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NSAIDs Exacerbated Respiratory Disease (N-ERD)

Updated: May 2019
Updated: October 2013
Originally Posted: May 2006

Marek L. Kowalski, MD, PhD
Professor and Chairman, Department of Immunology, and Allergy,
Medical University of Łódź,  Poland

 

 

Aleksandra Wardzynska, MD, PhD
Department of Immunology, and Allergy, Medical University of Lodz,  Poland

Definition

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. Recently the term N-ERD (NSAIDs Exacerbated Respiratory Disease) has been proposed by members of  the EAACI Task Force on Diagnosis and Management of NSAID-Exacerbated Respiratory Disease to describe this clinical entity and to replace previously used terms: Aspirin Exacerbated Respiratory Disease (AERD), Aspirin-Triad, Aspirin-Sensitive Asthma, Aspirin-Induced Asthma or Samter's Syndrome3.

The prevalence of N-ERD in general population is unknown, respiratory symptoms following NSAID intake have been reported by 1.8% of the European population4. The incidence of N-ERD varies from 5.5%-12.4% in adult asthmatics (mean prevalence 7.1%) and increases to 14.9% in patients with more severe asthma5.

Clinical characteristics of aspirin triad

N-ERD 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 patients2. In addition, the majority of NSAIDs-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 N-ERD 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 NSAIDs-intolerant compared to tolerant patients with nasal polyposis. There is also clinical evidence that uncontrolled chronic rhinosinusitis often aggravates the course of asthma in these patients. Although N-ERD is one of the best characterized phenotypes of asthma, recent studies indicate the heterogeneity of this syndrome7. NSAIDs intolerant asthmatics may differ in terms of asthma control, intensity of upper airways inflammation, presence of blended (skin) reactions, blood eosinophil level and urinary LTE4 generation8, 9.

Pathophysiology of NSAIDs hypersensitivity

The mechanism of NSAIDs 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.10, 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 aspirin11, 12. 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 asthma13. 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 patients14. 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 asthma15, 16.

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 pathway17.

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 patients18. The latest research indicates the important role of innate immune response in N-ERD pathogenesis. It has been suggested that innate lymphoid cells (ILC 2), produced after TSLP and Il-33 stimulation, may be a source of mediators that drive tissue eosinophilia, mucus production and bronchial remodeling in NSAIDs intolerant asthmatics19.

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-intolerance20. More recently a differential gene expression profile with potent discriminative power has been reported in leukocytes of N-ERD patients21. Therefore, a genetic component may be important in the pathogenesis of the disease.

Diagnosis of NSAIDs-hypersensitivity

The diagnosis of -NSAIDs intolerance is based usually on a history of adverse reactions caused by the ingestion of NSAIDs. Although the most of these patients have a convincing history of NSAID-induced adverse reactions, in some individuals 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 (3). Nevertheless, oral, bronchial or intranasal challenges are time consuming and require special equipment and expertise, which is not always available.

Algorithm for N-ERD diagnosis proposed by the international panel is presented on Figure 1.

Currently none of available in vitro methods that have been proposed to confirm NSAIDs hypersensitivity can be recommended for routine diagnosis. 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. 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 N-ERD from ASA-tolerant asthmatics22. Similarly, the Aspirin Sensitive Patient Identification Test (ASPITest®), based on 15-HETE release measurement from PBL, has not yet been validated for the diagnosis of aspirin-hypersensitivity23.

Management of a patient with aspirin triad

Management of asthma and rhinosinusitis in an NSAIDs-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 N-ERD is diagnosed3.

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 N-ERD patients24, 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, NSAIDs-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 symptoms25. 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 N-ERD patients, they are not more effective than in NSAIDs-tolerant patients15, 16. 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 NSAIDs-sensitive patients with chronic rhinosinusits and NSAIDs-tolerant controls revealed that patients with ASA-triad responded less well to surgical intervention25. 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 N-ERD. 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 asthmatics15. In another study 6 weeks of treatment with zileuton in patients with N-ERD resulted in improvement in pulmonary function, although the magnitude of improvement did not exceed that observed in NSAIDs-tolerant patients in other studies16.

Available data indicate that although ALDs may be effective in relieving symptoms and improving respiratory function in some patients with N-ERD the degree of improvement is similar in ASA- sensitive and tolerant asthmatics. However, N-ERD 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 patients26.

Anti-IgE treatment and biologicals targeting eosinophilic inflammation (mepolizumab, reslizumab, benralizumab, dupilumab) seem to be promising therapeutic option in N-ERD patients, especially in difficult to treat asthmatics. Recent studies prove the effectiveness of biological drugs in reducing symptoms from the upper and lower respiratory tract in a proportion of N-ERD patients27, 28, 29.

Desensitization to aspirin and Aspirin Treatment after Desensitization (ATAD)

Most patients with N-ERD 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 tolerance30. 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  intervals31. 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 employed3.

ATAD results in alleviation of chronic upper and lower airway symptoms32. The effectiveness of this treatment has been proven in many observational and placebo – controlled studies33. 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 achieved30. In some patients, significant improvement in nasal and asthma symptoms and reduction in the dose or even discontinuation of oral steroids were already observed31 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. For greater effectiveness it has been suggested to combine ATAD with extensive nasal endoscopic surgery, starting aspirin desensitization two to six week after surgical intervention34.

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. ATAD may be associated with adverse effects including gastrointestinal irritation, rush, urticaria epistaxis and worsening of nasal or bronchial symptoms33. Since gastrointestinal side effects are the most common, in order to prevent adverse effects of ATAD appropriate measures (eradication of Helicobacter pylori before aspirin therapy, and drugs like PPI and H2-blokers) should be administered3. Considering these limitations, only a fraction of patients with N-ERD 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 NSAIDs-hypersensitive patients requiring chronic treatment with aspirin for  coronary heart disease or rheumatoid diseases35. 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 aspirin36. It has been reported that intranasal desensitization and prolonged treatment with soluble intranasal aspirin (Lysine-aspirin) has a beneficial effect on CRS, reducing recurrence rate for nasal polyps in ASA-treated groups as compared to placebo treated patients37.

Conclusions

Patients with N-ERD require comprehensive diagnostic and therapeutic approaches and pose a significant challenge for an allergist. N-ERD has been considered a distinct phenotype of bronchial asthma characterized by increased risk of uncontrolled upper and lower airway disease, however, recent data suggest existence of N-ERD sub-phenotypes (or even sub endotypes). These new observations may explain the heterogeneity in the responses  to various treatment modalities ( e.g. with antileukotriene drugs or ATAD) observed in N-ERD patients, and may have potential implications for development of endotype- targeted therapyFigure 2.

TABLE 1: NSAIDs tolerance in patients with cross-reactive type of hypersensitivity

Adapted from Kowalski ML, Makowska JS, Blanca M et al.. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy. 2011;66:818-2924.

Group A: NSAIDs cross-reacting in majority of hypersensitive patients (60–100%)

Diclofenac, Fenoprofen, Ibuprofen, Ketoprofen, Meclofenamate Nabumetone, Flurbiprofen, Indomethacin, Ketorolac, Mefenamic acid, Naproxen

Group B: NSAIDs cross-reacting in minority of hypersensitive patients (2–10%)

Rhinitis/asthma type

acetaminophen (doses below 1000 mg), meloxicam, nimesulide

Urticaria/angioedema type

Acetaminophen, meloxicam, nimesulide, selective COX-2 inhibitors (celecoxib, rofecoxib)

Group C: NSAIDs well tolerated by all hypersensitive patients*

Rhinitis/asthma type

selective cyclooxygenase inhibitors (celecoxib, parvocoxib), trisalicylate, salsalate

Urticaria/angioedema type

new selective COX-2 inhibitors (etoricoxib, pavocoxib)

*Single cases of hypersensitivity have been reported

TABLE 2: Indications for treatment with aspirin after desensitization (ATAD) in N-ERD patient

Adapted from Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy. 2019;74:28-393.

  • rhinosinusitis symptoms ( e.g. loss of smell) not responding to pharmacological treatment
  • highly recurrent nasal polyposis/hypertrophy
  • prevention of nasal polyps after sinus surgery
  • asthma symptoms difficult to control with standard therapy
  • need to reduce the dose  or withdraw chronic oral corticosteroids
  • need for anti-platelet treatment with aspirin of ischemic heart disease or stroke
  • need for chronic anti-inflammatory treatment ( e.g. in rheumatoid arthritis)

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