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Eur Respir J 2004; 24:420-425
Copyright ©ERS Journals Ltd 2004

Side-effects of fluticasone in asthmatic children: no effects after dose reduction

M.J. Visser1, E. van der Veer2, D.S. Postma1, L.R. Arends3, T.W. de Vries4, P.L.P. Brand5 and E.J. Duiverman6

Depts of 1 Pulmonology, 2 Pathology and Laboratory Medicine, 6 Paediatric Pulmonology, University Hospital Groningen, 3 Dept of Epidemiology and Biostatistics, Erasmus Medical Centre, Rotterdam, 4 Dept of Paediatrics, Medical Centre, Leeuwarden, and 5 Dept of Paediatrics, Division of Paediatric Pulmonology, Isala Klinieken, Zwolle, the Netherlands

CORRESPONDENCE: M.J. Visser, Dept of Pulmonology, University Hospital Groningen, P.O.Box 30,001, 9700 RB, Groningen, the Netherlands. Fax: 31 503619320. E-mail: M.Visser@int.azg.nl

Keywords: Adrenal cortex, bone metabolism, fluticasone, height, hyperresponsiveness

Received: February 25, 2004
Accepted April 20, 2004

This study was supported by GlaxoSmithKline (the Netherlands), De Stichting Astma Bestrijding, University Hospital Groningen and the University of Groningen.


   Abstract
TOP
 Abstract
Methods
 Results
 Discussion
 Acknowledgements
 References
 
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.

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
TOP
 Abstract
 Methods
Results
 Discussion
 Acknowledgements
 References
 
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) <80 µg) after stopping ICS 18. Study treatment consisted of either 200 µg·day–1 FP for 2 yrs (constant-dose group) or a high starting dose of FP (1,000 µg·day–1), followed by reductions every 2 months to 500, 200 and 100 µg·day–1 during the remaining 1.5 yrs (step-down group) in a double-blind protocol (fig. 1aGo). Patients were asked to bring all used and unused medication to each follow-up visit, and adherence to treatment was assessed by counting the medication "blisters" used. Randomisation was performed using a computer program with stratification for age, sex, duration of prior ICS use and PD20.



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  		Fig. 1.— a) Study design comparing different dosing schedules (step-down approach (–––); continuous approach (...)) of inhaled fluticasone propionate (FP) for 2 yrs in asthmatic children. b) Measurements of airways hyperresponsiveness (AHR), height, bonemarkers, cortisol metabolites and bone mineral density (BMD) were made during the study. Parts of this figure have been previously published 6. #: 200 µg·day–1; : 1,000 µg·day–1; +: 500 µg·day–1; §: 100 µg·day–1.

 
The study was approved by the medical ethics committees of the three participating centres.

Outcome measurements
Expiratory flow/volume curves were obtained with a Jaeger Masterlab pneumotachograph (Eric Jaeger GmbH, Würzburg, Germany) according to the guidelines of the European Respiratory Society 19. AHR to methacholine was measured using a dosimeter method as published previously 18. Patients kept symptom and peak flow diaries during the study. These data have been published previously and will not be reported here 6.

Height was measured at predetermined intervals (fig. 1bGo) by trained technicians, using a calibrated Harpenden stadiometer (Holtain, Crymych, UK). Growth velocity in cm·yr–1 was calculated from changes in height over time. Bone age of the left hand was determined at randomisation and after 1 and 2 yrs using the Tanner and Whitehouse method by a single blinded investigator 20. Tanner's pubertal stages were scored at each follow-up visit 21. BMD of the spine was measured by dual energy X-ray absorption from L1 to L4, using a Hologic QDR-4500 C Elite (Hologic, Bedford, MD, USA) 22.

Serum osteocalcin and amino-terminal propeptide of type-1 procollagen (P1NP), markers of bone formation, were measured using the immunoradiometric assay of Medgenix-H-Ost (Fleurus, Belgium) and radio-immunosorbent assay kit of Orion Diagnostica (Espoo, Finland), respectively. Urinary deoxypyridinoline (Dpyr) and pyridinoline (Pyr), products of bone degradation, were analysed for calcium and creatinine with a Chemistry Analyser (Merck Mega, Darmstadt, Germany) and for Dpyr and Pyr by high-performance liquid chromatography. Urinary excretion of Dpyr and calcium was corrected for urinary creatinine.

Total cortisol metabolite excretion was measured using 24 h urine (i.e. urine collected 24 h before) at preset visits (fig. 1bGo) by gas/liquid chromatography as described previously 23. The following major metabolites were determined: tetrahydrocortisone, tertahydrocortisol, allotetrahydrocortisol, {alpha}-cortol, {alpha}-cortolone, ß-cortol and ß-cortolone.

Statistical analysis
Comparisons between and within both treatment groups across time points were performed by a linear mixed model. These comparisons were made both when differences in FP doses between groups were large (first months of the study) and when they were small (fig. 1aGo). Two-tailed p-values of p<0.05 and 0.05<p<0.1 were considered to be statistically significant.


   Results
TOP
 Abstract
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Subjects
In total, 55 asthmatic children were included in the study: 27 were allocated to the constant-dose group and 28 to the step-down group. Baseline characteristics are shown in table 1Go; both treatment groups were comparable. During the 2-yr study, seven children were withdrawn: four from the step-down group (three due to exacerbation, one because of abnormal bone density) and three from the constant-dose group (two because of insufficient asthma control, one due to an exacerbation of asthma). Mean adherence to treatment was 94% in both groups and remained stable throughout the 2-yr study period.


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  		Table 1— Baseline characteristics at randomisation

 
Airways hyperresponsiveness
AHR deteriorated during the wash-out period after withdrawal of FP and improved in both groups after reinstitution of inhaled FP (fig. 2aGo). At 4 months treatment, a statistically significant difference was found between the two groups (500 µg·day–1 FP versus 200 µg·day–1 FP). Over the remainder of the 2-yr treatment period, AHR was comparable between the two groups (fig. 2aGo).



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  		Fig. 2.— a) Airways hyperresponsiveness to the provocative dose of methacholine causing a 20% drop in forced expiratory volume in one second (PD20) in asthmatic children during and after 2-yr treatment with different dosing schedules (step-down approach (–––); continuous approach (...)) of inhaled fluticasone propionate; b) urinary total cortisol metabolite excretion (µmol·24 h–1, corrected for creatinine excretion and body surface area during the 2-yr study period); c) standing height; and d) growth velocity. Parts of figure 2a and cGo have been previously published 6. Data are presented as mean values and bars represent standard error of the mean. *: p<0.05; **: p<0.01; ***: p<0.001; #: 0.1 (step-down versus constant-dose group).

 
Standing height
Children in the step-down group were slightly taller (mean 3.3 cm) at the start of the study than those in the constant-dose group (fig. 2cGo). Standing height increased comparably inchildren treated according to the step-down group and the constant-dose group during the 2-yr study. In addition, changes in bone age were similar in the two groups.

Growth velocity
Growth velocity was similar in the two groups at the start of the study (fig. 2dGo). A significant dose-dependent negative effect on growth velocity appeared after 2 months treatment (1,000 µg·day–1 FP versus 200 µg·day–1 FP). After tapering off 1,000 µg·day–1 FP, growth velocity increased when compared with the constant-dose group, which was significant at 6 months (200 µg and 100 µg FP versus 200 µg) and borderline significant at 4 and 8 months treatment (500 and 100 µg·day-1 FP versus 200 µg·day-1 FP, respectively). After 1 yr of treatment, growth velocity was significantly higher in the step-down group than in the constant-dose group (100 µg·day–1 FP versus 200 µg·day–1 FP), but this difference had disappeared at the end of the 2-yr treatment period.

Bone markers
Serum osteocalcin levels did not significantly differ between groups at randomisation (fig. 3a, b and cGo). Children treated with 1,000 and 500 µg·day–1 FP had significantly lower serum osteocalcin levels than children treated with 200 µg·day–1 FP (fig. 3aGo). When both groups used 200 µg·day–1 FP (at the 6-month visit) or 200 µg and 100 µg·day–1 FP (at the 8-month visit), serum osteocalcin levels were similar. Thereafter, osteocalcin levels increased during the 100 µg·day–1 FP treatment, whereas they remained stable in the group using 200 µg·day–1 FP constantly, which resulted in significantly higher osteocalcin levels in the step-down group (100 µg·day–1 FP). Both serum P1NP and the urinary Dpyr levels decreased significantly during treatment with 1,000 and 500 µg·day–1 FP compared with 200 µg·day–1 FP (fig. 3b and cGo). After 12 and 18 months treatment, a significantly higher P1NP level was present in the step-down group (100 µg·day–1 FP) compared with the constant-dose group (200 µg·day–1 FP; fig. 3bGo), which became similar after 24 months. Urinary Dpyr levels in the step-down group (100 µg·day–1 FP) were only significantly higher after 18 months treatment when compared with the constant-dose group (200 µg·day–1 FP; fig. 3b and cGo).



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  		Fig. 3.— Bone turnover markers of inhaled fluticasone propionate in asthmatic children during and after treatment with different dosing schedules (step-down approach (–––); continuous approach (...)). a) Serum osteocalcin levels (ng·mL–1); b) serum amino-terminal propeptide of type-1 procollagen (P1NP) levels (ng·mL–1); c) urinary deoxypyridinoline (Dpyr) levels (nMol·mMol–1 creatinine); and d) bone mineral density (BMD) z-score. Data are presented as mean values and bars represent standard error of the mean. *: p<0.05; **: p<0.01; ***: p<0.001 (step-down versus constant-dose group).

 
The results of the urinary Pyr levels were similar to the Dpyr levels (data not shown) and the ratio of urinary Pyr/Dpyr was similar between the two groups at all time points of the study.

Bone mineral density
BMD was similar at baseline, 1-yr and 2-yr treatment in both groups and changes between visits and between groups were not significant (fig. 3dGo).

24-h urinary cortisol metabolite excretion
After randomisation, urinary cortisol metabolite excretion was significantly lower during treatment with 1,000 and 500 µg·day–1 FP when compared to 200 µg·day–1 FP (fig. 2bGo). No further significant differences were found between the groups.


   Discussion
TOP
 Abstract
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study investigated the long-term side-effects of ICS inchildhood asthma in a prospective way. Children were either treated with a constant dose of FP (200 µg·day–1) or inaccordance with a step-down strategy, with a very high starting dose of FP (1,000 µg·day–1), tapering down over a period of 6 months to a low maintenance dose (100 µg·day–1). The current authors previously demonstrated that the step-down strategy was not superior to the constant-dose strategy over a 12-month period, with respect to symptoms, exacerbation rates, lung function and AHR 6. In addition, the present results show that the second year provided nodifferences in asthma control (200 µg·day–1 FP versus 100 µg·day–1 FP). The current study strongly suggests, therefore, that a step-down strategy is not superior to a constant-dose strategy in the long-term management of childhood asthma. It should be noted, however, that the children in this study had all been using ICS prior to entering the study, being school-aged children with mild-to-moderate persistent asthma. Further studies are needed to assess whether a step-down strategy is superior to a constant-dose treatment schedule in steroid-naïve children with newly diagnosed asthma or in children with mild or severe persistent asthma.

During the later stages of the study, when the dose of FP was ≤200 µg in both treatment groups, there were no between-group differences in terms of safety parameters. Standing height, growth velocity, serum P1NP, urinary Dpyr excretion, BMD and adrenal function as assessed by cortisol metabolite excretion were all comparable between groups atthe end of the study (figs 2 and 3GoGo). Moreover, most parameters did not change from baseline, when no ICS were used for a maximum of 8 weeks, to the end of the study in thegroup using a constant dose of 200 µg·day–1 FP (figs 2 and 3GoGo). These observations are in accordance with earlier work showing that maintenance treatment with a regular and constant dose of ICS, i.e. 200 µg·day–1 FP in the current study, has no systemic side-effects on bone turnover, height and adrenal cortical function 24–29.

Two parameters of bone metabolism did not follow this pattern. Initially, serum levels of osteocalcin, a parameter of bone formation, were lower in the step-down group when doses of 1,000 and 500 µg·day–1 FP were used, but increased when the FP dose was tapered off to 100 µg·day–1 to significantly higher levels than those in the constant-dose group (fig. 3aGo). Until now, no studies have examined the effects of different dosages of ICS on osteocalcin levels inchildren. Although one retrospective study and one nonrandomised open study showed reduced osteocalcin levels during ICS therapy, two randomised clinical trials showed no effect of beclomethasone in doses ≤400 µg·day–1 or 200 µg·day–1 FP on serum osteocalcin 30–33. The relevance of the dose-dependent effects of inhaled FP on serum osteocalcin levels observed in this study is unclear (fig. 3aGo). Nevertheless, it is not reflected in effects on BMD, which remained stable throughout the study (fig. 3dGo). The current authors' results, like others, suggest that serum osteocalcin and BMD represent different phases of bone metabolism, with biochemical bone markers reflecting continuous remodelling and BMD reflecting long-term structural changes 33.

The current study clearly shows a negative direct effect ofhigh-dose FP on biochemical bone turnover parameters, which abate after treatment with lower doses for ≤2 yrs. Throughout the study, BMD did not differ significantly between the two study arms, suggesting no detrimental effect of overall long-term use of FP on BMD in asthmatic children. Within the group treated with a constant dose of 200 µg·day–1 FP, a trend towards a decrease in BMD in the first year was observed, which became statistically significant in the second year of treatment. This result should be interpreted with caution. It contrasts with the Childhood Asthma Management Program study where 200 µg of budesonide·day–1, given during 4–6 yrs, did not affect BMD 7.

Moreover, the current study was not double-blinded with placebo and other long-term studies with FP in children are lacking. Finally, the step-down group used a higher cumulative dose of FP during the first year (120,000 µg) than the constant-dose group (72,000 µg); nevertheless, changes in BMD in the step-down group were not significant. Thus, there were no significant differences in BMD changes over time between the two study groups and, if anything, a worsening of BMD only in the group treated with the overall lowest dose. Clearly, further long-term studies are needed toevaluate effects of low-dose ICS treatment on BMD in children.

The most prominent finding of the current study is themarked negative effects of high-dose FP (1,000 and 500 µg·day–1) on growth velocity and adrenal cortical function (fig. 2Go) and on biochemical markers of bone turnover and BMD (fig. 3Go). A reassuring finding is that these effects areshort-lived and fully reversible when the dose of FP is tapered down. Furthermore, prolonged use of ICS may provide less negative effects than short-term therapy 34. In any case, the magnitude of the observed findings warrants a note of caution because it suggests a clear potential for clinically relevant side-effects if high dosages of FP are continued for prolonged periods of time. Indeed, clinically relevant growth suppression and adrenal failure have been described anecdotally in children receiving high-dose FP therapy 15, 35–38.

In conclusion, the current study shows that maintenance therapy with inhaled fluticasone propionate in dosages of ≤200 µg·day–1 appears to be safe in the long-term management of childhood asthma. Nevertheless, marked reduction of growth velocity, biochemical bone turnover and adrenal cortical function occurs during treatment with high dosages of inhaled fluticasone propionate. Given the current findings that high-dose fluticasone propionate therapy is no more effective than a "regular dose" and that it may cause clinicallysignificant side-effects, it is proposed that high dosages of inhaled fluticasone propionate should be prescribed for exceptions, e.g. in persistent severe asthma. These results provide a guideline to use the lowest effective dose ofinhaled corticosteroids in order to prevent systemic side-effects.


   Acknowledgements
TOP
 Abstract
 Methods
 Results
 Discussion
 Acknowledgements
References
 
The authors thank A.W.A. Kamps for including the children and collecting the data, D.A. Piers for performing the bone mineral density measurements, and J.C. van der Molen and G. Hofstede for performing the laboratory measurements during the study.


   References
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 Abstract
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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A. D. Smith, J. O. Cowan, K. P. Brassett, G. P. Herbison, and D. R. Taylor
Use of Exhaled Nitric Oxide Measurements to Guide Treatment in Chronic Asthma
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