Cholinergic urticaria: novel aspects of pathogenesis, diagnosis and management

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Cholinergic urticaria (CholU) is a chronic inducible urticaria, characterised by itchy pinpoint wheals up to 3 mm in diameter, surrounded by a prominent flare, that occur following an exposure to characteristic triggers such as active or passive heating, physical exercise, emotions, hot or spicy foods.

Key pathophysiologic mechanisms include immediate hypersensitivity to autologous sweat antigens, functional sweating disorders, impaired acethylcholine metabolism, abnormal skin vascular permeability and disturbed skin innervation.

Clinical manifestations of CholU may vary from typical itchy pinpoint urticarial lesions, angioedema to anaphylaxis. Atypical CholU forms include cholinergic pruritus, cholinergic dermographism, cold cholinergic urticaria and persistent cholinergic erythema.

The diagnosis of cholinergic urticaria relies on patient’s history, clinical manifestations and challenge tests.

Treatment options include nonsedating H1 antihistamines in standard or increased doses. The evidence is accumulating for the use of biological treatment with omalizumab in cholinergic urticaria. The prospect of personalized treatment of cholinergic urticaria include autologous sweat desensitization.

The main research efforts in ColdU are directed at optimizing diagnostic approaches and developing innovative therapeutic options.

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About the authors

Elena Yu. Borzova

I.M. Sechenov First Moscow State Medical University (Sechenov University); Veltischev Research and Clinical Institute for Pediatrics

Author for correspondence.
ORCID iD: 0000-0003-1587-9137
SPIN-code: 4779-7664

MD, Dr. Sci. (Med.), Professor

Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, Moscow; Moscow

Christina Yu. Popova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

ORCID iD: 0000-0002-7855-6207

Postgraduate Student

Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, Moscow

Marcin Kurowski

Medical University of Lodz

ORCID iD: 0000-0002-0653-7533

MD, Professor, Clinics of Immunology and Allergy

Poland, Lodz

Maia T. Rukhadze

Center of Allergy and Immunology; Teaching University Geomedi

ORCID iD: 0000-0002-1413-8161

MD, Dr. Sci. (Med.), Professor

Georgia, Tbilisi; Tbilisi

Razvigor Darlenski

Trakia University

ORCID iD: 0000-0002-4220-8040

MD, Dr. Sci. (Med.)

Bulgaria, Stara Zagora

Viktoriya A. Zaborova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

ORCID iD: 0000-0001-5044-1152

MD, Dr. Sci. (Med.), Professor

Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, Moscow

Vladislav V. Kurshev

I.M. Sechenov First Moscow State Medical University (Sechenov University)

SPIN-code: 2766-3925

MD, Cand. Sci. (Med.), Assistant

Russian Federation, 4/1 Bolshaya Pirogovskaya street, 119991, Moscow


  1. Araviyskaya ER, Sokolovsky EV, Gallyamova YuA. Russian Society of Dermatologists and Cosmetologists. Federal clinical guidelines for the management of patients with urticaria. Federal clinical guidelines. Dermatovenerology 2015: Skin diseases. Sexually transmitted infections. 5th ed. revised and updated. Moscow: Delovoy Express; 2016. 768 p. (In Russ).
  2. Danilycheva IV, Ilyina NI, Luss LV, et al. Federal clinical guidelines. Urticaria. Russian Allergological Journal. 2018;(5):47–62. (In Russ).
  3. Magerl M, Altrichter S, Borzova E, et al. The definition, diagnostic testing, and management of chronic inducible urticarias ― The EAACI/GA(2)LEN/EDF/UNEV consensus recommendations 2016 update and revision. Allergy. 2016;71(6):780–802. doi: 10.1111/all.12884
  4. Fukunaga A, Washio K, Hatakeyama M, et al. Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management. Clin Auton Res. 2018;28(1):103–113. doi: 10.1007/s10286-017-0418-6
  5. Ruft J, Asady A, Staubach P, et al. Development and validation of the Cholinergic Urticaria Quality-of-Life Questionnaire (CholU-QoL). Clin Exp Allergy. 2018;48(4):433–444. doi: 10.1111/cea.13102
  6. Maurer M. Urticaria and angioedema. Chem Immunol Allergy. 2014;100:101–104. doi: 10.1159/000358614
  7. Duke WW. Urticaria caused specifically by the action of physical agents. J Am Med Assoc. 1924;5:3–9. doi: 10.1001/jama.1924.02660010007002
  8. Zuberbier T, Althaus C, Chantraine-Hess S, Czarnetzki BM. Prevalence of cholinergic urticaria in young adults. J Am Acad Dermatol. 1994;31(6):978–981. doi: 10.1016/s0190-9622(94)70267-5
  9. Godse K, Farooqui S, Nadkarni N, Patil S. Prevalence of cholinergic urticaria in Indian adults. Indian Dermatol Online J. 2013;4:62–63. doi: 10.4103/2229-5178.105493
  10. Moore-Robinson M, Warin RP. Some clinical aspects of cholinergic urticaria. Br J Dermatol. 1968;80(12):794–799. doi: 10.1111/j.1365-2133.1968.tb11948.x
  11. Rujitharanawong Ch, Tuchinda P, Chularojanamontri L, et al. Cholinergic urticaria: clinical presentation and natural history in a tropical country. BioMed Research International. 2020;1:6. doi: 10.1155/2020/7301652
  12. Mikhailov P, Berova N, Andreev VC. Physical urticaria and sport. Cutis. 1977;20(3):381–390.
  13. Kaplan AP, Gray L, Shaff RE, et al. In vivo studies of mediator release in cold urticaria and cholinergic urticaria. J Allergy Clin Immunol. 1975;55:394–402. doi: 10.1016/0091-6749(75)90078-0
  14. Dice JP. Physical urticaria. Immunol Allergy Clin North Am 2004;24:225–246. doi: 10.1016/j.iac.2004.01.005
  15. Sawada Y, Nakamura M, Hino R, Tokura Y. Cholinergic urticaria: studies on the muscarinic cholinergic receptor M3 in anhidrotic and hypohidrotic skin. J Investig Dermatol. 2010;130(11):2683–2686. doi: 10.1038/jid.2010.188
  16. Adachi J, Aoki T, Yamatodani A. Demonstration of sweat allergy in cholinergic urticaria. J Dermatol Sci. 1994;7(2):142–149. doi: 10.1016/0923-1811(94)90088-4
  17. Kurzen H, Schallreuter KU. Novel aspects in cutaneous biology of acetylcholine synthesis and acetylcholine receptors. Exp Dermatol. 2004;13(Suppl 4):27–30. doi: 10.1111/j.1600-0625.2004.00258.x
  18. Bito T, Sawada Y, Tokura Y. Pathogenesis of cholinergic urticaria in relation to sweating. Allergol Int. 2012;61(4):539–544. doi: 10.2332/allergolint.12-RAI-0485
  19. Commens CA, Greaves MW. Tests to establish the diagnosis in cholinergic urticaria. Br J Dermatol. 1978;98:47–51. doi: 10.1111/j.1365-2133.1978.tb07332.x
  20. Magnus IA, Thompson RH. Cholinesterase levels in the skin in cholinogenic urticaria and pruritus. Br J Dermatol. 1956;68:283–289. doi: 10.1111/j.1365-2133.1956.tb12819.x
  21. Takahashi K, Soda R, Kishimoto T, et al. The reactivity of dispersed human lung mast cells and peripheral blood basophils to acetylcholine. Arerugi. 1992;41:686–692.
  22. Sawada Y, Nakamura M, Bito T, et al. Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis. J Investig Dermatol. 2014;134:276–279. doi: 10.1038/jid.2013.244
  23. Shelley WB, Shelley ED, Ho AK. Cholinergic urticaria: acetylcholine-receptor-dependent immediate-type hypersensitivity reaction to copper. Lancet. 1983;1(8329):843–846. doi: 10.1016/s0140-6736(83)91386-7
  24. Horikawa T, Fukunaga A, Nishigori C. New concepts of hive formation in cholinergic urticaria. Curr Allergy Asthma Reports 2009;9:273–279. doi: 10.1007/s11882-009-0038-x
  25. Soter NA, Wasserman SI, Austen F, Regis McFadden E. Release of mast-cell mediators and alterations in lung function in patients with cholinergic urticaria. NEJM. 1980;302(11):604–608. doi: 10.1056/NEJM198003133021104
  26. Murphy GM, Greaves MW, Zollman PE, Winkelmann RK. Cholinergic urticaria, passive transfer experiments from human to monkey. Dermatologica. 1988;177(6):338–340. doi: 10.1159/000248603
  27. Illig L, Heinicke A. Zur Pathogenese der cholinergischen Urticaria. IV. Zur Frage einer echten Antigen-Antikörperreaktion [On the pathogenesis of cholinergic urticaria. IV. On the problem of a true antigen-antibody reaction]. Arch Klin Exp Dermatol. 1967;229(4):360–371.
  28. Sabroe RA, Grattan CE, Francis DM, et al. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol. 1999;140:446–452. doi: 10.1046/j.1365-2133.1999.02707.x
  29. 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. 2009;160:426–428. doi: 10.1111/j.1365-2133.2008.08862.x
  30. Hiragun T, Ishii K, Hiragun M, et al. Fungal protein MGL_1304 in sweat is an allergen for atopic dermatitis patients. J Allergy Clin Immunol. 2013;132(608-615):e604. doi: 10.1016/j.jaci.2013.03.047
  31. 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;3:173–178. doi: 10.1159/000057877
  32. Abajian M, Schoepke N, Altrichter S, et al. Physical urticarias and cholinergic urticarias. Immunol Allergy Clin North Am 2014;34(1):73–88. doi: 10.1016/j.iac.2013.09.010
  33. Dai X, Okazaki H, Hanakawa Y, et al. Eccrine sweat contains IL-1a, IL-1b and IL-31 and activates epidermal keratinocytes as a danger signal. PLoS One. 2013;8(7):e67666. doi: 10.1371/journal.pone.0067666
  34. Nakamizo S, Egawa G, Miyachi Y, Kabashima K. Cholinergic urticaria: pathogenesis-based categorization and its treatment options. J Eur Acad Dermatol Venereol. 2011;26:114–116. doi: 10.1111/j.1468-3083.2011.04017.x
  35. James MP, Eady RA, Kobza-Black A, et al. Physical urticaria: a microscopical and pharmacological study of mast cell involvement, abstracted. J Invest Dermatol. 1980;74:451.
  36. Haas N, Schadendorf D, Henz BM. Differential endothelial adhesion molecule expression in early and late whealing reactions. Int Arch Allergy Immunol. 1998;115(3):210–214. doi: 10.1159/000023902
  37. Winkelmann RK. The histology and immunopathology of dermographism. J Cutan Pathol. 1985;12(6):486–492. doi: 10.1111/j.1600-0560.1985.tb00447.x
  38. Federal clinical guidelines for the treatment of urticaria. Russian Association of Allergologists and Immunologists; 2019. (In Russ).
  39. Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria. Allergy. 2018;73:1393–1414. doi: 10.1111/all.13397
  40. Maurer M, Fluhr JW, Kha DA. How to approach chronic inducible urticaria. J Allergy Clin Immunol Pract. 2018;6(4):1119–1130. doi: 10.1016/j.jaip.2018.03.007
  41. Komarow HD, Arceo S, Young M, et al. Metcalfe dissociation between history and challenge in patients with physical urticaria. J Allergy Clin Immunol Pract. 2014;2(6):786–790. doi: 10.1016/j.jaip.2014.07.008
  42. Vadas P, Sinilaite А, Chaim M. Cholinergic urticaria with anaphylaxis: an underrecognized clinical entity. J Allergy Clin Immunol Pract. 2016;4(2):284–291. doi: 10.1016/j.jaip.2015.09.021
  43. Montgomery MD. Cholinergic urticaria and exercise-induced anaphylaxis. Curr Sports Med Rep. 2015;14(1):61–63. doi: 10.1249/jsr.0000000000000111
  44. Ilyina NI, Zabolotskikh IB, Astafyeva NG, et al. Anaphylactic shock. Clinical recommendations of the Russian Association of Allergologists and Clinical Immunologists and the All-Russian Public organization “Federation of Anesthesiologists and Resuscitators”. Bulletin of Intensive care named after A.I. Saltanov. 2020;(3):15–26. (In Russ). doi: 10.21320/1818-474X-2020-3-15-26
  45. Petalas K, Kontou-Fili K, Gratziou C. Bronchial hyperresponsiveness in patients with cholinergic urticaria. Ann Allergy Asthma Immunol. 2009;102(5):416–421. doi: 10.1016/S1081-1206(10)60514-5
  46. Mayou SC, Kobza Black A, Eady RA, Greaves MW. Cholinergic dermographism. Br J Dermatol. 1986;115(3):371–377. doi: 10.1111/j.1365-2133.1986.tb05754.x
  47. Oda Y, Fukunaga A, Tsujimoto M, et al. Combined cholinergic urticaria and cold-induced cholinergic urticaria with acquired idiopathic generalized anhidrosis. Allergol Int. 2015;64:214–215. doi: 10.1016/j.alit.2014.12.004
  48. Maltseva N, Borzova E, Fomina D, et al. COLD-CE steering committee. Cold urticarial ― What we know and what we do not know. Allergy. 2021;76(4):1077–1094. doi: 10.1111/all.14674
  49. Murphy GM, Black AK, Greaves MW. Persisting cholinergic erythema: a variant of cholinergic urticaria. Br J Dermatol. 1983;109(3):343–348. doi: 10.1111/j.1365-2133.1983.tb03551.x
  50. Shoenfeld Y, Harari Z, Sheonfeld Y, Keren G. Cholinergic urticaria. A seasonal disease. Arch Intern Med. 1981;141:1029–1030. doi: 10.1001/archinte.141.8.1029
  51. Rho NK. Cholinergic urticaria and hypohidrosis: a clinical reappraisal. Dermatology. 2006;213:357–358. doi: 10.1159/000096205
  52. Altrichter S, Koch K, Church MK, Maurer M. Atopic predisposition in cholinergic urticaria patients and its implications. J Eur Acad Dermatol Venereol. 2016;30:2060–2065. doi: 10.1111/jdv.13765
  53. Washio K, Fukunaga A, Onodera M, et al. Clinical characteristics in cholinergic urticaria with palpebral angioedema: report of 15 cases. J Dermatol Sci. 2017;85:135–137. doi: 10.1016/j.jdermsci.2016.11.001
  54. Anaphylactic shock. In: Allergology. Federal clinical recommendations. Ed. by R.M. Khaitov, N.I. Ilyina. Moscow: Farmarus Print Media; 2014. Р. 35–47. (In Russ).
  55. Itakura A, Tani Y, Kaneko N, Hide M. Impact of chronic urticaria on quality of life and work in Japan: Results of a real-world study. J Dermatol. 2018;45(8):963–970. doi: 10.1111/1346-8138.14502
  56. Poon E, Seed PT, Greaves MW, Kobza-Black A. The extent and nature of disability in different urticarial conditions. Br J Dermatol. 1999;140(4):667–671. doi: 10.1046/j.1365-2133.1999.02767.x
  57. Borzova EY. Diagnosis of chronic induced urticarial. Russian Allergological Journal. 2019;16(2):5–13. (In Russ).
  58. Kiistala R, Kiistala U. Local cholinergic urticaria at methacholine test site. Acta Derm Venereol. 1997;77(1):84–85.
  59. Volcheck GW, Li JT. Exercise-induced urticaria and anaphylaxis. Mayo Clin Proc. 1997;72(2):140–147. doi: 10.4065/72.2.140
  60. Payls JD, Cross D. Food-dependent exercise-induced anaphylaxis to corn. J Allergy Clin Immunol. 1998;101:853–854. doi: 10.1016/s0091-6749(98)70317-3
  61. Bonini M, Palange P. Anaphylaxis and sport. Curr Opin Allergy Clin Immunol. 2014;14(4):323–327. doi: 10.1097/ACI.0000000000000074
  62. Bennett JR. Anaphylaxis attributed to exercise: considerations for sports medicine specialists. Phys Sportsmed. 2015;43(1):1–12. doi: 10.1080/00913847.2015.1000233
  63. Maulitz RM, Pratt DS, Schocket AL. Exercise-induced anaphylactic reaction to shellfish. J Allergy Clin Immunol. 1979;63(6):433–434. doi: 10.1016/0091-6749(79)90218-5
  64. Foong R, Giovannini M, Toit G. Food-dependent exercise-induced anaphylaxis. Curr Opin Allergy Clin Immunol. 2019;19(3):224–228. doi: 10.1097/ACI.0000000000000531
  65. Kounis NG, Kounis GN, Soufras GD. Exercise-induced urticaria, cholinergic urticaria, and Kounis syndrome. J Pharmacol Pharmacother. 2016;7(1):48–50. doi: 10.4103/0976-500X.179355
  66. Castells MC, Horan RF, Sheffer AL. Exercise-induced anaphylaxis. Curr Allergy Asthma Rep. 2003;3(1):15–21. doi: 10.1007/s11882-003-0005-x
  67. Luong KV, Nguyen LT. Aquagenic urticaria: report of a case and review of the literature. Ann Allergy Asthma Immunol. 1998;80:483–485. doi: 10.1016/S1081-1206(10)63071-2
  68. Kawakami Y, Gokita M, Fukunaga A, Nishigori C. Refractory case of adrenergic urticaria successfully treated with clotiazepam. J Dermatol. 2015;42:635–637. doi: 10.1111/1346-8138.12855
  69. Muraro A, Roberts G, Worm M, et al. EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026–1045. doi: 10.1111/all.12437
  70. Kobza Black A, Aboobaker J, Gibson JR, et al. Acrivastine versus hydroxyzine in the treatment of cholinergic urticaria. A placebo-controlled study. Acta Dermatovenereol. 1988;68:541–544.
  71. Zuberbier T, Aberer W, Burtin B, et al. Efficacy of cetirizine in cholinergic urticaria. Acta Dermatovenereol. 1995;75:147–149. doi: 10.2340/0001555575147149
  72. Zuberbier T, Munzberger C, Haustein U, et al. Double-blind crossover study of high-dose cetirizine in cholinergic urticaria. Dermatology. 1996;193:324–327. doi: 10.1159/000246281
  73. Wosny K, Weller K, Werner A, et al. Antihistamine updosing reduces disease activity in difficult-to-treat cholinergic urticaria patients. J Allergy Clin Immunol. 2016;138(5):1483–1485.e9. doi: 10.1016/j.jaci.2016.05.026
  74. Dressler C, Werner RN, Eisert L, et al. Maurer M. Chronic inducible urticaria: a systematic review of treatment options. J Allergy Clin Immunol. 2018;141(5):1726–1734. doi: 10.1016/j.jaci.2018.01.031
  75. Ghazanfar MN, Holm JG, Thomsen SF. Omalizumab for cholinergic urticaria: 6 months prospective study and systematic review of the literature. Dermatol Ther. 2020;33(6):e14010. doi: 10.1111/dth.14010
  76. Gastaminza G, Azofra J, Nunez-Cordoba JM, et al. Efficacy and safety of omalizumab (xolair) for cholinergic urticaria in patients unresponsive to a double dose of antihistamines: a randomized mixed double-blind and open-label placebo-controlled clinical trial. J Allergy Clin Immunol Pract. 2019;7(5):1599–1609.e1. doi: 10.1016/j.jaip.2018.12.025
  77. Metz M, Ohanyan T, Church MK, Maurer M. Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci. 2014;73(1):57–56. doi: 10.1016/j.jdermsci.2013.08.011
  78. Maurer M, Metz M, Brehler R, et al. Omalizumab treatment in patients with chronic inducible urticaria: a systematic review of published evidence. J Allergy Clin Immunol. 2018;141(2):638–649. doi: 10.1016/j.jaci.2017.06.032
  79. Sabroe RA. Failure of omalizumab in cholinergic urticaria. Clin Exp Dermatol. 2010;35(4):e127–129. doi: 10.1111/j.1365-2230.2009.03748.x
  80. Ujiie H, Shimizu T, Natsuga K, et al. Severe cholinergic urticaria successfully treated with scopolamine butylbromide in addition to antihistamines. Clin Exp Dermatol. 2006;31(4):588–589. doi: 10.1111/j.1365-2230.2006.02117.x
  81. Feinberg JH, Toner CB. Successful treatment of disabling cholinergic urticaria. Mil Med 2008;173(2):217–220. doi: 10.7205/milmed.173.2.217
  82. Sheraz A, Halpern S. Cholinergic urticaria responding to botulinum toxin injection for axillary hyperhidrosis. Br J Dermatol. 2013;168(6):1369–1370. doi: 10.1111/bjd.12200
  83. La Shell MS, England RW. Severe refractory cholinergic urticaria treated with danazol. J Drugs Dermatol. 2006;5(7):664–667.
  84. Kozaru T, Fukunaga A, Taguchi K, et al. Rapid desensitization with autologous sweat in cholinergic urticaria. Allergol Int. 2011;60(3): 277–281. doi: 10.2332/allergolint.10-OA-0269
  85. Tanaka T, Ishii K, Suzuki H, et al. Cholinergic urticaria successfully treated by immunotherapy with partially purified sweat antigen. Arerugi. 2007;56:54–57.

Supplementary files

Supplementary Files
1. Fig. 1. Triggers of cholinergic urticarial. ХнК ― cholinergic urticaria.

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2. Fig. 2. Typical urticarial lesions in cholinergic urticaria: a ― in a male patient aged 33; б ― in a female patient aged 41.

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