Wheat-dependent exercise-induced anaphylaxis: subtypes, diagnosis, and management.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is an IgE-mediated food allergy with allergic symptoms ranging from intermittent urticaria to severe anaphylaxis that occurs when wheat ingestion is combined with augmenting cofactors such as exercise, non-steroidal anti-inflammatory drugs, or alcohol. In most cases, patients are identified by sensitization to ω5-gliadins in the gluten fraction of wheat. ω5-gliadin-negative subtypes of WDEIA are often difficult to diagnose and may be caused by Tri a 14 (wheat lipid transfer protein), after percutaneous sensitization with hydrolyzed wheat proteins, or, in rare cases, by cross-reactivity to grass pollen. Diagnosis is established based on the patients' history in combination with serum IgE profile, skin testing, basophil activation tests, and challenge tests with cofactors. Individual dietary counselling remains the central pillar in the management of WDEIA patients. A completely wheat-free diet is a possible option. However, this appears to promote tolerance less than continued regular consumption of gluten-containing cereals in the absence of cofactors. All patients should have an emergency set for self-treatment including an adrenaline autoinjector and receive adequate instruction. More data are needed on sublingual immunotherapy for WDEIA, a potentially promising therapeutic prospect. This article provides an overview of current knowledge on the diagnosis and management of WDEIA including an optimized challenge protocol using wheat gluten and cofactors.

[Cereal related complaints in children]. / Granengerelateerde klachten bij kinderen.

There's a lot of attention for gluten-free diets on social media. Doctors get many questions about gluten sensitivity or possible wheat allergy. With some basic knowledge, it's easier to give answers to these questions and to prevent unnecessary and sometimes harmful diets. This article gives basic information about cereals, gluten, grasses and their crossreactivity. We give an overview about the differences between celiac disease, gluten sensitivity and IgE-mediated wheat allergy. We also describe diagnostics, treatment and natural history of coeliakie, gluten sensitivity and wheat or cereal allergy.

Oral Wheat Immunotherapy: Long-Term Follow-Up in Children with Wheat Anaphylaxis.

INTRODUCTION: There has been substantial increase in food allergies in recent decades. The management of severe food allergy often includes strict avoidance and medical therapies. However, oral immunotherapy (OIT) is a promising treatment option for these patients, which is still being investigated. METHODS: The study recruited children from 2 years onward with a history of wheat anaphylaxis who had been referred to the Mofid Children Hospital. Wheat allergy was confirmed by a double-blind placebo-controlled food challenge. OIT was started to reach 5.28 g of wheat protein supplied in 60 g of bread. Besides immunologic measurements, a second and third oral food challenge (OFC) was performed after 3 months and 1 year of maintenance therapy to evaluate the long-term efficacy of wheat OIT (WOIT). RESULTS: Seventeen patients completed the 3-month maintenance phase; 8 of them demonstrated negative OFCs. All of the 9 with positive OFCs were asked to continue the daily consumption of 60 g of bread for another year. Three patients with positive OFCs were followed for 1 more year and were asked to continue eating 60 g of bread every other day. The serum level of wheat sIgE was significantly increased at the end of the buildup phase (p = 0.026) and dramatically dropped at the end of the maintenance phase (p = 0.022). CONCLUSION: To conclude, WOIT is an effective and safe modality of treatment if it is administered under strict supervision.

Slow low-dose oral immunotherapy: Threshold and immunological change.

BACKGROUND: We examined the feasibility, efficacy and safety of slow low-dose oral immunotherapy (SLOIT) for egg, milk, wheat allergies, with accepted severity-stratified initial and maintenance doses. METHODS: Children with food allergies defined by low-dose oral food challenges (LD-OFCs) to hen's egg (cumulative protein dose up to 983 mg, n = 133), cow's milk (287 mg, n = 50), and wheat (226 mg, n = 45) were recruited. Participants were divided into two groups [SLOIT and control (complete avoidance]) based on their preferences. Participants who selected SLOIT were instructed to take the safe dose daily, with monthly increases, aiming to increase the dose by 10 times in one year. The primary outcome was the proportion of participants who passed the LD-OFCs following 1 year of therapy. RESULTS: The participants in SLOIT group ingested their antigen 92.9% of the therapy's day on average. The proportion of participants who passed LD-OFCs was 35.9% (61/170) in the SLOIT group and 8.7% (4/46) in the control group (P < .001); no large differences were observed among allergens. Among the subjects who failed LD-OFCs, the median change in the total dose in the LD-OFC was 235% (interquartile range: 100%-512%) in the SLOIT group and 100% (42%-235%) in the control group (P < .001). Provoked allergic symptoms were observed in only 0.58% (280/48,486) per programmed intake and approximately 50% of the SLOIT group did not experience any obvious allergic symptoms throughout therapy. CONCLUSIONS: SLOIT showed significant feasibility, efficacy and safety, providing a promising option to manage patients with severe food allergies.

Induction of Oral Tolerance by Pepsin-Digested Gliadin Retaining T Cell Reactivity in a Mouse Model of Wheat Allergy.

BACKGROUND: Wheat is known as the most widely consumed food all over the world. Although many types of wheat allergy have been recognized, their treatment still has a long way to go due to the complex pathogenesis. Oral immunotherapy (OIT) is under investigation for the treatment of wheat allergies. Previous studies have demonstrated that OIT using intact wheat allergens can induce tolerance, but is accompanied by a high risk of anaphylactic reactions. OBJECTIVES: Our objective was to prepare modified wheat allergens with hypoallergenic and tolerance-inducing properties to reduce adverse effects during immunotherapy. METHODS: Wheat gliadin was degraded by hydrolysis with pepsin and trypsin, and then the hydrolysate was deamidated with hydrochloric acid. The IgE-binding capacity and T cell reactivity of the degraded gliadins were evaluated in vitro. Pepsin-digested gliadin (peptic-GLI) was applied in a mouse model to investigate whether it would induce oral tolerance. RESULTS: Degradation with pepsin decreased IgE-binding capacity and maintained T cell reactivity. Oral administration of peptic-GLI to mice before sensitization and challenge with gliadin could significantly suppress the production of IgE, IgG1, and type 2 T helper cytokines. Moreover, the development of anaphylactic reactions and allergic responses of the small intestine induced by gliadin challenge were inhibited by oral administration of peptic-GLI. CONCLUSIONS: The findings of this study indicate that peptic-GLI with low allergenicity and potential for tolerance induction may become useful in wheat immunotherapy with less adverse effects.

Low-dose-oral immunotherapy for children with wheat-induced anaphylaxis.

BACKGROUND: Oral immunotherapy (OIT) use in patients with wheat anaphylaxis is not well studied. We assessed the efficacy of low-dose OIT for patients with wheat-induced anaphylaxis. METHODS: Eligible subjects were aged 5-18 years with a history of wheat anaphylaxis and confirmed symptoms during oral food challenge (OFC) to 53 mg of wheat protein. After admission to the hospital for a 5-day buildup phase, patients in the OIT group gradually increased wheat ingestion to 53 mg/day and then ingested 53 mg daily at home. One year later, they underwent 53- and 400-mg OFCs after OIT cessation for 2 weeks. The historical control group was defined as patients who avoided wheat during the same period. RESULTS: Median wheat- and ω-5 gliadin-specific immunoglobulin E (sIgE) levels were 293 and 7.5 kUA /L, respectively, in the OIT group (16 children). No patients dropped out. Within 1 year, 88% of patients in the OIT group reached 53 mg. After 1 year, 69% and 9% patients passed the 53-mg OFC and 25% and 0% passed the 400-mg OFC in the OIT and control groups (11 children), respectively (P = .002 and 0.07, respectively). In the OIT group, wheat- and ω-5 gliadin-sIgE levels significantly decreased to 154 and 4.1 kUA /L, respectively, at 1 year, and wheat- and ω-5 gliadin-specific IgG and IgG4 levels significantly increased at 1 month. Anaphylaxis developed 7 times and promptly improved without adrenaline. CONCLUSION: For patients with wheat anaphylaxis, low-dose OIT safely induces immunologic changes, achieves low-dose desensitization, and may allow for a 400 mg dose.

Exercise-induced allergic reactions on desensitization to wheat after rush oral immunotherapy.

BACKGROUND: The effect of oral immunotherapy (OIT) on wheat allergy is promising in terms of the potential to obtain desensitization; however, the frequency of exercise-induced allergic reactions on desensitization (EIARDs) and the associated risk factors remain to be determined. METHODS: Twenty-five patients underwent rush OIT for wheat allergy, and 21 achieved the full-dose intake of wheat products (5 g of wheat protein). Exercise-provocation tests were repeatedly performed after the ingestion of a full-dose wheat product. The time-course of the levels of the specific IgEs (sIgE) to wheat extract, total gliadin, deamidated gliadin, recombinant gliadin components (α/ß-, γ- and ω-5-), and glutenin (high and low molecular weight) components was analyzed using ImmunoCAP® , ELISA, or IgE immunoblotting. RESULTS: Fourteen patients (66.7%) were diagnosed as EIARD+, which remained 5 years after rush OIT in 11 patients (52.4%). There were no differences in the clinical backgrounds of the EIARD+ and EIARD- patients. However, EIARD+ patients showed significantly higher sIgE levels to all gliadin and glutenin components than EIARD- patients before OIT. The sIgE levels to each component decreased equally after 1 and 2 years of OIT. On IgE immunoblotting, sera from all patients reacted to the multiple gluten bands, and some reacted to the water-soluble bands. The intensity of all IgE-reactive bands also became equally lighter after OIT. CONCLUSIONS: EIARDs were frequently observed and remained for a long period after successful OIT for wheat allergy. None of the specific wheat components were found to contribute to EIARDs.

Gluten-related disorders: Celiac disease, wheat allergy, and nonceliac gluten sensitivity.

The consumption of gluten-free products is becoming an increased alimentary habit in the general population. The scientific unfounded perception suggesting that the avoidance of gluten would improve health or that gluten could be toxic for humans are fostering medically unjustified adherences to a gluten-free diet. Currently, only patients diagnosed with celiac disease are advised to follow a strict lifelong gluten-free diet. In the same way, patients diagnosed with IgE-mediated wheat allergy must avoid exposure to wheat in any form. In that context, a third disorder, called nonceliac gluten sensitivity, characterized by distress after gluten consumption and in which neither celiac disease nor IgE-mediated allergy plays a role, has gained increased attention in the last years. Although important scientific advances have been made in the understanding of the pathologic mechanisms behind nonceliac gluten sensitivity, this disorder is still a matter of active debate in the scientific community. In the present review, the most recent advances in the immunopathology, diagnostic biomarkers and susceptibility determinants of gluten-related diseases are summarized and discussed. Furthermore, an updated overview of the new potential therapies that are currently underway for the treatment of gluten-related disorders is also provided.

Advances in Molecular Mechanisms of Wheat Allergenicity in Animal Models: A Comprehensive Review.

The prevalence of wheat allergy has reached significant levels in many countries. Therefore, wheat is a major global food safety and public health issue. Animal models serve as critical tools to advance the understanding of the mechanisms of wheat allergenicity to develop preventive and control methods. A comprehensive review on the molecular mechanisms of wheat allergenicity using animal models is unavailable at present. There were two major objectives of this study: To identify the lessons that animal models have taught us regarding the molecular mechanisms of wheat allergenicity and to identify the strengths, challenges, and future prospects of animal models in basic and applied wheat allergy research. Using the PubMed and Google Scholar databases, we retrieved and critically analyzed the relevant articles and excluded celiac disease and non-celiac gluten sensitivity. Our analysis shows that animal models can provide insight into the IgE epitope structure of wheat allergens, effects of detergents and other chemicals on wheat allergenicity, and the role of genetics, microbiome, and food processing in wheat allergy. Although animal models have inherent limitations, they are critical to advance knowledge on the molecular mechanisms of wheat allergenicity. They can also serve as highly useful pre-clinical testing tools to develop safer genetically modified wheat, hypoallergenic wheat products, novel pharmaceuticals, and vaccines.

Allergen immunotherapy for food allergy from the Asian perspective: key challenges and opportunities.

Introduction: Prevalence of food allergy is rising in different regions of the world. Asia has not been spared from this epidemic, but epidemiological data have revealed a different pattern of food allergens in this continent. Allergen-specific immunotherapy (AIT) for food allergy, which has been revolutionary as the main focus of research in recent years, needs to be adapted for the different populations in Asia. Areas covered: Recent evidence shows increasing popularity and superiority of AIT over strict food avoidance as the cornerstone of food allergy management. Asia is a distinctive continent with specific food allergy triggers, in particular, seafood, and wheat. Peanut, on the contrary, is not a common food allergen in most parts of Asia. The common Asian food allergens, as well as the rapidly developing food-specific AIT in this region will be covered in this article. Expert commentary: Evidence on oral immunotherapy for wheat allergy and preclinical data on shellfish AIT are promising. Further work should be done on resolving cross-sensitization between environmental allergens with wheat and shellfish allergens, and a modified AIT approach to enhance the safety and effectiveness of food-specific immunotherapy.

Multicenter, randomized, double-blind, placebo-controlled clinical trial of vital wheat gluten oral immunotherapy.

BACKGROUND: Wheat is a common food allergen that can cause anaphylaxis. OBJECTIVE: We sought to determine the efficacy and safety of vital wheat gluten (VWG) oral immunotherapy (OIT). METHODS: After baseline double-blind, placebo-controlled food challenge (DBPCFC), 46 patients with wheat allergy (median age, 8.7 years; range, 4.2-22.3 years) were randomized 1:1 to low-dose VWG OIT or placebo, with biweekly escalation to 1445 mg of wheat protein (WP). After a year 1 DBPCFC, active subjects continued low-dose VWG OIT for another year and underwent a year 2 DBPCFC and, if passed, a subsequent off-therapy DBPCFC. Placebo-treated subjects crossed over to high-dose VWG OIT (maximum, 2748 mg of WP). RESULTS: The median baseline successfully consumed dose (SCD) was 43 mg of WP in both groups. At year 1, 12 (52.2%) of 23 low-dose VWG OIT-treated and 0 (0%) of 23 placebo-treated subjects achieved the primary end point of an SCD of 4443 mg of WP or greater (P < .0001); median SCDs were 4443 and 143 mg, respectively. At year 2, 7 (30.4%) of 23 low-dose VWG OIT-treated subjects were desensitized to an SCD of 7443 mg of WP; 3 (13%) achieved sustained unresponsiveness 8 to 10 weeks off therapy. Among placebo-treated subjects who crossed over to high-dose VWG OIT, 12 (57.1%) of 21 were desensitized after 1 year (median SCD, 7443 mg of WP; nonsignificant vs low-dose VWG OIT). At year 1, skin prick test responses and wheat- and omega-5 gliadin-specific IgE levels did not differ between groups; the low-dose VWG OIT median specific IgG4 level was greater than placebo (wheat, P = .0005; omega-5 gliadin, P = .0001). Year 1 SCDs correlated with wheat-specific (rho = 0.55, P = .0003) and omega-5 gliadin-specific (rho = 0.51, P = .001) IgG4 levels in all subjects. Among 7822 low-dose VWG OIT doses in year 1, 15.4% were associated with adverse reactions: 0.04% were severe, and 0.08% subjects received epinephrine. Among 7921 placebo doses, 5.8% were associated with adverse reactions; none were severe. CONCLUSIONS: Low- and high-dose VWG OIT induced desensitization in about one half of the subjects after 1 year of treatment. Two years of low-dose VWG OIT resulted in 30% desensitization, and 13% had sustained unresponsiveness.

Oral Immunotherapy to Wheat in Allergic Asthmatic Female: A Case Report.

Wheat is the most commonly grown cereal. Immunological reaction to wheat may be IgE or T-cell- mediated. Asthma could be induced by inhaled flour or by exposure to allergens present in bakery products. In patients with IgE-mediated allergy to wheat proteins there is no specific therapy, except oral immunotherapy (OIT). There are few data regarding OIT with wheat protein in allergic patients. We present a case of a 32-yearold female patient, who worked for 5 years in wheat and bakery products industry, who developed an occupational asthma and chronic urticaria after flour inhalation or ingestion of foods that containit. The patient underwent wheat  OIT, that  was well-tolerated with no severe reaction during treatment. We may conclude that wheat OIT is a safe therapy and may induce symptoms improvement in allergic asthma and urticaria in patients with wheat allergy. Wheat OIT may induce tolerance to allergic patients.

One Child's Food Fight: A Case Study of Oral Immunotherapy Treatment for Food Allergies.

The prevalence of food allergy has risen dramatically in the last two decades. Primary care providers encounter food-allergic children on a daily basis. Although the standard of care has traditionally been strict avoidance of the allergen and advisement to carry an epinephrine autoinjector in case of an accidental exposure resulting in a severe reaction, food allergy research has progressed in the past decade concerning various immunotherapies that may provide an alternate treatment strategy. Oral immunotherapy (OIT), performed under the supervision of an allergist, is the most widely studied of these therapies. In the past, OIT has been available in the realm of clinical trials, but it is now being offered by a small but increasing number of allergists in private practice throughout the United States. Pediatric primary care clinicians should be aware of both the risks and possible benefits of this treatment, because they are likely to encounter patients who may inquire about OIT in their practices. In this case report, use of OIT will be reviewed in the treatment of a food-allergic child.

A Multicenter Evaluation of Diagnosis and Management of Omega-5 Gliadin Allergy (Also Known as Wheat-Dependent Exercise-Induced Anaphylaxis) in 132 Adults.

BACKGROUND: Omega-5 gliadin allergy (also known as wheat-dependent exercise-induced anaphylaxis) is a rare allergy to wheat that often presents with intermittent severe anaphylaxis in the context of a cofactor, such as exercise. OBJECTIVE: To undertake a detailed clinical characterization of the largest cohort of patients with omega-5 gliadin allergy to date. METHODS: We retrospectively analyzed the demographic characteristics, presentation, investigation, and management of 132 patients presenting with omega-5 gliadin allergy in 4 UK centers. RESULTS: There were significant delays in diagnosis of 1 to 5 years (40% of patients) and more than 5 years (29% of patients). The commonest cofactors were exercise (80%), alcohol (25%), and nonsteroidal anti-inflammatory drugs (9%). A minority of patients (11%) had no identifiable cofactor. The level of specific IgE to omega-5 gliadin does not predict the severity of allergic reactions. Patients who adhered to a gluten-free diet and those who avoided wheat in combination with exercise achieved the largest reductions in subsequent allergic reactions of 67% and 69%, respectively. CONCLUSION: Omega-5 gliadin allergy is a rare wheat allergy that presents with severe anaphylaxis. The diagnosis is frequently delayed, and therefore we recommend that all adult patients presenting with anaphylaxis of unclear cause should have omega-5 gliadin specific IgE tested. A gluten-free diet or avoidance of wheat-based meals in combination with exercise (if the cofactor is exercise) helps to significantly decrease the risk of future allergic reactions. However, antihistamines and an epinephrine autoinjector must always be prescribed because one-third of patients continue to have allergic reactions despite dietary advice.

Wheat oral immunotherapy was moderately successful but was associated with very frequent adverse events in children aged 6-18 years.

AIM: This study investigated oral immunotherapy (OIT) for children aged 6-18 years with wheat allergies. METHODS: Well-cooked wheat spaghetti was given to 100 children with wheat allergies every day for 17 weeks, increasing from 0.3 to 2000 mg of wheat protein, followed by three- and nine-month maintenance phases. Blood samples were taken before therapy and at follow-up visits. The study was carried out in 2009-2015 in four Finnish paediatric allergology units. RESULTS: The children (67% male) had a mean age of 11.6 years (range 6.1-18.6), and 57 were using wheat daily 16 months after the initiation of therapy. Allergic symptoms occurred in 94/100 children: mild in 34, moderate in 36 and severe in 24. Specific immunoglobulin E (IgE) for ω-5-gliadin was significantly higher in patients who did not reach the target dose and were related to the intensity of reactions. CONCLUSION: The majority (57%) of children with wheat allergies could use wheat in their daily diet 16 months after the initiation of OIT, but 94/100 had adverse reactions and 60 were moderate or severe. Specific IgE to ω-5-gliadin may provide a biomarker for how much wheat can be tolerated and the intensity of the reactions to immunotherapy.