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(Chest. 2002;122:1566-1570.)
© 2002 American College of Chest Physicians

Correlation Between Cysteinyl Leukotriene Release From Leukocytes and Clinical Response to a Leukotriene Inhibitor*

Takeshi Terashima, MD, PhD; Kazuhisa Amakawa, MD; Akiko Matsumaru, PhD and Kazuhiro Yamaguchi, MD, PhD, FCCP

* From the Department of Internal Medicine (Drs. Terashima and Matsumaru), Tokyo Dental College, Ichikawa General Hospital, Chiba; and Department of Internal Medicine (Drs. Amakawa and Yamaguchi), School of Medicine, Keio University, Tokyo, Japan.

Correspondence to: Takeshi Terashima, MD, PhD, Department of Internal Medicine, Tokyo Dental College, Ichikawa General Hospital, 5-11-13, Sugano, Ichikawa, Chiba, 272-0824, Japan; e-mail: terasima{at}tdc.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Antileukotriene drugs are widely used in patients with bronchial asthma, but not all patients show significant clinical improvements, and no factors have been identified that are correlated with the clinical response to these drugs. This study was designed to examine the factors correlated with a response to a leukotriene receptor antagonist, pranlukast, in patients with asthma.

Design: WBC counts, IgE, and ex vivo leukotriene release from leukocytes were measured, and 31 patients with asthma were treated with pranlukast, a leukotriene receptor antagonist, for 4 weeks.

Measurements: Outcome measurements included twice-daily peak expiratory flow rate (PEFR), daytime and nocturnal symptoms, and frequency of ß2-agonist use. Subjects with a reduction of > 20% in symptom scores or ß2-agonist use, or an improvement of PEFR of > 10% were designated as responders; others were designated as nonresponders. Logistic regression analysis assessed the efficacy of models using various allergic markers correlated with the response to pranlukast.

Results: There were 16 responders and 15 nonresponders. The release of cysteinyl leukotrienes from the leukocytes of the responders was higher than that of the nonresponders (p < 0.05). There was a significant correlation between the clinical response and the release of cysteinyl leukotrienes, but not demographic features, WBC counts, percentage of eosinophils, or serum IgE levels (p < 0.05). Subjects with a release of cysteinyl leukotrienes of > 3,500 pg/mL were 11.0 times more likely to respond to pranlukast than those with < 3,500 pg/mL (95% confidence interval, 2.0 to 60.5).

Conclusion: Cysteinyl leukotriene release from leukocytes is correlated with leukotriene receptor antagonist response.

Key Words: bronchial asthma • cysteinyl leukotrienes • leukotriene receptor antagonist • pranlukast


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The role of cysteinyl leukotrienes (leukotriene C4, D4, and E4) in bronchial asthma has been clearly established. These leukotrienes are produced and released from proinflammatory cells, including eosinophils and mast cells, and are at least 1,000 times more potent bronchoconstrictors than histamine or methacholine in normal subjects and patients with asthma.1 2 3 4 Leukotrienes mediate many of the pathophysiologic processes associated with asthma, including microvascular leakage, bronchoconstriction, and eosinophil recruitment into the airways.5 6 Since the structure of leukotrienes was described in 1979,7 considerable effort has been made to develop drugs that block leukotriene receptors or inhibit synthesis of leukotrienes. Challenge studies using a number of leukotriene receptor antagonists have shown that leukotrienes play an important part in the early and late responses to bronchoconstriction induced by inhaled antigen8 9 and exercise.10

Four oral antileukotriene drugs are now available for the treatment of asthma: montelukast, zafirlukast, and pranlukast, and a 5-lipoxygenase inhibitor, ziluton. Clinical studies11 12 have shown improvements of FEV1, improvements in daytime and nocturnal asthma symptom scores, and reductions in reliever ß2-agonist use in patients with asthma treated with antileukotriene drugs. The 1997 Expert Panel Report 2 listed antileukotriene drugs as possible alternatives to inhaled corticosteroids as the preferred therapy for the treatment of adult patients with mild persistent asthma.13 Considerable new evidence is available that likely broadens the indications for their use. However, studies14 15 16 17 18 indicate that not all patients treated with an antileukotriene drug will have a significant clinical improvement, and no factors have been identified that reliably predict the clinical response to these drugs, including age, atopic state, or urinary leukotriene excretion. As with any new drug treatment, it is imperative to have clinical follow-up 2 to 4 weeks after initiating therapy. We postulated that the ex vivo release of cysteinyl leukotrienes from peripheral blood obtained from asthmatic patients would have a correlation with the response to antileukotriene drugs. To test the hypothesis, blood samples were obtained from asthmatic patients before treatment with pranlukast. Clinical response was assessed by an improvement of peak expiratory flow rate (PEFR), ß2-agonist use, and asthma symptom scores.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Thirty-one adults with stable asthma were recruited from Tokyo Dental College, Ichikawa General Hospital (mean age, 41.4 years; range, 18 to 60 years). All subjects had a history of episodic dyspnea with wheezing, and a documented increase in FEV1 of > 20%, either spontaneously or after inhalation of ß2-agonist. None of the subjects had other pulmonary or cardiovascular diseases. None of the subjects had respiratory tract infections or exacerbations of asthma for at least 4 weeks before the study or during the period of the study. All of the subjects were nonsmokers. Thirteen patients had extrinsic asthma and showed elevated specific IgE antibodies in the serum. Eighteen patients had intrinsic asthma with no history of allergic disease and no elevated levels of specific IgE antibodies. All patients continued their usual asthma treatments, inhaled corticosteroids, oral theophylline, oral ß2-agonists, and concomitant medications, throughout the course of the study. The protocol was approved by the ethics committee of Tokyo Dental College. All patients gave informed, written consent before participating in the study.

Study Measurements
Blood samples were obtained during an observation period before the trial. Total serum IgE levels and specific IgE antibodies were measured using fluorescence-enzyme immunoassay. WBC and differential counts were determined from Coulter counter leukocyte measurements (model SE-9000; Sysmex; Kobe, Japan) and manual differential counting by personnel who were unaware of the status of subjects from whom the samples were obtained.

Release of Cysteinyl Leukotrienes From Peripheral Blood
Two milliliters of ethylenediamine tetra-acetic acid blood were taken from each patient by venipuncture. Leukocytes were isolated by dextran sedimentation of the whole blood for 90 min at room temperature. The leukocyte concentration range in the final assay was 1 to 2 x 106/mL. The leukocytes in the upper layer of the dextran sedimentation were centrifuged (1,500 revolutions per minute for 15 min at 4°C) and resuspended in 2 mL of stimulation buffer (Buhlmann Laboratories; Allschwil, Switzerland) containing 10 ng/mL of interleukin-3. Two hundred microliters of the leukocyte suspension was stimulated with 50 µL of high-affinity IgE receptor antibody (Buhlmann Laboratories), which binds to domain 1 on the {alpha} subunit of the high-affinity IgE receptor. After a 40 min incubation at 37°C, the supernatants were recovered from centrifuged samples (3,000 revolutions per minute for 5 min at 4°C), and then stored at - 80°C. The detection of cysteinyl leukotrienes was performed by enzyme-linked immunosorbent assay according to the protocol of the manufacturer (Buhlmann Laboratories). The sensitivity of the assay was 100 pg/mL. The monoclonal antibody used in the present assay detected leukotriene C4, D4, and E4.

Protocol
Subjects provided complete medical histories and underwent physical examinations and baseline measurements for safety assessments 4 weeks before the trial. Patients received a peak flowmeter (Vitalograph; Buckingham, UK) and a practice diary card at the prestudy visit. The patients were issued a diary card and asked to record asthma symptoms and measures for a 4-week pretrial period. This included twice-daily entries of three PEFR measurements, ß2-agonist usage, and the severity of symptoms, if any. In addition, a 4-point scale was used to assess the severity of cough, wheeze, and breathlessness: 0 = absence of symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms; the maximal total score was 9. Patients measured their PEFR at home twice daily with a peak flowmeter, before the morning dose and after the evening dose of their medication. Each time, three values were recorded, and the highest value was used on the diary card. Each inhalation of ß2-agonist was also recorded on the diary card, and the number of puffs of rescue ß2-agonist was totaled each day. The average from the last week before the trial served as the baseline value. The patients were then prescribed pranlukast, 225 mg bid, for 4 weeks, and they continued to record asthma symptoms and measures. The efficacy of pranlukast was evaluated from the results of symptom assessments, rescue ß2-agonist use, and home PEFR measurements. The average from the last week of the 4-week treatment period with pranlukast served as the posttreatment value. Responders were defined as patients who had either a reduction of > 20% in their symptom score, a reduction of > 20% in their use of ß2-agonist, or an improvement of PEFR > 10% mean change from baseline value; others were classified as nonresponders.15

Statistical Analysis
Demographic data from the responders and the nonresponders were compared by {chi}2 analysis. Clinical data before and after treatment were compared by paired t tests. Laboratory data and the ex vivo release of cysteinyl leukotriene from the responders and nonresponders were analyzed with the Mann-Whitney rank-sum test. Logistic regression analysis assessed the efficacy of models using various allergic markers correlated with response to pranlukast. A p value of < 0.05 was considered statistically significant. Analyses were performed with statistical software (SAS Software, 2nd Edition; SAS Institute; Cary, NC).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There was a reduction (> 20%) in the asthma symptom scores in 13 patients, a decrease (> 20%) in ß2-agonist use in 12 patients, and an increase (> 10%) in PEFR in 16 patients after 4 weeks of pranlukast treatment. None of the subjects reported any adverse reaction to pranlukast. The sex ratio and mean age of the responders were not significantly different from those of the nonresponders. The demographic features (atopic or nonatopic, aspirin-sensitive or not) were similar in the two groups (Table 1 ). No differences among the groups were found in the percentage of patients receiving various medications, including inhaled corticosteroids.


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  		Table 1.. Patient Demographics and Asthma Characteristics*

 
The severity of asthma at baseline was similar in the two groups (Table 2 ). There was no significant difference in mean symptom scores, rescue ß2-agonist inhaler use, and PEFR in the two groups. All patients in the two groups were symptomatic at baseline. The PEFR (mean ± SEM) was 269 ± 23 L/min (69.6 ± 3.9% of the best PEFR) in the responders and 265 ± 24 L/min (70.7 ± 4.1% of the best PEFR) in the nonresponders.


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  		Table 2.. Baseline Clinical Data*

 
Mean asthma symptom scores, rescue ß2-agonist inhaler use, and PEFR improved in the responders, but not in the nonresponders (Table 3 ). In the responders, PEFR improved to 339 ± 24 L/min (82.1 ± 2.9% of the best PEFR). In the nonresponders, the improvement was small and not significantly different compared with the baseline value.


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  		Table 3.. Clinical Data After Treatment*

 
The ex vivo release of cysteinyl leukotrienes from the leukocytes of the responders was significantly higher than that from the nonresponders (p < 0.05; Table 4 ). Among the responders, there was no significant relationship between the amount of cysteinyl leukotrienes and the degree of the improvement. Serum IgE levels, WBC counts, and percentage of eosinophils and basophils at baseline were not significantly different between the responders and the nonresponders.


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  		Table 4.. Baseline Laboratory Data*

 
Logistic regression analysis was used to compare the correlation with the response to pranlukast. We classified the subjects into two groups according to age, WBC counts, percentage of eosinophils, serum IgE levels, and the ex vivo release of cysteinyl leukotrienes (Table 5 ). The ex vivo release of cysteinyl leukotrienes, but not age, WBC counts, percentage of eosinophils, or serum IgE levels, had a significant correlation (p < 0.05). Subjects who had an ex vivo release of cysteinyl leukotrienes of > 3,500 pg/mL were 11.0 times more likely to respond to pranlukast than those with < 3,500 pg/mL (95% confidence interval, 2.0 to 60.5; p < 0.05).


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  		Table 5.. Demographic Features and Laboratory Data Correlated With Clinical Response to Pranlukast

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study shows for the first time, that the clinical response to pranlukast is correlated with an elevated ex vivo release of cysteinyl leukotriene from leukocytes. Furthermore, we show that age, total WBC counts, percentage of eosinophils, percentage of basophils, and serum IgE had no correlation, consistent with previous reports.14 15 16

The relatively low percentage of responders to pranlukast (52%) was similar to previous reports8 10 18 and emphasizes the importance of predicting responders. Furthermore, the degree of clinical response in our study ranged from no improvement to an increase in PEFR of 40%. These results agree with other studies in asthmatics that reported variable improvement in FEV1 by leukotriene D4-receptor antagonist10 or 5-lipoxygenase inhibitor.17 Possible explanations for the observed variability include variability in the efficacy of pranlukast, or genetic polymorphisms in pathway receptors. We propose, however, that the asthma of the responders may be predominantly mediated by cysteinyl leukotriene pathways, whereas the asthma of the nonresponders may be provoked by other mediators such as histamine.19 However, even the nonresponders showed a small but clinically insignificant response to pranlukast, which suggests that cysteinyl leukotriene pathways may play some role in these asthmatics also.

There were no significant interactions between concomitant use of other medications and clinical response or the release of cysteinyl leukotrienes from leukocytes ex vivo in our study. This result is similar to those of a clinical study using montelukast that reported similar improvements of FEV1 with or without inhaled corticosteroids.12 The effects of corticosteroids on the release of leukotrienes are controversial. It has been observed that in vitro treatment of stimulated human eosinophils decreased leukotriene C4 synthesis.20 Plasma levels of leukotriene E4 were decreased during oral corticosteroids treatment.21 Conversely, inhaled corticosteroids had no effect on the urinary leukotriene E4 excretion.22 The results of our studies and other clinical studies12 22 suggest that these medications may have a small effect, if any, on the release of cysteinyl leukotrienes from leukocytes.

Among the responders, the level of ex vivo cysteinyl leukotriene release was not related to the degree of clinical improvement. One explanation for this discrepancy would be a variable plasma concentration of pranlukast. Alternatively, the degree to which the leukotriene receptor is inhibited by pranlukast in the lungs may vary among subjects. Finally, it is possible that even the responders may have had varying degrees of coexisting asthma-inducing pathways that were not responsive to pranlukast.

The observation that the ex vivo release of cysteinyl leukotrienes varied among asthmatics may provide clues about the way asthma is mediated in some patients. The exact cellular sources of cysteinyl leukotrienes are unknown but may include myeloid cells such as neutrophils, eosinophils, monocytes, basophils, and B lymphocytes, which contain substantial amounts of 5-lipoxygenase.6 Among these cells, eosinophils, basophils, and monocytes are known to release leukotriene C4.6 The fact that responders had higher levels of ex vivo cysteinyl leukotrienes than the nonresponders but did not differ in total WBC, percentage of eosinophils, or percentage of basophils suggests that the leukocytes of the responders may contain more cysteinyl leukotrienes or have much more potential to release them. Once stimulated by mediators such as IgE or cytokines, the leukocytes release the cysteinyl leukotrienes that play an important role in the responders.

In theory, urinary leukotriene E4 levels may be another biomarker of leukotriene receptor antagonist response, but are likely too variable. Although increased urinary leukotriene E4 levels are well documented in asthmatics exposed to antigen,23 aspirin,24 and exercise,18 the increase is highly variable and can be very small.18 23 In fact, an increase is often not possible to induce in some patients with stable asthma.18 Furthermore, treatment with a 5- lipoxygenase inhibitor showed small and variable reductions in urinary leukotriene E4 but large and homogeneous reductions in the ex vivo release of leukotriene B4.18 Therefore, the ex vivo cysteinyl leukotriene release we showed in this study is likely to be a more robust and less variable marker of leukotriene receptor antagonist response.

Antileukotriene drugs are now widely used as the first-line therapy in patients with mild persistent asthma. They are generally well tolerated, and the relatively few side effects could potentially translate to improved patient compliance.14 15 Furthermore, pranlukast has a "steroid sparing" effect and is known to prevent asthma exacerbations during the reduction of high-dose inhaled corticosteroids.25 However, in some patients, the same strategy can result in rare but serious consequences such as eosinophilic endomyocarditis, pulmonary infiltrates, and cardiomyopathy, characteristic of Churg-Strauss syndrome (CSS).26 Although the causal relationship between pranlukast, steroid reduction, and CSS is unclear, the ability to predict pranlukast response could reduce the risk of CSS in nonresponders. Currently, pranlukast is a relatively expensive drug and requires a trial period of a minimum of 4 weeks to see improvements. Thus, the ability to predict response would be not only economically beneficial, but would ensure that nonresponders received other appropriate treatment much sooner.

We conclude that the ex vivo release of cysteinyl leukotrienes from leukocytes is correlated with the clinical response to pranlukast and could be an effective biomarker to predict the response in mild asthmatics. A prospective study with many more patients will be needed to establish this. It is important that this work now be repeated in patients with moderate to severe asthma—a group with the most to gain from the benefits of antileukotriene drugs, but in whom the risks of failed treatment are higher.


   Footnotes
 
Abbreviations: CSS = Churg-Strauss syndrome; PEFR = peak expiratory flow rate

This study was supported in part by a grant from the Japanese Ministry of Education, Science, and Culture.

Received for publication November 9, 2001. Accepted for publication May 16, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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