The effect of leukotriene-modifier drugs on aspirin-induced asthma and rhinitis reactions.

BACKGROUND: Leukotrienes (LTs) appear to be crucial mediators of aspirin (ASA)-induced lower respiratory tract reactions. Therefore, it is logical to assume that leukotriene-modifier drugs (LTMDs) might block these reactions. OBJECTIVE: The aim of this study was to determine whether concomitant treatment with LTMDs was associated with a reduction of ASA-provoked lower respiratory tract reactions in patients with aspirin-exacerbated respiratory disease (AERD), when compared to AERD patients who were not treated with LTMDs. Secondly, if ASA-induced lower respiratory tract reactions were prevented in LTMD-treated patients, was there then a higher prevalence of upper respiratory reactors or, alternatively, a higher prevalence of blocked reactions ('non-reactors') in this group. METHODS: Of 271 patients suspected by history of having AERD, 96 were taking cys-LT receptor antagonists (cys-LTRAs) and 12 were taking zileuton at the time of oral ASA challenges. A matched control group of 163 patients was not receiving LTMDs. All subjects underwent standard oral ASA challenges. Reactions were classified as follows: classic [naso-ocular combined with a 20% or > decline in forced expiratory volume of 1 s (FEV1)]; pure lower (20% or > decline in FEV1 without naso-ocular); partial asthma (naso-ocular + 15-20% decline in FEV1); upper only (naso-ocular with < 15% decline in FEV1); negative (no reactions). RESULTS: In patients treated with cys-LTRAs, there were significant reductions in numbers of patients with ASA-induced bronchospastic reactions and a concomitant increase in upper respiratory reactors. There were no significant differences in mean provoking doses of ASA or the percent changes in FEV1 values in both groups. In the 12 patients receiving zileuton, no reactions to ASA (16%) were similar to the cys-LTRA-treated group (11%) and the control group (15%). CONCLUSION: During oral ASA challenges, LTMD treatment appeared to shift target organ responses from both upper and lower respiratory tracts to upper tract alone. LTMD blocking of the entire respiratory tract did not appear to occur.

Lack of cross-reactivity between rofecoxib and aspirin in aspirin-sensitive patients with asthma.

BACKGROUND: Patients with aspirin-sensitive respiratory disease experience cross-reactions to all nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase enzymes. With the introduction of antiarthritis drugs, which selectively inhibit cyclooxygenase-2, questions are raised as to whether cross-reactivity occurs between aspirin and these new cyclooxygenase-2 inhibitors. OBJECTIVE: The goal of this study was to determine whether rofecoxib cross-reacts in aspirin-sensitive patients with asthma. METHODS: Sixty patients with asthma underwent doubleblinded, placebo-controlled oral challenges with rofecoxib (12.5 mg, 25 mg, and 2 placebos) over 48 hours in our General Clinical Research Center. The next day, aspirin sensitivity was proven in each of the 60 patients through use of single-blinded oral aspirin challenges. RESULTS: None of the 60 patients experienced any symptoms, changes in nasal examination findings, or declines in FEV(1) values during their challenges with rofecoxib. All 60 patients experienced typical naso-ocular and asthmatic reactions to aspirin with a mean provoking dose of 61 mg. The exact 1-sided CI for the probability of rofecoxib inducing crossreactions in aspirin-sensitive patients with asthma is calculated to be between 0% and 0.05%. CONCLUSION: Given that none of the 60 patients reacted to rofecoxib and given the statistical power of this large sample size, we conclude that cross-reactivity between aspirin and rofecoxib does not occur in patients with aspirin-sensitive respiratory disease. This does not exclude rofecoxib from participating in other types of reactions, including immune recognition after prior treatment with the drug. From the standpoint of the mechanisms involved in aspirin-induced respiratory reactions, this study strongly supports inhibition of cyclooxygenase-1 as the essential initiator of these types of reactions.

Lack of effect of the 5-lipoxygenase inhibitor zileuton in blocking oral aspirin challenges in aspirin-sensitive asthmatics.

BACKGROUND: Leukotrienes (LTs) have been implicated as major mediators of aspirin-(ASA)-induced respiratory reactions. It was therefore logical to assume that an inhibitor of 5-lipoxygenase (5-LO), such as zileuton, given before and during oral challenges with ASA, might prevent ASA-induced respiratory reactions. Indeed, in prior studies, pretreatment of ASA-sensitive respiratory disease patients with leukotriene modifiers eliminated or attenuated respiratory reactions upon re-challenge with the previously established provoking dose of ASA. However, doses higher than the provoking doses were not administered during these reported studies. OBJECTIVE: We wished to determine whether zileuton pretreatment could prevent ASA-induced respiratory reactions in our six volunteers with aspirin-sensitive respiratory disease when ASA challenge doses were started below the usual provoking dose of 60 mg and then increased until a respiratory reaction occurred. METHOD: Aspirin sensitivity was established previously in all six patients during a prior ASA oral challenge. In this study, pretreatment with zileuton 600 mg qid was initiated 7 days prior to, and continued during oral ASA challenges. Patients underwent single-blind oral ASA challenges with escalating doses of ASA, every 3 hours, according to our standard protocol. RESULTS: All six patients reacted to doses of ASA between 45 and 325 mg. Four patients experienced bronchospasm (FEV1 declined 19% to 53%) while receiving zileuton. All six had naso-ocular reactions. Concentrations of urine LTE4 also increased significantly (mean 334 pg/mg Cr at baseline, increasing to 1024 pg/mg Cr at respiratory reactions). CONCLUSIONS: During ASA challenges, zileuton, in standard doses of 600 mg qid was associated with increased synthesis of LTs in five of six patients and naso-ocular reactions in all six patients, as well as bronchospasm in four patients.

5' flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States.

BACKGROUND: Approximately 10% of patients with asthma have a distinct clinical entity in which their symptoms are exacerbated by aspirin and most other nonsteroidal anti-inflammatory agents. These individuals typically have significant basal overproduction of cysteinyl leukotrienes, and within their biosynthetic pathway, the terminal enzyme, leukotriene C(4) synthase (LTC(4)S), is significantly overexpressed. A single nucleotide polymorphism consisting of an adenine (A) to cytosine (C) transversion -444 nucleotides upstream of the ATG translation start site in the LTC(4)S gene has been associated with a relative risk of 3.89 for the aspirin-intolerant phenotype in Polish patients. OBJECTIVE: These studies were undertaken to further investigate the functional effect of this allele in LTC(4)S gene expression and subsequently to determine whether an association between the presence of this polymorphism and aspirin-intolerant asthma existed within patients of the United States. METHODS: Functionality of the C-444 allele was assessed by using promoter-reporter constructs and transient transfection assays in the THP-1 monocytic cell line. Genotyping was performed on 137 unaffected control subjects, 33 patients with aspirin-tolerant asthma, and 61 patients with aspirin-intolerant asthma from the United States. RESULTS: Promoter-reporter constructs containing the C-444 allele revealed no significant upregulatory or downregulatory effects in the transcription of the LTC(4)S gene. The LTC(4)S genotype distribution was consistent with the Hardy-Weinberg equilibrium in patients with aspirin-tolerant asthma and unaffected control subjects but not in patients with aspirin-intolerant asthma; however, the distributions were not significantly different among the phenotype groups. CONCLUSIONS: Our data demonstrate that the C-444 allele in the LTC4S gene is not statistically different among patients with the aspirin-intolerant asthmatic phenotype, patients with the aspirin-tolerant asthmatic phenotype, and unaffected control subjects in the United States. This finding, along with the lack of functionality of this polymorphism, suggest that it is not related to a specific asthma phenotype and may represent a population-stratified polymorphism within patients of eastern European descent.

Approach to the patient with a history of adverse reactions to aspirin or NSAIDs: diagnosis and treatment.

Aspirin and nonsteroidal antiinflammatory drugs can induce several different reactions. It is incumbant upon the astute physician to recognize the differences between these reactions, the clinical settings in which they occur, and the management of each type of reaction. In this article, I have attempted to clarify and simplify, as much as possible, the approach I take in addressing the problems of adverse reactions to these drugs. In addition, the problems of cross-reactions are explained in terms of COX-1 and 2 isoenzymes. Aspirin desensitization and treatment with daily ASA are also addressed.

Monosodium glutamate and asthma.

Allen et al. (1987) conducted oral monosodium glutamate (MSG) challenges with 32 asthmatic volunteers and reported that 14 reacted to MSG. Another study by Moneret-Vautrin (1987) also reported MSG-induced asthma attacks in 2 of 30 asthmatic patients. Four additional studies have been conducted and none has confirmed the results of the above authors. These studies, by Schwartzstein et al. (1987), Germano (1991), Woods et al. (1998) and Woessner et al. (1999), challenged a total of 45 patients who gave a history of asthma attacks in oriental restaurants. None of these patients experienced asthmatic reactions after ingesting MSG (one-sided confidence interval of 0-0.066). Another 109 asthmatic patients, without a history of asthma in oriental restaurants, also did not react to ingestion of MSG (one-sided confidence interval of 0-0.027). With a confidence interval < 0.05 there is a >95% probability that MSG history-negative asthmatic patients are not sensitive to MSG. For the MSG history-positive asthmatics, 45 patients, in well-performed studies, underwent negative challenges to MSG, contrasting with two studies reporting positive challenges. Allen et al. (1987) and Moneret-Vautrin (1987), who reported positive MSG challenge results, performed studies with the following characteristics: 1) single blinded, conducted after discontinuing essential antiasthma medications; 2) used effort-dependent peak expiratory flow rate measurement of lung function; 3) added AM bronchodilators in some patients; 4) ignored wandering baselines on the placebo challenge days; and 5) conducted some challenges in the AM and some at night. In summary, the existence of MSG-induced asthma, even in history-positive patients, has not been established conclusively.

Montelukast is only partially effective in inhibiting aspirin responses in aspirin-sensitive asthmatics.

BACKGROUND: Leukotrienes have been implicated as major mediators of ASA-induced respiratory reactions. In several prior studies, pretreatment of ASA-sensitive respiratory disease (ASRD) patients with leukotriene modifiers have sometimes allowed subjects to tolerate previously established provoking doses of oral ASA or inhalation ASA-lysine, without respiratory reactions. OBJECTIVE: The purpose of this study was to examine whether ASA-provoked respiratory reactions would be blocked or attenuated by pretreatment with a cystLT1 receptor antagonist, montelukast, particularly if ASA doses were increased above their threshold doses. METHODS: Baseline ASA oral challenges were performed. Eight to 12 days later, following pretreatment with montelukast 10 mg daily, threshold and then escalating doses of ASA were used during repeat oral ASA challenges. The differences in responses between baseline and montelukast protected ASA oral challenges were then compared. RESULTS: Nine of 10 patients, despite pretreatment with montelukast, experienced at least naso-ocular reactions during their second oral ASA challenges. In four of nine patients, asthmatic reactions also occurred. In comparing baseline and montelukast protected ASA challenges, there were no statistically significant differences in their responses. CONCLUSIONS: Pretreatment with montelukast allowed only one patient to proceed through all challenge doses of ASA without any reactions. The remaining nine patients enjoyed only partial protection from respiratory reactions. Montelukast pretreatment was generally not effective in altering upper airway reactions and only partly effective in altering lower airway reactions.

Association of urinary leukotriene E4 excretion during aspirin challenges with severity of respiratory responses.

BACKGROUND: Asthmatics with aspirin- (ASA) sensitive respiratory disease (ASRD) have a spectrum of respiratory reactions during oral ASA challenge that vary in severity and are temporally associated with leukotriene (LT) formation. OBJECTIVE: This study investigates the relationship of the severity of ASA-induced respiratory reactions to urinary LTE(4) excretion. METHODS: Asthmatics with suspected ASRD underwent oral ASA challenges. Urinary LTE(4) levels were measured at baseline, during the reaction, and after acute ASA desensitization. RESULTS: Asthmatics who had respiratory reactions during oral ASA challenges were divided into 3 groups: asthmatics with naso-ocular reactions and <15% decline from baseline FEV(1) values (group 1), asthmatics with a decline in FEV(1) of 20% to 30% (group 2), and asthmatics with a decline in FEV(1) of >30% (group 3). There were no significant differences in age, baseline FEV(1) values, use of inhaled corticosteroids, daily prednisone doses, prednisone bursts, duration of reactions, or average provoking doses of ASA among the groups. At baseline group 3 asthmatics had significantly higher urinary LTE(4) levels than those in groups 1 or 2. At the time of respiratory reaction to ASA, the urinary LTE(4) levels rose significantly in all groups but were significantly greater among group 3 asthmatics compared with those in groups 1 and 2. CONCLUSION: The severity of the respiratory reactions during oral ASA challenges was associated with the degree of elevation of baseline LTE(4) synthesis. Our results suggest that asthmatics with ASRD have a spectrum of respiratory tract reactions in which leukotrienes play a distinguishing role.

Monosodium glutamate sensitivity in asthma.

BACKGROUND: Questions have been raised since the early 1980s about monosodium glutamate (MSG) and provocation of asthma. Because MSG is widely available as a chemical in both natural foods and as an additive in many prepared foods, the need to define the relationship of MSG to asthma is of great importance. OBJECTIVE: The purpose of this study was to determine whether MSG ingestion induces asthma attacks in asthmatic subjects. METHODS: With single-blind, placebo-controlled screening challenges, 100 subjects with asthma (30 subjects with a history of Oriental restaurant asthma attacks; 70 subjects with a negative history) were challenged with 2.5 g of MSG. A total of 78 patients were proved to have aspirin-sensitive asthma. RESULTS: No patient had a significant fall in FEV(1 ) value or the development of asthma symptoms during the MSG challenge. The mean change in FEV(1 ) with MSG challenge was no different from that of placebo challenge. Subjects with an MSG-positive history showed no significant percent decrease in FEV(1 ) values after placebo challenges compared with MSG 2.5 g oral challenge (P =.28). In the group with an MSG-negative history, there was no statistical difference in the change in lowest FEV(1 ) values between the placebo and MSG challenges (P =.44). The exact 1-sided 95% confidence interval (CI) for the probability of MSG sensitivity in individuals with aspirin-sensitive asthma (negative history) is 0% to 0.04%. When combined with previous studies that did not demonstrate MSG-provoked asthma, the 95% CI is 0% to 0.03%. For patients with an MSG-positive history, the exact 1-sided 95% CI for the probability of MSG sensitivity in this study was 0% to 0.07%, which is somewhat wider because of the smaller sample size. CONCLUSIONS: MSG challenges in subjects with and without a perceived sensitivity to MSG failed to induce signs or symptoms of asthma. Therefore in view of the poorly conducted studies that proposed that MSG induced asthma and the subsequent studies that failed to confirm those findings, it is important to maintain a healthy skepticism about the existence of MSG sensitivity in individuals with asthma.

Aspirin-induced asthma: advances in pathogenesis and management.

In some patients with asthma, aspirin (ASA) and all nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase enzymes (cyclooxygenase-1 and -2) precipitate asthmatic attacks and naso-ocular reactions. This distinct clinical syndrome, called aspirin-induced asthma (AIA), is characterized by a typical sequence of symptoms, intense eosinophilic inflammation of nasal and bronchial tissues, combined with overproduction of cysteinyl-leukotrienes (Cys-LTs). At baseline, cys-LT urinary excretion is augmented, and ASA administration leads to its further temporary increase. After ASA challenge, cys-LTs are released into nasal and bronchial secretions and can be collected in the urine. LTC4 synthase, the terminal enzyme for cys-LT production, is markedly overexpressed in eosinophils and mast cells from bronchial biopsy specimens of most patients with AIA. An allelic variant of LTC4 synthase that enhances enzyme transcription is associated with AIA. Avoiding ASA and nonsteroidal anti-inflammatory drugs does not prevent progression of the inflammatory disease. Corticosteroids continue to be the mainstay of therapy, and anti-LT drugs are also indicated for treatment of the underlying disease. After ASA desensitization, daily ingestion of high doses of ASA reduces inflammatory mucosal disease symptoms, particularly in the nasal passages, in most patients with AIA.

Osteonecrosis of the femoral head in patients with inflammatory arthritis or asthma receiving corticosteroid therapy.

The utilization of corticosteroids in the management of acute and chronic inflammatory processes, such as asthma or inflammatory arthritis, has been implicated in the adverse effects of multiple organ systems. One potential area of these negative consequences in the use of corticosteroids is the development of osteonecrosis of the femoral head. A direct time/dosage relationship for treatment with corticosteroids of patients with an established diagnosis of asthma or inflammatory arthritis and femoral osteonecrosis is unknown. A prospective study was undertaken to evaluate the use of corticosteroids and the incidence of osteonecrosis of the femoral head and potentially establish a time/dosage relationship in this patient population. No direct relationship between corticosteroid dosage and the development of femoral head osteonecrosis in 1420 hip-years was demonstrated at 10-year follow up.

Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: long-term outcomes.

BACKGROUND: Aspirin-sensitive patients with asthma experience continuous inflammation of their nasal and sinus tissues, complicated by recurrent sinusitis, which frequently leads to asthma attacks. Systemic corticosteroid therapy and sinus or polyp surgery are currently required to control underlying rhinosinusitis, and bursts of corticosteroids are used for asthma control. OBJECTIVE: After aspirin desensitization therapy, objective measures of respiratory disease activity, linked to the need for systemic corticosteroids and sinus surgery, were studied to determine whether any changes occurred. METHODS: Sixty-five aspirin-sensitive patients with asthma underwent aspirin challenge, followed by aspirin desensitization and daily treatment with aspirin over 1 to 6 years (mean, 3.1 years). Clinical outcome measurements before aspirin desensitization treatment and during follow-up were analyzed for the larger group of 65 patients and subgroups (29 patients receiving therapy for 1 to 3 years and 36 patients receiving therapy for 3 to 6 years). RESULTS: In the larger group of 65 patients, there were significant reductions in numbers of sinus infections per year (median, 6 to 2), hospitalizations for treatment of asthma per year (median, 0.2 to 0), improvement in olfaction (median, 0 to 2), and reduction in use of systematic corticosteroids (mean, 10.2 to 2.5 mg) with p values less than 0.0001. Numbers of sinus and polyp operations per year were significantly reduced (median, 0.2 to 0; p = 0.004), and doses of nasal corticosteroids (in micrograms) were significantly reduced (mean dose, 139 to 106 micrograms, p = 0.01). Emergency department visits and use of inhaled corticosteroids were unchanged. CONCLUSIONS: The results support a role for aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma.

Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects.

OBJECTIVE: Cross-sensitivity between aspirin and acetaminophen in aspirin-sensitive asthmatic patients has been reported with frequencies ranging from 0% to 29%. The relationship is dose-dependent for acetaminophen challenges, ranging between 300 and 100 mg. METHODS: To determine the prevalence of cross-sensitivity to high-dose acetaminophen, we performed single-blind acetaminophen oral challenges with 1000 mg and 1500 mg in 50 aspirin-sensitive asthmatic patients and in 20 non-aspirin-sensitive asthmatic control subjects. RESULTS: Overall, 17 of 50 (34%) of aspirin-sensitive asthmatic patients reacted to acetaminophen in doses of 1000 to 1500 mg (95% confidence interval: 20% to 49%). By contrast, none of the 20 non-aspirin-sensitive asthmatic patients reacted to acetaminophen (95% confidence interval: 0% to 14%). This difference was highly significant (p = 0.0013), supporting the hypothesis that cross-sensitivity between aspirin and acetaminophen is unique in aspirin-sensitive asthmatic patients. CONCLUSION: Although high-dose ( > 1000 mg) acetaminophen cross-reactions with aspirin were significant with respect to frequency (34%), such reactions included easily reversed bronchospasm in only 22%, and were generally mild. We recommended that high doses of acetaminophen (1000 mg or greater) should be avoided in aspirin-sensitive asthmatic patients.

Hydrocortisone sodium succinate does not cross-react with aspirin in aspirin-sensitive patients with asthma.

BACKGROUND: Bronchospasm after intravenous hydrocortisone treatment has been reported in some patients with aspirin-sensitive respiratory disease. OBJECTIVE: This study was designed to determine the prevalence of sensitivity to hydrocortisone among patients with aspirin-sensitive respiratory disease. METHODS: We performed double-blind, placebo-controlled challenges with aspirin and 100 mg of hydrocortisone sodium succinate administered intravenously in 53 subjects. RESULTS: Forty-five of the 53 subjects (85%) undergoing oral aspirin challenge experienced respiratory reactions to aspirin. Forty-four of these 45 patients had neither naso-ocular, cutaneous, nor respiratory reactions to hydrocortisone sodium succinate. One aspirin-sensitive subject had bronchospasm and a naso-ocular reaction to hydrocortisone sodium succinate and a naso-ocular reaction with minimal bronchospasm to methylprednisolone sodium succinate. After desensitization to aspirin, and while receiving maintenance aspirin therapy, this subject again reacted to hydrocortisone sodium succinate with bronchospasm and naso-ocular reaction. CONCLUSION: We conclude that aspirin-sensitive patients with asthma are not preferentially sensitive to hydrocortisone and that hydrocortisone sodium succinate does not cross-react or cross-desensitize with aspirin.

Inhibition of monocyte leukotriene B4 production after aspirin desensitization.

Aspirin-sensitive patients may be desensitized through a graded series of exposures to aspirin. We investigated the underlying mechanism of aspirin desensitization by measuring the release of leukotrienes B4 and C4 from calcium ionophore-stimulated peripheral blood monocytes. Compared with monocytes from normal volunteers (n = 5), monocytes from patients with aspirin-sensitive asthma (n = 10) released increased amounts of thromboxane B2 (1060 +/- 245 pg/ml vs 456 +/- 62 pg/ml), leukotriene B4 (861 +/- 139 pg/ml vs 341 +/- 44 pg/ml), and leukotriene C4 (147 +/- 31 pg/ml vs 56 +/- 6 pg/ml) at baseline. After aspirin desensitization, thromboxane B2 release was almost completely suppressed in both groups. Leukotriene B4 release was significantly decreased in the aspirin-sensitive group (484 +/- 85 pg/ml) but not in the normal subject group (466 +/- 55 pg/ml). The need for prednisone decreased significantly after patients were desensitized to aspirin (10.4 +/- 2.2 mg/day to 1.6 +/- 2.8 mg/day). These results demonstrate that desensitization to aspirin results in decreased monocyte leukotriene B4 release. On the basis of the bronchospastic and inflammatory potential of leukotrienes, the decrease in leukotriene release may contribute to the clinical improvement seen after aspirin desensitization.