AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Exercise-induced anaphylaxis (EIA) is a syndrome in which patients experience the symptoms of anaphylaxis, which occur only after increased physical activity. The symptoms include pruritus and urticaria (typically with giant hives), and, without emergency intervention, the patient may develop hypotension and collapse. Now increasingly recognized as more children and teenagers participate in physical activities and sports, EIA quite possibly will become more common in the future. Those affected by the syndrome are typically accomplished athletes and have a history of atopy, but anyone can be affected.

The types of physical activities that have triggered episodes of EIA have included walking, dancing, racquet sports, swimming, jogging, bicycling, skiing, basketball, and sprinting. Hot humid weather and cold weather can precipitate episodes in some patients. If a patient has recurrent EIA, the episodes tend to be worse in the summer months. The first reported case of EIA was in 1979 by Maulitz and coworkers and was food-related, occurring in a 31-year-old patient who had ingested shellfish prior to long-distance running. Since then, many different allergens have been reported in the literature to have caused EIA, including shrimp, oyster, celery, cheese sandwiches, pizza, wheat gliadin, eggs, peaches, grapes, chick peas, pears, poppy seeds, and snails (which have been reported to have cross-reactivity with dust mites).

In 1980, Sheffer and Austen provided the first report of patients with EIA. Sixteen patients, aged 12-54 years, experienced EIA without a specific allergen exposure. Ten of these patients had onset of EIA in their teenage years, indicating that those who care for pediatric patients should be aware of this syndrome.

EIA has been categorized in a few different ways in the literature. Classic EIA is the most common type. Sheffer and Austen (1980) originally described 4 phases in the sequence of symptomatology of classic EIA. A prodromal phase is characterized by fatigue, warmth, pruritus, and cutaneous erythema. The early phase follows, with the urticarial eruption that progresses from giant hives (about 10-15 mm in diameter) to become confluent and may include angioedema of the face, palms, and soles. Then, the fully established phase occurs, which can include hypotension, syncope, loss of consciousness, choking, stridor, nausea, and vomiting and can last 30 minutes to 4 hours. The final phase is the late or postexertional phase, which is characterized by prolonged urticaria and headache persisting for 24-74 hours.

Another type of EIA is variant-type EIA, which is similar to classic EIA, except the typical giant hives are not observed. In their place are small punctate skin lesions, more typical of cholinergic urticaria, but the syndrome does lead to hypotension and collapse if allowed to progress. The variant type of EIA accounts for approximately 10% of cases.

Familial EIA has been described involving patients with a family history of EIA and atopy. No inheritance pattern has been established.

Two forms of food-dependent EIA have been described. Inherent in the definition of food-dependent EIA is that the food or exercise alone does not produce symptoms. First, specific-food EIA exists in which a specific food is known to be the offending allergen. Second, non–specific-food EIA exists in which no specific food is known, but eating any food prior to exercise causes symptoms of EIA.

The last type of EIA described is medication- or drug-dependent EIA. This category includes patients who develop the syndrome only after ingesting a specific medication and then exercising. The offending medications that have been reported include nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, antibiotics, and cold remedies.

Pathophysiology

In EIA, an exercise-induced lowering of the mast cell degranulation threshold exists, which causes the release of histamine and other mediators and leads to the progression from pruritus and urticarial rash to the symptoms of anaphylaxis. In the food-dependent subset, this process is influenced by immunoglobulin E (IgE) mast cell sensitization by a known or unknown food. If the offending food is known, the amount of the specific food ingested has an effect on whether the patient has symptoms. The mechanism by which exercise lowers the mast cell degranulation threshold is unknown. Previous observations suggest that increased physical activity has a direct effect on mast cell releasability and does not result in an increased sensitivity to histamine.

Once the histamine and other mast cell mediators, including leukotrienes, are released, they cause the smooth muscle contraction responsible for the wheezing and GI symptoms. The histamine and other mast cell mediators also cause the vascular dilatation that leads to the escape of plasma into the tissues, causing urticaria and angioedema, and results in hypotension and shock.

Frequency

United States

Prevalence is not well established. In one study, 9% of total episodes of childhood anaphylaxis and 20% of episodes in children older than 8 years were triggered by exercise.

International

Case reports from Germany, Italy, Japan, United States, and Thailand are provided in the literature.

Mortality/Morbidity

Deaths of children have been reported, but they are rare. Infrequently, patients must alter their lifestyle and physical activity significantly; in some patients, the syndrome causes them to be unable to perform daily activities without the risk of anaphylactic syndrome.

Race

No racial predilection is known.

Sex

One study showed a slight male predominance, but most other studies show no overwhelming difference between sexes.

Age

EIA has been reported from as young as 4 years into adulthood. In a study of 16 patients, 10 patients (63%) had onset in their teenage years.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Pediatric patients with EIA typically are athletic or involved in school or otherwise organized sports, and they typically have a history of atopy and/or a family history of atopy or possibly of EIA.

• Typical episodes occur after exercise on a particularly hot, humid, or cold day.
• History of ingesting aspirin or other nonsteroidal anti-inflammatory drug, a meal, or a specific food prior to exercising may exist.
• In women, the episodes can be more frequent and more severe before and during menstrual cycles.
• The history of an episode most likely includes the initial pruritus and giant hives associated with the onset of the symptoms.
• As the syndrome progresses, the patient may report nausea, cramping, diarrhea, vomiting, tinnitus, vertigo, pruritus, difficulty breathing, chest tightness, and wheezing; a syncopal episode may occur.
• The history may be obtained from a paramedic who responded to the collapse of a child. In this case, the patient's history may include loss of consciousness or variable consciousness.
• In several minutes or hours after the episode, the patient may report only a headache that can persist for up to 3 days.

Physical

The physical examination should start with the airway, breathing, and circulation (ABCs).

• The most emergent assessments are those of airway maintenance and level of consciousness. One must rule out laryngeal obstruction.
• Simultaneously assess for hypotension.
• The rest of the physical examination should include looking for the typical features of EIA, including urticaria and giant hives, angioedema, wheezing, and stridor.

Causes

Risk factors for EIA include personal or family history of EIA or atopy, male sex (in one study), exposure to food allergen, and extremes of weather. Beta-blocker medications can aggravate anaphylactic episodes.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Cholinergic urticaria
Idiopathic anaphylaxis
Exercise-induced asthma
Vocal cord dysfunction
Mastocytosis

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• Serum histamine levels are increased during anaphylactic episodes. Increased serum tryptase levels have been reported in some patients.
• In one study, laboratory tests included assessments of whole-complement activity (CH50), C3 and C4 complement proteins, immunoglobulin classes, and blood chemistries; results were within the reference range.

Imaging Studies

• No imaging studies are routinely recommended.

Other Tests

• Radioallergosorbent testing (RAST), allergy skin testing, food-challenge testing, exercise-challenge testing, exercise food–challenge testing, and methacholine-challenge testing all are potential ways to obtain valuable information about patients suspected of having EIA.

Procedures

• No procedures are routinely recommended.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

• Discontinue exercise at the first sign of cutaneous erythema, pruritus, urticaria or malaise.
• Subcutaneous epinephrine is the drug of choice if the symptoms progress to anaphylaxis.
• Airway maintenance, oxygen therapy, fluid resuscitation, vasoactive drugs, and cardiopulmonary support should be used if necessary.
• Patients can be treated with oral antihistamines (eg, diphenhydramine [Benadryl], hydroxyzine [Atarax], cetirizine [Zyrtec], loratadine [Claritin]) during EIA episodes and prophylactically to prevent the onset of episodes, but studies on their effectiveness are lacking.
• • Histamine2-receptor (H2) blockers, such as cimetidine (Tagamet) and the tricyclic antidepressant doxepin hydrochloride, have been tried in patients whose symptoms are not controlled on an H1 blocker alone, but the effectiveness has not been established.
  • Prophylactic sodium bicarbonate and cromolyn sodium have been suggested as preventative treatments as well but have not been used extensively.
  • Ketotifen, an H1-receptor antagonist, mast cell stabilizer, and up-regulator of beta-adrenergic receptors, has been used and found helpful in the treatment of EIA, but it is not available in the United States.
• Prevention remains the best treatment for patients who have EIA. For food- or drug-dependent EIA, avoiding the offending food or drug 12 hours prior to exercise is essential, and, if no offending food is known, avoiding the ingestion of any food 6-8 hours prior to exercise is sometimes necessary. The history of the use of aspirin or other nonsteroidal anti-inflammatory drug prior to the onset of an exercise-induced anaphylaxis episode is important. The avoidance of these medications prior to exercise is indicated in such a patient.
• Patients must be instructed on the proper use of emergency injectable epinephrine, or EpiPen, and have at least one available and with them when exercising. Patients should always exercise with a partner knowledgeable about the syndrome and its emergent nature. This exercise partner should be trained in the use of an EpiPen. Patients with EIA should wear a medical alert bracelet with instructions for use of epinephrine.

Surgical Care

Patients with EIA require surgical intervention only if they need emergent tracheostomy or central line access.

Consultations

• Allergist - For diagnostic workup, preventive measure, and therapy
• Critical care specialist - During acute episode

Diet

If an offending food is identified, avoidance of this food for at least 12 hours prior to exercise is mandatory for the successful prevention of EIA episodes. Patients must also monitor the amount ingested of the offending food because greater volume seems to have a direct correlation with frequency and severity of episodes. If food is a trigger but no specific food is identified, then avoiding all food for 6-8 hours prior to exercise is sometimes recommended. Food avoidance strategies must be tailored to the individual patient with help from a physician.

Activity

Some patients with EIA must limit their physical activity significantly to avoid the progression of episodes. Discontinuation of exercise at the earliest symptom is crucial to stop the progression of the episode.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

If the syndrome has progressed to anaphylaxis, then subcutaneous epinephrine or emergency self-injectable epinephrine (eg, EpiPen) is the drug of choice (DOC). Other medications considered to be potentially helpful prophylactically and during an episode are antihistamines.

Drug Category: Sympathomimetic agents

Epinephrine, either SC or IM, is the DOC for the treatment of severe anaphylaxis in a patient with EIA. Epinephrine antagonizes the effects of the chemical mediators, including histamine and leukotrienes, on smooth muscle and blood vessels.

Drug Category: Antihistamines

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.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Admit to the pediatric intensive care unit (PICU) if a need for mechanical ventilation and/or cardiac monitoring is present.
• Admit to the pediatric floor for monitoring if the patient recovers from the episode.
• Arrange for injectable epinephrine teaching while the patient is in the hospital.

Further Outpatient Care

• Arrange for a food and over-the-counter medication diary; remind the patient of prevention techniques; and perform exercise-challenge testing, food-challenge testing, skin prick testing, and RAST testing.

In/Out Patient Meds

• Inpatient medications include subcutaneous epinephrine, fluid resuscitation as needed, cardiovascular support as needed, and an antihistamine for urticaria and pruritus.
• Outpatient medications include prophylactic antihistamines and EpiPen injection.

Transfer

• Patients in whom the episode has progressed to the point of needing cardiovascular and pulmonary support, including mechanical ventilation, require transfer to an appropriate facility capable of that level of care.

Deterrence/Prevention

• Prevention remains the best treatment for patients who have EIA. Avoiding offending food 12 hours prior to exercise is essential, and, if no offending food is known, then the patient should avoid eating any food 6-8 hours prior to exercise. If aspirin or nonsteroidal anti-inflammatory drugs are suspected as the trigger, these medications should be avoided prior to future exercise.
• Instruct patients on the proper use of emergency injectable epinephrine, or EpiPen, and have at least one available and with them when exercising. Patients should wear a medical alert bracelet with instructions on the use of epinephrine.
• Patients should always exercise with a partner knowledgeable about the syndrome and its emergent nature as well as the proper treatment. This partner needs to be instructed on the proper use of an EpiPen.

Complications

• Hypotension, shock, loss of consciousness, airway compromise, and death are possible complications.

Prognosis

• The prognosis of EIA depends upon the preventative techniques employed by the patient.
• • Patients can usually avoid the progression of an EIA attack by ceasing exercise at any indication of pruritus or urticaria.
  • Some patients with EIA are instructed to avoid any exercise for 6-8 hours after eating any food, to avoid exercise for 12 hours after eating the offending food (if known), to abstain from use of aspirin or other nonsteroidal anti-inflammatory drugs prior to exercise, and to modify their exercise in extremes of temperature.

Patient Education

• Patients must understand the emergent nature of EIA and the proper use of emergency injectable epinephrine.
• • Instruct patients with EIA 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.
  • Teach patients with EIA to limit exercise and be cautious in temperature extremes.
  • In the food- or medicine-dependent variants, the patient needs to have knowledge of the offending food or medication (if known) and know how long to refrain from exercise after eating.
  • Educate patients with EIA about the need to exercise with a partner who is aware of EIA and the emergent nature of an episode.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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Article Last Updated: Jun 15, 2006