Specific Oral Tolerance Induction Research Articles

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update – XIII – Oral immunotherapy for CMA – Systematic review

BackgroundAllergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. ObjectiveTo systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. MethodsWe searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). ResultsWe identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2–8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%–91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6–30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12–770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%–10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. ConclusionsModerate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Polymorphic Variants of Interleukin-13 R130Q and Interleukin-4 T589C in Children with and without Cow's Milk Allergy.

Cow’s milk allergy (CMA) is one of the most frequent types of food allergy. The aim of the study was to investigate whether IL-13 R130Q and IL-4 T589C polymorphisms are associated with the risk of CMA in young Ukrainian children. A total of 120 children (age range: 1–3 years) participated in the study and were divided into two groups: CMA (n = 60) and healthy controls (CNT, n = 60). The CMA group had two subgroups: specific oral tolerance induction (SOTI, n = 30) and milk elimination diet (MED, n = 30). The CNT group had two subgroups: positive family history of allergy (+FHA, n = 24) and negative family history of allergy (−FHA, n = 36). In the CMA group, molecular genetic testing of CC, CT, and TT genotypes of single nucleotide IL-4 T589C gene polymorphisms showed significantly higher rates of the CC genotype compared to healthy controls (92.2% vs. 58.8%; p < 0.01). In the CMA group, molecular genetic testing of GG, GA, and AA genotypes of single nucleotide IL-13 R130Q gene polymorphisms showed significantly higher rates of GA and AA polymorphic locus genotypes compared to healthy controls (43.5% vs. 22.4%, p < 0.05 and 8.7% vs. 0%, p < 0.05, respectively). In future studies, the genotypic and allelic distribution of these polymorphic variants will be determined in children with CMA and healthy children.

Life-threatening anaphylaxis in children with cow's milk allergy during oral immunotherapy and after treatment failure.

BackgroundOral immunotherapy (OIT) is a promising therapeutic approach for children with persistent IgE‐mediated cow's milk allergy (CMA) but data are still limited.ObjectiveTo analyze the prevalence of life‐threatening anaphylaxis in children with persistent CMA undergoing OIT and to evaluate potential risk factors.MethodsThis is a retrospective cohort study among children with persistent CMA undergoing OIT over a 20‐year period, following a specific Oral Tolerance Induction protocol. Adverse reactions during the whole period and data on long‐term outcome were registered. Descriptive and nondescriptive statistics were used to describe data.ResultsThree hundred forty‐two children were evaluated. During OIT, 12 children (3.5%) presented severe anaphylactic reactions that needed an adrenaline injection. None required intubation, intensive care unit (ICU) admission, or showed a fatal outcome. Five of them abandoned OIT, five reached unrestricted diet and the others are still undergoing OIT. As far as outcome is concerned, 51.2% reached an unrestricted diet; 13.5% are at the build‐up stage; and 28.0% (97 patients) stopped the OIT. Among these 96 children, 6.3% experienced a severe reaction induced by accidental ingestion of milk with two fatal outcomes.ConclusionsThe risk of life‐threatening reactions was nearly two times lower (3.5% vs. 6.3%) among patients assuming milk during OIT than in those who stopped the protocol. A trend in favor of more severe reactions, requiring ICU admission, or fatal, was shown in patients who stopped OIT.

ДІАГНОСТИЧНІ ПРЕДИКТОРИ ФОРМУВАННЯ ТОЛЕРАНТНОСТІ ПРИ ЕЛІМІНАЦІЙНІЙ ДІЄТІ У ДІТЕЙ З АЛЕРГІЄЮ ДО БІЛКІВ КОРОВ’ЯЧОГО МОЛОКА

Background. Cow's milk protein allergy is a topical issue in pediatrics. This disease affects 2-3% of young children. Methods. The study included 30 children with a confirmed cow’s milk protein allergy and a prescribed milk elimination diet. The children were observed for 36 months. The molecular profile was evaluated by detecting the major components of milk (Bos d 8, Bos d 5, Bos d 4), minor (Bos d 6), and cross-reactive with serum albumin (Fel d 2, Can f 3). Results. The study group included 46.7% of boys. The mean age of the subjects was 14.5±3.18 months. Nine of the 25 analyzed factors were identified in the course of our work by the method of logistic regression with progressive selection, which in combined action affect the formation of tolerance to cow's milk proteins in allergic children. There are three clinical examples of calculating the prediction of the complete tolerance development in the elimination diet in children with cow's milk protein allergy. Conclusions. Independent predictors that reduce the likelihood of the tolerance development in the elimination diet, have identified: skin test to milk, Bos d 8, Bos d 5, Bos d 4, Bos d 6. Independent predictors of the tolerance development in the elimination diet are: milk-specific IgE, total IgE, Fel d 2, Can f 3. Low probability of tolerance development by elimination therapy is a recommendation for prescribing treatment to a patient by specific oral tolerance induction.

A Case Study on the Specific Oral Tolerance Milk Induction in 2-YearOld Child

Cow’s milk allergy is the most common food allergies in toddlers. Therapeutic approach of cow’s milk allergy consists of eliminating milk and its derivatives from the diet or specific oral tolerance induction. Use of an elimination diet deprives children of the nutrients and minerals they need for harmonious physical development. Specific oral tolerance induction is an alternative treatment option to gradually expose children to the food that is causing the allergy and let their bodies adapt, so that children can still get the beneficial nutrients.

Wheat allergy – clinical implications and management

Grain allergies are common food allergies, that are typically but not only seen in individuals with other associated food allergies. The immunologic responses to grain proteins can be IgE and/or non-IgE mediated. Wheat allergy is the most common of the cereal grain allergies. It usually begins in early childhood and is outgrown by adolescence, although some retain it beyond the teenage years. Immunoglobulin E (IgE)-mediated wheat allergy is reported to affect 0.2 to 1.3 percent of children in Europe and 0.4 percent of children in the United States. The onset of wheat allergy in adulthood is typically not seen, unless it is related to an occupational exposure. Epidemiologic data for the other grains is largely missing. Immunoglobulin E (IgE)-mediated food-triggered reactions generally occur immediately, within minutes to two hours after ingestion. These reactions can present with skin, oropharyngeal, upper and lower respiratory tract, gastrointestinal tract, and/or cardiovascular signs and symptoms. The reactions can vary from mild cutaneous reactions to life-threatening anaphylaxis. Positive diagnose is based on determining the plasmatic level of specific IgE and performing skin prick test for wheat, methods that have poor specificity and sensitivity in predicting oral food challenge test outcomes. The gold standard test remains oral food challenge (OFC) test for wheat. Most of the studies have proven its utility, even in children with high levels of wheat specific IgE. The diagnose of non-IgE mediated reactions is based on clinical presentation and plasmatic levels of specific antibodies, other than IgE. The management of grain allergy does not differ from that of other food allergies. It requires instructions on avoidance and treatment of reactions in the event of accidental exposure. It includes education about grain alternatives. It also includes monitoring for nutritional issues and for the resolution of the allergy. Preliminary data on specific oral tolerance induction to wheat through oral desensitization protocols have shown some promise in children, but it is still considered an experimental therapy.

Specific oral immunotherapy in food allergic patients: transient or persistent tolerance?

IntroductionThe first therapeutic choice for food allergy is avoidance of the responsible food, but when this approach is not possible, specific oral desensitization could be considered as a good alternative. It is not clear yet whether the acquired tolerance is transient or persistent.AimWe report on a subset of 13 patients of a larger study, treated successfully with specific oral tolerance induction who experienced secondary loss of tolerance after a period of allergen avoidance.Material and methodsThirteen patients affected by IgE-mediated food allergy: to cow milk (3 patients), to hen egg (3 patients), to cod fish (2 patients), to peanuts (1 patient) and to corn (1 patient) confirmed by a complete allergological workup and a double-blind placebo-controlled food challenge (DBPCFC), were treated with sublingual-oral desensitization. After the interruption of the maintenance phase, the laboratory tests were performed and 12 of 13 patients underwent DBPCFC.ResultsOral specific desensitization was completed successfully in all the 13 reported patients. At different times after the end of treatment, they decided, on their own initiative, to stop the ingestion of incriminated food. A new food allergen re-exposure caused adverse reactions in 12 of 13 patients. The detection of specific IgE and IgG4 during the period of allergen avoidance showed an increase in or a stable level of specific IgE and a decrease in specific IgG4 in 8 patients.ConclusionsAccording to our experience, the tolerance obtained through the desensitizing treatment is transient and so the regular allergen intake is necessary for its maintenance.

Immunological Changes in Specific Oral Tolerance Induction for Cow's Milk Allergy

Immunological Changes in Specific Oral Tolerance Induction for Cow's Milk Allergy

Specific oral tolerance induction in childhood.

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

Dietary n-3 long chain polyunsaturated fatty acids in allergy prevention and asthma treatment

The rise in non-communicable diseases, such as allergies, in westernized countries links to changes in lifestyle and diet. N-3 long chain polyunsaturated fatty acids (LCPUFA) present in marine oils facilitate a favorable milieu for immune maturation and may contribute to allergy prevention. N-3 LCPUFA can suppress innate and adaptive immune activation and induce epigenetic changes. Murine studies convincingly show protective effects of fish oil, a source of n-3 LCPUFA, in food allergy and asthma models. Observational studies in human indicate that high dietary intake of n-3 LCPUFA and low intake of n-6 PUFA may protect against the development of allergic disease early in life. High n-6 PUFA intake is also associated with an increased asthma risk while n-3 LCPUFA may be protective and reduce symptoms. The quality of the marine oil used has impact on efficacy of allergy prevention and several observations link in particular n-3 LCPUFA DHA to allergy suppression. Randomized controlled trials indicate that optimal timing, duration and dosage of n-3 LC-PUFA is required to exert an allergy protective effect. Supplementation during early pregnancy and lactation has shown promising results regarding allergy prevention. However these findings should be confirmed in a larger cohort. Although clinical trials in asthma patients reveal no consistent clinical benefits of n-3 LCPUFA supplementation on lung function, it can suppress airway inflammation. Future food-pharma approaches may reveal whether adjunct therapy with dietary n-3 LCPUFA can improve allergy prevention or immunotherapy via support of allergen specific oral tolerance induction or contribute to the efficacy of drug therapy for asthma patients.

English

To assess modifications in baseline specific IgE- and anti-IgE- and antigen-specific-mediated basophil activation in egg-allergic children. The values were compared before and after the children completed specific oral tolerance induction (SOTI) with egg. We studied 28 egg-allergic children who completed SOTI with egg. The basophil activation test and specific IgE determinations with egg white, ovalbumin, and ovomucoid were performed in all 28 children. A decrease in antigen-specific activation with egg white, ovalbumin, and ovomucoid was observed only at the 2 lowest concentrations used (5 and 0.05 ng/mL). Baseline activation was higher in patients with multiple food allergies and in those who developed anaphylaxis during SOTI; this activation decreased in both groups after completion of SOTI. A significant decrease was also observed in specific IgE values for egg white, ovalbumin, and ovomucoid after tolerance induction. Food tolerance induction is a specific process for each food that can be mediated by immunologic changes such as a decrease in specific IgE values and in specific and spontaneous basophil activation.

Safety and effectiveness of specific oral tolerance induction to cow's milk

Results In 23 patients we started a standard cluster protocol using unheated CM (UCM) oral ingestion of increasing doses, always in a hospital setting, until reaching the target dose of 200 mL/day. In 2 cases, SOTI was performed with baked milk (BM). Among 23 who started SOTI with UCM, 12 completed the protocol successfully, 7 are still ongoing, 2 were changed to BM and in 3 patients SOTI failed to improve the condition, for a variety of reasons, including unresponsive gastric pain (2) and de novo diagnosis of eosinophilic esophagitis (1). Of the 4 patients who started or were changed to BM, 2 ended the protocol with (complete or partial) success, one is still ongoing and the last one was not able to progress beyond 0.5 mL. In summary, SOTI were completed with success in 14 patients (56%) 12 with UCM and 2 with BM, and failed to improve the condition in 4 cases 3 with UCM and 1 with BM. In 7 patients the protocol is still ongoing 6 with UCM and 1 with BM. There were adverse reactions in 80% of cases, 3 of which with severe reactions (anaphylaxis), always in the induction phase.

Diagnosis and treatment of pediatric food allergy: an update.

The prevalence of pediatric food allergy and anaphylaxis has increased in the last decades, especially in westernized countries where this emerging phenomenon was marked as a “second wave” of the allergic epidemic. Over recent years great advances have been achieved in the field of in vitro allergy testing and component-resolved diagnosis has increasingly entered clinical practice. Testing for allergen components can contribute to a more precise diagnosis by discriminating primary from cross-reactive sensitizations and assessing the risk of severe allergic reactions.The basic concept of the management of food allergy in children is also changing. Avoidance of the offending food is still the mainstay for disease management, especially in primary health care settings, but it severely affects the patients’ quality of life without reducing the risk of accidental allergic reactions. There is a growing body of evidence to show that specific oral tolerance induction can represent a promising treatment option for food allergic patients. In parallel, education of food allergic patients and their caregivers as well as physicians about anaphylaxis and its treatment is becoming recognized a fundamental need. International guidelines have recently integrated these new evidences and their broad application all over Europe represents the new challenge for food allergy specialists.

Severe Food Allergy to Cow's Milk Treated with Oral Immunotherapy Along with Omalizumab

E S D A Y 842 Successful Specific Oral Tolerance Induction with Hake in an Allergic Child Detecting Fish in Cooking Steam Carmen M. Damelio, MD; Departament of Allergy Clinica Universidad de Navarra, PAMPLONA, Spain. RATIONALE: To describe a specific oral tolerance induction (SOTI) protocol with hake in a child suffering urticaria/angioedema upon fish cooking steam exposure. METHODS: A 6-year old girl who presented at 9 month of age acute urticaria after eating different types of fish (i.e. hake, sole). Skin prick test rendered positive results and since then she avoided fish. Subsequently she suffered several acute urticaria episodes after accidental intakes and even when exposed to tuna fish cooking steam. Comorbidities: mild and controlled atopic dermatitis, no bronchial asthma. A SOTI protocol was decided to apply. Sensitization was evaluated by Prick-to-prick (T1), specific IgE (sIgE) and IgG4 (sIgG4) to hake during the induction phase (T2) and when finalized (T3). SOTI to hake was performed using frozen hake loin, starting with lyophilized hake and when 20gr. were tolerated, we used cooked hake until reaching 40gr. RESULTS: The induction phase of the SOTI lasted 11 months until 40gr of hake were reached suffering one anaphylaxis, related to an infectious process and 5 episodes of abdominal pain requiring antihistamines in only 2 of them. After one month in maintenance-phase, eating 40gr of hake daily without reactions, she tolerated 50gr of bass, 50gr. of tuna, 50gr. of monkfish uneventfully. No atopic dermatitis exacerbation was observed. sIgE against hake (T1:3.31kUA/L; T2: 3.98kUA/L; T3: 2.02kUA/L) and wheal size for hake prick-to-prick (T1: 13x11mm; T2: 10x6mm; T3: 7x5mm) decreased during induction phase whereas hake sIgG4 levels increased (T2: 12.7kU/L, T3: 39.2kU/L). CONCLUSIONS: In our case, SOTI with hake induces tolerance to bass, tuna and monkfish.

Safety of Specific Oral Tolerance Induction (SOTI) with Partially Hydrolyzed Cereals in Correlation to Wheat-Protein IgE

A major drawback of specific oral tolerance induction (SOTI) using standard food products is the possibility of severe side effects. The purpose of this study was to correlate safety of SOTI using partially hydrolyzed Cereals (pHC) in children diagnosed for IgE-mediated allergy to wheat with specific IgE titers to various wheat proteins.

Successful Specific Oral Tolerance Induction with Hake in an Allergic Child Detecting Fish in Cooking Steam

Successful Specific Oral Tolerance Induction with Hake in an Allergic Child Detecting Fish in Cooking Steam

Reintroduction of Cow’s Milk in Milk-Allergic Children

Even though cow's milk protein allergy (CMPA) is one of the most common food allergies in childhood, its prognosis is generally good and cow's milk (CM) is usually reintroduced in the patient's diet. The natural history of CMPA shows heterogeneity and is closely related to the immunological and clinical phenotype by which CMPA presents. Children with non-IgE-mediated CMPA tend to develop tolerance at an earlier age and at a higher percentage compared to those with IgE-mediated disease. In subjects with severe symptoms CMPA may persist for longer or ever. Although, the majority of children will outgrow their allergy, the individual timing of tolerance acquisition is largely unknown. Most of the current guidelines on the diagnosis and management of CMPA suggest reevaluation of milk-allergic children every 6-12 months, and reintroduction of CM after a negative Oral Food Challenge (OFC). However, OFC procedure is time consuming, expensive and not without risk. Clinical variables and the measurements of sIgE levels and SPT wheal sizes to crude (whole) CM protein and individual milk protein components may provide some useful prognostic information in the course of CMPA. However, no clear-cut clinical or laboratory criteria exist to predict which children and at what age are more likely to pass a repeat (reintroduction) OFC. The identification of factors that could accurately predict the outcome of reintroduction OFC and the timing of tolerance development would be extremely useful in daily clinical practice. Until recently, reintroduction of CM was commonly attempted when children with CMPA were more likely to have become tolerant. Over the last years, a different approach in the management of milk and egg allergy has emerged with specific oral tolerance induction (SOTI) as a promising method for the treatment of food allergies. Furthermore, a number of studies have shown evidence that introduction of heated milk and egg protein into the diet of allergic patients may induce the acquisition of tolerance. Still, the question of when and how to reintroduce cow's milk in milk-allergic children remains challenging and further research in this important field is necessary to provide both clinicians and anxious parents with the desirable answer.

Cow’s Milk Allergy in Children, from Avoidance to Tolerance

Food allergy is the primary cause of anaphylaxis in paediatric age affecting roughly 4% of children and their families worldwide, and requiring changes in dietary habits. The prognosis for food allergy in children has traditionally been regarded as good for the most frequent allergens, however the prognosis for cow's milk allergy in the pediatric age is currently considered to be worse than previously believed. There is now enough evidence that measures of avoidance for children at risk did not have any preventive effect whatsoever, but they still came to be counterproductive by avoiding the physiological interaction between food allergens and gastrointestinal mucosal immune system. Programs of specific oral tolerance induction (SOTI) have obtained interesting results in the treatment of food allergy supporting the idea that antigen exposure through gastrointestinal section is important to allow the development of tolerance. Nevertheless this approach is not yet considered "ready" for community recommendations. In this paper we describe our experience in the field of SOTI in children with cow's milk allergy.

Food Dependent Exercise Induced Anaphylaxis Treatment With Specific Oral Tolerance Induction Using IFN-Gamma

Food dependent exercise induced anaphylaxis (FDEIA) was induced by exercise within three or four hours after ingestion of specific allergenic foods. There is no specific treatment method. The avoidance of allergenic food with exercise is the only way to treat the FEDIA.

母乳中の鶏卵アレルゲンの存在形態と生物学的役割

Recently, the focus of allergy treatment has changed from prevention to tolerance induction, and hyposensitization using Specific Oral Tolerance Induction (SOTI) for food allergy and SubLingual ImmunoTherapy (SLIT) for hay fever have been attracting attention. We found that food proteins ingested maternally exist as IgA immune complexes in breast milk, thereby inducing oral tolerance in the offspring. Breast milk is typically the first meal for humans, and may thus represent the first natural drinkable vaccination against food allergens for babies. In this report, evidence supporting this hypothesis and recent knowledge regarding its application are reviewed. We hope that this report will stimulate the re-evaluation of breast-feeding based on the mammalian origin.