The Journal of Allergy and Clinical Immunology: In Practice
Original ArticleFood-Dependent Exercise-Induced Wheals, Angioedema, and Anaphylaxis: A Systematic Review
Introduction
Food-dependent exercise-induced allergic reactions are characterized by their onset in response to exercise after the intake of culprit foods.1 The most dangerous manifestion is food-dependent exercise-induced anaphylaxis (FDEIA), which is different from both exercise-induced anaphylaxis and food-induced anaphylaxis. In FDEIA, the combination of exercise and food intake is required for signs and symptoms of anaphylaxis to develop.1,2
An FDEIA is subclassified according to the culprit food.3,4 Some patients only develop exercise-triggered anaphylaxis after eating a specific kind of food, whereas other patients develop exercise-triggered anaphylaxis after eating any food. The spectrum of FDEIA reactions across patients and events ranges from mild to life-threatening.2,3,5
Anaphylaxis is characterized by respiratory involvement, reduced blood pressure or associated symptoms, and/or gastrointestinal symptoms as a result of exposure to a known allergen trigger.6 In response to exercise after eating, some patients present with wheals and/or angioedema alone without signs and symptoms of anaphylaxis and without progression to anaphylaxis. However, there were some reports of a dose-response such that the same patient developed stand-alone cutaneous symptoms with exercise of lower intensity or duration, but experienced anaphylaxis when exercising harder or longer.7,8 Conversely, in 2 patients, similar exercise and food intake resulted in stand-alone urticaria and/or angioedema on one occasion and anaphylaxis on another.7,9 More studies are needed to better characterize dose-response relevance and mechanisms. The rates of patients who develop wheals and/or angioedema, anaphylaxis, or both in response to exercise after eating is currently unknown.
The FDEIA symptoms most often occur during exercise within 2 hours after food ingestion,1 3,4,10 and usually resolve within 24 hours with medication. However, the differences in the time it takes for reactions to occur and what influences them are still poorly understood. The same holds true regarding the type of culprit food, the types of exercise and activities that elicit them, and the role of cofactors, such as nonsteroidal anti-inflammatory drugs and alcohol consumption.2,10,11
The diagnosis of FDEIA is based on patient history and provocation testing with food challenge and exercise, which is the diagnostic gold standard.2,12,13 Any FDEIA provocation testing should be performed in a hospital under expert supervision with available equipment and medications to treat anaphylaxis. Antihistamine (AH) treatment is discontinued 7 days before provocation testing,14 after which patients eat culprit foods followed by exercise on a treadmill 1 to 2 hours later.2,13,15,16 The occurrence of symptoms, including wheals, respiratory distress, syncope, and/or abdominal pain, confirm FDEIA; however, a negative test result does not rule out FDEIA.2,12 It currently remains largely unclear what proportion of patients with suspected FDEIA show positive provocation test results and whether this depends on the food-dependent exercise-induced signs and symptoms that they develop in real life.
The aforementioned data and findings highlight the considerable gaps in our understanding of the clinical manifestations, culprit foods and exercises, the effect of comorbidities and cofactors, and the use and efficacy of treatment in patients with food-dependent exercise-induced allergic reactions, including FDEIA.1,3,7,10,17,18 The reasons for this knowledge gap include the absence of controlled studies and the lack of a comprehensive review of the many case reports and case series that have been published on FDEIA, especially in recent years. In an effort to bridge this gap, we set forth to systematically review reports specific to food-dependent exercise-induced wheals, angioedema, and anaphylaxis to characterize the clinical manifestations, the laboratory investigations that confirm the diagnosis, the culprit foods and exercises that trigger reactions, the comorbidities, the treatment options, and the outcomes of treatment in this patient population.
Section snippets
Protocol and registration
The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) protocol was followed in this systematic review.19 We searched the literature published in the PubMed, Scopus, and Embase databases before July 1, 2021. The search terms were “food-dependent exercise-induced urticaria,” “food-dependent exercise-induced angioedema,” “food-dependent exercise-induced anaphylaxis,” “food allergy-dependent exercise-induced urticaria,” “food allergy-dependent exercise-induced angioedema,”
Food-dependent exercise-induced allergic reactions, in most but not all patients, present as anaphylaxis together with wheals, angioedema, or both
Of 722 patients with food-dependent exercise-induced allergic reactions reported by 231 studies, 575 (79.6%) had anaphylaxis with wheals and/or angioedema (FDEI-A+/W∨A+). Twenty-seven patients (3.7%) had anaphylaxis without wheals or angioedema (FDEI-A+/W∨A–). The remaining 120 patients (16.6%) had stand-alone wheals and/or angioedema with no anaphylaxis (FDEI-A–/W∨A+) (Table I). Of note, of those 120 FDEI-A–/W∨A+ patients who were reported by 37 publications, 112 patients were described, in 29
Discussion
This first systematic review of more than 200 studies reporting on more than 700 patients with food-dependent exercise-induced allergic reactions, including FDEIA, provides comprehensive insights into their clinical manifestations, time course, culprit foods and exercises, augmenting factors, comorbidities, treatments, and treatment outcomes.
As expected, most patients with food-dependent exercise-induced allergic reactions experience signs and symptoms of anaphylaxis, most commonly respiratory
Acknowledgments
The authors gratefully acknowledge Assistant Professor Chulaluk Komoltri for assistance with statistical analysis.
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No funding has been received for this study.
Conflicts of interest: The authors declare that they have no relevant conflicts of interest.