Aspirin Exacerbated Respiratory Disease (AERD)
including asthma, rhinitis and nasal polyps
Posted: May 2006
ASA - acetysalicylic acid
NSAIDs – nonsteroidal anti-inflammatory drugs
CRS – chronic rhinosinusitis
COX - cyclooxygenase
LOX - lipoxygenase
A subpopulation of asthmatic patients reacts with acute dyspnea usually accompanied by nasal symptoms, rhinorrhea and/or nasal congestion within two hours after ingestion of aspirin. These patients have the "aspirin triad," which consists of chronic rhinosinusitis, complicated by polyps, severe bronchial asthma, and intolerance to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). The terms Aspirin-Exacerbated Respiratory Disease (AERD), Aspirin Sensitive Asthma, and Sampter's Syndrome have been proposed to describe "aspirin-triad".
The incidence of ASA-intolerance varies from 5%-10% in mild asthmatics and up to 24% in patients with more severe asthma.
ASA-intolerant patients usually suffer from a severe form of asthma requiring chronic treatment with moderate to high doses of inhaled glucocorticosteroids; oral glucocorticoids are necessary to control asthma in many of these patients. In addition, the majority of aspirin-intolerant asthmatics have nasal and sinus symptoms. The incidence of sinusitis, as demonstrated by CT scans, is up to 100% and the frequency of nasal polyps may be as high as 90%. Rhinosinusitis is protracted and the nasal polyps tend to recur following polypectomy, for example, the recurrence rate for nasal polyps in ASA-intolerant patients is almost three times higher than in intrinsic asthmatics and seven times higher than in atopic asthmatics. Polypoid hypertrophy of the mucosa is not just limited to the nasal cavity, it usually involves all sinuses and is more extensive in ASA-intolerant compared to ASA-tolerant patients with nasal polyposis. There is also clinical evidence that uncontrolled chronic rhinosinusitis often aggravates the course of asthma in these patients.
The mechanism of aspirin-intolerance in asthmatic patients is not immunological but is related to pharmacological properties of ASA and other NSAIDs. Only NSAIDs that are strong or at least moderate inhibitors of COX-1, an enzyme that converts arachidonic acid into prostaglandins, thromboxanes and prostacycline, can cause reactions in ASA-intolerant patients. It is postulated that inhibition of COX-1 by aspirin or other NSAIDs triggers a biochemical cascade which causes asthma. In fact, a local deficiency in prostaglandin E2 synthesis was found in nasal polyps, epithelial cells and bronchial fibroblasts from ASA-intolerant patients, suggesting a basal defect in this regulatory mechanism which may be further exacerbated by aspirin.
In addition, ASA-induced reactions involve release of mast-cell and eosinophil-derived mediators including enhanced production of cysteinyl leukotrienes, increased amounts of which can be detected post-challenge in bronchial or nasal fluid or in urine. Cysteinyl leukotrienes may also be important mediators of persistent airway inflammation since basal levels of these metabolites are elevated compared to ASA-tolerant asthmatics. Furthermore, LTC4 synthase, an enzyme involved in transformation of arachidonic acid to cysteinyl leukotrienes, is over-expressed in the bronchial mucosa and leukotriene receptors are over expressed in the nasal mucosa. However, for unknown reasons, leukotriene receptor antagonists or 5-lypoxygenase inhibitors only partially prevent ASA-induced reactions and are not more effective in improving bronchial or nasal symptoms in ASA-intolerant than ASA-tolerant patients, thus questioning the pivotal role of leukotrienes in this form of asthma.
Other arachidonic acid metabolites generated by the 5-lipoxygenase pathway have been associated with aspirin-intolerance. For example, aspirin triggers 15-HETE generation in nasal polyp epithelial cells and peripheral blood leukocytes from aspirin-intolerant but not aspirin-tolerant patients suggesting the presence of a specific abnormality of the 15-LOX pathway in these patients. Upregulation of 15-lipoxygenase and decreased production of lipoxin A4, an anti-inflammatory 15-LO metabolite found in leukocytes and nasal polyp tissue from ASA-intolerant patients, further points to a distinctive but not yet understood role for the 15-lipoxygenase pathway.
The pathogenesis of chronic eosinophilic inflammation in the airway mucosa and of nasal polyps in ASA-intolerant patients is not fully understood, but is not related to exposure to aspirin or other NSAIDs, because simple aspirin avoidance does not improve the course of the asthma. Impairment in regulation of local apoptosis of eosinophils and/or involvement of Staphylococcus aureus enterotoxin have been implicated in the pathophysiology of the eosinophilic inflammation in the airway mucosa of these patients.
Several single nucleotide polymorphisms in candidate genes coding molecules related mainly to the arachidonic acid metabolic pathway, e.g., LTC4 synthase, 5-LOX, prostaglandin EP or leukotriene LT1 receptors, were found to be associated with ASA-intolerance. Therefore, a genetic component may be important in the pathogenesis of the disease.
The diagnosis of ASA-intolerance is based usually on a history of adverse reactions caused by the ingestion of NSAIDs. Although the majority of ASA-intolerant patients have a convincing history of NSAID-induced adverse reactions, in some patients, confirmation by controlled aspirin challenge is necessary. Oral aspirin challenge is the gold standard to confirm the diagnosis. Nasal or bronchial provocation with lysine-ASA, which is available in Europe, may be a valuable alternative diagnostic tool. Nevertheless, oral, bronchial or intranasal challenges are time consuming and require special equipment and expertise, which is not always available.
In vitro tests which could distinguish aspirin-tolerant from aspirin-intolerant individuals are currently under investigation. Although a few studies demonstrate that aspirin triggers the release of LTC4 from peripheral blood leukocytes (PBL), the differences between ASA-intolerance and ASA-tolerant subjects are only quantitative and not always reproducible.
Aspirin triggers the in vitro generation of the arachidonic acid metabolite, 15-hydroxyicosatetrenoic acid (15-HETE), from nasal polyp epithelial cells and peripheral blood leukocytes from ASA-intolerant patients, but not from ASA-tolerant asthmatics or healthy subjects. Aspirin triggered 15-HETE release from PBL mimicks, to some extent, the reaction to aspirin observed in vivo. In some patients release of 15-HETE can be triggered by other non-selective cyclooxygenase inhibitors, naproxen or ibuprofen, but not the COX-2 selective NSAID, celecoxib. Furthermore, misoprostol, a synthetic PGE analogue, shown to prevent aspirin-induced asthmatic reactions, inhibits 15-HETE generation in vitro triggered by aspirin. The Aspirin Sensitive Patient Identification Test (ASPITest®), based on 15-HETE release measurement from PBL, may be sensitive and specific, and thus confirm the history of aspirin-intolerance.
A basophil activation test based on cytofluorimetric measurement of surface molecule CD63 expression has been proposed as a confirmatory test to diagnose aspirin-intolerance. Although preliminary studies indicated a sensitivity of 41% and specificity of 100%, further studies in larger and more clearly defined patient populations are necessary to estimate the real utility of this test in aspirin-hypersensitive asthmatics.
Management of asthma and rhinosinusitis in the ASA-intolerant patient is similar to treatment of other forms of asthma and rhinosinusitis. However, there are several important differences when aspirin-intolerance is diagnosed.
Avoidance of NSAIDs and use of alternative analgesics
Patient education and careful avoidance of ASA and other NSAIDs is important because NSAIDs can cause severe asthma leading to hospitalization in an intensive care unit and even intubation. Therefore, ideally, the aspirin-intolerance should be confirmed by a challenge test.
Alternative antipyretic or analgesic drugs, such as acetaminophen, less than 1000 mg given once every six to eight hours are preferred. Preferential COX-2 inhibitors, e.g., nimesulide and meloxicam, are tolerated by most, but not all, ASA-intolerant subjects. Oral challenge in the office is necessary to ensure that patients are able to tolerate COX-2 inhibitors. Selective preferential COX-2 inhibitors, such as rofecoxib, are tolerated by almost all aspirin-intolerant asthmatics although reports of potential cardiovascular side effects may limit their use. Recent reports including randomized controlled trials have demonstrated that significant cardiovascular toxicity is associated not only with rofecoxib (already withdrawn) but also with celecoxib, valdecoxib and parecoxib, suggesting that this is a class effect of selective NSAIDs.
Mangement of chronic rhinosinusitis and nasal polyposis
Successful management of chronic rhinosinusitis is essential and may result in the improvement of asthmatic symptoms. Nasal decongestants and antihistamines are of limited value but topical glucocorticoids are quite effective. In many patients, nasal surgery is needed to relieve the symptoms of chronic sinusitis, nasal obstruction, and to remove nasal polyps. Surgery may consist of a polypectomy and functional endoscopic sinus surgery with or without ethmoidectomy. However, the surgery does not affect the underlying inflammatory component of the disease and nasal polyps tend to recur, therefore, medical treatment post surgery with nasal glucocorticosteroids, is necessary.
Management of asthma
Inhaled glucocorticosteroids, often combined with long acting beta-2 agonists, are the most effective drugs to control asthma. Leukotriene modifiers may be useful to both improve asthma and rhinosinusitis in ASA-intolerant patients.
Another approach to treat ASA-intolerant rhinosinusitis and asthma is to desensitize the ASA-intolerant asthmatic by the gradual administration of increasing doses of aspirin. If the aspirin is stopped by the patient for more than several days, aspirin desensitization is again necessary before aspirin can be resumed on a regular basis. Following desensitization and with the continued administration of daily aspirin, many aspirin-intolerant patients will experience some alleviation of both nasal and bronchial symptoms and have decreased recurrence of nasal polyps. However this procedure should only be undertaken by trained specialist.
Indications for aspirin desensitization are listed in table 1.
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Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. Szczeklik A, Stevenson DD J Allergy Clin Immunol 2003 111: 913-21.
Berges_Gimeno MP, Simon RA, Stevenson DD. Early effects of aspirin desensitization treatment in asthmatic patients with aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol 2003, 90: 338-4
Corrigan C, Mallett K, Ying S, Roberts D, Parikh A, Scadding G, Lee T. Expression of the cysteinyl leukotriene receptors cysLT(1) and cysLT(2) in aspirin-sensitive and aspirin-tolerant chronic rhinosinusitis. J Allergy Clin Immunol. 2005;115:316-22
Kowalski M.L., Ptasinska A, Bienkiewicz B Pawliczak R, L. DuBuske. Aspirin-triggered 15-HETE generation in peripheral blood leukocytes is a sensitive and specific and Aspirin Sensitive Patients Identification Test (ASPITest). Allergy 2005, 60:1139-45.
Potential indications for aspirin desensitization in aspirin hypersensitive asthmatics.
- Coronary heart disease –
- need for chronic treatment with aspirin
- Aspirin hypersensitive asthma/rhinosinusitis
- patients with severe nasal polyposis
- patients not responding to pharmacological treatment
- significant corticosteroid-induced side effects
- Indications for anti-inflammatory treatment
- rheumatoid arthritis