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1.  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
2.  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
3.  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
4.  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
5.  Oral immunotherapy induces local protective mechanisms in the gastrointestinal mucosa 
Background
Oral immunotherapy (OIT) is a promising treatment for food allergy. Studies are needed to elucidate mechanisms of clinical protection, and to identify safer and potentially more efficacious methods for desensitizing patients to food allergens.
Objective
We established a mouse model of OIT in order to determine how dose or form of antigen may affect desensitization, and to identify mechanisms of desensitization.
Methods
Increasing doses of egg white or ovomucoid as OIT were administered orally to sensitized mice. Impact of OIT on anaphylaxis elicited by oral allergen challenge was determined. Allergen-specific antibody and cytokine responses, and mast cell and basophil activation in response to OIT was measured. Gene expression in the small intestine was studied by microarray and real-time PCR.
Results
OIT resulted in desensitization but not tolerance of mice to the allergen. OIT did not result in desensitization of systemic effector cells, and protection was localized to the gastrointestinal tract. OIT was associated with significant changes in gene expression in the jejunum, including genes expressed by intestinal epithelial cells. Extensively heated ovomucoid that does not trigger anaphylaxis when given orally to sensitized mice was as efficacious as native ovomucoid in desensitizing mice.
Conclusions
OIT results in clinical protection against food-induced anaphylaxis through a novel mechanism that is localized to the intestinal mucosa and is associated with significant changes in small intestinal gene expression. Extensively heating egg allergen decreases allergenicity and increases safety while still retaining the ability to induce effective desensitization.
doi:10.1016/j.jaci.2012.04.009
PMCID: PMC3367084  PMID: 22554705
Oral immunotherapy; Food allergy; Heated egg allergen; Mucosal immunology
7.  Mechanisms underlying differential food-allergic response to heated egg 
Background
Egg white proteins are usually subjected to heating, making them edible for the majority of egg-allergic children.
Objective
We sought to investigate the underlying mechanisms responsible for the reduced allergenicity displayed by heat-treated egg white allergens.
Methods
C3H/HeJ mice were orally sensitized with ovalbumin (OVA) or ovomucoid (OM) and challenged with native or heated proteins to evaluate their allergenicity. Immunoreactivity was assessed by immunoblotting using sera from egg-allergic children. In vitro gastrointestinal digestion of native and heated OVA and OM was studied by SDS-PAGE and liquid chromatography. Intestinal uptake of intact native and heated OVA and OM by human intestinal epithelial (Caco-2) cells was investigated. Rat basophil leukemia (RBL) cells passively sensitized with mouse serum and human basophils passively sensitized with egg-allergic children’s serum were used to assess the effector cell activation by heated, digested and transported OVA and OM.
Results
Heated OVA and OM did not induce symptoms of anaphylaxis in sensitized mice when administered orally. Heating did not completely destroy IgE-binding capacity of OVA or OM but enhanced in vitro digestibility of OVA. Digestion of both OVA and OM diminished mediator release in RBL assay and basophil activation. Heating of allergens prevented transport across human intestinal epithelial cells in a form capable of triggering basophil activation or T cell activation.
Conclusions
Heat treatment reduces allergenicity of OVA and OM. This is partially due to the enhanced gastrointestinal digestibility of heated OVA and the inability of heated OVA or OM to be absorbed in a form capable of triggering basophils.
Clinical implications
Reduced allergenicity of heated egg white proteins partially resulting from altered digestion and absorption in the gastrointestinal tract may explain the clinical tolerance of extensively heated egg in the majority of egg-allergic children.
Capsule summary
The majority of egg-allergic children tolerate extensively heated egg. This study demonstrates that the decreased allergenicity of heated ovalbumin and ovomucoid in large part results from altered digestion and processing in the gastrointestinal tract.
doi:10.1016/j.jaci.2011.01.057
PMCID: PMC3530263  PMID: 21377717
egg allergy; ovalbumin; ovomucoid; heat treatment; heating; gastrointestinal digestion; antigen absorption; mice oral sensitization; anaphylaxis; basophil activation; passive sensitization
8.  Children in the New York Inner City Have High Rates of Food Allergy and IgE-Sensitization to Common Foods 
Short summary
IgE-mediated food sensitization and allergy are common in inner city children, even in the absence of reported clinical reactivity. Clinicians caring for this population should maintain a high index of suspicion for food allergy.
doi:10.1016/j.jaci.2011.04.024
PMCID: PMC3129386  PMID: 21555148
food allergy; sensitization; inner city
9.  Dietary baked-milk accelerates resolution of cow's milk allergy in children 
Background
The majority (∼75%) of cow's milk-allergic children tolerate extensively heated-(baked-) milk products. Long-term effects of inclusion of dietary baked-milk have not been reported.
Objective
We report on the outcomes of children who incorporated baked-milk products into their diets.
Methods
Children evaluated for tolerance to baked-milk (muffin) underwent sequential food challenges to baked-cheese (pizza) followed by unheated-milk. Immunologic parameters were measured at challenge visits. The comparison group were matched to active subjects (using age, sex, and baseline milk-specific IgE) to evaluate the natural history of tolerance development.
Results
Over a median of 37 months (range 8-75 months), 88 children underwent challenges at varying intervals (range 6-54 months). Among 65 subjects initially tolerant to baked-milk, 39 (60%) now tolerate unheated-milk, 18 (28%) tolerate baked-milk/baked-cheese and 8 (12%) chose to avoid milk strictly. Among the baked-milk-reactive subgroup (n=23), 2 (9%) tolerate unheated-milk, 3 (13%) tolerate baked-milk/baked-cheese, while the majority (78%) avoid milk strictly. Subjects who were initially tolerant to baked-milk were 28 times more likely to become unheated-milk-tolerant compared to baked-milk-reactive subjects (P<.001). Subjects who incorporated dietary baked-milk were 16 times more likely than the comparison group to become unheated-milk-tolerant (P<.001). Median casein IgG4 levels in the baked-milk-tolerant group increased significantly (P<.001); median milk IgE values did not change significantly.
Conclusions
Tolerance of baked-milk is a marker of transient IgE-mediated cow's milk allergy whereas reactivity to baked-milk portends a more persistent phenotype. The addition of baked-milk to the diet of children tolerating such foods appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
Clinical implications
Addition of dietary baked-milk is safe, convenient, and well-accepted by patients. Prescribing baked-milk products to milk-allergic children represents an important shift in the treatment paradigm for milk allergy.
Capsule summary
The majority of cow's milk-allergic children tolerate extensively baked-milk products, which is a marker of transient IgE-mediated cow's milk allergy. Dietary baked-milk appears to accelerate development of unheated-milk tolerance compared to strict avoidance.
doi:10.1016/j.jaci.2011.04.036
PMCID: PMC3151608  PMID: 21601913
cow's milk allergy; milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation
10.  Future Therapies for Food Allergies 
Food allergy is an increasingly prevalent problem in westernized countries and there is an unmet medical need for an effective form of therapy . A number of therapeutic strategies are under investigation targeting foods that most frequently provoke severe IgE-mediated anaphylactic reactions (peanut, tree nuts, shellfish) or are most common in children, such as cow’s milk and hen’s egg. Approaches being pursued are both food allergen-specific and non-specific. Allergen-specific approaches include oral, sublingual and epicutaneous immunotherapy (desensitization) with native food allergens, and mutated recombinant proteins, which have decreased IgE-binding activity, co-administered within heat-killed E.coli to generate maximum immune response. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for food-allergic patients. Non-specific approaches include monoclonal anti-IgE antibodies, which may increase the threshold dose for food allergen in food-allergic patients, and a Chinese herbal formulation, which prevented peanut-induced anaphylaxis in a mouse model, and is currently being investigated in clinical trials. The variety of strategies for treating food allergy increases the likelihood of success and gives hope that accomplishing an effective therapy for food allergy is within reach.
doi:10.1016/j.jaci.2010.12.1098
PMCID: PMC3066474  PMID: 21277625
food allergy; oral immunotherapy; sublingual immunotherapy; probiotics; epicutaneous immunotherapy; desensitization; milk allergy; peanut allergy; egg allergy; anti-IgE; anti-IgE therapy; anti-IL-5 therapy
11.  Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy 
Background
Results from large-scale epitope mapping using peptide microarray have been shown to correlate with clinical features of milk allergy.
Objectives
We sought to assess IgE and IgG4 epitope diversity and IgE affinity in different clinical phenotypes of milk allergy and identify informative epitopes that may be predictive of clinical outcomes of milk allergy.
Methods
Forty-one subjects were recruited from a larger study on the effects of ingesting heat-denatured milk proteins in milk-allergic individuals. Using food challenges, subjects were characterized as clinically reactive to all forms of milk (n = 17), tolerant to heated milk (HM) products (n = 16), or outgrown their milk allergy (n = 8). Eleven non-milk allergic, healthy volunteers served as controls. Peptide microarray was performed using the previously published protocol.
Results
Milk allergic subjects had increased epitope diversity as compared to those who outgrew their allergy. HM tolerant subjects had IgE binding patterns similar to those who had outgrown their allergy, but IgG4 binding patterns that were more similar to the allergic group. Binding to higher numbers of IgE peptides was associated with more severe allergic reactions during challenge. There was no association between IgG4 peptides and clinical features of milk allergy. Using a competitive peptide microarray assay, allergic patients demonstrated a combination of high and low affinity IgE binding whereas HM tolerant subjects and those who had outgrown their milk allergy had primarily low affinity binding.
Conclusions
Greater IgE epitope diversity and higher affinity as determined by peptide microarray were associated with clinical phenotypes and severity of milk allergy.
doi:10.1016/j.jaci.2009.12.017
PMCID: PMC2841053  PMID: 20226304
Milk allergy; Peptide microarray; IgE pitope; IgE affinity; IgG4 epitope
12.  Epinephrine Treatment is Infrequent and Biphasic Reactions Are Rare in Food-Induced Reactions During Oral Food Challenges in Children 
Background
Data about epinephrine utilization and biphasic reactions in childhood food-induced anaphylaxis during oral food challenges are scarce.
Objective
To determine the prevalence and risk factors of reactions requiring epinephrine and the rate of biphasic reactions during oral food challenges (OFCs) in children.
Methods
Reaction details of positive OFCs in children between 1999 and 2007 were collected using a computerized database. Selection of patients for OFCs was generally predicated on ≤50% likelihood of a positive challenge and a low likelihood of a severe reaction based on the clinical history, specific IgE levels, and skin prick tests (SPTs).
Results
A total of 436 of 1273 OFCs resulted in a reaction (34%). Epinephrine was administered in 50 challenges (11% of positive challenges, 3.9% overall); for egg (n=15, 16% of positive OFCs to egg), milk (n=14, 12%), peanut (n=10, 26%), tree nuts (n=4, 33%), soy (n=3, 7%), wheat (n=3, 9%), and fish (n=1, 9%). Reactions requiring epinephrine occurred in older children (median 7.9 vs. 5.8 years, P<0.001), and were more often caused by peanuts (P=0.006) when compared to reactions not treated with epinephrine. There was no difference in the gender, prevalence of asthma, history of anaphylaxis, specific IgE level, SPTs, or amount of food administered. Two doses of epinephrine were required in 3/50 patients (6%) reacting to wheat, cow’s milk, and pistachio. There was one (2%) biphasic reaction. No reaction resulted in life-threatening respiratory or cardiovascular compromise.
Conclusion
Older age and reactions to peanuts were risk factors for anaphylaxis during oral food challenges. Reactions requiring multiple doses of epinephrine and biphasic reactions were infrequent.
doi:10.1016/j.jaci.2009.10.006
PMCID: PMC2798852  PMID: 20004784
food allergy; autoinjector; self-injectable; epinephrine; children; anaphylaxis; oral food challenge; food-induced anaphylaxis; peanut allergy; tree nut allergy; cow’s milk allergy; milk allergy; egg allergy; allergic reaction
13.  Definition, etiology, and diagnosis of food protein-induced enterocolitis syndrome 
Purpose of review
Food protein-induced enterocolitis syndrome (FPIES) is a poorly understood non-IgE-mediated food hypersensitivity, primarily affecting infants and toddlers. There are few data regarding pathophysiology of FPIES that suggest local intestinal imbalance between TNF-α and TGF-β. Patients frequently present with multiple reactions, which are characterized by projectile, repetitive emesis, dehydration, lethargy, and failure to thrive. Despite the severity of presentation, the diagnosis is frequently delayed, and patients often undergo extensive and invasive evaluation prior to reaching the diagnosis.
Recent findings
Reviews published in the last year provide a general approach to diagnosis and management of FPIES and aim to increase awareness and understanding of FPIES among general pediatricians.
Summary
Multicenter studies are necessary to reevaluate and modify the oral food challenge criteria. Research on the pathophysiology of FPIES reactions is necessary to provide insight into the evidence-based approach to diagnosis and management of FPIES. Registries are needed to understand the phenotype, triggers, and prevalence of FPIES.
doi:10.1097/ACI.0000000000000055
PMCID: PMC4011631  PMID: 24686276
allergic enterocolitis; food allergy; food protein-induced enterocolitis syndrome

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