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1.  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
2.  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
3.  Implementing specific oral tolerance induction to milk into routine clinical practice: experience from first 50 patients 
Background
Although the natural history of cow’s milk allergy is to resolve during childhood or adolescence, a small but significant proportion of children will remain allergic. Specific oral tolerance induction to cow’s milk (CM-SOTI) provides a treatment option in these children with continuing allergy with high success rates. However current sentiment limits widespread availability as existing reports advise that it is too soon to translate CM-SOTI into routine clinical practice.
Methods
In January 2007 we implemented a slow up-dosing CM-SOTI program. Eligible subjects were identified at routine visits to our children’s allergy clinic. Persisting cow’s milk allergy was confirmed from recent contact symptoms or a positive baked milk challenge. As allergic symptoms are common during CM-SOTI, families were provided with ready dietetic access for advice on dosing and symptom treatment. Subjects were continuously monitored at subsequent clinic visits or telephonically, where no longer followed, for a median of 49 months.
Results
The first 50 subjects (35 males) treated ranged in age from 5.1 to 15.8 years (median 10.3 years). Full tolerance (250 mL) was achieved in 23 subjects, 9 without any symptoms, and a further 9 achieved partial tolerance with continued ingestion. Eighteen children failed to achieve any regular milk ingestion; 11 because of persistent or significant symptoms whilst 8 withdrew against medical advice. Allergic symptoms were predominantly mild to moderate in severity, although 2 cases needed treatment with inhaled salbutamol and a further 2 required intramuscular adrenaline. Clinical tolerance, both full and partial, persists beyond 5 years.
Conclusion
We have demonstrated that a CM-SOTI program can be successfully and safely implemented as routine clinical practice with acceptable compliance during prolonged home up-dosing, despite frequent allergic symptoms, and for up to 4 years after starting treatment. CM-SOTI can thus be put into practice more widely where there is appropriate support.
doi:10.2147/JAA.S53281
PMCID: PMC3913504  PMID: 24511241
cow’s milk allergy; specific oral tolerance induction; oral desensitization; compliance; safety
4.  Heated Allergens and Induction of Tolerance in Food Allergic Children 
Nutrients  2013;5(6):2028-2046.
Food allergies are one of the first manifestations of allergic disease and have been shown to significantly impact on general health perception, parental emotional distress and family activities. It is estimated that in the Western world, almost one in ten children have an IgE-mediated allergy. Cow’s milk and egg allergy are common childhood allergies. Until recently, children with food allergy were advised to avoid all dietary exposure to the allergen to which they were sensitive, in the thought that consumption would exacerbate their allergy. However, recent publications indicate that up to 70% of children with egg allergy can tolerate egg baked in a cake or muffin without apparent reaction. Likewise, up to 75% of children can tolerate baked goods containing cow’s milk, and these children demonstrate IgE and IgG4 profiles indicative of tolerance development. This article will review the current literature regarding the use of heated food allergens as immunotherapy for children with cow’s milk and egg allergy.
doi:10.3390/nu5062028
PMCID: PMC3725491  PMID: 23739144
egg; milk; allergy; heated allergens; tolerance; oral; immunotherapy
5.  Ovomucoid Is Not Superior to Egg White Testing in Predicting Tolerance to Baked Egg 
BACKGROUND
Children with egg allergy may tolerate baked egg products. Ovomucoid specific IgE (sIgE) antibody levels have been suggested to predict outcomes of baked egg challenges.
OBJECTIVE
We determined the relationship of ovomucoid and egg white sIgE levels and egg white skin prick test (SPT) wheal size with baked egg challenge outcome.
METHODS
Retrospective review of 1186 patients who underwent ovomucoid sIgE blood testing. Subset analysis was of 169 patients who underwent baked egg food challenges.
RESULTS
Egg white sIgE, ovomucoid sIgE, and egg white SPT were different among those eating regular egg, eating baked egg only, or avoiding all egg (P < .001 for all). One hundred forty-two of 169 patients (84.0%) passed baked egg challenges. We were able to establish >90% predictive values for passing baked egg challenge for egg white sIgE, ovomucoid sIgE, and egg white SPT. No patient with egg white SPT wheal <3 mm failed a baked egg challenge. Receiver operating characteristic curve analysis of egg white sIgE, ovomucoid sIgE, and egg white SPT showed areas under the curve of 0.721, 0.645, and 0.624, respectively. No significant difference was observed among these immunologic parameters in their abilities to predict baked egg challenge outcome (P = .301).
CONCLUSION
Most children with egg allergy in this study passed baked egg challenges. Ovomucoid sIgE, although a useful clinical predictor of baked egg tolerance, was not superior to egg white SPT or sIgE in predicting outcome of baked egg challenge.
doi:10.1016/j.jaip.2013.04.002
PMCID: PMC3761974  PMID: 24013255
Egg allergy; Baked egg; Heated egg; Ovomucoid; Egg white; Food challenge
6.  Presence of functional, autoreactive human milk-specific IgE in infants with cow’s milk allergy 
Summary
Background
Occasionally, exclusively breastfed infants with cow’s milk allergy (CMA) remain symptomatic despite strict maternal milk avoidance.
Objective
To determine whether or not persistence of symptoms could be due to sensitization against endogenous human milk proteins with a high degree of similarity to bovine allergens.
Methods
Ten peptides representing known bovine milk IgE-binding epitopes [α-lactalbumin (ALA), β- and κ-casein] and the corresponding, highly homologous human milk peptides were labelled with sera from 15 breastfed infants with CMA, aged 3 weeks to 12 months, and peptide (epitope)-specific IgE antibodies were assessed. Nine of the 15 breastfed infants became asymptomatic during strict maternal avoidance of milk and other major food allergens; six infants remained symptomatic until weaned. Ten older children, aged 5–15 years, with CMA were also assessed. The functional capacity of specific IgE antibodies was assessed by measuring β-hexosaminidase release from rat basophilic leukaemia cells passively sensitized and stimulated with human and bovine ALA. Results A minimum of one human milk peptide was recognized by IgE antibodies from 9 of 15 (60%) milk-allergic infants, and the majority of older children with CMA. Genuine sensitization to human milk peptides in the absence of IgE to bovine milk was occasionally seen. There was a trend towards specific IgE being detected to more human milk peptides in those infants who did not respond to the maternal milk elimination diet than in those who did (P = 0.099). Functional IgE antibody to human ALA was only detected in infants not responding to the maternal diet.
Conclusions and Clinical Relevance
Endogenous human milk epitopes are recognized by specific IgE from the majority of infants and children with CMA. Such autoreactive, human milk-specific IgE antibodies appear to have functional properties in vitro. Their role in provoking allergic symptoms in infants exclusively breastfed by mothers strictly avoiding dietary milk remains unclear.
doi:10.1111/j.1365-2222.2011.03864.x
PMCID: PMC3780604  PMID: 22092935
atopic eczema; autoreactivity; cow’s milk allergy; cross-reactivity; endogenous protein; human milk; IgE antibodies; infants; RBL assay; sensitization; SPOT method
7.  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
8.  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
9.  Skin Testing With Water Buffalo’s Milk in Children With Cow’s Milk Allergy 
Background
Cow’s milk allergy is the most common food allergy in young children. In areas outside the United States, milk from other mammals has been studied as a possible and desirable alternative for children with cow’s milk allergy.
Objectives
We chose to further investigate water buffalo’s milk as an alternative for cow’s milk allergic children in the United States.
Methods
Children with cow’s milk allergy were skin prick tested with water buffalo’s milk. Additionally, subjects were followed clinically for 1 year after the test to determine how many of the subjects had persistent cow’s milk allergy.
Results
In total, 30 children, age 8 months to 8 years, were skin prick tested to water buffalo’s milk with 73% (22/30) having a positive test. All children with a negative water buffalo’s milk skin test also had a negative cow’s milk skin test. In follow-up, most (7 of 8) of the children with a negative skin prick test (SPT) to water buffalo’s milk were found to have outgrown their cow’s milk allergy. In comparison, all of the subjects with a positive skin test to water buffalo’s milk had persistent cow’s milk allergy. After adjusting for this, we determined that 96% (22/23) of the children with persistent cow’s milk allergy were positive on skin testing to water buffalo’s milk.
Conclusions
In this population, the vast majority of children with persistent cow’s milk allergy were positive on skin prick testing to water buffalo’s milk. These results indicate that water buffalo’s milk is unlikely to be a successful alternative for children with cow’s milk allergy.
doi:10.1089/pai.2009.0016
PMCID: PMC3218082  PMID: 22102769
10.  A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy 
Background
Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals.
Objective
We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow’s milk allergy.
Methods
Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT.
Results
Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86–314 kUa/L) versus 14.6 kUa/L (range, 0.93–133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg (P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase.
Conclusions
Milk OIT appears to be efficacious in the treatment of cow’s milk allergy. The side-effect profile appears acceptable but requires further study.
doi:10.1016/j.jaci.2008.09.030
PMCID: PMC3764488  PMID: 18951617
Cow’s milk; food allergy; IgE; prognosis; desensitization; tolerance; oral immunotherapy
11.  End point prick test: could this new test be used to predict the outcome of oral food challenge in children with cow's milk allergy? 
Background
Cow's milk allergy (CMA) is the most frequent food allergy in childhood; the trend of CMA is often characterized by a progressive improvement to achieve tolerance in the first 4 to 5 years of life.
It has been observed that specific IgE (sIgE) towards cow's milk proteins decrease when the age increases.
Although food allergy can be easily diagnosed, it is difficult to predict the outcome of the oral food challenge (OFC), that remains the gold standard in the diagnosis of food allergy, by allergometric tests.
Methods
We considered 44 children with CMA diagnosed through OFC who returned to our Allergy and Immunology Pediatric Department between January to December 2010 to evaluate the persistence of allergy or the achievement of tolerance.
On the basis of the history, we performed both allergometric skin tests and OFC in children that were still following a milk-free diet, whereas only allergometric skin tests those that had already undergone spontaneous introduction of milk protein at home without presenting symptoms.
Objective
The aim of this study was to investigate the relationship between the persistence of CMA or the acquisition of tolerance and the results of the end point prick test (EPT).
Results and Discussion
The OFC with cow's milk was performed on 30 children, 4 children were excluded because of a history of severe reactions to cow's milk, and 10 because they had spontaneously already taken milk food derivates at home without problems. 16/30 (53%) children showed clinical reactions and the challenge was stopped, 14/30 (47%) did not have any reaction.
Comparing the mean wheal diameter of every EPT's dilution between the group of allergic children and the tolerant ones, we obtained a significant difference (p < 0.05) for the first 4 dilutions.
We have also calculated sensitivity (SE), specificity (SP), the positive predictive value (PPV) and the negative predictive value (NPV) for each EPT dilution.
Conclusions
EPT is a safe and cheap test, easy to be executed and that could provide good prediction of the outcome of OFC; so it might be used to avoid OFC-induced anaphylaxis in children affected by CMA. It can also help avoiding dietetic restrictions in tolerant children who show sensitization towards cow's milk proteins.
doi:10.1186/1824-7288-37-52
PMCID: PMC3220633  PMID: 22053846
Cow's milk proteins allergy; end point prick test; food oral challenge; tolerance
12.  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
13.  Extensively hydrolysed casein formula supplemented with Lactobacillus rhamnosus GG maintains hypoallergenic status: randomised double-blind, placebo-controlled crossover trial 
BMJ Open  2012;2(2):e000637.
Objective
To evaluate the hypoallergenicity of an extensively hydrolysed (EH) casein formula supplemented with Lactobacillus rhamnosus GG (LGG).
Design
A prospective, randomised, double-blind, placebo-controlled crossover trial.
Setting
Two study sites in Italy and The Netherlands.
Study participants
Children with documented cow's milk allergy were eligible for inclusion in this trial.
Interventions
After a 7-day period of strict avoidance of cow's milk protein and other suspected food allergens, participants were tested with an EH casein formula with demonstrated hypoallergenicity (control, EHF) and a formula of the same composition with LGG added at 108 colony-forming units per gram powder (EHF-LGG) in randomised order in a double-blind placebo-controlled food challenge (DBPCFC). After absence of adverse reactions in the DBPCFC, an open challenge was performed with EHF-LGG, followed by a 7-day home feeding period with the same formula.
Main outcome measure
Clinical assessment of any adverse reactions to ingestion of study formulae during the DBPCFC.
Results
For all participants with confirmed cow's milk allergy (n=31), the DBPCFC and open challenge were classified as negative.
Conclusion
The EH casein formula supplemented with LGG is hypoallergenic and can be recommended for infants and children allergic to cow's milk who require an alternative to formulae containing intact cow's milk protein.
Trial registration number
http://ClinicalTrials.gov Identifier: NCT01181297.
Article summary
Article focus
Hypoallergenic extensively hydrolysed (EH) cow's milk-based or amino acid-based formulae are recommended for management of cow's milk allergy in formula-fed infants.
Although Lactobacillus rhamnosus GG (LGG) has over 25 years of safe use as a dietary probiotic, the safety and hypoallergenic status of EH casein formula supplemented with LGG has not yet been demonstrated.
Key messages
Supplementing the EH casein formula with LGG to provide additional benefits does not change its hypoallergenic status.
The LGG-supplemented EH formula can be safely used for management of cow's milk allergy in infants and children.
Strengths and limitations of this study
Testing the LGG-supplemented EH formula in a properly designed double-blind placebo-controlled food challenge in accordance with accepted European Society of Pediatric Gastroenterology and Nutrition (ESPGHAN) and American Academy of Pediatrics standards to establish hypoallergenicity is a major strength of this study.
One limitation is the potentially low novelty of our finding. Because LGG is the most used dietary probiotic, accumulated safety data for LGG as a stand-alone dietary supplement in infants and adults are available.
doi:10.1136/bmjopen-2011-000637
PMCID: PMC3298831  PMID: 22396223
Cow's milk protein; cow's milk allergy; extensively hydrolysed formula; double-blind placebo-controlled food challenge; hypoallergenic formula; infant; Lactobacillus GG
14.  Egg baked in product open oral food challenges are safe in selected egg-allergic patients 
Allergy & Rhinology  2014;5(2):e110-e112.
Egg allergy is one of the most common food allergies in children. Most egg-allergic children are able to tolerate egg baked in product (EBP) and will likely outgrow his/her egg allergy. By introducing EBP in the diet of an egg-allergic child, diet can be expanded and family stress can be reduced. Recent evidence suggests that children who tolerate EBP and continue to consume it will have quicker resolution of egg allergy than those who strictly avoid EBP; therefore, we aimed to evaluate the egg-allergic children who underwent EBP oral food challenge (OFC) in our allergy clinic to help define any specific predictors to be used in predicting the outcome of such challenges. We performed a retrospective chart review and 43 egg-allergic patients underwent EBP OFC in our outpatient allergy office from January 2011 to December 2012 were excluded. Nine patients who did not have a prior history of symptomatic egg ingestion. Clinical characteristics and laboratory findings of the remaining 34 patients were all recorded and analyzed. Of the remaining 34 patients, 22 (64.7%) were boys. Average age of first reaction to egg was 12.90 months, with average age at EBP OFC of 71.32 months. The average of the most recent skin-prick test wheal size was 10.10 mm and serum-specific IgE to egg white was 3.21 kU/L. Twenty-eight of the 34 patients (82.4%) passed the EBP OFC. Of the six patients who failed, none required epinephrine. After analysis of all of the clinical characteristics and laboratory findings, no risk factors, such as skin-prick test wheal size, were identified to be associated with an increased risk of failing EBP OFC. EBP OFC is a valuable tool to assess tolerance. As seen in our group of patients, the majority of egg-allergic patients pass EBP OFC. Thus, OFC should be considered as a clinical tool to expand a patient's diet and to improve quality of life as early as possible. Because we were unable to determine any clinical or laboratory predictors helpful to select egg-allergic patients who are likely to pass EBP OFC, additional prospective studies are necessary to determine the ideal egg-allergic patient who is likely to pass EBP OFC.
doi:10.2500/ar.2014.5.0092
PMCID: PMC4124576  PMID: 25198996
Baked egg; baked egg oral food challenge; egg allergy; egg baked in product; egg baked in product oral food challenge; food allergy; oral food challenge; serum-specific IgE; skin-prick testing
15.  The usefulness of casein-specific IgE and IgG4 antibodies in cow's milk allergic children 
Background
Cow's milk allergy is one of the most common food allergies among younger children. We investigated IgE antibodies to milk, and IgE and IgG4 antibodies to casein, α-lactalbumin and β-lactoglobulin in cow's milk allergic (CMA) and non-allergic (non-CMA) children in order to study their clinical usefulness.
Methods
Eighty-three children with suspected milk allergy (median age: 3.5 years, range: 0.8-15.8 years) were diagnosed as CMA (n = 61) or non-CMA (n = 22) based on an open milk challenge or convincing clinical history. Their serum concentrations of allergen-specific (s) IgE and IgG4 antibodies were measured using ImmunoCAP®. For the sIgG4 analysis, 28 atopic and 31 non-atopic control children were additionally included (all non-milk sensitized).
Results
The CMA group had significantly higher levels of milk-, casein- and β-lactoglobulin-sIgE antibodies as compared to the non-CMA group. The casein test showed the best discriminating performance with a clinical decision point of 6.6 kUA/L corresponding to 100% specificity. All but one of the CMA children aged > 5 years had casein-sIgE levels > 6.6 kUA/L. The non-CMA group had significantly higher sIgG4 levels against all three milk allergens compared to the CMA group. This was most pronounced for casein-sIgG4 in non-CMA children without history of previous milk allergy. These children had significantly higher casein-sIgG4 levels compared to any other group, including the non-milk sensitized control children.
Conclusions
High levels of casein-sIgE antibodies are strongly associated with milk allergy in children and might be associated with prolonged allergy. Elevated casein-sIgG4 levels in milk-sensitized individuals on normal diet indicate a modified Th2 response. However, the protective role of IgG4 antibodies in milk allergy is unclear.
doi:10.1186/1476-7961-10-1
PMCID: PMC3398319  PMID: 22212305
casein; cow's milk allergy; IgE; IgG4; ImmunoCAP
16.  423 Multiple Manifestations of Food Allergy in a Patient with a Change of Eating Habits 
Background
Food-induced allergic reactions are responsible for a variety of symptoms and disorders involving the skin, gastrointestinal and respiratory tracts and can be attributed to IgE-mediated and non–IgE-mediated (cellular) mechanisms.
Food allergy frequency varies according to age, local diet, and many other factors. The diagnosis of food allergy is based on clinical history, skin prick test (SPT), food specific IgE and more recently atopy patch tests (APT). If needed the use of an oral food challenge to confirm allergy or tolerance.
Methods
Describes the case of a patient with multiple manifestations of food allergy after eating habit change.
Results
Man 20 years with a history of food allergy to egg in childhood (at date in remission) asthma and rhinitis and urticaria in contact to cats. He presents an atopic dermatitis, recurrent abdominal pain and diarrhea 18 months after change in eating habits (he became vegetarian). He also presents oral syndrome with cow's milk. The patient had 4 episodes of anaphylaxis post prandial grade 3. In 3 of them the patient ate goat cheese and the other cow cheese. Also 2 of the episodes were associated with exercise. Skin prick tests with goat`s cheese: 13 mm, cow´s milk: 8 mm wheat: 3 mm, corn 3 mm, chicken 3.5 mm, egg yolk: 3.5 mm, avocado and rice 3 mm. Atopy patch test: (+ +) goat`s milk (+) peanuts and coffee. Total IgE 686 IU/mL.
Foods with positive results were excluded from the diet and a complete remission of atopic dermatitis, abdominal pain, diarrhea and anaphylaxis was observed. All foods were reintroduced successfully except milk of goats and cows milk. The patient is currently asymptomatic.
Conclusions
The literature describes different kinds of manifestations of food allergy: immediate hypersensitivity (IgE mediated), delayed hypersensitivity (T lymphocytes mediated) and mixed. Highlights in this case an adult patient with a history of atopy who makes changes in eating habits, developping a food allergy to goat´s and cow s milk, with immediate (anaphylaxis, oral syndrome) and delayed manifestations (atopic dermatitis and chronic diarrhea).
doi:10.1097/01.WOX.0000412186.25382.27
PMCID: PMC3512613
17.  421 Cow's Milk Allergy and Persistent Changes in a Multiple Food Allergy, A Case Report 
Background
Cow's milk allergy (CMA) is the most common food allergy. Clinical manifestations are mediated immediate hypersensitivity and delayed. The allergy study include: specific IgE, prick and patch test. Regarding treatment, this is based on the exclusion diet and the replacement of cow's milk hydrolysates extensive.
Virtually all infants who have cow's milk allergy develop this condition in the first year of life, with clinical tolerance developing in about 80 percent by their fifth birthday.
Methods
Describe the case of a child with CMA, which moves without tolerance and also become sensitized to other foods.
Results
Female with 6 years of age. At 9 months presents watery diarrhea, weight loss and intermittent rash. Initial study (2006): Upper endoscopy: Duodenitis chronic nonspecific, total IgE: 72.60 IU/mL, IgE specific to cow's milk 10.40 IU/mL (Class III) and prick test positive. Exclusion diet starts to cow's milk, its derivatives and beef. Patient improvement. At 2 years, begins with rhinitis and diarrhea reappears with low weight. Colonoscopy (2007): Subacute nonspecific colitis histology. At 3 years old facial angioedema, throat and rash are associated with eating chicken, turkey, carrot and orange juice. New tests: specific IgE cow's milk, 24. 7 IU/mL (class IV), class II chicken. Prick test positive. At 4 years enter kindergarten, restarts with diarrhea and occasional angioedema. Cow's milk specific IgE (January 2009): 66, 6 IU/mL (class V). January 2010: 5 years post anaphylactic shock milk pudding. Besides diarrhea 10 times a day, intermittently throughout the year. Year 2011: intermittent diarrhea and specific IgE to cow's milk is kept in class V.
Conclusions
In this case the patient with CMA which evolved atypically because it has not been able to acquire tolerance. Moreover, awareness is added to other foods during their evolution. A recent study indicated a lower rate of development of clinical tolerance. As assessed by passing a milk challenge, 5 percent were tolerant at age 4 and 21 percent at age 8. Patients with persistent milk allergy have higher cow's milk sIgE levels in the first 2 years of life. Approximately 35 percent developed allergy to other foods.
doi:10.1097/01.WOX.0000412184.40629.eb
PMCID: PMC3512946
18.  Role of specific IgE and skin-prick testing in predicting food challenge results to baked egg 
Allergy and Asthma Proceedings  2012;33(3):275-281.
Previous studies suggest that children with egg allergy may be able to tolerate baked egg. Reliable predictors of a successful baked egg challenge are not well established. We examined egg white–specific IgE levels, skin-prick test (SPT) results, and age as predictors of baked egg oral food challenge (OFC) outcomes. We conducted a retrospective chart review of children, aged 2–18 years, receiving an egg white–specific IgE level, SPT, and OFC to baked egg from 2008 to 2010. Fifty-two oral baked egg challenges were conducted. Of the 52 challenges, 83% (n = 43) passed and 17% (n = 9) failed, including 2 having anaphylaxis. Median SPT wheal size was 12 mm (range, 0–35 mm) for passed challenges and 17 mm (range, 10–30 mm) for failed challenges (p = 0.091). The negative predictive value for passing the OFC was 100% (9 of 9) if SPT wheal size was <10 mm. Median egg white–specific IgE was 2.02 kU/L (range, <0.35–13.00 kU/L) for passed challenges and 1.52 kU/L (range, 0.51–6.10 kU/L) for failed challenges (p = 0.660). Receiver operating characteristic (ROC) curve analysis for SPT revealed an area under the curve (AUC) of 0.64. ROC curve analysis for egg white–specific IgE revealed an AUC of 0.63. There was no significant difference in age between patients who failed and those who passed (median = 8.8 years versus 7.0 years; p = 0.721). Based on our sample, SPT, egg white–specific IgE and age are not good predictors of passing a baked egg challenge. However, there was a trend for more predictability with SPT wheal size.
doi:10.2500/aap.2012.33.3544
PMCID: PMC3372532  PMID: 22584194
19.  Role of specific IgE and skin-prick testing in predicting food challenge results to baked egg 
Allergy and Asthma Proceedings  2012;33(3):275-281.
Previous studies suggest that children with egg allergy may be able to tolerate baked egg. Reliable predictors of a successful baked egg challenge are not well established. We examined egg white–specific IgE levels, skin-prick test (SPT) results, and age as predictors of baked egg oral food challenge (OFC) outcomes. We conducted a retrospective chart review of children, aged 2–18 years, receiving an egg white–specific IgE level, SPT, and OFC to baked egg from 2008 to 2010. Fifty-two oral baked egg challenges were conducted. Of the 52 challenges, 83% (n = 43) passed and 17% (n = 9) failed, including 2 having anaphylaxis. Median SPT wheal size was 12 mm (range, 0–35 mm) for passed challenges and 17 mm (range, 10–30 mm) for failed challenges (p = 0.091). The negative predictive value for passing the OFC was 100% (9 of 9) if SPT wheal size was <10 mm. Median egg white–specific IgE was 2.02 kU/L (range, <0.35–13.00 kU/L) for passed challenges and 1.52 kU/L (range, 0.51–6.10 kU/L) for failed challenges (p = 0.660). Receiver operating characteristic (ROC) curve analysis for SPT revealed an area under the curve (AUC) of 0.64. ROC curve analysis for egg white–specific IgE revealed an AUC of 0.63. There was no significant difference in age between patients who failed and those who passed (median = 8.8 years versus 7.0 years; p = 0.721). Based on our sample, SPT, egg white–specific IgE and age are not good predictors of passing a baked egg challenge. However, there was a trend for more predictability with SPT wheal size.
doi:10.2500/aap.2012.33.3544
PMCID: PMC3372532  PMID: 22584194
Anaphylaxis; baked egg challenge; egg allergy; food allergy; food challenge; IgE; ImmunoCap; ovomucoid; RAST; skin prick test
20.  Skin prick testing with extensively heated milk or egg products helps predict the outcome of an oral food challenge: a retrospective analysis 
Background
Cow’s milk and hen’s egg are the most frequently encountered food allergens in the pediatric population. Skin prick testing (SPT) with commercial extracts followed by an oral food challenge (OFC) are routinely performed in the diagnostic investigation of these children. Recent evidence suggests that milk-allergic and/or egg-allergic individuals can often tolerate extensively heated (EH) forms of these foods. This study evaluated the predictive value of a negative SPT with EH milk or egg in determining whether a child would tolerate an OFC to the EH food product.
Methods
Charts from a single allergy clinic were reviewed for any patient with a negative SPT to EH milk or egg, prepared in the form of a muffin. Data collected included age, sex, symptoms of food allergy, co-morbidities and the success of the OFC to the muffin.
Results
Fifty-eight patients had negative SPTs to the EH milk or egg in a muffin and underwent OFC to the appropriate EH food in the outpatient clinic. Fifty-five of these patients tolerated the OFC. The negative predictive value for the SPT with the EH food product was 94.8%.
Conclusions
SPT with EH milk or egg products was predictive of a successful OFC to the same food. Larger prospective studies are required to substantiate these findings.
doi:10.1186/1710-1492-8-5
PMCID: PMC3394206  PMID: 22591833
21.  The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy 
Pediatric Allergy and Immunology  2010;21(4p1):577-585.
Reche M, Pascual C, Fiandor A, Polanco I, Rivero-Urgell M, Chifre R, Johnston S, Martín-Esteban M. The effect of a partially hydrolysed formula based on rice protein in the treatment of infants with cow’s milk protein allergy. Pediatr Allergy Immunol 2010: 21: 577–585. © 2010 John Wiley & Sons A/S
Infants diagnosed with allergy to cow’s milk protein (CMP) are fed extensively hydrolysed cow’s milk formulas, modified soy formulas or even amino acid-based formulas. Hydrolysed rice protein infant formulas have become available and have been shown to be well tolerated by these infants. A prospective open, randomized clinical study to compare the clinical tolerance of a new hydrolysed rice protein formula (HRPF) with an extensively hydrolysed CMP formula (EHF) in the feeding of infants with IgE-mediated cow’s milk allergy. Ninety-two infants (46 boys and 46 girls, mean age 4.3 months, range 1.1–10.1 months) diagnosed with IgE-mediated cow’s milk allergy were enrolled in the study. Clinical tolerance to the formula products was tested. Clinical evaluation included skin prick tests with whole cow’s milk, soya and rice as well as antigens of CMP (beta-lactoglobulin, alpha-lactalbumin, casein and bovine seroalbumin), HRPF and EHF and specific IgE determinations to CMP using CAP technology. Patients were randomized to receive either an EHF based on CMP or a new HRPF. Follow-up was at 3, 6, 12, 18 and 24 months. Growth parameters were measured at each visit. One infant showed immediate allergic reaction to EHF, but no reaction was shown by any infant in the HRPF group. The number of infants who did not become tolerant to CMP during the study was not statistically different between the two groups. Measurement of IgE levels of infants allergic to CMP during the study showed no significant differences between the two formula groups. Growth parameters were in the normal range and similar between groups. In this study, the HRPF was well tolerated by infants with moderate to severe symptoms of IgE-mediated CMP allergy. Children receiving this formula showed similar growth and development of clinical tolerance to those receiving an EHF. In accordance with current guidelines, this HRPF was tolerated by more than 90% of children with CMP allergy and therefore could provide an adequate and safe alternative to CMP-hydrolysed formulas for these infants.
doi:10.1111/j.1399-3038.2010.00991.x
PMCID: PMC2904490  PMID: 20337976
cow’s milk protein allergy; hydrolysed rice protein formula; extensively hydrolysed cow’s milk protein formula
22.  Invariant natural killer T cells from food allergic versus non-allergic children exhibit differential responsiveness to milk-derived sphingomyelin 
Background
A key immunological feature of food allergy (FA) is the presence of a T-helper-2 (Th2)-type cytokine bias. Ligation of the invariant natural killer T cell (iNKT) T cell receptor (TCR) by sphingolipids (SL) presented via the CD1d molecule leads to copious secretion of Th2-type cytokines. Major food allergens (e.g. milk, egg) are the richest dietary source of SL (food-SL). Nonetheless, the role of iNKTs in FA is unknown.
Objective
To investigate the role of iNKTs in FA and to assess whether food-SL-CD1d complexes can engage the iNKT-TCR and induce iNKT cell functions.
Methods
Peripheral blood mononuclear cells from 15 children allergic to cow's milk (FA-MA), 12 children tolerant to cow's milk but with allergy to egg (FA-NMA) and 13 healthy controls were incubated with α-galactosylceramide (αGal), cow's milk-sphingomyelin-[SM] or hen's egg-ceramide-[CE]. iNKTs were quantified and their cytokine production and proliferation were assessed. Human CD1d tetramers loaded with milk-SM or egg-CE were used to determine food-SL binding to the iNKT-TCR.
Results
Milk-SM, but not egg-CE, can engage the iNKT-TCR and induce iNKT-proliferation and Th2-type cytokine secretion. FA-children, especially those with MA, had significantly fewer peripheral blood (PB) iNKTs and their iNKTs exhibited a greater Th2-response to αGal and milk-SM compared to iNKTs of healthy controls.
Conclusion
iNKTs from FA-children, especially those with MA, are reduced in number and exhibit a Th2-bias in response to αGal and milk-SM. These data suggest a potential role for iNKTs in FA.
Clinical Implications
Milk-SM activate PB-iNKTs to produce Th2-cytokines and this effect is greater in FA-MA-children. Hence, SL contained in milk may promote an iNKT cell-mediated-Th2-type-cytokine bias that facilitates sensitization to food allergens.
doi:10.1016/j.jaci.2011.02.026
PMCID: PMC3129401  PMID: 21458849
Food allergy; invariant natural killer T cells; sphingolipids
23.  Markers of gut mucosal inflammation and cow’s milk specific immunoglobulins in non-IgE cow’s milk allergy 
Background
Allergy to cow’s milk protein (CMP) may cause gastrointestinal (GI) symptoms in the absence of CMP specific IgE. The immunological mechanisms involved in such disease are not fully understood. Therefore we examined markers of gut mucosal inflammation and the immunoglobulin profiles in children with Gl symptoms suspected of cow’s milk protein allergy (CMPA).
Patients and methods
We prospectively recruited infants and young children (n = 57; median age 8.7 months) with gastrointestinal complaints suspected of CMPA. The diagnosis of CMPA was made using the double-blind, placebo-controlled food challenge. Serum and stool samples were collected during CMP-free diet and after both placebo and active challenges. We analyzed the stool samples for calprotectin, human β-defensin 2 and IgA. In serum, we analyzed the levels of β-lactoglobulin and α-casein specific IgA, and IgG antibodies (total IgG and subclasses IgG1 and IgG4). Control group included children with e.g. dermatological or pulmonary problems, consuming normal diets.
Results
Fecal calprotectin levels were higher in the challenge positive group (n = 18) than in the negative (n = 37), with respective geometric means 55 μg/g [95% confidence interval 38–81] and 29 [24–36] μg/g (p = 0.0039), during cow’s milk free diet. There were no significant inter-group differences in the fecal β-defensin and IgA levels. The CMP specific IgG and IgA were not elevated in patients with CMPA, but the levels of β-lactoglobulin-IgG4 (p = 0.0118) and α-casein-IgG4 (p = 0.0044), and total α-casein-IgG (p = 0.0054) and -IgA (p = 0.0050) in all patient samples (regardless of CMPA diagnosis) were significantly lower compared to the control group using dairy products.
Conclusions
Despite cow’s milk elimination in children intolerant to cow’s milk there might be ongoing low-grade inflammation in the gut mucosa. CMP specific IgG or IgA should not be used to diagnose non-IgE CMPA. The observed frequency of impaired CMP specific total IgA, IgG and IgG4 production in patients following cow’s milk free diet warrants further studies.
doi:10.1186/2045-7022-4-8
PMCID: PMC3946153  PMID: 24598281
24.  Natural Course of Cow's Milk Allergy in Children with Atopic Dermatitis 
Journal of Korean Medical Science  2011;26(9):1152-1158.
Cow's milk is one of the most common food allergens in children with atopic dermatitis (AD). This study was conducted to describe the natural course of cow's milk allergy in children with AD, and to identify factors predictive of outcome. To accomplish this, we reviewed the medical records of 115 children who were diagnosed with AD and cow's milk allergy before 24 months of age to evaluate their clinical characteristics and prognostic factors. During a follow-up period of 24 to114 months, the median age for tolerance to cow's milk was found to be 67 months. Multivariate analysis using the Cox proportional hazard model revealed that the peak cow's milk-specific IgE level within 24 months after birth was the most important factor for prediction of the outcome of cow's milk allergy. In conclusion, half of the children younger than 24 months of age with AD and cow's milk allergy could tolerate cow's milk at 67 months of age. The peak cow's milk-specific IgE level within the first 24 months of birth is useful to predict the prognosis of cow's milk allergy in children with AD.
doi:10.3346/jkms.2011.26.9.1152
PMCID: PMC3172651  PMID: 21935269
Milk; Food Hypersensitivity; Immunoglobulin E; Prognosis
25.  Camel Milk Is a Safer Choice than Goat Milk for Feeding Children with Cow Milk Allergy 
ISRN Allergy  2011;2011:391641.
Background. Various sources of mammalian milk have been tried in CMA. Objectives. To determine whether camel milk is safer than goat milk in CMA. Methods. Prospective study conducted at Hamad Medical Corporation between April 2007 and April 2010, on children with CMA. Each child had medical examination, CBC, total IgE, cow milk-specific IgE and SPT. CMA children were tested against fresh camel and goat milks. Results. Of 38 children (median age 21.5 months), 21 (55.3%) presented with urticaria, 17 (39.5%) atopic dermatitis, 10 (26.3%) anaphylaxis. WBC was 10, 039 ± 4, 735 cells/μL, eosinophil 1, 143 ± 2, 213 cells/μL, IgE 694 ± 921 IU/mL, cow's milk-specific-IgE 23.5 ± 35.6 KU/L. Only 7 children (18.4%) tested positive to camel milk and 24 (63.2%) to goat milk. 6 (15.8%) were positive to camel, goat, and cow milks. Patients with negative SPT tolerated well camel and goat milks. Conclusions. In CMA, SPT indicates low cross-reactivity between camel milk and cow milk, and camel milk is a safer alternative than goat milk.
doi:10.5402/2011/391641
PMCID: PMC3658853  PMID: 23724227

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