What is cholinergic urticaria

Cholinergic urticaria is a common physical urticaria that is caused by sweating ¹. It is sometimes referred to as heat bumps, as the rash appears as very small (1-4mm) weals surrounded by bright red flares.

Exercise is the most common precipitating event for cholinergic urticaria, but any stimulus that causes sweating, including elevated environmental temperature, hot food, sauna baths, immersion in hot water, gustatory stimuli, emotional stress, and hemodialysis ², can bring on an urticarial attack in some persons. Exercise and hot baths exacerbate pruritus and provoke lesions in previously unaffected areas.

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 ³. 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% ⁴.

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.

Cholinergic urticaria can be divided into the following four subtypes ⁵:

• Cholinergic urticaria with poral occlusion
• Cholinergic urticaria with acquired, generalized hypohidrosis with idiopathic pure sudomotor failure and localized hypohidrosis showing sweat gland eosinophilic infiltration ⁶
• Cholinergic urticaria with sweat allergy
• Idiopathic cholinergic urticaria

Figure 1. Cholinergic urticaria

Figure 2. Cholinergic urticaria

Cholinergic urticaria causes

A rise in core body temperature resulting in sweating causes the rash in cholinergic urticaria. Common triggers include:

• Exercise
• Hot baths/showers
• Fever
• Occlusive dressings
• Eating spicy foods
• Emotional stress

It is not uncommon for patients with cholinergic urticaria to have another associated physical urticaria, such as dermographism, cold urticaria or pressure urticaria.

Autonomic functions are normal in cholinergic urticaria. In one 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.

Mast cells seem to be critically involved in cholinergic urticaria. In fact, cholinergic urticaria has been used to study mast cell activity ⁷. 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, 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 ⁸.

One report showed positive immediate sensitivity to sweat with passive transfer ⁹. 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 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.

Cholinergic urticaria symptoms

The rash appears rapidly, usually within a few minutes of sweating, and can last from 30 minutes to an hour or more before fading away. The mean duration is around 80 minutes.

Cholinergic urticaria symptoms are sufficiently uncomfortable to cause many patients to change their patterns of activity to prevent attacks.

Hepatocellular injury, angioedema, asthma, anaphylactoid reactions, and even anaphylactic reactions are also reported. The angioedema may be palpebral ⁶.

Persons with cardiorespiratory symptoms include patients with increased pulmonary resistance with acetylcholine challenge, which may be a limiting factor in certain occupations (eg, those relating to aerospace).

One form of cholinergic urticaria, sometimes called cholinergic erythema, is believed to show persistent and individual macules of short duration, but with new macules continually appearing at adjacent sites.

Typical signs and symptoms of cholinergic urticaria include:

• Itching, burning, tingling, warm sensation preceding the onset of numerous small weals with surrounding bright red flares
• Rash is often very itchy
• Rash may appear anywhere on the body but is more prominent on the upper trunk and arms. It does not affect the palms or soles and rarely the armpits.
• Sometimes the tiny weals join together to form a large swelling
• Patients who are more severely affected may experience systemic symptoms such as headaches, salivation, palpitations, fainting, shortness of breath, wheezing, abdominal cramps and diarrhoea
• Rarely, patients with cholinergic urticaria can have more severe reactions such as anaphylaxis so should probably not exercise alone.

Duration

Cholinergic urticaria persists for a number of years. Most patients retain a tendency to develop it for many years. It may improve after botulinum toxin injection for axillary hyperhidrosis ¹⁶.

In one series of 22 persons, the average duration of cholinergic urticaria was 7.5 years, with a range of 3-16 years. In 7 patients on follow-up study, however, some retained the cholinergic urticaria tendency for 30 years.

In a large series from an urticaria clinic, however, cholinergic urticaria had the shortest course from onset to 50% remission (34 months) ¹⁷.

Cholinergic urticaria may be associated with anaphylaxis with upper and/or lower airway obstructive symptoms, gastrointestinal involvement, and cardiovascular manifestations. Cholinergic urticaria with anaphylaxis has been characterized as under recognized ¹⁸.

Who gets cholinergic urticaria ?

People who are more likely to suffer from cholinergic urticaria include:

• Those who already suffer from generalized chronic urticaria
• People with allergic type conditions, e.g. asthma, rhinitis, atopic dermatitis (eczema).

It occurs in both men and women, but appears to be more common in men than women. The condition tends to first appear in people aged between 10 and 30 years and persists for a number of years before it becomes less severe or goes away altogether. The natural course of cholinergic urticaria is quite variable, with most patients experiencing slow resolution over several years.

Diagnostic Considerations

Some reports of chronic urticaria include patients with cholinergic urticaria, but the morphology is different. It is important to differentiate cholinergic urticaria from other forms of physical urticaria ¹⁹.

Aquagenic urticaria appears in response to cold water and hot water. In patients exposed to tap water at room temperature, the lesions resemble those of cholinergic urticaria.

In adrenergic urticaria, wheals are surrounded by vasoconstriction ²⁰. In addition, the response to epinephrine and norepinephrine is diagnostic.

Commonly, patients with one physical urticaria tend to have another physical urticaria as well, sometimes precipitated by the same stimulus.

Cholinergic urticaria may be accompanied by cold urticaria, pressure urticaria, and even aquagenic urticaria.

Differential Diagnoses

• Acute Urticaria
• Chronic Urticaria
• Contact Urticaria Syndrome
• Urticarial Vasculitis
• Dermographism Urticaria
• Pressure Urticaria
• Solar Urticaria.

Diagnostic tests

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 ²¹.

Cholinergic urticaria treatment

Once the cause of the rash is identified, it may be possible to avoid situations that trigger it. However, in many cases it is difficult to stop sweating, particularly in warm climates and if exercising is part of a daily routine. Sometimes rapid cooling can prevent an attack. For most patients regular administration of an oral antihistamine such as cetirizine can be helpful in preventing the condition from arising. The response to cetirizine is important because some of the antihistaminic effect has been attributed to antimuscarinic activity. Some data suggest that a combination of H1 and H2 blockers is more effective than combining different H1 blockers ²². The antimuscarinic cholinergic methanthelinium bromide has also been suggested as a therapeutic option ²³.

For patients with both cold urticaria and cholinergic urticaria, ketotifen (where available) may be helpful. About 62% of patients experience a reduction in wheals, and 68% of patients report reduced itching. Cardiorespiratory symptoms also reportedly respond to ketotifen.

Danazol is another agent that can be beneficial for patients with cholinergic urticaria, ostensibly because it elevates antichymotrypsin levels.

Topically applied benzoyl scopolamine and oral scopolamine butylbromide, where available, may be helpful in blocking the appearance of cholinergic urticaria lesions after challenge ²⁴.

Beta-blockers such as propranolol ²⁵, leukotriene inhibitors and immunosuppressives have also been reported to be useful ²¹, ²⁶. However, cholinergic urticaria in some patients may be refractory.

Sometimes, an attack of cholinergic urticaria can be aborted by rapid cooling. Ultraviolet (UV) light has been beneficial in some patients with the condition, but one must be circumspect about contraindications to UV light.

Rapid desensitization with autologous sweat has been reported in patients resistant to conventional therapy who have sweat hypersensitivity ²⁷.

In evaluating any response to therapy, one must always consider that cholinergic urticaria can clear spontaneously.

Diet

Modifying one’s diet may be helpful because cholinergic urticaria attacks can sometimes result from hot foods and beverages, highly spiced foods, and alcohol.

Prevention of cholinergic urticaria

Patients with cholinergic urticaria should avoid the precipitating factors. These factors, in some persons, include exercise and any activity that causes sweating, such as elevated environmental temperature, hot food, sauna baths, immersion in hot water, gustatory stimuli, emotional stress, and hemodialysis.

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