Exercise-Induced Anaphylaxis

Exercise-induced anaphylaxis (EIA) is a rare disorder in which anaphylaxis occurs after physical activity. ^[1] The symptoms may include pruritus, hives, flushing, wheezing, and GI involvement, including nausea, abdominal cramping, and diarrhea. If physical activity continues, patients may progress to more severe symptoms, including angioedema, laryngeal edema, hypotension, and, ultimately, cardiovascular collapse. Cessation of physical activity usually results in immediate improvement of symptoms. (See Clinical Presentation.)

Sheffer and Austen described 4 phases in the sequence of the anaphylaxis attack—prodromal, early, fully established, and late—in a case series of 16 patients aged 12-54 years with exercise-induced anaphylaxis. ^[2] Prodromal symptoms included a feeling of fatigue, generalized warmth and pruritus, and cutaneous erythema. The early phase featured generalized urticaria. In fully established attacks, symptoms included choking, respiratory stridor, GI colic, nausea, and vomiting. Late sequelae included frontal headaches that persisted for 24-72 hours. (See Clinical Presentation.)

Vigorous forms of physical activity such as jogging, tennis, dancing, and bicycling are more commonly associated with exercise-induced anaphylaxis, although lower levels of exertion (eg, walking and yard work) are also capable of triggering attacks. In a long-term follow-up study, the physical activity most often associated with exercise-induced anaphylaxis was jogging. ^[3] Other reports have implicated running, soccer, raking leaves, shoveling snow, and horseback riding. ^[4] (See Etiology.)

Exercise-induced anaphylaxis attacks are not consistently elicited by the same type and intensity of physical activity in a given patient. Co-factors such as foods, alcohol, temperature, drugs (eg, aspirin and other nonsteroidal anti-inflammatory drugs), humidity, seasonal changes, and hormonal changes are important in the precipitation of attacks. ^[1] (See Etiology.)

A distinct subset of exercise-induced anaphylaxis is food-dependent exercise-induced anaphylaxis (FDEIA), in which anaphylaxis develops only if physical activity occurs within a few hours after eating a specific food. Neither food intake nor physical activity by itself produces anaphylaxis. ^[5]

The foods most commonly implicated in food-dependent exercise-induced anaphylaxis are wheat, shellfish, tomatoes, peanuts, and corn. ^[6] However, the disorder has been reported with a wide variety of foods, including fruits, seeds, milk, soybean, lettuce, peas, beans, rice, and various meats.

One case report described a patient who developed symptoms of anaphylaxis only after simultaneous ingestion of 2 foods (wheat and umeboshi) prior to exercise. ^[7] In the nonspecific form of food-dependent exercise-induced anaphylaxis, eating any food prior to exercise induces anaphylaxis. ^[8]

Inhalant allergens have also been implicated in exercise-induced anaphylaxis. In a case report, a 14-year-old boy presented with severe exercise-induced anaphylaxis after the ingestion of Penicillium mold–contaminated food and running in the school. ^[9] In another case report, a 16-year-old girl presented with exercise-induced anaphylaxis after ingestion of wheat flour contaminated with storage mites. ^[10]

Familial exercise-induced anaphylaxis has been described in patients with a family history of exercise-induced anaphylaxis and atopy. ^[11] Seven males from 3 generations were described with cutaneous and respiratory symptoms induced by physical activity. ^[12]

Prevention remains the best treatment for patients with exercise-induced anaphylaxis (see Treatment and Management). Reducing physical activity to a lower level may diminish the frequency of attacks. In patients whose attacks are associated with ingestion of food, avoiding the offending food for 12 hours prior to exercise is essential. If no offending food is known, then the patient should avoid eating any food 6-8 hours prior to exercise. Patients should avoid exercise in extremely humid, hot, or cold weather and during the allergy season.

Patients should be instructed on the proper use of emergency injectable epinephrine (Adrenaclick, EpiPen, Twinject) and have one available at all times. Patients should wear a medical alert bracelet with instructions on the use of epinephrine. (See Medication.)

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The pathophysiology of exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis is not well understood. The exercise-specific factor, or combination of factors, responsible for causing the attacks remains unclear. ^[13]

Cutaneous mast cell degranulation and elevations of plasma histamine ^[14] and tryptase ^[15] have been documented in exercise-induced anaphylaxis. Therefore, mast cell activation and release of histamine and other mediators is believed to be responsible for the clinical manifestations of exercise-induced anaphylaxis, as with other forms of anaphylaxis. In patients with exercise-induced anaphylaxis, the threshold for mast cell degranulation is lowered, although the specific physiologic or cellular events responsible for lowering this threshold are unknown.

During exercise, endogenous endorphins are released. Endorphins are known to be mast cell secretagogues, ^[16] although the exact mechanism of this effect in the setting of exercise-induced anaphylaxis remains unknown.

By definition, patients with food-dependent exercise-induced anaphylaxis are able to tolerate ingestion of the causative food without difficulty in the absence of exercise and are also able to exercise without difficulty in the absence of exposure to the causative food. This suggests that this disorder involves temporary loss of tolerance as a result of some physiologic change induced by the combination of physical activity and the causative food.

Multiple theories have been proposed to explain food-dependent exercise-induced anaphylaxis. Intestinal permeability increases during exercise; thus, allergenic proteins may have greater access to the gut-associated immune system. ^[17] Nonsteroidal anti-inflammatory drugs (NSAIDs) and alcohol can act as co-triggers for food-dependent exercise-induced anaphylaxis and exercise-induced anaphylaxis by their ability to increase intestinal permeability. ^[18]

Food-dependent exercise-induced anaphylaxis may be associated with abnormalities of the autonomic nervous system. In one study, autonomic function was tested in 4 children with food-dependent exercise-induced anaphylaxis and 4 normal controls. ^[19] After exercise challenge, the parasympathetic nervous system activity increased in the test group, whereas the responsiveness of the sympathetic nervous system was reduced compared with controls.

Transglutaminase is activated during exercise and is capable of binding to gliadin moieties (specifically omega-5 gliadin) in wheat to form larger, potentially immunogenic complexes that demonstrate increased immunoglobulin E (IgE) binding and cross-linking. ^[20] This theory suggests that exercise may induce changes in the processing of specific allergens, which may lead to increased allergenicity.

In a controlled study in 16 adults with a history of wheat-dependent, exercise-induced anaphylaxis (WDEIA) and omega-5-gliadin-specific IgE, prospective oral food challenges (OFCs) with increasing amounts of gluten alone, or in combination with one or more co-factors, were performed until symptoms developed. Plasma gliadin levels were elevated by higher gluten doses, gluten and exercise, or gluten and acetylsalicylic acid (ASA) plus alcohol. Positive plasma gliadin threshold levels differed by more than 100-fold (median 628 pg/mL, range 15–2111). In some patients, exercise was not an essential trigger for symptoms. ^{[21, 22]}

Epitope recognition may influence the severity of allergic clinical reactions, as is the case for peanut allergy. ^[23] Exercise-specific factors may facilitate the immunologic process of epitope recognition.

Exercise mobilizes and activates intestinal immune cells, which disrupts the normal balance between pro-inflammatory and anti-inflammatory responses. ^[24] Dysregulation of this process in patients with food-sensitized immune cells could be involved in exercise-induced reactions.

Exercise may result in changes in mucosal tissue osmolality, which may result in basophil histamine release. ^[25] A case report demonstrated increased basophil histamine release in response to hyperosmolar medium in a patient with food-dependent exercise-induced anaphylaxis compared with normal controls. ^[26]

The exact prevalence of exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis is not well established. Although both disorders have been reported around the world, ^{[3, 4, 27]} few attempts to systemically establish prevalence rates have been made.

A questionnaire study of 76,229 junior high students in Japan showed prevalence of exercise-induced anaphylaxis in this population to be 0.03% and food-dependent exercise-induced anaphylaxis to be 0.017%. ^[4] An older study from Japan reported a higher prevalence of 0.21% for food-dependent exercise-induced anaphylaxis among junior high students. ^[27]

Exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis are usually sporadic, although familial cases have been reported. ^{[11, 12]}

In a large cohort of patients with exercise-induced anaphylaxis including 279 patients, females predominated 2:1 versus males. ^[28] Another study did not show a sex predilection. ^[4]

Cases of exercise-induced anaphylaxis have been reported in children as young as 3 years. Typical age of onset is adolescent age to the third decade of life. In a 10-year retrospective study by Sheffer et al, the average age of onset was 26 years, with a range from 3 years to 66 years at the time of onset. ^[3]

Patients must understand the emergent nature of exercise-induced anaphylaxis and the proper use of emergency injectable epinephrine (Adrenaclick, EpiPen, Twinject).

Instruct patients with exercise-induced anaphylaxis on the ways to abate a full attack by recognizing the early warning signs and symptoms and taking the steps to prevent the progression of the syndrome. This includes limiting exercise and being cautious in temperature extremes.

Patients with the food-dependent or medicine-dependent variants of exercise-induced anaphylaxis need to be aware of the offending food or medication (if specific ones can be identified) and know how long to refrain from exercise after eating.

Educate patients with exercise-induced anaphylaxis about the need to exercise with a partner who is aware of exercise-induced anaphylaxis and the emergent nature of an episode.

The prognosis of patients with exercise-induced anaphylaxis is generally favorable. Most patients experience fewer and less severe attacks over time. Although rare, several fatalities have been attributed to exercise-induced anaphylaxis or food-dependent exercise-induced anaphylaxis. ^{[29, 30]} No cure for this disorders exists. With appropriate lifestyle changes, however, patients may be able to reduce or eliminate episodes of anaphylaxis, and prompt intervention can abort those episodes that do occur.