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(Chest. 2006;130:1726-1732.)
© 2006 American College of Chest Physicians

Improvements in Distal Lung Function Correlate With Asthma Symptoms After Treatment With Oral Montelukast*

Monica Kraft, MD, FCCP; Charles B. Cairns, MD; Misoo C. Ellison, PhD; Juno Pak, BS; Charles Irvin, PhD and Sally Wenzel, MD, FCCP

* From the Departments of Medicine (Dr. Kraft) and Surgery (Dr. Cairns), Duke University Medical Center, Durham, NC; the Department of Medicine (Drs. Ellison and Wenzel, and Mr. Pak), National Jewish Medical and Research Center, Denver, CO; and the Department of Medicine (Dr. Irvin), University of Vermont Medical Center, Burlington, VT.

Correspondence to: Monica Kraft, MD, FCCP, Associate Professor of Medicine, Duke University Medical Center, MSBR M201D, Durham, NC 27710; e-mail: Monica.Kraft{at}duke.edu

Abstract

Study objectives: The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy. We hypothesized that treatment with montelukast, an oral cysteinyl-leukotriene receptor antagonist, would improve both proximal and distal lung physiology in patients with mild asthma.

Design: Randomized, double-blind, crossover design.

Setting: Academic referral center.

Patients: Subjects with mild asthma limited to using short-acting inhaled ß2-agonists.

Interventions: Nineteen subjects with mild asthma underwent a baseline assessment of lung function, lung mechanics, and symptoms, followed by randomization to therapy with montelukast, 10 mg taken in the evening, or placebo in a crossover, double-blind fashion. Each treatment phase lasted 4 weeks, with a 2-week washout period. A repeat evaluation was performed during the last week of each treatment phase.

Measurements and results: Montelukast resulted in improvement in (mean ± SD) proximal and distal lung function parameters (change in FEV1: montelukast, 0.16 ± 0.06 L; placebo, –0.05 ± 0.05 L; p = 0.008); change in specific conductance: montelukast, 7.2 ± 2.9% predicted; placebo, –17 ± 8% predicted; p = 0.007; change in % predicted residual volume [RV]: montelukast, 18.4 ± 8.3% predicted; placebo, 3.0 ± 2.9% predicted; p = 0.05). Improvement in symptoms (ie, wheeze and chest tightness) correlated with improvements in RV while receiving montelukast, but not while receiving placebo (Pearson coefficients: 0.55 and 0.66, respectively; p < 0.008 and 0.04, respectively).

Conclusions: The systemically acting oral agent montelukast improves proximal and distal lung physiology. Improvements in distal lung function correlate with improvements in asthma symptoms.

Key Words: asthma • distal lung • montelukast • pulmonary physiology • residual volume

In patients with mild, moderate, and severe asthma, the distal lung has been shown to be an active area of inflammation.123 Distal inflammation has been demonstrated pathologically in specimens obtained by bronchoscopy with transbronchial biopsy in subjects with chronic asthma with significant inverse correlations observed between alveolar tissue eosinophil levels and FEV1.23 While the inverse correlation between the number of eosinophils per volume of alveolar tissue and the percentage of overnight fall in FEV1 has been reported as –0.54,2 the FEV1 is generally considered a measure of large and small airway physiology such that this association may not entirely explain the physiologic impact of small airway inflammation.4 In addition to inflammation, data suggest that the distal lung also undergoes remodeling, as demonstrated by the reduced elastin fiber content and abnormal alveolar attachments, with the latter thought to result in a loss of elastic recoil and a reduction in FEV1.5

Montelukast, a systemically delivered leukotriene receptor antagonist, is used in the treatment of asthma.67 It has been shown to improve symptoms and lung function, and is administered orally, hence systemically. While the improvements in FEV1 are generally modest (6 to 10%), asthma symptoms and quality of life appear to be improved to a greater degree with montelukast administration than is FEV1.89 There has been speculation about whether symptom improvement with the systemic delivery of montelukast could be due to systemic effects on both the small and large airways.10 In this study, we hypothesized that the disparity in the magnitude of improvement in FEV1 vs symptoms seen with montelukast therapy may be due to its impact on measures of distal lung function.

Materials and Methods

Subjects
Nineteen subjects 18 to 60 years of age with asthma, as defined by the American Thoracic Society,11 were recruited for the study. Subjects were required to have had a diagnosis of asthma for at least 6 months, to demonstrate an increase in FEV1 or FVC of ≥ 200 mL and 12% after receiving therapy with an inhaled bronchodilator, or to have a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of < 8 mg/mL. In addition, they were required to demonstrate a residual volume (RV) of ≥ 140% predicted. The RV was selected to evaluate the effect of montelukast on air trapping, as Kraft and colleagues12 demonstrated that the RV was highly correlated with peripheral airways resistance (Rp) and suggested that it could be used as a surrogate for distal lung disease in asthma patients. The conditions of asthmatic patients were maintained with inhaled ß2-agonists only. Exclusion criteria included the use of oral or inhaled corticosteroids, leukotriene receptor antagonists, cromolyn, nedocromil, or theophylline preparations within 4 weeks of study, the use of long-acting inhaled or oral ß2-agonists within 48 h of the study, a smoking history of > 5 pack-years, any cigarette use within the last year, or significant concomitant illness. All subjects signed an informed consent form that was approved by the National Jewish Medical and Research Center Institutional Review Board.

Protocol
Subjects underwent a baseline physiologic assessment, which included spirometry, and the measurement of lung volumes and lung mechanics. Subjects were then entered into the crossover treatment trial if the above inclusion criteria were met. Subjects were randomized to receive either montelukast, 10 mg orally in the evening, or placebo for 4 weeks in a double-blind crossover fashion, with a 2-week washout period between treatment phases. During each treatment phase, subjects kept a diary of their symptoms, rating cough, chest tightness, wheeze, shortness of breath (SOB), and sputum production each morning and evening by employing a scale of 0 to 3, as previously described.13 A physiologic assessment was performed at the end of weeks 1 and 4 of each treatment phase.

Lung Mechanics and Lung Volumes
Prior to the determination of lung volumes and lung mechanics, subjects underwent esophageal balloon placement. The balloon (10 cm long and filled with 0.5 mL of air) was passed into the lower portion of the esophagus. Initial positioning was determined by the presence of a maximal pressure swing with a minimal cardiogenic artifact, as previously described, and was assessed by the occlusion test.14 To control for volume history, two large total lung capacity (TLC) breaths preceded the pressure-volume (PV) determination.

The PV curve was obtained while the patient was seated in a body plethysmograph by asking the subject to slowly inhale from functional residual capacity (FRC) or thoracic gas volume (TGV) to TLC, and then slowly back down to RV. During this breathing cycle, a shutter was briefly closed (approximately 1 s) after panting at a frequency just under 1 Hz. The plateau pressure was selected to determine static PV characteristics, including the coefficient of retraction (ie, maximal pressure/TLC ratio) and upstream resistance, with the latter calculated as the initial slope of the relationship between maximal expiratory flow and lung static recoil pressure.1415 If the shutter was closed above functional residual capacity, this was adjusted for end-expiratory volume. A determination of TGV using esophageal pressure allowed for the relation of PV characteristics to absolute lung volume. The upstream resistance, a measure of small airway caliber, was determined as the pressure difference between the alveoli and the equal pressure point (ie, alveolar pressure – pleural pressure) that is required to produce a maximum flow of 1 L/s (expressed in centimeters of H2O per liter per second). It was calculated by evaluating a plot of elastic recoil pressure and the maximum expiratory flow rate (V max) at lung volumes below 60% of the vital capacity as elastic recoil pressure/maximum expiratory flow rate ratio.16

Three to four technically acceptable maneuvers were performed, and the values were averaged. After the PV maneuver, plethysmographic measurements of airway resistance (expressed as the reciprocal of airway resistance corrected for lung volume, or specific conductance [sGaw]), lung volumes, and spirometry were measured in triplicate. The TLC was calculated by the sum of TGV – ERV + IVC (where ERV is expiratory reserve volume, and IVC is inspiratory vital capacity). The mean airway resistance and lung volumes with the best FEV1 were used for the following analysis. All expiratory times were at least 6 s, and an acceptable plateau was reached according to the recommendations of the European Respiratory Society and the American Thoracic Society.17

Statistical Analysis
Data are presented as the mean ± SD. In order to compare the effects of montelukast and placebo on the changes in lung function and lung mechanics, a linear mixed-effects model was utilized to evaluate carryover, sequence, and treatment effects.18 Because we were interested in increases or decreases from the steady state, (ie, changes from the baseline measurements), we examined the change in each variable for each treatment period between the randomization visit (or the visit immediately following the 2-week washout period) and the visit occurring after 4 weeks of treatment. Asthma symptoms were correlated with changes in pulmonary function using the Pearson correlation analysis comparing subjects while receiving montelukast and while receiving placebo. Carryover effects were tested at a 10% significance level, and sequence/treatment effects were tested at the 5% significance level. All data analyses were carried out using a statistical software package (SAS; SAS Institute, Inc; Cary, NC).

Results

Subjects
Nineteen subjects met inclusion criteria, and their baseline characteristics are presented in Table 1 . The subjects were considered to have mild asthma when FEV1 was 83% predicted, TLC was 107% predicted, and the geometric mean of the PC20 was 0.79 mg/mL.


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  		Table 1. Subject Characteristics*

 
Lung Physiology
See Table 2 for a summary of lung function studies prior to each treatment period and the change with montelukast and placebo, respectively. The p values represent a comparison between the change in the variable while the patient was receiving montelukast vs the change in the same variable while they were receiving placebo. The change in FEV1 was significant, decreasing by 0.05 ± 0.5 L while patients was receiving placebo and improving by 0.16 ± 0.06 L while they were receiving montelukast (p = 0.008). With regard to lung volumes, the change in percent predicted RV while patients were receiving montelukast was also significant compared to patients receiving placebo, increasing by 3.06 ± 3.8% predicted while they were receiving placebo and decreasing by 18.68 ± 8.41% predicted while they were receiving montelukast (p = 0.05 for the change in percent predicted RV). The absolute RV also decreased, but this change only trended toward statistical significance (p = 0.075). The absolute and percent predicted sGaw improved significantly while patients were receiving montelukast (p = 0.006 and 0.007, respectively, for the change in absolute and percent predicted sGaw).


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  		Table 2. Lung Function Studies With Montelukast and Placebo*

 
Despite their relatively small impairments in FEV1 and lung volumes, these patients with mild asthma demonstrated significant abnormalities in the coefficient of retraction and elastic pressure at 100% of TLC (Table 2). The reduction in these values below 80% predicted suggests a loss of elastic recoil. Upstream resistance was also elevated, which is indicative of increased small airway resistance, as the normal range is 1.5 to 3.0 cm H2O/L/s.16 There were no clinically significant improvements in PV variables after montelukast therapy.

Symptom Assessment
Treatment with montelukast significantly improved morning and evening wheeze (p = 0.0016 and 0.04, respectively), morning SOB (p = 0.02), and evening cough compared to treatment with placebo (p = 0.03).

Correlations of Physiology and Symptoms
The change in absolute RV during treatment with montelukast correlated significantly with changes in morning wheeze and chest tightness, with Pearson correlation coefficients of 0.66 and 0.55, respectively (p = 0.008 and 0.04, respectively) [Fig 1 ]. In contrast, the improvements in the FEV1, FEV1/FVC ratio, and sGaw did not correlate with an improvement in symptoms. There were no significant correlations with asthma symptom changes and changes in sGaw.


Figure 1
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  		Figure 1. Scatterplots depicting correlations between the change in RV vs the changes in morning chest tightness, wheezing, and SOB while the patient is receiving placebo (top left, A, middle left, C, and bottom left, E) and montelukast (top right, B, middle right, D, and bottom right, F). Pearson correlations were as follows: top left, A: r = 0.2, p = 0.41; top right, B: r = 0.55, p = 0.04; middle left, C: r = 0.28, p = 0.28; middle right, D: r = 0.64, p = 0.008; bottom left, E: r = 0.17, p = 0.52; bottom right, F: r = 0.51, p = 0.06.

 
Discussion

This study demonstrates that therapy with montelukast significantly improves asthma symptoms as well as physiology in both the proximal and distal lung compartments. The improvement in more proximal lung physiology is reflected by improvements in sGaw, while the distal lung compartment improvements are perhaps best reflected by a reduction in RV. The FEV1, a global measure of airway function, reflects the physiology of both the proximal and distal lung compartments, the conditions of which were also improved with montelukast therapy. Despite the improvement in large airway physiology reflected by improvements in FEV1 and sGaw, a unique finding of this study was the improvement in RV that correlated significantly with symptom improvement.

The mechanism driving the improvement in proximal and distal lung function with montelukast therapy is not known, but cysLT1 receptors have been reported by Evans19 to be present in both the large and small airways. Given the systemic delivery of montelukast, delivery to the proximal and distal lung compartments is expected. With regard to corticosteroids, Hauber and colleagues20 evaluated the effect of flunisolide hydrofluoroalkane (HFA) on proximal and distal airway inflammation in asthma as determined by bronchoscopy specimens obtained with endobronchial and transbronchial biopsies. They demonstrated that treatment with flunisolide HFA improved inflammation in both compartments, presumably due to improved distal lung delivery, as particle size is significantly decreased with HFA preparations. FEV1 also improved, but improvements in lung volumes and symptoms with flunisolide HFA were not assessed. Furthermore, Mansell and colleagues21 demonstrated that whole-lung allergen challenge resulted in increased airways resistance and RV. The authors hypothesized that mucosal edema and serous transudation in addition to bronchospasm can lead to airways obstruction and air trapping. It is possible that the addition of montelukast therapy, with its anti-inflammatory effects delivered systemically, can produce physiologic benefits in both lung compartments in asthma patients.

The significant relationship between improvement in asthma symptoms and distal lung physiology suggests that this region of the lung is important in asthma pathobiology, and is not always well reflected by changes in the FEV1. Studies demonstrating an improvement in asthma exacerbations without significant changes in FEV1 have been reported.2223 In addition, we have shown that lung volumes correlate with distal lung inflammation,24 suggesting that improvements in distal lung inflammation can improve airway physiology as represented by lung volumes instead of the FEV1. Wagner and colleagues,25 employing a wedged bronchoscopic technique, measured Rp directly, and found it to be elevated in patients with mild asthma who had normal spirometry findings; the conductance (1/Rp) correlated with bronchial hyperresponsiveness. These investigators also demonstrated that significantly more histamine was required in healthy subjects to cause a 100% increase in Rp (log PC100) than in asthmatic subjects.25 In asthmatic subjects, the log PC100 correlated with whole-lung responsiveness to histamine (r = 0.847; p < 0.05). Kraft and colleagues12 extended these observations by demonstrating that the direct measurement of peripheral resistance via bronchoscopy in asthmatic subjects directly correlated with the RV.12 Clearly, the FEV1 is an important measurement in asthma patients, but we suggest that it does not provide complete information on the physiologic dysregulation associated with asthma. We suggest that lung volumes may be a better surrogate for distal lung inflammation.

This investigation also demonstrated that subjects with mild asthma exhibit a significant loss of elastic recoil, a phenomenon that is usually associated with emphysema and, more recently, with more severe asthma.26 Lung elastic recoil measurements such as pulmonary static elastic recoil pressure, the transpulmonary pressure at TLC, have traditionally been able to distinguish asthma from COPD.27 More recent studies have raised doubts concerning this distinction, as several investigators have reported282930 a loss of elastic recoil in asthma patients, particularly in those with severe asthma. Lung recoil is thought to be a property of the lung parenchyma, which is a cable and membrane-tensed structure with major forces borne at the air-liquid interface, but with a contribution from septal elastin. Mauad and colleagues5 have reported reduced elastin fiber content in the distal lung in asthma patients. Moreover, they demonstrated abnormal alveolar attachments in the airways of patients with fatal asthma, and hypothesized that this mechanism was responsible for the loss of elastic recoil in patients with asthma and emphysema. If this is indeed the mechanism responsible for loss of recoil, such structural changes would not be expected to improve with therapy with antiinflammatory agents such as montelukast, which was used in this study. However, air trapping due to small airway inflammation and edema, as hypothesized by Mansell and colleagues,21 could be improved with the administration of a systemic antiinflammatory agent such as montelukast, as was seen in this study.

Conclusion

In summary, we determined that the systemic delivery of montelukast, at doses used clinically for the treatment of asthma, improved proximal and distal lung function in patients with mild asthma, particularly in those patients with evidence of air trapping, as demonstrated by an increase in RV. These improvements in distal lung function correlated significantly with improvements in asthma symptoms. This finding may explain why, in the face of modest FEV1 improvements with montelukast therapy, symptoms improve and exacerbations decrease.10 We suggest that both proximal lung function (sGaw) and distal lung function (lung volumes) should be incorporated into future asthma intervention trials to better assess the site and mechanism of physiologic improvements.

Footnotes

Abbreviations: HFA = hydrofluoroalkane; PC20 = provocative concentration of methacholine causing a 20% fall in FEV1; PV = pressure-volume; Rp = peripheral airways resistance; RV = residual volume; sGaw = specific conductance; SOB = shortness of breath; TGV = thoracic gas volume; TLC =total lung capacity

This research was supported by Merck, Inc.

Drs. Kraft, Irvin, and Wenzel have served as speakers and consultants for Merck, Inc. Dr. Cairns received salary support and has been a speaker for Merck, Inc. Dr. Ellison and Mr. Pak have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication January 11, 2006. Accepted for publication June 14, 2006.

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