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.)

To see complete information on Pediatric Anaphylaxis, please go to the main article by clicking here.

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.

Exercise-induced anaphylaxis (EIA) is characterized by signs and symptoms of anaphylaxis in the setting of physical activity. If physical exertion continues, symptoms progress in severity. Premonitory symptoms of exercise-induced anaphylaxis attacks include diffuse warmth, pruritus, erythema, and sweating. These are followed by typical urticarial lesions and angioedema that can progress to include GI symptoms, laryngeal edema, and/or vascular collapse.

Symptoms may begin at any stage of exercise. Cessation of the physical activity usually results in immediate improvement or resolution of symptoms. However, some patients may experience vascular collapse even after exercise cessation.

The frequency of symptoms during exercise varies among patients with exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis. Most patients exercise regularly but experience attacks only occasionally. In patients with food-dependent exercise-induced anaphylaxis, episodes typically occur when the person exercises 1-3 hours after eating. The duration of exercise prior to the development of symptoms may range from less than 30 minutes to a maximum of 45 minutes.

The most common signs and symptoms, along with their relative frequency of occurrence, are as follows:[1]

• Pruritus (92%)

• Urticaria (86%)

• Angioedema (72%)

• Flushing (70%)

• Shortness of breath (51%)

• Dysphagia (34%)

• Chest tightness (33%)

• Syncope (32%)

• Profuse sweating (32%)

• Headache (28%)

• GI symptoms, including nausea, diarrhea, and colicky pain (28%)

• Choking, throat constriction, hoarseness (25%)

Clinicians should also carefully review the events leading up to the episode of anaphylaxis with a special focus on the following:

• Was each of the attacks associated with exercise? If not, then other causes of anaphylaxis should be investigated

• Do symptoms subside when the patient stops physical activity?

• Do activities that raise body temperature in the absence of exercise (eg, hot baths, saunas, or showers) induce symptoms? Symptoms triggered by changes in core body temperature are suggestive of cholinergic urticaria

• Are any medications, changes in environment, or other exposures associated with the episodes?

• What foods has the patient eaten before each episode?

Patients with exercise-induced anaphylaxis commonly experience attacks for over 10 years, with an average of 14 attacks per year, before their disorder is diagnosed. The frequency of attacks is diminished in patients who have avoided known triggers or reduced their physical activity.

Physical examination findings may be highly variable in patients with exercise-induced anaphylaxis or food-dependent exercise-induced anaphylaxis. Signs of chronic allergic disease such as eczema, “allergic shiners,” and boggy nasal mucosa suggestive of allergic rhinitis may be noted.

A careful skin examination should be performed to evaluate for dermatographism and urticaria pigmentosa, which are characteristic findings in mastocytosis. Urticaria pigmentosa is characterized by oval or round red-brown macules, papules, or plaques. Mastocytosis may present with anaphylaxis that is precipitated by exercise and in response to various different triggers; therefore, excluding this disorder is important.

Cardiac examination should be performed to exclude abnormal heart sounds because exercise-induced cardiac disorders are also in the differential.

Respiratory symptoms

During an episode, severe angioedema of the tongue and lips may obstruct airflow. Laryngeal edema may manifest as throat constriction and stridor. Hoarseness, change in voice, dysphagia, or a sensation of choking may occur. Bronchospasm, airway edema, and increased mucus production may manifest as wheezing and chest tightness.

Cardiovascular symptoms

Tachycardia usually occurs as a compensatory response to reduced intravascular volume and endogenous catecholamine release during an episode. Hypotension can occur secondary to capillary leak, vasodilatation, and myocardial depression. Cardiovascular collapse and shock can occur in the absence of other findings and patients may present with syncope.

Cutaneous symptoms

Hives can occur anywhere on the body. The lesions are generally large (giant hives) and are erythematous, raised, and highly pruritic. Angioedema is also commonly observed. These lesions involve the deeper dermal layers of skin. It is usually nonpruritic and nonpitting. Generalized flushing and profuse sweating may also be observed.

Gastrointestinal symptoms

Vomiting, diarrhea, and colicky abdominal pain are frequently observed.

In an attack of acute exercise-induced anaphylaxis or food-dependent exercise-induced anaphylaxis, as with anaphylaxis in general, the focus should be on acute resuscitation and the emergency ABCs (airway, breathing, circulation). Maintenance of a patent airway and monitoring for circulatory collapse are critical.

Admit patients with exercise-induced anaphylaxis (EIA) to the intensive care unit (ICU) if mechanical ventilation and/or cardiac monitoring is required. Admit to the inpatient ward for monitoring if the patient recovers from the episode. Arrange for injectable epinephrine teaching while the patient is in the hospital.

If symptoms progress to anaphylaxis, intramuscular epinephrine is the drug of choice. Airway maintenance, oxygen therapy, fluid resuscitation, and cardiopulmonary support should be used if necessary. Surgical intervention is indicated only for patients who need emergent tracheostomy or central line access.

Long-term management of exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis must be individualized to each patient, because the severity, frequency, intensity of exercise needed to trigger anaphylaxis and the possible association with other co-triggers all vary. Other medications, such as oral steroids, leukotriene-modifying agents, and omalizumab, are either unstudied or reported only in isolated cases.

Patients should be educated to recognize the prodromal manifestations of exercise-induced anaphylaxis so that physical activity can be discontinued at the earliest warning signs and the progression to vascular collapse can be prevented.

To see complete information on Pediatric Anaphylaxis, please go to the main article by clicking here.

In an attack of acute exercise-induced anaphylaxis or food-dependent exercise-induced anaphylaxis, as with anaphylaxis in general, the focus should be on acute resuscitation and the emergency ABCs (airway, breathing, circulation). Maintenance of a patent airway and monitoring for circulatory collapse are critical.

Admit patients with exercise-induced anaphylaxis (EIA) to the intensive care unit (ICU) if mechanical ventilation and/or cardiac monitoring is required. Admit to the inpatient ward for monitoring if the patient recovers from the episode. Arrange for injectable epinephrine teaching while the patient is in the hospital.

If symptoms progress to anaphylaxis, intramuscular epinephrine is the drug of choice. Airway maintenance, oxygen therapy, fluid resuscitation, and cardiopulmonary support should be used if necessary. Surgical intervention is indicated only for patients who need emergent tracheostomy or central line access.

Long-term management of exercise-induced anaphylaxis and food-dependent exercise-induced anaphylaxis must be individualized to each patient, because the severity, frequency, intensity of exercise needed to trigger anaphylaxis and the possible association with other co-triggers all vary. Other medications, such as oral steroids, leukotriene-modifying agents, and omalizumab, are either unstudied or reported only in isolated cases.

Patients should be educated to recognize the prodromal manifestations of exercise-induced anaphylaxis so that physical activity can be discontinued at the earliest warning signs and the progression to vascular collapse can be prevented.

To see complete information on Pediatric Anaphylaxis, please go to the main article by clicking here.

Intramuscular epinephrine is the drug of choice for acute attacks of exercise-induced anaphylaxis (EIA) or food-dependent exercise-induced anaphylaxis (FDEIA). Early administration of intramuscular epinephrine is associated with decreased mortality in patients with anaphylaxis.[36]

Other medications play an ancillary role in the treatment of anaphylaxis. H1-antihistamines relieve itch and hives, but they do not relieve airway obstruction or shock. Beta2-adrenergic agonists relieve bronchospasm, but they do not relieve upper airway obstruction or shock. Glucocorticoids might prevent protracted or biphasic symptoms, but they do not provide rapid relief of upper or lower airway obstruction, shock, or other symptoms of anaphylaxis.

If the syndrome has progressed to anaphylaxis, then intramuscular epinephrine or emergency self-injectable epinephrine (eg, Adrenaclick, EpiPen, Twinject) is the drug of choice.

Class Summary

Epinephrine, administered intramuscularly, is the drug of choice for the treatment of severe anaphylaxis in a patient with exercise-induced anaphylaxis. Epinephrine antagonizes the effects of the chemical mediators, including histamine and leukotrienes, on smooth muscle and blood vessels.

Epinephrine (Adrenaclick, EpiPen, EpiPen Jr, Twinject)

Epinephrine should be administered intramuscularly in the mid-anterolateral thigh. This agent possesses alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. The beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Class Summary

These agents are used to treat minor allergic reactions and anaphylaxis. They prevent histamine response in sensory nerve endings and blood vessels. These agents are more effective in preventing histamine response than in reversing it. They act by competitive inhibition of histamine at the H1 receptor. This mediates the wheal-and-flare reactions, bronchial constriction, mucus secretion, smooth muscle contraction, edema, hypotension, CNS depression, and cardiac arrhythmias.

Diphenhydramine (Benadryl, Benylin)

Diphenhydramine is indicated for symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Class Summary

Beta-agonists relax bronchial smooth muscle by action on beta2 -receptors, with little effect on cardiac muscle contractility. These agents are used in the prevention of exercise-induced bronchospasm.

Albuterol

Albuterol is indicated for the prevention of exercise-induced bronchospasm and for adults and children aged 4 years and older for the treatment or prevention of bronchospasm with reversible obstructive airway disease.

Class Summary

Corticosteroids help to control severe allergic conditions intractable to conventional treatment in patients with serum sickness and drug reactions. Corticosteroids may prevent protracted or biphasic symptoms during acute anaphylaxis. However, they do not provide rapid relief of upper or lower airway obstruction, shock, or other symptoms of anaphylaxis.

Prednisone

Prednisone is an immunosuppressant for the treatment of allergic reactions. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil activity.