GENERAL MEDICAL CONDITIONS

Cholinergic Urticaria and Exercise-Induced

Anaphylaxis
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Stefan L. Montgomery, MD

the most common. CU is the second

Abstract
most common physical urticaria (2).
In this article, we will present the physical manifestations of two similar
conditions. The first is cholinergic urticaria. This is chronic urticaria pre-
cipitated by an elevated body temperature. The second is exercise-induced CU V Causes and Symptoms
anaphylaxis. Anaphylaxis can be idiopathic, a result of a specific allergenic CU is induced by exercise, elevation
trigger (food, medication, or insect sting), or exercise induced. We will in body temperature, strong emotions,
focus on the third subtype. We describe the causes, symptoms, patho- ingestion of hot or spicy foods, or
physiology, testing, treatment, and prognosis of these two conditions. showering in hot water (4). CU is
characterized by generalized flushing,
an urticarial rash (2- to 4-mm wheal
Introduction surrounded by macular erythema), and pruritus (11). Many
Two physical manifestations of disease are described and patients note a tingling, itching, or burning sensation of the
differentiated here. The first is cholinergic urticaria (CU). skin before the appearance of the hives. As the response
This is chronic urticaria precipitated by an elevated body progresses, the macules may coalesce to form large areas of
temperature. CU is believed to account for approximately erythema that become more difficult to recognize as CU.
5% of all cases of chronic urticaria and approximately 30% Lesions can appear anywhere on the body, but it typically
of all cases of physical urticaria (4). begins on the trunk and neck and spreads distally to involve
The second is exercise-induced anaphylaxis (EIA). Ana- the face and extremities. In rare cases, CU has been reported
phylaxis can be idiopathic, a result of a specific allergenic to progress to include systemic symptoms such as hypoten-
trigger (food, medication, or insect sting), or exercise in- sion, angioedema, and bronchospasm (4). CU induced by
duced (8). We will focus on the third subtype. EIA was de- exercise usually presents about 6 min after the onset of
scribed over three decades ago. While rare, several hundred exercise. The symptoms and physical findings increase for
cases have been reported since and the incidence of EIA approximately 12 to 25 min (12).
appears to be increasing possibly due to the popularity of
physical fitness in developed countries. The true prevalence CU V Pathophysiology
of this condition is unknown, and, although only one death CU has been associated with elevated levels of histamine
has been reported, it is probably not an accurate statistic (3). in the serum during an attack. Adachi et al. reported a
group of patients who seemed to have a Type I allergy to
their own sweat. Twenty patients underwent autologous
CU V Epidemiology sweat testing and demonstrated an immediate skin reaction.
No easily accessible incidence data is available on CU. What A subgroup of patients with symptoms suggestive of CU
is known, however, is that 15% to 20% of the population will may have allergic urticaria that is manifest only when they
experience urticaria of some type during their lifetime. The sweat (4). Fukunaga et al. (6) attempted to differentiate two
most common type is allergic urticaria, whether from drugs, subgroups of patients with CU on the basis of diluted sweat
insect bites, foods, illness, or chemical contact. The other type reaction. One group had a positive skin reaction to diluted
is physical urticaria, which is commonly due to scratching, sweat. Another distinct group had a positive reaction to an
pressure, warmth, or cold. Of these, dermatographism is autologous serum skin testing. They labeled the groups non-
follicular (responding to autologous sweat and not to autolo-
Stefan Montgomery, MD, Family and Sports Medicine, Orangeburg, SC
gous serum) and follicular (responding weakly to autologous
Address for correspondence: Stefan Montgomery, MD, ATC, 2850 Pelham sweat and strongly to autologous serum) (6).
Ct., Orangeburg, SC 29118; E-mail: [email protected].

1537-890X/1401/61Y63
CU V Testing
Current Sports Medicine Reports The presentation of the lesions of classic CU in the con-
Copyright * 2015 by the American College of Sports Medicine text of typical inciting triggers is often enough to suggest the

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Copyright © 2014 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
diagnosis strongly, but confirmatory testing should be con- or horseback riding were reported less frequently, but no
ducted. Confirmation is done by provocation testing using a exercise was reliably safe (3).Trigger foods that have been
variety of methods. Classically the methacholine injection reported include Crustacea (shrimp and crab), wheat, grains,
should be positive in patients with CU. An intradermal injec- nuts, fruits, vegetables, legumes, and seeds. Less commonly
tion of 0.01 mg of methacholine in 0.1-mL saline produces a implicated foods are meats, eggs, and cow’s milk. Interestingly
local area of hives and is diagnostic. Unfortunately only about there is a case reported in an individual with food-dependent
one-third of patients with CU demonstrate a positive test. EIA (FDEIA) provoked by ingestion of tofu before exercise;
Therefore this procedure cannot be used to rule out the diag- however ingestion of soy milk had no such effect, suggesting
nosis. Specific provocative challenges may be needed and may the significance of food processing (7). With FDEIA, the in-
use the inciting event suspected in a particular patient. These gestion of the causative agent could be delayed for as much as
challenges could include exercise, bathing, or ingestion of 6 h. Aspirin and nonsteroidal anti-inflammatory drugs have
certain foods. The best diagnostic test is one that measurably been the most frequently reported medications in connection
raises the patient’s core body temperature. To perform the test, with EIA, followed by penicillin and cephalosporins (3). EIA
a patient should be submerged partially in a hot water bath at is caused by the sudden release of basophil and mast cell
40-C until the core body temperature has increased by at least mediators (7).
0.7-C. The appearance of generalized urticaria confirms the
diagnosis of CU (4). EIA V Testing
The gold standard for testing is an exercise challenge,
CU V Treatment especially with FDEIA. A serum tryptase level drawn within
Identification and avoidance of known triggers are the first 30 min of anaphylaxis supports the diagnosis of EIA since
steps in controlling CU. Bathing in hot water and performing this is a mast cell activation by-product (3).
strenuous exercise during hot weather are to be avoided.
Medical therapy is predominantly oral antihistamines. Hy- EIA V Treatment
droxyzine is the classic agent of choice and generally is be- This condition is treated in a similar fashion to any ana-
lieved to be more effective than other antihistamines. A low phylactic event. Subcutaneous or intramuscular epinephrine
dose should be initiated and increased gradually until the is the first line for symptom control. Epinephrine may need
urticaria is controlled, which typically occurs at doses of 100 to be given by IV if the athlete is in severe shock. Diphen-
to 200 mg divided over 24 h. Oral anticholinergic agents have hydramine also is given via IM or IV (25 to 50 mg). Corti-
not been shown to be effective (4). One case report of using a costeroids are used to prevent a delayed (biphasic) reaction.
preexercise beta blocker (propranolol at a dosage of 80 mg Transfer to an acute care facility for further monitoring is
twice daily) prevented debilitating symptoms of CU. Un- warranted due to the potential for rebound anaphylaxis. It
fortunately this has not been studied extensively due to the is essential for any athlete diagnosed with EIA to carry an
observed adverse effects of beta-blockers in allergic and epinephrine autoinjector while exercising (8). Ranitidine
anaphylactic conditions (1). 150 mg or cimetidine 20 mg can be used to block the va-
sodilatation and vascular permeability associated with the
CU V Prognosis H2 response (3). In addition, the combination of cetirizine
The prognosis for CU is generally favorable. Hirschmann and montelukast has been helpful in preventing symptoms
reported only 31% of patients with persistence of symp- on an exercise challenge (10). Some studies have cited that
toms greater than 10 years. Sibbald estimated that the aver- cromolyn pretreatment before exercise has been helpful. In
age duration of symptoms is 7.5 years, with a range of 3 to 16 addition, attempts of pretreatment with sodium bicarbonate
years. before exercise to avoid the drop in blood pH secondary to
histamine elevation have been made (5). In patients with
EIA V Presentation and Symptoms FDEIA, there appears to be development of a tolerance to
Most of the cases of EIA present within 45 min of institut- exercise over time, with a decreased frequency of attacks.
ing exercise (3). The main symptoms of EIA include broncho- The theory is that, over time, exercise will lead to a lessened
spasm, laryngospasm, and/or vascular collapse. Other symptoms inflammatory response of leukocytes and proinflammatory
include sudden fatigue, warmth, flushing (7), sudden itching, cytokine release as well as a down-regulation of toll-like re-
gastrointestinal upset, hives, throat tightness, vocal changes, ceptor 4 expression on the surface of immune cells. This di-
and trouble breathing. In contrast to CU, the wheal is 10 to minishes the overall immune response to exercise. In fact,
15 mm in EIA (5). If left unchecked, urticaria, bronchospasm, one 10-year study showed either stabilization or regression of
and airway edema progress to vascular collapse (8). episode severity in 93% of patients (9).

EIA V Causes and Pathophysiology Conclusions

Attacks have been linked with jogging, aerobics, dancing, CU can be differentiated from EIA using the size of the
tennis, bicycling, racquetball, swimming, and skiing. Mini- rash (2- to 4-mm wheal in CU vs 10- to 15-mm wheal in
mal exertion, such as walking or walking briskly, was noted EIA). In addition, the emergency nature of EIA makes it a
as a trigger in many cases. Jogging was the activity most more worrisome condition. The acute treatment differences
frequently reported, but its relative frequency may reflect the (oral antihistamines in CU versus epinephrine and IV or
popularity of this exercise in the U.S. population. Additional IM antihistamines in EIA) and later use of corticosteroids
reports have implicated other types of exercise, such as run- and oral antihistamines in EIA lead to a much different
ning, sprinting, and soccer. Raking leaves, shoveling snow, treatment course. Exercise challenge is still useful in both

62 Volume 14 & Number 1 & January/February 2015 Cholinerg Urticari Exercise Induced Anaphylax

Copyright © 2014 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
conditions. In addition, methacholine injection and passive 5. Dutau G, Micheau P, Juchet A, et al. Exercise and food-induced anaphylaxis.
Pediatr. Pulmonol. 2001; (23):48Y51.
warming in CU versus serum tryptase elevations in EIA
6. Fukunaga A, Bito T, Tsuru K, et al. Responsiveness to autologous sweat and
differentiate the testing and clinical picture. It is useful for serum in cholinergic urticaria classifies its clinical subtypes. J. Allergy Clin.
any sports medicine practitioner to be familiar with these Immunol. 2005; 116:397Y402.
rare but distinct entities. 7. Jaqua NT, Peterson MR, Davis KL. Exercise-induced anaphylaxis: a case
report and review of the diagnosis and treatment of a rare but potentially life-
threatening syndrome. Case Rep. Med. 2013: 610726.
The author declares no conflicts of interest and does not have any
financial disclosures. 8. Lebrun CM. Care of the high school athlete: prevention and treatment of
medical emergencies. Instr. Course Lect. 2006; 55:687Y702.
9. Miller CW, Guha B, Krishnaswamy G. Exercise-induced anaphylaxis: a se-
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