Continuous versus intermittent inhaled corticosteroids for mild persistent asthma in children: not too much, not too little.

The goal of asthma treatment is to prevent exacerbations, achieve daily asthma control and prevent adverse effects with a minimum of medication. In preschoolers, children and adolescents with mild persistent asthma, the most effective therapy remains daily use of low-dose inhaled corticosteroids. Why then consider intermittent therapy over maintenance inhaled corticosteroids? The intermittent approach is attractive to patients and families for a variety of reasons, including fear of corticosteroid side effects, the erroneous concept that no symptoms equate to no disease and ease of compliance with medications administered for symptoms rather than on a daily basis. Indeed, pharmacy records clearly show that most children with asthma infrequently renew their prescriptions for controller medications, suggesting that they may not understand, perceive or agree with the need for daily therapy, despite ongoing healthcare resources utilisation and excess use of rescue b2-agonist. This practice is also endorsed by physicians who recommend an asthma controller at the onset of an exacerbation for a short period. 5 In vogue since the 1990s without, until recently, any supporting evidence, the practice of prescribing intermittent therapy over continuous therapy may have stemmed from: (1) the uncertain benefit of daily inhaled corticosteroids in patients in whom there is diagnostic uncertainty (viral wheeze vs asthma), phenotype hesitation (intermittent vs persistent) or a paucity of evidence for therapy (eg, preschoolers); (2) conflicting evidence regarding the long-term benefit of daily therapy as a disease modifier (eg, lung function, quality of life, airway remodelling); (3) concerns about side effects of daily inhaled corticosteroids; and (4) in the absence of trials, unconvincing evidence of the harm or lack of efficacy of intermittent therapy. Admittedly, these factors may contribute to the ‘giving-up to poor compliance’ popular approach to avoid the time and energy required to repeatedly convince patients that the benefits of daily therapy outweigh possible harms. 9 10 These reasons must be carefully addressed. The scientific evaluation of intermittent controller therapy has started with adjustable single inhaler therapy in patients with persistent asthma receiving a daily combination of inhaled corticosteroids and fast long-acting b2-agonists (ie, formoterol) in adults, 12 then in children. It extended to patients with intermittent asthma on no maintenance controller in whom placebo-controlled trials examined ‘as-needed’ combination therapy in adults and ‘as-needed’ inhaled corticosteroids 16 or leukotriene receptor antagonists monotherapy in children. The recent randomised control trials testing intermittent versus continuous controller monotherapy in adults 19 and children 21 with mild persistent asthma are the focus of this commentary. In a 6-month, three-arm trial, Boushey et al evaluated as needed budesonide (800 mg/day for 10 days) in adults with mild persistent asthma who were taking 400 mg daily budesonide or placebo; they observed no significant group difference in morning peak expiratory flow (PEF) rate and in exacerbations. However, maintenance monotherapy was clearly superior in improving forced expiratory volume in one second (FEV1), airway hyper-reactivity, asthma control, symptom-free days and markers of eosinophilic inflammation. Intermittent budesonide was no different from daily zafirlukast and the authors appropriately emphasised the need for further studies before endorsement. In a 6-month, four-arm trial, Papi and colleagues evaluated daily 100 mg of hydrofluoroalkane (HFA)-beclomethasone versus as needed two puffs of 50 mg of HFA-beclomethasone dipropionate (BDP) and 100 mg salbutamol combined in a single inhaler. There was no significant group difference in morning PEF, exacerbations, symptoms and rescue b2-agonists use; thus, the authors concluded that both strategies were equivalent. The evidence in paediatrics is also limited to two trials, but several ongoing studies will shed more light on the topic in the near future (NCT00675584; NCT00394329). Turpeinen and colleagues designed an 18-month, 3-arm randomised controlled trial to carefully examine the efficacy and the safety profile of intermittent therapy in children with newly diagnosed asthma (mean baseline FEV1 of 85% of the predicted value). All groups received rescue 800 mg/day of budesonide for 10 days and rescue terbutaline for exacerbations. After 6 months of identical therapy with 800 mg/day of budesonide for 1 month and 400 mg for 5 months, daily low-dose (200 mg/day) budesonide was associated with 60% fewer exacerbations and fewer withdrawals due to exacerbations requiring rescue oral corticosteroids than the intermittent group. There was no significant difference in symptom-free days, morning PEF and FEV1, although for several variables the values for the intermittent group were intermediate between that of daily budesonide and cromoglycate. Finally, Martinez and colleagues examined in children with persistent asthma (mean baseline FEV1 of 100% of the predicted value), daily 100 mg of HFA-beclomethasone versus as-needed 100 mg of HFA-beclomethasone combined with 200 mg salbutamol in a single inhaler. There was no group difference between daily and as-needed beclomethasone in any outcomes, with the exception of expired nitric oxide, which was significantly lower throughout the study for daily beclomethasone. How does one reconcile these findings? In an emerging field of a new therapy, the absence of group difference in certain outcomes always raises the issue as to whether the findings are evidence of no effect (real equivalence) or no evidence of effect (lack of power). Giving the size of the confidence intervals, the latter is at play for several outcomes. This issue Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada; Research Centre, CHU Sainte-Justine, Montreal, Quebec, Canada