Review and feature article
Aspirin or Other Nonsteroidal Inflammatory Agent Exacerbated Asthma

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Aspirin-exacerbated respiratory disease (AERD) is an asthma phenotype with a prevalence that ranges from 2% to 25% of the asthma population. The 2% prevalence applies to patients with mild and 25% to severe, persistent asthma. COX-1–inhibiting nonsteroidal anti-inflammatory drugs, including aspirin, aggravate the preexisting upper and lower respiratory disease, sometimes in a life-threatening manner. The upper airway disease is characterized by an eosinophilic, hyperplastic rhinosinusitis with polyps. Eosinophilia, both peripheral and in the airways with Th2 inflammation, characterizes this disease. The role of allergic sensitivity in AERD is unclear, even though more than 30% of affected patients produce specific IgE to environmental allergens. Clinically, the respiratory symptoms are not usually associated with allergen exposure. The mechanism responsible for this phenotype is likely related to leukotriene (LT) metabolism because patients who are affected compared with patients who were aspirin tolerant, produce greater amounts of cysteinyl LTs. The synthesis of cysteinyl LTs is further increased after aspirin challenge and symptom exacerbation. Eosinophilia as well as a variety of other biologic markers, for example, Th2 cytokines, peripheral blood periostin, and LT enzymes and receptors, are associated with AERD both in the blood and in respiratory mucosa. These markers may help identify patients with AERD, but aspirin or other nonsteroidal anti-inflammatory drugs challenge is the primary means to confirm the diagnosis. A variety of single nucleotide polymorphisms and genes are associated with AERD, but the studies to date are limited to select populations and have not conclusively demonstrated a uniform genetic pattern in subjects with this disease. Treatment of AERD can be challenging because the nasal symptoms, including polyposis, are often refractory to both surgery and medical treatment, and the asthma can be difficult to control. Aspirin desensitization, followed by daily aspirin administration, can improve both upper and lower respiratory tract symptoms in up to 60% of individuals.

Section snippets

Demographics

The actual prevalence of AERD remains uncertain, with reports that range from 2% to 25%.7, 8, 9, 10 The figures vary, depending on the population surveyed; adults or those with more severe asthma have a higher prevalence of AERD than children or those with mild asthma; the prevalence in adolescence may approach that of adulthood. The evidence to date supports a prevalence of less than 10% in general populations of adults and adolescents with asthma. The apparent prevalence also is increased if

Clinical Characteristics

Rhinorrhea and nasal congestion usually are the first symptoms to develop in the course of the disease. The nasal symptoms are perennial and commonly refractory to pharmacotherapy, with worsening after ingestion of NSAIDs. With time, nasal symptoms become persistent and associated with anosmia, noninfectious recurrent and chronic sinusitis, and nasal polyposis. A patients with AERD develops bronchospasm, which is often severe and life-threatening, within 1 to 3 hours after ingestion of aspirin

Comorbidities

There is evidence of atopic disease in at least one-third of patients with AERD, although the clinical importance of IgE specific to inhaled allergens in its pathogenesis is minimal. However, coexisting allergic respiratory disease may contribute to the disease burden of patients with AERD and should be appropriately treated. Staphylococcal exotoxin-specific IgE, present in the mucosa of patients who are affected, along with the exotoxin, may play an important role with upper airway disease and

Pathophysiology

The pathogenesis of AERD is closely linked with dysregulation of LT synthesis. Synthesis of LTs is increased with individuals who are affected and increases further after aspirin challenge. Aspirin affects arachidonic acid metabolism, important in both the prostaglandin (PG) and LT pathways. However, the key mechanism or mechanisms that related LTs and AERD are undetermined. The various factors associated with the pathophysiology of AERD are summarized in Table I, Table II to III.14, 15 LT

Genetics

The European Network on Aspirin-induced Asthma found that 6% of subjects with AERD had a family history of aspirin hypersensitivity.10 Case reports of AERD that occur in families, the first one of which was reported in 1972,16 support the genetic contribution to this disease. However, the low penetrance within families and the lack of a defined pathogenesis makes the search for genetic linkages complicated and confusing. There are relatively small studies in multiple ethnicities, and many of

Biomarkers

There is a 15-fold increase in eosinophils and other cells that expressed LTC4 synthase in bronchial biopsy specimens of individuals with AERD when compared with subjects without asthma, which is a 4-fold increase when compared with ATA.22 The mechanisms for this increase in eosinophils are not clear, but elevated levels of cysteinyl leukotrienes (cysLT) likely play a role. CysLT levels are increased at baseline in urine and in exhaled air, and rise abruptly after aspirin challenge. CysLT1

Relationship to Statistically Defined Asthma Phenotypes

The heterogeneity of asthma with variable symptom profiles and response to medications necessitate the use of statistical, latent class analyses to identify phenotypes in large cohorts. The analysis generally applied is an unsupervised classification strategy that uses a hierarchical, bottom-up clustering algorithm method.27, 28 AERD is associated with more frequent exacerbations and reduced quality of life in a post hoc cluster analysis of difficult-to-treat asthma, as defined by the treating

Definition

In the strictest sense, the AERD phenotype requires confirmation by a blinded aspirin or other NSAID challenge. However, such challenges can be life threatening and expensive, and are unavailable in many clinics. For clinical purposes, a modified definition of AERD may be accepted in patients who fulfill the other 4 specified criteria listed in Table IV. Note that with this definition, a clinical history of aspirin reactions is not absolutely required if all the other criteria are met. The

Recommendation for Information to Be Obtained to Determine AERD Phenotype

  • 1.

    Does ASA or another NSAID cause wheeze or shortness of breath, chest discomfort, or nasal symptoms?

  • 2.

    Is there evidence of chronic sinusitis?

  • 3.

    Is there evidence of nasal polyps with hyposmia?

  • 4.

    Is there peripheral blood eosinophilia?

  • 5.

    Did asthma symptoms begin after age 20 years?

Research Questions and Future Directions

  • 1.

    Determine whether prior respiratory infection contributes to the onset of AERD.

  • 2.

    Determine whether there is a therapeutic value for 5-lipoxygenase inhibitors or other modulators of the LTs or PG pathways compared with LT receptor inhibitors in AERD.

  • 3.

    Clarify the role of Th2-regulated allergic responses to inhaled allergens in the development of AERD.

  • 4.

    Clarify the relationship of upper airway inflammation and pathobiology of nasal polyps with lower airway inflammation and asthma in AERD.

  • 5.

    Determine the

Conclusion

AERD and its recognition are important clinically to avoid the inadvertent administration of aspirin and other NSAIDs in the care of these patients. AERD is characterized by severe respiratory disease, both rhinosinusitis and asthma, and is one of the best defined asthma phenotypes, even though the essential pathogenetic mechanisms remain elusive. The association of AERD with altered LT metabolism and increased LT production support the critical role of LTs in its pathogenesis. The complexity

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    No funding was received for this work.

    Conflicts of interest: D. K. Ledford is a member of the Joint Council of Allergy Asthma and Immunology; receives travel support from the American Academy of Allergy, Asthma & Immunology; has received consultancy fees from Genentech and GlaxoSmithKline; is employed by the Veterans Affairs (VA), University of South Florida, Morsani College of Medicine, and the Academic Allergy Asthma and Immunology Associates of Tampa Bay; has provided expert testimony for Shook Hardy Bacon, Saieva and Stine, Richard Benjamin Wilkinson, and Fowler White Burnett; has received research support from Chugai Data Safety (NCT01986933) as a Board member, Forest Pharmaceuticals (NCT01572792, NCT01966107), Merck (NCT01700192), Circassia (NCT02150343), Teva (NCT02031640), and Genentech (NCT01264939, NCT02191072); has received lecture fees from Meda, Genentech, Novartis, Merck, and AstraZeneca; receives royalties from UpToDate, Springer, and Informa; and has received payment for the development of educational presentations from Novartis. S. E. Wenzel has received research support from GlaxoSmithKline (NCT02164513), Genentech (NCT02164513), and Sanofi-Aventis (NCT01854047), has received consultancy fees from Novartis, GlaxoSmithKline, AstraZeneca, and Boehringer-Ingelheim; has received travel support from AstraZeneca, GlaxoSmithKline; and has received fees for participation in review activities from ICON. R. F. Lockey is on the World Allergy Organization Board; has received consultancy fees from Merck and Genentech; is employed by the University of South Florida and the Veterans Affairs Hospital; has received research support from ALA Pharmaceuticals; has received lecture fees from Merck and AstraZeneca; receives royalties from Informa Publishing; and has received travel support from the World Allergy Organization.

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