ORIGINAL ARTICLE

Anti-inammatory Properties of Montelukast, a Leukotriene Receptor Antagonist in Patients With Asthma and Nasal Polyposis
C Schper,1 O Noga,2 B Koch,1 R Ewert,1 SB Felix,1 S Glser,1 G Kunkel,2 B Gustavus2
1

Department of Internal Medicine B Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, Greifswald, Germany 2 Department of Pneumology and Infectious Diseases, Charit, University Medicine, Berlin, Germany

Abstract
Background: Leukotrienes, especially LTC4, are important inammatory mediators in allergic and nonallergic inammation of the entire airways. Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase. Objective: To examine the inuence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inammatory markers in nasal lavage uid in patients with bronchial asthma and nasal polyps, and determine its dependency on aspirin sensitization. Methods: Twenty-four patients (7 women, 17 men; median age, 55.5 years) with nasal polyps and controlled asthma (n=12 with aspirin intolerance) were treated with 10 mg montelukast once daily for 6 weeks in a blinded, placebo-controlled fashion. The placebo phase was randomly assigned 4 weeks before (n=12) or after treatment (n=12). Symptom score, rhinoendoscopy, rhinomanometry, smears for eosinophils, and nasal lavages for the determination of different mediators were performed. Results: Compared to placebo, there were signicant improvements in the nasal symptom score and airow limitation as well as a reduction in the inammatory mediators in nasal lavage uid after treatment. Furthermore, reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment. Conclusion: Leukotriene 1 receptor blockade led to a signicant decrease in eosinophil inammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage uid of patients with nasal polyps and asthma, with or without aspirin intolerance. Key words: Polyposis nasi. ASA intolerance. Leukotrienes. Eosinophils. ECP. Substance p. Neurokinin A. Montelukast. Nasal lavage.

Resumen
Antecedentes: Los leucotrienos, especialmente el LTC4, son mediadores inamatorios importantes en la inamacin alrgica y no alrgica de todas las vas respiratorias. Son de especial inters las numerosas teoras relativas a la patogenia de la intolerancia al cido acetilsaliclico, con la hiperproduccin de leucotrienos y la inhibicin de la ciclooxigenasa posteriores. Objetivo: Estudiar la inuencia de montelukast, un antagonista del receptor de cisteinil-leucotrienos, sobre los sntomas clnicos y los marcadores inamatorios del lquido de lavado nasal en pacientes con asma bronquial y plipos nasales, as como determinar su grado de dependencia de la sensibilizacin al cido acetilsaliclico. Mtodos: Veinticuatro pacientes (7 mujeres, 17 hombres; mediana de edad: 55,5 aos) con plipos nasales y asma controlada (n = 12 con intolerancia al cido acetilsaliclico) fueron tratados con 10 mg de montelukast una vez al da durante 6 semanas siguiendo un diseo ciego y controlado con placebo. La fase con placebo se asign aleatoriamente 4 semanas antes (n = 12) o despus del tratamiento (n = 12). Se llevaron a cabo la puntuacin de los sntomas, rinoendoscopias, rinomanometras, frotis para detectar eosinlos y lavados nasales para determinar los diferentes mediadores.

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Resultados: En comparacin con placebo, se observaron mejoras signicativas en la puntuacin de los sntomas nasales y en la limitacin del ujo areo, as como una reduccin de los mediadores inamatorios en el lquido de lavado nasal despus del tratamiento. Asimismo, se observ una menor cantidad de eosinlos en los frotis nasales y en la sangre perifrica 2 y 6 semanas despus del tratamiento. Conclusin: La inhibicin del receptor de leucotrienos de tipo 1 dio lugar a una disminucin signicativa de la inamacin mediada por eosinlos acompaada de una reduccin de otros mediadores como la neurocinina A y la sustancia P en el lquido de lavado nasal de pacientes con plipos nasales y asma, con o sin intolerancia al cido acetilsaliclico. Palabras clave: Poliposis nasal, intolerancia al AAS, leucotrienos, eosinlos, ECP, sustancia P, neurocinina A, montelukast, lavado nasal.

Introduction
Airway inammation incorporates pathophysiological processes that lead to variant forms of airow limitation and rhinitis, which occur frequently and impair quality of life [1,2]. In this context, leukotrienes (LTs) are important mediators of upper and lower airway inammation [3,4], promoting inammatory cell recruitment and the production of different cytokines and stimulating airway remodeling and mucus secretion [3]. Despite a great deal of scientic progress, the complex interplay of existing pathways in airway inammation is not completely understood. This interplay includes concepts of neurogenic inammation [5] that focus on inammation caused by neuropeptides such as substance P and neurokinin A, the role of neurotrophins such as nerve growth factor or brain-derived neurotrophic factor in airway inammation [6,7], and the interaction of these pathways with LTs. Polyposis nasi is a common disease with unknown etiology [8]. There is essentially no therapy available with long-term effects, and only corticosteroids are suitable and helpful as a long-term strategy. Several studies have demonstrated the antiinammatory properties of corticosteroids, with decreases in eosinophils, eosinophil cationic protein (ECP), interleukin 5 (IL-5), vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1) [9]. However, the local application of steroids is not sufcient in most cases, hence the need for oral corticosteroids. This therapy, however, is limited by the undesired actions of these drugs. In some patients with asthma, aspirin (acetylsalicylic acid, ASA) and all nonsteroidal anti-inammatory drugs (NSAIDs) that inhibit the cyclooxygenase enzymes cox-1 and cox-2 trigger asthmatic attacks and naso-ocular reactions. This clinical syndrome is characterized by eosinophilic inammation of nasal and bronchial tissue, often associated with nasal polyps, combined with an increased release of cysteinyl-LTs (CysLTs). LTC4 synthetase is markedly overexpressed in eosinophils and mast cells from bronchial biopsy specimens of most patients treated with ASA. Avoiding NSAIDs does not prevent the progression of inammation, and corticosteroids continue to be the mainstay of therapy; however, anti-LT drugs are also indicated for the treatment of this underlying disease [10]. Nasal polyposis (NP) can also be described as a chronic

inammatory disease of the upper respiratory tract leading to the production of edematous polyps in the nasal cavities which are responsible for persistent nasal obstruction [11,12]. NP is a common disease that is normally treated by surgical intervention, and symptoms improve in more than 85% of cases [13]. The surgical removal of polyps, however, is often only a short-term solution since the recurrence rate of eosinophilic polyps is extremely high, especially in untreated ASA-sensitive patients [14]. The etiology of NP is not yet completely understood. Only corticosteroids are suitable as a long-term treatment strategy; they are helpful in 50% of patients, leading to decreased symptoms and lower recurrence rates. However, recurrence rates still range from 3% to 10%. NP is frequently combined with bronchial asthma (25%-30% of cases) or ASA intolerance [8,15,16]. The triad of ASA intolerance, bronchial asthma, and polyposis nasi (Sampter syndrome) is well-known in the literature [3]. LTs and prostaglandins are products of arachidonic acid metabolism, and are key mediators in acute and chronic inammatory diseases of the airways [17,18]. In ASA-intolerant patients, the 5-lipoxygenase pathway is activated, most likely in mast cells, leading to the rapid production of LTs [19]. CysLTs mediate inammatory and contractile processes through specific interaction with cell surface receptors belonging to the G protein-coupled receptor family. Pharmacological studies have identied 2 classes of CysLT receptors: CysLT1 receptors and CysLT2 receptors. While CysLTs can function as agonists for both types of receptors, CysLT1s are expressed in leukocytes, in the lung, and in airway smooth muscle [20]. LTC4 and D4 are 1000-fold more potent than histamine [21]. LT modiers such as the CysLT1 receptor antagonist montelukast are a relatively new class of anti-inammatory drugs, with increasing applications in areas such as asthma therapy [22]. Besides the mast cell, the eosinophil granulocyte is the key cell for acute allergic, late-phase and nonspecic chronic inammation. Eosinophils are the main source of LTs [23]. The aim of this study was to examine the inuence of the CysLT receptor antagonist montelukast on the clinical symptoms and markers of nasal lavage in neurogenic and eosinophil inammation in patients with bronchial asthma and nasal polyps, and its dependency on ASA sensitization.

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Materials and Methods

Study Design This study had a single-blind, randomized, placebocontrolled, crossover design. Ten mg of montelukast was given once daily in the evening for 6 weeks. The placebo phase was 4 weeks either before (Group 1) or after (Group 2) montelukast treatment. The patients visited the clinic every 2 weeks. All visits were scheduled between 8 AM and 10 AM. Symptom scores and peak ow data for nasal and bronchial symptoms were documented on diary cards every morning and evening. The nasal symptom scores were calculated as 2-week mean values. Nasal airway function and clinical examination were performed at baseline and after every 14 days of treatment. Short-acting 2-agonists were not used for at least 8 hours before lung function testing. All participants gave informed consent and the study was approved by the local ethics committee. Patients Twenty-four patients (17 men), with a median age of 55.5 years (range, 32-66 years), were enrolled. They all had nasal polyps and mild to moderate asthma. Six patients in each group (group 1 and 2) also had clinically documented ASA intolerance. Asthma was diagnosed by history, physical examination, and lung function testing (Body-Lab II, Erich Jaeger, Wrzburg, Germany), bronchial challenge with inhaled acetylcholine, and bronchial reversibility with inhaled salbutamol (0.2 mg). Allergy with rhinitis or asthma was diagnosed by history. Sensitivity was conrmed by a skin prick test (SPT) for the most common inhalant allergens (house dust mites, animal allergens, and grass, tree, and herb pollen) performed at baseline. Additionally, specic serum immunoglobulin (Ig) E (CAP class, 1; Pharmacia CAP System) and total IgE (Pharmacia Diagnostics, Uppsala, Sweden) were measured. All patients had previously undergone sinus surgery and had a long history of nasal polyposis. Exclusion Criteria Excluded from the study were pregnant and nursing women and patients who had used local anti-inammatory or antiallergic drugs (eg, corticosteroids, antihistamines, or disodium cromoglycate) in the 3 weeks prior to enrolment, oral corticosteroids in the last 6 weeks, or polypectomy in the last 6 months. No patient was on immunotherapy. All the patients were nonsmokers, and none had any systemic disease. Inhaled steroids (ICS) and bronchodilators were allowed, but the ICS dosage was kept stable during the trial and changes in short-acting 2-agonist consumption were documented. Clinical Symptoms Patients were instructed to record their nasal and pulmonary symptoms on diary cards daily throughout the trial period. The clinical score for the major nasal symptoms included obstruction, sneezing, itching, rhinorrhea, quality of

smell, and pulmonary symptoms related to dyspnea, quality of sputum, and cough. Additionally, 2-agonist consumption was recorded. The severity of symptoms was graded on a 4-point scale based on the difculty of tolerating the symptoms and interference with daily activities and sleeping. The number of sneezes within the last 12 hours was counted and transformed into a score, with 0, 0 sneezes; 1,1-4 sneezes; 2, 5-9 sneezes; and 3, 10 sneezes. The total nasal symptom score of 0 to 12 was calculated by adding these scores for each patient. The rhinoscopic examination was performed by the same physician at baseline and after treatment to conrm nasal blockage, rhinorrhea, and irritation on a 4-point rating scale (0, absent; 1, mild; 2, moderate; and 3, severe). Within the study design rhinorrhea was estimated by signs of hypersecretion at the moment of examination, nasal blockage was judged by local congestion of the nasal mucous membranes, and irritation was dened as an increased local hyperemia of nasal mucous membranes. Rhinomanometry To analyze the degree of nasal airway obstruction, nasal peak inspiratory ow (cm/s) and nasal airway resistance (expressed in Pa/[cm/s]) were measured by anterior rhinomanometry (Rhinotest MP 500; Allergopharma Joachim Ganzer KG, Reinbeck, Germany) of each nostril, calculated at a pressure of 150 Pa, with merging of values from the left and right nostril. Repeated measurements were performed and the mean of 5 values was recorded provided the coefcient of variation was less than 5%. Olfactometry The quality of smell was tested with a modied olfactometric test containing different aromas. The test included odor discrimination and threshold for each nostril. The results achieved were merged to a 4-point score of 0, normal smell; 1, mild impaired smell; 2, moderate impaired smell; and 3, no smell. Nasal Lavage Procedure Nasal lavage (NAL) was performed by instilling 5 mL of sterile saline (preheated to 37C) into each nasal cavity using a tube connected to a syringe inserted into the foam rubber-closed nostril. After 10 seconds, each uid sample was collected by repeated aspiration from both nasal cavities and the surface of the inferior turbinate and placed in polypropylene tubes, which were immediately placed on ice. After centrifugation at 1000 g for 10 minutes at 4C and removal of cellular elements, the supernatants were aliquoted for the different assays and stored at 80C until analysis. The recovery of aspirated lavage uid was 868%. Assessment of Mediators Assessment of nasal lavage and measurement of CysLTs, soluble ICAM-1 (sICAM-1), human serum albumin (HSA), and ECP were performed as described previously [24]. The peptides SP and NKA were measured with highly specic competitive commercial enzyme-linked immunosorbent

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(ELISA) kits in 50 L of lavage uid in duplicate. SP (Cayman Chemical; Ann Arbor, Michigan, USA) was measured to pg/mL of lavage uid (minimal detectable concentration, 7.8 pg/mL). NKA (Peninsula Laboratories, INC. Belmont, California, USA) was similarly measured to ng/mL of lavage fluid (minimal detectable concentration, 0.06-0.08 ng/mL). Nasal Cytology Nasal smears were taken from the inferior turbinate following lavage using a cotton wool swab dampened with physiological saline. The sampled cells were transferred to glass slides by gentle rolling and air-dried overnight. Eosinophils stained by the May-Grnwald-Giemsa technique were counted from smears by the differentiation of 100 cells, and the results were expressed as a percentage of total cell count. All specimens were examined by the same microscopists and 2 investigators in a blinded fashion. Blood Samples Blood samples were taken for differential counts (of absolute eosinophil and leukocyte numbers) before and at the end of each study period. Lung Function Spirometry (Body-Lab II) was performed at baseline, after 2 and 6 weeks of treatment with montelukast, and after 4 weeks on placebo. Peak-ow measurements (mini-Wright; Clement Clarke, Harlow, UK) were measured twice daily in the morning (AM peak expiratory ow [PEF], 8 AM-10 AM) and evening (PMPEF, 6 PM-8 PM) in triplicate before medication, and the best effort was documented by the patients on their diary cards. Statistical Analysis Data are expressed as meansSEM or as median and range. Clinical scores and concentrations of cysLTs, ECP, substance P, neurokinin A, sICAM-1, histamine, and albumin in NAL uids, and eosinophil counts were compared using the Wilcoxon signedrank test (pretreatment/posttreatment), and treatment versus placebo was compared using the Mann-Whitney U test. A value of P<.05 was considered signicant. The variables from the patients diary cards were calculated as 2-week averages of daily values during the treatment period, at baseline, and at the end of the placebo phase. Differences in sex, atopy and ASA intolerance were examined by the Fisher exact test. The Spearman correlation coefcient (r) was calculated to analyze possible correlations between pairs of parameters, with signicance set at P<.05. Statistical tests were performed using SPSS/PC, version 16.0 (SPSS Inc. Chicago, USA).

(9 men) with a median age of 54.5 years (range, 32-65 years) were included in Group I; 4 of the patients had atopy. In Group II, there were also 12 patients (8 men); the median age was 57.5 years (range, 35-66 years) and 6 of the patients had atopy. In each group, 6 patients had ASA intolerance. Group I started with a 4-week placebo phase and continued with 6 weeks of montelukast treatment while group II started with treatment and continued with placebo. Nasal Symptoms The overall nasal symptom scores during treatment with montelukast showed a signicant reduction in all areas (P<.05). The improvement started in the rst 2 weeks and remained signicant throughout the active treatment phase compared to the placebo phase. During montelukast treatment, the mean scores decreased from 1.8 to 0.6 for nasal blockage, from 1.5 to 0.6 for rhinorrhea, and from 0.6 to 0.25 for itching. In a similar manner, the quality of smell improved from 2.0 to 0.3 and the total symptom score improved from 5.9 to 1.75 (P<.001). No signicant changes in symptoms were observed during the placebo period. Rhinoscopical Findings There was a signicant reduction in edema, hypersecretion, blockage, and total symptom score under treatment, as measured by mean scores at baseline and after 6 weeks of treatment (Figure 1). Rhinomanometry Nasal airway ow increased signicantly (P<.01) during montelukast treatment compared to placebo (Figure 2). Mediator Levels in NAL Fluid Mean NAL uid concentrations of SP, NKA, cysLTs, ECP, and albumin decreased signicantly compared to baseline levels during treatment with montelukast, whereas no such changes were observed during the placebo period (Table 1). The baseline values of both groups showed no signicant differences; there were also no differences between either of the 2 treatment groups or either of the 2 placebo groups (data not shown). Eosinophils Signicant reductions in eosinophils in nasal smears and peripheral differential blood were seen during the treatment phase after 2 and 6 weeks (Figure 3) (P<.01), whereas these values remained unchanged during the placebo phase. Lung Function

Results
Clinical Data All 24 patients completed both treatment periods, and no adverse effects were observed during the trial. Twelve patients

The improvement in lung function was maintained over the 6-week period, as shown by spirometry recorded at the clinic visits and by daily peak ow recordings at home (Table 2). At the end of the 6 weeks of treatment, there was a trend (not signicant) of a 5% increase in forced expiratory volume in the rst second (FEV1) (mean increase, 0.2 L).

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A
2 1.8 1.6 1.4 Score 1.2 1 0.8 0.6 0.4 0.2 0 Baseline 6 w ML Placebo

C
2

1.8 1.6 1.4 Score 1.2 1 0.8 0.6 0.4 0.2 0 Baseline 6 w ML

Placebo

2 1.8 1.6 Score

6 5 4 Score

1.4 1.2 1 0.6 0.4 Baseline 6 w ML Placebo

*
2 1 0 Baseline 6 w ML Placebo

Figure 1. A, Secretion score measured by anterior rhinoscopy; baseline vs 6 weeks (6 w) of treatment vs placebo. B, Irritation score measured by anterior rhinoscopy; baseline vs 6 weeks of treatment vs placebo. C, Obstruction score measured by anterior rhinoscopy; baseline vs 6 weeks of treatment vs placebo. D, Total symptom score measured by anterior rhinoscopy; baseline vs 6 weeks of treatment vs placebo. *P<.05 baseline vs treatment group (Wilcoxon test). #P<.05 treatment group vs placebo (Mann-Whitney U test). 700 600 Flow [ccm/s; Pa150] 500 400 300 200 100 0 Baseline 6 w ML Placebo Figure 2. Nasal airway ow (ccm/s) at a pressure of 150 Pa; baseline vs 6 weeks (6 w) of treatment vs placebo. **P<.01 baseline vs treatment group (Wilcoxon test). ##P<.01 treatment group vs placebo (MannWhitney U test). ## ** Table 1. Mediator Concentrations Measured in Nasal Lavage Fluida Baseline (Groups I/II) (n=24) SP, pg/mL NKA, ng/mL cICAM-1, ng/mL ECP, ng/mL CysLTs, pg/mL HSA, g/mL 36.310.1 1.20.3 0.80.1 46.922 12032 40.46.1 MLPT (Groups I/II) (n=24) 13.93.1** 0.200.1*** 0.660.1*** 9.14.2** 54.314.4* 20.14.3** Placebo (Groups I/II) (n=24) 34.88.5## 2.00.7## 0.920.1## 29.813## 105.324.6# 48.77.3

Abbreviations: cICAM, circulating intercellular adhesion molecule-1; CysLTs, cysteinyl-leukotrienes (LTC4, LTD4, LTE4); ECP, eosinophil cationic protein; HSA, human serum albumin; MLPT, montelukast posttreatment; NKA, neurokinin A; SP, substance P. a Data are shown as meansSEM. * P<.05; ** P<.01; *** P<.001. Baseline vs treatment group (Wilcoxon test). # P<.05; ## P<.01. MLPT vs placebo (Mann-Whitney U test).

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25 20 Eosinophils NAL, % 15 * 10 5 0 Baseline 2 w ML 6 w ML *

Daily use of 2-agonists was signicantly reduced with montelukast treatment compared to placebo. There was also a signicant improvement in pulmonary symptoms and PEF (Table 2) after 6 weeks of treatment. No significant differences in signs, symptom scores, endoscopic ndings, or mediator concentrations were found between patients with ASA intolerance and those without, regardless of whether they had started with montelukast or placebo rst. Additional statistical tests made with subgroups showed that the results obtained were not due to the sequence of participation in the different groups (data not shown).

Placebo

Discussion
The observed decrease in inammatory mediators (LTs, ECP, sICAM-1, and neuropeptides) and HSA in NAL and the reduction in eosinophils in nasal smears in the present study indicate the ability of montelukast to reduce inammatory mediators and cell migration in the nose. The onset of action is prolonged, with the maximum therapeutic effect seen after 6 weeks of treatment. These improvements are probably based on the control of nasal polyp inammation and possibly of polyp growth. The anti-inammatory effect of montelukast observed in our study was accompanied by signicant improvements in nasal symptoms, nasal airway ow, lung function parameters (FEV1 % of predicted not signicant, PEF) and pulmonary symptoms. The above results indicate that monotherapy with the leukotriene1-receptor antagonist montelukast is an effective treatment for patients with polyposis nasi. The results are compatible with earlier reports in patients with bronchial asthma or aspirin triad disease. Dahlen et al [25] showed in a double-blind, placebo-controlled study that the 5-lipoxygenase inhibitor Zileuton, given at 600 mg once daily for 6 weeks, decreased pulmonary and especially nasal symptoms, supporting the theory that LTs are the main inammatory mediators in this disease. In the present study, there were no

0.8 0.7 Eosinophils/nL Blood 0.6 0.5 0.4 0.3 0.2 0.1 0 Baseline 2 w ML 6 w ML Placebo * * #

Figure 3. Eosinophils in nasal lavage (NAL) uid as a %; baseline vs 2 weeks (2 w) of treatment with 10 mg montelukast (ML) once daily (OD) vs 6 weeks of treatment with 10 mg ML OD vs placebo; *P<.05 baseline vs treatment group (Wilcoxon test); #P<.05 treatment group vs placebo (Mann-Whitney U test). B, Eosinophils in blood per nL; baseline vs 2 weeks of treatment with 10 mg ML OD vs 6 weeks of treatment with 10 mg ML OD, vs placebo; *P<.05 baseline vs treatment group (Wilcoxon test); #P<.05 treatment group vs placebo (Mann-Whitney U test).

Table 2. Lung Function Tests and Peak Expiratory Flow Measurementsa Group Baseline Montelukast 2 wk FEV1, % predicted FEV1, L PEF, L/min Ib IIc Ib IIc Ib IIc 88.111.6 87.49.8 3.41.0 3.00.9 436122 46299 9210.5 90.19.3 3.50.8 3.10.8 490150 500100 6 wk 93.112.2 918 3.60.9 3.20.8 510102d 50991d 2 wk 87.611.4 86.19.2 3.30.8 2.90.8 484122 456111 Placebo 4 wk 87.811.2 85.79.6 2.90.8 2.80.8 476113 447110

Abbreviations: FEV1, forced expiratory volume in the rst second; PEF, peak expiratory ow. a Data are shown as meansSEM. b Placebo for 4 weeks followed by montelukast for 6 weeks (10 mg once daily). c Montelukast for 6 weeks (10 mg once daily) followed by placebo for 4 weeks. d P<.05; Wilcoxon test, baseline vs 6 weeks treatment.

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differences between patients with or without ASA intolerance. In the study by Dahlen et al, nasal symptoms signicantly improved compared to placebo, with increasing improvement noted over the 6-week study period [25]. Parnes et al [26] reported that 26 (72%) of 36 patients with nasal polyps treated with zarkulast or zileuton experienced a signicant improvement in nasal symptoms. Ragab et al [27], in turn, demonstrated that an additional three months of montelukast therapy combined with intranasal and inhaled corticosteroids produced subjective and objective improvements in nasal symptoms and function as well as signicant improvements in lung function in patients with nasal polyposis, with or without ASA intolerance. In our study, we only saw an improvement in peak ow values after 6 weeks of therapy. The reduction in 2-agonist use and improvement in asthma symptoms and FEV1 (none of which were signicant) varied between 1% and 15% for the variables recorded and might be explained by successful asthma treatment before the add-on therapy with montelukast. However, our study extends previous observations by examining inflammatory components that contribute to eosinophil accumulation in nasal polyps such as cysLTs, sICAM-1, and neuropeptides such as substance P. The pathophysiology of nasal polyps is still not completely understood, although a number of contributing factors have been proposed including recurrent infections, allergies, ASA intolerance, and genetic factors [16]. Bachert et al [28] found, along with elevated IL-5, ECP, and eotaxin, increased amounts of albumin in polyp tissue compared to normal nasal mucosa; the combination was proposed as a matrix phenomenon responsible for polyp formation. The authors, however, were unable to name specic mediators as the pathophysiological facilitators behind polyp formation. In our study, the neurogenic component via the release of the neuropeptides SP and NKA was signicantly reduced. This can be explained by the reduced release of neuropeptides by LTs from c-sensory nerve bres and reduced local eosinophil inammation with a consequent reduction in the release of SP or NKA or reduced release from peripheral cells such as eosinophils or mast cells. These ndings predominantly explain the clinical improvements observed in terms of reduced nasal blockage, secretions, and itching as well as improved smell, all objectively evaluated by anterior rhinoscopy, olfactometry, and rhinomanometry. Furthermore, in bronchial asthma an additional effect of bronchodilatation was observed. The reduction in cysLTs in NAL after therapy with montelukast is probably the main reason for the improved nasal airow noted, as in human studies, increased nasal blood ow has been seen after intranasal challenge with LTs [29]. The decreased levels of cysLTs, ECP, and HSA in the NAL uid as well as the reduction in eosinophils with the improvement of nasal symptoms show the importance of these mediators and cells in the pathophysiology of nasal polyps. CysLTs promote eosinophil recruitment in the airways, and eosinophils, in turn, release these LTs. Montelukast indirectly leads to a decrease in LT concentration in the airways by reducing mucosal leakage, with a subsequent reduction in eosinophil migration and LT and ECP formation [3,4]. The reduction of eosinophils by montelukast could be due to a

reduction in transendothelial eosinophil migration, a shortening of eosinophil survival, or a combination of both; this question remains to be answered in further studies. In the post-montelukast placebo period, the benecial effect was reversed. We were unable to nd any predictive parameter for responsiveness to montelukast. The results of the present study show that various components in nasal polyp inammation are affected by montelukast. Receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in mediators linked to neurogenic inammation in the NAL uid of patients with nasal polyps and asthma, with or without aspirin intolerance. The improved symptoms, the rhinoscopic ndings, and the bronchial/nasal ow demonstrate clinical relevance and emphasize a potential role of montelukast in nasal polyposis.

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Manuscript received April 9, 2010; accepted for publication, June 28, 2010.

Christoph Schper

Department of Internal Medicine B Friedrich-Loefer-Str. 23a 17475 Greifswald, Germany E-mail: [email protected]

J Investig Allergol Clin Immunol 2011; Vol. 21(1): 51-58

2011 Esmon Publicidad