Chauhan B, Chartrand C, and Ducharme F.‘Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults.’ The Cochrane Database of Systematic Reviews. 2013;2:CD009611.
What Is This Review About?
The review compared the efficacy and safety of intermittent versus daily inhaled corticosteroids (ICS), either budesonide or beclomethasone delivered via dry powder inhalers (DPIs), meter dose inhalers (MDIs) or nebulisers, in the management of children and adults with ‘mild persistent’ asthma. The duration of the interventions ranged from 12 to 52 weeks. The primary outcome was the number of patients experiencing one or more exacerbations requiring rescue oral corticosteroids. Secondary clinical outcomes included the number of exacerbations requiring emergency department visits or hospital admission, asthma control, markers of inflammation, safety and withdrawal rates. This commentary will concentrate primarily on the results from the paediatric trials.
What Are the Findings?
Compared with children in the intermittent ICS group, children in the daily ICS group had the following:
- No statistically significant difference in exacerbation rates requiring oral corticosteroids but with wide confidence intervals (CIs) (for adult and paediatric trials combined, relative risk 1.97; 95% CI 0.87–1.32)
- Better asthma control with a significantly higher proportion of asthma control days, significantly lower daily and cumulative use of β2 agonist
- A lower fraction of exhaled nitric oxide suggesting less airway inflammation.
- Slightly lower linear growth (mean difference 0.41 cm, 95% CI 0.13–0.69) in pre-pubertal children.
What Are the Findings Based on?
Four paediatric randomised controlled trials were included in this Cochrane review: two involved pre-school children,[3, 4] and two involved school-aged children.[2, 5] Each of the trials had a low risk of bias. All trials compared daily with intermittent ICS, with varying dosage and methods of administering ICS. In addition, Martinez and Papi[2, 3] had a placebo arm, whereas Turpenin's trial had an open-labelled disodium cromoglycate arm. Intention-to-treat analysis was applied in all the trials. Although the primary outcome chosen for this Cochrane review was not the original primary outcome intended for all of the included trials, the data were obtained directly from the authors. Subgroup analyses were performed on different exacerbation protocols, age of study population, duration of trials, and the different severity of airway obstruction of included subjects and showed consistent findings. See Fig. 1 for an example of this for different age groups.
However, there are a few clinical differences between the trials that should be noted when interpreting the result of this Cochrane review. Firstly, the different definitions of ‘persistent asthma’ and hence study population may have influenced the result of the primary outcome. Turpeinen and Papi enrolled children with persistent symptoms of asthma prior to the initiation of medical therapy, whereas Martinez and Zeiger included children who had already been initiated on controller therapy and whose asthma symptoms were controlled during the run-in period. Hence, the study question that Turpeinen and Papi addressed could be interpreted as to whether intermittent ICS is a suitable initiating treatment for children with mild or moderate untreated asthma, whereas Martinez and Zeiger's study question is whether intermittent ICS is a suitable step-down therapy for children whose asthma are controlled while on daily ICS. Further, in the two pre-school children trials from Papi and Zeiger, the study population consisted of recurrent wheezers (more than three to four episodes of wheeze in the last 6–12 months) whose diagnosis of persistent asthma was yet to be confirmed. This could lead to important participant differences between trials with implications for the applicability of the results to individual children.
Another factor to consider is the difficulty of determining equipotent ICS dose to allow comparison between trials using different types, formulation and dose of ICS. For example, both 400 mcg/day of budesonide given via a DPI and 0.5mg/day of budesonide nebulised are considered a low dose of ICS in children; the European guideline suggests that a low daily dose of budesonide should be <200 mcg/day delivered via DPI compared with <400 mcg/day in the US guideline. In the included trials, Martinez and Zeiger used low daily doses of ICS, whereas Papi used a medium daily dose of ICS and Turpeinen commenced with medium then tapered to low doses of ICS. Further, the ICS most commonly prescribed for Australian children is fluticasone MDI, which is not studied in any of the trials.
Implications for Practice
Based on current knowledge, the use of intermittent ICS as an initiating treatment for persistent asthmatics or as a step-down treatment for controlled asthmatics is not recommended. The goal for the management of asthmatic children remains prescribing the lowest effective dose of daily ICS or non-steroidal controller therapy (such as montelukast) to gain control, and once the control is maintained, to wean the treatment to ensure minimal adverse effects.