Fluticasone or montelukast for preschool children with asthma-like symptoms: Randomized controlled trial

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Abstract

Rationale

Beneficial effects of anti-inflammatory therapy such as fluticasone propionate (FP) and montelukast (Mk) have been demonstrated in preschool children with asthma. However, comparative studies are lacking in this age group. Therefore, we conducted a study to evaluate and compare the effect of FP and Mk in preschool children with asthma-like symptoms.

Methods

In this multicenter, randomized, placebo-controlled, double-blind, double-dummy trial, children aged 2–6 years with asthma-like symptoms were included. In total, 63 children were randomly allocated to receive FP (25), Mk (18) or placebo (20) for 3 months. The primary outcome was the daily symptom score (wheeze, cough, shortness of breath) as recorded by caregivers in a symptom diary card. Secondary endpoints were rescue medication free days, blood eosinophils and lung function (interrupter technique and forced oscillation technique (FOT)).

Results

During the 3 months study period, symptoms improved in all 3 groups, with a statistically significant difference between FP and placebo in favor of the FP group (p=0.021). A significant reduction in circulating eosinophils after 3 months of treatment was found in the Mk group only (p=0.008), which was significantly different from the change found in the placebo group (p=0.045). With the exception of frequency dependence (measured by FOT), which showed a difference between FP and Mk after 3 months of treatment in favor of the FP group (p=0.048), no differences in lung function within or between groups were found.

Conclusions

In spite of a lack of power, our results suggest that FP has a beneficial effect on symptoms and Mk on blood eosinophil level as compared to placebo. Except for a difference in one lung function parameter after 3 months between FP and Mk in favor of the FP group, this study revealed no differences between FP and Mk.

Introduction

Respiratory symptoms like cough, wheeze or shortness of breath are common in preschool children. By 6 years of age many children will have outgrown their symptoms, while a minority of children will go on to develop persistent symptoms and eventually be diagnosed with asthma [1]. The crucial issue is the difficulty in accurately diagnosing asthma in preschool children. For clinicians it is difficult to distinguish children with persistent asthma from those with transient respiratory symptoms. The consequence of this diagnostic dilemma is that an adequate therapeutic choice—maintenance therapy with inhaled corticosteroids (ICS), or leukotriene-receptor antagonists (LTRA), or just symptomatic treatment with a bronchodilator—is challenging. Treatment with anti-inflammatory agents in preschool children with assumed asthma might be prescribed in order to improve symptom control, lung function and to prevent airway remodeling. ICS and LTRA are anti-inflammatory agents that have become important therapeutic strategies in the management of asthma in adults and school-aged children [2]. In school-aged children the efficacy of ICS as well as LTRA has been demonstrated. Nevertheless, ICS appeared to be more effective than LTRA in asthma in adults and school-aged children [3], [4], [5], [6], [7]. In preschool children with asthma, beneficial effects of ICS on symptoms and lung function have been found [8], [9]. Effects on the natural history of asthma or wheeze (e.g. a disease-modifying effect) of ICS, however, have not been demonstrated [10], [11]. The effectiveness and safety of Montelukast (Mk), an LTRA, have been demonstrated in young children (aged 2–5 years) with persistent [12] or intermittent asthma [13]. So far, studies comparing the effectiveness of ICS and LTRA in preschool children have been performed only in retrospective or open label designs and showed no differences between the two treatment regimes with regard to asthma-related health-care resource utilization [14], or β2-agonist or oral steroids use [15]. Until the results of clinical trials in preschool children with symptoms suggestive of asthma become available it will remain unclear as to whether monotherapy with ICS or monotherapy with LTRA should be recommended in this difficult-to-diagnose age group.

Clinical trials in young children predominantly rely on the use of subjective outcome measurements, such as symptom-assessment by the child's caregivers. So far, few studies have included objective outcome measurements such as inflammatory parameters or lung function to evaluate the effectiveness of medication [9], [16], [17], [18], [19]. The standard measurement for measuring lung function—spirometry—is not suitable for use in preschool children, but the development of non-invasive lung function techniques such as the interrupter [20] and forced oscillation technique (FOT) [21], [22], which require only passive cooperation, enables us to measure characteristics of the airways in preschool children. Both resistance and reactance of the total respiratory system are measured by the FOT. In addition, the frequency dependence of the resistance can be calculated. Frequency dependence might be an appropriate measure in preschool children with recurrent wheeze as it is a sensitive parameter of small airways patency [22].

We therefore carried out a randomized controlled trial to evaluate and compare the effectiveness of fluticasone propionate (FP) and Mk monotherapy as compared to placebo using subjective as well as objective outcome parameters in preschool children with asthma-like symptoms.

Section snippets

Recruitment

Pediatricians from three outpatient clinics (secondary care) in The Netherlands approached potential participants. Children aged 2–5 years with asthma-like symptoms (wheeze, cough and/or shortness of breath) of sufficient severity to justify the use of prophylactic asthma treatment were eligible for inclusion. Children and parents who were willing to participate were invited for a screening visit at one of the three centers. ICS or LTRA use was not allowed for a period of 4 weeks preceding the

Study population

In the period between September 2002 and September 2004, 105 subjects were approached. Of these 105 children, parents of 70 children agreed to participate and those children entered the run-in period after the screening visit. In 10 of the 35 children whose parents refused to participate refusal was due to the severity of the child's respiratory symptoms: specifically, these parents were afraid that their child might be allocated to the placebo group. Subsequently, seven children did not meet

Discussion

To our best knowledge this is the first study designed, using subjective as well as objective measures, to evaluate and compare the effect of Mk or FP monotherapy vs. placebo in preschool children with asthma-like symptoms. Although we acknowledge that our study sample is too small to draw definite conclusions, in spite of a lack of power, we would like to emphasize the importance of our study findings below.

With respect to our main outcome parameter—the daily symptom score—an improvement in

Financial support

This trial was financially supported by an unrestricted grant from Merck Sharp and Dohme.

Conflicts of interest statement

All authors state that they do not have any special financial interest concerning this manuscript.

Acknowledgement

We thank Dr. Juliet M. Foster for her critical review of the English.

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