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1.  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.
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
2.  Basophil Reactivity, Wheal Size and Immunoglobulin Levels Distinguish Degree of Cow’s Milk Tolerance 
In our previous study, about 75% of cow’s milk-allergic children tolerated baked-milk products, which improved their prognosis and quality of life.
We sought to identify biomarkers of varying degrees of clinical tolerance among a cohort of cow’s milk-allergic children.
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.
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.
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.
PMCID: PMC3493710  PMID: 22819512
Cow’s milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation; biomarker; basophil activation
3.  Skin prick testing with extensively heated milk or egg products helps predict the outcome of an oral food challenge: a retrospective analysis 
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.
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.
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%.
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.
PMCID: PMC3394206  PMID: 22591833
4.  Milk and Soy Allergy 
Cow’s milk allergy (CMA) affects 2% to 3% of young children and presents with a wide range of immunoglobulin E (IgE-) and non-IgE-mediated clinical syndromes, which have a significant economic and lifestyle impact. Definitive diagnosis is based on a supervised oral food challenge (OFC), but convincing clinical history, skin prick testing, and measurement of cow’s milk (CM)-specific IgE can aid in the diagnosis of IgE-mediated CMA and occasionally eliminate the need for OFCs. It is logical that a review of CMA would be linked to a review of soy allergy, as soy formula is often an alternative source of nutrition for infants who do not tolerate cow’s milk. The close resemblance between the proteins from soy and other related plants like peanut, and the resulting cross-reactivity and lack of predictive values for clinical reactivity, often make the diagnosis of soy allergy far more challenging. This review examines the epidemiology, pathogenesis, clinical features, natural history and diagnosis of cow’s milk and soy allergy. Cross-reactivity and management of milk allergy are also discussed.
PMCID: PMC3070118  PMID: 21453810
cow’s milk; soy; bovine; allergy; cross-reactivity; diagnosis; management; natural history; pediatric; children
5.  The Natural History of IgE-Mediated Food Allergy: Can Skin Prick Tests and Serum-Specific IgE Predict the Resolution of Food Allergy? 
IgE-mediated food allergy is a transient condition for some children, however there are few indices to predict when and in whom food allergy will resolve. Skin prick test (SPT) and serum-specific IgE levels (sIgE) are usually monitored in the management of food allergy and are used to predict the development of tolerance or persistence of food allergy. The aim of this article is to review the published literature that investigated the predictive value of SPT and sIgE in development of tolerance in children with a previous diagnosis of peanut, egg and milk allergy. A systematic search identified twenty-six studies, of which most reported SPT or sIgE thresholds which predicted persistent or resolved allergy. However, results were inconsistent between studies. Previous research was hampered by several limitations including the absence of gold standard test to diagnose food allergy or tolerance, biased samples in retrospective audits and lack of systematic protocols for triggering re-challenges. There is a need for population-based, prospective studies that use the gold standard oral food challenge (OFC) to diagnose food allergy at baseline and follow-up to develop SPT and sIgE thresholds that predict the course of food allergy.
PMCID: PMC3823325  PMID: 24132133
food allergy; natural history; tolerance; skin prick test; serum-specific immunoglobulin E; hen’s egg; peanut; cow’s milk
6.  Skin Testing With Water Buffalo’s Milk in Children With Cow’s Milk Allergy 
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.
We chose to further investigate water buffalo’s milk as an alternative for cow’s milk allergic children in the United States.
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.
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.
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.
PMCID: PMC3218082  PMID: 22102769
7.  Basophil activation test discriminates between allergy and tolerance in peanut-sensitized children 
Most of the peanut-sensitized children do not have clinical peanut allergy. In equivocal cases, oral food challenges (OFCs) are required. However, OFCs are laborious and not without risk; thus, a test that could accurately diagnose peanut allergy and reduce the need for OFCs is desirable.
To assess the performance of basophil activation test (BAT) as a diagnostic marker for peanut allergy.
Peanut-allergic (n = 43), peanut-sensitized but tolerant (n = 36) and non–peanut-sensitized nonallergic (n = 25) children underwent skin prick test (SPT) and specific IgE (sIgE) to peanut and its components. BAT was performed using flow cytometry, and its diagnostic performance was evaluated in relation to allergy versus tolerance to peanut and validated in an independent population (n = 65).
BAT in peanut-allergic children showed a peanut dose-dependent upregulation of CD63 and CD203c while there was no significant response to peanut in peanut-sensitized but tolerant (P < .001) and non–peanut-sensitized nonallergic children (P < .001). BAT optimal diagnostic cutoffs showed 97% accuracy, 95% positive predictive value, and 98% negative predictive value. BAT allowed reducing the number of required OFCs by two-thirds. BAT proved particularly useful in cases in which specialists could not accurately diagnose peanut allergy with SPT and sIgE to peanut and to Arah2. Using a 2-step diagnostic approach in which BAT was performed only after equivocal SPT or Arah2-sIgE, BAT had a major effect (97% reduction) on the number of OFCs required.
BAT proved to be superior to other diagnostic tests in discriminating between peanut allergy and tolerance, particularly in difficult cases, and reduced the need for OFCs.
PMCID: PMC4164910  PMID: 25065721
Anaphylaxis; basophil activation test; CD203c; CD63; diagnosis; flow cytometry; food allergy; peanut allergy; ROC curve; BAT, Basophil activation test; CRD, Component-resolved diagnosis; DBPCFC, Double-blind placebo-controlled food challenge; fMLP, Formyl-methionyl-leucyl-phenylalanine; NA, Non–peanut-sensitized nonallergic; OFC, Oral food challenge; PA, Peanut-allergic; PPV, Positive predictive value; PS, Peanut-sensitized but tolerant; P-sIgE, Peanut-specific IgE; ROC, Receiver-operating characteristic; sIgE, Specific IgE; SPT, Skin prick test
8.  75 Efficacy of Slow Oral Immunotherapy for Cow's Milk Allergy 
The World Allergy Organization Journal  2012;5(Suppl 2):S41-S42.
Efficacy and safety of slow oral immunotherapy (SOIT) is not yet clear, especially regarding tolerance acquisition.
We recruited 32 cow's milk (CM) allergy confirmed by oral food challenge (OFC). Twenty-five subjects were enrolled as SOIT group, and remaining 7 were as control. The inclusion criteria were as follows; (1) CM allergy without anaphylaxis confirmed by OFC just before the trial, and (2) children >4 years. In SOIT group, they were asked to take small amount of CM at home after the OFC. The initial dose was about 1/4 of the threshold eliciting positive objective symptoms, and it was built up to 200 mL CM depends on the symptoms (build up phase). After reaching 200 mL, they were asked to take 200 mL CM daily until the asymptomatic duration lasting for more than 3m (maintenance phase). The subjects, who completed maintenance phase, underwent OFC to confirm the tolerance acquisition after the cessation of CM ingestion for 2w (confirm-OFC). In control group, they had eliminated CM completely and underwent the confirm-OFC after 9.8 ± 2.9 m (mean ± SD). We investigated the endpoints (adverse reactions, medical treatments, results of confirm-OFC, and laboratory findings), prospectively.
In SOIT group (n = 25) and control group (n = 7), the average age was 6.6y and 4.7y, respectively. The average threshold was 52 mL and 17 mL, and the CM specific IgE was 17.6 Ua/mL/9.9 Ua/mL, respectively. The average period of build up and maintenance phases in SOIT group was 80d (n = 25) and 98d (n = 15), respectively. The frequency of adverse reactions in all of build up (1973d) and maintenance phases (2924d) were 13.5% (mild symptoms)/2.3% (moderate symptoms) and 1.7% (mild)/0.3% (moderate), respectively. No patient had administered adrenaline during SOIT. Fifteen subjects in SOIT and 7 in control underwent the confirm-OFC. In SOIT, 8 subjects (53.3%) passed the confirm-OFC, whereas 2 (28.6%) passed in control. There was no statistically significant difference regarding tolerance acquisition between these 2 groups (P = 0.277).
This study suggests that SOIT for about 1/2 year induces desensitization effectively for CM allergy without severe adverse reactions. Further and longer study would be required to prove accelerated tolerance acquisition by SOIT.
PMCID: PMC3513047
9.  Clinical and laboratory factors associated with negative oral food challenges 
Allergy and Asthma Proceedings  2012;33(6):467-473.
Children with food-specific IgE (FSIgE) ≤2 kUa/L to milk, egg, or peanut (or ≤5kUa/L to peanut without history of previous reaction) are appropriate candidates for oral food challenge (OFC) to investigate resolution of food allergy, because these FSIgE cutoffs are associated with ∼50% likelihood of negative OFC. This study was designed to identify characteristics of children undergoing OFC, based on these FSIgE levels, who are most likely to show negative OFC. We collected demographics, severity of previous reaction, history of atopic diseases, total IgE and FSIgE values, and skin tests results on children who underwent OFCs to milk, egg, or peanut, based on the recommended FSIgE cutoffs. We identified independent factors associated with negative OFCs. Four hundred forty-four OFCs met our inclusion criteria. The proportions of negative OFCs performed based on FSIgE cutoffs alone were 58, 42, and 63% to milk, egg, and peanuts, respectively. Regression models identified independent factors associated with negative OFCs: lower FSIgE levels (all three foods), higher total IgE (milk), consumption of baked egg products (egg), and non-Caucasian race (eggs and peanuts). Combinations of these factors identified subgroups of children with proportions of negative OFCs of 83, 75, and 75% for milk, eggs, and peanuts, respectively. Combinations of clinical and laboratory elements, together with FSIgE values, might identify more children who are likely to have negative OFCs compared with current recommendations using FSIgE values alone. Once validated in a different population, these factors might be used for selection of patients who are most likely to show negative OFCs.
PMCID: PMC3522388  PMID: 23394503
Children; food allergy; food specific IgE; oral food challenge; regression models; skin test; total IgE
10.  Dietary baked-milk accelerates resolution of cow's milk allergy in children 
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.
We report on the outcomes of children who incorporated baked-milk products into their diets.
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.
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.
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.
PMCID: PMC3151608  PMID: 21601913
cow's milk allergy; milk allergy; tolerance; extensively heated; baked; immunotherapy; immunomodulation
11.  423 Multiple Manifestations of Food Allergy in a Patient with a Change of Eating Habits 
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.
Describes the case of a patient with multiple manifestations of food allergy after eating habit change.
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.
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).
PMCID: PMC3512613
12.  A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow’s milk allergy 
Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals.
We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow’s milk allergy.
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.
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.
Milk OIT appears to be efficacious in the treatment of cow’s milk allergy. The side-effect profile appears acceptable but requires further study.
PMCID: PMC3764488  PMID: 18951617
Cow’s milk; food allergy; IgE; prognosis; desensitization; tolerance; oral immunotherapy
13.  Epinephrine Treatment is Infrequent and Biphasic Reactions Are Rare in Food-Induced Reactions During Oral Food Challenges in Children 
Data about epinephrine utilization and biphasic reactions in childhood food-induced anaphylaxis during oral food challenges are scarce.
To determine the prevalence and risk factors of reactions requiring epinephrine and the rate of biphasic reactions during oral food challenges (OFCs) in children.
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).
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.
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.
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
14.  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.
To evaluate the hypoallergenicity of an extensively hydrolysed (EH) casein formula supplemented with Lactobacillus rhamnosus GG (LGG).
A prospective, randomised, double-blind, placebo-controlled crossover trial.
Two study sites in Italy and The Netherlands.
Study participants
Children with documented cow's milk allergy were eligible for inclusion in this trial.
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.
For all participants with confirmed cow's milk allergy (n=31), the DBPCFC and open challenge were classified as negative.
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 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.
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
15.  421 Cow's Milk Allergy and Persistent Changes in a Multiple Food Allergy, A Case Report 
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.
Describe the case of a child with CMA, which moves without tolerance and also become sensitized to other foods.
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.
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.
PMCID: PMC3512946
16.  74 Analysis of IGE, IGE Rast Value and Prick Test in Wheat or Hen's Egg-Allergy Infants Treated with Slow Specific Oral Tolerance Induction Therapy 
Food allergy primarily causes anaphylaxis in children. Food such as egg, cow milk, wheat and peanut are common allergen in Japan.
In this study total IgE, IgE RAST value and prick test are evaluated to monitor the efficacy outcome in wheat or hen's egg-allergy infants treated with slow specific oral tolerance induction (sSOTI) therapy.
The 3 infants suffered from IgE-mediated food allergy (wheat: 2 years 8 or 10 months old boy [threshold dose 25 g] and girl [0.7 g], hen's egg: 4 years 9 months old girl [1.8 g]), diagnosed, by food challenge, as allergy to wheat and egg. Then, the patients were treated with sSOTI either with hard-boiled egg or wheat noodle at home daily starting with 0.1 g, respectively, increased to a dose of 60 g egg or 100 g wheat, every one to 2 weeks in double dose of the weight, until tolerance was taken on. The daily maintenance dose was 10 g for each food. Four weeks later confirmed was evolution of tolerance by re-challenge. The safety and efficacy of the sSOTI therapy were confirmed in these infants. Total IgE levels were increased after SOTI therapy whereas IgE RAST value to causative antigen such as egg and wheat, contrastingly reduced. IgE RAST value to some other food as cow's milk, reduced coincidently by bystander inhibition. IgE RAST value to a food, negative in prick test, was increased again, whereas that to a food, positive in the test, was carried on.
The results indicates that sSOTI therapy induced causative antigen-specific IgE-mediated tolerance in children with wheat or egg allergy, and the set of total IgE increased, reduced IgE RAST value and positive prick test was of service to evaluate evolution of tolerance in slow SOTI therapy.
PMCID: PMC3512876
17.  The safety and efficacy of sublingual and oral immunotherapy for milk allergy 
Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.
We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow’s milk (CM) allergy.
We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG4 levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.
Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG4 levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.
OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.
PMCID: PMC3437605  PMID: 22130425
Food allergy; immunotherapy; milk allergy; basophil; spontaneous histamine release
18.  493 The Prevalence of Food Allergy in Children under 2 Years in Three Cities in China 
The World Allergy Organization Journal  2012;5(Suppl 2):S173-S174.
To estimate the prevalence and clinical features of food allergy in children aged 0 to 2 years.
From January to February, 2009 and January to May, 2010, all well-infants and young children between the age of 0-2 years attending routine health visits at the Department of Primary Child Care, in Chongqing, Zhuhai and Hangzhou were invited to participate the study. Parents completed questionnaires and all children were skin prick tested to a panel of 10 foods (egg white, egg yolk, cow milk, soybean, peanut, wheat, fish, shrimp, orange and carrot). Based on the results of SPT and medical history, the subjects should undergo the suspected food elimination and oral food challenge under medical supervision. Food allergy was confirmed by the food challenge test.
There were 1,687 children recruited by the consent of their parents. Of 1,687 children approached, 1,604 (550 for Chongqing, 573 for Zhuhai and 481 for Hangzhou) fulfilled the study criteria for diagnosing food allergy. 100 children were confirmed to have challenge-proven food allergy in 3 cities (40 for Chongqing, 33 for Zhuhai and 27 for Hangzhou). The prevalence of food allergy in 0 to 2 years old children in Chongqing was 7.3%, in Zhuhai was 5.8% and in Hangzhou was 5.5%. There was no significant difference in the prevalence of food allergy in children under 2 years among the 3 cities, and the average prevalence for food allergy in children under 2 years was 6.2%. Egg was the most common allergen, followed by cow milk.
The prevalence of food allergy in 0 to 2 years old children in China was 5.5% to 7.3%. There was no significant difference in the prevalence of food allergy in children under 2 years among the 3 cities. Egg was the most common allergen, followed by cow milk.
PMCID: PMC3512627
19.  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.
PMCID: PMC2904490  PMID: 20337976
cow’s milk protein allergy; hydrolysed rice protein formula; extensively hydrolysed cow’s milk protein formula
20.  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.
PMCID: PMC3372532  PMID: 22584194
21.  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.
PMCID: PMC3372532  PMID: 22584194
Anaphylaxis; baked egg challenge; egg allergy; food allergy; food challenge; IgE; ImmunoCap; ovomucoid; RAST; skin prick test
22.  Distinct parameters of the basophil activation test reflect the severity and threshold of allergic reactions to peanut 
The management of peanut allergy relies on allergen avoidance and epinephrine autoinjector for rescue treatment in patients at risk of anaphylaxis. Biomarkers of severity and threshold of allergic reactions to peanut could significantly improve the care for patients with peanut allergy.
We sought to assess the utility of the basophil activation test (BAT) to predict the severity and threshold of reactivity to peanut during oral food challenges (OFCs).
The severity of the allergic reaction and the threshold dose during OFCs to peanut were determined. Skin prick tests, measurements of specific IgE to peanut and its components, and BATs to peanut were performed on the day of the challenge.
Of the 124 children submitted to OFCs to peanut, 52 (median age, 5 years) reacted with clinical symptoms that ranged from mild oral symptoms to anaphylaxis. Severe reactions occurred in 41% of cases, and 57% reacted to 0.1 g or less of peanut protein. The ratio of the percentage of CD63+ basophils after stimulation with peanut and after stimulation with anti-IgE (CD63 peanut/anti-IgE) was independently associated with severity (P = .001), whereas the basophil allergen threshold sensitivity CD-sens (1/EC50 × 100, where EC50 is half maximal effective concentration) value was independently associated with the threshold (P = .020) of allergic reactions to peanut during OFCs. Patients with CD63 peanut/anti-IgE levels of 1.3 or greater had an increased risk of severe reactions (relative risk, 3.4; 95% CI, 1.8-6.2). Patients with a CD-sens value of 84 or greater had an increased risk of reacting to 0.1 g or less of peanut protein (relative risk, 1.9; 95% CI, 1.3-2.8).
Basophil reactivity is associated with severity and basophil sensitivity is associated with the threshold of allergic reactions to peanut. CD63 peanut/anti-IgE and CD-sens values can be used to estimate the severity and threshold of allergic reactions during OFCs.
PMCID: PMC4282725  PMID: 25567046
Basophil activation test; peanut; peanut allergy; threshold; severity; sensitivity; CD63; CD203c; CD-sens; double-blind; placebo-controlled food challenge; CD63 peanut/anti-IgE, Ratio of the percentage of CD63+ basophils at 100 ng/mL of peanut extract to the percentage of CD63+ basophils after stimulation with anti-IgE; CD-sens, Basophil allergen threshold sensitivity; DBPCPC, Double-blind, placebo-controlled peanut challenge; EC50, Half maximal effective concentration; LEAP, Learning Early About Peanut Allergy; PA, Peanut allergy; PE, Peanut extract; SPT, Skin prick test
23.  The natural history of milk allergy in an observational cohort 
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.
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.
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.
PMCID: PMC3691063  PMID: 23273958
Milk allergy; natural history; food allergy; IgE
24.  Cow’s milk allergy: evidence-based diagnosis and management for the practitioner 
European Journal of Pediatrics  2014;174:141-150.
This review summarizes current evidence and recommendations regarding cow’s milk allergy (CMA), the most common food allergy in young children, for the primary and secondary care providers. The diagnostic approach includes performing a medical history, physical examination, diagnostic elimination diets, skin prick tests, specific IgE measurements, and oral food challenges. Strict avoidance of the offending allergen is the only therapeutic option. Oral immunotherapy is being studied, but it is not yet recommended for routine clinical practice. For primary prevention of allergy, exclusive breastfeeding for at least 4 months and up to 6 months is desirable. Infants with a documented hereditary risk of allergy (i.e., an affected parent and/or sibling) who cannot be breastfed exclusively should receive a formula with confirmed reduced allergenicity, i.e., a partially or extensively hydrolyzed formula, as a means of preventing allergic reactions, primarily atopic dermatitis. Avoidance or delayed introduction of solid foods beyond 4–6 months for allergy prevention is not recommended.
Conclusion: For all of those involved in taking care of children’s health, it is important to understand the multifaceted aspects of CMA, such as its epidemiology, presentation, diagnosis, and dietary management, as well as its primary prevention.
PMCID: PMC4298661  PMID: 25257836
Allergy; Children; Infants; Pediatrics
25.  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.
PMCID: PMC3172651  PMID: 21935269
Milk; Food Hypersensitivity; Immunoglobulin E; Prognosis

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