The role of leukotriene receptor antagonists in exercise induced bronchoconstriction in children

Background

The prevention of exercise induced bronchoconstriction (EIB) is one of the key goals in the clinical management of asthma in children [1]. The pathophysiology of EIB is thought to be caused by changes in airway physiology triggered by the inhalation of large volumes cold, dry air during exercise. The severity of EIB has been strongly linked to the extent of airway inflammation, measured by the presence of inflammatory cells such as eosinophils and cysteinyl leukotrienes, and by the degree of the child’s airway hyperresponsiveness. EIB normally peaks within 10–15 min after exercise and may result in dyspnoea, cough, chest tightness and reduced exercise tolerance [2]. As physical activity and exercise form an essential component of a child’s physical and psychosocial development, the importance of control of EIB extends beyond symptom control.

While inhaled corticosteroids (ICSs) remain the primary management strategy in the prevention and attenuation of bronchoconstriction, a growing body of evidence suggests that combined therapy improves clinical outcomes in children with asthma complicated by EIB. Short acting beta agonists (SABAs) such as salbutamol can be used effectively prior to exercise, however their relatively short duration of action limits their benefit. Children often engage in unplanned physical activity, which can make EIB prophylaxis difficult [3]. There is a role for a medication which is long acting and effective in preventing bronchoconstriction. Long acting beta agonists (LABAs) such as salmeterol can be used as a prophylactic add-on therapy in children with asthma and EIB; however they may be associated with tolerance and adverse clinical events [4].

Leukotriene receptor antagonists (LTRAs), such as montelukast, may provide a suitable option for additional therapy in this clinical setting [1].

Objectives

This paper aims to assess the role that LTRAs might have in the attenuation of EIB in children with chronic asthma. This systematic review was conducted by assessing the results of randomised placebo-controlled clinical trials (RTCs) and relevant subanalyses in order to answer the following questions:

1. What is the efficacy of LTRAs in preventing EIB either alone or in combination with inhaled corticosteroids in children with symptomatic asthma.

2. Does the efficacy of LTRAs vary depending on the clinical characteristics of the underlying asthma.

Methods

Results

A PRISMA flow diagram for systematic reviews is shown in Figure 1. A total of 22 records were identified through the above computer-based searching. Following removal of duplicates and careful selection based on eligibility criteria, 7 studies were identified. The details of these studies are outlined in Tables 1–7.

Figure 1

Revman study selection flow chart.

The studies found consisted of five randomised control trials and two clinical reviews. All studies required subjects to be children (<18 years old) with asthma. Most of the studies required their subjects to have a fall of ≥15%–20% in FEV1 following exercise and several of them required subjects to have a baseline FEV1 of ≥70% predicted value which would indicate moderate to mild airway obstruction at rest. All of the studies included LTRAs (montelukast) as a potential therapy for EIB.

All randomised control trials measured exercise induced bronchoconstriction with the exercise challenge test. This test normally consists of 6–8 min treadmill exercise, which aims to increase heart rate to 85% of the predicted maximum. This test is positive if the FEV1 falls by ≥10%, however a ≥15% reduction is considered diagnostic of EIB. A baseline FEV1 is established and FEV1 measured both before EC and at different time intervals following exercise to obtain an accurate result (e.g., 1, 3, 5, 10, 15, 20 and 30 min post EC) [2].

All studies measured the mean maximum percentage fall in FEV1 following the EC test. Three crossover trials compared montelukast to a placebo or an inhaled LABA (salmeterol) on the same subjects at two different treatment stages, separated by a washout period which ranged from 7 to 10 days. All patients involved in these studies received regular ICS as their baseline treatment.

Peroni et al. report that on day 1 of treatment, a fall of mean FEV1 from baseline of 19% was associated with patients administered the active drug compared to 28.2% among those who received the placebo [1]. Montelukast therapy further improved the FEV1% predicted status of patients on day 3 of treatment, with a 14.89% fall from baseline associated the active drug, compared to 25.54% among placebo recipients. This study demonstrated the benefits of montelukast therapy, with a significantly reduced fall in FEV1 from baseline following EC, and improved outcomes after 3 days of therapy. The therapeutic benefits were sustained for up to 8 h post-treatment. Wasfi et al. evaluated the onset and duration of therapeutic effect, following a single dose of montelukast in a crossover study [3]. This study measured maximum percentage fall in FEV1 after EC, 2 and 24 h post-treatment. The maximum percentage fall in FEV1 following a single dose of montelukast was 15.33% after 2 h, and 12.92% after 24 h, thus comparing favourably to the 2 h fall of 20% and a 24 h fall of 17.25% after placebo administration. The results of this trial demonstrate that a single dose of montelukast provides rapid EIB control, and that this positive response is sustained over 24 h, compared to the placebo outcome. One crossover study found that when compared to inhaled salmeterol, montelukast significantly reduced the mean maximum percentage decrease in FEV1 (13.8% associated with salmeterol vs. 10.6% with montelukast) [4]. This study demonstrated a greater efficacy associated with montelukast therapy, compared to treatment with a LABA. Furthermore, it was demonstrated that greatest improvement is associated with prolonged montelukast treatment.

Stelmach et al. compared five different treatment regimens and their efficacy in controlling EIB over a 4 week period [7]. The lowest maximum percentage fall in FEV1 following EC was in the budesonide and montelukast combined therapy groups (12.1%), and the montelukast monotherapy groups (11.5%). The largest maximum percentage fall in FEV1 compared to baseline, indicating the group with poorest EIB control, was associated with the placebo group (26.6%) and the budesonide and formoterol co-treatment group (18.9%). This study concluded that budesonide combined with montelukast is an effective treatment regimen for children with EIB.

Two of the studies used the FEV1 area under the curve (AUC) on the time response curve as an outcome to measure EIB. Effective treatment showed an increased AUC over a given time period when compared to a control. One study [3] measured the AUC for the first 60 min post-exercise and found montelukast to be significantly more effective at attenuating EIB than placebo [3]. The results for AUC obtained by Stelmachet al. demonstrate that co-administration of budesonide with montelukast, and montelukast monotherapy were significantly more efficacious than treatment with budesonide alone or budesonide with formoterol. There were no significant differences between the budesonide with montelukast and montelukast-only groups in terms of AUC result. One clinical practice review stated that while Stelmach et al. demonstrated the efficacy of montelukast in preventing EIB, the length of the trial (4 weeks) was insufficient to conclude that montelukast is superior to ICS in the treatment of EIB.

Some of the studies examined the relationship of montelukast with rescue medications. Wasfi et al. found that the percentage of participants needing rescue SABAs at EC, 2 h post-treatment was 1.6% for the montelukast group and 3.1% for the placebo group [2]. The percentage requiring SABAs at EC 24 h post-treatment was 0% for montelukast and 3.2% for the placebo group. Fogel et al. showed that response to albuterol (SABA) rescue after EC was significantly greater with montelukast [4]. These results demonstrate that while the need for rescue bronchodilators following exercise may be slightly reduced in patients receiving montelukast, the response to SABAs is significantly improved in patients receiving a 4 week montelukast regimen.

Bonsignore et al. defined EIB as post exercise FEV1 of <10% of baseline [6]. This study measured the effect of exercise training and montelukast therapy in children with mild asthma managed with SABA monotherapy. A history of EIB was not required for this study. Children took part in 12 weeks of aerobic training and received either placebo or montelukast during this time. The study found that training increased maximal workload and peak minute ventilation in both groups. Bronchial responsiveness was measured using methacholine. The methacholine dose needed to cause ≥20% fall in FEV1 increased in both groups after training. A decreased slope of FEV1 decline at increasing methacholine dose was found in the montelukast group. EIB prevalence was reduced by 50% in both groups following training. The study also measured markers of airway inflammation in exhaled breath condensation (EBC) and found that exhaled nitric oxide (eNO) and cysteinyl leukotriene concentration were unaffected in both groups. pH in EBC was decreased in both groups. Subjects treated with montelukast showed fewer asthma exacerbations compared with the same period the previous year. This study showed the benefit of aerobic training in mild asthma and demonstrated that montelukast protected against exacerbations of asthma and resulted in decreased EIB.

Risk of bias

Tables 8–14 outline the risk of bias in the articles we identified through computer based-searching as described above.

Discussion

This systematic review demonstrates the benefits of LTRA therapy in the management of children with chronic asthma complicated by EIB. The approach to asthma management differs according to the age of the child and the severity of symptoms. The British Thoracic Society (BTS) Guidelines on Asthma Management [9] divides children into three age groups; <5 years old, 5–12 years old and >12 years old. In children <5 years old, LTRAs are considered as first choice add-on therapy to ICS in poorly controlled asthma and as a first line prophylaxis in children who are unable to tolerate corticosteroids. In children 5–12 years old and >12 years old, LTRAs are normally only considered following no response to LABAs and an increased ICS dose. This systematic review confirms that montelukast is an effective preventer of EIB both as monotherapy and a useful add-on medication when combined with ICS. In one study, montelukast provided greater protection against EIB when compared to ICS and LABA combination therapy [7]. Previous studies have demonstrated the loss of protective effects of LABAs over time due to tolerance. A study by Zarkovic et al. [10] revealed the loss of protection against bronchoconstricting factors after the first week of treatment with salmeterol, with a complete lack of protection after 6 months. A study which examines the long term tolerance of LTRAs may be beneficial. SABAs have been shown to provide greater protection from EIB compared to montelukast when taken before exercise [11], however their efficacy relies on correct administration techniques and does not account for spontaneous unplanned physical activity which is common in children.

Adverse effects of LTRAs have been reported in a small number of patients (<2%). Reported side effects include: headache, dyspepsia, anaphylaxis, angioedema, dizziness, dyspepsia, muscle weakness, myalgias, leukopenia, elevated transaminases, sleep disorders and behavioural changes [12].

Conclusions

One important observation of this systematic review is the inter-patient variability of response to montelukast in patients with EIB. Previous studies have reported that between 35% and 75% of patients (children and adults) are non-responders to montelukast. Few of the studies in this systematic review identified the numbers of “non-responders”. Genetic variability may influence leukotriene production and subsequent response to LTRAs [12]. This is an issue which could be addressed in further studies [13].