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Current Drug Targets - Inflammation & Allergy, 2002, 1, 1-11

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Diagnosis, Prevention and Treatment of Aspirin-Induced Asthma and Rhinitis G. Bochenek, K. Bánska1 , Z. Szabó2 , E. Nizankowska, and A. Szczeklik* Department of Medicine, Jagiellonian University School of Medicine, Cracow, Poland Abstract: Bronchial asthma is not a homogenous disease. Several variants of asthma can be distinguished. One of them is aspirin-induced asthma. In this distinct clinical syndrome, aspirin and most other nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase-1 precipitate rhinitis and asthma attacks. This type of asthma affects 510% of adult asthmatics, but remains largely underdiagnosed. The natural history of aspirin-induced asthma (AIA) has been described, based on an extensive pan-European survey. Aspirin provocation tests with improved diagnostic accuracy have been developed, although no in-vitro tests has been found to be of diagnostic value. Recent interest in AIA has been stirred by the finding of alterations in arachidonate metabolic pathways, leading to cysteinyl-leukotriene overproduction. LTC4 synthase is overexpressed in bronchi and its mRNA is upregulated in peripheral blood eosinophils. The gene coding for LTC4 synthase exists in two common alleles, one of which appears to be associated with a severe, steroid-dependent type of asthma. New highly specific COX-2 inhibitors appear to be a safe alternative for patients with aspirin-induced asthma.

INTRODUCTION Salicylic acid was a key component of medical treatment throughout history. In the 5th century BC, Hippocrates has already used a bitter powder from the bark of the willow tree to treat aches and pains. Edmund Stone, an 18th century Anglican clergyman, discovered the beneficial substance of willow bark, which was later characterized as salicin. German industrial chemist Felix Hoffman acetylated salicylic acid in an attempt to find a compound less irritating to the stomach. His superiors at Bayer and Co. named the new drug aspirin in 1897. Today, Americans consume about 80 billion aspirin tablets a year, and more than 50 non-prescription drugs contain aspirin as the principal active ingredient [30]. It was unknown how aspirin worked until 1971, when Sir John Vane reported the results of studies showing that aspirin inhibits the production of prostaglandins (PGs) [131]. Irreversible acetylation of prostaglandin H synthase (PGHS) by aspirin inhibits mostly its COX-1 activity, decreasing the synthesis of PGs and generally reducing inflammation. It is also responsible for the anti-aggregatory effect of aspirin on platelets [3] and for the diminition of the house-keeping protective prostaglandin functions, causing gastric ulcers, renal failure and worsening of hypertension control [3]. Its gastrointestinal toxicity is in connection with loss of the cytoprotective effects of PGE2 and PGI2 in

*Address correspondence to this author at the 31-066 Krakow, ul. Skawinska 8, Poland; Tel.: (+48 12) 4305169; Fax: (+48 12) 4305203; Email: [email protected] 1Present address: National Institute of Lung Diseases, Bratislava, Slovakia 2Present address: Korányi National Institute of Pulmonology, Budapest, Hungary 1568-010X/02 $35.00+.00

gastric mucosa. Inhibition of COX-2 and induction of apoptosis in cells by aspirin could be involved in the decrease of a colorectal cancer incidence [35,60]. Aspirin (acetylsalicylic acid, ASA) and other non-steroid anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs against several types of pain, ache and inflammation all over the world. Aspirin is also known to reduce the risk of heart attacks and protect the cardiovascular system. It has been reported that adverse reactions due to NSAIDs make up 21-25% of all adverse effects due to drugs [27]. Aspirin is a common precipitating factor of lifethreatening attacks of asthma and 25% of asthmatic patients requiring mechanical ventilation were found to be aspirinintolerant [61,84]. In 1922 Widal and colleagues [137] described for the first time association of aspirin intolerance, asthma and nasal polyps. It is a distinct clinical syndrome, called also aspirin triad, and affects 5-10 % adult asthmatics. Since Szczeklik et al. [114] showed that not only aspirin but also other NSAIDs, which inhibit cyclooxygenase, could provoke similar adverse reactions, the more comprehensive term "analgesic intolerance" has also been used.

CLINICAL PICTURE OF ASPIRIN ASTHMA AND RHINITIS (AIAR)

INDUCED

Aspirin intolerance is a hallmark of AIAR [46], which runs in a typical clinical course. Usually within an hour after aspirin ingestion an acute asthma develops, often accompanied by rhinorrhea, nasal congestion, conjunctival irritation and sometimes flush of the head and neck.

© 2002 Bentham Science Publishers Ltd.

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Current Drug Targets - Inflammation & Allergy, 2002, Vol. 1, No. 1

Occasionally, aspirin intolerance is manifested only in upper respiratory tract as attack of rhinitis with discharge, sneezing and/or nasal obstruction. Rarely urticaria or gastrointestinal symptoms appear. Hypotension with the loss of consciousness, which is undistinguishable from anaphylactic reaction, is a rare, but possible manifestation of aspirin intolerance. A variety of anti-inflammatory drugs, with different molecular structure, but a common mode of action, i.e. inhibition of cyclooxygenase enzyme, precipitate symptoms. The intensity of adverse reaction depends on this inhibiting potency, dosage and also individual sensitivity [114]. Intravenous hydrocortisone hemisuccinate may also sporadically provoke bronchoconstriction in AIAR [78,119]. Amalgam alloy was recently described as the trigger of AIAR exacerbation [139]. The pattern of the disease is common all over Europe. First, there appears rhinitis, which becomes persistent. It is difficult to treat and lead to the loss of smell in 55 % of patients. Physical examination often reveals nasal polyps [120]. Hyperplastic rhinosinusitis associated with aspirin intolerance is more severe and changes in paranasal sinuses are more advanced than in rhinosinusitis of aspirin-tolerant patients [50]. Inflammation in nasal mucosa is eosinophilic, as in the bronchial tree. The cause of abundant eosinophilia in airways of patients with AIAR is unclear. Fibroblasts and epithelial cells from polyps of aspirin intolerant patients generate mixture of cytokines, which could be partially responsible for enhanced recruitment, activation, and prolonged survival of eosinophil [122]. It is of interest, that aspirin intolerance was described also in patients with non-allergic rhinitis with eosinophilia syndrome (NARES), e.g. the syndrome which is also characterized by severe eosinophilic inflammation of nasal mucosa, considered by some authors to be an early stage of aspirin triad [68]. Usually two years after the onset of rhinitis first symptoms of asthma with aspirin intolerance develop [120]. Asthma in AIAR is severe, requiring oral steroid treatment in more than half of the patients. Asthma and aggressive nasal polyposis run protracted course, despite the avoidance of aspirin and NSAIDs [120]. Aspirin-induced asthma and rhinitis thus constitutes a remarkable model for studying mechanisms, which operate in asthma, rhinitis and nasal polyposis. The European Network on Aspirin-Induced Asthma (AIANE) [120] recently investigated the natural history and clinical characteristics of AIAR on a large scale. 500 cases of AIAR from 10 European countries were studied; females outnumbered males by 2.3:1. Familiar occurrence was quite rare [123]. There was a close association between age and order of appearance of the main symptoms. Generally persistent rhinitis was the first symptom of the disease occurring during the third decade, often after a viral-like respiratory illness. Atopy, present in a third of patients, led to earlier manifestation of rhinitis and asthma, but not of aspirin intolerance or nasal polyposis [120]. The symptoms

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appeared on average 3 years earlier in females and clinical course is more progressive and severe than in males. Fifteen percent of AIAR patients were unaware of intolerance of aspirin or other NSAIDs and it was recognized only after performance of provocation tests. It means that aspirin intolerance is quite often underdiagnosed, which may have grave consequences for patients.

PATHOGENESIS OF AIAR The pathogenesis of AIAR remains obscure. Overproduction of cysteinyl-leukotrienes (cys-LTs) in the bronchial tree and inhibition of prostaglandin synthesis by COX inhibitors appear to be main factors in the pathogenesis. The Cyclooxygenase Pathway The most discussed and widely accepted theory is the cyclooxygenase theory [111], which suggests that the pharmacological action of NSAIDs, namely specific inhibition of the enzyme COX in the respiratory tract, alters arachidonic acid metabolism in AIAR. The evidence, which supports the COX theory, is as follows: (1) NSAIDs with anti-COX activity precipitate bronchoconstriction in aspirinsensitive patients, while NSAIDs deprived of this activity are well-tolerated; (2) there is a positive correlation between the potency of NSAIDs to inhibit COX in vitro and their potency to induce asthma attacks in the sensitive patients [114]; (3) after aspirin desensitization, cross-desensitization to other NSAIDs which inhibit COX also occurs. The arachidonic acid cascade divides into two major pathways: cyclooxygenase (COX) and leukotriene pathways. Both of them play an important role in the production of inflammatory and anti-inflammatory mediators. Prostanoids (prostaglandins, prostacyclin, thromboxane A2) are generated by prostaglandin-H2 synthase (PGHS) and leukotrienes by 5lipoxygenase (5-LO). PGHS, which is also known as COX, is the key enzyme of prostanoid pathway. It exists in 2 isoforms (COX-1 and COX-2); both proteins are encoded by different gene [42]. Differences in cyclooxygenase active site between two isoenzymes could be responsible for selectivity of COXinhibitors [34,40,58,87]. The non-selective COX-inhibitors much more powerfully block COX-1 than COX-2 [34,133]. Recent studies with selective COX-2 inhibitors showed that inhibition of COX-1 is most likely responsible for the asthmatic attacks triggered by aspirin and other non-selective COX-inhibitors [117]. COX-1, the constitutive form of the enzyme, is expressed in most tissues. Immunostaining for it does not differ in bronchial biopsies from AIAR, ATA and normal subjects [71]. COX-2 is expressed at a low basal level in airway resting cells and nasal mucosa, and can be rapidly induced by cytokines, growth factors, endotoxin, lipopolysaccharide and

Aspirin-Induced Asthma and Rhinitis

other inflammatory stimuli [6,67]. Sousa et al. [106] found in bronchial biopsies of asthmatic patients that there was a significant increase in the epithelial and submucosal cellular expression of COX-2. There was an increase in the percentage of COX-2 expressing mast cells and eosinophils in AIAR subjects. On the other hand, Picado et al. [85] reported a marked downexpression of COX-2 mRNA in nasal polyps from AIAR patients. There are differences between COX-1 and COX-2 knockout mouse model sensitized by ovalbumin [32]. COX-1 deficiency led to a more severe phenotype, distinguished by doubled number of eosinophils, activation of macrophages in bronchoalveolar fluid. Increased levels of LTB4 and cys-LTs were observed only in COX-1 knockout allergic mice. The Leukotriene Pathway Of primary importance in AIAR is the chronic overproduction of cys-LTs, even in the absence of aspirin challenge. The basal production is two- to ten-fold higher in AIAR [53]. Cys-LTs are potent bronchoconstrictors, cause mucosal edema, vasoconstriction and mucus hypersecretion, and are important chemoattractants for eosinophils in human airways [90]. Their biologic activities are mediated through interaction with cys-LT receptors [29]. Cys-LT1 receptor is expressed in human lung smooth-muscle cells and macrophages, in peripheral blood eosinophils and CD34+ cells, monocytes, basophils and B-lymphocytes [59,94]. The critical role of cys-LTs in the pathogenesis of AIAR has been confirmed by the efficacy of leukotriene antagonist drugs [18,20]. Enhanced baseline cys-LT levels increase further significantly after oral or bronchial aspirin provocation [12,13]. They are detected in urine [13,47], in nasal lavage [28] and in bronchial lavage fluid [102]. No correlation was found between urinary LTE4 excretion and baseline FEV1 [104]. The challenge tests reduce levels of PGE2 and thromboxane B2 in urine and BAL fluid, at the same time that cys-LT levels rise markedly [103,124]. The rate-limiting key enzyme for cys-LT production is LTC4-synthase (LTC 4S). Chronic overexpression of LTC4synthase in the bronchial mucosa [92] and in the blood eosinophils [93] is the likely reason for persistent basal cysLT overproduction in AIA lung. Enhanced baseline cys-LT level in BAL fluid of AIAR patients and the bronchial responsiveness to lysine-aspirin correlated uniquely and alone with the counts of LTC4S + cells in bronchial biopsy [16]. The profound overexpression of LTC4S is explained partly only by a genetic polymorphism of its gene. A single nucleotide polymorphism (A-C transversion) in the promoter region of LTC4S gene suggests that it could affect binding of transcription factors. The –444C allelic frequency was found significantly higher in severe AIAR patients as compared with ATA or healthy subjects and this group responded to aspirin challenge with significantly higher overproduction of cys-LTs as measured by urinary excretion of LTE4 [93]. Therefore this allelic variant can predispose to severe form of AIAR. However, presence of this genetic

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background does not ensure the development of the disease [13,123]. Failure of the Inhibitory Mechanisms in AIAR A hypothesis of a possible failure of mechanisms inhibiting inflammation in asthma, especially in its severe forms, is based on several laboratory and clinical studies. Here we discuss three types of molecular mechanisms that might be involved. 1/ Role of Prostaglandins Concentration of PGE in human airway epithelial lining fluid is ten-to-fifty times higher than concentrations of other cyclooxygenase products. PGE2 is the dominant cyclooxygenase product of airway epithelium and smooth muscles [76] and is produced also by fibroblasts and some immunocompetent cells. Prostaglandins have evidently dual role, e.g. pro- and anti-inflammatory, and balance between them might be responsible for ongoing inflammation or its resolution in many diseases. Immunocompetent cells markedly increase their eicosanoids synthesis when stimulated. Whereas stimulation of COX-2 increases eicosanoid synthesis, recently described early induction of lipid body formation, containing eicosanoids in leukocytes, constitutes earlier mechanism for enhancing the synthesis of eicosanoid mediators of inflammation, which is independent from cyclo-oxygenase [8]. Prostaglandin E2 is in vitro inhibitor of inflammatory mediator release from mast cells, eosinophils and macrophages [83]. It slows down leukotriene synthesis [14] and inhibits LTB4 and superoxide release from polymorphonuclear leukocytes [38]. Prostaglandin E2 has very intriguing role in aspirin intolerance and its defective synthesis might be one of molecular disturbances observed in AIAR [4], although it is not clear at which regulatory point. Prostaglandin synthesis is regulated by multiple factors (cytokines, hormones, NO) and on several regulatory points. Inflammatory cytokines induce over-expression of COX-2 and through this mechanism the prostaglandin synthesis increases [77]. Prostaglandin synthesis is suppressed by adrenal corticosteroids at the level of phospholipase A2, [31], although usual therapeutic dosage of steroids (e.g. 60 mg of prednisone a day or its equivalent) does not suppress eicosanoid biosynthesis in all cell types with corticosteroid receptors and capacity for both eicosanoid or leukotriene production [96]. Results from animal models confirmed, that also female hormones, like progesterone and 17-betaestradiol, are able to inhibit PGE2 synthesis by down regulation of COX-2 [95]. In fact, asthma attacks in some female asthmatics are closely related to their menstruation cycle. Also in AIAR female sex evidently influences the course of the disease. In females symptoms occur more often and earlier than in men and the disease runs more severe and progressive course [50].

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In the early studies with aspirin intolerant patients it was noticed, that ability of NSAIDs to induce bronchoconstriction correlates with their in vitro potency to inhibit prostaglandin synthesis [114]. In one study PGE2 and TXB2 were surprisingly increased in BAL fluid of aspirin intolerant asthmatics before challenge. Inhaled lysineaspirin quickly diminished the prostaglandin formation in their respiratory tract [102]. The same reduction of PGE2 synthesis after aspirin challenge was observed in nasal lavages from both aspirin tolerant and aspirin intolerant patients [86]. In aspirin intolerant patients depressed basal generation of PGE2 by epithelial cells from nasal polyps was registered [51]. It is not clear, if this defect is primary or secondary, e.g. caused by frequent steroid treatment used in these patients. Inhibition of PGE2 generation in nasal polyps could also result from the down-regulation of COX-2, the phenomenon described in nasal mucosa of patients with AIAR [85]. PGE2 in lower respiratory tract has been studied more extensively than in upper airways. PGE2 produces bronchodilation in normal subjects, but can provoke transient bronchoconstriction in asthmatic subjects [56]. In aspirin intolerant patients pre-treatment with PGE2 evidently attenuates bronchoconstrictive response to inhaled aspirin [116]. Because eicosanoid milieu in AIAR is characterized by enhanced cys-LT production, reduced synthesis of PGE2 after COX inhibition could be one of the mechanisms by which NSAIDs lead to severe deterioration in AIAR [90]. 2/ Lipoxins Lipoxins belong to trihydroxytetraene containing mediators, which are produced by transcellular biosynthesis during cell-to-cell interactions in pathological states. During the biosynthesis of lipoxins from arachidonic acid, leukotriene biosynthesis is blocked. Thus, there exists inverse relationship between leukotriene and lipoxin biosynthesis [97]. Anti-inflammatory effect of lipoxins is also manifested by inhibition of neutrophil transmigration with potency equivalent to that of dexamethasone [127] and also inhibition of LTC4-stimulated bronchoconstriction [11]. Aspirin intolerant asthmatics seem to exhibit decreased capacity for generation of lipoxins, another group of antiinflammatory substances [92]. Decreased capacity to produce another “brake” mechanism, e.g. protective lipid mediators in a milieu with excessive production of leukotrienes, might perpetuate severe inflammation observed in AIAR. 3/ Endogenous Nitric Oxide (NO) Generation of NO is closely related to activation or inhibition of cyclooxygenase. In healthy subjects NO is synthesized by epithelium of respiratory tract in small undetectable amounts. Basal synthesis is controlled by constitutive isoform of nitric oxide syntethase (NOS-III), expressed on epithelial and endothelial cells. Constitutive isoforms have probably homeostatic and protective function, whereas the role of

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inducible NOS is not fully understood. Under inflammatory conditions expression of inducible isoform (NOS II) is increased, mainly in inflammatory cells and myocytes [89] and it is responsible for increased NO generation by lungs in inflammatory conditions [129]. Pro-inflammatory action of NO is mediated through activation of enzymes like cyclooxygenase or metalloproteases [57]. There is laboratory evidence for balance-keeping and self-regulatory mechanisms between prostaglandin synthesis and NO generation [63]. In case of a functionally abnormal COX enzyme molecule, which is suspected in AIAR patients [125], this balance might be disturbed, leading to more severe inflammation.

DIAGNOSIS OF ASPIRIN INDUCED ASTHMA AND RHINITIS Clinical picture and patient’s history can rise a suspicion of AIAR. Challenge tests with aspirin are the cornerstones of diagnosis and are considered to be the only reliable confirmation test available [88]. The protocols of provocation tests differ between various centers. Oral, bronchial and nasal challenge tests with aspirin are used in specialized centers for research of aspirin intolerance. Different route of administration can influence PD20 which is the most frequently registered parameter [72]. This is probably caused by different resorption and metabolism rates between topical and systemic challenges. All three types of tests have their specific diagnostic value in aspirin intolerance. In order to make challenge procedure more simple, less time-consuming and comparative, Nizankowska and al. [72] developed 2-day procedure for carrying out both oral and inhalation provocation tests with the cumulative aspirin doses increasing in geometric progression. Challenge day is always preceded by a placebo day, in order to exclude patients with bronchial instability. Oral challenge with aspirin appears to be slightly more sensitive method (6989%), than bronchial challenge test (60-77 %), because it mimics the natural exposure to the drug and induces wider spectrum of clinical symptoms in patients with aspirin intolerance. However, the difference is not statistically significant [72]. Bronchial challenge has equal specificity than oral test, but induces milder and usually local reactions. Because it consumes less time than oral challenge test, this method is probably more suitable for studies on the influence of pharmacological agents on the asthmatic aspirininduced response [23]. Nasal challenge tests may safely and quickly confirm the role of certain agents (allergens, drugs) in patients with nasal symptoms. In future they can be used in investigations for new pharmacological agents active in upper respiratory tract [62]. AIAR is a good candidate for this type of tests, because nasal symptoms are the first which appear in the natural history and often remain patient’s dominant complain [120]. Nasal challenge test with aspirin is fast, easy to carry out and free of life threatening systemic or bronchial side effects. It has also high enough sensitivity


and specificity [81] comparable to other challenge tests. It is recommended as a useful quick first-line in vivo test or in patients with unstable asthma. More than that, in a small subgroup of patients in which aspirin intolerance is manifested only by upper respiratory symptoms, it is a method of choice. Because sensitivity of nasal challenge test with aspirin measured by anterior rhinomanometry is 86.7 %, negative results do not exclude aspirin intolerance. Suspected patients should undergo either acoustic rhinometry (in case of severe asthma or low lung functions) or oral challenge test as the next step. In approximately 20% of patients anterior rhinomanometry evaluation is not possible, because it requires generation of nasal flow, which is sometimes difficult, if the patient has severe anatomical obstruction in at least one nostril [66]. Unlike anterior rhinomanometry is devoid of this limitation and it appears to be more objective and sensitive method, than classic rhinomanometry.

PREVENTION AND TREATMENT OF AIAR The general rules concerning treatment of AIAR do not differ from the recently accepted guidelines for the management of asthma [36,41]. Most patients suffer from the moderate or severe persistent asthma. These observations were recently confirmed by a multicenter study comprising 500 patients with AIAR (European Network on AspirinInduced Asthma-AIANE) [120]. In this study 80% of patients were treated with inhaled corticosteroids in relatively high doses (800-2000 µg per day) and 51% of them oral corticosteroids at a dose corresponding to 8 mg prednisone per day. Twenty four percent of the patients were treated with intravenous corticosteroids during 12 months preceding the registration in the AIANE database. However, there are some differences that distinguish aspirin-sensitive asthmatics from other patients with asthma. These patients should avoid aspirin and other nonsteroidal anti-inflammatory drugs (NSAID) that inhibit cyclooxygenase. The physician ought to warn the patients with AIAR about potential adverse effects of NSAID. The patients should receive the list of contraindicated drugs with their generic and trade names. Avoidance of aspirin should be understood as a necessary precaution but not a specific therapy, because it does not alter the course of any of the components of AIAR. If necessary, the patients can usually take paracetamol. However, sporadic cases of adverse reactions following high dose paracetamol were reported in patients with AIAR [99]. For this reason, it is safer to begin therapy with one fourth and then one half of the tablet and monitor the patient for 1-2 hours. Generally, the dose 1000 mg should not be exceeded [99]. Patients with AIAR can also safely receive salicylamide, salicylate sodium, choline magnesium trisalicylate [113], benzydamine, chloroquine, azapropazone [118] and dextropropoxyphene. These drugs are weak inhibitors of COX or are devoid of anticyclooxygenase activity. Unfortunately, they have mild anti-inflammatory effects and are moderate analgesics. Recently, a new generation of NSAID was introduced into the market. Nimesulide and meloxicam, preferential COX-2 inhibitors,


more strongly inhibit COX-2 then COX-1. They are tolerated well by AIAR patients in lower doses, but higher doses may provoke typical adverse reactions, like dyspnoe and rhinorrhea [1,5,7,48,79]. Nimesulide was tolerated very well by patients with AIAR at a dose of 100 mg, but a higher dose of 400 mg it induced mild bronchoconstriction [7]. In another study, in which the cumulative dose of 200 mg nimesulide was administered to AIAR patients during the challenge procedure, about 3.5% untoward reactions following its administration were observed [1]. Another preferential COX-2 inhibitor, meloxicam has been also tested, among aspirin-sensitive asthmatics [130]. After low doses of meloxicam, mild bronchoconstriction was observed in 2 out of 19 patients studied, whereas 3 of them demonstrated rhinorrhea. After higher doses of the drug, the patients had more severe bronchospasm with 25% drop in FEV1. More promising are preliminary studies with highly selective COX-2 inhibitors: rofecoxib and celecoxib. In 12 patients with aspirin-intolerance, increasing doses of rofecoxib were administered in a double blind, cross over design. All patients tolerated the drug well. Bronchospasm or any other untoward symptoms were not observed. In the second part of this study the patients received on an open basis 25 mg rofecoxib without any adverse effects. The drug did not influence the urinary excretion of LTE4 and 9α,11βPGF 2 [117]. Similarly, celecoxib given in increasing doses as well as in the therapeutic dose of 200 mg was tolerated well by aspirin-sensitive asthmatics and it had no effect on the pulmonary function of the patients [22]. In another study, coming from Japan, 17 asthmatics with confirmed sensitivity to aspirin received 200 mg celecoxib or placebo in a double blind, cross over design [140]. None of the subjects demonstrated any adverse effect after celecoxib administration, nor could they discriminate between celecoxib and placebo. In two patients with hypersensitivity to NSAID as well as to nimesulide the tolerance of rofecoxib was very good [25]. This new group of NSAID could be a safe alternative for patients with aspirin-intolerance. However, more studies, on larger groups of patients are needed. Another strategy to administer aspirin or potent NSAID to aspirin-sensitive patients exists. It is possible to induce the state of aspirin tolerance and to maintain it by “aspirin desensitization”. Several protocols of this procedure have been described [9,52,106]. Generally, the state of “aspirin desensitization” is achieved by administration of increasing oral doses of aspirin over a period 2-5 days until the dose of 600 mg is achieved. Then, aspirin is given regularly at a daily dose of 600-1200 mg [52,107]. After each dose of aspirin there is a refractory period of 2-5 days duration, when aspirin and other NSAID can be taken. When aspirin is discontinued, the sensitivity gradually returns over 6-7 days. This is important for patients sensitive to aspirin who often need to use regularly NSAID, because they suffer from rheumatic diseases, degenerative joint diseases, migraines, chronic or recurrent headaches, or they need aspirin for preventive reasons because of ischaemic heart disease. On the other hand the desensitization may decrease the severity of asthma or lead to improvement in nasal symptoms [49,52,106]. The potential effectiveness of topical lysineacetylsalicylate in the prevention of recurrence of nasal polyps after surgery has been reported [80]. In the recent

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study lysine-acetylsalicylate endonasal inhalation prevented growth of nasal polyps and attenuated nasal symptoms [75]. If an aspirin-sensitive patient has increasing problems with sinusitis, recurrent nasal polyps, requiring surgical intervention or a severe asthma, the aspirin desensitization followed by daily aspirin therapy may be occasionally considered. A state of desensitization can be maintained for months if aspirin is taken regularly, i.e. every day or every second day in therapeutic doses. Sometimes, this procedure has to be discontinued because of severe gastrointestinal disturbances. The mechanism of aspirin-desensitization in patients with AIAR is not clear. It was suggested that the state of tolerance might be the result of a depletion of mast cell mediators [108,142]. There are observations that desensitization is related to cyclooxygenase inhibition by aspirin [39,115]. If aspirin blocks cyclooxygenase irreversibly, a new enzyme must be synthesized to replace molecules inactivated by that drug. The mechanism of desensitization may lead to reduction in airway responsiveness to LTE4 because of downregulation of cysLT receptors [2]. Another explanation for aspirin desensitization is diminished production of cys-LTs, since this procedure decreases LTB4 production by monocytes [45]. There is still another drug that should be taken with caution by patients with AIA. Sporadically these patients are hypersensitive to intravenous hydrocortisone hemisuccinate [120]. It could lead to bronchoconstriction or even severe attacks of asthma [24,78,119]. Therefore, it is prudent to advice the use of other than intravenously administered hydrocortisone hemisuccinate in acute exacerbation of AIAR. The patients tolerate well methylprednisolone, dexamethasone or betamethasone. The mechanism of that reaction is not clear. Inhibitory effect of hydrocortisone on prostanoid biosynthesis has been hypothesized [119]. Tartazine, a yellow azo dye used for coloring drinks, foods, drugs and cosmetics was cited in earlier reports as a cause of bronchospasm similar to that evoked by aspirin. More recent multicenter, controlled studies did not confirm these observations and indicated that such reactions are very rare in aspirin-sensitive subjects [101,133,135]. Tartrazine is not COX inhibitor [33]. Therefore, exceptional tartrazineinduced reactions are rather coincidental in AIAR patients. When antileukotriene drugs have been launched, they became a promising group of drugs in AIAR. These drugs either inhibit cys-LTs synthesis by blocking 5-LO or its activator 5-LO-activating protein (FLAP) or block specific cys-LTs receptors. Pretreatment with antileukotrienes prevented or attenuated the acute aspirin-precipitated nasal and bronchial reactions [10,17,20,44,70]. However, in one study, when provoking doses of ASA were exceeded, 4 out of 6 patients studied experienced bronchospasm, all 6 had nasoocular reactions despite 7-day pretreatment with 5lipoxygenase inhibitor, zileuton [82]. In another study bronchodilation after single dose of an antileukotriene drug has been demonstrated [20]. The bronchodilation lasted for a minimum of 9 hours and strongly correlated with the severity of asthma in individual patients. It indicates that the baseline upregulation of cys-LTs has an effect on intrinsic airway tone. Good therapeutic efficacy on chronic treatment

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of AIAR with anti-leukotriene drugs has been demonstrated in two recent trials. In the first one, tolerability of zileuton has been examined in a double-blind placebo-controlled, cross-over study [21]. The drug (600 mg qid) or placebo, was given to 40 AIAR patients regularly for 6 weeks. The treatment was added to existing therapy, which included medium to high doses of inhaled or oral corticosteroids. Zileuton improved acute and chronic pulmonary function, expressed as both an increased FEV1 from baseline, and higher morning and evening peak expiratory flow rate (PEFR) values when compared with placebo, despite lower requirement for rescue bronchodilators. The drug also decreased nasal dysfunction, produced a remarkable return of smell and diminished rhinorrhea. It also caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and partially inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 supporting the hypothesis that the drug acted through inhibition of leukotriene biosynthesis. In the second study, cys-LT antagonist montelukast (MK-0476) was administered to 80 AIAR patients not fully controlled on inhaled or oral corticosteroids in a double blind, placebo-controlled, parallel-group, 4-week study [19,54]. The patients received oral montelukast 10 mg or placebo once daily at bedtime. When compared with placebo, montelukast significantly improved parameters of asthma control like FEV1, PEFR and diminished the use of β2-mimetics. Patients on montelukast had less exacerbations of asthma, more asthma free days and their asthma specific quality of life was improved. In the recent study, pre-treatment of 16 aspirinsensitive patients with pranlukast, another cys-LTs receptor antagonist widely used in Japan, significantly decreased bronchospastic reactions precipitated by sulpiryne (COXinhibitor) or metacholine [140]. Pranlukast showed little effect on urinary LTE4 excretion. However, failures of antileukotriene drugs to prevent life-threatening reactions after taking COX inhibitors have been also reported [26,65]. There have been several cases of patients, including patients with AIAR who developed Churg-Strauss syndrome (eosinophilic vasculitis and granulomatosis) in association with zafirlukast therapy [15,136]. It has been assumed that these patients already had vasculitis and reduction or withdrawal of concomitant systemic corticosterids after introducing zafirlukast therapy only disclosed the disease. However, 2 patients with Churg-Strauss syndrome after zafirlukast, who did not receive systemic steroids, were reported [37]. Prostaglandin E2 (PGE2), produced by different cells of the bronchial mucosa, might be a powerful local protective factor preventing bronchoconstriction in response to numerous stimuli. If altered PGE2 production is involved in pathogenesis of AIAR, its substitution could inhibit aspirin induced bronchoconstriction in patients sensitive to aspirin. Inhaled PGE2 attenuated bronchoconstriction precipitated by aspirin [98,116]. Similarly, misoprostol an oral stable analogue of PGE1 caused the same effect, although its inhibitory potency was weaker than that of inhaled PGE2 [116,126]. However, in another study misoprostol given to aspirin sensitive asthmatics at a daily dose of 800-1600 µg showed no significant effect on the course of the disease [134].



Salbutamol protected against asthma attacks provoked by aspirin through a mechanism rather unrelated to its bronchodilator property [116]. Salmeterol, long acting β2mimetic, significantly attenuated aspirin-precipitated bronchoconstriction precipitated by lysine-aspirin in AIAR patients [112]. The drug interfered with the eicosanoid metabolism, i.e. it diminished the rise in urinary excretion of LTE 4 and stable prostaglandin D2 metabolite (PGD-M) after aspirin provocation.

represent the “gold standard” for the surgery. Because surgery does not affect an underlying inflammatory component of the disease and many patients suffer from anosmia, topical steroids are indicated following operation.

AIAR

=

Aspirin induced asthma and rhinitis

Based on a virus hypothesis of AIAR [110], Yoshida et coll. examined the efficacy of acyclovir, an inhibitor of the DNA polymerase [141]. The drug at a dose of 400 mg, given before the provocation with sulpiryne (COX-inhibitor) protected against asthma attacks through mechanisms unrelated to its bronchodilator property but related to the improvement of bronchial hypersensitivity to sulpiryne. Acyclovir also attenuated urinary LTE4 excretion precipitated by sulpiryne. It suggests that this drug except its antiviral activity could also protect against analgesics-induced bronchoconstriction, probably by inhibition of cys-LTs release. This trial stays in agreement with an earlier report [128] but it needs further confirmation.

ATA

=

Aspirin tolerant asthma

ASA

=

Acetylsalicylic acid (aspirin)

NSAIDs

=

Nonsteroidal anti-inflammatory drugs

COX

=

Cyclooxygenase

cys-LTs

=

Cysteinyl leukotrienes

PGE2

=

Prostaglandin E 2

PGD2

=

Prostaglandin D2

Recently, roxitromycin in a dose of 150 mg once daily was administered to 14 aspirin-tolerant asthmatics for 8 weeks period in order to evaluate its anti-inflammatory effect [100]. The therapy did not improve the values of PC20sulpiryne and had no effect on the urinary excretion of LTE4. However, blood and sputum eosinophils as well as serum and sputum eosinophilic cationic protein (ECP) were significantly decreased. The authors concluded, that although roxithromycin does not have antileukotriene effects, it has an antiinflammatory property associated with eosinophilic infiltration. Because many patients with AIAR suffer from severe asthma and need high doses of oral corticosteroids, cyclosporin as a drug possessing the “corticosterid sparing” effect has been studied in aspirin-sensitive patients with severe, corticosteroid dependent asthma [73,74]. Apart from selected cases, cyclosporin neither improved asthma symptoms nor allowed to reduce the doses of oral corticosteroids.

PGD-M.

=

Prostaglandin D2 metabolite

PGI2

=

Prostaglandin I2

LTB4

=

Leukotriene B4

LTC4

=

Leukotriene C4

LTE4

=

Leukotriene E4

TXB2

=

Thromboxane B2

5-LO

=

5-Lipoxygenase

FLAP

=

5-LO-Activating protein

NO

=

Nitric oxide

NOS

=

Nitric oxide synthase

Chronic eosinophilic rhinosinusitis concerns more than 90 % of patients with AIAR and frequently leads to the development of nasal polyps. Its management does not differ from treatment of other forms of rhinitis, however, several points need to be taken into consideration. Nasal decongestants and antihistamines are used, but they give only transient and limited relief. Topical corticosteroids are particularly effective in most of aspirin-sensitive patients with rhinosinusitis [50,62,69]. In severe cases, their use should be preceded by 7-10 days period of oral corticotherapy. When purulent rhinosinusitis is present, treatment with antibiotics together with corticosteroids is required. The benefits from treatment with antileukotriene drugs have been also observed [69]. Positive effects of aspirin desensitization have been mentioned before [52,107]. In many patients surgical procedures are needed to relieve chronic sinusitis and to remove nasal polyps. As most of aspirin-intolerant patients suffer from diffuse polypoid growth, polypectomy alone should be avoided as the effects are short-lived [43]. Endonasal, optically aided techniques

FEV1

=

Forced expiratory volume in 1 second

PEFR

=

Peak expiratory flow rate

BAL

=

Bronchoalveolar lavage

ABBREVIATIONS

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