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Cholinergic Urticaria in a Jogger

Ruling Out Exercise-Induced Anaphylaxis

Tod M. Sweeney, MD; William W. Dexter, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 31 - NO. 6 - JUNE 2003


In Brief: Cholinergic urticaria is a systemic response to a rise in core temperature that can be brought on by exercise, as in this case of a 24-year-old jogger. Many cases, however, are mild. The exact pathophysiology for the release of histamines is unknown, but the resulting rash can be distressing for patients. The challenge for physicians is to differentiate exercise-induced urticaria from exercise-induced anaphylaxis, a potentially life-threatening condition. Effective management includes patient education, antihistamine use, if needed, and avoidance of precipitating triggers, such as strenuous exercise or hot showers.

Iholinergic urticaria is a clinical condition typically seen in young adults that is characterized by generalized flushing, an urticarial rash (usually a 2- to 4-mm wheal surrounded by macular erythema), and pruritus. The precipitating factor is rapid elevation of the core temperature by 1.8°F (1°C)1 or more. The exact pathophysiology is not fully understood, but current theory holds that acetylcholine (ACH) is released, inducing mast cell degranulation, and the subsequent histamine release causes an urticarial reaction.

Both skin and respiratory problems are seen frequently in athletes, and the clinician must be able to differentiate exercise-induced urticaria from the more common, and distinct, exercise-induced asthma and the more severe exercise-induced anaphylaxis. Though the symptoms of exercise-induced urticaria are often mild, they can be quite disabling for those more severely affected. Precise diagnosis, based on a thorough history and confirmed with an exercise challenge, is key to effective prophylactic treatment.

Case History

An otherwise healthy 24-year-old woman, who was reestablishing an exercise regimen after a sedentary winter, went out for a midafternoon jog with a friend. Fifteen minutes into the run, her friend noticed that her body was very flushed and the patient noticed four or five red bumps on the left side of her neck that had begun to itch. The joggers decided to quit early, and the symptoms resolved within 30 minutes.

Two days later, the patient again went for a run, and after 20 minutes she began to feel flushed and hot, and her entire body itched. She ran for an additional 5 minutes, but her breathing became more labored, and she had to quit because of faintness, nausea, and abdominal pain. She reported no wheezing. These symptoms resolved after 30 minutes; however, upon returning home, her roommate noticed a diffuse rash over her neck and trunk that resolved over the next 2 to 3 hours. At the urging of her roommate, she saw a physician the next day.

Physical exam. The patient was a well-developed, well-nourished woman in no acute distress. Her skin, lung, and cardiovascular exams were completely normal. Her history was otherwise notable for mild allergic rhinitis, which was common in her family, and she was under a great deal of stress.

Differential diagnosis and tests. Although the history was suggestive of cholinergic urticaria, the differential diagnosis included classic (a rash of 5- to 10-mm hives), variant (smaller wheals), familial, or food-dependent exercise-induced anaphylaxis (table 1). Exercise-induced asthma, a distinct clinical and pathophysiologic entity, was also included in the list.

TABLE 1. Differentiating Exercise-Induced Urticaria, Anaphylaxis, and Asthma

Sign or Factor Cholinergic 
Urticaria
Classic
 Anaphylaxis 
Variant
 Anaphylaxis 
Familial
 Anaphylaxis 
 Food-Dependent 
Anaphylaxis
 Asthma 

Exercise is only precipitantXXXX
Exercise and/or other precipitantXX
Small urticaria commonXX
Large urticaria commonXXX
Vascular collapse commonXXXX
Bronchospasm*XX
Laryngeal edema†XXXX

*A reversible constriction of the small airways in the lower respiratory tract characterized by wheezing.
†Swelling and constriction of the large airway in the upper respiratory tract characterized by inspiratory stridor.

Rather than sending the patient out to jog and risking anaphylaxis, it was decided to perform a carefully supervised exercise challenge. The following day, the patient returned, and 12 minutes into a graded treadmill test she became flushed, developed a small (2- to 4-mm) urticarial rash involving her neck and upper chest, and became extremely itchy. Mild expiratory wheezes were noted when exercise terminated at 15 minutes. A histamine level, assessed from blood drawn after the challenge, was elevated at 22 ng/mL.

Diagnosis and treatment. Based on the patient's history and the above findings, the diagnosis of cholinergic urticaria was made. A selective H1-receptor antagonist (loratadine, 10 mg once a day) was started and the patient did extremely well, returning to exercise 1 week later. She was able to taper the use of the medication (same dose but less often) over the next 3 months. The medication was used primarily as a preventive measure for aerobic exercise. She also modified her exercise routine to prevent a sudden rise in core temperature by doing a slower warm-up before full exertion.

An Allergy to Exercise

Cholinergic urticaria is a clinical problem that represents 4% to 7% of cases of urticaria.2 A recent study demonstrated that the highest prevalence was found in those age 26 to 28.3 The precipitating factor is a rapid elevation of the core body temperature through a mechanism such as exercise, hot showers, fever, or anxiety.4 Of these, exercise is the most common. Symptoms of generalized flushing, an urticarial rash of 2- to 4-mm wheals surrounded by macular erythema (figure 1), and pruritus usually occur within 10 minutes of starting exercise and peak between 20 and 30 minutes. The rash typically begins on the neck and upper thorax and spreads distally. In severe cases, the lesions may coalesce, and angioedema may develop with associated bronchospasm, although urticaria is not usually associated with vascular collapse. Patients may also have cholinergic symptoms such as lacrimation, salivation, and diarrhea. Recovery usually occurs spontaneously in 2 to 4 hours provided there are no systemic symptoms.4 Despite initial resolution, episodes often recur.

The pathophysiology is poorly understood, but the condition seems to result from an excessive cholinergic response to body warming. Current theory is that ACH is released, which induces mast cell degranulation, and the subsequent histamine release causes an urticarial reaction. It is not clear whether this is related to increased ACH release, or whether there is increased ACH receptor sensitivity. A reduction in the amount of protease inhibitor alpha1-antichymotrypsin might also lead to inhibition of a second protease resulting in mast cell degranulation.4 Several small studies have consistently found histamine levels to be elevated, though research has not been able to identify the specific cascade causing the ACH release.4

That neurogenic reflexes may also play a role is supported by an experiment in which a tourniquet was tied to the distal forearm of a patient who had cholinergic urticaria, the hand was placed in warm water, and urticaria did not occur. After removal of the tourniquet, the hand was again placed in warm water, and a generalized urticarial reaction occurred. Therefore, a central perception of the temperature change appears to be followed by an efferent reflex, leading to the urticaria.5

Exercise-Induced Anaphylaxis

Although an uncommon clinical entity, exercise-induced anaphylaxis is a potentially life-threatening systemic response to exercise. The distinction between urticaria and anaphylaxis is based on the precipitating event, the morphology of the urticaria, and any association with vascular collapse (see table 1). Among the various forms of exercise-related conditions, the signs and symptoms may overlap, leading to the conclusion that these may not be distinct entities but rather a single syndrome with various modes of expression.4 Epidemiologic studies6,7 of anaphylaxis have found an age range from 4 to 74 years, with a mean age at onset of about 25 years. The frequency of attacks can range from a single episode to many. The severity of the response can be decreased with early discontinuation of exercise.

Many patients in these studies were well-trained athletes with a history of atopy. Jogging seemed to be the most common activity, but several other activities such as bicycling, racket sports, walking, and skiing have been implicated.6 The classic form occurs only in response to exercise and not in response to a warm bath, emotional stress, or fever.4 Almost half of all patients are atopic.7 Foods may trigger an attack, usually within 2 to 3 hours of ingestion. Nonsteroidal anti-inflammatory drugs (NSAIDs),8 hot weather, and increased pollen counts1 also have been associated with an increased likelihood of exercise-induced anaphylaxis.

The typical symptom complex includes a generalized flushing sensation, warmth, and pruritus accompanied by the development of large (10- to 15-mm) hives that can become confluent and angioedematous, affecting the hands, face, and larynx. Respiratory symptoms may include chest tightness, wheezing, stridor, and choking caused by laryngeal edema. Nausea, vomiting, and gastrointestinal colic may occur as well. Symptoms of vascular collapse may include hypotension, light-headedness, and transient loss of consciousness.4 Extreme attacks can be associated with vascular headaches that can last up to 72 hours.1

As with urticaria, the pathophysiology of exercise-induced anaphylaxis is not fully understood. Passive warming does not trigger this response. Exercise challenges have shown serum histamine levels to be elevated, yet the symptom reproducibility was not as consistent as with cholinergic urticaria. Several studies have demonstrated that mast cell activation plays a role, yet the cause of the release of histamine from the mast cell is unclear.4

Diagnostic Keys

Diagnosis and differentiation of cholinergic urticaria and exercise-induced anaphylaxis are based on a careful history. The physical exam is most useful during an attack; otherwise, its utility is limited. Cholinergic urticaria is generally diagnosed by a history of a constellation of symptoms (see table 1).

Provocative tests, such as passive elevation of core temperature with a warming blanket or extremity immersion in hot (104°F [40°C]) water, have been helpful for indeterminate cases. A patient who has cholinergic urticaria will develop urticaria and may have an elevated histamine level. A patient who has exercise-induced anaphylaxis generally will not.

A skin challenge for cholinergic urticaria has also been performed by injecting methacholine chloride (100 µg in 0.1 mL of saline solution) intradermally. Patients with a positive test will experience a localized hive and occasional satellite lesions. This test has a high specificity, but the sensitivity is only 33%9; therefore, it should be used only as a confirmatory test.

An exercise challenge can be useful for diagnosing both cholinergic urticaria and exercise-induced anaphylaxis. It is the most reliable test for cholinergic urticaria, but reproducing the symptoms in an office or lab environment can be difficult because of variability in symptom occurrence, particularly with exercise-induced anaphylaxis. Therefore, a negative exercise challenge test does not rule out these disorders.4 The test must be performed in a controlled situation with resuscitative equipment available in case anaphylaxis occurs. Histamine levels are consistently elevated in cholinergic urticaria, and other studies have noted decreases in pulmonary function.4 Thus, checking histamine levels and pulmonary function at baseline, during exercise, and after exercise might prove beneficial.

Targeting Treatment

The key to treatment is maintaining a high degree of clinical suspicion. Preventive strategies include activity modification at the first signs of symptoms. For cholinergic urticaria, the H1-receptor antagonists (selective antihistamines) are often the first line of treatment. Hydroxyzine hydrochloride is generally effective, and this may in part be due to its anticholinergic properties. One of the limiting factors with first-generation H1-receptor antagonists is drowsiness. Thus, nonsedating agents may be preferred. If the patient continues to have symptoms, then other H1-receptor antagonists or the addition of an H2-receptor antagonist should be considered4 (table 2).

TABLE 2. Steps in Managing Cholinergic Urticaria and Exercise-Induced Anaphylaxis

Nonpharmacologic ManagementPharmacologic ManagementEmergency Management

Step 1Search for other
precipitating causes
H1-receptor antagonists, eg, hydroxyzine   
hydrochloride 25-100 mg po q 6-8 hr,
or loratadine 10 mg po qd; doxepin
hydrochloride (tricyclic antidepressant)
25-150 mg po qd can be added for
refractory cases

Subcutaneous epinephrine
Step 2Modify exercise regimen, eg, slower   
warm-up period before full exertion,
reducing intensity and duration, or
changing ambient conditions

H2 antagonists, eg, ranitidine
hydrochloride 150 mg po bid,
or famotidine 20-40 mg po qd
Establish airway; administer
intravenous fluids
Step 3   Have patient avoid all food for
3 hr before exercise

Mast cell stabilizers, eg, cromolyn
sodium 200 mg po qid
Cardiovascular support

For patients with exercise-induced anaphylaxis, use of H1-receptor antagonists and avoidance of triggers (eg, NSAIDs, eating within 3 hours of exercise) are the first line of preventive therapy. If symptoms persist, an H2 antagonist can be added. Doxepin hydrochloride has been tried in addition if H1 and H2 blockers are unsuccessful.4 Some case reports show mast cell stabilizers and sodium bicarbonate to be helpful in specific situations.4 Anticholinergics, beta-blockers, and phosphodiesterase inhibitors have not been shown to be helpful. Anaphylaxis should be treated with subcutaneous epinephrine and adherence to cardiac life support protocols. Because treatment can be difficult, the mainstay of therapy is modification of an individual's exercise program, including reducing intensity and duration and changing the ambient conditions. Graduated programs to develop tolerance have worked for some athletes.4 The bottom line for exercise-induced anaphylaxis is that exercising with a partner and always carrying a self-injectable epinephrine kit are essential.

Essential Differential

Cholinergic urticaria and exercise-induced anaphylaxis are allergic reactions that, while uncommon, will be encountered in practice by those caring for athletes. A high degree of clinical suspicion facilitates early recognition. Making the correct diagnosis depends on the history, precipitating events, urticarial morphology, and the presence or absence of systemic vascular symptoms. Once the appropriate diagnosis is made, patient education and effective treatments can be implemented. Improvement depends on exercise modification and avoidance of known precipitants.

References

  1. Virant FS: Exercise. Immunol Allergy Clin North Am 1995;15(3):575-581
  2. Casale TB, Sampson HA, Hanifin J, et al: Guide to physical urticarias. J Allergy Clin Immunol 1988;82(5 pt 1):758-763
  3. Zuberbier T, Althaus C, Chantraine-Hess S, et al: Prevalence of cholinergic urticaria in young adults. J Am Acad Dermatol 1994;31(6):978-981
  4. Volcheck GW, Li JT: Exercise-induced urticaria and anaphylaxis. Mayo Clin Proc 1997;72(2):140-147
  5. Kaplan AP: Urticaria and angioedema, in Middleton E Jr, et al (eds): Allergy: Principles and Practice, ed 5. St Louis, Mosby, 1998, pp 1104-1122
  6. Wade JP, Liang MH, Sheffer AL: Exercise-induced anaphylaxis: epidemiologic observations. Prog Clin Biol Res 1989;297:175-182
  7. Sheffer AL, Austen KF: Exercise-induced anaphylaxis. J Allergy Clin Immunol 1984;73(5 pt 2):699-703
  8. Horan RF, Sheffer AL, Briner WW Jr: Physical allergies. Med Sci Sports Exerc 1992;24(8):845-848
  9. Kaplan AP: Exercise-induced hives. J Allergy Clin Immunol 1984;73(5 pt 2):704-707


Dr Sweeney is a family practice and sports medicine physician at New West Physicians in Arvada, Colorado. Dr Dexter is the primary care sports medicine fellowship director at the Maine Medical Center in Portland, Maine. Address correspondence to Tod M. Sweeney, MD, New West Physicians, 7950 Kipling St, Suite 101, Arvada, CO 80005.

Disclosure information: Drs Sweeney and Dexter disclose no significant relationship with any manufacturer of any commercial product mentioned in this article. Famotidine and ranitidine hydrochloride are mentioned in this article for an unlabeled use.


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