Aspirin Sensitive Asthma

REVIEW ARTICLE Aspirin Sensitive Asthma Winfried J. Randerath, Wolfgang Galetke SUMMARY Introduction: We present a review of aspirin sensitive asthma, a major cause of recurrent nasal polyps and of refractory intrinsic asthma. Methods: Selective literature review, taking into account the authors' own clinical data. Results and discussion: Aspirin sensitive asthma (ASA) is initially characterized by nasal symptoms such as vasomotor rhinitis, anosmia and recurrent nasal polyps. During the course of the illness, patients develop severe intrinsic asthma, often requiring treatment with systemic steroids, and acute asthma exacerbations induced by the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). About 10% of adult asthmatics are aspirin sensitive. The overproduction of cysteinyl leukotrienes due to polymorphisms of key enzymes of the arachidonic acid metabolic pathway is a major pathophysiologic factor. Investigation entails nasal, inhalational or with greater risk of side effects oral challenge tests. Avoidance of NSAIDs alone does not influence the severity of the course of ASA. Aspirin desensitization has proven effective both in improving asthma and rhinosinusitis. Leukotriene receptor antagonists offer a new therapeutic approach. Dtsch Arztebl 2007; 104(46): A 3178 83 Key words: asthma, aspirin, non-steroidal anti-inflammatory drugs, adaptive desensitization, leukotrienes O nly a few years after acetylsalicylic acid (aspirin) had been patented in 1899, initial intolerance reactions were reported, and the first death due to an aspirin-induced asthma attack was reported in 1920. In 1922, Widal et al. published the first report on the coincidence of sensitivity to aspirin, bronchial asthma, and nasal polyps the classic "aspirin triad" (e1). This review of aspirin sensitive asthma presents the clinical pathology, current pathophysiological considerations, and modern therapeutic approaches. Differences to allergic pathologies are outlined clearly. The authors emphasize that abstention measures do not influence the course of disease but that adaptive deactivation and leukotriene receptor antagonists are confirmed treatment options. The authors conducted a selective literature search by hand-searching Medline for the search terms "aspirin sensitive asthma," "analgetics induced asthma," "leukotrienes," "desensitization," "lipoxygenase," "cyclooxygenase." The final search was conducted on 8 January 2007. The authors also included their own clinical data. Clinical practice The diagnosis of aspirin sensitive asthma is mostly made only once an asthma attack has been triggered after administration of a non-steroidal anti-inflammatory drug (NSAID). Such an event usually leads to the incorrect assumption that the analgesic is the cause of the illness. In reality, however, the acute intolerance reaction is the end point of a disease course that usually started 1 to 2 decades previously with nasal symptoms. Those affected usually develop vasomotor rhinitis for which no allergic cause can be established. As a rule, anosmia and nasal polyps develop subsequently, and polyps are often treated with repeated surgery (1). The surgical procedures are usually unsuccessful, and the polyps sometimes recur after only a few weeks. These phenomena are often accompanied by chronic inflammatory changes to the nasal sinuses. These symptoms mean that patients usually receive long term care primarily from specialists in ear, nose, and throat medicine, who have a key role in recognizing the disease (box 1). Non-allergic chronic rhinitis/sinusitis or nasal polyps has to prompt a suspicion of aspirin sensitive asthma, even if at this point, no acute intolerance symptoms have occurred after administration of an analgesic. Institut für Pneumologie an der Universität Witten/Herdecke, Klinik für Pneumologie und Allergologie, Zentrum für Schlaf- und Beatmungsmedizin, Krankenhaus Bethanien, Solingen: Prof. Dr. med. Randerath, Dr. med. Galetke Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 1

BOX 1 Cardinal symptoms of aspirin sensitive asthma Vasomotor rhinitis Nasal polyps Anosmia Intrinsic asthma Intolerance reaction to aspirin or NSAIDs BOX 2 Cross intolerances All NSAIDs of the COX inhibitor type Sulfides (E 220-227) Alcoholic beverages (containing sulfide) Naturally occurring salicylates Citrus fruit Nuts Grapes Most patients later develop so-called intrinsic asthma non-allergic asthma that can be managed only by broad-based therapy. More than half the patients need treatment with systemic steroids. NSAIDs have no part in the development and course of the disease but are of importance in the intolerance reactions. An acute intolerance reaction is usually the final step in the development of the disease. 30 to 45 minutes after administration of an analgesic, an asthma attack occurs, which is often accompanied by nasal and conjunctival irritations and/or transient erythema on the head and neck. The symptoms persist for many hours, and systemic therapy with bronchospasmolytic drugs and corticosteroids is often required. A single dose can result in respiratory arrest and the need for ventilation. No dose dependency exists. Even minimal dosages can result in a reaction in people with the intolerance. Asthma attacks triggered by NSAIDs are not rare. In France, up to 25% of asthma patients who needed ventilation in an emergency situation between 1983 and 1988 had taken an NSAID beforehand (2). In addition to this typical course, acute intolerance reactions may occur in individual patients who do not have nasal polyps or intrinsic asthma. These can take the shape of urticaria or angioedema. Intolerance to analgesics can be the cause of chronic urticaria (3, 4). Cross intolerances to other drugs are of particular interest. All NSAIDs can cause acute symptoms. What the drugs have in common is not their chemical structure but their effective mechanism of inhibiting cyclo-oxygenase (COX). The stronger the COX inhibiting mechanism of a drug, the higher the risk that it may cause an intolerance reaction (5). Paracetamol (US: acetaminophen), a weak COX inhibitor, is often well tolerated, but it is recommended as an alternative treatment only after prior testing. Conversely, analgesics that do not influence cyclo-oxygenase (opioids) are well tolerated. In addition to cross intolerance to other NSAIDs, many patients have described an exacerbation of symptoms after consuming alcohol, which is due to sulfides (sulfide asthma) (box 2) (6). Asthmatic reactions have also been described for food additives such as tartrazine, benzoic acid, or glutamate. No association with intolerance to analgesics has been established, however (e2). Epidemiology Aspirin sensitive asthma affects mainly women from the 3rd decade of life. Familial clustering has not been observed. Initial manifestations in childhood or after the 60th year of life are rare (7). 4 to 11% of adult asthma patients are intolerant to analgesics (8). Analgesic intolerance occurs only rarely in association with allergic asthma. The risk of analgesic intolerance in the normal population is less than 1%, whereas for the combination of Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 2

BOX 3 High risk for analgesic intolerance in one or more of the diseases listed Intrinsic bronchial asthma Perennial rhinitis Nasal polyps Urticaria/angioedema bronchial asthma and nasal polyps it is 50%; in nasal polyps alone, 15%; in perennial rhinitis, 6.4%; and in urticaria/angioedema 20 to 30% (box 3). Patients with allergic asthma therefore do not have to abstain from NSAIDs altogether. However, patients with nasal polyps or the combination with intrinsic asthma should avoid these substances (6). Pathophysiology The pathophysiology of aspirin sensitive asthma has not been fully explained. Some crucial aspects have been described, however. Intolerance to analgesics is not an allergic phenomenon, even though the intolerance reaction may resemble an immediate allergic reaction (pseudoallergy). The pathology is mediated not via specific immunoglobulin E antibodies, however, but via genetic disruptions of the arachidonic acid metabolic pathway, which lead to an excess production of inflammatory mediators. Arachidonic acid is released from phospholipids in the cellular membrane and further converted via the cyclo-oxygenase pathway into prostaglandins or via the lipoxygenase pathway into leukotrienes. The end products of the lipoxygenase pathway are the leukotrienes LTC4, LTD4, and LTE4 (cysteinyl leukotriene, Cys-LT). The Cys-LT, by stimulating the leukotriene-1 receptor, trigger all clinical manifestations of the asthmatic reaction: bronchospasm, increased vascular permeability, and mucus secretion (diagram) (9). In aspirin sensitive asthma, a shift to the metabolic pathways occurs towards Cys-LT formation and an increased sensitivity of the mucosa to these mediators. The following factors are important in this mechanism: Cyclo-oxygenase inhibition by NSAIDs Polymorphism of enzymes of the arachidonic acid metabolic pathway Eosinophilic infiltration of the mucosa Increased density of Cys-LT 1 receptors Inhibition of PGE 4 formation. Diverse observations seem to support an influence of genetic factors. Polymorphisms of the cysteinyl leukotriene receptors 1 and 2 and several promoter genes have been shown. Further, HLA-DBP1*0301 was found in several studies more frequently in patients with aspirin sensitive asthma than in healthy subjects and asthma patients with tolerance to aspirin. The carriers of this trait were mainly female, had lower FEV 1 measurements, more often had nasal polyps and rhinosinusitis the classic features of aspirin sensitive asthma. HLA-DBP1*0301 may therefore be a marker of aspirin sensitive asthma (10). Currently these observations are of importance for scientific studies but not for everyday clinical practice. Acetylsalicylic acid results in irreversible inhibition of cyclo-oxygenase, which in turn leads to increased formation of lipoxygenase products. A raised concentration of leukotrienes can be found in nasal secretions, blood, and urine in patients with analgesic intolerance. Cyclo-oxygenase exists in at least 2 isoforms, COX-1 and COX-2. Substances, which do not cause analgesic intolerance, barely inhibit COX-1, and COX-2 to a far lesser degree than aspirin. Highly specific inhibitory substances of COX-2 seem to be well tolerated in aspirin sensitive asthma. In patients with intolerance to analgesics, the leukocytes of the nasal mucosa have a higher density of binding sites of Cys-LT 1 receptors than in healthy subjects or patients who have nasal polyps but not aspirin sensitive asthma. This means that the mucosa in analgesic intolerant subjects are more sensitive to Cys-LT. Further, the Cys-LT are formed to an increasingly larger extent, which is due to an overproduction of the important enzyme Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 3

DIAGRAM Arachidonic acid metabolic pathway: simplified representation of leukotriene biosynthesis in the arachidonic acid metabolic pathway. Arachidonic acid is converted by lipoxygenase via unstable intermediate stages into the cysteinyl leukotrienes LTC4, LTD4, LTE4. The lipoxygenase has to be converted into its active form by the 5-lipoxygenase activating protein (FLAP). The cysteinyl leukotrienes stimulate to varying degrees the leukotriene receptor (LTD4 or LT1 receptor) and thus trigger partial symptoms of bronchial asthma. Leukotriene receptor antagonists block the effect of the already developed cysteinyl leukotrienes at this point, whereas other substances block their formation on the lipoxygenase or FLAP. Aspirin and other NSAIDs inhibit cyclo-oxygenase in aspirin sensitive asthma, which favors the shift to leukotriene formation. leukotriene C4 (LTC4) synthase. Polish studies have found polymorphisms of the gene of LTC4 synthase (LTC4S-444A>C) that was most often associated with the clinical picture of aspirin sensitive asthma. These results have not been confirmed in other populations so far (10). By contrast, in Koreans a polymorphism of the lipoxygenase was found. Genetic variations of the thromboxan A2 receptor, the Cys-LT2 receptors, and the prostaglandin E 2 receptors are found to a greater extent in patients with aspirin sensitive asthma. The formation of prostaglandin E 2 may be inhibited, which normally reduces the formation of the leukotrienes. This also results in a larger load of the organism with Cys-LT (11 13). A central aspect of aspirin sensitive asthma is the infiltration of the nasal mucosa and the deep respiratory pathways with eosinophilic granulocytes. These are found in large numbers in resected nasal polyps, for example, which should not be misinterpreted as a sign of an allergic process. The accumulation of inflammatory cellular elements is due on the one hand to the increased formation of chemotactic factors and on the other hand to a delay in the programmed cell death of the eosinophils (apoptosis). It contributes crucially to the formation and tendency for recurrence of the polyps (14, 15). The eosinophilic granulocytes are the main source of LTC 4 synthase, which correlates with the increased release of leukotrienes and the hypersensitivity of the mucosa. The chronic inflammation of the mucosa may be due to a sustained viral infection or the formation of auto-antibodies (16). Aspirin sensitive asthma is characterized by specific inhibition of cyclo-oxygenase and an increase in key enzymes of the leukotriene synthesis. Excess leukotrienes are formed, and the increased density of receptors results in increased sensitivity (17). Diagnosis As aspirin sensitive asthma is a pseudoallergy, skin test or determining specific IgE antibodies to aspirin or other NSAIDs always yield negative results. Currently there is no reliable in-vitro method to diagnose aspirin sensitive asthma, so that provocation tests are vital. Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 4

Since oral provocation tests can result in severe reactions including massive asthma attacks and shock these are the diagnostic end point. The far less risky nasal and inhalation provocation tests are conducted by using lysine-acetylsalicylic acid. For nasal provocation, Schapowal et al. found in patients with analgesic-induced rhinosinusitis a sensitivity of 93% and a specificity of 97% (1). In other studies that included patients without apparent rhinosinusitis, the sensitivity was much lower, at 38%, although the specificity was high. Nasal provocation is thus confirmation in a positive case and does not exclude analgesic intolerance in a negative case; it should always be followed by inhalation provocation (18). The threshold dose that triggers an intolerance reaction is much lower than for oral provocation. Inhalation provocation rarely has side effects, and systemic reactions can therefore be avoided in most cases. After the test is over, monitoring is recommended for 6 to 8 hours in order to capture delayed reactions (19). The sensitivity of inhalation provocation is around 77% and the specificity 93% (20). If inhalation provocation yields a negative result, oral provocation can be applied subsequently if the suspicion has not been ruled out (sensitivity 89%; specificity 93%) (20). All types of tests should be conducted under clinical conditions while the patient is being monitored by a team well versed in dealing with anaphylactoid reactions. Treatment Therapeutic methods include Basic treatment for asthma Total abstention from NSAIDs and use of substitute preparations Anti-inflammatory and surgical treatment of nasal polyps and chronic sinusitis Adaptive deactivation (desensitization) Use of leukotriene antagonists. Basic therapy for asthma consists of anti-inflammatory treatment with inhaled steroids and short acting beta agonists tailored to individual needs. If the disease course is more severe, long acting beta agonists and possibly systemic steroids are required. Hydrocortisone hemisuccinate should not be used, however, as intolerance reactions have been observed in patients taking these preparations (e3). Other glucocorticoids are well tolerated, however. In patients who are not being adaptively deactivated, all NSAIDs have to be avoided even in the emergency setting. Anti-inflammatories of choice are mainly glucocorticosteroids. Paracetamol (US: acetaminophen) can often be used for its antipyretic properties. Since this is an NSAID, it can be recommended in analgesic intolerant patients only after provocation under clinical conditions. This also holds true for substances that inhibit primarily COX-2 (for example, meloxicam) and that are tolerated by most patients with aspirin sensitive asthma. In a scenario of regular use, however, the cardiovascular side effects will have to be borne in mind (21). For analgesia, opioids, such as dextropropoxyphene, and salicylamide are available. By adhering to these measures, acute intolerance reactions can often be avoided and the intrinsic asthma stabilized. Since the intolerance of NSAIDs is not the cause of the illness but only an epiphenomenon of a biochemical imbalance, the course of the disease remains unchanged while the drugs are not used. In this scenario, adaptive desactivation is available. As early as in 1922, Widal described the phenomenon of a refractory period during which no new symptoms can be triggered after an acute intolerance reaction. This refractory phase lasts for 2 to 7 days. The aim of adaptive deactivation is to reach the tolerance phase and maintain it (22). Treatment immediately follows inhalation provocation and should be performed in specialized centers. The achieved final dose of mostly 500 mg acetylsalicylic acid is then taken daily by the patients. Lee et al. have recently shown a reduction in nasal surgery, improved sense of smell, sinus symptoms, and asthma. The number of hospital admissions was reduced significantly to 13% and the dose of systemic steroids to 33% of the baseline value (23). The main thing is, however, that in most patients the recurrence of nasal polyps can be avoided or a shrinking of existing polyps can be achieved. Many patients regain their sense of smell, nasal breathing is improved, and the hypersensitivity of the airways is reduced. Patients who require NSAIDs because of cardiovascular or rheumatic disorders can use these under adaptive deactivation. Surgical measures often do not result in lasting success. In spite of this, surgery for nasal polyps is of great importance because the shrinking of polyps under adaptive deactivation Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 5

can take a long time. It may also make sense to perform surgery first and then start adaptive deactivation so as to avoid recurrence. Adaptive deactivation is very effective but also has disadvantages: it requires a high degree of compliance. If daily administration of aspirin is interrupted the patient loses tolerance after the refractory period. If the patient then restarts treatment a renewed intolerance reaction can be expected. Further, the side effects of taking NSAIDs long term will have to be taken into consideration. A new therapeutic option is provided in the shape of leukotriene receptor antagonists (for example, montelukast). Leukotriene antagonists interfere specifically with the pathological mechanism because they block the effect of leukotrienes, which are produced to excess in aspirin sensitive asthma. These substances have been shown to help stabilize bronchial asthma. The intolerance reaction is weakened or even avoided. Montelukast significantly improves lung function parameters, reduces the number of asthma exacerbations, the symptoms, and the need for emergency medication in patients with aspirin sensitive asthma (24). Whether the nasal symptoms are also affected remains to be seen. Salmeterol, a long acting beta receptor agonist, interferes with the arachidonic acid metabolic pathway and weakens the intolerance reaction (e4). To clear up chronic rhinosinusitis, decongestant drugs and antihistamines can be used, but these have mostly not been successful in the long term much like nasal polypectomy. In contrast, nasal glucocorticosteroids, such as fluticasone, may have a positive effect (25). Conclusion Patients with recurrent nasal polyps or intolerance reactions to NSAIDs should not hesitate to undergo provocation tests. Avoiding the substances in isolation does not improve their asthma. Adaptive deactivation can have a favorable outcome for nasal and asthmatic symptoms. To improve asthma, leukotriene receptor antagonists are available. Conflict of Interest Statement Professor Randerath is a member of the National Advisory Board-MSD. This entails giving presentations and receiving travel support. Mr Galetke has no conflict of interests according to the guidelines of the International Committee of Medical Journal Editors. Manuscript received on 26 January 2007; final version accepted on 12 July 2007. Translated from the original German by Dr Birte Twisselmann. REFERENCES For e-references please refer to the additional references listed below. 1. Schapowal AG, Simon HU, M. Schmitz-Schumann: Phenomenology, pathogenesis, diagnosis and treatment of aspirin-sensitive rhinosinusitis. Acta oro-rhino-laryngologica belg 1995; 49: 235 50. 2. Marquette CH, Saulnier F, Leroy O et al.: Long-term prognosis for near-fatal asthma. A 6-year follow-up study of 145 asthmatic patients who underwent mechanical ventilation for near-fatal attack of asthma. Am Rev Respir Dis 1992; 146: 76 81. 3. Karl S, Brederlow C, Bruckbauer HR, Vocks E: Intoleranzreaktionen auf Acetylsalizylsäure bei bestehender Grunderkrankung. Allergologie 1994; 17: 239 41. 4. Stevenson DD: Diagnosis prevention and treatment of adverse reactions to aspirin and nonsteroidal antiinflammatory drugs. J Allergy Clin Immunol 1984; 74: 617 22. 5. Szczeklik A, Gryglewski RJ, Czerniawska-Mysik G: Relationship of inhibition of prostaglandin biosynthesis by analgesia to asthma attacks in aspirin-sensitive patients. Br Med J 1975; 1: 67 9. 6. Randerath W: Das Analgetika-Asthma-Syndrom. In: Randerath W (Hrsg.): Bronchialtherapeutika. Medizinisch- Pharmakologisches Kompendium Band 17. Stuttgart: Wissenschaftliche Verlagsgesellschaft 2007; 123 33. 7. Estrada-Rodriguez JL, Florido-Lopez JF, Belchi-Hernandez J et al.: Asthma in children and ASA intolerance. J Investig Allergol Clin Immunol 1993; 3: 315 20. 8. Jenkins C, Costello J, Hodge L: Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004; 328: 434. 9. Lewis RA, Austen KF, Sobermann RJ: Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990; 323: 645 55. 10. Kim SH, Park HS: Genetic markers for differentiating aspirin-hypersensitivity. Yonsei Med J 2006; 47: 15 21. 11. Arm JP, Lee TH: Evidence for a specific role of leukotriene E4 in asthma and airway hyperresponsiveness. In: Dahlén SE (ed): Advances in prostaglandin, thromboxane and leukotriene research. New York: Raven Press Ltd. 1994; 227 40. 12. Cowburn AS, Sladek K, Soja J et al.: Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest 1998; 101: 834. Dtsch Arztebl 2007; 104(46): A 3178 83 www.aerzteblatt.de 6

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