eMedicine Specialties > Dermatology > Allergy & Immunology

Urticaria, Cholinergic

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Updated: Jul 1, 2009

Introduction

Background

Cholinergic urticaria is one of the physical urticarias brought on by a physical stimulus. Although the physical stimulus might be considered to be heat, the actual precipitating cause is sweating.

Additional eMedicine articles on urticaria, including Urticaria, Acute; Urticaria, Chronic; Urticaria, Contact Syndrome; Urticaria, Dermographism; Urticaria, Papular; Urticaria, Pressure; and Urticaria, Solar, may be of interest.

Pathophysiology

Mast cells seem to be critically involved; cholinergic urticaria has been used to study mast cell activity.¹ 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 alpha 1-antichymotrypsin level, as seen in some other forms of urticaria, is present, and 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.

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. One report showed positive immediate sensitivity to sweat with passive transfer. Some investigators, but not others, have reported positive passive transfer. Another group has reported a follicular pattern of cholinergic urticaria in sweat-sensitized patients but not in patients without prominent sensitivity. Patients with AD and cholinergic urticaria both develop skin reactions and histamine release of basophils in response to autologous sweat.²

Autonomic functions are normal in cholinergic urticaria. One patient with cholinergic urticaria developed an accentuated response in a positive copper test site, perhaps from either vasodilatation or augmentation of neurologic stimulation. 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 were observed in 1 second forced expiratory volumes, maximal midexpiratory flow rates, and specific conductance. An increase in residual volume was also detected.

Frequency

United States

The prevalence of cholinergic urticaria is variable. Moore-Robinson and Warin³ found that about 0.2% of patients in an outpatient dermatologic clinic had cholinergic urticaria. However, many published series have found cholinergic urticaria to be common. 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 study. The prevalence is 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 is also reported.

Sex

Cholinergic urticaria occurs in both men and women, but it seems to be more common in men than in women.

Age

• Cholinergic urticaria usually begins 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 study. Cholinergic urticaria persists for a number of years. Most patients retain the tendency for many years.
• In one series of 22 persons, the average duration of cholinergic urticaria was 7.5 years, with a range of 3-16 years, but, in 7 patients on follow-up study, some patients retained the cholinergic urticaria tendency for 30 years.
• In another study, almost 96% of patients with cholinergic urticaria were men, with a mean age of 22 years, whereas in another group, 31 women and 25 men had cholinergic urticaria.

Clinical

History

• Cholinergic urticaria lesions appear rather rapidly, usually within a few minutes after the onset of sweating, and they last from a half-hour to an hour or more, with a mean duration of about 80 minutes.
• Cholinergic urticaria symptoms are sufficiently uncomfortable to cause many patients to change their patterns of activity to prevent attacks.
  • Cholinergic urticaria symptoms seem to follow any stimulus to sweat. 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 it is an increase or a decrease in the weighted average body temperature.
  • 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.
• Exercise is the most common precipitating event for cholinergic urticaria, but any activity that causes sweating, including elevated environmental temperature, hot food, sauna baths, immersion in hot water, gustatory stimuli, emotional stress, and hemodialysis,⁴ can bring on an urticaria attack in some persons.
• 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.

Physical

• Often in cholinergic urticaria, itching, burning, tingling, warmth, or irritation precedes the onset of numerous small (1-4 mm in diameter) pruritic wheals with large surrounding flares (see Media File 1).

Close-up view shows small urticarial wheals within large erythematous flares.

• Cholinergic urticaria lesions may appear anywhere on the body, except on the palms or the soles and rarely in the axillae. Sometimes, flares are the only presentation.
• Patients who are more severely affected with cholinergic urticaria may experience systemic symptomatology, such as fainting, abdominal cramping, diarrhea, salivation, and headaches.
  • Hepatocellular injury, angioedema, asthma, anaphylactoid, and even anaphylactic reactions are also reported.
  • 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.
• Cholinergic dermographism comprises a localized distribution of typical tiny wheals that appear after stroking the skin of some patients with cholinergic urticaria.
• A localized form of cholinergic urticaria and a presentation with cold-induced urticarial lesions may occur.
  • Patients with this condition experienced 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.
• 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.⁵
  • Superficial obstruction of the acrosyringium has sometimes been associated with acquired generalized hypohidrosis.⁶

Causes

• Exercise and hot baths exacerbate pruritus and provoke lesions in previously unaffected areas.
• Other diagnostic considerations for cholinergic urticaria are as follows:
  • Some reports of chronic urticaria include patients with cholinergic urticaria, but the morphology is different. However, other physical urticarias with similar lesions, such as aquagenic urticaria, exist.
    • Aquagenic urticaria appears in response to water at both cold temperatures and hot temperatures; when exposed to tap water at room temperature, the lesions resemble those of cholinergic urticaria.
    • In adrenergic urticaria, wheals are surrounded by vasoconstriction, and the response to epinephrine and norepinephrine is positive.
  • 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

Other Problems to Be Considered

Adrenergic urticaria
Aquagenic urticaria

Workup

Laboratory Studies

• 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).
  • 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 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 (eg, D-tubocurarine).
  • Cholinergic dermographism can be reproduced by stroking the skin, by using methyl acetylcholine, or by using other stimuli that cause sweating.

Treatment

Medical Care

• Sometimes, an attack of cholinergic urticaria can be aborted by rapid cooling.
• Antihistamines, including cetirizine, are helpful for cholinergic urticaria. The response to cetirizine is important because some of the antihistaminic effect has been attributed to antimuscarinic activity.
• UV light has been beneficial in some patients with cholinergic urticaria, but one must be circumspect about contraindications to UV light.
• Aspirin aggravated the urticaria in 52% of patients with cholinergic urticaria, which is similar to other forms of urticaria.
• 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 can be beneficial for patients with cholinergic urticaria, ostensibly because it elevates antichymotrypsin levels.
• Beta-blockers, such as propranolol, have been reported to be useful in cholinergic urticaria.⁷
• In evaluating any response to therapy, one must always consider that cholinergic urticaria can clear spontaneously.
• Both topically applied benzoyl scopolamine and oral scopolamine butylbromide, where available, may be helpful in blocking the appearance of cholinergic urticaria lesions after challenge.⁸

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.

Medication

The goals of pharmacotherapy for cholinergic urticaria are to reduce morbidity and to prevent complications.⁹ Other approaches include treatment of cholinergic urticaria with anti–immunoglobulin E therapy, and combination therapy (eg, cetirizine, montelukast, and propanolol).¹⁰

Antihistamines

These agents may control itching by blocking effects of endogenously released histamine.

Cetirizine (Zyrtec)

Forms a complex with histamine for H1 receptor sites in blood vessels, GI tract, and respiratory tract.

Dosing

Adult

5-10 mg PO qd

Pediatric

<2 years: Not established
2-5 years: 2.5 mg PO qd
>5 years: Administer as in adults

Interactions

Increases CNS toxicity of depressants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hepatic or renal dysfunction; doses higher than 10 mg/d may cause drowsiness

Loratadine (Claritin)

Selectively inhibits peripheral histamine H1 receptors.

Dosing

Adult

10 mg/d PO on empty stomach

Pediatric

<2 years: Not established
2-6 years: 5 mg/d PO on empty stomach
>6 years: Administer as in adults

Interactions

Ketoconazole, erythromycin, procarbazine, and alcohol may increase levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Initiate therapy at lower dose in liver impairment

Desloratadine (Clarinex)

Long-acting tricyclic histamine antagonist selective for H1 receptor. A major metabolite of loratadine, which after ingestion is extensively metabolized to active metabolite 3-hydroxydesloratadine.

Dosing

Adult

5 mg PO qd

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Limited data exist; erythromycin and ketoconazole increase desloratadine and 3-hydroxydesloratadine plasma concentrations, but no increase was observed in clinically relevant adverse effects, including QTc

Contraindications

Documented hypersensitivity to desloratadine or loratadine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Decrease dose in hepatic impairment; rarely causes pharyngitis or dry mouth

Follow-up

Deterrence/Prevention

Patients with cholinergic urticaria should avoid the precipitating factors. These factors 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, because these can bring on a cholinergic urticaria attack in some persons.

Patient Education

For excellent patient education resources, visit eMedicine's Allergy Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Hives and Angioedema.

Multimedia

Media file 1: Close-up view shows small urticarial wheals within large erythematous flares.

References

1. Soter NA, Wasserman SI. Physical urticaria/angioedema: an experimental model of mast cell activation in humans. J Allergy Clin Immunol. Nov 1980;66(5):358-65. [Medline].

2. Takahagi S, Tanaka T, Ishii K, et al. Sweat antigen induces histamine release from basophils of patients with cholinergic urticaria associated with atopic diathesis. Br J Dermatol. Feb 2009;160(2):426-8. [Medline].

3. Moore-Robinson M, Warin RP. Some clinical aspects of cholinergic urticaria. Br J Dermatol. Dec 1968;80(12):794-9. [Medline].

4. Confino-Cohen R, Goldberg A, Magen E, Mekori YA. Hemodialysis-induced rash: a unique case of cholinergic urticaria. J Allergy Clin Immunol. Dec 1995;96(6 Pt 1):1002-4. [Medline].

5. Kobayashi H, Aiba S, Yamagishi T, et al. Cholinergic urticaria, a new pathogenic concept: hypohidrosis due to interference with the delivery of sweat to the skin surface. Dermatology. 2002;204(3):173-8. [Medline].

6. Itakura E, Urabe K, Yasumoto S, Nakayama J, Furue M. Cholinergic urticaria associated with acquired generalized hypohidrosis: report of a case and review of the literature. Br J Dermatol. Nov 2000;143(5):1064-6. [Medline].

7. Ammann P, Surber E, Bertel O. Beta blocker therapy in cholinergic urticaria. Am J Med. Aug 1999;107(2):191. [Medline].

8. Tsunemi Y, Ihn H, Saeki H, Tamaki K. Cholinergic urticaria successfully treated with scopolamine butylbromide. Int J Dermatol. Oct 2003;42(10):850. [Medline].

9. Feinberg JH, Toner CB. Successful treatment of disabling cholinergic urticaria. Mil Med. Feb 2008;173(2):217-20. [Medline].

10. Metz M, Bergmann P, Zuberbier T, Maurer M. Successful treatment of cholinergic urticaria with anti-immunoglobulin E therapy. Allergy. Feb 2008;63(2):247-9. [Medline].

11. Czubalski K, Rudzki E. Neuropsychic factors in physical urticaria. Dermatologica. 1977;154(1):1-4. [Medline].

12. Fukunaga A, Bito T, Tsuru K, et al. Responsiveness to autologous sweat and serum in cholinergic urticaria classifies its clinical subtypes. J Allergy Clin Immunol. Aug 2005;116(2):397-402. [Medline].

13. Hirschmann JV, Lawlor F, English JS, et al. Cholinergic urticaria. A clinical and histologic study. Arch Dermatol. Apr 1987;123(4):462-7. [Medline].

14. Jorizzo JL. Cholinergic urticaria. Arch Dermatol. Apr 1987;123(4):455-7. [Medline].

15. Khakoo G, Sofianou-Katsoulis A, Perkin MR, Lack G. Clinical features and natural history of physical urticaria in children. Pediatr Allergy Immunol. Jun 2008;19(4):363-6. [Medline].

16. Kierland RR. Physical allergies. AMA Arch Derm Syphilol. Jul 1953;68(1):61-8. [Medline].

17. Mihara S, Hide M. Adrenergic urticaria in a patient with cholinergic urticaria. Br J Dermatol. Mar 2008;158(3):629-31. [Medline].

18. Nakazato Y, Tamura N, Ohkuma A, Yoshimaru K, Shimazu K. Idiopathic pure sudomotor failure: anhidrosis due to deficits in cholinergic transmission. Neurology. Oct 26 2004;63(8):1476-80. [Medline].

19. Tupker RA, Doeglas HM. Water vapour loss threshold and induction of cholinergic urticaria. Dermatologica. 1990;181(1):23-5. [Medline].

20. Warin R, Champion R. Urticaria. Philadelphia, Pa: WB Saunders; 1974:136-44.

Keywords

urticaria, cholinergic urticaria, heat-induced urticaria, sweat-induced urticaria, micropapular urticaria, stress-induced urticaria

Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Mark G Lebwohl, MD, Chairman, Department of Dermatology, Mount Sinai School of Medicine
Mark G Lebwohl, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Abbott Laboratories Honoraria Consulting; Actelion Honoraria Consulting; Amgen Honoraria Consulting; Astellas Honoraria Consulting; Centocor Honoraria Consulting; DermiPsor Honoraria Consulting; Galderma  Consulting; Genentech Honoraria Consulting; Helix BioMedix Honoraria Consulting; Medicis Honoraria Investigator

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Christen M Mowad, MD, Associate Professor, Department of Dermatology, Geisinger Medical Center
Christen M Mowad, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Jere D. Guin, MD, FACP^†, Former Professor Emeritus, Department of Dermatology, University of Arkansas for Medical Sciences, and Jerri Hoskyn, MD, to the development and writing of this article.

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