eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Exercise-Induced Anaphylaxis

William B Stratbucker, MD, MS,, Assistant Professor of Pediatrics, Michigan State University; Director of Research, Pediatrics Residency Program, Helen DeVos Children's Hospital
Paul H Sammut, MBBCh, FAAP, FCCP, Medical Director of the Pediatric Intensive Care Unit, Associate Professor, Department of Pediatrics, Section of Pulmonology, University of Nebraska Medical Center

Updated: May 8, 2009

Introduction

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, exercise-induced anaphylaxis may 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 exercise-induced anaphylaxis 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 exercise-induced anaphylaxis, the episodes tend to be worse in the summer months. The first reported case of exercise-induced anaphylaxis 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.¹

Since then, many different allergens have been reported in the literature to have caused exercise-induced anaphylaxis, including shrimp, oyster, celery, cheese sandwiches, pizza, wheat gliadin,² eggs, peaches, grapes, pomegranites,³ chick peas,⁴ pears, poppy seeds, soybean,⁵ 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 exercise-induced anaphylaxis.⁶ Sixteen patients, aged 12-54 years, experienced exercise-induced anaphylaxis without a specific allergen exposure. Ten of these patients had onset of exercise-induced anaphylaxis in their teenage years, indicating that those who care for pediatric patients should be aware of this syndrome.

Exercise-induced anaphylaxis has been categorized in a few different ways in the literature. Classic exercise-induced anaphylaxis is the most common type. Sheffer and Austen (1980) originally described 4 phases in the sequence of symptomatology of classic exercise-induced anaphylaxis.⁶ 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 exercise-induced anaphylaxis is variant-type exercise-induced anaphylaxis, which is similar to classic exercise-induced anaphylaxis, 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 exercise-induced anaphylaxis accounts for approximately 10% of cases.

Familial exercise-induced anaphylaxis has been described involving patients with a family history of exercise-induced anaphylaxis and atopy. No inheritance pattern has been established.

Two forms of food-dependent exercise-induced anaphylaxis have been described. Inherent in the definition of food-dependent exercise-induced anaphylaxis is that the food or exercise alone does not produce symptoms. First, specific-food exercise-induced anaphylaxis in which a specific food is known to be the offending allergen is recognized. Second, nonspecific-food exercise-induced anaphylaxis in which no specific food is known, but eating any food prior to exercise causes symptoms of exercise-induced anaphylaxis is also recognized.⁷

The last type of exercise-induced anaphylaxis described is medication-dependent or drug-dependent exercise-induced anaphylaxis. 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 exercise-induced anaphylaxis, an exercise-induced lowering of the mast cell degranulation threshold occurs, 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.^8,9

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

Exercise-induced anaphylaxis 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

History

Pediatric patients with exercise-induced anaphylaxis (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 exercise-induced anaphylaxis.

• Typical episodes occur after exercise on a particularly hot, humid, or cold day.
• History of ingesting aspirin or other nonsteroidal anti-inflammatory drug (NSAID), a meal, or a specific food prior to exercising may be noted.
• 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 as long as 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 exercise-induced anaphylaxis, including urticaria and giant hives, angioedema, wheezing, and stridor.

Causes

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

Differential Diagnoses

Asthma
Syncope

Other Problems to Be Considered

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

Workup

Laboratory Studies

• Serum histamine levels are increased during anaphylactic episodes, including exercise-induced anaphylaxis (EIA). 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

Medical Care

• Discontinue exercise at the first sign of cutaneous erythema, pruritus, urticaria or malaise to prevent worsening exercise-induced anaphylaxis (EIA).
• 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 exercise-induced anaphylaxis 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 exercise-induced anaphylaxis but is not available in the United States.
• Prevention remains the best treatment for patients who have exercise-induced anaphylaxis. For food-dependent or drug-dependent exercise-induced anaphylaxis, 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 (NSAID) 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 exercise-induced anaphylaxis should wear a medical alert bracelet with instructions for use of epinephrine.

Surgical Care

• Patients with exercise-induced anaphylaxis 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 exercise-induced anaphylaxis 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 exercise-induced anaphylaxis 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

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.

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.

Epinephrine (EpiPen, EpiPen Jr)

DOC in the treatment of an anaphylactic episode in a patient with EIA. Administer epinephrine either SC, if at a medical facility, or IM with a self-injectable EpiPen. Possesses alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects of epinephrine include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.

Dosing

Adult

0.3-0.5 mL (0.3-0.5 mg) of aqueous epinephrine 1:1000 concentration SC; dose may need to be repeated
EpiPen: 2 mL of epinephrine injection contained in adult EpiPen, which delivers 0.3 mg of epinephrine or 0.3 mL of 1:1000 concentration aqueous epinephrine; inject into the anterolateral aspect of the thigh, through clothing if necessary; do not inject EpiPen into the buttock or IV

Pediatric

<30 kilograms: 0.01 mL/kg (0.01 mg/kg) of aqueous epinephrine 1:1000 concentration SC; dose may need to be repeated
>30 kilograms: Administer as in adults
EpiPen: 0.15 mg of epinephrine contained in EpiPen Jr is recommended for children <30 kg; doses can be individualized by the prescribing doctor

Interactions

Administration to patients on medications that may sensitize the heart to arrhythmias (eg, digitalis, mercurial diuretics, quinidine) is generally not recommended; tricyclic antidepressants or MAOIs may increase pressor response to epinephrine

Contraindications

No absolute contraindications in a life-threatening situation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Accidental injection with EpiPen into the hands or feet may result in loss of blood flow to the affected area; do not inject EpiPen into the buttock or IV; use with caution in patients with heart disease; anginal pain may be induced in patients with coronary insufficiency; patients with hyperthyroidism, cardiovascular disease, hypertension, and diabetes may be theoretically at greater risk of developing adverse reactions, as well as elderly patients, pregnant women, pediatric patients <30 kg using an EpiPen, and pediatric patients <15 kg using an EpiPen Jr

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.

Diphenhydramine (Benadryl, Benylin)

For symptomatic relief of symptoms caused by release of histamine in allergic reactions.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 400 mg/d
10-50 mg IV/IM q6-8hprn; not to exceed 400 mg/d

Pediatric

5 mg/kg/d or 150 mg/m²/d PO/IV/IM divided tid/qid; not to exceed 300 mg/d

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syr dosage form to patient taking medications that can cause disulfiramlike reactions

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer disease, or urinary tract obstruction; xerostomia may occur

Follow-up

Further Inpatient Care

• Admit patients with exercise-induced anaphylaxis (EIA) 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 radioallergosorbent testing (RAST) testing.

Inpatient & Outpatient Medications

• 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 exercise-induced anaphylaxis. 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 (NSAIDs) 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 exercise-induced anaphylaxis depends on the preventative techniques employed by the patient.
  • Patients can usually avoid the progression of an exercise-induced anaphylaxis attack by ceasing exercise at any indication of pruritus or urticaria.
  • Some patients with exercise-induced anaphylaxis 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 NSAID prior to exercise, and to modify their exercise in extremes of temperature.

Patient Education

• Patients must understand the emergent nature of exercise-induced anaphylaxis and the proper use of emergency injectable epinephrine.
  • 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.
  • Teach patients with exercise-induced anaphylaxis 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 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.

References

1. Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol. Jun 1979;63(6):433-4. [Medline].

2. Lee JY, Yoon S, Ye YM, Hur GY, Kim S, Park HS. Gliadin-specific IgE in wheat-dependent exercise-induced anaphylaxis. Allergy Asthma Proc. Nov-Dec 2008;29(6):614-21. [Medline].

3. Gangemi S, Mistrello G, Roncarolo D, Amato S, Minciullo PL. Pomegranate-dependent exercise-induced anaphylaxis. J Investig Allergol Clin Immunol. 2008;18(6):491-2. [Medline].

4. Orhan F, Karakas T. Food-dependent exercise-induced anaphylaxis to lentil and anaphylaxis to chickpea in a 17-year-old boy. J Investig Allergol Clin Immunol. 2008;18(6):465-8. [Medline].

5. Adachi A, Horikawa T, Shimizu H, et al. Soybean beta-conglycinin as the main allergen in a patient with food-dependent exercise-induced anaphylaxis by tofu: food processing alters pepsin resistance. Clin Exp Allergy. Jan 2009;39(1):167-73. [Medline].

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Keywords

exercise-induced anaphylaxis, EIA, food-dependent exercise-induced anaphylaxis, drug-dependent exercise-induced anaphylaxis, medicine-dependent exercise-induced anaphylaxis, physical urticaria, pruritus, NSAIDs, shock, hypotension, anaphylaxis syndrome, nausea, cramping, diarrhea, vomiting, tinnitus, vertigo, pruritus, difficulty breathing, chest tightness, treatment, diagnosis

Contributor Information and Disclosures

Author

William B Stratbucker, MD, MS,, Assistant Professor of Pediatrics, Michigan State University; Director of Research, Pediatrics Residency Program, Helen DeVos Children's Hospital
William B Stratbucker, MD, MS, is a member of the following medical societies: American Academy of Pediatrics and Wilderness Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Paul H Sammut, MBBCh, FAAP, FCCP, Medical Director of the Pediatric Intensive Care Unit, Associate Professor, Department of Pediatrics, Section of Pulmonology, University of Nebraska Medical Center
Paul H Sammut, MBBCh, FAAP, FCCP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Lung Association, American Thoracic Society, and International Society for Heart and Lung Transplantation
Disclosure: Nothing to disclose.

Medical Editor

C Lucy Park, MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago
C Lucy Park, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Medical Association, Chicago Medical Society, Clinical Immunology Society, and Illinois State Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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