Exercise-induced Anaphylaxis Research Articles

Alpha/Beta Gliadin MM1 Is a Novel Antigen for Wheat-Dependent Exercise-Induced Anaphylaxis

Introduction: Screening for ω-5 gliadin specific IgE antibody (sIgE) has high diagnostic utility in cases of suspected wheat-dependent exercise-induced anaphylaxis (WDEIA); however, negative cases may require confirmatory tests, such as the oral challenge test. Thus, newly identified allergens that can be used for the serological diagnosis of WDEIA are needed. This study aimed to identify additional sIgE biomarkers of WDEIA. Methods: Forty-two patients with WDEIA (5 negative/37 positive for ω-5 gliadin sIgE) were enrolled. For comparison, 8 patients with immediate-type wheat allergy without WDEIA and 20 healthy controls without wheat allergy were also enrolled. Extracted wheat proteins were separated by 2D-PAGE. Proteins that reacted with serum IgE antibody in 2D Western blotting (2D-WB) were identified using mass spectrometry. Recombinant proteins were synthesized in Escherichia coli, and the antigenicity was tested using ELISA and the basophil activation test. Results: In 2D-WB, nine proteins reacted with the serum IgE antibody from at least 60% of patients with WDEIA (n ≥ 25/42). ELISA revealed that alpha/beta gliadin MM1 exhibited the highest positive immunoreactivity in 23 of 26 patients who were positive for ω-5 gliadin sIgE (88%) and in 5 of 5 patients who were negative for ω-5 gliadin sIgE (100%). Alpha/beta gliadin MM1 exhibited significantly higher basophil activation in 14 patients with WDEIA when compared to 5 individuals without a wheat allergy. Conclusions: Alpha/beta gliadin MM1 sIgE exhibited the highest seropositivity, even among patients who were negative for ω-5 gliadin sIgE. The inclusion of alpha/beta gliadin MM1 in allergen-sIgE tests may improve the sensitivity for diagnosing WDEIA.

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.

Chapter 13, Food-Dependent Exercise-Induced Anaphylaxis (FDEIA)

本稿では2021年に発行された食物アレルギー診療ガイドラインにおける食物依存性運動誘発アナフィラキシー（food-dependent exercise-induced anaphylaxis，FDEIA）のセクションに関して，2016年ガイドラインの記載内容からの主な変更点について解説する．

Revisiting the Definition of Anaphylaxis.

Anaphylaxis is a common phenomenon that has been studied for many decades. Despite this, there is still disagreement among organizations regarding the precise definition for anaphylaxis. This article discusses the difference between the proposed definitions of anaphylaxis. Furthermore, the most up-to-date literature on specific subtypes of anaphylaxis is reviewed, and implications for clinical practice are discussed. Recent literature on various subtypes of anaphylaxis has been conducted. This has helped clarify guidelines for conditions such as allergy to radiocontrast media, idiopathic anaphylaxis, and food-dependent exercise-induced anaphylaxis. Recent literature has also studied available biomarkers for anaphylaxis and the cost-effectiveness of current standard-of-care prescription of epinephrine autoinjectors. Anaphylaxis is an increasingly more frequent phenomenon and remains a hot topic in current research. Much progress has been made in clarifying the definition of anaphylaxis and differentiating between subtypes, but more research is needed to identify a readily available biomarker for anaphylaxis and identify the standard of care for various subtypes of anaphylaxis.

Anaphylaxie induite par l’exercice après consommation de viandes : implication de l’alpha 1-3 galactose

We present the case of a 74-year-old patient diagnosed with exercised-induced anaphylaxis after meat consumption and alpha 1-3 galactose involvement. Food-dependent exercise-induced anaphylaxis represents about 5% of anaphylaxis [1]. In this case, the patient made an effort following a meal containing meat, then presented urticaria and respiratory discomfort. The skin tests were positives for pork and pork kidney. Anti-alpha 1-3 galactose IgE were strongly positive, involving this allergen. Eviction of meat before physical effort allowed any recurrence.

The advances of allergen component detection in IgE-mediated food allergy

There are many types in food allergy, and the most common is mediated by IgE. Currently, the diagnosis of food allergy mainly relied on skin prick test and serum specific IgE of allergen extract, which can not identify cross-sensitization. Component-resolved diagnosis (CRD) can identify the major allergen components and cross-components of food allergens, which plays an important role in dietary guidance, prognosis monitoring and diagnosis of special types of IgE-mediated food allergy. This article enumerates clinical characteristics of the IgE-mediated common food allergies, such as milk, egg and seafood allergy, and special type of food allergy, such as cat pork syndrome, oral allergy syndrome, α-gal syndrome and food-dependent exercise-induced anaphylaxis, summarizes the advances of CRD in these types of IgE-mediated food allergy, in order to provide an evidence for the diagnosis, treatment and prevention of IgE-mediated food allergy.

Toward reducing the immunogenic potential of wheat flour: identification and characterization of wheat lines missing omega-5 gliadins encoded by the 1D chromosome.

Eleven wheat lines that are missing genes for the 1D-encoded omega-5 gliadins will facilitate breeding efforts to reduce the immunogenic potential of wheat flour for patients susceptible to wheat allergy. Efforts to reduce the levels of allergens in wheat flour that cause wheat-dependent exercise-induced anaphylaxis are complicated by the presence of genes encoding omega-5 gliadins on both chromosomes 1B and 1D of hexaploid wheat. In this study, we screened 665 wheat germplasm samples using gene specific DNA markers for omega-5 gliadins encoded by the genes on 1D chromosome that were obtained from the reference wheat Chinese Spring. Eleven wheat lines missing the PCR product corresponding to 1D omega-5 gliadin gene sequences were identified. Two of the lines contained the 1BL·1RS translocation. Relative quantification of gene copy numbers by qPCR revealed that copy numbers of 1D omega-5 gliadins in the other nine lines were comparable to those in 1D null lines of Chinese Spring, while copy numbers of 1B omega-5 gliadins were like those of Chinese Spring. 2-D immunoblot analysis of total flour proteins from the selected lines using a specific monoclonal antibody against the N-terminal sequence of omega-5 gliadin showed no reactivity in regions of the blots containing previously identified 1D omega-5 gliadins. Interestingly, RP-UPLC analysis of the gliadin fractions of the selected lines indicated that the expression of omega-1,2 gliadins was also significantly reduced in seven of the lines, implying that 1D omega-5 gliadin and 1D omega-1,2 gliadin genes are tightly linked on the Gli-D1 loci of chromosome 1D. Wheat lines missing the omega-5 gliadins encoded by the genes on 1D chromosome should be useful in future breeding efforts to reduce the immunogenic potential of wheat flour.

A Narrative Mini Review on Current Status of Hypoallergenic Wheat Development for IgE-Mediated Wheat Allergy, Wheat-Dependent Exercise-Induced Anaphylaxis

Immunoglobulin E (IgE)-mediated food allergies to wheat that develop after school age typically shows a type of wheat-dependent exercise-induced anaphylaxis (WDEIA). At present, avoidance of wheat products or postprandial rest after ingesting wheat is recommended for patients with WDEIA, depending on the severity of the allergy symptoms. ω5-Gliadin has been identified as the major allergen in WDEIA. In addition, α/β-, γ-, and ω1,2-gliadins, high and low molecular weight-glutenins, and a few water-soluble wheat proteins have been identified as IgE-binding allergens in a small proportion of patients with IgE-mediated wheat allergies. A variety of approaches have been manufactured to develop hypoallergenic wheat products that can be consumed by patients with IgE-mediated wheat allergies. In order to analyze such approaches, and to contribute to the further improvement, this study outlined the current status of these hypoallergenic wheat productions, including wheat lines with a reduced allergenicity that are mostly constructed for the patients sensitized to ω5-gliadin, hypoallergenic wheat by enzymic degradation/ion exchanger deamidation, and hypoallergenic wheat by thioredoxin treatment. The wheat products obtained by these approaches significantly reduced the reactivity of Serum IgE in wheat-allergic patients. However, either these were not effective on some populations of the patients, or low-level IgE-reactivity to some allergens of the products was observed in the patients. These results highlight some of the difficulties faced in creating hypoallergenic wheat products or hypoallergenic wheat lines through either traditional breeding or biotechnology approaches in developing hypoallergenic wheat completely safe for all the patients allergic to wheat.

Food-dependent exercise-induced anaphylaxis to orange, with possible underlying thaumatin-like protein allergy

Food-dependent exercise-induced anaphylaxis to orange, with possible underlying thaumatin-like protein allergy

Prospects for the treatment of gluten-associated diseases: on our daily bread, celiac disease, gluten proteins and more…

Food safety all over the world is largely dependent on production of grains that are cultivated in 60% of agricultural lands. Wheat is the main food for millions of people and one of the three most commonly cultivated grain cultures worldwide, along with corn and rice. Modern wheat is a product of gene engineering interventions aimed at increased productivity, yields, nutrient quota, and storage time, as well as immunogenic properties. However, the consumption of gluten, a proline and glutamine-rich wheat, rye and barley protein, triggers gluten-dependent disorders, such as celiac disease, wheat allergy, baker's asthma and wheat-dependent exercise-induced anaphylaxis. This group of disorders are curable provided the correct diagnosis has been made and strict lifelong gluten-free diet is implemented. Continuous patient's adherence to the gluten-free diet is associated with a number of medical and paramedical challenges, and the adherence level of the most compliant patients does not exceed 80%. The paper discuss other treatment strategies to improve the nutrition of people with gluten-sensitive disorders, in particular, the reduction grain gluten content, gluten sequestration in the gut before its digestion, prevention of gluten absorption and subsequent immune cell activation, and administration of tissue transglutaminase 2 inhibitors.

Efficacy and safety of omalizumab in adult patients with wheat-dependent exercise-induced anaphylaxis: Reduction of in vitro basophil activation and allergic reaction to wheat

BackgroundIn patients with wheat-dependent exercise-induced anaphylaxis (WDEIA), anaphylactic shock occurs frequently, therefore avoidance of wheat products is recommended. We aimed to evaluate efficacy and safety of long-term omalizumab treatment for adult patients with WDEIA. MethodsIn this phase 2, multicentre single-arm trial, 20 adult patients with WDEIA were enrolled (UMIN 000019250). All patients were administered 150–600 mg of omalizumab subcutaneously and evaluations (basophil activation and blood examination) were performed at regular intervals during administration period (0–48 weeks) and observation period (48–68 weeks). Primary endpoint was proportion of the patients who achieved a basophil activation rate below 10% with fractionated wheat preparations, and secondary endpoint was proportion of the patients with no allergic reactions after wheat products ingestion. ResultsDuring the omalizumab treatment, more than 80% of the patients achieved the basophil activation rate less than 10% against all fractionated wheat preparations, and 68.8% of the patients who achieved the primary endpoint experienced no allergic reaction. During the observation period, the proportion of the patients who achieved a basophil activation rate below 10% decreased gradually, and the proportion of patients with positive allergic reactions increased gradually thereafter and reached maximum of 46.7%. Severe adverse events were not observed during the study. ConclusionsLong-term omalizumab treatment is safe and effective for adult patients with WDEIA when assessed by basophil activation rate with wheat allergens as well as allergic reactions after lifting of restrictions on wheat intake. However, this is not enough to achieve desensitization.

Dupilumab for Treatment of Food-Dependent, Exercise-Induced Anaphylaxis: Report of One Case

Food-dependent, exercise-induced anaphylaxis (FDEIA) is a potentially life-threatening disorder that often occurs with exercise, and patients typically have eaten a specific food within hours before disease onset. This disease is exceedingly rare, with a prevalence of 0.02%. No well-recognized prevention or treatment strategy has been available for FDEIA except avoiding triggers strictly. Here we report an 11-year-old boy with a history of recurrent anaphylaxis of unknown etiology more than 10 times within two years. As the anaphylactic symptoms had not been controlled after traditional treatments, the patient was given subcutaneous injection of dupilumab seven times within 33 weeks. During dupilumab treatments, the patient was exposed to culprit mushrooms plus exercises at least twice a month but without notable anaphylaxis. Thus, dupilumab may improve the allergic reactions in FDEIA patients.

Food allergy

Food allergy is one of the adverse food reactions, which is developed by immunological reactions. Food allergy is increasing in prevalence among children and adults. In the diagnosis, food challenge is confirmative with history and laboratory tests. Avoidance of culprit food is the only preventive method, especially in patients with severe symptoms. In some food allergies, crossreactivity among allergens should be considered. Latex-fruit/vegetable syndrome and pollen food allergy syndrome are well-understood phenotypes of food allergy related to cross reaction. Red meat allergy is recently described as one of tick-borne diseases. In a rare phenotype of food-dependent exercise-induced anaphylaxis, factors affecting the absorption of food allergen are important in its pathophysiology.

Current situation of anaphylaxis in Japan: Data from the anaphylaxis registry of training and teaching facilities certified by the Japanese Society of Allergology – secondary publication

BackgroundAnaphylaxis is a potentially fatal severe systemic hypersensitivity reaction that causes symptoms in multiple organs such as the skin, respiratory tract, and gastrointestinal tract; however, no nationwide epidemiological survey on anaphylaxis has been conducted in Japan. This survey aimed to elucidate the triggers and treatment of anaphylaxis in Japan. MethodsBetween February 2015 and October 2017, we prospectively collected clinical data on the triggers and treatment of patients who developed anaphylaxis or were admitted to the emergency room with anaphylaxis in the training and teaching facilities of the Japanese Society of Allergology. ResultsThis study included 79 of the 451 affiliated facilities (18%), and a total of 767 patients were enrolled; 73% of them were aged <18 years and 7% had in-hospital triggers. The most common triggers were food (68%), drugs (12%), food-dependent exercise-induced anaphylaxis (5%), insects (4%), and oral immunotherapy (3%), with drugs being the most common in-hospital trigger and food being the most common out-of-hospital trigger. Intramuscular injection of adrenaline was administered therapeutically to 38% of the patients, with 10% requiring multiple doses. Adrenaline auto-injectors were used in 12% of out-of-hospital patients. ConclusionsThe present survey revealed the most common triggers and treatments for anaphylaxis in Japan. Self-management and adrenaline administration as first-line treatment may not be done sufficiently. Therefore, it is necessary to thoroughly educate and train patients and physicians about anaphylaxis.

Idiopathic Anaphylaxis? Analysis of Data from the Anaphylaxis Registry for West Pomerania Province, Poland.

The most common causes of anaphylaxis, according to various authors and depending on the age of the studied groups, are: Hymenoptera venom, food, and medications. Unfortunately, we are not always able to indicate the cause of anaphylaxis. There are data in the literature where as many as 41% of all cases are idiopathic anaphylaxis. Since the introduction of new diagnostic methods such as molecular diagnostics (MD) in our centre, the percentage of idiopathic anaphylaxis in the Anaphylaxis Register has significantly decreased. The purpose of this study was to identify possible causes of idiopathic anaphylaxis in patients with a history of moderate to severe anaphylactic reactions. After using MD, the causative agent was found in another 29 people. The proportion of people with idiopathic anaphylaxis in the Registry decreased from 9.2% to 3.5%. There were no significant differences in the incidence, although men appear to be slightly more common in primary idiopathic anaphylaxis. The mean age of primary idiopathic anaphylaxis was 40 years, but this was as high as 51 for anaphylaxis with alpha-gal allergy. Exercise may or may not be present as a cofactor despite its established role, e.g., in wheat-dependent exercise-induced anaphylaxis (WDEIA). In most of the analyzed cases, i.e., 70%, the reaction took place within an hour. The longest time interval from exposure to the development of symptoms is in the case of alpha-gal allergy; in this analysis, it was at least 5 h after ingestion of the so-called "red meat". Patients are not aware of the disease, or further attacks cannot be prevented. As many as 80% had idiopathic anaphylaxis prior to visiting the centre, and 80% developed anaphylaxis after visiting the centre, which emphasizes the need to not stop the medical team in their search for the causes. As many as 93% of cases required medical intervention, of which adrenaline was used only in 34.5%, antihistamines in 86%, systemic glucocorticosteroids (sCS) in 75%, and fluids in 62% of cases. A total of 83% of patients received an emergency kit for self-administration. Idiopathic anaphylaxis can be resolved as known-cause anaphylaxis after a thorough medical history and, if possible, without exposing the patient after using appropriate, modern in vitro diagnostic methods, including molecular diagnostics. The diagnosis of idiopathic anaphylaxis should extend the diagnosis to include alpha-gal syndrome, LTP syndrome and WDEIA.

A Case of Food-dependent Exercise-induced Anaphylaxis Diagnosed by Provocation Test with Spear Squid After the Pretreatment with Asprin

16 歳，男性。夕食時にヤリイカを含む寿司を摂取した約 1 時間後，歩行帰宅途中に眼瞼浮腫，全身に蕁麻疹が出現した。前医を受診し，収縮期血圧低下を認めアナフィラキシーショックと診断され加療された。食物アレルギー精査目的に当科に紹介受診となり，食物依存性運動誘発アナフィラキシー（fooddependent exercise-induced anaphylaxis：FDEIA）を疑い精査を行った。イカを含む数種の魚介類の特異的 IgE 抗体が陽性であった。Prick-prick test ではヤリイカのみ陽性となった。ヤリイカを原因食物として疑い，入院下で運動負荷誘発試験を施行した。運動とヤリイカの摂取のみでは症状誘発はされなかったが，アスピリン 1.5 g を内服しヤリイカ 50 g の摂取と 30 分間の運動との組み合わせで眼瞼浮腫を生じた。以上よりヤリイカによる FDEIA と診断した。本症は診断のために詳細な問診と特異的 IgE 抗体の測定，プリックテスト，食物負荷試験が重要であるが必ずしも再現性は高くない。食物負荷試験と運動の組み合わせでは偽陰性となることがあり，自験例の結果より増強因子であるアスピリンを投与することも重要であることが示唆された。

Is it worth already in the first step exceeding the 3-g protein limit for the oral food challenge for food protein-induced enterocolitis syndrome?

Is it worth already in the first step exceeding the 3-g protein limit for the oral food challenge for food protein-induced enterocolitis syndrome?

Hypoallergenic Wheat Line (1BS-18H) Lacking ω5-Gliadin Induces Oral Tolerance to Wheat Gluten Proteins in a Rat Model of Wheat Allergy.

The early ingestion of food can prevent the onset of food allergy related to inducing oral tolerance (OT). We developed the Hokushin wheat line as a hypoallergenic wheat (1BS-18H) lacking ω5-gliadin, a major allergen of wheat-dependent exercise-induced anaphylaxis (WDEIA). The 1BS-18H wheat had lower ability of sensitization for ω5-gliadin compared with Hokushin wheat. Here, we evaluated the induction of OT to gluten and ω5-gliadin by the early consecutive ingestion of 1BS-18H gluten using a rat model of wheat allergy. Rats were subcutaneously immunized with commercial gluten or native ω5-gliadin following the daily oral administration of gluten. The daily oral administration of 1BS-18H gluten for 5 days before immunization suppressed the increase in gluten- or ω5-gliadin-specific IgE and IgG1 antibodies induced by immunization to a level similar to Hokushin gluten. Intravenous challenge with gluten or ω5-gliadin did not decrease the rectal temperature in rats with OT induced by 1BS-18H or Hokushin gluten, although it was decreased in non-OT rats. In conclusion, the early consecutive ingestion of 1BS-18H wheat before sensitization induced OT to gluten and ω5-gliadin. These findings support the benefit of 1BS-18H wheat to prevent wheat allergy including WDEIA by consecutive ingestion in humans.

Matavhengig treningsindusert anafylaksi under graviditet

Pregnant women with rare comorbid diagnoses need a safe delivery plan. This case report describes labour and delivery in a patient with food-dependent exercise-induced anaphylaxis.

Clinical features and outcomes of patients with wheat-dependent exercise-induced anaphylaxis: a retrospective study

BackgroundWheat-dependent exercise-induced anaphylaxis (WDEIA) is a serious and potentially life-threatening form of wheat allergy. Further episodes can only be prevented by avoiding wheat ingestion or avoiding exercise after wheat intake. Anaphylaxis may recur in some patients post-diagnosis. This study aimed to analyze the clinical features and management/outcomes of WDEIA in China.MethodsWe retrospectively analyzed the clinical characteristics, and laboratory testing of 197 patients with WDEIA. After diagnosis, the patients were followed up as outpatients to evaluate dietary/exercise choice and clinical outcomes.ResultsAmong the 197 WDEIA patients (median age, 37 years), 53.8% were male and 28.4% had other allergic disorders. The median duration of anaphylaxis before diagnosis was 16 months. Significant delays in diagnosis (> 1 years) were recorded in 52.7% of the patients, which has not decreased by years (P = 0.064). Exercise (83.8%), alcohol (12.2%), and nonsteroidal anti-inflammatory drugs (7.1%) were the most common cofactors. The most common clinical features were urticaria (100%), loss of consciousness (82.7%), dyspnea (50.8%), and hypotension (47.2%). Of the 197 eligible patients, 155 responded (78.7%), and 124 (80.0%) of which had no anaphylaxis post-diagnosis. A wheat-free diet prevented future anaphylaxis in 91.7% of the patients, followed by the avoidance of wheat combined with exercise (87%) and reduced wheat intake combined with exercise avoidance (80.5%).ConclusionThe diagnosis of WDEIA is frequently delayed. Therefore, when patients present with unexplained anaphylaxis, the possibility of WDEIA should be considered. A wheat-free diet or avoiding wheat combined with exercise or reduced wheat combined with exercise avoidance helps to significantly reduce the onset of future anaphylaxis. However, approximately one-fifth of patients continue to experience anaphylaxis post-diagnosis. Thus, these patients must always carry epinephrine autoinjectors.