Aspirin Exacerbated Respiratory Disease (AERD)
Posted: October 2013
(Updated; originally posted May 2006)
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 or other non steroidal anti-inflammatory drugs (NSAIDs) (1,2). These patients have the "aspirin triad," which consists of chronic rhinosinusitis, complicated by polyps, severe bronchial asthma, and intolerance to aspirin and other NSAIDs. The term Aspirin-Exacerbated Respiratory Disease (AERD) has been accepted to describe this clinical entity and to replace previously used terms: Aspirin-Triad, Aspirin-Sensitive Asthma, Aspirin-Induced Asthma or Samter's Syndrome.
The incidence of AERD varies from 5%-10% in mild asthmatics and up to 24% in patients with more severe asthma in Europe and Australia, but may be much lower in some regions, for example, a prevalence of 0.57% has been reported in patients with chronic rhinosinusitis (CRS) in China (3,4,5).
AERD patients usually suffer from moderate or severe forms 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 (2). In addition, the majority of aspirin-intolerant asthmatics have nasal and sinus symptoms. The incidence of rhinosinusitis, as demonstrated by CT scans, is up to 100%, and the frequency of nasal polyps may be as high as 90% (6). Rhinosinusitis is protracted and the nasal polyps tend to recur following polypectomy: the recurrence rate for nasal polyps in AERD patients is several times higher than in aspirin-tolerant asthmatics after standard polypectomy but also after Functional Endoscopic Sinus Surgery (FEES). 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 Acetylsalicylic Acid (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-hypersensitivity in asthmatic patients is not immunological but is related to pharmacological properties of ASA and other NSAIDs. As originally documented in 1975 by Andrew Szczeklik et al (7), only NSAIDs that are strong or at least moderate inhibitors of prostaglandins (more specifically, 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-hypersensitive patients, suggesting a basal defect in this regulatory mechanism which may be further exacerbated by aspirin (8, 9).
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 asthma (10). 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. More recently, it has been documented, that platelet-adherent leukocyte interaction may drive the production of cysteinyl leukotriene in these patients (11). 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-hypersensitivity. 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 asthmatics 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 has been implicated in the pathophysiology of the eosinophilic inflammation in the airway mucosa of these patients (12).
Several single nucleotide polymorphisms in candidate genes coding molecules related mainly to the arachidonic acid metabolic pathway, for example, LTC4 synthase, 5-LOX, prostaglandin EP or leukotriene LT1 receptors, were found to be associated with ASA-intolerance (13). More recently a differential gene expression profile with potent discriminative power has been reported in leukocytes of AERD patients (14). 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-hypersensitive 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 (15). 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-intolerant and ASA-tolerant subjects are only quantitative and not always reproducible. Similarly, basophil activation test based on cytofluorimetric measurement of surface CD63 or CD203c molecules upon stimulation with aspirin or other NSAIDs do not yield consistent results in discriminating AERD from ASA-tolerant asthmatics (16). 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 (17). Preliminary reports suggested that The Aspirin Sensitive Patient Identification Test (ASPITest®), based on 15-HETE release measurement from PBL, may be also useful to confirm the history of aspirin-intolerance; however, further studies are required to confirm a discriminative value of this test (18, 19).
Management of asthma and rhinosinusitis in an ASA-hypersensitive patient is similar to treatment of other forms of asthma and rhinosinusitis. However, there are several important additional treatment modalities to be considered when aspirin-hypersensitivity is diagnosed (20).
Avoidance of NSAIDs and use of alternative analgesics
Patient education and careful avoidance of ASA and other NSAIDs which are strong COX-1 inhibitors is important because COX-1 inhibitors can cause severe asthma leading to hospitalization in an intensive care unit and even intubation. Therefore, ideally, the aspirin-hypersensitivity should be confirmed by a challenge test.
In general three groups of NSAIDs can be distinguished based on their capacity to induce hypersensitivity reactions in AERD patients (15). Table 1
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, such as nimesulide and meloxicam, are tolerated by most, but not all, ASA-intolerant subjects. Selective preferential COX-2 inhibitors, such as celecoxib or valdecoxib, are tolerated by almost all aspirin-intolerant subjects. However, oral challenge (tolerance test) in the office is recommended to ensure that patients are able to tolerate COX-2 inhibitors.
Mangement of chronic rhinosinusitis and nasal polyposis
Successful management of chronic rhinosinusitis is essential and may result in the improvement of asthmatic symptoms (21). Topical steroids are quite effective in controlling symptoms of rhinitis and may slow down recurrence of nasal polyps. Antibiotics should be used whenever infectious component is evident. Although antileukotriene drugs (ALD) may also alleviate symptoms of chronic rhinosinusitis and improve nasal patency in AERD patients, they are not more effective than in ASA-tolerant patients (22). Surgical procedures (polypectomy, functional endoscopic sinus surgery or ethmoidectomy) are usually needed to relieve symptoms of chronic rhinosinusitis at certain stages of the disease and to remove polypoid tissue from sinuses. Assessment of the outcome of endoscopic surgery in ASA-sensitive patients with chronic rhinosinusits and ASA-tolerant controls revealed that patients with ASA-triad responded less well to surgical intervention (23). Because surgery does not affect the underlying inflammatory component of rhinosinusitis, medical treatment with topical steroids is also necessary post-surgery. Antileukotrienes and/or chronic oral aspirin after desensitization may also be considered as the follow up treatment after surgery.
Management of asthma
Inhaled glucocorticosteroids in relevant doses, often in combination with long acting beta-2 agonists are the most effective drugs for controlling asthmatic inflammation and asthma symptoms in patients with AERD. In some patients chronic treatment with oral prednisone may be necessary to control the disease. Addition of a leukotriene receptor antagonist such as montelukast to standard anti-inflammatory therapy (inhaled glucocorticosteroids, theophyline, short acting β2-agonists) improved respiratory function and alleviated clinical symptoms over the 4-week treatment period in a group of aspirin sensitive asthmatics (24). In another study 6 weeks of treatment with zileuton in patients with AERD resulted in improvement in pulmonary function, although the magnitude of improvement did not exceed that observed in ASA-tolerant patients in other studies (25).
Available data indicate that although ALDs may be effective in relieving symptoms and improving respiratory function in some patients with AERD the degree of improvement is similar in ASA- sensitive and tolerant asthmatics (26). However, AERD patients bearing variant C allele of LTS4 synthase and HLA DRB1*301 allele seem to respond better to antileukotrienes, thus pointing to the importance of a pharmacogenetic approach to treatment of this apparently heterogenous population of asthmatic patients (27).
Desensitization to asthma
Most patients with AERD can be desensitized to aspirin: following the initial adverse reaction, repeating of the dose is tolerated by more that 50% of patients, and further incremental aspirin challenges lead to a tolerance (28). Once the patient tolerates 600 mg of aspirin he is considered “desensitized” and then can take aspirin on a daily basis indefinitely without further adverse respiratory reactions. Desensitization can be also achieved silently, for instance, without evoking initial adverse reaction providing the challenge starts with a sub threshold dose and then the dose is slowly increased in appropriate intervals (29). In order to maintain the tolerance a patient has to ingest aspirin on regular, usually daily basis – the tolerance state disappears after 2-5 days without aspirin with the full hypersensitivity returning after 7 days. Several protocols of desensitization have been proposed allowing for completing the procedure usually within 3 to 5 days. The standard protocol of desensitization is an extension of the oral aspirin challenge protocol and all the safety precautions recommended for the challenge should be employed.
The ingestion of aspirin after desensitization results in alleviation of chronic upper and lower airway symptoms (30). When the patients were treated with aspirin for 6 months to 6 years a significant reduction in hospitalization, emergency room visits, outpatient visits, and need for nasal/sinus surgery were observed, and in some patients, a reduction in daily oral prednisone doses could be achieved (31). In some patients, significant improvement in nasal and asthma symptoms and reduction in the dose or even discontinuation of oral steroids were already observed (32) within the first four weeks of treatment with aspirin. The clinical benefit is usually seen within the first 6 months of desensitization and continues to be effective for up to 5 years of follow-up. The potential effect of aspirin desensitization and treatment may be limited because: a) not all patients can be desensitized because of the severity or non-stability of underlying asthma, b) desensitization is contraindicated because of concomitant gastric/peptic ulcer disease, c) patients’ drop-out related to gastric intolerance of aspirin, and d) clinical improvement can be achieved in some but not all patients. Considering these limitations, only a fraction of patients with AERD will benefit from aspirin desensitization, and at present it is not possible to identify these patients before the procedure is implemented. Aspirin given after desensitization may be also a valuable solution for ASA-hypersensitive patients requiring chronic treatment with aspirin for rheumatoid diseases or coronary heart disease (33). Table 2 summarizes indications for ASA-desensitization in patients with asthma and hypersensitivity to NSAIDs.
Desensitization can also be achieved after repeated intranasal application of lysine aspirin (34). It has been reported that intranasal desensitization and prolonged treatment with soluble intranasal aspirin (Lysine-aspirin) has a beneficial effect on CRS, reducing recurrency rate for nasal polyps in ASA-treated groups as compared to placebo treated patients (35). However, such beneficial effects of nasal route were not confirmed by other studies and similar improvement in nasal symptoms after intranasal aspirin could be obtained in ASA-tolerant patients with nasal polyps questioning specificity of this approach for patients with AERD.
AERD is a distinct phenotype of bronchial asthma characterized by increased risk of uncontrolled upper and lower airway disease (36). Patients with AERD require comprehensive diagnostic and therapeutic approaches and pose a significant challenge for an allergist.
TABLE 1: NSAIDs tolerance in patients with cross-reactive type of hypersensitivity
(from Kowalski et al 2011r) (15)
Group A: NSAIDs cross-reacting in majority of hypersensitive patients (60–100%)
Group B: NSAIDs cross-reacting in minority of hypersensitive patients (2–10%)
acetaminophen (doses below 1000 mg)
selective COX-2 inhibitors (celecoxib, rofecoxib)
Group C: NSAIDs well tolerated by all hypersensitive patients*
selective cyclooxygenase inhibitors (celecoxib, parvocoxib)
new selective COX-2 inhibitors (etoricoxib, pavocoxib)
*Single cases of hypersensitivity have been reported
TABLE 2: Potential indications for aspirin desensitization in aspirin hypersensitive asthmatics
- Coronary heart disease –
- need for chronic treatment with aspirin
- 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
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