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1.  Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease 
Nature genetics  2014;46(8):895-900.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in European EoE cases and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replication of the 5q22 locus (meta-analysis p = 1.9×10−16), we identified association at 2p23 (encoding CAPN14, p = 2.5×10−10). CAPN14 was specifically expressed in the esophagus, dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13, and located in an epigenetic hotspot modified by IL-13. There was enriched esophageal expression for the genes neighboring the top 208 EoE sequence variants. Multiple allergic sensitization loci were associated with EoE susceptibility (4.8×10−2 < p < 5.1×10−11). We propose a model that elucidates the tissue specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13–inducible esophageal response involving CAPN14.
doi:10.1038/ng.3033
PMCID: PMC4121957  PMID: 25017104
2.  Egg-white-specific IgA and IgA2 antibodies in egg-allergic children: is there a role in tolerance induction? 
Background
Decreased serum food-specific-IgA antibodies have been associated with allergic disease in cross-sectional, case-control studies. The purpose of this study was to prospectively compare egg-white-(EW)-specific-IgA and IgA2 levels between egg-allergic children and children tolerating egg.
Methods
Seventeen egg allergic children were followed prospectively. Total IgA, EW-specific-IgA and EW-specific-IgA2 levels were measured in their sera with a sensitive ELISA. As negative controls were used children with no previous history of egg allergy. Egg-allergic children with or without concomitant milk allergy were evaluated as additional controls with measurement of casein-specific-IgA.
Results
After 2.5±0.9 years, 9 out of 17 allergic children became tolerant and 8 remained allergic to baked egg. Baseline EW-specific-IgA2 levels were significantly lower in the egg-allergic subjects (median 23.9ng/ml) compared with the negative control subjects (99.4ng/ml) and increased significantly by 28% over the study time period in 8 out of the 9 allergic children that became tolerant to baked egg. There was no significant change over time in EW-specific-IgA in any of the study groups. Non-milk-allergic subjects with concomitant egg allergy had almost 3-fold higher casein-specific-IgA levels than the milk- and egg-allergic subjects (P=0.025).
Conclusions
These results suggest a potential role for allergen-specific-IgA2 antibodies in the induction of food tolerance. Furthermore, they support the hypothesis that immature or impaired production of allergen-specific-IgA2 may be associated with the pathophysiology of food allergy, a defect that seems to be selective for the culprit allergen.
doi:10.1111/pai.12143
PMCID: PMC4134474  PMID: 24118158
food allergy; egg white; immunoglobulin A; neutralizing antibodies; tolerance induction
3.  World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics 
Background
Prevalence of allergic diseases in infants, whose parents and siblings do not have allergy, is approximately 10% and reaches 20–30% in those with an allergic first-degree relative. Intestinal microbiota may modulate immunologic and inflammatory systemic responses and, thus, influence development of sensitization and allergy. Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention.
Objective
The World Allergy Organization (WAO) convened a guideline panel to develop evidence-based recommendations about the use of probiotics in the prevention of allergy.
Methods
We identified the most relevant clinical questions and performed a systematic review of randomized controlled trials of probiotics for the prevention of allergy. We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. We searched for and reviewed the evidence about health effects, patient values and preferences, and resource use (up to November 2014). We followed the GRADE evidence-to-decision framework to develop recommendations.
Results
Currently available evidence does not indicate that probiotic supplementation reduces the risk of developing allergy in children. However, considering all critical outcomes in this context, the WAO guideline panel determined that there is a likely net benefit from using probiotics resulting primarily from prevention of eczema. The WAO guideline panel suggests: a) using probiotics in pregnant women at high risk for having an allergic child; b) using probiotics in women who breastfeed infants at high risk of developing allergy; and c) using probiotics in infants at high risk of developing allergy. All recommendations are conditional and supported by very low quality evidence.
Conclusions
WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents, clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding, and whether to give them to infants.
Electronic supplementary material
The online version of this article (doi:10.1186/s40413-015-0055-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s40413-015-0055-2
PMCID: PMC4307749  PMID: 25628773
Allergy; Prevention; Probiotics; Practice guidelines; GRADE
4.  Role of maternal elimination diets and human milk IgA in development of cow’s milk allergy in the infants 
Background
The role of maternal avoidance diets in the prevention of food allergies is currently under debate. Little is known regarding the effects of such diets on human milk (HM) composition or induction of infant humoral responses.
Objective
To assess the association of maternal cow’s milk (CM) avoidance during breastfeeding with specific IgA levels in HM and development of cow’s milk allergy (CMA) in infants.
Methods
We utilized HM and infant serum samples from a prospective birth cohort of 145 dyads. Maternal serum and HM samples were assessed for casein and beta-lactoglobulin (BLG)-specific IgA and IgG by ELISA; 21 mothers prophylactically initiated a strict maternal CM avoidance diet due to a sibling’s history of food allergy and 16 due to atopic eczema or regurgitation/vomiting seen in their infants within the first 3 months of life. Infants’ sera were assessed for casein and BLG-specific IgG, IgA and IgE; CMA was confirmed by an oral food challenge. The impact of HM on BLG uptake was assessed in transcytosis assays utilizing Caco-2 intestinal epithelial cell line.
Results
Mothers avoiding CM had lower casein- and BLG-specific IgA in HM than mothers with no CM restriction (p=0.019 and p=0.047). Their infants had lower serum casein- and BLG-specific IgG1 (p=0.025 and p<0.001) and BLG-specific IgG4 levels (p=0.037) and their casein- and BLG-specific IgA levels were less often detectable than those with no CM elimination diet (p=0.003 and p=0.007). Lower CM-specific IgG4 and IgA levels in turn were associated with infant CMA. Transcytosis of BLG was impaired by HM with high, but not low levels of specific IgA.
Conclusions
Maternal CM avoidance was associated with lower levels of mucosal specific IgA levels and development of CMA in infants.
Clinical relevance
HM IgA may play a role in preventing excessive, uncontrolled food antigen uptake in the gut lumen and thereby in the prevention of CMA.
doi:10.1111/cea.12228
PMCID: PMC4038099  PMID: 24164317
Breast feeding; breast milk; human milk; cow’s milk; avoidance; restriction diet; infants; cow’s milk allergy; IgA; secretory IgA; epithelium
5.  Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy 
Background
History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy.
Objective
We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk.
Methods
Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study.
Results
There was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01).
Conclusion
Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA.
doi:10.1016/j.jaci.2014.10.007
PMCID: PMC4282723  PMID: 25457149
Atopic dermatitis; peanut sensitization; peanut allergy; environmental peanut exposure; dust; AD, Atopic dermatitis; CoFAR, Consortium of Food Allergy Research; EPE, Environmental peanut exposure; FLG, Filaggrin; IQR, Interquartile range; LLQ, Lower limit of quantitation; LR, Logistic regression; OR, Odds ratio; PA, Peanut allergy; sIgE, Specific IgE; SPT, Skin prick test
6.  Treatments for food allergy: how close are we? 
Immunologic research  2012;54(0):83-94.
Food allergy continues to be a challenging health problem, with prevalence continuing to increase and anaphylaxis still an unpredictable possibility. While improvements in diagnosis are more accurately identifying affected individuals, treatment options remain limited. The cornerstone of treatment relies on strict avoidance of the offending allergens and education regarding management of allergic reactions. Despite vigilance in avoidance, accidental ingestions and reactions continue to occur. With recent advances in the understanding of humoral and cellular immune responses in food allergy and mechanisms of tolerance, several therapeutic strategies for food allergies are currently being investigated with the hopes of providing a cure or long-term remission from food allergy.
doi:10.1007/s12026-012-8309-3
PMCID: PMC4276337  PMID: 22434517
Food; Allergy; Anaphylaxis; Treatment; Tolerance
9.  Guidelines for the Diagnosis and Management of Food Allergy in the United States 
Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.
doi:10.1016/j.jaci.2010.10.007
PMCID: PMC4241964  PMID: 21134576
food; allergy; anaphylaxis; diagnosis; disease management; guidelines
10.  The Sophora Flavescens flavonoid compound trifolirhizin inhibits acetylcholine induced airway smooth muscle contraction 
Phytochemistry  2013;95:259-267.
Asthma is a serious health problem worldwide, particularly in industrialized countries. Despite a better understanding of the pathophysiology of asthma, there are still considerable gaps in knowledge as well as a need for new classes of drugs. ASHMI™ (Anti-asthma Herbal Medicine Intervention) is an aqueous extract of Ganoderma lucidum (Fr.) P. Karst (Ling Zhi), Sophora flavescens Aiton (Ku Shen) and Glycyrrhiza uralensis Fisch. ex DC (Gan Cao). It prevents allergic asthma airway hyper-reactivity in mice and inhibits acetylcholine (ACh) induced airway smooth muscle (ASM) contraction in tracheal rings from allergic asthmatic mice. The purpose of this research was to identify individual herb(s) and their active compound(s) that inhibit ASM contraction. It was found that Sophora flavescens (S. flavescens), but not Ganoderma lucidum (G. lucidum) or Glycyrrhiza uralensis (G. uralensis) aqueous extracts, inhibited ASM contraction in tracheal rings from asthmatic mice. Bioassay-guided isolation and identification of flavonoid fractions/compound(s) via methylene chloride extraction, preparative HPLC fractionation, and LC-MS and NMR spectroscopic analyses showed that trifolirhizin is an active constituent that inhibits acetylcholine mediated ASM contraction or directly relaxes pre-contracted ASM independent of β2-adrenoceptors.
doi:10.1016/j.phytochem.2013.07.023
PMCID: PMC4118489  PMID: 23993294
Sophora flavescens; Leguminosae; Asthma; Traditional Chinese herbal medicine; ASHMI; Ku Shen; trifolirhizin; airway smooth muscle contraction
11.  Glycyrrhiza uralensis flavonoids present in anti-asthma formula, ASHMI™, inhibit memory Th2 responses in vitro and in vivo 
Phytotherapy research : PTR  2012;27(9):1381-1391.
Allergic asthma is associated with Th2-mediated inflammation. Several flavonoids were isolated from Glycyrrhiza uralensis, one of the herbs in the anti-asthma herbal medicine intervention, ASHMI. The aim of this investigation was to determine whether Glycyrrhiza uralensis flavonoids have inhibitory effects on memory Th2 responses in vitro, and antigen induced Th2 inflammation in vivo. The effects of three Glycyrrhiza uralensis flavonoids on effector memory Th2 cells, D10.G4.1 (D10 cells), were determined by measuring Th2 cytokine production. Isoliquiritigenin, 7, 4’-dihydroxyflavone (7, 4’-DHF) and liquiritigenin significantly suppressed IL-4 and IL-5 production in a dose dependent manner, 7, 4’-DHF being most potent. It was also evaluated for effects on D10 cell proliferation, GATA-3 expression and IL-4 mRNA expression, which were suppressed, with no loss of cell viability. Chronic treatment with 7, 4’-DHF in a murine model of allergic asthma not only significantly reduced eosinophilic pulmonary inflammation, serum IgE levels, IL-4 and IL-13 levels, but also increased IFN-γ production in lung cell cultures in response to antigen stimulation.
doi:10.1002/ptr.4862
PMCID: PMC3593755  PMID: 23165939
Glycyrrhiza uralensis; flavonoids; D10. G 4.1; Th2 cytokines; GATA-3; Murine model of asthma
12.  Intestinal Permeability in Children with Food Allergy on Specific Elimination Diets 
BACKGROUND
Children with food allergy have been shown to have increased small intestinal permeability (IP) following ingestion of the offending food as well as during elimination diets. We investigated IP in asymptomatic food-allergic children during an elimination diet to identify clinical characteristics associated with altered IP.
METHODS
Urinary recovery ratios of lactulose and mannitol (L/M) were determined five hours following ingestion of 7.5 g of lactulose and 2 g of mannitol in 131 cow’s milk- and egg-allergic children. An L/M ratio of ≥0.025 was considered abnormal based upon previously established laboratory internal references. A chart review was conducted to assess the clinical characteristics of these patients.
RESULTS
A total of 50 (38%) of the 131 children (median 6.7, range 4.8 – 8.9 years); 66.2% male) with food allergy had elevated IP while asymptomatic on strict elimination diets. Age and height negatively correlated with IP. However, in the regression model analysis, abnormal IP was associated with shorter stature independently of age. Otherwise, food allergic patients with increased IP were comparable in gender, nutritional status, age of onset of food allergy, history of reactions, atopic diseases and family history of food allergies to those with normal IP.
CONCLUSIONS
Elevated IP was found in about one-third of asymptomatic food-allergic children on elimination diets and was associated with shorter stature. Our results suggest that increased IP may be an intrinsic trait in a subset of food allergic children. However, large, prospective studies are necessary to determine the role of impaired intestinal barrier in food allergy.
doi:10.1111/pai.12106
PMCID: PMC3774110  PMID: 23909601
food allergy (hypersensitivity); egg allergy; CM allergy; intestinal permeability; lactulose/mannitol ratio
13.  Potential non-T cells source of interleukin-4 in food allergy 
Background
Recently, a study from the Consortium of Food Allergy Research (CoFAR) showed that allergen-induced IL-4 expression in CD25+ mononuclear cells was increased in allergic patients. However, they did not find the expected increase in GATA-3 expression, suggesting that allergen-induced IL-4 might not be of T-cell origin. We sought to determine whether other cell types were responsible for the increased IL-4 expression in the CD25+ cell population.
Methods
Comparing six allergic patients and six healthy controls, we analyzed the CD25+ isolated population from PBMC for the presence of potential IL-4-expressing non-T cells. We also compared spontaneous expression levels of surface markers (CD203c, CD63, CD25, and HLA-DR) on basophils from whole blood of 42 peanut-allergic patients and from 12 non-atopic controls. Expression of these markers was also evaluated following basophil activation in eight peanut-allergic patients selected from the previous cohort.
Results
In addition to CD4+ T cells, a substantial proportion of non-T cells were found in the CD25 +-isolated cell population: basophils, NK, and NK-T cells with a mean percentage ± s.e.m. of 5.24 ± 0.63%, 6.65 ± 1.01%, and 6.01 ± 1.04%, respectively. The majority of these cells exhibited positive intracytoplasmic staining for IL-4. Expression of CD63 and CD25 was significantly higher in allergic patients compared with controls (p < 0.05). Interestingly, we found a significantly higher proportion of activated basophils expressing HLA-DR, compared with non-activated basophils (p < 0.05).
Conclusions
Our results support the suggested key role of non-T cells secreting IL-4 in food allergy, particularly basophils, which may also play a central role in antigen presentation.
doi:10.1111/pai.12207
PMCID: PMC4139148  PMID: 24576111
basophils; NK cells; NK-T cells; interleukin-4; TH2 response; food allergy
14.  A Phase 1 Study of Heat/Phenol Killed, E. coli-Encapsulated, Recombinant Modified Peanut Proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the Treatment of Peanut Allergy 
Allergy  2013;68(6):803-808.
Background
Immunotherapy for peanut allergy may be limited by the risk of adverse reactions.
Objective
To investigate the safety and immunologic effects of a vaccine containing modified peanut proteins.
Methods
This was a Phase 1 trial of EMP-123, a rectally administered suspension of recombinant Ara h 1, Ara h 2 and Ara h 3, modified by amino acid substitutions at major IgE binding epitopes, encapsulated in heat/phenol killed E. coli. Five healthy adults were treated with 4 weekly escalating doses after which 10 peanut allergic adults received weekly dose escalations over 10 weeks from 10mcg to 3063mcg, followed by 3 biweekly doses of 3063 mcg.
Results
There were no significant adverse effects in the healthy volunteers. Of the 10 peanut allergic subjects [4 with intermittent asthma, median peanut-IgE 33.3kUA/L (7.2–120.2), median peanutskin prick test wheal 11.3mm (6.5–18)], 4 experienced no symptoms, one had mild rectal symptoms, and the remaining 5 experienced adverse reactions preventing completion of dosing. Two were categorized as mild but the remaining three were more severe, including one moderate reaction and two anaphylactic reactions. Baseline peanut IgE was significantly higher in the 5 reactive subjects (median 82.4 versus 17.2kUA/L, p=0.032), as was baseline anti-Ara h 2 IgE (43.3 versus 8.3, p=0.036). Peanut skin test titration and basophil activation (at a single dilution) were significantly reduced after treatment but no significant changes were detected for total IgE, peanut IgE, or peanut IgG4.
Conclusions
Rectal administration of EMP-123 resulted in frequent adverse reactions, including severe allergic reactions in 20%.
doi:10.1111/all.12158
PMCID: PMC3663889  PMID: 23621498
15.  Mucosal Immunology of Food Allergy 
Current biology : CB  2013;23(9):R389-R400.
Food allergies are increasing in prevalence at a higher rate than can be explained by genetic factors, suggesting a role for as yet unidentified environmental factors. In this review, we summarize the state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in IgE sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors such as dietary factors and microbiota in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Finally, we discuss recent developments in our understanding of immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy.
doi:10.1016/j.cub.2013.02.043
PMCID: PMC3667506  PMID: 23660362
17.  Food Allergy: An Enigmatic Epidemic 
Trends in immunology  2013;34(8):390-397.
Food allergy is a common disease that is rapidly increasing in prevalence for reasons that remain unknown. Current research efforts are focused on understanding the immune basis of food allergy, identifying environmental factors that may contribute to its rising prevalence, and developing immunotherapeutic approaches to re-establish immune tolerance to foods. Technological advances such as peptide microarray and MHC class II tetramers have begun to provide a comprehensive profile of the immune response to foods. The burgeoning field of mucosal immunology has provided intriguing clues to the role of the diet and the microbiota as risk factors in the development of food allergy. The purpose of this review is to highlight significant gaps in our knowledge that need answers in order to stem the progression of this disorder that is reaching epidemic proportions.
doi:10.1016/j.it.2013.04.003
PMCID: PMC3943426  PMID: 23648309
IgE; anaphylaxis; mucosal immunology; microbiota; Th2; Treg; immunotherapy
18.  The natural history of milk allergy in an observational cohort 
Objective
There are few studies on the natural history of milk allergy. Most are single-site and not longitudinal, and these have not identified a means for early prediction of outcomes.
Methods
Children aged 3 to 15 months were enrolled in an observational study with either (1) a convincing history of egg allergy, milk allergy, or both with a positive skin prick test (SPT) response to the trigger food and/or (2) moderate-to-severe atopic dermatitis (AD) and a positive SPT response to milk or egg. Children enrolled with a clinical history of milk allergy were followed longitudinally, and resolution was established by means of successful ingestion.
Results
The cohort consists of 293 children, of whom 244 were given a diagnosis of milk allergy at baseline. Milk allergy has resolved in 154 (52.6%) subjects at a median age of 63 months and a median age at last follow-up of 66 months. Baseline characteristics that were most predictive of resolution included milk-specific IgE level, milk SPT wheal size, and AD severity (all P < .001). Baseline milk-specific IgG4 level and milk IgE/IgG4 ratio were not predictive of resolution and neither was expression of cytokine-inducible SH2-containing protein, forkhead box protein 3, GATA3, IL-10, IL-4, IFN-γ, or T-bet by using real-time PCR in CD25-selected, casein-stimulated mononuclear cells. A calculator to estimate resolution probabilities using baseline milk IgE level, SPT response, and AD severity was devised for use in the clinical setting. Conclusions: In this cohort of infants with milk allergy, approximately one half had resolved over 66 months of follow-up. Baseline milk-specific IgE level, SPT wheal size, and AD severity were all important predictors of the likelihood of resolution.
doi:10.1016/j.jaci.2012.10.060
PMCID: PMC3691063  PMID: 23273958
Milk allergy; natural history; food allergy; IgE
19.  Basophil Reactivity, Wheal Size and Immunoglobulin Levels Distinguish Degree of Cow’s Milk Tolerance 
Background
In our previous study, about 75% of cow’s milk-allergic children tolerated baked-milk products, which improved their prognosis and quality of life.
Objective
We sought to identify biomarkers of varying degrees of clinical tolerance among a cohort of cow’s milk-allergic children.
Methods
132 subjects were initially classified as baked-milk-reactive, baked-milk-tolerant or “outgrown milk allergy” based on oral food challenges. The baked-milk tolerant group was then divided into 3 groups based upon the amount and degree of heat-denatured milk protein that they could tolerate. Serum was analyzed for allergen-specific IgE and IgG4, basophil reactivity was assessed in whole blood stimulated with serial 10-fold dilutions of milk protein, and prick skin tests were performed to commercial milk extract. Activated basophils were defined using flow cytometry as CD63brightCD203c+CD123+HLA-DRdim/−CD41a− lineage−. Data were analyzed using the Jonckheere-Terpstra test.
Results
Significant differences across the five clinical groups were seen for median casein- and milk-specific IgE, casein-specific IgG4 and casein IgE/IgG4; milk-specific to non-specific basophil activation ratio, median basophil reactivity, and spontaneous basophil activation (CD203c expression following stimulation with RPMI); and milk PST wheal diameters. Casein- and milk-specific IgE, milk-specific basophil reactivity and milk prick skin test wheal diameter are all significantly greater among milk-allergic patients who react to baked-milk than among those who tolerate it.
Conclusions
The majority of milk-allergic patients are able to tolerate some forms of baked-milk in their diets. Different phenotypes of cow’s milk-allergic children can be distinguished by casein- and milk-specific IgE, milk-specific basophil reactivity, and milk prick skin test mean wheal diameters. Spontaneous basophil activation is greater among patients with more severe clinical milk reactivity.
doi:10.1016/j.jaci.2012.06.003
PMCID: PMC3493710  PMID: 22819512
Cow’s milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation; biomarker; basophil activation
20.  Utility of casein-specific IgE levels in predicting reactivity to baked milk 
Summary
Based on data from a large cohort of milk allergic children, our results show that measurement of casein-specific IgE is a helpful diagnostic indicator for predicting reactivity to baked milk, showing the greatest area under the receiver operating characteristic curve of parameters tested.
doi:10.1016/j.jaci.2012.06.049
PMCID: PMC3517693  PMID: 22921870
Cow’s milk; baked milk; casein; milk allergy; food allergy; diagnosis; children; hypersensitivity; specific IgE; specific IgG4
21.  Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens 
Background
Peanut-allergic subjects have highly stable pathologic antibody repertoires to the immunodominant B cell epitopes of the major peanut allergens Ara h 1-3.
Objective
We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires.
Methods
Measurements of total peanut-specific IgE (psIgE) and psIgG4 were made with CAP-FEIA. We analyzed sera from 22 OIT subjects and 6 controls and measured serum specific IgE and IgG4 binding to epitopes of Ara h 1-3 using a high-throughput peptide microarray technique. Antibody affinity was measured using a competitive peptide microarray as previously described.
Results
At baseline, psIgE and psIgG4 diversity were similar between subjects and controls, and there was broad variation in epitope recognition. After a median 41 months of OIT, polyclonal psIgG4 increased from a median 0.3 mcg/mL (IQR 0.1-0.43) at baseline to 10.5 mcg/mL (3.95-45.48) (p<0.0001) and included de novo specificities. PsIgE was reduced from a median baseline of 85.45 kUA/L (23.05-101.0) to 7.75 kUA/L (2.58-30.55) (p<0.0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated subjects, several subjects generated new IgE specificities even as the total psIgE decreased. Global epitope-specific shifts from IgE to IgG4 binding occurred, including at an informative epitope of Ara h 2.
Conclusion
OIT differentially alters Ara h 1-3 binding patterns. These changes are variable between subjects, not observed in controls, and include a progressive polyclonal increase in IgG4, with concurrent reduction in IgE amount and diversity.
doi:10.1016/j.jaci.2012.10.048
PMCID: PMC3529994  PMID: 23199605
peanut allergy; oral immunotherapy; IgE; IgG4; peptide microarray; epitope; B cell; antibody affinity
22.  Sublingual immunotherapy for peanut allergy: a randomized, double-blind, placebo-controlled multicenter trial 
Background
There are presently no available therapeutic options for peanut-allergic patients.
Objective
To investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT).
Methods
After a baseline oral food challenge (OFC) of up to 2g of peanut powder (~50% protein) (median successfully consumed dose [SCD] 46mg), 40 subjects, aged 12–37 (median 15) years, were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5g OFC was performed after 44 weeks followed by unblinding; placebo subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5g OFC. Week 44 OFCs from both groups were compared to baseline OFCs; subjects successfully consuming 5g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders.
Results
After 44 weeks of SLIT, 14/20 (70%) subjects receiving peanut SLIT were responders compared to 3/20 (15%) subjects receiving placebo (p<0.001). In peanut-SLIT responders, median SCD increased from 3.5mg to 496mg. After 68 weeks of SLIT, median SCD significantly increased to 996mg (compared to week 44, p=0.05). The median SCD at the Week 44 crossover OFC was significantly higher than baseline (603mg vs 71mg; p=0.02). 7/16 (44%) crossover subjects were responders; median SCD increased from 21mg to 496mg among responders. Of 10,855 peanut doses through Week 44 OFCs, 63.1% were symptom-free; excluding oral/pharyngeal symptoms, 95.2% were symptom-free.
Conclusions
Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared to placebo. Longer duration of therapy showed statistically significant increases in the SCD.
doi:10.1016/j.jaci.2012.11.011
PMCID: PMC3550002  PMID: 23265698
peanut allergy; sublingual immunotherapy; desensitization; food allergy
23.  Precautionary labelling of foods for allergen content: are we ready for a global framework? 
Food allergy appears to be on the rise with the current mainstay of treatment centred on allergen avoidance. Mandatory allergen labelling has improved the safety of food for allergic consumers. However an additional form of voluntary labelling (termed precautionary allergen labelling) has evolved on a wide range of packaged goods, in a bid by manufacturers to minimise risk to customers, and the negative impact on business that might result from exposure to trace amounts of food allergen present during cross-contamination during production. This has resulted in near ubiquitous utilisation of a multitude of different precautionary allergen labels with subsequent confusion amongst many consumers as to their significance. The global nature of food production and manufacturing makes harmonisation of allergen labelling regulations across the world a matter of increasing importance. Addressing inconsistencies across countries with regards to labelling legislation, as well as improvement or even banning of precautionary allergy labelling are both likely to be significant steps forward in improved food safety for allergic families. This article outlines the current status of allergen labelling legislation around the world and reviews the value of current existing precautionary allergen labelling for the allergic consumer. We strongly urge for an international framework to be considered to help roadmap a solution to the weaknesses of the current systems, and discuss the role of legislation in facilitating this.
doi:10.1186/1939-4551-7-10
PMCID: PMC4005619  PMID: 24791183
Allergen labelling; Food allergy; Legislation; Precationary allergen labelling; Anaphylaxis; Allergen avoidance; Mandatory labelling
24.  DIETARY BAKED EGG ACCELERATES RESOLUTION OF EGG ALLERGY IN CHILDREN 
Background
Baked egg is tolerated by a majority of egg-allergic children.
Objective
To characterize immunologic changes associated with ingestion of baked egg and evaluate the role that baked egg diets plays in the development of tolerance to regular egg.
Methods
Egg-allergic subjects who tolerated baked egg challenge incorporated baked egg into their diet. Immunologic parameters were measured at follow-up visits. A comparison group strictly avoiding egg was used to evaluate the natural history of the development of tolerance.
Results
Of the 79 subjects in the intent-to-treat group followed for a median of 37.8 months, 89% now tolerate baked egg and 53% now tolerate regular egg. Of 23 initial baked egg-reactive subjects, 14 (61%) subsequently tolerated baked egg and 6 (26%) now tolerate regular egg. Within the initially baked egg-reactive group, subjects with persistent reactivity to baked egg had higher median baseline egg white (EW)-specific IgE levels (13.5 kUA/L) than those who subsequently tolerated baked egg (4.4 kUA/L; P=0.04) and regular egg (3.1 kUA/L, P=0.05). In subjects ingesting baked egg, EW-induced SPT wheal diameter and EW-, ovalbumin-, and ovomucoid-specific IgE levels decreased significantly, while ovalbumin- and ovomucoid-specific IgG4 levels increased significantly. Subjects in the per-protocol group were 14.6 times more likely to develop regular egg tolerance than subjects in the comparison group (P < 0.0001), and they developed tolerance earlier (median 50.0 versus 78.7 months; P<0.0001).
Conclusion
Initiation of a baked egg diet accelerates the development of regular egg tolerance compared to strict avoidance. Higher serum EW-specific IgE level is associated with persistent baked and regular egg reactivity, while initial baked egg reactivity is not.
doi:10.1016/j.jaci.2012.06.006
PMCID: PMC3428057  PMID: 22846751
egg allergy; hen’s egg allergy; baked egg; heated egg; food allergy; egg tolerance; oral food challenge; egg allergy immunotherapy
25.  Allergic Reactions to Foods in Preschool-Aged Children in a Prospective Observational Food Allergy Study 
Pediatrics  2012;130(1):e25-e32.
OBJECTIVE:
To examine circumstances of allergic reactions to foods in a cohort of preschool-aged children.
METHODS:
We conducted a prospective, 5-site observational study of 512 infants aged 3 to 15 months with documented or likely allergy to milk or egg, and collected data prospectively examining allergic reactions.
RESULTS:
Over a median follow-up of 36 months (range: 0–48.4), the annualized reaction rate was 0.81 per year (367/512 subjects reporting 1171 reactions [95% confidence interval: 0.76–0.85]). Overall, 269/512 (52.5%) reported >1 reaction. The majority of reactions (71.2%) were triggered by milk (495 [42.3%]), egg (246 [21.0%]), and peanut (93 [7.9%]), with accidental exposures attributed to unintentional ingestion, label-reading errors, and cross-contact. Foods were provided by persons other than parents in 50.6% of reactions. Of 834 reactions to milk, egg, or peanut, 93 (11.2%) were attributed to purposeful exposures to these avoided foods. A higher number of food allergies (P < .0001) and higher food-specific immunoglobulin E (P < .0001) were associated with reactions. Of the 11.4% of reactions (n = 134) that were severe, 29.9% were treated with epinephrine. Factors resulting in undertreatment included lack of recognition of severity, epinephrine being unavailable, and fears about epinephrine administration.
CONCLUSIONS:
There was a high frequency of reactions caused by accidental and nonaccidental exposures. Undertreatment of severe reactions with epinephrine was a substantial problem. Areas for improved education include the need for constant vigilance, accurate label reading, avoidance of nonaccidental exposure, prevention of cross-contamination, appropriate epinephrine administration, and education of all caretakers.
doi:10.1542/peds.2011-1762
PMCID: PMC3382915  PMID: 22732173
food allergy; IgE-mediated allergic reaction; epinephrine

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