Reviews and Feature Articles
Aspirin-induced asthma: Advances in pathogenesis, diagnosis, and management,☆☆

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Abstract

In some asthmatic individuals, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygen-ase 1 (COX-1) exacerbate the condition. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by an eosinophilic rhinosinusitis, nasal polyposis, aspirin sensitivity, and asthma. There is no in vitro test for the disorder, and diagnosis can be established only by provocation challenges with aspirin or NSAIDs. Recent major advances in the molecular biology of eicosanoids, exemplified by the cloning of 2 cysteinyl leukotriene receptors and the discovery of a whole family of cyclooxygenase enzymes, offer new insights into mechanisms operating in AIA. The disease runs a protracted course even if COX-1 inhibitors are avoided, and the course is often severe, many patients requiring systemic corticosteroids to control their sinusitis and asthma. Aspirin and NSAIDs should be avoided, but highly specific COX-2 inhibitors, known as coxibs , are well tolerated and can be safely used. Aspirin desensitization, followed by daily aspirin treatment, is a valuable therapeutic option in most patients with AIA, particularly those with recurrent nasal polyposis or overdependence on systemic corticosteroids. (J Allergy Clin Immunol 2003;111:913-21.)

Section snippets

Definition

The term ASA-exacerbated respiratory disease4 is the best description of the aggressive and continuous inflammatory disease of the airways, combined with exacerbation of asthma and rhinitis attacks, after ingestion of ASA and most nonsteroidal anti-inflammatory drugs (NSAIDs). However, most physicians refer to this condition as ASA-induced asthma (AIA), the aspirin triad , ASA sensitivity , or ASA-intolerant asthma . We will use the term ASA-induced asthma because of its widespread use and

Prevalence

Based on patients' histories alone, the incidence of ASA sensitivity in asthmatic adults is 3% to 5%, but this percentage doubles or triples when adult asthmatic patients are prospectively challenged with ASA. Three large population-based sampling studies, using specifically designed questionnaires, were recently concluded. In a random sample of 4300 adult women and men in southern Finland,5 the prevalence of reported ASA intolerance causing shortness of breath or attacks of asthma was 1.2%,

Clinical Presentation

The natural history and clinical characteristics of AIA were recently described in 500 patients from 10 European countries, each having a diagnosis of AIA confirmed by ASA provocation tests.8 AIA developed according to a characteristic sequence of symptoms: persistent rhinitis appeared at an average age of 30 years and was followed by asthma, ASA sensitivity, and nasal polyposis. In women, who outnumbered men at a ratio of2.3:1, the onset of symptoms occurred significantly earlier and the

Diagnosis

The presence of AIA should be suspected in cases presenting (a) a history of attacks of dyspnea (asthma) associated with ingestion of ASA and other NSAIDs, (b) chronic and intractable nasal congestion and watery rhinorrhea, particularly if allergy skin tests are negative, (c) nasal polyposis, (d) pansinusitis by computed tomography scanning, and (e) severe attacks of asthma without apparent cause requiring hospitalization in an intensive care unit.

Diagnosis can be established with certainty

Cyclooxygenase pathways

Twenty-eight years ago it was proposed29 that ASA-precipitated attacks of asthma are not due to an allergic reaction but result from inhibition of cyclooxygenase (COX) by ASA-like drugs in the airways of sensitive patients. Confirmation of this proposition by various groups3 led to the formulation of the COX theory.30

It is now well recognized that there are at least 2 COX enzymes, COX-1 and COX-2, coded by 2 different genes. Their role in asthma has been reviewed previously.31 Most recently,

Prevention

To prevent life-threatening reactions, patients with AIA should avoid ASA, all products containing it, and other analgesics that inhibit COX-1. Thus, the education of physicians, pharmacists, and patients is important in the survival of patients with AIA.

Patients with AIA can safely ingest sodium salicylate, salicylamide, choline magnesium trisalicylate, benzydamine, chloroquine, azapropazone, and dextropropoxyphen.3, 75 Unfortunately, all of these are poor analgesics and have only mild

Treatment

The general rules concerning treatment of the asthma associated with AIA do not differ from the accepted guidelines for the management of asthma.77 Most patients have moderate or severe persistent asthma, and approximately one half of them require chronic treatment with systemic corticosteroids to control the disease.8

Conclusions

AIA, or ASA-exacerbated respiratory disease, characterizes a relatively common subgroup of asthma patients, accounting for 10% to 15% of all asthmatic individuals. Despite this observation, the disorder is underrecognized and undiagnosed patients are particularly vulnerable to catastrophic asthma attacks after ingesting ASA and the older NSAIDs. LT modifier drugs prevent ASA-induced asthma attacks only in some patients, leaving other patients with AIA unprotected. There is complete

References (102)

  • ID Pavord et al.

    Bronchoprotective role for endogenous prostaglandin E2

    Lancet

    (1995)
  • M Pierzchalska et al.

    Deficient prostaglandin E2 production by bronchial fibroblasts of asthmatic patients with special reference to aspirin-induced asthma

    J Allergy Clin Immunol

    (2003)
  • Y Obase et al.

    Effects of pranlukast on chemical mediators in induced sputum on provocation tests in atopic and aspirin-intolerant asthmatic patients

    Chest

    (2002)
  • Y Kawagishi et al.

    Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma

    J Allergy Clin Immunol

    (2002)
  • M Sanak et al.

    Leukotriene C4 synthase promoter polymorphism and risk of aspirin-induced asthma

    Lancet

    (1997)
  • R Van Sambeek et al.

    5′Flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States

    J Allergy Clin Immunol

    (2000)
  • M Sanak et al.

    Leukotriene C4 synthase polymorphism and aspirin-induced asthma

    J Allergy Clin Immunol

    (2001)
  • JL Zhao et al.

    Cell-specific transcription of leukotriene C4 synthase involves a Kruppel-like transcription factor and Sp1

    J Biol Chem

    (2000)
  • J Takasaki et al.

    The molecular characterisation and tissue distribution of the human cysteinyl leukotriene CysLT(2) receptor

    Biochem Biophys Res Commun

    (2000)
  • S O'Sullivan et al.

    Increased urinary excretion of the prostaglandin D2 metabolite 9α, 11β-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction

    J Allergy Clin Immunol

    (1996)
  • S Yoshida et al.

    Effect of acyclovir on bronchoconstriction and urinary leukotriene E4 excretion in aspirin-induced asthma

    J Allergy Clin Immunol

    (1998)
  • A Szczeklik et al.

    Clinical patterns of hypersensitivity to nonsteroidal antiinflammatory drugs and their pathogenesis

    J Allergy Clin Immunol

    (1977)
  • RA Settipane et al.

    Cross-sensitivity with acetaminophen in aspirin sensitive subjects with asthma

    J Allergy Clin Immunol

    (1989)
  • AE Tattersfield et al.

    Asthma

    Lancet

    (2002)
  • CR Zeiss et al.

    Refractory period to aspirin in a patient with aspirin-induced asthma

    J Allergy Clin Immunol

    (1976)
  • DD Stevenson et al.

    Aspirin-sensitive asthma: tolerance to aspirin after positive oral aspirin challenges

    J Allergy Clin Immunol

    (1980)
  • WW Pleskow et al.

    Aspirin desensitization in aspirin sensitive asthmatic patients: clinical manifestations and characterization of the refractory period

    J Allergy Clin Immunol

    (1982)
  • M Berges-Gimeno et al.

    Treatment with aspirin desensitization in patients with aspirin exacerbated respiratory disease

    J Allergy Clin Immunol

    (2003)
  • UR Juergens et al.

    Inhibition of monocyte leukotriene B4 production following aspirin desensitization

    J Allergy Clin Immunol

    (1995)
  • DD Stevenson et al.

    Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics

    Ann Allergy Asthma Immunol

    (2000)
  • A Szczeklik et al.

    Montelukast for persistent asthma

    Lancet

    (2001)
  • MF Widal et al.

    Anaphylaxie et idiosyncrasie

    Presse Med

    (1922)
  • M Samter et al.

    Intolerance to aspirin. Clinical studies and consideration of its pathogenesis

    Ann Int Med

    (1968)
  • J Hedman et al.

    Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study

    Int J Epidemiol

    (1999)
  • L Kasper et al.

    Prevalence of asthma with aspirin hypersensitivity in the adult population of Poland

    Allergy

    (2003)
  • H Vally et al.

    The prevalence of aspirin-intolerant asthma (AIA) in Australian asthmatic patients

    Thorax

    (2002)
  • A Szczeklik et al.

    : Natural history of aspirin-induced asthma

    Eur Respir J

    (2000)
  • G Bochenek et al.

    The atopy trait in hypersensitivity to nonsteroidal anti-inflammatory drugs

    Allergy

    (1996)
  • AF Kalyoncu et al.

    Occurrence of allergic conditions in asthmatic with analgesic intolerance

    Allergy

    (1999)
  • EA Pastorello et al.

    Atopy and intolerance of antimicrobial drugs increase the risk of reactions to acetaminophen and nimesulide in patients allergic to nonsteroidal anti-inflammatory drugs

    Allergy

    (1998)
  • MP Berges-Gimeno et al.

    The natural history and clinical characteristics of aspirin exacerbated respiratory disease

    Ann Allergy Asthma Immunol

    (2002)
  • DD Stevenson et al.

    Sensitivity to aspirin and nonsteroidal anti-inflammatory drugs

  • M Setkowicz et al.

    NSAIDs sensitivity in chronic idiopathic urticaria: selective involvement of cyclooxygenase-1 and overproduction of cysteinyl-leukotrienes

    J Allergy Clin Immunol

    (2003)
  • G Bochenek et al.

    Testing for aspirin hypersensitivity

    Allergy

    (2002)
  • E Niz.ankowska et al.

    Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma

    Eur Respir J

    (2000)
  • S Bianco et al.

    Aspirin-induced tolerance in aspirin-induced asthma detected by a new challenge technique

    IRCS J Med Sci

    (1977)
  • G Melillo et al.

    Report of the INTERASMA Working Group on standardization of inhalation provocation tests in aspirin-induced asthma

    Allergy

    (2001)
  • A Alonso-Llamazares et al.

    Nasal provocation test (NPT) with aspirin: a sensitive and safe method to diagnose aspirin-induced asthma (AIA)

    Allergy

    (2002)
  • SM Nasser et al.

    Leukotrienes in aspirin-sensitive asthma

  • AL De Weck et al.

    Cellular antigen stimulation test (CAST): a new dimension in allergy diagnosis

    Allergy Clin Immunol News

    (1993)
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    ☆☆

    Reprint requests: Donald D. Stevenson, MD, Division of Allergy, Asthma and Immunology, Department of Medicine, Scripps Clinic and The Scripps Research Institute, 10066 N Torrey Pines Road, La Jolla, CA 92037.

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