Moderate vs Low ICS Doses May Not Give Added Benefit in Childhood Asthma

From MedscapeCME Clinical Briefs

News Author: Laurie Barclay, MD
CME Author: Charles P. Vega, MD

December 8, 2010 — Compared with low doses, moderate doses of inhaled corticosteroids (ICSs) may not give an added benefit to children with mild to moderate persistent asthma, according to the results of a systematic review and meta-analysis reported online December 6 in Pediatrics.

"...ICSs are currently considered the first-line treatment for persistent childhood asthma; however, uncertainty remains regarding the optimal dose," write Linjie Zhang, MD, PhD, from the Maternal and Child Health Unit, Faculty of Medicine, Federal University of Rio Grande in Rio Grande, Brazil, and colleagues.

"The most recent asthma guidelines recommend a dose of up to 400 μg/day beclomethasone dipropionate (BDP)-hydrofluoroalkane equivalent for children with mild-to-moderate persistent asthma, but these recommendations are generally based on results from individual randomized trials rather than a body of evidence that has been critically appraised by a systematic review."

The reviewers searched MEDLINE for articles published between 1950 and August 2009 describing randomized controlled trials that compared 2 or more different ICS doses in children aged 3 to 18 years with persistent asthma.
The analyses focused on study endpoints of morning and evening peak expiratory flow, forced expiratory volume in 1 second, asthma symptom score, use of β2-agonists, withdrawal for lack of efficacy, and adverse events.
The investigators used meta-analyses to compare moderate doses of ICSs (300 - 400 μg/day) vs low doses of ICSs (≤ 200 μg/day beclomethasone equivalent).

The 14 included randomized controlled trials enrolled a total of 5768 asthmatic children and evaluated 5 ICSs. Moderate vs low doses were slightly but statistically significantly more effective in improving forced expiratory volume in 1 second among children with mild to moderate asthma, based on the pooled standardized mean difference from 6 trials (standardized mean difference, 0.11; 95% confidence interval, 0.01 - 0.21). However, other efficacy outcomes were not significantly different between the 2 doses, and there was no evidence of a dose-response relationship at low to moderate doses. Local adverse events were uncommon.

"Compared with low doses, moderate doses of ICSs may not provide clinically relevant therapeutic advantage in children with mild-to-moderate persistent asthma," the study authors write. "Additional RCTs [randomized controlled trials] are needed to clarify the dose-response relationship of ICSs in persistent childhood asthma."

Limitations of this study include an unclear risk for bias in the included trials, as well as nonuniform reporting of continuous efficacy outcome results and incomplete reporting of data collection and adverse events. Because of the language limitation, 1 small randomized trial conducted in Germany was not included.

"Although ICSs are generally considered safe treatment for children with asthma, the potential systemic adverse effects such as adrenal suppression, linear growth retardation, and effects on bone mass, are still of concern," the study authors conclude. "A limited number of studies included in this review assessed adverse effects of ICSs given at different doses on linear growth and on hypothalamic-pituitary-adrenal function, and their findings were inconsistent. There are no suitable data for investigating dose-response relationship of systemic adverse effects of ICSs."

Dr. Zhang has received grants from the Brazilian government agency CAPES for postdoctoral training in the Institute for Clinical Research and Health Policy Studies (Tufts Medical Center, Boston, Massachusetts).

Pediatrics. Published online December 6, 2010.
Clinical Context

ICSs are first-line therapy for children with persistent asthma, but the long-term use of these medications among children raises concerns regarding significant long-term adverse effects. This issue was addressed in a review by Allen, which was published in Advances in Pediatrics in 2006. He notes that the use of ICSs alone at small doses does not appear to be associated with any significant systemic adverse events. Although ICSs can retard vertical linear growth when given at high doses, ICS use alone does not appear to affect final adult height. Routine ICS use also should not lead to significant adrenal suppression or bone loss.

Although ICSs at low doses may be safe for children, are they effective enough? The current study examines the dose response to ICSs among children with persistent asthma.