Food-dependent Exercise-induced Anaphylaxis: The Need for Better Understanding and Management of the Disease.

Food-dependent exercise-induced anaphylaxis (FDEIA) is characterized by the onset of anaphylaxis during or soon after physical exercise preceded by ingestion of a causative food, while the food and exercise are each tolerated separately. The first case of FDEIA was reported by Maulitz et al.1 in 1979 as a late allergic reaction to shellfish following vigorous exercise. Wheat is the most common cause of FDEIA, but other grains, seafood, peanut, egg, milk, Rosaceae fruits and vegetables have also been reported as causes of FDEIA.23 In some cases, symptoms may be triggered by any meal followed by exercise regardless of the food type.4 Although FDEIA is frequently reported in young adults, epidemiologic studies are rare. A Japanese group reported the prevalence of FDEIA at 0.017% among junior high school students and 0.0047% among elementary school students.25 In a multicenter anaphylaxis registry in Korea, the proportion of FDEIA was 1.2% and 3.1% in children and adults, respectively.6 Recently, the concept of FDEIA has been expanded and described as “food-dependent cofactor-augmented anaphylaxis” or “cofactor-induced food allergy.”78 Reported cofactors other than physical exercise are aspirin, other analgesics, alcohol, stress, and infections.

Although increased levels of serum histamine and tryptase levels during FDEIA attacks indicate immunoglobulin E (IgE) -dependent degranulation of mast cells, the pathophysiology of FDEIA is not fully understood. Several theories to explain the mechanism of FDEIA are as follows: (i) activation of tissue transglutaminase during exercise resulting in conjugation between food allergen peptides and tissue transglutaminase, followed by IgE binding; (ii) increased gastrointestinal permeability and facilitation of allergen absorption into the circulating blood by exercise and other cofactors such as aspirin; (iii) transport of allergens to tissues containing mast cells by blood flow redistribution during exercise; and (iv) increased plasma noradrenaline levels inducing anaphylactoid symptoms.9101112

In most cases the diagnosis of FDEIA is made clinically based on the history of signs and symptoms consistent with anaphylaxis that have occurred during or within hours of exercise explicitly preceded by specific food ingestion, without any diagnosis that explains the clinical presentation. Typically, no symptoms are induced by exercise alone or ingestion of the culprit food in the absence of exercise. Skin testing or in vitro testing for food-specific IgE is generally essential during the evaluation of FDEIA to confirm the sensitization to the causative food(s). A positive provocation testing that combines the food and exercise is the most confirmative diagnostic method, but it is not easy to implement in an actual clinical setting. Moreover, a negative challenge does not completely exclude the diagnosis because there is significant variability among patients in the intensity and duration of exercise, the amount of food to trigger symptoms, and the presence of additional cofactors necessary to reproduce symptoms. Basophil activation test combined with appropriate allergens may provide useful information in diagnosing FDEIA,8 but is a rather demanding procedure to be carried out in the clinical setting.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is the most frequent type of FDEIA cases, and ω-5 gliadin was first reported in 1999 as a major allergen of WDEIA in Finnish adults by Palosuo et al.13 Other studies supporting ω-5 gliadin as the major allergen in WDEIA were serially published in the early 2000s.1415 Consequently, the development of wheat cultivars with reduced ω-5 gliadin content and studies on their allergenicity in WDEIA patients were followed. In 2011, Altenbach et al.16 reported the technique to silence the expression of genes encoding ω-5 gliadins, and a lower sensitization capacity of the deletion line lacking the ω-5 gliadin locus was reported in the guinea pig by a Japanese group.17 Waga and Skoczowski18 found a considerable reduction (about 30%) in the immunoreactivity of genotypes lacking all ω-gliadins, but an increase in some α- and γ-gliadins were also noted. In this issue of the Allergy Asthma Immunol Res, Lee et al.19 demonstrated the allergenicity of the new cultivar (ω5D) which has selective deletions in the ω-5 gliadins as well as some i- and m-type low-molecular-weight glutenins and γ-gliadins in 14 WDEIA and 7 classic wheat allergic patients. The specific IgE binding to the glutenins and gliadins by ω5D was significantly attenuated to about one-fourth compared to the wild-type cultivar in WDEIA patients, while no significant difference was noticed in classic wheat allergic patients. Although some low-molecular-weight glutenin subunits, ω-5 or γ-gliadins and other glutenins remain in the ω5D cultivar as reported in this new cultivar, ω5D can be considered an alternative dietary candidate for WDEIA patients, allowing a safer consumption of wheat in patients with mild-to-moderate sensitivity.

The management of FDEIA is mainly composed of appropriate treatment in cases of acute anaphylactic symptoms and education to prevent further episodes.20 Physical exercise should be stopped immediately at any early warning signs of anaphylaxis to prevent progression to life-threatening severe symptoms, and intramuscular epinephrine should be administered promptly. In general, it is proposed to refrain from physical exercise for 4–6 hours after causative food intake but there is no standardized recommendation for the optimal prevention of FDEIA. Patients’ quality of life may be significantly impaired, especially in WDEIA patients because wheat is one of the staple foods in the human diet. For FDEIA patients to minimize the risk of recurrence and not to have excessive restrictions on their daily life due to the disease, further research toward the clarification of the disease mechanism is needed, and a specific and effective preventive plan based on evidence should be provided. Additional research on all aspects of FDEIA, including the development of hypoallergenic alternatives, will provide better treatment and improve patients’ quality of life.