Identifying Exercise Allergies: Exercise-Induced Anaphylaxis and Cholinergic Urticaria
Tom Terrell, MD, MPhil; David O. Hough, MD*; Raquelle Alexander, MDTHE PHYSICIAN AND SPORTSMEDICINE - VOL 24 - NO. 11 - NOVEMBER 96
In Brief: Exercise-related allergies vary from the benign rash of cholinergic urticaria to life-threatening exercise-induced anaphylaxis. Rapid diagnosis is essential, but it can be difficult to tell the two conditions apart. The size of the wheals and the patient history provide the best clues. Giving epinephrine and taking steps to protect the patient's airway, breathing, and circulation are standard treatment for exercise-induced anaphylaxis. Effective management for less severe cases involves exercising with a partner, keeping self-injectable epinephrine on hand, and avoiding exercise before and after meals. Prophylactic antihistamines are more effective for cholinergic urticaria than for exercise-induced anaphylaxis.
Of the various allergies that sports medicine professionals encounter, exercise-induced anaphylaxis and cholinergic urticaria are among the most underappreciated. Though the conditions are rare, it's important to become familiar with them because they can be life threatening. This review of two cases of exercise-induced anaphylaxis and one case of cholinergic urticaria is intended to help physicians diagnose and treat patients who have sports-related allergies.
A 20-year-old male college soccer player presented after having had three episodes of diffuse urticaria associated with a sensation of throat thickening, audible wheezing, and mild shortness of breath. Each episode occurred within 1 hour of completing strenuous exercise. The first had occurred in the early evening at practice, starting with discrete hives on the extremities that quickly spread over his entire body, and progressing to dysphagia and mild symptoms of stridor within minutes. The episode resolved 30 minutes after he stopped exercising. The second episode occurred midday in hot, humid conditions while the patient was playing football on a beach during spring break.
His symptoms—facial and lip swelling and dysphagia—were treated with prednisone and diphenhydramine. Playing volleyball while on prednisone produced no symptoms. The most recent episode had occurred while he was playing soccer and involved perioral and facial swelling, mild dysphagia, and scattered truncal hives measuring 10 to 20 mm in diameter.
The patient's medical history was negative for atopic disease, viral respiratory infection, or other medical problems. He denied any allergies. His family history was positive for allergic rhinitis. The physical exam revealed no significant skin lesions. The patient's nasal passages had mild bilateral edema with mucus. The remaining physical exam was normal.
The diagnosis was exercise-induced anaphylaxis with an atypical form of urticaria.
The patient was taught about the signs and symptoms of anaphylaxis and about when to self-administer epinephrine. He was prescribed loratadine 10 mg once a day to be taken 1 hour before exercise and diphenhydramine hydrochloride 25 to 50 mg as needed for hives.
The patient did well using this regimen, even while running in hot summer conditions. He stopped taking his medications 5 months after the first episode and did not have a relapse until 11 months later. After the relapse, allergy skin testing performed by another physician demonstrated atopy. While playing beach football he had a relapse that consisted of periorbital edema, skin itching, and scratchy voice with a lump in the throat, followed after several minutes by diffuse, pruritic hiving and anterior chest tightness with a cough. After a cool shower, his symptoms resolved in 1 hour without treatment.
After this episode, his physician discontinued treatment with prophylactic antihistamines because of the possibility of masking the early warning signs of anaphylaxis. (Most allergists would not discontinue antihistamines for this reason.) The patient was instructed to take loratadine for pruritus associated with hiving, after symptoms of early anaphylaxis have resolved. Instructions on when and how to administer epinephrine were reinforced. The patient was advised to wear a medical alert bracelet and to exercise with a partner during cool times of the day.
An 18-year-old female college runner presented after having two episodes of severe lightheadedness, dyspnea, chest tightness, scalp pruritus, chills, and tunnel vision 5 minutes into vigorous runs. Subsequently, she developed a feeling of warmth over her face and upper body but no urticaria. She had no cough, dysphagia, or wheals and was not sure if she had had throat tightness. Taking a hot shower made the condition worse. A third episode was similar, but without lower-respiratory-tract symptoms. The episodes had occurred within 3 hours after meals.
The patient's history was significant for possible mild exercise-induced bronchospasm. Her family history revealed cat-induced allergic rhinitis. The exam was otherwise normal. Prick skin testing demonstrated isolated 2+ reactions to soy and pecan. Spirometry and exercise bronchoprovocation studies were normal.
The diagnosis was exercise-induced anaphylaxis with very mild exercise-induced bronchospasm.
Because her exercise-induced anaphylaxis might have had a food allergy component, the patient was asked to keep a food diary with future episodes, to avoid soy products, and to avoid exercise within 4 hours after meals. She was prescribed injectable epinephrine for anaphylaxis episodes and diphenhydramine as needed for hiving. She was lost to further follow-up.
A 32-year-old woman presented with hives of 2 months duration on her arms, legs, and jaw line. The patient said her hives were worse in the evening and were exacerbated by hot showers, but not by exercise or sweating. She reported lip swelling but no face swelling. She denied having shortness of breath, breathing problems, nasal symptoms, sneezing, and watery eyes.
The patient's medical history was noncontributory; she took no medicines and denied medicine allergies. Her family history was significant for allergies. Her social history revealed that she had been making stressful wedding plans. The physical exam revealed small, nonconfluent hives of about 5 mm diameter on her arms; there was no dermatographism. Physical exam was otherwise unremarkable. Allergy testing was negative for dust, mold, and pollens.
The diagnosis was chronic cholinergic urticaria with angioedema.
Treatment included 25 mg hydroxyzine hydrochloride three to four times daily and 10 mg loratadine each day. Her symptoms abated in about 2 weeks, and she takes hydroxyzine as needed for occasional hives with hot showers.
What Sparks a Reaction?
The three major differential diagnoses considered in the case presentations are the physical urticarias: classic exercise-induced anaphylaxis, exercise-induced anaphylaxis variant syndrome, and cholinergic (generalized heat) urticaria. A familial form of exercise-induced anaphylaxis also exists(1).
Exercise-induced anaphylaxis was described first by Maulitz et al in 1979 (2). It is more common in young people (the mean age at onset was 25 years), and the condition is twice as common in women as in men (3). Clinical features include a flushing sensation, pruritus, gastrointestinal complaints such as vomiting, and throat tightness or choking (table 1: not shown). Diffuse, large urticarial wheals, angioedema, bronchospasm, and hypotension may occur (4-11). Exercise-induced anaphylaxis may also progress to angioedema or full-fledged anaphylaxis. Angioedema sometimes presents with painful swelling of the face, extremities, and oral cavity.
In exercise-induced anaphylaxis variant syndrome, the wheals are smaller (2 to 4 mm) punctate lesions, and patients more frequently progress to anaphylaxis.
As the name implies, exercise-induced anaphylaxis occurs only with exercise, but various environmental, physiologic, hormonal, drug, and food stimuli have been reported as contributing factors (12). Humid, warm, and cold conditions are known precipitants. Some individuals are more likely to experience symptoms if they are exposed to pollens or grasses. Drugs such as aspirin, nonsteroidal anti-inflammatories, over-the-counter cold remedies, and antibiotics have been shown to increase the risk of symptoms in patients who have exercise-induced anaphylaxis (3). Increased emotional responses and menses may be cofactors in exercise-induced anaphylaxis episodes. The patient in case 2 might have had food-related exercise-induced anaphylaxis. Celery has been associated with 13 reported cases of exercise-induced anaphylaxis (3), and wheat, shellfish (2,13), and hazelnuts have also been implicated; however, any food may interact with chemical neuropeptides released during exercise to trigger an exercise-induced anaphylaxis episode.
Cholinergic urticaria is an allergic response to passive warming or exercise and is characterized by small (2 to 4 mm) pruritic papules. It very rarely leads to shock or anaphylaxis (12). Studies have shown that it is most common in young people. In a study (14) of high school and university students aged 15 to 35, the highest prevalence was observed in the 26-to-28 age-group.
The major precipitating factor for cholinergic urticaria is any process that raises the core body temperature by 0.5°C to 1.5°C (0.9°F to 2.7°F), such as hot showers, anxiety, and exercise. By contrast, exercise-induced anaphylaxis does not occur without exercise.
The physical urticarias are IgE-mediated allergic reactions. Physical urticarias are chronic urticarias in which wheals can be reproduced by a physical stimulus (eg, cold, heat, pressure, vibration, light, exercise, water). The final pathway for exercise-induced anaphylaxis and cholinergic urticaria is the same: Antigen exposure cross-links the IgE antibodies on mast cells, which causes the release of histamine and other mediators. Mast cell degranulation and the release of histamine and other mediators lead to symptoms (15). Food may coprecipitate exercise-induced anaphylaxis through an IgE-mediated response when IgE antibodies to a specific food are present, or through a non-IgE-mediated response when gastrin and other hormones react with other neuropeptides released during exercise (16). Etiologic theories involving respiratory heat loss and water loss have also been proposed (17). One study (16) suggests that a central perception of temperature change is followed by an efferent reflex that leads to cholinergic urticaria.
History, Signs, and Symptoms
The patient history plays a key role in differentiating exercise-induced anaphylaxis and cholinergic urticaria. Features that distinguish exercise-induced anaphylaxis from cholinergic urticaria are summarized in table 2 (not shown) (18). Cues such as the onset of symptoms with exercise or certain precipitating factors may point to one or the other. Cholinergic urticaria is more reproducible with exercise. In addition, patients who have cholinergic urticaria are more likely to have bronchospasm, whereas patients who have exercise-induced anaphylaxis are more likely to have upper-airway obstruction.
The symptoms the patient is experiencing during current episodes are the most accurate predictors of progression to anaphylaxis. Patients who have a history of anaphylaxis are less likely to have cholinergic urticaria. Clinical history is not predictive for future oropharyngeal edema and impending airway obstruction.
Exercise-induced anaphylaxis. Classic exercise-induced anaphylaxis is characterized by giant (10 to 25 mm) urticarial wheals that may coalesce. Other symptoms include cutaneous flushing, gastrointestinal problems, pruritus, and headache. In severe cases, the patient may have angioedema of the oropharynx and hands with stridor from upper-airway obstruction. The signs and symptoms of full-blown anaphylaxis include hypotension, syncope, and vascular collapse.
Exercise-induced anaphylaxis occurs exclusively with exercise, but some symptoms may be reproducible in a controlled, closely supervised lab that is prepared to treat acute anaphylaxis (10). However, allergists and primary care sports medicine physicians do not use exercise testing to make the diagnosis of exercise-induced anaphylaxis. Symptoms may begin within 5 minutes of starting exercise and typically abate within 30 minutes to 4 hours after exercise, though headache may persist longer. Wade et al (3) described the experiences of 199 patients who had classic exercise-induced anaphylaxis. Symptoms were usually precipitated by moderate-to-hard exercise, most frequently while jogging. Not surprisingly, attacks typically occurred early in activity, and exercising in a warm or humid environment or after eating increased the likelihood of attacks (3). The most common symptom early in an episode was pruritus (92%). Attacks averaged twice a week, though frequency varied widely (3).
Two thirds of patients who have exercise-induced anaphylaxis have a family history of atopy, and half are atopic, which is not true of the other physical urticarias.
Cholinergic urticaria. The hallmark of cholinergic urticaria is smaller (2 to 4 mm) pruritic papules that are surrounded by macular erythema (12). The rash usually occurs in a follicular distribution and appears on the neck, upper trunk, and proximal limbs. In severe reactions, lesions may coalesce into giant hives, and angioedema may develop. Patients who have cholinergic urticaria may have headache, palpitations, abdominal cramps, diarrhea, sweating, flushing, bronchospasm, or angioedema. Shortness of breath and wheezing occur more than with exercise-induced anaphylaxis. Decreases in forced expiratory volume in 1 second (FEV1) and wheezing have been demonstrated in both spontaneous and experimentally induced cholinergic urticaria attacks (18).
An attack usually occurs 2 to 30 minutes after a precipitant, and it lasts from 20 to 90 minutes (19). On average, patients have the condition 7.5 years (10). One study (20) demonstrated only a 14% spontaneous remission rate.
When the diagnosis is unclear from clinical history alone, laboratory and diagnostic tests are rarely helpful for exercise-induced anaphylaxis and cholinergic urticaria. The lab tests are nonspecific and expensive.
Exercise-induced anaphylaxis. Serum histamine evaluation is not useful because the level usually peaks within 30 minutes after anaphylaxis onset. However, serum tryptase levels, as a referral lab study, peak within 60 to 90 minutes of the onset of anaphylaxis and may provide evidence of mast cell activation if drawn within 3 hours (21). Other factors, such as systemic mastocytosis and drug effects (aspirin use), may also cause nonspecific histamine and tryptase elevations. Exercise challenge tests are risky and nonspecific.
Cholinergic urticaria. The most specific diagnostic test for cholinergic urticaria involves passively warming an extremity with a heating blanket or warm water immersion to raise patients' core temperature by 0.5°C to 1.5°C (0.9°F to 2.7°F). In those who have cholinergic urticaria, serum histamine will increase with or without urticaria symptoms. The methacholine challenge test involves injecting methacholine with saline subcutaneously and watching for a cholinergic urticaria reaction. The test is not routine because the sensitivity is only 50% (22).
The first step in acute treatment for patients who present with hives, pruritus, and flushing and who have not been previously diagnosed as having exercise-induced anaphylaxis or cholinergic urticaria involves having patients stop exercising, getting them to a cool place, and administering an injection of diphenhydramine. If symptoms progress to wheezing, throat tightness, or lightheadedness, patients should receive an injection of epinephrine. If patients' symptoms resolve, the physician prescribes 10 mg oral loratadine, monitors patients closely, then sends them home with injectable epinephrine.
Exercise-induced anaphylaxis. Some patients who have exercise-induced anaphylaxis progress to full-blown anaphylaxis. When more advanced symptoms occur, injectable epinephrine is indicated. A repeat dose may be given in 15 to 20 minutes if the symptoms progress or do not resolve. Patients who have very mild symptoms, however, may not require epinephrine. Their symptoms may resolve within 5 to 10 minutes with minimal treatment. A clinician's experience and comfort level with treating this condition will dictate when he or she feels epinephrine is indicated. Acute treatment of anaphylaxis follows the standard ABC (airway, breathing, circulation) protocol: Place an intravenous line; give oxygen, intravenous fluids, epinephrine, and diphenhydramine; and transport the patient to an emergency room (19). Patients who have developed anaphylaxis should be referred to an allergist.
Long-term treatment for exercise-induced anaphylaxis mandates intensive education of the patient and sports medicine team about the nature of the disease and its precipitants. Wearing a medical alert bracelet is essential. Patients should always carry injectable epinephrine that can be administered by trainers, coaches, or teammates when needed. Patients who have exercise-induced anaphylaxis should exercise with a partner during cool times of the day. In food-dependent cases, patients should avoid exercise within 4 hours after meals, and avoid eating celery or shellfish. If pruritus, cutaneous flushing, or throat tightness develops, the athlete should cease exercise and seek a cool place. If symptoms do not resolve within 5 to 10 minutes of exercise cessation, injectable epinephrine should be administered. If symptoms progress to lightheadedness, hives, throat tightness, or increased wheezing, injectable epinephrine should be given immediately. If epinephrine is given, the patient should be taken to an urgent care facility.
Prophylactic treatment for exercise-induced anaphylaxis has been largely unsuccessful, unproved, and controversial. However, the mainstream treatment approach is to prescribe antihistamines. The majority of studies (23) have failed to show symptom improvement with antihistamines; however, a few studies (7) have shown a reduction in symptoms associated with histamine release. One study (7) showed similar benefits with tricyclic antidepressants (doxepin hydrochloride) and inhaled cromolyn sodium, but these medications are not used. Though allergists routinely prescribe sedating or nonsedating antihistamines (7), a minority feel that these medications may mask the early warning signs and symptoms of anaphylaxis, such as cutaneous itching and rash.
To our knowledge, no study has demonstrated the utility of pairing antihistamines with histamine2 receptor blockers for patients who have exercise-induced anaphylaxis or cholinergic urticaria. H2 blockers used alone have no impact on the condition because of the pathophysiology involved in histamine release.
Patients who have exercise-induced anaphylaxis should not be prescribed beta blockers because they reduce the response to epinephrine—a beta agonist.
Cholinergic urticaria. Treatment for patients who have established cholinergic urticaria involves a dose of diphenhydramine or hydroxyzine at the time of flare-up. They are usually also taking hydroxyzine chronically, so it is safe to give a dose of diphenhydramine or another antihistamine.
Prophylactic treatment with antihistamines is effective for patients who have cholinergic urticaria. In one study (20), 63% of patients who had cholinergic urticaria reported improvement with antihistamines. Treatment typically includes oral hydroxyzine hydrochloride at a dosage up to 50 mg four times a day. A consistent exercise program with gradual increases in intensity may help patients avoid a cholinergic urticaria reaction (11). Because of the small risk of anaphylaxis, injectable epinephrine may be prescribed with clear instructions on indications and method of use.
A Risk-Reduction Role
Exercise-induced anaphylaxis and cholinergic urticaria are two allergic syndromes that those who care for sports teams or treat athletes may encounter. Rapid recognition and initiation of treatment for these entities can result in early resolution of the allergic mast-cell-mediated response before anaphylactic symptoms develop. Proper treatment may enable individuals to continue intense exercise.
Dr Terrell is a sports medicine physician at Resurgens Orthopaedics in Atlanta and a past primary care sports medicine fellow at Michigan State University in East Lansing, Michigan. *Dr Hough died September 26, 1996 (see News Briefs). He was director of sports medicine and of the primary care sports medicine fellowship program at Michigan State University Sports Medicine in the Department of Family Practice at Michigan State. He was a fellow of the American College of Sports Medicine and the American Medical Society for Sports Medicine. Dr Alexander is an allergist in Asheville, North Carolina. Address correspondence to Tom Terrell, MD, MPhil, 600 Professional Dr, Suite 100, Lawrenceville, GA 30245.