European Respiratory Journal 2004 24: 420-425; DOI: 10.1183/09031936.04.00023904
Abstract
To assess long-term effects and side-effects of fluticasone propionate [FP], a 2-yr study was performed, comparing a step-down dose approach [1,000 µg·day−1, with reductions every 2 months to 500, 200 and 100 µg·day−1 for the remainder of the study] versus a constant dose [200 µg·day−1].
In 55 children with chronic persistent asthma, aged 6–10 yrs, airways hyperresponsiveness [AHR] and systemic side-effects [height, bone parameters and adrenal cortical function] were assessed at predetermined intervals in a double-blind prospective 2-yr study.
AHR improved after 4 months treatment with 1,000 µg·day−1 FP followed by 500 µg·day−1, without significant differences during long-term treatment between the two approaches. Dose-dependent reduction of growth velocity, adrenal cortical function and biochemical bone turnover was found during therapy with 1,000 and 500 µg·day−1 FP when compared with 200 µg·day−1.
In conclusion, doses of 1,000 and 500 µg·day−1 fluticasone propionate are associated with marked reductions of growth velocity, bone turnover and adrenal cortical function. However, conventional doses [≤200 µg·day−1 fluticasone propionate] appear to be safe in the long-term management of childhood asthma. From a safety point of view, high doses of fluticasone propionate should only be prescribed in exceptions, e.g. in persistent severe asthma.
- Adrenal cortex
- bone metabolism
- fluticasone
- height
- hyperresponsiveness
This study was supported by GlaxoSmithKline [the Netherlands], De Stichting Astma Bestrijding, University Hospital Groningen and the University of Groningen.
Inhaled corticosteroids [ICS] are the cornerstone of asthma treatment. As these drugs are highly effective in improving symptoms, lung function, airways hyperresponsiveness [AHR] and quality of life in asthmatic children, they are recommended as controller therapy in all but the mildest forms of childhood asthma 1–4.
Although current guidelines advise treatment with ICS indoses ≤400 µg·day−1, it has been advocated to start ICS therapy in childhood asthma with a high dose, in order to reduce airway inflammation powerfully, and to subsequently taper off to the lowest effective dose [“step-down” strategy] 4. It is also advocated to double the dose of ICS when asthma deteriorates. As a result, high dosages of ICS are frequently used, but very limited data is available on the effects and side-effects of high-dose ICS therapy in children 5. In a previous report on the same study, the current authors have shown an initial improvement in AHR in children with asthma during high-dose fluticasone propionate therapy [FP; 1,000 µg·day−1 for 2 months, followed by 2 months of 500 µg·day−1] compared with children treated witha constant dose of 200 µg·day−1 FP 6. When the dose of FP was tapered to 100 µg·day−1, no differences were found between asthmatic children treated with this step-down approach and children using 200 µg·day−1 FP during the full1-yr follow-up. Thus, the step-down approach does not appear to be superior to a constant-dose approach of FP in children with chronic persistent asthma.
Concerns regarding the adverse effects of ICS on growth in children have been relieved by recent reports showing normal height during ICS treatment for 4–6 yrs and normal final height at adult age after long-term ICS therapy [budesonide, mean dose 400 µg·day−1] 7, 8. Although effects of ICS on bone mineral density [BMD] in adults have been described, studies in children did not demonstrate reduction of BMD during ICS treatment 7, 9–13. Even during long-term treatment, therefore, ICS appear to be safe, but clinically relevant systemic side-effects have been reported anecdotally 14–17.
The current report deals with the second year of follow-up of a previously published double-blind study that was designed to compare effects of different dosage schedules of FP during 2-yr follow-up in these asthmatic children, focusing on systemic side-effects.
Methods
Study subjects and study design
Recruitment of patients and the study design have been published previously 6. Briefly, 55 asthmatic children, 6–10 yrs of age, with a diagnosis of mild-to-moderate persistent asthma were recruited from the outpatient clinics of three participating hospitals [University Hospital Groningen, Groningen, and Medical Centre, Leeuwarden, and Isala Klinieken, Zwolle, The Netherlands]. Patients were randomised to treatment with FP [Diskhaler®; GlaxoWellcome, Zeist, the Netherlands] when they developed AHR [defined as the provocative dose of methacholine causing a 20% drop in forced expiratory volume in one second [PD20]