Asthma and lower airway disease
Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing

https://doi.org/10.1016/j.jaci.2008.09.029Get rights and content

Background

Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity.

Objectives

We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing.

Methods

In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome.

Results

The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices.

Conclusions

In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Section snippets

Patients

Patients were recruited between February and October 2004 at 5 clinical centers. The protocol was reviewed and approved by the Childhood Asthma Research and Education (CARE) Network Protocol Review Committee and then by the institutional review boards at each center. Written informed consent was obtained from the parents of each participant. The trial was monitored by the CARE Network Data and Safety Monitoring Board.

Inclusion criteria were age 12 to 59 months and having experienced at least 2

Subject characteristics

Of 351 patients enrolled, 238 were randomized, and 220 completed the trial or reached the criteria for treatment failure (Fig 1). The 3 treatment groups were well matched for demographic features, pretrial morbidity (including health care use), atopic features, and baseline quality of life, with the exception of a higher proportions of male children in the budesonide and montelukast groups (Table I). Further characteristics of this cohort have been described previously.27 Children with positive

Discussion

We have demonstrated that, in preschool children with moderate-to-severe intermittent wheezing, neither budesonide nor montelukast initiated at early signs of RTI increase the proportion of EFDs over a 12-month period relative to conventional therapy, nor was there an effect on oral corticosteroid rescue, asthma health care use (urgent care visits, emergency department visits, or hospitalizations), or quality of life. However, budesonide or montelukast initiated at early signs of RTI

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      These challenges include the learned overuse or over-reliance on SABAs and underuse of ICS, which typically occurs in patients with poor adherence to ICS therapy; parents’ and caregivers’ safety concerns regarding regular use of ICS; the long-standing recommendation in the initial phase of the stepwise asthma management to use SABA alone on an as-needed basis during times of acute illness instead of an anti-inflammatory medication such as an ICS, despite evidence showing the presence of underlying airway inflammation of asthma even in patients with infrequent or recent-onset asthma symptoms; the highly variable activity level of pediatric asthma; the adjustments in medications occurring after a review of symptoms in a previous period of time rather than from the first onset of symptoms;20 and other factors that have been associated with suboptimal adherence to inhaled controller therapy, such as the typical episodic nature of pediatric asthma, a lack of perceived necessity (especially in patients with infrequent symptoms), and perceived and actual side effects.7 The results of the present study are in good agreement with previously published studies in the literature reporting not only the efficacy but also the cost-effectiveness of the use of ICS on an intermittent or as-needed basis.9,10,21-29 The use of ICS on an intermittent or as-needed basis does not refer to a single strategy, but rather includes heterogeneous strategies with different criteria for initiating ICS therapy (at the first sign of an upper respiratory tract infection, when signs and symptoms of an AE are already evident, or when a SABA is needed), with or without ICS use during stable periods of the disease.

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    Supported by grants 5U10HL064287, 5U10HL064288, 5U10HL064295, 5U10HL064307, 5U10HL064305, and 5U10HL064313 from the National Heart, Lung, and Blood Institute. This study was carried out in part in the General Clinical Research Centers at Washington University School of Medicine (M01 RR00036) and National Jewish Medical and Research Center (M01 RR00051). This trial is registered at ClinicalTrials.gov as NCT00000622.

    Disclosure of potential conflict of interest: L. B. Bacharier has received honoraria from AstraZeneca, Genentech, GlaxoSmithKline, Merck, and Aerocrine and has served on an advisory board for Schering-Plough. R. S. Zeiger has served as a consultant for Aerocrine, AstraZeneca, Dynavax, Genentech, Merck, Novartis, and GlaxoSmithKline and has received research support from Sanofi-Aventis, Teva Pharmaceuticals, Merck, AstraZeneca, GlaxoSmithKline, and Genentech. S. J. Szefler has served as a consultant for AstraZeneca, GlaxoSmithKline, Aventis, Genentech, and Merck and has received research support from the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI), and Ross Pharmaceuticals. F. D. Martinez has received lecture fees from Merck and Pfizer; has served on an advisory board for Merck and MedImmune; and has served as a consultant for GlaxoSmithKline and Pfizer. R. F. Lemanske has received speaker honoraria from Merck; has served as a consultant for GlaxoSmithKline; and has received research support from the NHLBI. C. A. Sorkness has served on the speakers' bureau and as a consultant for GlaxoSmithKline and has received research support from GlaxoSmithKline and Pharmaxis. W. J. Morgan has served as a consultant for the Cystic Fibrosis Foundation and Genentech, has served as a speaker for Aerocrine, and has received research support from the NIH. I. M. Paul has served as a consultant for the Consumer Healthcare Products Association, McNeil Consumer Healthcare, and Reckitt Benckiser Healthcare International and has received research support from GlaxoSmithKline and the National Honey Board. T. Guilbert has served as a consultant, speaker, or both for GlaxoSmithKline, AstraZeneca, Peerpoint Medical Education Institute, Merck, Schering-Plough, Genentech/Novartis, and Antidote (formerly World Medical Conferences CME programs) and has received research support from Altus Pharmaceuticals, Inspire Pharmaceuticals, and the NIH. M. Krawiec has served on the speakers' bureau of Merck and GlaxoSmithKline, has served as a consultant for Novartis and Parexel, and has received research support from the American Lung Association. R. Covar has received honoraria from Aerocrine and has received research support from Ross Abbott Laboratories. G. Larsen has served on an asthma advisory board for Genentech and has received research support from the NIH. M. Mellon has served as a speaker, consultant, or both for AstraZeneca and Schering-Plough. V. M. Chinchilli has received research support from the NHLBI. The rest of the authors have declared that they have no conflict of interest.

    For the names of the members of the Childhood Asthma Research and Education Network, see Appendix E1 in this article's Online Repository at www.jacionline.org.

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