Deliberations of Exhaled Leukotrienes and Quality of Life in Asthmatic Patients

In this study, we have shown elevation of cys-LTs in EBC in a group of patients with stable asthma receiving inhaled corticosteroids. The increased levels of cys-LTs may indicate the presence of continuing inflammation in the airways despite treatment with inhaled corticosteroids. MacFarlane et al found a strong correlation between increased cys-LTs and eosinophilia in induced sputum. Elevated levels of cys-LT in EBC have been also found in adults and children with mild-to-moderate asthma treated with inhaled corticosteroids. However, in some studies, there were difficulties in detecting any cys-LTs in breath condensate. We were unable to detect cys-LTs in a significant number of patients. This may be because the values obtained by measuring cys-LTs with currently available assays are often close to the limit of detection; assays that are more sensitive in detecting cys-LTs may be available in the future.

Inflammation in airways of patients with asthma may persist despite treatment with inhaled steroids. Duncan et al and Louis et al have shown a wide range of sputum eosinophilia despite treatment with inhaled corticosteroids. The reason for that could be the inadequate dosage of inhaled corticosteroids, or that treatment with corticosteroids was unable to fully control the inflammatory process in asthma. Indeed in a study in patients with severe asthma treated with inhaled corticosteroids, there was an elevation of leukotriene excretion in urine, which could indicate that the cys-LT pathway in asthmatic airway inflammation remains relatively unaffected by corticosteroids. Also, in children with moderate-to-severe asthma treated with inhaled corticosteroids, there was an elevation of LTE4 in urine. Furthermore, in a study with BAL, there was elevation of cys-LTs despite treatment with high doses of corticosteroids. One explanation of these finding could be that inhaled corticosteroids have only a small effect on 5-lipoxygenase. This may imply that even in asthmatic patients with normal lung function and good symptomatic control of their disease, suppression of inflammation is incomplete. This suggests that the addition of a leukotriene antagonist may be beneficial in blocking the effects of residual cys-LTs, Our study shows that treatment with 10 mg of montelukast significantly reduces concentrations of cys-LTs, and this is associated with the improvement in an AQL questionnaire. The benefits of adding a leukotriene antagonist to treatment with inhaled corticosteroids in patients with asthma have been shown in several previous studies. Treatment with a leukotriene receptor antagonist may reduce eosinophils in circulating blood and in the airways. In the study by Laviolette et al, combined therapy with inhaled beclomethasone and montelukast resulted in almost total suppression in blood eosinophil numbers. In children with corticosteroid-dependent asthma, montelukast reduced eosinophil cationic protein in sputum.

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Children with mild asthma

Our study also showed an elevation of exhaled LTB4 levels in our patients treated with inhaled corticosteroids, in agreement with previous studies in adults and children. Subsequently, levels of LTB4 have fallen significantly after treatment with montelukast. However, after 2 weeks of discontinuation of treatment, there was a slight but not significant rise in exhaled LTB4 levels that coincided with the fall of AQL scores. LTB4 is a potent chemoat-tractant that activates neutrophils and T-lympho-cytes. An LTB4 antagonist reduces neutrophil influx into airways of asthmatic patients at 24 h after airway antigen challenge. The reduction in cys-LTs and LTB4 after treatment with leukotriene antagonist is unexpected and difficult to explain. However, a recent study showed that montelukast inhibits 5-lipoxygenase, the rate-limiting enzyme in the biosynthesis of leukotrienes. This could explain the decrease of leuko-trienes during treatment with montelukast in our study (

We measured inflammatory markers in EBC. EBC provides access to volatile and nonvolatile respiratory compounds, and the measurements are reproducible. EBC is noninvasive, safe, and easy to perform even in patients with severe airways obstruction. EBC can be measured regularly to monitor airway inflammation. All of our patients were recruited from general practice clinics, confirming the feasibility of performing such studies in a primary care setting.

Despite elevated levels of exhaled cys-LTs and LTB4, the levels of NO remained normal. This may indicate a limitation of NO as an accurate monitor of the control of inflammation in patients treated with inhaled corticosteroids. It may also suggests that NO is more sensitive to the inhibitory effects of corticosteroids than are exhaled cys-LTs and LTB4.

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In our study, the addition of montelukast to inhaled corticosteroid had no additional bronchodi-lator effect. This result was not surprising to us since all our patients were receiving inhaled corticosteroids and were clinically stable. Similarly, Robinson et al and Currie et al found no benefit of cys-LT antagonists on respiratory function. Monitoring respiratory function on its own can therefore miss the potentially beneficial effects of cys-LT antagonist in patients receiving inhaled corticosteroids. Other data and research on this topic you can find in our category:

Respiratory function

In this study, considerable improvement was seen in all domains of the AQL questionnaire. This improvement was noticed after 2 weeks of treatment and was maintained after 4 weeks. A possible explanation of the improvements in AQL scores could be an additional antiinflammatory effect of montelukast.

However, stopping treatment with montelukast caused deterioration in AQL scores. Similarly, Currie et al found benefit of treatment with monte-lukast on surrogate inflammatory markers in corticosteroid treated asthmatics, but without any changes in respiratory function tests. Also Strauch et al and Tamaoki et al have found improvement in AQL scores in patients treated with montelukast. In addition Tamaoki at al also found that montelukast prevented deterioration of asthma after reduction of inhaled corticosteroids. Price et al also reported benefit of treatment with montelukast on a specific quality of life questionnaire, but in this study there was also improvement in respiratory function tests. It seems therefore that symptoms-score grading is more sensitive that these respiratory function tests in the assessment of treatment and should be used as an adjunct to objective measurements of markers of inflammation. We have found no significant correlation between the changes in exhaled cys-LTs and AQL scores and also between the changes in exhaled LTB4 and AQL scores. One of the explanations for this could be that we have only studied a relatively small group of patients. However, in a recent analy-sis of the few much larger studies, only a very weak correlation was found between clinical outcomes and quality of life. The explanation for this finding was the possible “noise” of measurements, and that quality of life is a distinct component of asthma health status, which could be responsible for the lack of significant correlation in our study.

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In conclusion, we have found elevated levels of exhaled cys-LTs and LTB4 in patients with stable asthma treated with inhaled corticosteroids. This suggests that inflammation may persist in airways despite treatment with corticosteroids. Adding an antileukotriene provides a complementary role in the control of asthma and improvement in AQL questionnaire scores. However, for a better understanding the role of treatment with the leukotriene receptor antagonist montelukast in patients receiving with inhaled corticosteroids, further studies using doubleblind protocols are required.

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