Original Article
Food-Dependent Exercise-Induced Wheals, Angioedema, and Anaphylaxis: A Systematic Review

https://doi.org/10.1016/j.jaip.2022.06.008Get rights and content

Background

Food-dependent exercise-induced wheals, angioedema, and anaphylaxis remain insufficiently characterized.

Objective

We systematically reviewed the literature on clinical manifestations, laboratory investigations, culprit foods, triggering exercise, comorbidities, and treatment outcomes.

Methods

Using predefined search terms and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations, we searched 3 electronic databases to identify relevant literature published before July 2021.

Results

Of 722 patients (median age 25 years; 55.4% male) from 231 studies (43 cohort studies, 15 cases series, and 173 case reports), 79.6% and 3.7% had anaphylaxis with and without wheals and/or angioedema, respectively. The remaining 16.6% had wheals and/or angioedema without anaphylaxis. The duration from eating to exercising and from exercising to symptom onset ranged from 5 minutes to 6 hours (median 1 hour) and from 5 minutes to 5 hours (median 30 minutes), respectively, and virtually all patients exercised within 4 hours after eating and developed symptoms within 1 hour after exercising. Wheat was the most common culprit food. Running was the most common trigger exercise. Most patients were atopic, and 1 in 3 had a history of urticaria. Aspirin and wheat-based products were the most frequent augmenting factors. On-demand antihistamines, corticosteroids, and epinephrine were commonly used and reported to be effective. Patients who stopped eating culprit foods before exercise no longer developed food-dependent exercise-induced allergic reactions.

Conclusions

Food-dependent exercise-induced allergic reactions are heterogeneous in their clinical manifestations, triggers, and response to treatment. Patients benefit from avoidance of culprit foods before exercise, which highlights the need for allergological diagnostic workup and guidance.

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.

References (252)

  • M. Geller

    Clinical management of exercise-induced anaphylaxis and cholinergic urticaria

    J Allergy Clin Immunol Pract

    (2020)
  • A.M. Feldweg

    Food-dependent, exercise-induced anaphylaxis: diagnosis and management in the outpatient setting

    J Allergy Clin Immunol Pract

    (2017)
  • C.-J. Tam et al.

    Food-dependent exercise-induced anaphylaxis: a review

    J Nurse Pract

    (2017)
  • G. Du Toit

    Food-dependent exercise-induced anaphylaxis in childhood

    Pediatr Allergy Immunol

    (2007)
  • T.E. Dribin et al.

    Severity grading system for acute allergic reactions: a multidisciplinary Delphi study

    J Allergy Clin Immunol

    (2021)
  • M.S. Shaker et al.

    Anaphylaxis—a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis

    J Allergy Clin Immunol

    (2020)
  • N.R. de Silva et al.

    Food dependant exercise induced anaphylaxis a retrospective study from 2 allergy clinics in Colombo, Sri Lanka

    Allergy Asthma Clin Immunol

    (2015)
  • J. Staikuniene et al.

    Wheat-dependent exercise-induced anaphylaxis following laparoscopic adjustable gastric banding procedure associated with Helicobacter pylori infection

    Eat Weight Disord

    (2014)
  • A. Gülsen et al.

    Lipid transfer protein sensitization in an apple-allergic patient: a case report from Northern Europe

    Eur Ann Allergy Clin Immunol

    (2019)
  • E. Morita et al.

    Food-dependent exercise-induced anaphylaxis

    J Dermatol Sci

    (2007)
  • M.J. Christensen et al.

    Exercise lowers threshold and increases severity, but wheat-dependent, exercise-induced anaphylaxis can be elicited at rest

    J Allergy Clin Immunol Pract

    (2018)
  • F. Benito-Garcia et al.

    Diagnosis and prevention of food-dependent exercise-induced anaphylaxis

    Expert Rev Clin Immunol

    (2019)
  • T. Asaumi et al.

    Provocation tests for the diagnosis of food-dependent exercise-induced anaphylaxis

    Pediatr Allergy Immunol

    (2016)
  • K. Brockow et al.

    Using a gluten oral food challenge protocol to improve diagnosis of wheat-dependent exercise-induced anaphylaxis

    J Allergy Clin Immunol

    (2015)
  • A. Fiocchi et al.

    Exercise-induced anaphylaxis after food contaminant ingestion in double-blinded, placebo-controlled, food-exercise challenge

    J Allergy Clin Immunol

    (1997)
  • R.A. Bruce et al.

    Exercising testing in adult normal subjects and cardiac patients

    Pediatrics

    (1963)
  • Y. Aihara et al.

    Frequency of food-dependent, exercise-induced anaphylaxis in Japanese junior-high-school students

    J Allergy Clin Immunol

    (2001)
  • M. Al-Nesf et al.

    Two cases of food-dependent exercise-induced anaphylaxis with different culprit foods

    Ann Thorac Med

    (2014)
  • D. Moher et al.

    Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement

    Syst Rev

    (2015)
  • M. Couto et al.

    Cow's milk dependent exercise-induced urticaria after oral tolerance induction in an adolescent

    Allergol Immunopathol (Madr)

    (2012)
  • V. De Luque Piñana et al.

    Sulfite-dependent excercise urticaria

    Allergy

    (2013)
  • R. Gomes et al.

    Tri a 19 and wheat exercised-dependent urticaria

    Allergy

    (2015)
  • E. Magen et al.

    A case of food-dependent exercise-induced angioedema

    J Allergy Clin Immunol Pract

    (2019)
  • M. Calvani et al.

    Food-dependent exercise-induced urticaria/angioedema caused by lipid transfer protein in two children

    Isr Med Assoc J

    (2015)
  • S. Kivity et al.

    The effect of food and exercise on the skin response to compound 48 80 in patients with food-associated exercise-induced urticaria-angioedema

    J Allergy Clin Immunol

    (1988)
  • A. Agulló-García et al.

    Series of 12 cases of wheat-dependent exercise-induced allergy in Aragon, Spain

    Rev Clin Esp

    (2019)
  • G. Hayman et al.

    Clinical features of wheat-dependent exercise-induced allergy—a case series

    Allergy

    (2010)
  • A. Wolańczyk-Medrala et al.

    Food-dependent exercise-induced anaphylaxis—sequence of causative factors might be reversed

    Ann Agric Environ Med

    (2010)
  • W. Medrala et al.

    Naproxen increases the severity of food-dependent exercise-induced anaphylaxis: a case report

    J Investig Allergol Clin Immunol

    (2014)
  • R. Shiratsuki et al.

    A case of pork-cat syndrome that developed as food-dependent exercise-induced anaphylaxis

    Acta Derm Venereol

    (2020)
  • J.M. Kidd et al.

    Food-dependent exercise-induced anaphylaxis

    J Allergy Clin Immunol

    (1983)
  • O. Fukutomi et al.

    Abnormal responses of the autonomic nervous system in food-dependent exercise-induced anaphylaxis

    Ann Allergy

    (1992)
  • O. Hameed et al.

    Food-dependent exercise-induced anaphylaxis: a series of three cases

    Br J Dermatol

    (2012)
  • A. Romano et al.

    Diagnostic work-up for food-dependent, exercise-induced anaphylaxis

    Allergy

    (1995)
  • A. Romano et al.

    Food-dependent exercise-induced anaphylaxis: clinical and laboratory findings in 54 subjects

    Int Arch Allergy Immunol

    (2001)
  • T. Wang et al.

    A case of freshwater fish-dependent exercise-induced anaphylaxis

    Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi

    (2019)
  • L. Airaksinen et al.

    Occupational rhinitis, asthma, and contact urticaria caused by hydrolyzed wheat protein in hairdressers

    Ann Allergy Asthma Immunol

    (2013)
  • A. Tanaka et al.

    Wheat-dependent exercise-induced anaphylaxis occurred in OAS patient after using soap containing hydrolyzed wheat proteins: effect of soap on keratinocyte inflammasome

    World Allergy Organ J

    (2012)
  • M. Aihara et al.

    Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation

    Br J Dermatol

    (2002)
  • A. Tewari et al.

    The difficulties of diagnosing food-dependent exercise-induced anaphylaxis in childhood—a case study and review

    Pediatr Allergy Immunol

    (2006)
  • Y. Aihara et al.

    The necessity for dual food intake to provoke food-dependent exercise-induced anaphylaxis (FEIAn): a case report of FEIAn with simultaneous intake of wheat and umeboshi

    J Allergy Clin Immunol

    (2001)
  • Y. Kato et al.

    Food-dependent exercise-induced anaphylaxis with a high level of plasma noradrenaline

    J Dermatol

    (2007)
  • J.M. García-Menaya et al.

    Rye-dependent exercise-induced anaphylaxis

    Ann Allergy Asthma Immunol

    (2016)
  • K. Palosuo et al.

    A novel wheat gliadin as a cause of exercise-induced anaphylaxis

    J Allergy Clin Immunol

    (1999)
  • D. Torchia et al.

    Multiple physical urticarias

    Postgrad Med J

    (2008)
  • H. Kano et al.

    Clinical courses of 18 cases with food-dependent exercise- induced anaphylaxis

    Jpn J Allergol

    (2000)
  • N. Murayama et al.

    Data on various allergen specific IgEs and prospective treatments on food-dependent exercise-induced anaphylaxis

    Data Brief

    (2018)
  • J.H. Choi et al.

    Wheat-dependent, exercise-induced anaphylaxis: a successful case of prevention with ketotifen

    Ann Dermatol

    (2009)
  • S. Harada et al.

    A case of food-dependent exercise-induced anaphylaxis due to wheat: intake of aspirin and wheat without exercise-induced anaphylaxis

    Skin Res

    (1997)
  • L. Sude Gucer et al.

    Omalizumab in the treatment of wheat-dependent exercise-induced anaphylaxis: case report

    Rev Fr Allergol

    (2020)
  • Cited by (0)

    No funding has been received for this study.

    Conflicts of interest: The authors declare that they have no relevant conflicts of interest.

    View full text