By Feinberg, Jeff H Toner, Charles B
ABSTRACT A 22-year-old African American U.S. sailor presented with an intermittent pruritic eruption precipitated by mild activity for the last 2 years. She developed an extremely pruritic papular rash that would quickly coalesce into larger wheals following any exercise, light activity such as vacuuming, or taking hot showers. This condition had been getting progressively worse, preventing her from successfully completing her physical readiness test and other required physical training for the last 2 years. Previous treatment with antihistamines and steroids had failed to control her symptoms. She was diagnosed with cholinergic urticaria, successfully controlled with a combination of cetirizine, montelukast, and propanolol. She has since been returned to full military duty and is able to exercise regularly. CASE REPORT
A 22-year-old African American female in the U.S. Navy presented with a 2-year history of exercise-associated rash. Almost immediately after starting exercise, she would develop extremely pruritic papules beginning on her arms that would quickly increase in both number and size, spreading to her trunk and extremities. She also had occasional involvement of her central face and postauricular neck. Although symptoms had been present for 2 years, they had increased significantiy 15 months before presentation, at which time she had noticed she had stopped sweating. At the time of presentation, she could not tolerate even light activity such as vacuuming or housecleaning without eliciting an outbreak of the rash. hot showers would provoke a similar response. She denied associated chest pain, shortness of breath, abdominal pain, nausea, vomiting, diarrhea, wheezing, and lightheadedness with her episodes. Symptoms would typically last an hour, although on several occasions, they would last until aborted by the administration of either diphenhydramine or epinephrine. She had one documented episode of edema of the lips, but no difficulty swallowing. Hydroxyzine (Atarax) afforded minimal improvement in pruritus, but it was too sedating and did little to prevent her outbreaks. She had also tried loratadine (Claritin), ranitidine (Zantac), and oral steroids without any sustained success. Her condition and associated symptoms have prevented her from participating in mandatory physical training and passing the physical readiness test.
Her past medical history is unremarkable and is notable for no previous history of seasonal allergic rhinitis, atopy, or other allergies. Her only medication is loratadine, 10 mg daily, for symptom control. She had no other history of skin rashes. Her examination was equally unremarkable with no cutaneous lesions. She did not exhibit dermatographism. Skin-prick allergy testing was remarkable for 2+ reactions to pecan tree aUergens, and 1 + to molds, with a 3+ reaction to histamine, and a 0 reaction to control. Pulmonary spirometry tests were unremarkable. Intradermal methacholine chloride challenge (0.1 mg of methacholine in 0.1 mL normal saline intradermally) caused the development of small satellite lesions. Provocative exercise treadmill testing yielded a stable blood pressure (systolic range: 120-130 mm Hg; diastolic range: 76-82 mm Hg) and an appropriate increase in pulse (range, 82- 128). After 18 minutes of testing, the patient stopped the test due to fatigue and lightheadedness. Her body temperature had increased from 97.2 to 99.4[degrees]F and she was sweating. At 21 minutes from the start of the test, she developed an outbreak of small, 2-mm papules (Fig. 1) over her trunk and extremities. By 47 minutes, the number of papules had increased and had begun to coalesce into wheals (Fig. 2), the largest confluent lesion measuring five centimeters. Repeat pulmonary spirometry after the exercise provocation test was essentially unchanged.
The patient was diagnosed with cholinergic urticaria (CU), given cetirizine HCL (Zyrtec), 10 mg twice a day, which provided significant improvement, but incomplete resolution. Montelukast (Singulair), 10 mg once a day, and propanolol HCL (Inderal), 20 mg twice a day, were added. Since she became stable on the regimen, she is able to shower, clean her house, and exercise. Her perspiration has returned to normal. She now participates in command physical training, running 1.5 miles with minimal irritation and no outbreaks.
DISCUSSION
The physical urticarias are a unique subgroup of the chronic urticarias which can occur through a variety of mechanisms, including allergic, idiopathic, cytotoxic, and autoimmune. Physical urticarias have a wide variety of triggers as well, including water, heat, cold, exercise, sunlight, pressure, and vibration.
CU was first described by Duke in 1924, as a subset of the physical urticarias. Thirty percent of patients with physical urticarias have CU. The majority of the cases occur over the age of 20 and the peak incidence between 26 and 28 years of age.1 Symptoms are brought on by an increase in heat, physical exercise, spicy foods, or extreme emotions. Of those with CU, exercise is the most provocative factor, able to cause an outbreak in 89%. Passive warming (sauna or hot bath) can cause symptoms in 80%, while strong emotions can lead to an attack in 60%; finally, spicy food is able to trigger an attack in 29%.2 The condition will usually improve with time and 14% of CU patients can develop spontaneous remission.3 CU can evoke significant disability to those afflicted with the disease. The level of disability, based on Dermatology Life Quality Index, is similar to severe atopic dermatitis and is much greater than psoriasis or acne.4
CU begins as 1- to 3-mm wheals with surrounding flare typically about the extremities and truncal skin.3 It less commonly involves the face and neck with episodes following a precipitating event by 10 minutes and resolves within 2 to 4 hours spontaneously.1 It may be preceded by pruritic or tingling sensation.3 Atopic dermatitis occurs concurrently in 30% of the cases.2 CU typically limited to skin involvement, however, it can have a more systemic appearance, blurring the line between it and exercise-induced anaphylaxis. Abdominal pain, nausea, diarrhea, in addition to respiratory symptoms have been described, initiated by exercise or emotional stress.5 Some of the earlier reported cases were more likely exercise-induced anaphylaxis, a condition which was not independently described until the 1980s.6,7 It can certainly coexist with exercise-induced anaphylaxis.8 Reduction in FEV1 without full- blown anaphylaxis has been described as well.9
Pathogenesis is still a matter of debate; it is likely that CU represents a multifactorial pathogenesis, and the disease process itself is not entirely homogenous. Histamine is believed to be a central mediator, as histamine levels are generally increased after an episode of CU, as are eosinophil and neutrophil chemotactic factors.7,9 The newer theories focus on sweat itself being fundamental in the pathogenesis. Fukunaga et al.10 studied 18 patients with CU and 10 controls by injecting saline-dmited sweat (1/ 100) and filtered serum intradermally and compared reactions, as well as the ability of sweat to induce histamine release from the basophil in vitro.10 They concluded that CU involves a hypersensitivity or autoimmunity to sweat. Furthermore, they determined that CU should be subdivided clinically and pamologically among those with a foliicular appearance and those with a nonfolicular appearance. The foliicular type was characterized by a weaker reaction to autologous sweat, greater sensitivity to autologous serum, and a negative methacholine skin test There is further evidence from Murphy et al.11 that a serum factor may be responsible, as evident by a localized reaction to heat in monkeys that received an intradermal injection of serum from patients with CU. The nonfolicular subtype described by Fukunaga et al.10 had an increased incidence of hypersensitivity to sweat, an increased sweat- induced histamine release from basophils, as well as a positive methacholine skin test. They demonstrated mat autologous sweat itself stimulated histamine release from basophils in a majority of those with CU, especially the nonfolicular type. This reaction was absent in controls. Additionally, Adachi et al.12 proved that patients with CU can have an aUergic reaction to their own excreted sweat. These findings suggest that the local skin reactions in CU may be more akin to an allergic contact dermatitis. Interestingly, CU has also been present in those with anhydrosis and hypohidrosis. Kobayashi et al.13 put forth that since CU can be induced in those with hypohidrosis, it may be that the sweat itself infiltrates into the surrounding dermis and stimulates mast cell degranulation. Although our patient initially presented with a complaint of anhydrosis, it is unlikely that she actually had that condition, as she easily perspired when properly challenged. In her case, it is more likely that her symptoms of CU are triggered below her normal sweating threshold leading her to stop the physical activity before any noticeably induced perspiration.
Another pathogenic theory involves an increased sympathetic tone which in turn stimulates the postganglionic cholinergic fibers to the eccrine sweat glands.2 Acetylcholine causes mast cell degranulation leading to the typical wheal presentation. The increased acetylcholine activity can be a result of increased acetylcholine levels, decreased Cholinesterase activity, or increased acetylcholine receptor either sensitivity or number. However, a generalized increase in receptor sensitivity is unlikely based on studies involving pupillary response, blood pressure and pulse.14 Diagnosis is frequently a clinical one with a typical history and eliciting factors. Confirmation is best done by provocation testing. Skin testing, to include skin prick and intradermal injections, is also possible but usually only positive in those with moderate to severe disease.14,15 The methacholine skin challenge involves injecting 0.01 mg of methacholine in 0.1 mL of saline solution intradermally and looking for satellite lesions.15 Although the test is fairly specific, it only has a sensitivity of 30 to 50%.2,3,16
Provocative testing is the gold standard and best done under a controlled environment with either a bath test or an exercise test- usually a bike ergometer, step, or running test. The goal is to raise the core body temperature and thereby induce the CU. Many prefer using a 40[degrees]C bath or hot shower to induce the typical wheals of CU. If there is a question of aquagenic urticaria, the same can be done with a sauna or keeping some body parts dry. If an exercise challenge is to be done, care must be taken to properly exclude exercise-induced anaphylaxis or perform the test under more stringent circumstances. It is the preferred method at our institution to perform a Bruce protocol exercise stress test with full resuscitative capabilities.
There are few well-designed placebo controlled studies involving the treatment of CU and, of those, the number of patients involved is usually still small. Nonpharmacological treatment consists of avoidance of precipitating factors or a cooling bath. There has been some benefit shown by use of a desensitization program and the fact that outbreaks lessen after a severe outbreak.17
Antihistamines are the cornerstone of pharmacological treatment of CU. H1 blockers, specifically hydroxyzine (Atarax), have been shown to decrease both pruritus and lesion count versus placebo.18 Cetirizine is less sedating and very effective. In two separate double-blind studies, Zuberbier et al. showed cetirizine had a significantly greater response than placebo with an increase in mild or symptom-free days from 51 to 74.19 In his second study, 13 patients had a significant reduction in wheal formation, pruritus, and erythema compared with placebo.20
Danazol, an attenuated androgen, has been used successfully in treating refractory CU. Berth-Jones21 described successful monotherapy with danazol in a 19-year-old male with a history of CU for 3 years. Wong et al.22 did a double-blind placebo controlled crossover study with 17 males with CU. The primary endpoint was wheal count and change in biochemical markers. Danazol produced a significant decrease in wheal count (pruritus was not assessed), from 150 wheals after a standard exercise protocol to 39 wheals after 4 weeks of treatment. However, because danazol is a strong androgenizing agent it should be avoided or given with extreme caution in females.
An experimental asthma drug, not currently available in the U.S., Ketotifen has been shown to be effective in refractory cases. Three of four subjects had symptoms suppressed with 8 mg per day, which is four times the usual dose.23 The usual dose of 2 mg has not been shown to be as effective.24
Both beta blockers and calcium channel blockers have been tried. Beta blockers have been shown to be effective in refractory cases in several case reports.25,26 Pigatto et al.27 studied the efficacy of nimodipine (Nimotop) in a study of 32 patients with physical urticarias, of which 8 had CU. In the CU subgroup, nimodipine was not superior to terfenadine. Because of its anticholinergic side effects, oral scopolamine butylbromide at 10 mg three times a day has been reported in a case report to be effective in controlling CU with minimal side effects.28
In conclusion, CU has a high lifetime prevalence, with a course that can occasionally be debilitating. The diagnosis can typically be made on clinical grounds alone with no need for diagnostic or laboratory work up. Treatment regimens should be individualized for best results.
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LCDR Jeff H. Feinberg, MC(FS) USN*; CDR Charles B. Toner, MC USN[dagger]
* Marine Helicopter Squadron One, 2100 Rowell Road, Quantico, VA 22134.
[dagger] National Naval Medical Center, 8901 Rockville Pike Road, Bethesda, MD 20889.
This manuscript was received for review in January 2007. The revised manuscript was accepted for publication in July 2007.
Copyright Association of Military Surgeons of the United States Feb 2008
(c) 2008 Military Medicine. Provided by ProQuest Information and Learning. All rights Reserved.
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