Acute effects of antileukotrienes on sinonasal polyposis and sinusitis.

Abstract

Recently, leukotrienes have been implicated in the mediation of bronchoconstriction and inflammatory changes in asthma. Leukotriene levels have also been shown to be elevated in patients with asthma as well as in those with sinonasal polyposis and sinusitis. The leukotriene synthesis inhibitor zileuton and the leukotriene receptor antagonist zafirlukast have been shown to produce subjective and objective improvements in patients with mild to moderate asthma. Given these findings, we evaluated the efficacy of these two medications in controlling sinonasal polyposis and their associated symptoms.

We treated 40 patients diagnosed with sinonasal polyposis and sinusitis with either zileuton or zafirlukast. No other change was made in their standard therapy. Outcome measures included subjective interviews and questionnaire responses, as well as office endoscopic examinations and chart reviews.

At study's end, 36 patients were available for evaluation. Twenty-six had taken zafirlukast, five had taken zileuton, and five others had switched from zafirlukast to zileuton. Overall, 26 patients (72%) experienced subjective improvement in their symptomatology after starting their medication. Statistically significant improvement was noted with respect to headache, facial pain and pressure, ear discomfort, dentalgia, purulent nasal discharge, postnasal drip, nasal congestion and obstruction, olfaction, and fever. An objective alleviation, or at least stabilization, of sinonasal polyposis was seen in 50% of the patients. Four patients (11%) discontinued their medication because of side effects.

We conclude that antileukotrienes might play a significant role in controlling polyposis and symptoms secondary to sinonasal disease, and they might be a viable alternative to long-term oral steroid therapy and repeated surgical debridement.

Introduction

Leukotrienes are cytokines, which belong to a larger group of molecules known as eicosanoids. They are derived from arachadonic acid, a fatty acid that is attached to cell membrane phospholipids in a variety of mammalian cells. Leukotrienes have been implicated in the pathogenesis of asthma in that they cause bronchoconstriction, increase mucosal edema and mucus production, and stimulate inflammatory cell infiltration. [1-5] Furthermore, leukotriene synthesis inhibitors and leukotriene receptor antagonists have produced clinically significant improvements in patients with mild to moderate asthma. [6-11]

The etiologic factors that cause sinonasal polyposis are still unclear, but there is evidence that cell-mediated immunity might play a role in its pathogenesis. [12-14] Leukotrienes have been shown to be elevated in some patients with sinonasal polyposis, especially those in whom polyposis defies conventional modalities of treatment. [15-17] These modalities include oral and topical steroids, immune modulators such as antihistamines, and desensitization and repeated surgical debridement. Although these modalities are effective in most patients, undesirable surgical complications and adverse side effects from the long-term use of medications can occur.

No studies to date have addressed the possible role of antileukotrienes in the control of sinonasal polyposis and sinusitis. In this preliminary study, we have begun to address the use of two specific antileukotrienes, zileuton and zafirlukast, in the management of sinonasal polyposis and sinusitis.

Materials and methods

We treated 40 patients who had sinonasal polyposis and sinusitis with one of two antileukotrienes: zafirlukast (20 mg po bid) or zileuton (600 mg po qid). The choice of medication was determined by the surgeon's preference. Liver function tests were obtained on all patients 1 month following the start of medication. Patients were otherwise managed in a routine manner typical of the standard treatment for sinonasal polyposis and sinusitis, including endoscopic examinations.

Symptoms were assessed by in-person and telephone interviews as well as by questionnaire responses. In the questionnaire, patients were asked to assess the severity and duration of 22 different symptoms: sinus headache, facial pain and pressure, ear pain and pressure, toothache, clear rhinorrhea, purulent rhinorrhea, postnasal drip, nasal congestion and obstruction, olfaction, fever, fatigue, irritability, cough, sore throat, chills, myalgia, epiphora, itchy eyes, and ophthalmoplegia. Data were analyzed with the Wilcoxon matched-pairs test.

Results

Thirty-six patients were available for evaluation. They had been followed for at least 1 month while on the medication. The mean duration of medication use was 7.4 months. All patients had been diagnosed with sinonasal polyposis and chronic sinusitis. Fourteen of these patients had also been diagnosed with asthma, including two who had Samter's triad (sinonasal polyposis, asthma, and aspirin sensitivity). Twenty-six patients were prescribed zafirlukast, five were given zileuton, and five who started on zafirlukast subsequently were switched to zileuton, because of either a lack of response or adverse effects. Oral steroids had been or were being used by 26 patients. Thirty patients completed a thorough questionnaire regarding the severity and duration of sinonasal symptomatology.

Overall, 26 of the 36 patients (72%) experienced improvement in their symptomatology after starting antileukotriene therapy. No patient experienced a worsening of symptoms. The remaining 10 patients (28%) experienced no change. With respect to the two different medications, 19 of the 26 patients who started on zafirlukast experienced overall improvement (73%), while the remaining seven noticed no change. Of the five patients who were switched from zafirlukast to zileuton, two (40%) experienced improvement after the switch.

With respect to specific symptoms among the entire group, significant improvement was seen in terms of sinus headache (p[less than]0.0l), facial pain (p[less than].05), facial pressure (p[less than]0.05), ear pain and pressure (p[less than]0.0l), dentalgia (p[less than]0.05), purulent anteriornasal discharge (p[less than]0.0l), postnasal drip (p[less than]0.0l), nasal congestion (p[less than]0.0l), nasal obstruction (p[less than'(less thas [less than][less thsn]0.0l), olfaction (p[less than]0.0l), and fever (p[less than]0.0l).

There were significant improvements (p[less than]0.0l) in the duration of some symptoms-specifically, sinus headache, purulent anterior nasal discharge, postnasal drip, nasal congestion, nasal obstruction, and olfaction.

A subjective improvement in the degree of sinonasal polyposis was observed in 18 patients (50%); no change was seen in 15 (42%), and a worsening was seen in three (8%). To date, 15 of the 26 patients (58%) who had previously required oral steroids for polyp control havenot required further steroid therapy. There were no statistically significant differences in outcomes between the group of 14 patients who had asthma and the group of 22 who did not.

With respect to drug-related adverse effects, five patients reported dryness (13.9%), four patients reported headache (11%), three each reported myalgia and gastrointestinal upset (8.3%), and two each reported dizziness and nausea (5.5%). One patient each experienced lymphocytosis, increased salivation, cough, fatigue, and palpitations (2.7%). Finally, one patient reported a combination of decreased libido, improved memory, and insomnia. Four patients were forced to discontinue drug therapy because of side effects, including one patient on zafirlukast who experienced an elevation in liver enzyme levels.

Discussion

The etiology and pathophysiology of sinonasal polyposis has yet to be clearly elucidated. There is evidence that cell-mediated immunity might play a role in its pathogenesis. [11-13] There are distinctly different categories of polyps that occur in the nose and sinuses, the vast majority of which are related to allergies and asthma. A small percentage of patients has Samter's triad.

Patients with sinonasal polyposis and patients with asthma all have elevated leukotriene levels. In recent years, the significant role that leukotrienes play in the pathogenesis of asthma has been clarified. [1-5] production has been shown to constrict airway smooth muscle, increase mucosal edema via vascular leakage, and increase mucus production. Leukotrienes also stimulate the infiltration of inflammatory cells, such as eosinophils, mast cells, and basophils, in which leukotrienes are found in great concentrations. Although the role of high leukotriene levels in patients with asthma has been examined, [6-11] its role in sinonasal polyposis has not received as much attention. [15-17]

The purpose of this preliminary report is to document the progress of our ongoing investigation into the use of zileuton and zafirlukast as therapeutic options in the management of sinonasal polyposis and sinusitis.

Mechanisms of action. The synthesis of leukotrienes begins with the cleavage of arachadonic acid from cell membranes via the action of phospholipase [A.sub.2] Intracellularly, arachadonic acid is converted sequentially to 5hydroperoxyeicosatetraenoic acid (5-HPETE) and then to leukotriene [A.sub.4] ([LTA.sub.4]) by 5-lipoxygenase and 5-lipoxygenase-activating protein. [LTA.sub.4] is converted to leukotriene [C.sub.4] ([LTC.sub.4]) synthase, and is then transported into the extracellular microenvironment, where it is converted to leukotriene [D.sub.4] ([LTD.sub.4]) by the action of [alpha] glutamyltranspeptidase. A variety of dipeptidases convert [LTD.sub.4] to the last member of the chain, leukotriene [E.sub.4] ([LTE.sub.4]). [LTC.sub.4], and [LTE.sub.4] all contain cysteine and are known as cysteinyl leukotrienes (C-LTs). (Previously, these three leukotrienes were known collectively as the slow-reactive substance of anaphylaxis, which was implicated in the pathophysiology of allergy and allergic reactions). Cells known to produce and store large amounts of C-LTs are mast cells, eosinophils, macrophages, and basophils. The target receptor for C-LTs, which lead to the cascade of events that result in allergic reactions as well as airway hyperresponsiveness in asthmatics, is the cysteinyl leukotriene receptor type 1 ([CysLt.sub.1]).

Leukotriene production can be inhibited by targeting any of the enzymes along the pathway that leads to it. The only enzyme that has been successfully inhibited thus far is 5-lipoxygenase. This enzyme prevents the conversion of arachadonic acid to 5-HPETE, which is subsequently converted to [LTA.sub.4]. Another successful method of blocking the action of leukotrienes is to selectively block the receptor [CysLt.sub.1]. In our study, we used two different medications: zileuton and zafirlukast. Zileuton, a 5-lipoxygenase inhibitor, prevents the formation of leukotrienes. Zafirlukast, a [CysLt.sub.1] receptor antagonist, blocks leukotriene activity by preventing it from binding to the receptor. Although these medications have different modes of action, both prevent leukotriene activity.

Therapeutic efficacy. Our study showed that in patients with sinonasal polyposis and sinusitis, certain symptoms improved significantly after antileukotriene therapy was initiated. These symptoms were sinus headache, facial pain and pressure, ear pain and pressure, dental pain, purulent anterior nasal discharge, postnasal drip, nasal congestion, nasal obstruction, olfaction, and fever. With respect to their duration, symptoms that showed statistically significant improvement were sinus headache, purulent anterior nasal discharge, postnasal drip, nasal congestion, nasal obstruction, and olfaction.

It must be noted that in addition to being treated with antileukotriene therapy, all of these patients continued to receive routine treatment of their sinonasal disease. All patients were on nasal steroids, and some were being treated concurrently with oral steroids. However, more that half of the patients who had required oral steroids previously to control their polyps had not needed them while they were on one of the antileukotrienes. In addition, some of these patients were also being treated with antihistamines. What is significant about these two classes of medications is that both of them have been shown to decrease the levels of leukotrienes in patients with sinonasal polyposis. [18-19]

It is clear that leukotrienes play a significant role in the pathophysiology of asthma and sinonasal polyposis. It is also clear that antileukotrienes have a positive impact on the health of patients with asthma. [6-11] Our study has shown that antileukotrienes might help control the progression of polyposis in the sinonasal cavity. As mentioned, a number of our patients were taking a variety of medications that have been well established in the management of sinusitis. They include glucocorticoids and antihistamines, both of which have been observed to act as antileukotrienes to some degree. No study to date has compared these two classes of medication with respect to the potency of their antileukotriene activity in vitro or in vivo. Only time and further study will clarify these issues.

In conclusion, our study of patients who had known sinus disease associated with nasal polyps attempted to determine whether antileukotriene therapy would affect their overall disease process. Our preliminary results indicate that the antileukotrienes zileuton and zafirlukast might play a role in the management of sinonasal polyposis and sinusitis. Improvement in a number of sinusitis-related symptoms as well as the alleviation, or at least stabilization, of polyposis was seen in a significant number of patients. The safety of these medications was reflected in the low degree of morbidity. Antileukotrienes thus might provide a safe and effective option in the management of sinonasal polyposis and sinusitis, and help patients avoid the need for long-term oral steroid therapy and repeated surgical debridement.

From the Division of Otolaryngology, Albany (N.Y.) Medical College.

Reprint requests: Steven M. Parnes, MD, Albany Medical College, Division of Otolaryngology, MC-41, 47 New Scotland Ave., Albany, NY 12208. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

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