Practice Essentials
Cholinergic urticaria is one of the physical urticarias brought on by a physical stimulus. Although this stimulus might be considered to be heat, the actual precipitating cause is sweating. The definition and diagnostic testing of cholinergic urticaria has been the subject of consensus panel recommendations. (See Etiology, Presentation, and Workup.) [1]
Cholinergic urticaria can be divided into the following 4 subtypes [2] :
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Cholinergic urticaria with poral occlusion
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Cholinergic urticaria with acquired, generalized hypohidrosis with idiopathic pure sudomotor failure and localized hypohidrosis showing sweat gland eosinophilic infiltration [3]
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Cholinergic urticaria with sweat allergy
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Idiopathic cholinergic urticaria
See also the Medscape Drugs & Diseases articles Acute Urticaria; Chronic Urticaria; Contact Urticaria Syndrome; Dermographism Urticaria; Papular Urticaria; Pressure Urticaria; and Solar Urticaria.
Pathophysiology
Autonomic functions are normal in cholinergic urticaria. In 1 study of cholinergic urticaria, muscarinic receptors were reduced, but binding was normal. Thermography ostensibly shows the areas of involvement.
Elevation of histamine levels can be detected at 5 minutes after exercise, reaching a peak of 25 ng/mL at 30 minutes in persons with cholinergic urticaria. Treadmill exercise produces a sensation of generalized skin warmth, followed by pruritus, erythema, urticaria, and transient respiratory tract symptoms consisting of shortness of breath, wheezing, or both. Statistically significant decreases have been observed in 1 second forced expiratory volumes, maximal midexpiratory flow rates, and specific conductance. An increase in residual volume may also detected.
(See Presentation and Workup.)
Physical examination
The most reliable way to reproduce cholinergic urticaria is to cause the patient to sweat from a stimulus, such as during exercise (eg, walking or running on a treadmill).
Cholinergic dermographism occurs in the form of localized distribution of typical tiny wheals that appear after stroking the skin of some patients with cholinergic urticaria.
A localized form of cholinergic urticaria with a presentation with cold-induced urticarial lesions may occur. [4] Patients with this condition were found to experience a generalized reaction to cold ambient air and cold water, but a negative response to the ice-cube test. Cold urticaria and cold-induced cholinergic urticaria may be seen in about 1% of patients with cold urticaria.
(See History.)
Workup
Traditionally, an intradermal injection of either 0.05 mL of 0.002% carbamylcholine chloride (carbachol) or 0.05 mL of 0.02% (0.01 mg) methacholine has been used to produce a flare-up of cholinergic urticaria containing characteristic wheals, often with satellites. This outcome occurs in about 51% of patients. The same flare-up may occur in persons without this condition, but it is usually smaller and without whealing.
Nicotinic acid has also been used at a dilution of 1:500,000 or 1:100,000. Lesions of cholinergic urticaria have even been reproduced by curare derivatives such as D-tubocurarine.
Cholinergic dermographism can be reproduced by stroking the skin, by using methyl acetylcholine, or by using other stimuli that cause sweating.
The demonstration of sweat-specific immunoglobulin E in cholinergic urticaria patients who are unable to provide sufficient sweat may be facilitated by use of iontophoresis with pilocarpine nitrate. [5]
See Treatment and Medication.
Etiology
Mast cells seem to be critically involved in cholinergic urticaria. In fact, cholinergic urticaria has been used to study mast cell activity. [6] Serum histamine, the principal mediator, rises in concentration with experimentally induced exercise, accompanied by eosinophil and neutrophil chemotactic factors and tryptase. A reduction of the alpha1-antichymotrypsin level, as seen in some other forms of urticaria, is present. The eruption is improved with danazol. These findings have prompted some to argue for proteases as a cause of histamine release.
Although mast cell release seems to be involved in cholinergic urticaria, less eosinophilic major basic protein is present than in many other forms of urticaria.
Possible allergy-based etiology
Several factors, including an increased incidence in patients with atopic dermatitis (AD), a marked sensitivity in some patients with anaphylactic and anaphylactoid reactions, and an immediate reactivity in some patients, suggest an allergic basis for cholinergic urticaria. [7]
One report showed positive immediate sensitivity to sweat with passive transfer. [8] Some investigators, but not others, have documented positive passive transfer. Another group has delineated a follicular pattern of cholinergic urticaria in sweat-sensitized patients, but not in patients without prominent sensitivity.
Patients with atopic dermatitis and those with cholinergic urticaria develop skin reactions and histamine release of basophils in response to autologous sweat. [9, 10] Most patients demonstrate immediate-type skin responses to their own sweat and satellite wheals after acetylcholine injection. The rest have positive autologous serum skin tests. [11] The pathogenesis may involve disordered immune responses to products of skin flora that are soluble in human sweat. Patients with atopic dermatitis and cholinergic urticaria demonstrate elevated immunoglobulin E against the fungal protein MGL1304 produced by Malassezia globosa. [12]
Body temperature
A crucial point in cholinergic urticaria is not the actual temperature of the skin surface, the average skin temperature, or even the core temperature, but an increase or a decrease in the weighted average body temperature. An increase in core body temperature may trigger cholinergic urticaria; some patients appear unaffected by exercise and other activity in the summer. [13]
Seasonal temperature
It has been suggested that 2 conditions are required to provoke seasonal cholinergic urticaria: heat induced by various cholinergic stimuli and a low ambient temperature. Indeed, some persons who report cholinergic urticaria symptoms only during the winter months apparently have a reaction only when exposed to heat or heat-producing exercise while not acclimatized to heat.
In cholinergic urticaria, whether skin lesions are provoked by passive heating of the body at rest (eg, saunalike conditions) or by active heating at a low ambient temperature is basically related to the thermoregulatory process.
Other associated factors
The prevalence of cholinergic urticaria is definitely higher in persons with urticaria; cholinergic urticaria affected 11% of a population with chronic urticaria in one study and 5.1% of persons with urticaria in another.
The prevalence is also higher in persons with atopic conditions (eg, asthma, rhinitis, atopic eczema), but this is by no means exclusive. A rare, familial form of cholinergic urticaria has also been reported.
Cholinergic urticaria may also occur in the setting of acquired forms of generalized absence or decrease in sweating. Some patients with acquired idiopathic generalized hypohidrosis are theorized to have a defect in the nerve-sweat gland junction. [14] Superficial obstruction of the acrosyringium has sometimes been associated with acquired generalized hypohidrosis. [15]
Aspirin aggravated the urticaria in 52% of patients with cholinergic urticaria, which is similar to other forms of urticaria.
Epidemiology
The prevalence of cholinergic urticaria is variable. Moore-Robinson and Warin found that about 0.2% of patients in an outpatient dermatologic clinic had cholinergic urticaria. [16] However, many published series have found cholinergic urticaria to be common. The prevalence of cholinergic urticaria is definitely higher in persons with urticaria.
The overall prevalence of cholinergic urticaria in one survey of 600 medical and engineering students in western India was 4%. [17]
Although the disorder occurs in both sexes, it seems to be more common in males than in females. In one study, almost 96% of patients with cholinergic urticaria were men.
Cholinergic urticaria usually first develops in people aged 10-30 years, with an average age at onset of 16 years in one study and a mean age of 22 years in another survey.
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Close-up view shows small urticarial wheals within large erythematous flares.
