Skip to main content

Advertisement

Log in

Mechanism of chronic urticaria exacerbation by aspirin

  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

In some patients with chronic idiopathic urticaria (CIU), aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase 1 (COX-1) precipitate wheals and swelling. There is no in vitro diagnostic, and diagnosis can be established only by provocation challenges with aspirin or other NSAIDs. Skin reactions triggered by aspirin are associated with the inhibition of cyclooxygenase, specifically COX-1, but not COX-2, and are characterized by overproduction of cysteinyl leukotrienes (cys-LTs). Aspirin and other NSAIDs should be avoided, but highly specific COX-2 inhibitors, known as coxibs, are well tolerated and can probably be safely used. Evidence has been accumulated that these reactions are due to the interference of aspirin-like drugs with arachidonic-acid metabolism. In this article, we discuss the mechanism of these reactions, and the characteristic course of aspirininduced urticaria and its management.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Pavel Kolkhir, Ana M. Giménez-Arnau, … Marcus Maurer

References and Recommended Reading

  1. Settipane GA: Landmark commentary: history of aspirin intolerance. Allergy Proc 1990, 11:251–251.

    Article  Google Scholar 

  2. Szczeklik A, Stevenson DD: Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol 2003, 111:913–921.

    Article  PubMed  CAS  Google Scholar 

  3. Szczeklik A, Nizankowska E, Duplaga M: Natural history of aspirin-induced asthma. AIANE Investigators. European Network on Aspirin-Induced Asthma. Eur Respir J 2000, 16:432–436.

    Article  PubMed  CAS  Google Scholar 

  4. Berges-Gimeno MP, Simon RA, Stevenson DD: The natural history and clinical characteristics of aspirin exacerbated respiratory disease. Ann Allergy Asthma Immunol 2002, 89:472–478.

    Google Scholar 

  5. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G: Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. Br Med J 1975, 1:67–69.

    Article  PubMed  CAS  Google Scholar 

  6. Folco G, Samuelsson B, Murphy RC: Novel Inhibitors of Leukotrienes. Basel-Boston: Birkhauser Verlag; 1999.

    Google Scholar 

  7. Chandrasekharan NV, Hu Dai, Lamar Turepu Roos K, et al.: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002, 99:13926–13931.

    Article  PubMed  CAS  Google Scholar 

  8. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G: Clinical patterns of hypersensitivity to nonsteroidal antiinflammatory drugs and their pathogenesis. J Allergy Clin Immunol 1977, 60:276–284.

    Article  PubMed  CAS  Google Scholar 

  9. Zembowicz A, Mastalerz L, Setkowicz M, et al.: Safety of cyclooxygenase 2 inhibitors and increased leukotriene synthesis in chronic idiophatic urticaria with sensitivity to non-steroidial anti-inflammatory drugs. Arch Dermatol 2003, 139:1577–1582. COX-2 inhibitors do not induce urticaria in patients with CIU who are sensitive to aspirin. Aspirin-induced urticaria is associated with overproduction of cys-LTs.

    Article  PubMed  CAS  Google Scholar 

  10. Nettis E, Di PR, Ferrannini A, Tursi A: Tolerability of rofecoxib in patients with cutaneous adverse reactions to nonsteroidial anti-inflammatory drugs. Ann Allergy Asthma Immunol 2002, 88:331–334. Rofecoxib, a COX-2 inhibitor, is a well-tolerated drug in patients with aspirin-induced urticaria, and it may represent a valid alternative drug in NSAID-sensitive patients.

    PubMed  CAS  Google Scholar 

  11. Johansson SGO, Hourihane J, Bousquet J, et al.: A revised nomenclature for allergy: an EAACI position statement from the EAACI nomenclature task force. Allergy 2001, 56:813–824. New classification of non-allergic drug hypersensitivity.

    Article  PubMed  CAS  Google Scholar 

  12. Stevenson DD, Sanchez-Borges M, Szczeklik A: Classfication of allergic and pseudoallergic reactions to drugs that inhibit cyclo-oxygenaze enzymes. Ann Allergy Asthma Immunol 2001, 87:1–4. Proposal of classification of allergic and pseudoallergic reactions to drugs that inhibit COX.

    Article  Google Scholar 

  13. Harada S, Horikawa T, Ashida M, et al.: Aspirin enhances the induction of type I allergic symptoms when combined with food and exercise in patients with food-dependent exerciseinduced anaphylaxis. Br J Dermatol 2001, 145:336–339.

    Article  PubMed  CAS  Google Scholar 

  14. Mastalerz L, Setkowicz M, Sanak M, Szczeklik A: Hypersensitivity to aspirin: common eicosanoid alterations in urticaria and asthma. J Allergy Clin Immunol 2004, 113:771–775. There are basic similarities between two distinct clinical syndromes. Clinical reactions after aspirin ingestion (either cutaneous or bronchial) are precipitated by drugs that inhibit COX-1, but not COX-2. Ingestion of aspirin leads to further, massive release of cys-LTs. Aspirin also releases PGD2 in both aspirin-sensitive asthmatics and in patients with CIU and history of NSAID intolerance.

    Article  PubMed  CAS  Google Scholar 

  15. Grzelewska-Rzymowska I, Szmidt M, Rozniecki J: Aspirinsensitive urticaria; clinical study. Pneumonol Alergol Pol 1993, 61:24–28.

    PubMed  CAS  Google Scholar 

  16. Henz BM: The spectrum of urticaria. In Urticaria—Clinical, Diagnostic and Therapeutic Aspects. Edited by Henz BM, Zuberbier T, Grabbe J, Monroe E. Berlin: Springer; 1998:1–17.

    Google Scholar 

  17. Moore-Robinson M, Warin RP: Effect of salicylates in urticaria. Br Med J 1967, 4:262–264.

    PubMed  CAS  Google Scholar 

  18. Asero R, Tedeschi A, Lorini M: Autoreactivity is highly prevalent in patients with multiple intolerances to NSAIDs. Ann Allergy Asthma Immunol 2002, 88:468–472. Some patients with NSAID hypersensitivity are characterized by the presence of circulating histamine-releasing factors. Their nature is still unclear.

    PubMed  CAS  Google Scholar 

  19. Aberer W, Bircher A, Romano A, et al.: Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. Allergy 2003, 58:854–863. There is no in vitro test diagnosing aspirin intolerance. Aspirin hypersensitivity needs to be confirmed by aspirin provocation test.

    Article  PubMed  CAS  Google Scholar 

  20. Nizankowska E, Bestynska-Krypel A, Cmiel A, Szczeklik A: Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J 2000, 15:863–869.

    Article  PubMed  CAS  Google Scholar 

  21. Stevenson DD, Simon RA: Sensitivity to aspirin and nonsteroidal anti inflammatory drugs. In Allergy Principle and Practice. Edited by Middleton E, Reed CE, Adkinson NF, Yunginger JW, Busse WW. St Louis: Mosby; 1998:1225–1234.

    Google Scholar 

  22. Bazan NG, Flower RJ: Lipid signals in pain control. Nature 2002, 420:136–138.

    Article  CAS  Google Scholar 

  23. Marone G, Lichtenstein LM, Galli SJ: Mast Cells and Basophils. San Diego: Academic Press; 2000.

    Google Scholar 

  24. Pachlopnik JM, Horn MP, Fux M, et al.: Natural anti-FceRIalfa autoantibodies may interfere with diagnostic tests for autoimmune urticaria. J Autoimmunity 2004, 22:43–51. It is recognized that chronic urticaria in a subpopulation of patients appears to have an autoimmune basis.

    Article  CAS  Google Scholar 

  25. Ferrer M, Kinet JP, Kaplan AP: Comparative studies of functional and binding assays for IgG anti-Fc_RI _ (_-subunit) in chronic urticaria. J Allergy Clin Immunol 1998, 101:672–676.

    Article  PubMed  CAS  Google Scholar 

  26. Kikuchi Y, Kaplan AP: Mechanisms of autoimmune activation of basophils in chronic urticaria. J Allergy Clin Immunol 2001, 107:1056–1062.

    Article  PubMed  CAS  Google Scholar 

  27. Felberg W, Kellaway CH: Liberation of histamine and formation of lysolecithin-like substances by cobra venom. J Physiol 1938, 94:187–226.

    Google Scholar 

  28. Murphy RC, Hammarstrom S, Samuelsson B: Leukotriene C: a slow-reacting substance from murine mastocytoma cells. Proc Natl Acad Sci U S A 1979, 76:4275–4279.

    Article  PubMed  CAS  Google Scholar 

  29. Lewis RA, Austen KF, Soberman RJ: Leukotrienes and other products of the 5 lipoxygenase pathway: biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990, 323:645–655.

    Article  PubMed  CAS  Google Scholar 

  30. Sala A, Folco G, Henson PM, Murphy RC: Pharmacological modulation of human platelet leukotriene C synthase. Biochem Pharmacol 1997, 53:905–908.

    Article  PubMed  CAS  Google Scholar 

  31. Jakobsson PJ, Mancini JA, Riendeau D, Ford-Hutchinson AW: Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activity. Biol Chem 1997, 272:22934–22939.

    Article  CAS  Google Scholar 

  32. Pierzchalska M, Mastalerz L, Sanak M, et al.: A moderate and unspecific release of cysteinyl leukotrienes by aspirin from peripheral blood leukocytes precludes its value for aspirin sensitivity testing in asthma. Clin Exp Allergy 2000, 30:1785–1791.

    Article  PubMed  CAS  Google Scholar 

  33. Celik G, Bavbek S, Misirligil Z, Melli M: Release of cysteinyl leukotrienes with aspirin stimulation and the effect of prostaglandin E2 on this release from peripherial blood leucocytes in aspirin-induced asthmatic patients. Clin Exp Allergy 2001, 31:1615–1622.

    Article  PubMed  CAS  Google Scholar 

  34. Pavord ID, Tattersfield AE: Bronchoprotective role for endogenous prostaglandin E2. Lancet 1995, 345:436–438.

    Article  PubMed  CAS  Google Scholar 

  35. Penrose JF, Spector J, Baldasaro M, et al.: Molecular cloning for human LTC4 synthase: organization, nucleotide sequence and chromosomal localization to 5q35. J Biol Chem 1996, 271:11356–11361.

    Article  PubMed  CAS  Google Scholar 

  36. Sanak M, Simon HU, Szczeklik A: Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma. Lancet 1997, 350:1599–1600.

    Article  PubMed  CAS  Google Scholar 

  37. Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A: Enhanced expression of the leukotriene C4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol 2000, 23:290–296.

    PubMed  CAS  Google Scholar 

  38. Van Sambeek R, Stevenson D, Baldasaro M, et al.: 5’Flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant phenotype in the United States. J Allergy Clin Immunol 2000, 106:72–76.

    Article  PubMed  Google Scholar 

  39. Sampson AP, Siddiqui S, Buchanan D, et al.: Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000, 55:528–531.

    Article  Google Scholar 

  40. Mastalerz L, Nizankowska E, Sanak M, et al.: Clinical and genetic features underlying the response of patients with bronchial asthma to treatment with a leukotriene receptor antagonist. Eur J Clin Invest 2002, 32:949–955.

    Article  PubMed  CAS  Google Scholar 

  41. Wedi B, Kapp A: Aspirin induced adverse skin reactions: new pathophysiological aspects. Thorax 2000, 55:570–571.

    Article  Google Scholar 

  42. Gamboa P, Sanz ML, Caballero R, et al.: The flow-cytometric determination of basophil activation induced by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) is useful for in vitro diagnosis of the NSAID hypersensitivity syndrome. Clin Exp Allergy 2004, 34:1448–1457.

    Article  PubMed  CAS  Google Scholar 

  43. Okazaki T, Ilea VS, Rosario NA: Regulatory role of prostaglandin E in allergic histamine release with observation on the responsiveness of basophil leucocytes and the effect of acetylsalicylic acid. J Allergy Clin Immunol 1977, 60:360–366.

    Article  PubMed  CAS  Google Scholar 

  44. Soter NA, Lewis RA, Corey EJ, Austen KF: Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4, and LTB4) in human skin. J Investig Dermatol 1983, 80:115–119.

    Article  PubMed  CAS  Google Scholar 

  45. Grzelewska-Rzymowska I: Chemotactic activity of serum granulocytes after aspirin with aspirin-sensitive urticaria who find themselves in a state of tolerance for this drug. Pneumonol Alergol Pol 1993, 61:357–361.

    PubMed  CAS  Google Scholar 

  46. Asero R: Risk factors for acetaminophen and nimesulide intolerance in patients with NSAID-induced skin disorders. Ann Allergy Asthma Immunol 1999, 82:554–558.

    PubMed  CAS  Google Scholar 

  47. Dahlén B, Nizankowska E, Szczeklik A, et al.: Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics. Am J Respir Crit Care Med 1998, 157:1187–1194.

    PubMed  Google Scholar 

  48. Lynch KR, O’Neill GP, Liu Q, et al.: Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 1999, 399:789–793.

    Article  PubMed  CAS  Google Scholar 

  49. Heise CE, O’Dowd BF, Figueroa DJ, et al.: Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem 2000, 275:30531–30536.

    Article  PubMed  CAS  Google Scholar 

  50. Pacor ML, Di Loranzo G, Corrocher R: Efficacy of leukotriene receptor antagonist in chronic urticaria: a double blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria and intolerance to food additives and/or acetylsalicylic acid. Clin Exp Allergy 2001, 31:1607–1614. Aspirin-induced urticaria patients seem to benefit more from leukotriene receptor antagonists than patients who tolerate aspirin well.

    Article  PubMed  CAS  Google Scholar 

  51. Zerbagci Z: The leukotriene receptor antagonist montelukast in the treatment of chronic urticaria: a single-blind, placebocontrolled, crossover clinical study. J Allergy Clin Immunol 2002, 110:484–488.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mastalerz, L., Setkowicz, M. & Szczeklik, A. Mechanism of chronic urticaria exacerbation by aspirin. Curr Allergy Asthma Rep 5, 277–283 (2005). https://doi.org/10.1007/s11882-005-0067-z

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11882-005-0067-z

Keywords

Navigation