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Fluticasone or Montelukast in Preschool Wheeze: A Randomized Controlled Trial Marta Krawiec, Agnieszka Strzelak, Katarzyna Krenke, Izabela Modelska-Wozniak, Joanna Jaworska and Marek Kulus CLIN PEDIATR published online 22 September 2014 DOI: 10.1177/0009922814550158 The online version of this article can be found at: http://cpj.sagepub.com/content/early/2014/09/20/0009922814550158

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research-article2014

CPJXXX10.1177/0009922814550158Clinical PediatricsKrawiec et al

Original Article

Fluticasone or Montelukast in Preschool Wheeze: A Randomized Controlled Trial

Clinical Pediatrics 1­–9 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922814550158 cpj.sagepub.com

Marta Krawiec, MD1, Agnieszka Strzelak, MD1, Katarzyna Krenke, PhD, MD1, Izabela Modelska-Wozniak, MD1, Joanna Jaworska, MD1, and Marek Kulus, Prof, MD1

Abstract Introduction. Approximately 30% of children younger than 3 years experience at least 1 episode of wheezing. Antiasthmatic medication is routinely prescribed, but its effectiveness remains unclear. Our study was aimed to evaluate the effect of anti-inflammatory treatment on frequency and severity of preschool wheeze episodes (PWEs). Methods. Children aged 6 to 36 months with the first up to the third PWE were randomly assigned to receive montelukast, fluticasone, or no treatment for 12 weeks. The outcome measures were the number of PWEs, the number of hospitalizations due to PWE, and the severity of respiratory symptoms. Results. There were no significant differences in outcome measures between the groups. However, tobacco-exposed children treated with fluticasone had significantly fewer PWEs (P = .01). Conclusion. Neither montelukast nor fluticasone has proven effective in the prevention of PWE recurrence. Children of smoking parents may benefit from fluticasone treatment after PWE. This observation requires confirmation in larger studies. Keywords preschool wheeze, management, fluticasone, montelukast, tobacco exposure, children

Introduction Wheezing disorders in early childhood (preschool wheeze) constitute a considerable diagnostic and therapeutic problem.1,2 Approximately 30% of children experience at least 1 episode of wheezing up to the age of 3 years.3 Despite that, most of the cases are benign, significant percentage of preschool wheezers requires urgent medical assistance at least once.4-6 Preschool wheeze is a heterogeneous condition encompassing several different phenotypes.1,7 While 60% of children will outgrow wheezing up to the schoolage (transient wheezing), for a minor percentage of patients it will occur to be the first manifestation of asthma.8 However, a long-term outcome of preschool wheeze is difficult to predict at the time of onset of symptoms.9,10 Therefore, preschool wheeze brings forth 2 main considerations for practitioners: (a) whether a child presenting with wheezing is at risk of subsequent development of asthma and (b) which treatment and of what duration is beneficial in terms of a long-term outcome. While the treatment of asthma is widely approved,7,11,12 the management of patients with recurrent wheezing not fulfilling the criteria for the diagnosis of asthma is still

under debate. As no univocal recommendations for pharmacological treatment of children with preschool wheeze have been published, asthma guidelines are commonly extrapolated for these patients. Thus, bronchodilators, inhaled corticosteroids (iCS), and antileukotriene (aLTR) agents (alone or in combinations) are frequently used in clinical practice in the hope of reducing the risk of recurrence.13 However, the efficacy of such long-term anti-inflammatory treatment has not been proven in the secondary prophylaxis of wheezing in children with preschool wheeze, not to mention its particular phenotypes. Therefore, the aim of our study was to address this particularly controversial issue by assessing the effect of 12-week anti-inflammatory treatment in children with preschool wheeze on frequency and severity of episodes over a 12-month period. 1

The Medical University of Warsaw, Warsaw, Poland

Corresponding Author: Marta Krawiec, Department of Pediatric Pneumonology and Allergy, The Medical University of Warsaw, Dzialdowska 1/3 St, Warsaw 01-184, Poland. Email: [email protected]

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Clinical Pediatrics

Methods Study Design and Participants This was an open-label, randomized trial. Children aged 6 to 36 months with the first up to the third episode of preschool wheeze (preschool wheeze episode [PWE]) admitted to the Children’s Hospital, The Medical University of Warsaw, Poland, between November 2007 and August 2010 were eligible for the study. PWE was diagnosed if clinical signs of dyspnea and wheeze on chest auscultation were present. Exclusion criteria included coexistence of pneumonia, bronchopulmonary dysplasia and other chronic pulmonary diseases, treatment with montelukast, iCS, or systemic corticosteroids 2 months prior to admission, and fourth or higher episode of wheezing suggestive of early childhood asthma.

who had PWE within 1 year. The secondary outcome measures were the number of PWEs in the first 12 weeks, the percentage of children who had PWE in the first 12 weeks, and the number of hospitalizations due to PWE (both in the first 12 weeks and within 1 year). Furthermore, in children for whom data from symptoms diaries were available, the symptoms severity assessment analysis was performed (additional outcome measures). All adverse events were recorded.

Randomization We used a computerized procedure to randomly assign children to receive montelukast, fluticasone, or no treatment.

Ethics Intervention If a diagnosis of PWE was made, the child was assessed for the eligibility for the study. During hospital stay subjects were treated according to the judgment of the treating physician (oxygen therapy, nebulized bronchodilators, nebulized fluticasone, systemic steroids, intravenous fluids). Study clinicians obtained the medical history from parents or caregivers, which included questions about history of allergic disease in the immediate family and household passive smoke exposure. On discharge, children were randomly assigned to receive either montelukast 4 mg orally once daily (in powder form) or low-dose fluticasone (12 months 2× 100 µg) through a valved spacer device with a face mask, or no treatment for 12 weeks. For the study period, salbutamol metered-dose inhaler through a valved spacer was accepted reliever medication in each group. At the study entry, parents were issued symptoms diary cards encompassing the 12 weeks treatment period. The following items were scored: sleep deprivation due to cough, sleep deprivation due to dyspnea, severity of symptoms (cough, wheezing, and dyspnea) observed during the day (4-point scale from 0 to 3 points, where score ≥2 meant intense cough), the need for reliever medication, the need for physician visit, emergency department visit, and hospitalization due to PWE. Subsequently, a telephone questionnaire was conducted 1 year after enrollment with questions related to number of PWEs, number of hospitalizations due to PWE, and side effects of treatment.

The study was approved by the Ethics Committee of The Medical University of Warsaw. Written informed consent was obtained from at least 1 parent of each participant before enrollment.

Sample Size Sample size based on the treatment success outcome (ie, the proportion of participants with no recurrent wheezing) was calculated by the use of Power and Sample Size Calculator free software. It was estimated that to show a difference in the treatment effect of 35% (70% of the participants receiving montelukast or fluticasone compared with 35% of the participants receiving no treatment) with α = .05 and 80% power, and assuming a 20% withdrawal rate, a sample size of 65 was sufficient.

Statistical Analysis All analyses were conducted using STATISTICA version 10 software. Continuous variables were expressed as medians as distribution was not normal. For dichotomous and continuous variables we used χ2 and Kruskal– Wallis test, respectively. For comparison of 2 independent groups (montelukast vs no treatment and fluticasone vs no treatment) Mann–Whitney U test was used. Two-tailed tests were used for all analyses. The differences between the study groups were considered significant at the P value

Fluticasone or montelukast in preschool wheeze: a randomized controlled trial.

Approximately 30% of children younger than 3 years experience at least 1 episode of wheezing. Antiasthmatic medication is routinely prescribed, but it...
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