5276) were followed up at 4 years of age with repeat oral food challenges, SPTs, and sIgE measurements (n = 103). Challenges were undertaken in all peanut-sensitized children at 1 and 4 years of age, irrespective of risk profile. RESULTS Peanut allergy resolved in 22% (95% CI, 14% to 31%) of children by age 4 years. Decreasing wheal size predicted tolerance, and increasing wheal size was associated with persistence. Thresholds for SPT responses and sIgE levels at age 1 year with a 95% PPV for persistent peanut allergy are an SPT-induced response of 13 mm or greater and an sIgE level of 5.0 kU/L or greater. Thresholds for SPT and sIgE results at age 4 years with a 95% PPV for persistent peanut allergy are an SPT response of 8 mm or greater and an sIgE level of 2.1 kU/L or greater. Ara h 2, tree nut, and house dust mite sensitization; coexisting food allergies; eczema; and asthma were not predictive of persistent peanut allergy. CONCLUSION These thresholds are the first to be generated from a unique data set in which all participants underwent oral food challenges at both diagnosis and follow-up, irrespective of SPT and sIgE results.

Filaggrin loss-of-function mutations do not predict food allergy over and above the risk of food sensitization among infants.

Diagnosed allergic disease (any) 1.26 0.67-2.37 .47 1.34 0.68-2.63 .40 0.956 0.44-2.08 .91 1.07 0.80-1.44 .63 Doctor-diagnosed eczema (any) 1.11 0.59-2.11 .74 1.49 0.74-2.99 .26 1.95 0.76-5.03 .17 1.17 0.83-1.63 .37 Sensitized (SPT1) 2.0§ 1.05-4.09§ .04§ 1.32 0.62-2.78 .47 1.27 0.55-2.93 .58 1.27 0.91-1.78 .17 SPT1 and eczema 2.0§ 0.89-4.48§ .10§ 1.48 0.63-3.50 .37 1.70 0.59-4.92 .33 1.5§ 0.96-2.42§ .07§ Food allergy (IgE mediated) 1.65 0.65-4.22 .30 0.85 0.33-2.20 .73 1.83 0.43-7.78 .41 1.17 0.67-2.02 .58 Diagnosed asthma — — — 1.55 0.38-6.23 .54 1.40 0.39-5.00 .61 — — — Allergic rhinitis and inhalant SPT1 — — — — — — 0.506 0.16-1.61 .25 — — —

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

Food allergy is mediated by a combination of genetic and environmental risk factors, potentially mediated by epigenetic mechanisms. CD4+ T-cells are key drivers of the allergic response, and may therefore harbor epigenetic variation in association with the disease phenotype. Here we retrospectively examined genome-wide DNA methylation profiles (~450 000 CpGs) from CD4+ T-cells on a birth cohort of 12 children with IgE-mediated food allergy diagnosed at 12-months, and 12 non-allergic controls. DNA samples were available at two time points, birth and 12-months. Case:control comparisons of CD4+ methylation profiles identified 179 differentially methylated probes (DMP) at 12-months and 136 DMP at birth (FDR-adjusted P value < 0.05, delta β > 0.1). Approximately 30% of DMPs were coincident with previously annotated SNPs. A total of 96 allergy-associated non-SNP DMPs were present at birth when individuals were initially disease-free, potentially implicating these loci in the causal pathway. Pathway analysis of differentially methylated genes identified several MAP kinase signaling molecules. Mass spectrometry was used to validate 15 CpG sites at 3 candidate genes. Combined analysis of differential methylation with gene expression profiles revealed gene expression differences at some but not all allergy associated differentially methylated genes. Thus, dysregulation of DNA methylation at MAPK signaling-associated genes during early CD4+ T-cell development may contribute to suboptimal T-lymphocyte responses in early childhood associated with the development of food allergy.

Characterization of plasma cytokines in an infant population cohort of challenge-proven food allergy

Sensitization to food allergens indicates the production of food‐specific IgE; however, sensitization is not a definite indicator of allergic reaction upon ingestion (N Engl J Med, 344, 2001, 30: J Allergy Clin Immunol, 120, 2007, 491). Currently, food challenge is the best approach to identify the presence or absence of allergy. While 95% positive predictive values (PPVs) thresholds for sIgE can assist with identifying increased likelihood of allergy among those who are sensitized, there are no specific biological markers that differentiate between allergic and sensitized individuals.

Specific oral tolerance induction in childhood

Food allergy continues to be a significant public health concern for which there are no approved treatments and management strategies primarily include allergen avoidance and pharmacological measures for accidental exposures. Food allergy is thought to result from either a failure to establish oral tolerance or the breakdown of existing oral tolerance, and therefore, experimental preventative and treatment strategies are now aimed at inducing specific oral tolerance. This may occur in infancy prior to the development of food allergy through the optimal timing of dietary exposure (primary oral tolerance induction) or as a treatment for established food allergy through oral immunotherapy (secondary oral tolerance induction). Trials examining the effectiveness of early dietary allergen exposure to prevent food allergy have yielded promising results for peanut allergy but not so for other allergens, although the results of several trials are yet to be published. Although infant feeding guidelines no longer advise to avoid allergenic foods and exposure to food allergens orally is an important step in inducing food tolerance by the immune system, evidence regarding the optimal timing, dose and form of these foods into the infants diet is lacking. Likewise, oral immunotherapy trials appear promising for inducing desensitization; however, the long‐term efficacy in achieving sustained desensitization and optimal protocols to achieve this is unknown. More research is needed in this emerging field.

Food for thought: progress in understanding the causes and mechanisms of food allergy.

Purpose of reviewThe community burden of food allergy appears to be rising, yet the causes and mechanisms are not completely understood. The purpose of this review is to provide a snapshot of the state of play of IgE food allergies, with a focus on recent advances. Recent findingsThere are still wide discrepancies regarding measures and definitions of food allergy. Even recent studies still rely on food sensitization, self-reporting, or parent-reporting rather than more robust measures. Population-based sampling strategies using objective measures are underway in some countries. Emerging data suggest substantial geographical and ethnic differences in food sensitization and allergy. Trans-cutaneous sensitization, particularly in those with eczema or filaggrin mutations, has been posited as a potential mechanism, as well as gut microbiota and genetics/epigenetics. Treatments for food allergy are still lacking, yet progress is being made, and immunotherapy appears more effective than dietary avoidance. Non-IgE food allergy remains drastically under-explored. SummaryFood allergy is a complex immune-mediated disease consisting of numerous environmental/genetic/epigenetic risk factors; yet interventions are likely to be simple and cost-effective.

Food allergic infants have impaired regulatory T cell responses following in vivo allergen exposure

Regulatory T cells (Tregs) are critical for development of oral tolerance, and studies suggest that dysfunction of Tregs may lead to food allergy. However, to date, no study has investigated Treg responses following in vivo exposure to peanut or egg allergens in humans.

Determination of the clinical egg allergy phenotypes using component-resolved diagnostics

IgE‐mediated egg allergy presents as one of the most common food allergies in children and is a food which is widely consumed all over the world. Measurement of egg white‐specific IgE levels has been shown to be a poor predictor of clinical phenotypes of egg allergy, including to raw egg white, but particularly to baked or cooked egg. Egg white and yolk contain more than 20 different glycoproteins, including ovomucoid, ovalbumin, ovotransferrin, alpha‐livetin, and the newly identified Gal d 6. Recent developments in component‐resolved diagnostic technology, including microarrays, have enabled us to improve the way in which we diagnose food allergy. This technology allows us to measure specific IgE antibodies to individual egg allergens which have been highly purified. Characterization of the major egg allergens could help profile the relevant binding epitopes to each region and may also help diagnose the different clinical phenotypes of egg allergy.