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  1. 1. Internal Medicine Journal 2005; 35: 240–246 REVIEW Aspirin-sensitive asthma K. MORWOOD,1 D. GILLIS,2 W. SMITH3 and F. KETTE3 1Queensland Health Pathology Service, Princess Alexandra Hospital Campus, Brisbane, Queensland, 2Immunology Department, Institute of Medical and Veterinary Science, 3Immunology Department, Royal Adelaide Hospital, Adelaide, South Australia, Australia Abstract of aspirin-sensitive asthma. The clinical management of Aspirin-sensitive asthma is a common and often under- aspirin-sensitive asthma is complicated by the lack of diag- diagnosed disease affecting up to 20% of the adult nostic testing, other than challenge procedures. Other asthmatic population. It is associated with more severe aspects of management include management of the under- asthma, requires increased use of inhaled and oral cortico- lying asthma and avoidance of NSAID in the majority steroids, more presentations to hospital and a risk of of patients. Other considerations in the management of life-threatening reactions with aspirin/non-steroid anti- patients with aspirin-sensitive asthma include the role inflammatory drug (NSAID) ingestion. Aspirin-sensitive of leukotriene modifying agents, aspirin desensitization, asthma is often accompanied by severe rhinosinusitis and the use of other agents, such as roxithromycin. The and recurrent nasal polyposis, causing significant impair- management of nasal polyposis in patients with aspirin- ment of patients’ quality of life. The pathogenesis of sensitive asthma often needs to be considered as a sepa- aspirin-sensitive asthma is complex and involves chronic rate issue, and requires a team approach. (Intern Med J eosinophilic inflammatory changes, with evidence of 2005; 35: 240–246) increased mast cell activation. The cyclo-oxygenase path- ways play a major role in the respiratory reactions that develop after aspirin ingestion. The cysteinyl-leukotrienes Key words: aspirin-sensitivity, asthma, nasal polyposis, have also been shown to play a role in the pathogenesis Samter’s triad, aspirin desensitization. Aspirin-like compounds have been used since the time of Beers described and characterized the aggressive mucosal Hippocrates (∼400 BC), when the bark of the white disease associated with aspirin sensitivity, thus the name ‘Samter’s Triad’ entered common usage.4 willow was used as an antipyretic agent. Its use was also described during Roman times, and again in the 1700s Urticaria, angioedema and anaphylaxis can occur as a as a treatment for ‘Ague’ (fever).1 The chemical struc- result of aspirin/non-steroidal anti-inflammatory drug ture was described and subsequently modified in the (NSAID) ingestion. There is also a subgroup of patients 1800s to produce the stable compound acetylsalicylic with chronic urticaria in whom the urticaria is exacer- acid, which is now called aspirin. Bayer released this bated by NSAID ingestion. This review will focus on onto the market in 1899 as an analgesic and antipyretic aspirin sensitivity as it relates to asthma and the upper agent.1,2 The benefits of aspirin as an analgesic, anti- respiratory tract, and will not discuss other aspirin asso- inflammatory and, more recently, antithrombotic agent ciated conditions further. have been increasingly recognized, and, with easy avail- ability, it is used widely throughout the community. EPIDEMIOLOGY Soon after it was marketed as an analgesic agent, it Estimates of the prevalence of aspirin sensitivity vary, was recognized that severe attacks of asthma could occur depending on the methodological approach. A questionnaire- after the ingestion of aspirin. In 1922, Widal et al. described based survey of three asthmatic populations in Western the clinical symptoms of aspirin sensitivity, asthma and Australia has shown the prevalence of aspirin sensitivity nasal polyps, and subsequently performed the first to be 10–11%.5 Two population-based surveys, conducted aspirin desensitization.3 Many years later, Samter and in Finland6 and Poland,7 have shown that the prevalence of aspirin-sensitive asthma was 1.2% and 0.6%, respec- tively in the general population, and 8.8% and 4.3%, Correspondence to: Karen Morwood, Immunology Registrar, Queensland Health Pathology Service, Princess Alexandra Hospital Campus, Ipswich respectively in patients with asthma. Another group has Road, Wooloongabba, Brisbane, Qld 4102, Australia. undertaken oral aspirin challenge on consecutive asth- Email: matic patients to find prevalence rates in the order of 15–20%,8 concluding that history alone is not a reliable Received 12 January 2004; accepted 15 October 2004. guide to aspirin sensitivity. Importantly, in the analysis Funding: None of this population of 500 aspirin-sensitive asthmatics, Potential conflicts of interest: There are no potential conflicts or funding 18% were unaware of their aspirin-sensitive status prior for the work to declare on hehalf of any of the authors.
  2. 2. Aspirin-sensitive asthma 241 had sinus surgery.12 The time to recurrence after surgery Table 1 Non-steroid anti-inflammatory drugs to avoid for nasal polyps is much shorter in patients with aspirin- Benzydamine Ketoprofen Phenylbutazone sensitive disease than in other patients with nasal polyps.14 Diclofenac Ketorolac Piroxicam Diflunisal Mefenamic acid Sulindac PATHOGENESIS Ibuprofen Meloxicam Tenoxicam Indomethacin Naproxen Tiaprofenic acid Reactions to aspirin resemble immediate hypersensitivity reactions, however, specific antibodies to aspirin/NSAID are rarely shown in aspirin-sensitive individuals. Addi- tionally there is cross-reactivity between NSAID that do not have structural similarities, thus suggesting pharma- to challenge.8 In patients with a history of asthma and cological rather than immunological mechanisms in the nasal polyps, the prevalence of aspirin sensitivity is majority of patients. increased to approximately 30%.9,10 Chronic inflammation CLINICAL ASPECTS Aspirin-sensitive asthma is a disease of chronic airways Aspirin-sensitive asthma is an acquired syndrome. Aspirin- inflammation, however, there are several important induced reactions occur 2–3 h after the ingestion of oral differences between asthmatics that are aspirin-sensitive aspirin or NSAID. The reactions are usually: broncho- and aspirin tolerant. spasm, profuse rhinorrhoea, conjunctival injection, peri- The bronchial mucosa of patients with aspirin-sensitive orbital oedema and generalized flushing. Patients may asthma has a marked eosinophilia, with four times more have any or all of these symptoms, and the reactions can eosinophils than other asthmatics, and 15 times more than normal bronchial mucosa.15 Studies have shown vary in individuals. absolute numbers of mast cells to be both increased16 Patients who develop the aspirin triad (asthma, nasal and decreased,17 however, there is consistently increased polyps, aspirin sensitivity) typically develop perennial rhinitis in their third decade, after a viral upper respira- mast cell activation. This is evident, both when the tory tract infection; in the subsequent 1–5 years asthma patient is stable, and after aspirin provocation, with and aspirin sensitivity develop. Nasal polyps become increased levels of the stable metabolites of prostaglandin clinically apparent within a further 5 years. Approxi- D2, and tryptase in plasma, however, urinary levels of these metabolites were not increased.15–18 mately 30% develop nasal polyps prior to the diagnosis of asthma, however, in less than 10% the diagnosis of The focus of much of the research on the pathogenesis asthma and nasal polyps is made simultaneously. Once of aspirin sensitivity has targeted abnormalities in the aspirin sensitivity develops it is usually lifelong.11,12 arachidonic acid pathway. Patients with aspirin-sensitive asthma have high Cyclo-oxygenase pathways frequency of admission to hospital, and more presenta- tions to the emergency department.12 Two surveys of Aspirin acts as an anti-inflammatory agent via the inhibi- aspirin-sensitive asthmatics have shown that approxi- tion of cyclo-oxygenase (COX) pathways, and several mately 80% of patients were on long-term inhaled or critical observations suggest that it is also involved in the oral steroids for control of their asthma, with 50% of aspirin-sensitive state. patients being on both inhaled and oral corticosteroids, The two major enzymes in this pathway are COX1, an with a mean dose equivalent of 8 mg/day of oral pred- enzyme that is constitutively expressed in airway mucosa, nisone. An additional 30% of the patients were on and COX2, an enzyme that is induced with pro- inhaled steroids alone, although at a higher average dose inflammatory signals. Recently, other COX enzymes, than the general asthmatic population. Twenty per cent including COX3 have been described, but their role in of patients had required intravenous steroids in the year aspirin sensitivity is yet to be fully delineated, however, prior to survey.11,12 In a survey of 145 patients who had COX3 appears to be inhibited by paracetamol, which required intubation for asthma, 25% were aspirin-sensi- neither COX1 or -2 are, and may explain the patients who are both aspirin and paracetamol sensitive.19 Both tive, thus suggesting that this group of patients has more severe asthma. Ingestion of aspirin was not necessarily COX1 and -2 are expressed in normal respiratory the cause of the reaction requiring intubation, which epithelium, and are not upregulated in the mucosa in patients with stable asthma or chronic bronchitis.20 demonstrates that they may have unstable disease despite appropriate avoidance.13 The evidence that the COX pathway is involved in Patients with aspirin-sensitive asthma often suffer respiratory tract reactions in aspirin-sensitive individuals from aggressive rhinosinusitis and nasal polyposis, with includes: • NSAID with COX1 inhibitory activity all produce the frequent recurrence after surgery despite avoidance of aspirin reaction in sensitive individuals21 aspirin. Patients with aspirin-sensitive asthma, 99% of • There is a correlation between the potency of COX 299 patients, were shown to have mucosal abnormalities on imaging of their sinuses. The patients in this cohort inhibition and potency to induce the bronchospasm. This is particularly related to COX1 inhibition22 had an average of 5.5 episodes of sinusitis requiring anti- • NSAID that lack COX1 inhibition do not produce a biotics per year, and they had undergone an average of reaction21 three sinus operations. Only 6% of patients had never Internal Medicine Journal 2005; 35: 240–246
  3. 3. 242 Morwood et al. • Prostaglandin E2 (PGE2) inhalation prevents the but this was not shown in a population in the USA; this aspirin reaction in patients who have challenge proven population included patients with mild, moderate and aspirin sensitivity.23 severe aspirin-sensitive asthma.36 In addition, there is diminished COX2 expression and Clinical evidence for the role of Cys-LT in the broncho- activation in nasal polyp tissue from aspirin-sensitive spasm, related to aspirin sensitivity, comes from the use patients.24 COX2 may inhibit COX1 activity and there- of leukotriene modifying drugs. These drugs do not fore decrease synthesis of cysteinyl leukotrienes. Therefore, block the reaction to aspirin in sensitive individuals; the reduction in COX2 activity in aspirin-sensitive indi- however, they convert the reaction from predominately viduals, along with inhibition of COX1 by aspirin, may bronchospasm to a predominately upper airways reac- together contribute to reduced PGE2 production, tion. This suggests that the Cys-LT play a greater role in resulting in the clinical manifestation of aspirin-induced the lower airways, however, do not account entirely for the aspirin-sensitive state.37 asthma. However, there is significant evidence that the above mechanism does not completely explain aspirin-induced DIAGNOSIS symptoms and signs. The abnormalities in the COX The history of a characteristic clinical reaction after pathways have been shown in nasal polyp tissue,25 but aspirin or NSAID ingestion, particularly in a member of not in the lower airways. The baseline levels of PGE2 and a susceptible subgroup (i.e. severe asthmatic, polypoid other prostanoids are not decreased in either broncho- rhinosinusitis or chronic urticaria) may be sufficient for alveolar lavage26 or nasal lavage27 when compared to diagnosis. The diagnosis of aspirin-sensitive asthma aspirin-tolerant patients, and these levels decrease to the should be confirmed with challenge if the history is same extent after aspirin challenge in both aspirin- unclear. Importantly, relying on a history of reaction sensitive and aspirin- tolerant asthmatics.26,27 Therefore, alone may be misleading.8 Aspirin sensitivity is an aspirin is likely to interfere with other inflammatory acquired phenomenon that often occurs after the onset pathways. of rhinitis, polyposis and asthma, thus patients may not Lipoxygenase pathways have had previous reactions to aspirin. Many asthmatic patients will avoid aspirin and NSAID because of the The cysteinyl leukotrienes (Cys-LT; LT C4, LT D4, LT perceived risk of reactions, also complicating the history. E4) induce bronchoconstriction, oedema formation and Several clinical features suggest an increased risk of mucus production in airways, and therefore are media- aspirin sensitivity in an asthmatic. These include: (i) tors of asthma. They may play an increased role in the severe asthma with chronic nasal congestion and profuse aspirin-sensitive asthmatics. These patients have increased baseline levels of cysteinyl leukotrienes in urine28 and rhinorrhea; (ii) recurrent nasal polyposis; (iii) sudden, exhaled air29 compared to aspirin-tolerant asthmatics. severe asthma with intensive care admissions and (iv) adult onset, non-allergic asthma.38–41 After aspirin challenge, the levels of Cys–LT increase significantly in urine,28 sputum, expired air and bronchial There is no reliable in vitro test for aspirin-sensitive lavage fluid30 in patients who are aspirin-sensitive, but asthma. The only validated diagnostic tool for aspirin sensitivity is challenge. Four methods for challenge have not in normal subjects, or aspirin-tolerant asthmatics. been reported in the literature: nasal, bronchial, oral and Whilst this increase is reproducible, the extent of its intravenous. increase does not allow it to be a useful diagnostic test. In addition to the increased levels of Cys-LT in Nasal and bronchial challenges aspirin-sensitive individuals, there is an increased Nasal and bronchial challenges are undertaken with responsiveness to Cys-LT. This can be explained by an L-lysine acetylsalicylate, a compound that is not avail- increase in the expression of Cys-LT1 receptor in nasal able in Australia. Guidelines for inhalational challenges mucosa of patients with aspirin-sensitive asthma, compared have been produced by the INTERASMA Working to patients with non-aspirin-sensitive rhinosinusitis or Group as these challenges are used frequently in other nasal polyposis. Additionally, aspirin desensitization countries.42 Inhalational bronchial challenges elicit lower leads to a decrease in the expression of this receptor, respiratory tract reactions only, and are a fast and easy suggesting a possible mechanism for the therapeutic method of challenge,43 with a similar specificity, but a benefit of aspirin desensitization in the aspirin-sensitive lower sensitivity than oral challenge.44 Nasal challenges patients.31 are also fast and easy, requiring only a 4-h stay in Other abnormalities in the lipoxygenase pathways hospital, however, they have a decreased sensitivity as include an increase in leukotriene C4 synthetase (LTC4S) compared to bronchial challenge. The predictive value in bronchial biopsies, and increased LTC4S messenger of a negative result on nasal challenge is only 78.6%. ribonucleic acid in their eosinophils of aspirin-sensitive Nasal challenge was introduced to try to improve the asthmatics compared with normal subjects and aspirin- tolerant asthmatics.32,33 A genetic polymorphism of the safety of the procedure, however, it can elicit either upper or lower respiratory tract reactions.45 LTC4S promoter has been described in severe steroid dependent, aspirin-sensitive asthmatics in Poland,34 and Oral challenge a Japanese study subsequently confirmed that this poly- Oral challenge with aspirin was introduced in the 1970s in morphism was more common in aspirin-sensitive asthmatics compared with aspirin-tolerant patients,35 Poland using a protocol of placebo and graded increments Internal Medicine Journal 2005; 35: 240–246
  4. 4. Aspirin-sensitive asthma 243 of aspirin over 4 days.40 Others have used shorter proto- medications may alter the target region of the aspirin cols with equal success.41 Oral aspirin challenge has a reaction, and that leukotrienes play a greater role in the sensitivity of 85% in those who give a history of aspirin pathogenesis of asthma in aspirin-sensitive individuals sensitivity, and is the current gold standard for diagnosis.41 and a lesser role in the sinonasal disease.46 Safety has been the main concern with regards to oral Prevention challenge. This has been addressed in a recent survey Total avoidance of all aspirin and NSAID medications is of patients undergoing aspirin challenge at the Royal usually recommended for patients with aspirin-sensitive Adelaide Hospital, with a 2-day challenge procedure in asthma/rhinitis, including avoidance of all non-selective the general recovery area. A total of 94 procedures in 82 COX inhibitors. Surveys of aspirin-sensitive asthmatic patients (including severe corticosteroid dependant asth- patients, presenting for review at specialist centres, show matics) was performed over 3 years, of which there were that 36% of these patients have had three or more reac- 44 positive challenges. Twelve patients required admis- tions to aspirin, 33% have had two reactions to aspirin sion, four for observation after a positive challenge, and and 22% have had a single reaction to aspirin.11 These eight for social or distance reasons. The patients with a data suggest that patients have not been counselled positive challenge who required admission needed addi- about the risk of repeat reactions, or about the cross tional bronchodilator treatment, but no other treatment reactivity of these medications (Table 1). for their reaction. No patients required admission to the There have been four double-blind, placebo-controlled intensive care unit. The average time to reaction was trials of challenge with COX2 inhibitors (two with 85 min, with a range of 30–180 min. The average dose Celecoxib (Searle, Chicago, USA), and two with to which patients reacted was 67.5 mg, with a range of Rofecoxib) in patients with challenge-proven aspirin- 10–100 mg. This survey confirms that oral aspirin chal- sensitive asthma. There were no positive reactions in lenge can be performed safely in this group of patients these trials. Some care should still be exercised with (unpublished data). these medications as there are isolated case reports of Intravenous challenge asthma with both Celecoxib and Rofecoxib, however, Intravenous challenge with L-lysine acetylsalicylate has they may be used safely in the majority of aspirin-sensi- tive patients.47–50 been performed, however, is not used routinely in most centres due to concerns about safety and protocols. Paracetamol is a weak inhibitor of COX1 and inhibits COX3, whilst low doses are usually tolerated by aspirin- sensitive asthmatics. Thirty-four per cent of patients MANAGEMENT with aspirin-sensitive asthma will have a cross-reaction General with acetaminophen (paracetamol) if it is given as doses of 1000 mg and then 1500 mg, based on single-blind The underlying asthma should be managed according to challenge in 50 aspirin-sensitive and 20 non-aspirin- standard guidelines with preventative therapies, including inhaled corticosteroids, long acting β-agonists and oral sensitive asthmatics.51 In all of the patients who reacted to acetaminophen, the reactions were mild and only corticosteroids when required. 22% of reactions were bronchospasm. Consequently, Leukotriene pathway modification patients with aspirin-sensitive asthma should be coun- A double-blind, placebo-controlled trial of the leukotriene- selled not to take more than 1000 mg of paracetamol, modifier montelukast was performed in patients with particularly as some new long-acting formulations contain aspirin-sensitive asthma, who were already on moderate more than the standard 500 mg of paracetamol per to high doses of glucocorticoids. The trial showed an tablet. Other analgesics that can be tolerated by aspirin- improvement in forced expiratory volume in 1 s (FEV1) sensitive asthmatics include dextropropoxyphene, codeine and peak expiratory flow rate, a decreased use of bron- and other narcotics. chodilators, fewer asthma symptoms and fewer asthma Desensitization exacerbations, suggesting that these drugs may have a role in some aspirin-sensitive asthmatics.37 This trial was It is possible to desensitize most or all aspirin-sensitive patients using incremental doses of aspirin over several short-term only and the steroid doses required for days. Tolerance can then be maintained with daily aspirin patient care remained stable. therapy. A randomized, double-blind, placebo crossover Leukotriene modifying medications cannot be relied trial of aspirin desensitization in 25 patients with aspirin- on to block the aspirin-induce respiratory reaction, as sensitive asthma, showed a significant improvement in shown in a study of 271 patients, suspected to have symptoms of rhino-sinusitis, and a decrease in the aspirin sensitivity by history, who underwent oral chal- amount of nasal corticosteroids required whilst on aspirin. lenge. Ninety-six of these patients were on leukotriene There was, however, no change in asthma medications, antagonists at the time of challenge. The percentage of lower respiratory symptoms or FEV1.52 patients who reacted to aspirin was similar in both The therapeutic role of aspirin desensitization has groups of patients, as was the dose of aspirin to which been addressed in three retrospective trials. One study they reacted. However, those patients on leukotriene compared 65 aspirin-sensitive patients who were desen- antagonists were less likely to develop bronchospasm, sitized with a control group who avoided all NSAID. and more likely to have upper airways or conjunctival Patients on aspirin had a lower number of hospital reactions. This suggests that the leukotriene-modifying Internal Medicine Journal 2005; 35: 240–246
  5. 5. 244 Morwood et al. admissions, emergency department visits, outpatient visits, function or response to challenge. This trial was not upper respiratory tract infections and sinus operations, powered to look at clinical outcomes, and further work compared to those avoiding NSAID. Additionally, there needs to be carried out to clarify the use of these agents in patients with aspirin-sensitive asthma.57 was a decrease in the total amount of systemic steroids and corticosteroid treatment courses in those being Polyps actively treated.53 Long-term follow up of 65 patients The management of nasal polyposis in these patients can desensitized prior to 1996, and 172 patients desensitized be very difficult. The initial treatment should be with between 1995 and 2000, showed that there was a intranasal steroids, however, higher than standard doses decreased number of sinus infections and courses of are often required.10 The leukotriene antagonists may prednisone, with improvement in smell, nasal, sinus and play a role, with the reduction of nasal symptoms with asthma symptoms when compared to the time prior to their use, as shown in an open audit of the use of monte- aspirin treatment. Complications of treatment were not luekast as add-on therapy in patients with and without addressed in this group. In the second study (from 1995 aspirin sensitivity.58 Operative intervention with poly- to 2000), there was a response to treatment rate of 67%, pectomy is useful for management of nasal obstruction, which was maintained for the duration of aspirin treat- headaches and reduction in number of infections,59,60 ment. Twenty-eight per cent ceased treatment, 14% for however, will not control disease in the long-term. complications of aspirin treatment, including 14 patients Patients will need treatment with either intranasal steroids with significant pain associated with gastritis, and two or leukotriene modifying medications for long-term patients with gastrointestinal haemorrhage; highlighting the potential risks of this treatment.54,55 control. Medical polypectomy with short course high dose oral steroids may be useful, but again the duration These trials suggest a benefit to treatment with aspirin of benefit may only be brief. Longer courses are limited desensitization, however, it is low-grade evidence and by the side-effect profile of oral corticosteroids. should be confirmed in larger randomized, placebo controlled trials. SUMMARY Current recommended indications for aspirin desensi- tization in aspirin-sensitive patients are: Whilst the clinical syndrome of aspirin-sensitive asthma • The need for aspirin or NSAID in the treatment of has been described for many years, there remains much rheumatic or thrombotic conditions to be known. Unravelling of the pathogenesis of the • Recurrent nasal polyposis requiring repeated surgery aspirin-sensitive state has started, however, the role of • Asthmatic patients who can only be controlled with each of the mechanisms in the production of the reaction unacceptably high doses of corticosteroids, either inter- is still unclear. The mechanism by which these patients mittent or continuous. can be desensitized and the place of desensitization as a After desensitisation, patients are maintained on treatment option remains uncertain. The best treatment aspirin, commonly at a dose of 600 mg twice per day. for these patients, including the role of leukotriene Aspirin is continued for at least 6–12 months, often modifying agents, aspirin desensitisation and macrolide indefinitely. The desensitized state is only maintained for antibiotics, requires clarification in prospective clinical 2–5 days after cessation of aspirin, so if doses are missed trials. Additionally, aspirin challenge remains the diag- for any reason for more than 48 h, aspirin should not nostic method of choice. Aspirin challenge can place the be restarted, as there is a risk of a severe aspirin reaction. patients at risk of a potentially life-threatening reaction, If aspirin is ceased or doses missed, and there is an and requires strict supervision by experienced clinicians. intention to continue on therapy, the graded dose desen- Laboratory-based diagnostic testing could potentially sitization procedure should be repeated.55 Aspirin replace challenge and aid in the management of these challenge and desensitization should only be performed patients. by those with experience in the procedure, in centres where monitoring facilities and high-level support are REFERENCES available, as whilst it is able to be performed safely, there is potential risk of life-threatening asthma. 1 Kohl F. A pharmacentical of the century will be 100. A historical vignette on the introduction of acetylsalicylic acid to the market in Other management options 1899. Schmerz 1999; 13: 341–6. 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