Antileukotriene therapy for the relief of sinus symptoms in aspirin triad disease.

From the Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee.

Reprint requests: Robert J. Toohill, MD, Department of Otolaryngology and Communication Sciences, Froedtert Memorial Lutheran Hospital, 9200 W. Wisconsin Ave., Milwaukee, WI53226. Phone: [phone]; fax: [phone].

Abstract

We studied the effect of antileukotriene therapy for the relief of sinus symptoms in patients with aspirin triad disease (ATD). We reviewed the charts of 18 ATD patients who had received antileukotriene therapy. All patients had undergone previous sinus surgery. We then designed a questionnaire to determine the level of each patient's symptoms of chronic rhinosinusitis before and after antileukotriene therapy. Responses were converted to symptom scores. For each patient, the role of therapy in the relief of sinus symptoms was evaluated in three ways: by total symptom scores, by self-reports of overall benefit, and by findings on endoscopic nasal examination.

Fifteen of the 18 patients completed the questionnaire. Symptom scores for both major and minor symptoms indicated that nine patients had improved following antileukotriene therapy; three other patients reported some overall benefit from therapy, despite no improvement in their symptom scores. Endoscopic nasal examination findings were consistent with the reports of overall benefit. We conclude that antileukotriene therapy is an effective treatment for most patients whose symptoms of chronic rhinosinusitis persist following sinus surgery.

Introduction

Aspirin triad disease (ATD) is a chronic inflammatory process that is associated with asthma, aspirin intolerance, and nasal polyposis. [1] ATD patients often come to otolaryngology clinics for management of sinonasal complaints.

Leukotrienes contribute to the pathogenesis of aspirin intolerance and asthma. [1,2] The triggering of ATD by aspirin or by nonsteroidal anti-inflammatory drugs (NSAIDs) is very selective and rare. The mechanism of this phenomenon is not known. Leukotrienes are the breakdown products of arachidonic acid metabolism. Arachidonic acid is metabolized to prostaglandins, leukotrienes, and epoxyeicosatrienoic acid by cyclooxygenase, lipoxygenase, and epoxygenase, respectively. When an aspirin product is taken by an ATD patient, the first two of these pathways are affected. Aspirin competitively binds to the platelet surface, thus inhibiting the activity of cyclooxygenase and the production of prostaglandins and thromboxane. This frees up large amounts of arachidonic acid. [3]

At the same time, aspirin stimulates 5-lipoxygenase activity, most likely in the mast cells, which leads to a rapid production of leukotrienes. [4] Leukotrienes cause bronchoconstriction, increased mucus secretion, and vascular permeability, [5-8] and they inhibit ciliary activity. [9] Overproduction of leukotrienes accounts for the abnormalities of ATD. [4] The recently developed antileukotriene agents montelukast [10] and zafirlukast [11] act as leukotriene receptor antagonists, while zileuton [12,13] acts as a leukotriene synthesis inhibitor. All three drugs diminish the effects of leukotrienes in asthma patients (figure 1).

Antileukotriene therapy diminishes the nasal response to aspirin and allergen challenge in patients with aspirin-sensitive asthma [4] and allergic rhinitis. [14] However, the effect of antileukotriene therapy on sinonasal symptoms in ATD patients has not been investigated. The purpose of this study was to determine the role of antileukotriene therapy in the relief of sinus symptoms in patients with ATD.

Materials and methods

We retrospectively reviewed the charts of all ATD patients enrolled in the otolaryngology clinic at the Medical College of Wisconsin who had received antileukotriene therapy. Patients were evaluated by three methods: symptom scores, subjective self-reports, and nasal endoscopy. A questionnaire was used to obtain the information on symptom scores and self-ratings.

The questionnaire was designed to assess the response to antileukotriene therapy and to determine the number of comorbid factors in each patient (figure 2). The questionnaire asked specific questions about each patient's general health and the effect of antileukotriene therapy on their sinus disease. In the general health section, questions concerned the personal and family medical history, alcohol and smoking habits, history of allergy, and duration of ATD. The effect of antileukotriene therapy on symptoms was evaluated by analyzing the answers to the specific questions regarding the degree of chronic rhinosinusitis and the overall benefit from antileukotriene therapy.

Patients reported the level of each major symptom (facial pain/pressure, facial congestion/fullness, nasal blockage, runny nose, and impaired sense of smell) and minor symptom (sinus headache, halitosis, fatigue, tooth pain, cough, and ear pain/fullness) before and after antileukotriene therapy. The degree of each symptom was quantified as a symptom score: 0 points for no symptoms, 1 point for mild symptoms, 2 points for moderate symptoms, and 3 points for severe symptoms. For each patient, major and minor symptom scores were added together to arrive at a total symptom score. To subjectively determine the overall benefit of antileukotriene therapy, patients were asked to describe their improvement as either none, slight, moderate, or very good. An objective assessment of the effect of antileukotriene therapy was based on the findings of an endoscopic nasal examination during each patient's most recent followup visit. Statistical comparisons of total symptom scores before and after antileukotriene therapy wer e made with Wilcoxon' s rank sum test.

Results

Subjects. We identified 18 patients with ATD who had received antileukotriene therapy. The 6 men and 12 women were aged 30 to 70 years (mean: 48 [plus or minus] 3). Followup information was available on 15 of the 18. A diagnosis of ATD was based on the patient's history of aspirin intolerance, asthma, and nasal polyposis. All patients had a history of nasal and/or asthma symptoms following aspirin intake. Following their diagnosis, all patients had strictly avoided aspirin and NSAIDs, but all had persistent symptoms of chronic rhinosinusitis despite medical and surgical therapy.

The duration of sinus disease in the 18 patients ranged from 2 to 26 years. Patients recognized their intolerance to aspirin after chronic rhinosinusitis and asthma developed. All patients had previously undergone paranasal sinus surgery: bilateral ethmoidectomy in 18, maxillary antrostomy in 15, sphenoidotomy in 14, osteoplastic flap with fat obliteration in three, and a modified endoscopic Lothrop procedure in one (table 1). Even so, symptoms of chronic rhinosinusitis persisted after surgery.

Antileukotriene therapy. Antileukotriene therapy consisted of either the leukotriene receptor antagonist zafirlukast at 20 mg twice a day or the 5-lipoxygenase inhibitor zileuton at 600 mg four times a day. During antileukotriene therapy, patients did not receive any antibiotics or nasal decongestants. All patients continued to take their medications for asthma.

Sixteen of the 18 patients had taken zafirlukast, and the other two had taken zileuton. The duration of antileukotriene therapy ranged from 1 to 15 months. Two patients reported adverse effects from zafirlukast (nausea); one of these patients did not continue therapy, while the other was switched to zileuton. One patient on zileuton experienced side effects (nausea, right upper quadrant abdominal pain) and was switched to zafirlukast.

Questionnaire. Fifteen of the 18 patients filled out the questionnaire. None of the patients reported a family history of ATD, aspirin intolerance, asthma, or nasal polyposis. Four patients had a history of surgery other than sinus surgery (hysterectomy, coronary artery bypass, tonsillectomy, appendectomy). Heartburn was reported by eight patients, thyroid disorders by three, depression by three, arthritis by three, and diabetes by one. A history of allergies to drugs was reported by eight patients, allergies to dust mites by three, and allergies to mold-pollen-grass by two. None of the patients was currently a smoker; five were former smokers, whose duration of smoke-free status ranged from 5 to 25 years.

The 15 patients who completed the questionnaire reported the level of their chronic rhinosinusitis symptoms before and after antileukotriene therapy (table 2). Major-symptom scores were significantly lower after antileukotriene therapy (range: 1-10; median: 5) than before treatment (range: 3-14; median: 8) (p=0.008) (figure 3). Similarly, minor-symptom scores were significantly lower after antileukotriene therapy (range: 0-10; median: 5) than before therapy (range: 0-17; median: 6) (p=0.01) (figure 4).

Overall benefit from antileukotriene therapy was reported by 12 of the 15 patients; benefit was judged to be slight by seven patients, moderate by two, and very good by three (table 2). Three of the 15 did not report any benefit. These findings were consistent with symptom scores in nine patients.

Endoscopic findings. Pretreatment findings on endoscopic nasal examination were available for 13 of the 15 patients. On examination, patients exhibited at least one of the following symptoms: mucosal edema or erythema, mucoid or purulent nasal discharge, polypoid lesions, and nasal crusting (table 2). Of the 15 patients, 11 underwent a posttreatment endoscopic nasal examination before they completed the questionnaire. At the time of the posttreatment endoscopic nasal examination, the duration of therapy had ranged from 1 to 12 months. Endoscopy showed no abnormalities in eight of the 15 patients, nasal crusting in two, and erythema with nasal crusting in one.

Discussion

The association of aspirin intolerance, asthma, and nasal polyposis is well recognized, [15-19] and our findings are compatible with these earlier reports. In the present study, most of the patients with ATD were women, and they had all three components of ATD. No patient reported a family history of aspirin intolerance; aspirin intolerance was frequently recognized after the patient had been diagnosed with chronic rhinosinusitis and asthma.

Leukotriene synthesis has been implicated in the pathogenesis of ATD. Elevated basal leukotriene levels have been found in aspirin-sensitive patients, and during aspirin-induced reactions further elevations in leukotriene E4 levels have been documented. [20,21] Leukotrienes were also found in the nasal secretions of patients with aspirin sensitivity after aspirin challenge. [22] During the aspirininduced nasal reactions, mast cells and eosinophils were also activated in aspirin-sensitive patients. [4,23] Both mast cells and eosinophils are a source of leukotrienes. An increased number of eosinophils has been found in nasal polyps of aspirin-sensitive patients with asthma. [24]

Treatment with aspirin during aspirin desensitization has been reported to lower the level of leukotriene C4 in nasal lavage fluid of aspirin-sensitive patients. [25] Aspirin desensitization treatment has also reduced the number of sinus surgeries and has improved olfaction. [26] Although some studies have found that patients with ATD had poor outcomes after sinus surgery, [1,27] this is believed to be attributable to the advanced stage of sinus disease in those patients. [23] Patients with ATD have also been reported to have a high risk for nonoperative complications of chronic rhinosinusitis. [1,27] Therefore, close long-term followup and intense medical management of chronic respiratory inflammation has been recommended. [1]

Recently developed antileukotriene agents can inhibit the effects of leukotrienes. Antileukotriene agents have been shown to reduce nasal symptoms [4,29] and leukotriene levels in lavage fluid [4,14] after aspirin challenge. Previous studies of aspirin-sensitive asthma patients have also shown that antileukotriene agents attenuate asthma-associated bronchoconstriction. [30]

The safety of several antileukotriene agents has been studied in clinical trials. The frequency of adverse events such as headache, gastritis, pharyngitis, and rhinitis was similar between zafirlukast-treated patients and placebo controls. [31] Clinically silent elevated liver enzymes have been reported in zileuton-treated patients. [32] Nausea, mild lower abdominal pain, and stomachache have also been reported in zileuton-treated patients. [33] Recently, montelukast has been shown to be beneficial in asthmatic adu1ts [34-36] and in 6- to 14-year-old asthmatic children, without causing significant adverse effects or elevating liver enzyme levels. [10]

In the present study, we retrospectively evaluated the effect of antileukotriene therapy on the relief of sinus symptoms in a group of patients with ATD. Our study showed that prior to antileukotriene therapy, all ATD patients continued to experience persistent symptoms of chronic rhinosinusitis despite having undergone sinus surgery. The benefit of antileukotriene therapy was determined by patient self-reports and by endoscopic nasal examinations during the most recent followup visit. Scores for both major and minor symptoms of chronic rhinosinusitis improved significantly after antileukotriene therapy. Most ATD patients reported an overall benefit from therapy. However, three patients who reported an overall benefit from therapy did not have a corresponding improvement in their symptom scores. One plausible explanation for this might be that our questionnaire was not sensitive enough to detect minor changes in the degree of symptoms. The self-reported effects of sinus disease on daily activities and on general health were also alleviated in some patients. Even though the endoscopic nasal examinations were not performed at the same time that the questionnaires were completed, the exam findings were consistent with the overall self-reports.

Our data do not compare any differences in the effect of the two different antileukotriene agents in our population. Larger, placebo-controlled comparison studies of all three antileukotriene agents are needed.

References

(1.) McFadden EA, Woodson BT, Fink JN, Toohill RJ. Surgical treatment of aspirin triad sinusitis. Am J Rhinol 1997;11:263-70.

(2.) Jung TT, Juhn SK, Hwang D, Stewart R. Prostaglandins, leukotrienes, and other arachidonic acid metabolites in nasal polyps and nasal mucosa. Laryngoscope 1987;97:184-9.

(3.) Smith WL, Borgeat P, Fitzpatrick FA. The eicosanoids: Cyclooxygenase, lipoxygenase, and epoxygenase pathways. In: Vance DE, ed. Biochemistry of Lipids, Lipoproteins, and Membranes. Amsterdam: Elsevier, 1991.

(4.) Fischer AR, Rosenberg MA, Lilly CM, et al. Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma. J Allergy Clin Immunol l994;94:l046-56.

(5.) Drazen JM, Austen KF, Lewis RA, et al. Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc Natl Acad Sci U S A 1980;77:4354-8.

(6.) Marom Z, Shelhamer JH, Bach MK, et al. Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro. Am Rev Respir Dis 1982;126:449-51.

(7.) Dahlen SE, Bjork J, Hedqvist P, et al. Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: In vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci U S A 1981;78:3887-91.

(8.) Hoover RL, Karnovsky MJ, Austen KF, et al. Leukotriene B4 action on endothelium mediates augmented neutrophil/endothelial adhesion. Proc Natl Acad Sci U S A 1984;81:2191-3.

(9.) Bisgaard H, Pedersen M. SRS-A leukotrienes decrease the activity of human respiratory cilia. Clin Allergy 1987;17:95-103.

(10.) Knorr B, Matz J, Bernstein JA, et al. Montelukast for chronic asthma in 6-to 14-year-old children: A randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998;279: 1181-6.

(11.) Krell RD, Aharony D, Buckner CK, et al. The preclinical pharmacology of ICI 204,219: A peptide leukotriene antagonist. Am Rev Respir Dis 1990;141:978-87.

(12.) Rubin P, Dube L, Braeckman R, et al. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase. Agents Actions Suppl 1991;35:103-16.

(13.) Carter GW, Young PR, Albert DH, et al. 5-Lipoxygenase inhibitory activity of zileuton. J Pharmacol Exp Ther 1991;256:929-37.

(14.) Knapp HR. Reduced allergen-induced nasal congestion and leukotriene synthesis with an orally active 5-lipoxygenase inhibitor. N Engl J Med 1990;323:1745-8.

(15.) Hirschberg VGS. Mitteilung uber einen Fall von Nebenwirkung des Aspirin. A case report on the side effects of aspirin. Dtsch Med Wochenschr 1902;28:416 and Allergy Proc 1990;l1:249-50.

(16.) Lockey RF, Rucknagel DL, Vanselow NA. Familial occurrence of asthma, nasal polyps and aspirin intolerance. Ann Intern Med 1973;78:57-63.

(17.) Falliers CJ. Familial coincidence of asthma, aspirin intolerance and nasal polyposis. Ann Allergy 1974;32:65-9.

(18.) Settipane GA, Pudupakkam RK. Aspirin intolerance. III. Subtypes, familial occurrence, and cross-reactivity with tartarazine. J Allergy Clin Immunol 1975;56:215-21.

(19.) Zeitz HJ. Bronchial asthma, nasal polyps, and aspirin sensitivity: Samter's syndrome. Clin Chest Med 1988;9:567-76.

(20.) Christie PE, Tagari P, Ford-Hutchinson AW, et al. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991;143:1025-9.

(21.) Smith CM, Hawksworth RJ, Thien FC, et al. Urinary leukotriene E4 in bronchial asthma. Eur Respir J 1992;5:693-9.

(22.) Kowalski ML, Sliwinska-Kowalska M, Igarashi Y, et al. Nasal secretions in response to acetylsalicylic acid. J Allergy Clin Immunol 1993;91:580-98.

(23.) Kowalski ML. Aspirin sensitive rhinosinusitis and asthma. Allergy Proc 1995;16:77-80.

(24.) Yamashita T, Tsuji H, Maeda N, et al. Etiology of nasal polyps asso-ciated with aspirin-sensitive asthma. Rhinol Suppl 1989-8:15-24.

(25.) Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Am Rev Respir Dis 1988;137:847-54.

(26.) Stevenson DD, Hankammer MA, Mathison DA, et al. Aspirin desensitization treatment of aspirin-sensitive patients with rhinosinusitis-asthma: Long-term outcomes. J Allergy Clin Immunol 1996;98:751-8.

(27.) McFadden EA, Woodson BT, Massaro EM, Toohill RJ. Orbital complications of sinusitis in the aspirin triad syndrome. Laryngoscope 1996;106:1103-7.

(28.) Kennedy DW. Prognostic factors, outcomes and staging in ethmoid sinus surgery. Laryngoscope 1992;102(Suppl 57):1-8.

(29.) Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 1995;151:1734-9.

(30.) Smith LJ, Geller S, Ebright L, et al. Inhibition of leukotriene D4-induced bronchoconstriction in normal subjects by the oral LTD4 receptor antagonist ICI 204,219. Am Rev Respir Dis 1990;141:988-92.

(31.) Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group. Am J Respir Crit Care Med 1994;150:618-23.

(32.) Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma: A randomized controlled trial. Zileuton Clinical Trial Group. JAMA 1996;275:931-6.

(33.) Rubin P, Dube L, Braeckman R, et al. Pharmacokinetics, safety, and ability to diminish leukotriene synthesis by zileuton, an inhibitor of 5-lipoxygenase. Agents Actions Suppl 1991;35:103-16.

(34.) Reiss TF, Altman LC, Munk ZM, et al. MK-0476, an LTD4 receptor antagonist, improves the signs and symptoms of asthma with a dose as low as 10mg once daily [abstract]. Am I Respir Crit Care Med 1995;151:A378.

(35.) Reiss TF, Chevinsky P, Noonan M, et al. MK-0476, an LTD4 receptor antagonist, exhibits a dose-related improvement in the once-daily treatment of patients with chronic asthma [abstract]. Eur Respir J 1995;319:289.

(36.) Reiss TF, Chevinsky P, Edwards T, et al. Montelukast (MK-0476), a cysLTl receptor antagonist, improves the signs and symptoms of asthma over a 3-month treatment period [abstract]. Eur Respir J 1996;9:273.

Type of previous sinus surgery and subsequent course of antileukotriene
therapy

    Previous                       Antileukotriene Duration of
Pt. sinus surgery                       agent      drug therapy
 1  E, [*] M, [+] S, [ss] MELP [n]   Zafirlukast      14 mo
 2  E, M, S                          Zileuton         15 mo
 3  E, M, S, OFFO [#]                Zafirlukast      14 mo
 4  E, M, S                          Zafiriukast       4 mo
 5  E, M, S                          Zafirlukast       8 mo
 6  E, M, S                          Zileuton         12 mo
 7  E, M, S, OFFO                    Zafirlukast       6 mo
 8  E, M, S                          Zafirlukast       5 mo
 9  E, M, S                          Zafirlukast      11 mo
10  E, M, S                          Zafirlukast      14 mo
11  E, M, S                          Zafirlukast       2 mo
12  E, M, S                          Zafirlukast       6 mo
13  E, M, S                          Zafirlukast      14 mo
14  E, M                             Zafirlukast      13 mo
15  E                                ZafirJukast       8 mo
16  E                                Zafirlukast      12 mo
17  E, OFFO                          Zafirlukast       1 mo
18  E, M, S                          Zafirlukast       5 mo


(*.)Bilateral ethmoidectamy
(+.)Maxillary antrostomy
(ss.)Sphenaidotomy
(n.)Modified endoscopic Lothrop procedure
(#.)Osteoplastic flap with fat obliteration
            Findings on pre- and posttreatment nasal endoscopy,
           and self-reported benefits of antileukotriene therapy

    Pretreatment               Posttreatment        Self-reported
Pt.  endoscopy                  endoscopy         benefit of therapy
 1  Edema, nasal discharge     Normal                 Slight
 2  Edema, nasal discharge     N/A [*]                Slight
 3  Edema, crusting            Crusting               Slight
 4  Nasal discharge, crusting  Normal                 Slight
 5  Nasal discharge            N/A                    Moderate
 6  Edema, erythema, crusting  Crusting               Very good
 7  N/A                        N/A                    Moderate
 8  Edema                      Normal                 Slight
 9  Edema                      Normal                 Very good
10  Edema, erythema, crusting, Normal                 Very good
     polypoid lesions
11  Edema, erythema, crusting  Erythema, crusting     Slight
12  Crusting                   Normal                 None
13  Edema, nasal discharge     Normal                 Slight
14  N/A                        N/A                    None
15  Erythema, crusting         Normal                 None


(*.)Not available.