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(Chest. 2003;124:1334-1340.)
© 2003 American College of Chest Physicians

Effect of Montelukast on Exhaled Nitric Oxide and Nonvolatile Markers of Inflammation in Mild Asthma*

Alessandra Sandrini, MD; Ivone M. Ferreira, MD, PhD; Carlos Gutierrez, MD, PhD; Jose R. Jardim, MD, PhD; Noe Zamel, MD, FCCP and Kenneth R. Chapman, MD, MSc, FCCP

* From the Asthma & Airway Centre of the Toronto Western Hospital (Drs. Sandrini, Ferreira, Gutierrez, Zamel, and Chapmen), Division of Respiratory Medicine, University Health Network, University of Toronto, Toronto, ON, Canada; and the Respirology Division (Dr. Jardim), Universidade Federal de Sao Paulo, Escola Paulista de Medicina, Sao Paulo, Brazil.

Correspondence to: Kenneth R. Chapman, MD, MSc, FCCP, Asthma and Airway Centre of The University Health Network, Suite 4–011 ECW, 399 Bathurst St, Toronto, ON, Canada M5T 2S8; e-mail: kchapman{at}ca.inter.net


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Leukotriene receptor antagonists appear to exert anti-inflammatory activity in asthma. We undertook the present study to evaluate the effect of montelukast on levels of exhaled nitric oxide (ENO) and two inflammatory markers, hydrogen peroxide (H2O2), and cysteinyl leukotrienes (cys-LTs), in the exhaled breath condensate of subjects with mild asthma.

Patients: Twenty stable subjects with mild asthma (15 women and 5 men; mean [± SD] age, 34.8 ± 12.6 years) were included in the study.

Intervention: A 1-week run-in period was followed by 2 weeks of treatment (with montelukast or placebo) that was administered in randomized, double-blind, crossover fashion. One week of washout followed each treatment arm.

Results: Montelukast significantly reduced the levels of ENO from baseline (median, 52.5 parts per billion [ppb]; 25th to 75th percentile, 37.8 to 101.8 ppb) during the entire treatment period (ie, day 1 to day 14), with the effect measurable as early as day 1 (median, 45.9 ppb; 25th to 75th percentile, 29.3 to 92.5 ppb) and with the maximal effect being observed on day 7 (median, 35.7 ppb; 25th to 75th percentile, 27.6 to 66.6 ppb). The levels of ENO did not change significantly with placebo therapy. Montelukast improved symptom score and reduced peak expiratory flow (PEF) variability. Changes in PEF variability correlated positively with changes in ENO (r = 0.46; p = 0.04). No significant changes in FEV1 or concentration of H2O2 in the exhaled breath condensate were observed. Levels of cys-LTs were undetectable in the exhaled breath condensate.

Conclusions: We concluded that montelukast reduces the levels of ENO in patients with mild asthma, a finding that is compatible with an anti-inflammatory effect of montelukast, and that ENO appears to be more sensitive in detecting this effect than FEV1 and H2O2 levels in the exhaled breath condensate.

Key Words: asthma • breath tests • hydrogen peroxide • leukotriene antagonists • leukotrienes • nitric oxide


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Nitric oxide is an important mediator of the inflammatory response in the airways. Levels of nitric oxide (NO) from the lower airways can be measured noninvasively in the exhaled breath (ie, exhaled NO [ENO]) by means of chemiluminescence. ENO levels are elevated in asthmatic patients compared to healthy nonasthmatic volunteers.1 2 The ENO level rises further during deterioration in asthma control3 4 and is reduced by corticosteroid therapy.2

Other nonvolatile metabolic products and inflammatory mediators present in the airways can be detected noninvasively through the collection and analysis of the exhaled breath condensate. Hydrogen peroxide (H2O2) is an important reactive oxygen metabolite that is considered to be a marker of oxidative stress and inflammation. It is formed by spontaneous or enzyme-catalyzed dismutation of superoxide anions (O2-), which are released by activated inflammatory cells such as macrophages, eosinophils, and neutrophils. H2O2 levels are increased in the exhaled breath condensate of adults5 6 and children7 with asthma and seem to decrease with inhaled steroid therapy.8 Cysteinyl leukotrienes (cys-LTs) are inflammatory mediators that are involved in airway inflammation in asthma patients.9 The levels of cys-LTs have been shown to be elevated in BAL fluid,10 urine,11 plasma,12 sputum,13 and, more recently, also in the exhaled breath condensate14 of patients with asthma. These substances are generated by a number of different inflammatory cells, including eosinophils, mast cells, and macrophages.

Leukotriene receptor antagonists (LTRAs) appear to exert anti-inflammatory effects in asthma patients, as it has been shown that they reduce the number of eosinophils in the bronchial mucosa,15 sputum,16 and blood,16 17 and reduce the number of lymphocytes and basophils in BAL fluid.18 More recently, one of these compounds, montelukast, has been shown to produce effects on airway remodeling in an animal model study.19 Thus, the main aim of this study was to determine whether montelukast reduces ENO levels in adults with mild asthma. Secondarily, we evaluated the effects of montelukast on two other noninvasive markers of inflammation, cys-LTs and H2O2 in the breath condensate.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects between the ages of 18 and 65 years who had asthma, as defined by the American Thoracic Society (ATS), were recruited. The study protocol was reviewed and approved by the University Health Network Research Ethics Board. All participants gave written informed consent. All participants were using inhaled, short-acting ß2-adrenergic agonists exclusively and had FEV1 values of >= 70% of predicted after ß-agonist therapy was withheld for at least 6 h. All participants had demonstrated either a > 12% improvement in FEV1 following the inhalation of 400 µg salbutamol or airway hyperresponsiveness to methacholine (ie, a provocative concentration of methacholine causing a 20% fall in FEV1 of <4 mg/mL) within the previous year and had ENO levels >= 20 parts per billion (ppb). None of the participants studied had received oral, nasal, inhaled, or IM corticosteroids during the preceding month, nor had they received any other treatment for asthma apart from inhaled short-term ß2-agonists. None of the patients had had asthma exacerbations or upper respiratory tract infections in the previous month. Current smokers or ex-smokers of more than 10 pack-years and patients with FEV1 of < 70% predicted were excluded. Other respiratory diseases or a history of life-threatening asthma also were considered to be exclusion criteria.

Study Design
After a screening visit (visit 1) and a 1-week run-in period when symptoms and peak expiratory flow (PEF) measurements were registered in a symptom and PEF card, patients were reevaluated (visit 2), and eligible patients were allocated in a randomized, double-blind, placebo-controlled fashion to two 2-week treatment periods with montelukast (10 mg daily) or matching placebo, with each treatment being followed by 1 week of washout. The tablets were taken in the evening, and visit 2 was considered to be the initial day of the first treatment arm. No other asthma medication, other than short-term ß2-agonists, was allowed during the study. ENO measurements were performed during visit 1 and visit 2 (baseline), on the 1st, 2nd, 7th, and 14th days of treatment periods (ie, visits 3, 4, 5, 6, 10, 11, 12, and 13), and on the 1st, 2nd, and 7th days of washout periods (ie, visits 7, 8, 9, 14, 15, and 16). Breath condensate collections and prebronchodilator and postbronchodilator spirometry were performed during all visits except visits 4 and 11. The measurements taken on the last day of washout period 1 were considered to be the baseline levels for the second treatment arm. The symptom scores, and frequency of ß2-agonists use, and the morning and evening PEF measurements were recorded continuously during the study. All visits were made at the same time of day. Compliance was assessed by the evaluation of the number of pills left in the bottles at the end of each treatment arm.

Measurements
The measurements of ENO were performed according to ATS recommendations, using an expiratory flow rate of 0.046 L/s.20 The exhaled breath condensate was collected using a commercial apparatus (Cryocond; Boehringer Ingelheim; Burlington, ON, Canada) that cools and freezes the exhaled air to -30°C while patients breathe at tidal volume, wearing nose clips, for 5 min. Frozen samples were stored at -70°C. H2O2 was measured as described previously.21 Cys-LTs were measured with a specific enzyme immunoassay (Cayman Chemical; Ann Arbor, MI). Spirometry was performed after ENO measurement and breath condensate collection using ATS standards.

Statistical Analysis
Repeated-measures analysis of variance and repeated-measures analysis of variance on ranks were used to compare variables by day, and within each treatment arm for normally distributed and nonnormally distributed variables, respectively. Factorial analysis was performed for interactions (ie, period, drug, and order). Post hoc analysis using Dunnet or Tukey tests was performed to isolate the different subgroup (day or week). Paired t test and Wilcoxon signed rank test were used for comparisons of differences between the treatments. The Spearman correlation coefficient was used to test the correlation between changes in exhaled NO levels over the course of treatments, and the clinical and functional response parameters. Values were expressed as the mean (± SD) and the median (25th to 75th percentile) for normally and nonnormally distributed variables, respectively.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Twenty subjects (15 women and 5 men; mean age, 34.8 ± 12.6 years) were enrolled and completed the study. All participants were never-smokers, except for one participant who had smoked 1 pack of cigarettes per day for 8 years (ie, 8 pack-years) and had not smoked during the last 12 years. Twelve subjects received placebo, and 8 subjects received montelukast in the first treatment arm. There were six missing visits in total, all due to nonasthma reasons. No interaction for order of treatment was found for any variable, supporting the fact that the no-carry-over effect had occurred. Baseline characteristics did not differ significantly between the two treatment arms for all variables and are summarized in Table 1 .


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  		Table 1. Baseline Measurements*

 
ENO
The median (25th to 75th percentile) values of ENO before, during, and after placebo and montelukast treatment are summarized in Table 2 . Montelukast treatment resulted in a significant reduction of ENO levels from day 1 of treatment to the last day of treatment (day 14), and the levels of ENO remained lower in comparison to baseline during the washout period. The maximal effect was observed on day 7, with a median difference from baseline for montelukast of -11.3 ppb (25th to 75th percentile, -16.8 to -4.6), and for placebo of a median difference of 1.5 (25th to 75th percentile, -1 to 9.9; p = 0.005). Changes in median ENO levels from baseline are shown in Figure 1 . There was a nonsignificant increase in ENO levels on the first day of washout in comparison with the last day of montelukast treatment. There was no significant change in ENO levels with placebo treatment.


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  		Table 2. ENO Levels Before, During, and After Each Treatment*

 


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  		Figure 1. Changes in median ENO levels from baseline during and after treatments. D = day of treatment; W = day of washout.

 
Analysis of the Breath Condensate
The mean (± SD) of H2O2 concentrations in the breath condensate before, during, and after placebo and montelukast treatment are shown in Table 3 . No significant changes in the concentration of H2O2 were detected with montelukast or placebo treatment.


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  		Table 3. Concentration of H2O2 in the Exhaled Breath Condensate Before, During, and After Treatments*

 
The levels of cys-LTs in the breath condensate were below the detection limit of the immunoassay kit (ie, 13 pg/mL) and therefore could not be detected for most of the samples.

FEV1, PEF, Asthma Symptoms, and Requirement for Short-term ß2-Agonists
Peak flow and peak flow variability values (as maximum amplitude percentage) were averaged from the 7-day records. There was no significant change in FEV1 and in morning or night PEF values during montelukast treatment. Peak flow variability fell significantly in the second week of treatment with montelukast (baseline, 3.17 ± 2.9%; week 1, 2.37 ± 1.8%; week 2, 1.42 ± 1.4%; p < 0.05). Daytime, nighttime, and total symptom scores (ie, nighttime + daytime symptom scores) were summed for each week of the study. A significant decrease in median total symptom score was observed in the first week of treatment with montelukast (baseline, 2 [25th to 75th percentile, 1 to 6.5]; week 1, 0.5 [25th to 75th percentile, 0 to 1.5], p < 0.05; week 2, 1 [25th to 75th percentile, 0 to 3]; week 3, 1.5 [25th to 75th percentile, 0 to 3]). No significant changes in relief medication use were detected with montelukast treatment. No changes in FEV1, PEF values, PEF variability, symptom scores, or use of relief medication were observed with placebo.

Relationship Among Changes in ENO, PEF, and Symptom Scores
A positive correlation between the decrease in ENO in the second week of treatment and the decrease in PEF variability in the same period was detected (r = 0.46; p = 0.04) [Fig 2 ]. No significant correlation between changes in ENO and changes in symptom scores were observed.



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  		Figure 2. Correlation between changes in ENO and in PEF variability from baseline during the second week of montelukast treatment (p = 0.04).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have shown that montelukast reduces the levels of ENO in patients with mild asthma, a finding that is compatible with an anti-inflammatory effect of this compound on the airways of patients with asthma. Corroborating our findings, previous studies also have demonstrated evidence of anti-inflammatory effects of LTRA based on their inhibitory effects on ENO. Bratton et al22 have demonstrated that treatment with montelukast for 4 weeks decreased on average the levels of ENO by approximately 33% in children with mild-to-moderate asthma. Our study described more precisely than previous studies the time course of such changes. Montelukast significantly reduced the levels of ENO from the first day of treatment, with the maximal effect occurring on the seventh day (median change, 22%), a fall that is similar to that seen with inhaled budesonide (800 µg twice daily) within 7 days of therapy.23 Similarly, Bisgaard et al24 have demonstrated that ENO levels are reduced by 20% after 2 weeks of treatment with montelukast in children with well-controlled asthma. In that study, the reduction in ENO levels persisted beyond the period of active treatment, which is similar to our own observation, with the ENO remaining below baseline during the 2-week washout period. Although we did not detect a carryover effect, levels of ENO that were lower than baseline persisted during the washout period. It is possible that the anti-inflammatory effect of montelukast persisted beyond the active treatment period. A longer washout period would have been helpful to determine when the ENO levels return to baseline after montelukast treatment.

The nonsignificant rise in ENO on the first day of washout could possibly represent a rebound phenomenon, but there are no data in the literature suggesting that LTRAs cause rebound effects on lung function, on clinical parameters, or on airway inflammation. Therapy with glucocorticoids reduces the levels of ENO without evidence of rebound following their withdrawal.2 3 23 25 Not all studies of LTRA therapy in asthma patients have shown an effect on ENO.26 Yamauchi et al26 have demonstrated that although pranlukast significantly reduced the percentage of sputum eosinophils, it did not have a major effect on ENO. Methodological differences might explain the contrast between those findings and ours. Yamauchi et al26 used nasal clips during ENO measurement, a technique that encourages the contamination of gases exhaled from the lower airway by NO-rich gases from the nasal cavity. The high mean baseline ENO levels (280.3 ± 41.39 ppb) reported by the authors, despite the high flow rate used to measure ENO (250 mL/s), support this assumption. The study was small (10 subjects) and also may have lacked sufficient power to detect an effect of pranlukast on ENO levels. Wilson and colleagues27 did not detect changes in ENO when montelukast was administered as add-on therapy in comparison with salmeterol in subjects with moderate asthma who had been treated with inhaled steroids. All subjects in this study were receiving at least 400 µg per day inhaled budesonide, and there was, therefore, little room for a decrease in ENO with montelukast therapy.27 We did not detect significant changes in the concentration of H2O2 in breath condensate following montelukast therapy, despite the fact that our patients had increased H2O2 concentrations in their exhaled breath condensate in comparison to normal values obtained previously in our laboratory.28 This lack of change might be a consequence of the mildness of the asthma in our patients. Studies have shown a correlation between asthma severity and H2O2 in breath condensate6 as well as an effect of inhaled corticosteroids8 on H2O2 levels in patients with moderate disease. The lack of detection of cys-LTs in the breath condensate in our study also might be related to the mildness of the asthma. A previous report14 has shown that cys-LT levels are increased in the breath condensate of subjects with moderate and severe disease, and is very close to the detection limit in subjects with mild asthma. The development of more sensitive methods for measuring cys-LTs in the breath condensate is needed.

In our study, changes in ENO occurred relatively quickly, and we must therefore note the possibility that the changes were the result of bronchodilation rather than reduced airways inflammation. We think it is unlikely that changes in airway caliber account for the changes in ENO that we measured. We were unable to detect changes in FEV1 despite a rapid and marked decrease in ENO levels. Therefore, we believe that changes in ENO levels with montelukast therapy likely reflect changes in airway inflammation rather than simply the relief of airways obstruction. ENO appears sensitive to changes in airway inflammation that are not detected by conventional measures of lung function, such as FEV1, in patients with mild asthma. Given the rapidity of ENO response following the initiation of montelukast therapy, it is tempting to speculate that the measurement of ENO could serve as an early indication of responsiveness to oral antileukotriene therapy in clinical practice. ENO has been suggested29 to be a better marker of control of disease than a marker of severity of asthma. More recently, the concept of ENO being a good marker of loss of control in asthma patients has been strengthened by a longitudinal study.4 Because our patients had mild, well-controlled disease, their baseline PEF variability, requirement for bronchodilators, and symptom scores were low. Despite that, we detected significant improvements in the diurnal variability of PEF and in symptom scores. The improvement in PEF variability correlated with the decrease in ENO levels. The exact relationship between PEF variability and airway inflammation remains to be clarified. Previous studies have demonstrated correlations between PEF variability and ENO30 31 and other markers of inflammation, such as sputum eosinophils,32 suggesting that PEF variability might reflect the underlying inflammation present in asthma patients. Thus, a decrease in airway inflammation resulting from montelukast therapy might be reflected by a decrease in PEF variability. It is possible that the changes in PEF variability with montelukast therapy mirror changes in airway hyperreactivity. However, airway reactivity was not an outcome variable in our study, and the relationship between airway hyperresponsiveness and PEF variability during asthma treatment is poorly defined. Further longitudinal studies evaluating the relationship between changes in PEF variability and bronchial responsiveness with LTRA treatment may be useful.

In summary, we have shown that montelukast therapy decreases the levels of ENO in patients with mild asthma, an effect that is evident as early as 1 day following treatment onset and persisting for <= 1 week following treatment cessation. Montelukast reduced peak flow variability and symptom scores in these patients with mild disease but had no discernible effect on FEV1 and on H2O2 concentration in breath condensate. The measurement of ENO appears to be a more sensitive outcome variable than conventional measures of lung function to detect the impact of LTRA therapy in patients with mild asthma.


   Acknowledgements
 
The authors thank the research coordinator Laura Cleland for her advice and regulatory help during the study, Jeffery. H. Tong for his technical assistance with the cys-LT analysis, and Rudolf Vogl for his technical advice during the H2O2 analysis.


   Footnotes
 
Abbreviations: ATS = American Thoracic Society; cys-LT = cysteinyl leukotriene; ENO = exhaled nitric oxide; H2O2 = hydrogen peroxide; LTRA = leukotriene receptor antagonists; NO = nitric oxide; PEF = peak expiratory flow; ppb = parts per billion

This study was made possible by a grant from CAPES, Brazil (to Dr. Sandrini) and by a research grant from Merck-Frosst Canada Inc.

Received for publication August 14, 2002. Accepted for publication May 16, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 737 - 741.
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