Food-dependent exercise-induced allergic reactions in Lipid Transfer Protein (LTP) hypersensitive subjects: new data and a critical reappraisal.

Summary: Background. Lipid transfer protein is the main cause of both primary food allergy and food-dependent exercise-induced allergic reactions (FDEIAR) in Italy. What characterizes LTP-hypersensitive patients with FDEIAR is still unclear. We investigated the key characteristics of LTP-hypersensitive patients with or without FDEIAR in a large cohort of individuals sensitized to this allergen. Methods. 1,203 food-allergic patients, diagnosed on the basis of unequivocal clinical history and presence of circulating food allergen-specific IgE were studied. Serum IgE reactivity was assessed using the Allergen ExplorerALEX® system (Macroarray Diagnostics, Vienna, Austria). Association of specific IgE reactivities with FDEIAR was investigated, and patients with and without FDEIAR sensitized to LTP were compared. Results. 116 subjects (9.6%) had FDEIAR. Among these, 77 (66.3%) were LTP-reactors and 16 (13.8%) were sensitized to Tri a 19 (omega-5-gliadin). Different LTPs and omega-5-gliadin emerged as the sole allergens clearly associated with FDEIAR. Severity of allergic reactions was paralleled the level of specific IgE to LTPs. Patients with FDEIAR showed significantly lower IgE levels than their counterparts with food allergy at rest, and displayed nearly identical IgE levels regardless of the severity of allergic reactions induced by exercise. Conclusions. FDEIAR are associated with specific allergens. Specific IgE levels in LTP-hypersensitive patients with FDEIAR show an intermediate titer between those simply sensitized and those showing classic food allergy.

[TWO SCHOOL-AGED CASES OF FRUIT GIBBERELLIN-REGULATED PROTEIN ALLERGY WHICH NEED INDIVIDUAL REMOVAL STRATEGY IN SCHOOL LUNCH].

Gibberellin-regulated protein (GRP) is a newly discovered allergen in systemic fruit allergies. The kind of fruits which cause allergy is extensive as GRP is universally included in plants. Two children with GRP allergy were reported. Case 1: A 6-year-old boy experienced anaphylaxis while running after school lunch, which included canned peaches. A skin prick test (SPT) and blood examination suggested that he had peach GRP allergy. Six months and three years later, he experienced a similar episode after eating apple and citrus flesh, respectively. Case 2: An 11-year-old boy experienced anaphylaxis while running after consuming canned peaches during school lunch. A SPT implied that he had peach GRP allergy. However, a similar episode occurred after eating strawberry flesh 18 months later.Patients with GRP allergy often have one or more allergies to fruits other than peaches, as in these cases, and relevant fruits differ depending on the case. Particularly, clinicians should recognize that apple and citrus fruits are frequently included in school lunches as fruit flesh and as flavoring or seasoning in ready-made sauces or dressings. Therefore, an appropriate removal strategy should be considered in school lunches depending on each case of GRP allergy.

[A CASE OF FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS DUE TO POLISHED RICE].

A 14-year-old girl presented to our hospital with food-dependent exercise-induced anaphylaxis (FDEIA), possibly caused by rice. Despite experiencing four previous episodes of suspected FDEIA, she did not seek medical attention at her own discretion. On the fifth occurrence of symptoms, the general practitioner suspected FDEIA and referred the patient to our hospital. The only common factor in all five episodes was the consumption of rice, leading to the examination of the patient under suspicion of FDEIA caused by rice. Skin prick test results were positive for bran and polished rice, and exercise after consumption of polished rice resulted in anaphylaxis. Therefore, we diagnosed FDEIA caused by polished rice. Immunoblotting confirmed the presence of immunoglobulin E reacting with 14-16kDa rice bran protein in the patient's serum. The immunoblot inhibition test suggested that the rice bran protein to which the patient's serum reacted was also present in polished rice and no wash rice. As the patient may experience FDEIA after ingestion of no wash rice or rice flour, she was advised to eliminate these from her diet, treating them similarly to brown rice or polished rice.

Appearance of food-dependent exercise-induced anaphylaxis as an inflammatory disease: a pediatric case report and differential diagnosis.

Anaphylaxis is the most serious of all allergic reactions. Despite advances in the knowledge of anaphylaxis, its clinical manifestations continue to be under-recognized. Indeed, proper diagnosis of anaphylaxis is often missed, and the treatment is delayed. The underlying causes are still under investigation globally. Inflammation represents the cornerstone of pathophysiology of anaphylaxis. Food-dependent exercise-induced anaphylaxis (FDEIA) is a rare clinical manifestation characterized by a chronological sequence in which food ingestion followed by physical exercise leads to anaphylaxis. Its mechanisms are yet to be fully explained. We report the case of a 14-year-old Chinese male who lost consciousness while undergoing physical activity at school. Several differential diagnoses were considered such as hypovolemic shock, septic shock, anaphylactic shock or neurological adverse event. Finally, the diagnosis of FDEIA was made. This case highlights the difficulties in diagnosing FDEIA and its management, especially when the clinical history is not complete and detailed.

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-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS IMPROVED BY OMALIZUMAB PRESCRIBED FOR IDIOPATHIC CHRONIC URTICARIA].

A 13-year-old male patient suffered several episodes of anaphylaxis during exercise after consuming wheat. Provocation tests (consisting of exercise after wheat ingestion) were conducted twice at our hospital. Both tests were positive, resulting in a diagnosis of food-dependent exercise-induced anaphylaxis (FDEIA) due to wheat. The patient was instructed to avoid exercise after wheat ingestion. The patient had also been previously diagnosed with idiopathic chronic urticaria, which was treated with antihistamines and leukotriene receptor antagonists. Since the idiopathic chronic urticaria worsened despite the use of these medications, 300 mg per four weeks of omalizumab was initiated. The patient's symptoms improved, and a third provocation test came back negative. The patient was asymptomatic without exercise restriction when treated with omalizumab. Omalizumab is not typically prescribed for treating food allergies and EIA in Japan; however, there are some reports on their effectiveness in treating them, suggesting omalizumab may also be helpful in resolving FDEIA symptoms.

Summation anaphylaxis: A challenging diagnosis.

Anaphylaxis is the most severe of allergic reactions. The most frequent triggers of anaphylaxis in childhood are food, insect venom, drugs, exercise, etc. In some cases, the presence of more than one trigger is necessary for the allergic reaction, while one trigger alone is tolerated. This rare condition is called summation anaphylaxis (SA). Food-dependent exercise-induced anaphylaxis is the most well-known SA. However, SA may also occur with the association between food and/or exercise plus one or more of the following other cofactors, such as drugs, especially non-steroidal anti-inflammatory (NSAID), alcohol, infections, temperature variation, and menstrual cycle. SA can explain some cases of idiopathic anaphylaxis, as well as cases of an apparent breakdown in a previously acquired tolerance for food, or finally, when faced with a suggestive clinical history of food allergy or exercise anaphylaxis and the provocation test is negative. In these situations, a more careful clinical history looking for other cofactors is necessary.

Novel insights regarding anaphylaxis in children - With a focus on prevalence, diagnosis, and treatment.

Anaphylaxis is a serious allergic reaction that occurs rapidly and causes a life-threatening response involving the whole body. This reaction often leads to difficulty in breathing and can result in death. The estimated prevalence of anaphylaxis is 0.05%-2%, which is reported to be increasing in children. Although drugs and venom are the most common causes of anaphylaxis in adults, food is the most common cause of anaphylaxis in children. An interesting association between food-dependent exercise-induced anaphylaxis (FDEIA) and oral immunotherapy (OIT) has recently been reported. A provocation test to determine the diagnostic and augmenting factors of FDEIA has been reported in recent years. Remarkably, several articles showed allergic symptoms without exercise in children with FDEIA and in those with FDEIA development after OIT. Regarding OIT, full-dose OIT poses a risk of adverse reactions, including anaphylaxis. Recent trials have shown the efficacy and safety of low-dose OIT in patients with food-induced anaphylaxis. In this review, we summarized the novel insights regarding anaphylaxis in the pediatric population.

A Case of Pork-cat Syndrome That Developed as Food-dependent Exercise-induced Anaphylaxis.

is missing (Short communication).

[ADULT ANAPHYLAXIS AT THE DEPARTMENT OF EMERGENCY MEDICINE OF TEIKYO UNIVERSITY HOSPITAL IN AN URBAN AREA OF TOKYO].

BACKGROUND: Anaphylaxis is a severe, potentially fatal, systemic allergic reaction. But its real-world evidence is limited. Both treatment of allergic symptoms and prevention of future anaphylactic episodes are clinically important. We have strongly recommended that patients visit our outpatient allergy clinic. OBJECTIVE: To classify the clinical features and triggers of anaphylaxis in patients (≥16 years old) in an urban area of Tokyo. METHODS: We used the medical records to analyze patients with anaphylaxis as the primary diagnosis who visited the emergency department in our hospital from January 2015 through December 2017. RESULTS: Among approximately 60000 patients who visited the emergency department, 181 subjects (mean age, 43.0; 44% male) were diagnosed with anaphylaxis. Fourteen of those patients had a systolic blood pressure of lower than 90mmHg. Upon arrival, 126 patients were treated with adrenaline. All patients recovered from the anaphylactic episode. Subsequently, 133 patients visited our outpatient allergy clinic. The trigger of the anaphylaxis were assessed; the most popular trigger was foods (n = 78), followed by drugs (n = 38), insect stings/bites or animal bites (n = 3) and others (n = 11). Adrenaline auto-injectors were prescribed to 84 patients. CONCLUSION: It is important for patients with anaphylaxis to undergo allergy testing after discharge from an emergency department. Collaboration between emergency medicine and allergy departments may be helpful for improving the patients' QOL through effective instruction and prevention of recurrent anaphylaxis.

[CHARACTERISTICS OF THE SYMPTOMS DURING FOOD AND EXERCISE PROVOCATION TESTS IN PATIENTS AFTER ORAL IMMUNOTHERAPY: COMPARISON WITH FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS].

OBJECTIVE: We aim to examine the characteristics of the symptoms induced by exercise provocation tests following allergen consumption in patients who have undergone oral immunotherapy (OIT). METHOD: Patients who were positive for exercise provocation tests in Miyagi Children's Hospital from April 2012 to January 2019 were retrospectively analyzed. Patients were classified into food-dependent exerciseinduced anaphylaxis (FDEIA) group and post-OIT-FDEIA group. RESULT: Six patients in the FDEIA group and 19 patients in the post-OIT-FDEIA group were analyzed. There were no significant differences in age, sex, and number of complications between the FDEIA and post-OIT-FDEIA groups, except for level of total serum immunoglobulin E. The median time from the start of exercise to onset of symptoms was 20 min in the FDEIA group and 25 min in the post-OIT-FDEIA group. The rate of adrenaline administration in post-OIT-FDEIA group was significantly lower. The median time from exercise to onset of severe symptoms requiring adrenaline was 32.5 min in the FDEIA group and 25 min in the post-OIT-FDEIA group. CONCLUSION: These data suggest that FDEIA and post-OIT-FDEIA patients can exhibit similar clinical symptoms, and all symptoms occurred in 60 minutes after exercise.

Identification of gibberellin-regulated protein as a new allergen in orange allergy.

BACKGROUND: To date, three orange allergens have been reported. However, it is still unclear whether gibberellin-regulated proteins (GRPs), identified as new allergens in other fruit allergies, are also involved in orange allergy. OBJECTIVE: To investigate the allergenicity of orange GRP and to determine the clinical characteristics of patients with orange allergy who are sensitized to orange GRP. METHODS: We enrolled 14 patients (four men, 10 women, mean age: 29.6 years) who were diagnosed with orange allergy based on relevant clinical history, positive skin test, and/or positive challenge test. Orange GRP (molecular weight: 6941.6 Da) was purified by ion-exchange column chromatography. To test for orange GRP-specific IgE, we performed ELISA, basophil activation tests, and skin prick tests. Cross-reactivity of orange GRP with native peach allergen nPru p 7 and Japanese apricot nPru m 7 was analysed by ELISA inhibition assays. IgE specific for orange, grapefruit, and peach allergens rPru p 1, rPru p 3, and rPru p 4 was measured using ImmunoCAP. RESULTS: Twelve of the 14 patients (85.7%) were positive for orange GRP allergy in at least one test: 71.4% (10/14) were positive by ELISA, 50% (3/6) were positive in the basophil activation test, and 100% (4/4) were positive in the skin prick test. ELISA inhibition assays revealed cross-reactivity of orange GRP with both nPru p 7 and nPru m 7. The patients showed variable positivity for specific IgE against orange, grapefruit, rPru p 1, rPru p 3, and rPru p 4 (57.1%, 71.4%, 7.1%, 0%, and 21.4%, respectively). The most frequent symptoms of orange GRP allergy were facial swelling and oropharyngeal symptoms. CONCLUSIONS AND CLINICAL RELEVANCE: Orange GRP may be involved in orange allergy and may be a cross-reactive allergen between citrus fruits and the Rosaceae family of fruits.

Exercise-Induced Anaphylaxis: Literature Review and Recent Updates.

PURPOSE OF REVIEW: This paper will review the pathophysiology, diagnosis, and treatment of exercise-induced anaphylaxis and food-dependent, exercise-induced anaphylaxis with an emphasis on novel studies published in the past several years. RECENT FINDINGS: Exercise-induced anaphylaxis (EIAn) is a clinical syndrome characterized by anaphylaxis during or shortly after physical exertion. The syndrome is broadly grouped into two categories: exercise-induced anaphylaxis and food-dependent, exercise-induced anaphylaxis (FDEIAn). Recent literature indicates that FDEIAn is a primary IgE-mediated food allergy which is augmented by several cofactors. Cofactors such as exercise, NSAIDs, and alcohol increase intestinal permeability and allow increased antigen uptake, thereby causing symptoms. The pathophysiology of EIAn is still under investigation. EIAn and FDEIAn are rare clinical syndromes characterized by symptoms during or shortly after exercise. Despite recent advances in the understanding of EIAn and FDEIAn, the pathophysiology of both conditions is not fully understood.

Food-dependent exercise-induced anaphylaxis in Japanese elementary school children.

BACKGROUND: In 2012, we clarified that the prevalence of food-dependent exercise-induced anaphylaxis (FDEIA) was 0.018% in junior-high students in Yokohama, Japan. Furthermore, although different from FDEIA, one student who had completed oral immunotherapy developed anaphylaxis during exercise after eating causative food. There have been few large-scale epidemiological studies of FDEIA, however, in elementary school children, therefore we conducted an epidemiological study in elementary school children in Yokohama to clarify the frequency and characteristic of FDEIA. METHODS: We sent a questionnaire regarding the occurrence of FDEIA to all 348 public elementary school nurses in Yokohama. We also compared the results with those for junior-high school that we previously reported. We excluded those children with a past history of immediate food allergy who had achieved desensitization status after oral immunotherapy, from FDEIA, and instead defined them as having desensitization status and exercise-induced anaphylaxis (DEIA). RESULTS: Of 348 school nurses, 317 responded (91.1%). Overall, eight of 170 146 children were diagnosed with FDEIA, which was significantly lower than the prevalence in junior-high school students (0.0047% vs 0.018%, P = 0.0009). The causative foods were wheat (n = 4), and soy, fruit, crustaceans, and squid (n = 1 each). Four children had DEIA and the causative foods were wheat and milk (n = 2 each). Multiple episodes occurred in five children with FDEIA and in three children with DEIA. CONCLUSIONS: FDEIA was far less common in elementary school than in junior-high school, and wheat was the major causative food. The new appearance of DEIA was notable. Decreasing episode recurrence remains an issue that needs to be resolved.

Anaphylaxis caused by lipid transfer proteins: an unpredictable clinical syndrome.

INTRODUCTION: Lipid transfer proteins (LTPs) are panallergens found in many plant foods. They are a common cause of food-induced anaphylaxis (FIA) in adults living in the Mediterranean area. LTPs have also been proposed as a main cause of food-dependent exercise-induced anaphylaxis (FDEIA). OBJECTIVES: Describe clinical characteristics and allergen sensitization profiles in patients with FIA related to LTP. MATERIALS AND METHODS: Forty-three patients were included, aged 3-52 years with a clinical history of FIA and proven sensitization to LTP. Patients were tested with a multiple plant food and pollen panel and specific IgE to LTP allergens. LTP sensitization was assessed by in vivo (Pru p 3, LTP extract) and/or by in vitro tests (specific IgE, ImmunoCAP/ISAC®). RESULTS: Median age of first anaphylactic episode was 24 years (range 2-51), 44% had asthma, 74% were atopic and 42% had pollinosis (olive, mugwort, plane tree, wall pellitory and cypress). Co-sensitization to profilins was found in 22%. Overall in our center, LTP-induced anaphylaxis represents 17% of all causes of FIA. Foods implicated in anaphylactic reactions were: fresh fruits 51%, tree nuts 42%, vegetables (including peanut) 40% and seeds 14%. Seven patients had FDEIA. CONCLUSIONS: LTPs are important allergens of FIA in Portugal. Clinical reactivity to several taxonomically unrelated plant foods may raise suspicion toward LTP sensitization. The association of LTP-induced anaphylaxis with pollinosis is relevant in our country. The unpredictable clinical expression depends on the effect of cofactors such as exercise. The management of avoidance plans can be challenging due to LTP being a widely cross-reacting allergen in plant foods.

An unusual case of wheat dependent exercise induced anaphylaxis (WDEIA) triggered by Tri a 14 in a pediatric patient: a case report.

Summary: Anakinra, one of the novel biological agents, is a recombinant human IL-1 receptor antagonist. It is preferred as an alternative drug for familial Mediterranean fever cases where colchicine is not sufficient or cannot be used due to its side effects. Like all other biologics, hypersensitivity reactions to anakinra are quite rare. This is the first case which was successfully desensitized with anakinra after a severe immediate-type hypersensitivity reaction. We report a case of WDEIA in an asthmatic boy admitted to our Unit with suspected mushroom acute toxicity. The symptoms occurred during a gym session, approximately 2 hours after the ingestion of a meal based on pasta and cooked mushroom found in the family's garden. Acute toxicity due to mushroom ingestion was then excluded. Triptase serum levels resulted elevated in acute phase and normal after 24 hours. Food specific IgE showed a sensitization to lipid transfer protein Pru p 3 and to Tri a 14. This case highlights that WDEIA is underdiagnosed, especially when patients are firstly visited in Emergency Unit. Moreover, Tri a 14 is seldom described as responsible for WDEIA, compared to omega 5 gliadin.

FOOD-DEPENDENT EXERCISE-INDUCED ANAPHYLAXIS DUE TO INGESTION OF MIKAN (CITRUS UNSHIU).

A 12-year-old girl was referred to our hospital owing to repeated anaphylactic reactions induced by exercise after meals. Food-dependent exercise-induced anaphylaxis (FDEIAn) was suspected. However, sequential tests of typical foods, including egg, milk, soy, and wheat, in combination with exercise, were all negative.The results of the skin prick test (SPT) for Citrus unshiu and specific IgE test for orange and grapefruit were positive. Although no symptoms were noted after an exercise challenge combined with the ingestion of only Citrus unshiu, an anaphylactic reaction was induced by additional acetyl-salicylic acid. From these results, she was diagnosed with FDEIAn due to the ingestion of Citrus unshiu. Because the SPT results for other citrus fruits (including orange, grapefruit, lemon, yuzu, sudachi, ponkan, and iyokan) were all positive, it was suggested that these fruits demonstrate cross-reactivity with each other. Since the girl eliminated citrus fruits from her diet, she has not developed any anaphylactic symptoms. Citrus fruits are not known to cause FDEIAn, but the findings of this case suggest that it is necessary to recognize them as a causative allergen of FDEIAn.