Relevant BNF section: 3.2
In the UK around 1 in 5 children will have been diagnosed as having asthma at some stage before they reach 15 years old.1 The use of inhaled corticosteroids has done much to reduce morbidity in these children and current British Guidelines recommend the use of inhaled corticosteroids in all but mild childhood asthma.2 However, there are concerns about the long-term safety of such treatment in growing children, and the benefits and risks of their use need careful evaluation. In this article we review the place of inhaled corticosteroids in childhood asthma.
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Relevant BNF section: 3.2
There are at least two clinical syndromes commonly regarded as asthma in children. In the first, 'classical' childhood asthma, the child has perennial but variable symptoms of wheeze and dyspnoea, often associated with atopy; in the second, 'viral episodic wheezing', the child has intermittent episodes of wheezing and dyspnoea induced by viral infection of the upper respiratory tract, but no symptoms between infections.3 This second type, which is not associated with atopy, is common in younger children (often under 3 years old). The natural history, response to treatment, and the place for inhaled corticosteroid, appear to be different for these two common patterns of illness. It should be emphasised, however, that some children's symptoms do not fit easily into these two categories, and that within each category the severity and frequency of attacks can vary.
The British Guidelines on Asthma Management recommend starting regular prophylaxis with inhaled anti-inflammatory therapy at Step 2, that is, in any child needing a short-acting β2-agonist for symptom relief more than once daily.2 The initial choice is between an inhaled corticosteroid and sodium cromoglycate, but an inhaled corticosteroid should be used if cromoglycate fails to reduce symptoms of asthma.
Licensed use in children
Three inhaled corticosteroid preparations are licensed in the UK for use in children.
Beclometasone dipropionate (BDP) is available for use, via a pressurised metered dose inhaler (MDI), with or without a large-volume spacing chamber, or as a dry powder from devices such as the Diskhaler. The maximum recommended dose for children is 400µg daily.
Budesonide can be given by MDI, with or without a spacer, and as a dry powder via a Turbohaler. The maximum recommended dose in children is 800µg daily. Budesonide is also licensed for use as a nebulised solution (0.5-1.0mg twice daily) in children over 3 months old.
Fluticasone propionate (FP) is available for use as an MDI, with or without a spacer, or as a dry powder from a Diskhaler or Accuhaler. It is licensed for use in children over 4 years old. FP should usually be introduced at half the daily dose of BDP or budesonide. The maximum recommended dose is 200µg daily.
Pressurised MDIs that use chlorofluorocarbon (CFC) propellants are gradually being phased out and replaced by non-CFC devices. A CFC-free formulation of BDP is already available for use in adults (▼Qvar - 3M), but at present no CFC-free device is licensed for use in children.
Reducing background symptoms
There is abundant evidence that in children with classical asthma, regular use of an inhaled corticosteroid reduces airway hyper-responsiveness, improves lung function, and ameliorates background symptoms (such as daytime or night-time wheeze or sleep disturbance). All three inhaled corticosteroids have been shown in double-blind, placebo-controlled trials to reduce background symptoms in pre-school and school-age children with mild or moderate asthma, when given in licensed doses by dry powder or MDI, with or without a spacer.4–7 Similar improvement has been reported in small double-blind trials in infants given budesonide via a large volume spacer with a face mask.8 A few double-blind placebo-controlled trials have included children with severe asthma,5,8,9 and other evidence of benefit in severely asthmatic children is suggested by uncontrolled case series and open studies.
In contrast to classical asthma, background symptoms are not a feature of typical viral episodic wheezing. From this point of view, therefore, taking a regular inhaled corticosteroid would not be expected to help a child with this type of asthma.
Randomised double-blind studies in children with classical asthma have shown that, in those who inhale corticosteroid daily, there is a fall in the frequency and severity of acute exacerbations.4,6,8 In a 1-year study in schoolchildren with mild or moderate persistent asthma, 5% of those given BDP 400µg daily withdrew from the trial because of an exacerbation, compared with 15% given placebo.4 In a long-term observational study, fewer hospital admissions for asthma occurred among children regularly inhaling budesonide compared with the pre-treatment period or with the admission rate in similar children not receiving inhaled corticosteroid therapy.10
On the limited evidence available, the position is different in children with viral episodic wheezing. In a double-blind study in 41 children (aged 8 months to 6 years) with predominantly episodic wheeze and little or no wheezing between episodes, daily budesonide (400µg via a spacer) for 4 months did not reduce the frequency or severity of attacks in comparison with placebo.11 In a community-based, placebo-controlled study involving 104 children (aged 7-9 years) with a history suggestive of viral episodic wheeze, daily treatment with BDP (400µg via Diskhaler) over the autumn and winter, improved lung function but did not reduce the frequency, severity or duration of wheezing attacks.12
Treating acute exacerbations
In patients with classical asthma who are already taking an inhaled corticosteroid, it is common practice to double the dose if their asthma deteriorates or at the first sign of an upper respiratory infection,2 but neither in schoolchildren nor in those under 5 years old is benefit proven.
Several small double-blind placebo-controlled studies have investigated whether high-dose inhaled corticosteroid (e.g. budesonide 800-1600µg twice daily) started at the first sign of an upper respiratory infection and given for about a week, could modify or prevent viral episodic wheezing in children under 5 years old.13,14 Overall, such treatment eased symptoms of wheeze and was preferred by parents to placebo, but did not reduce the need for intervention with an oral corticosteroid, hospital attendance or admission.
An open study in Denmark has followed 216 children (aged 3-11 years) with mild or moderate asthma for 1-3 years before, and for 2-6 years after, the start of regular treatment with a conventional dose of budesonide (given by MDI plus large-volume spacer, or Turbohaler).10 Compared to the pre-treatment phase, and to a group of 62 asthmatic children whose parents did not wish them to receive inhaled corticosteroids, growth in lung volumes and the increase in expiratory flow were greater, and severe exacerbations fewer, during treatment with budesonide.10 The lack of blinding or of a randomised control group means that the findings need to be treated with caution. Importantly, there are no controlled data on whether earlier, rather than later, introduction of inhaled corticosteroids confers any advantage in children.
FP is pharmacologically about twice as potent, microgram for microgram, as BDP.15 Comparisons with budesonide depend on the experimental model used,16 but most studies again suggest a 2:1 potency ratio for FP relative to budesonide. These potency differences are reflected in corresponding differences in dose when equivalent delivery devices are used (so that 100µg FP by MDI is considered clinically equivalent to 200µg BDP or budesonide by MDI). This does not necessarily imply superior efficacy for FP: when titrated to optimally effective doses, all three inhaled corticosteroids can be expected to produce a broadly similar clinical response. The clinical effect of each will depend not only on the dose given but on how much drug reaches the lungs, and this in turn depends on the type of inhaler chosen and how well the child can use it. Data comparing different inhaled corticosteroids apply only to the type of inhaler used in any given comparison and cannot be generalised.
Taken overall, there are insufficient data from double-blind controlled trials to draw firm conclusions on comparative efficacy. Differences in the ratio of safety to efficacy are therefore of greater interest in choosing between inhaled corticosteroids.
Local unwanted effects of inhaled corticosteroids, such as hoarseness and oropharyngeal candidiasis, are reduced by the use of a large-volume spacer (which lessens the proportion of the inhaled dose that is deposited in the oropharynx), and by mouth rinsing and gargling. Lactose-based dry powder formulations, which generally have a low pH, may cause erosive dental damage in children;17 use of a spacer, rinsing, and regular toothbrushing should counter this.
Of more concern is the fate of any absorbed and potentially systemically available corticosteroid. Inhaled corticosteroids can enter the blood in two ways: through absorption of the swallowed fraction, or via the lungs.18 The bioavailability of corticosteroid swallowed and absorbed from the gut is least with FP (<%), because the drug is rapidly and completely metabolised on first pass through the liver; it is highest with BDP (20-30%), while with budesonide it is around 11%.18
Absorption from the lungs avoids first-pass metabolism in the liver. Once absorbed from the lungs, the greater potency and affinity for glucocorticoid receptors, and longer retention in the tissues, might be expected to give FP greater systemic activity than BDP or budesonide. However, the extent of lung absorption will depend on how much of the administered dose reaches the lungs, and the ease with which the corticosteroid then enters the bloodstream, which may be slower with FP. Use of a large-volume spacer increases the proportion of the dose reaching the lungs (from at most 15% with a conventional MDI to perhaps 20-40%); as a result, the contribution of lung absorption to systemic effects is potentially greater. The same is true of any device that enhances deposition of drug in the lungs.
In children, the main concerns are whether inhaled corticosteroids can impair growth, bone turnover, or adrenocortical function.
Effects on growth
The study of growth in asthma, in particular separating the effects of treatment from those of the disease, is notoriously difficult. Compared with otherwise healthy children, those with asthma tend to have slower prepubertal growth velocity, later onset of puberty and a relatively delayed bone maturation whether or not they receive treatment with a corticosteroid.20,21 Growth retardation is, however, exaggerated by exposure to oral corticosteroid, in a dose- and duration-dependent manner22 and by severe or poorly controlled asthma.10
Studies of short-term growth
Using knemometry, which accurately measures short-term linear growth of the lower leg, brief placebo-controlled double-blind studies in schoolchildren with mild asthma, have shown dose-dependent slowing of growth with budesonide, inhaled via MDI plus spacer. However, over 8 weeks, this slowing was significant only with 800µg daily.23 In a small double-blind crossover study, BDP in doses of 400µg or 800µg daily, via Diskhaler, slowed lower leg growth significantly more than FP 200µg daily by Diskhaler.24 In another study, in 48 mildly asthmatic children, lower leg growth rates were similar with budesonide (via Turbohaler) and FP (Diskhaler) when compared at equal (200µg and 400µg daily) doses.25 How the findings of knemometry studies relate to long-term effects on standing height is not known.
Longer-term studies of statural growth
Measuring height in children is subject to marked intra- and inter-observer variation, while comparisons of height velocity are complicated by seasonal and year-by-year physiological changes in growth rate and by the variable age of onset of puberty. Many early studies on growth in children with asthma were open and uncontrolled and did not take adequate account of these factors. Better long-term studies are now being published.
Beclometasone dipropionate - A meta-analysis of 21 largely uncontrolled studies conducted before 1993, comparing attained with predicted heights in children with asthma, found no evidence that BDP, inhaled in doses of 200-900µg daily, affected final height.22 However, in several more recent randomised double-blind trials in schoolchildren with mild or moderate asthma, BDP (400µg by MDI or dry powder), taken daily for 7 months to 1 year, slowed growth by around 1.0-1.5cm per year when compared with placebo or an active comparator such as oral theophylline or inhaled salmeterol.4,26,27
Budesonide - In the only randomised placebo-controlled double-blind study to investigate statural growth during treatment with budesonide, 600µg, taken daily by MDI for 22 months, did not slow growth in asthmatic teenagers.28 In an observational study in schoolchildren with mild or moderate asthma, growth rate was the same during 2-6 years' treatment with budesonide in daily doses of up to 400µg daily (via MDI plus spacer or Turbohaler) as it was before the start of the treatment, and the same as growth in similar asthmatic children not treated with inhaled corticosteroid;10 at doses above 800µg budesonide daily, some slowing of growth could not be excluded.10
Fluticasone propionate - In a randomised double-blind trial involving 268 prepubertal children with mild or moderate asthma, FP (100-200µg given daily for 1 year by Diskhaler) caused no slowing of growth (compared with expected growth velocity or that found with placebo).7 In a double-blind study in 23 children with moderately severe asthma, those receiving FP 200µg daily (via MDI plus spacer) grew normally (5.75 cm per year; on the 50 percentile) while those receiving BDP (400µg daily) grew more slowly (4.94cm per year; 0.4 percentile).
Several studies suggest that the final adult height of children with asthma is normal, whether or not inhaled corticosteroids have been used in treatment.21,22,29 However, these data largely precede present day trends to wider use of inhaled corticosteroids in children with relatively mild asthma, and use of much bigger doses in children with severe asthma. Growth suppression can certainly occur if very high doses of corticosteroids (e.g. more than 1000µg FP daily, or equivalent) are inhaled,30 and may occur idiosyncratically at normal doses.31 It is therefore important that growth is monitored regularly in any child receiving an inhaled corticosteroid. Moreover, until growth is complete, it is prudent for any child needing a high maintenance dose (i.e. above the licensed recommendation) to be supervised by a paediatrician.
Effects on bone
There is at present no evidence to suggest that inhalation of corticosteroids long-term for childhood asthma is associated with increased risk of osteoporosis or fractures in children or adults. Cross-sectional and small longitudinal studies have generally found no detrimental effect on bone mineral density, as assessed by dual X-ray absorptiometry, in children who have received long-term (2-6 years) treatment with BDP, budesonide or FP in conventional doses.9,32,33 Some studies have shown a reduction in biochemical markers of bone and collagen turnover in children receiving budesonide or BDP at doses of 800µg daily,34,35 but the clinical importance of the findings is unknown.
Effects on adrenal function
Numerous studies have investigated the effect of inhaled corticosteroids on the hypothalamic-pituitary-adrenal (HPA) axis. Differences in study design, and in the sensitivity of the tests, have led to conflicting results, but it appears that all three inhaled corticosteroids have the potential for dose-dependent suppressive effects.16 The magnitude of these effects depends on the means of delivery, as well as the dose, systemic bioavailability and systemic potency of the corticosteroid.
Mild suppression of basal endogenous cortisol secretion by corticosteroids inhaled in normal therapeutic doses is unlikely to be clinically important. Suppression of the normal adrenal response to physiological stress would be potentially more serious, but several studies have shown a normal response to adrenocorticotrophin (Synacthen) during regular treatment with inhaled corticosteroids in licensed doses.5,26 With high doses, the potential for clinically important suppression is greater.,30 Differences between the inhaled corticosteroids are controversial: several direct comparisons suggest greater adrenal suppression with BDP than with equieffective doses of budesonide36 or FP.9,35 However, a recent meta-analysis, which included data from 27 randomised controlled studies (mainly in adults), concluded that, because of its steeper dose-response, the potential for systemic effects on the HPA axis is greatest with FP, especially at doses above 800µg daily.
Other systemic effects
Treatment of 157 children with budesonide (mean dose 504µg daily) for 3-6 years was not associated with development of posterior subcapsular cataract, bruising or voice changes compared to age-matched asthmatic children who had not been exposed to exogenous corticosteroids.37
Determining the dose
It is important that children requiring an inhaled corticosteroid receive an adequate, but not excessive, dose. For all three corticosteroids, the range of doses recommended at Step 2 in the British Guidelines exceeds the doses recommended in the licence.2 The doses recommended at Step 3 and Step 4, in children with severe or inadequately controlled asthma, are considerably higher (800-2000µg BDP daily, or equivalent). This reflects the importance given to gaining control of asthma as quickly as possible; once this has been achieved, the aim is gradually to reduce the daily dose (by 25-50% every 1-3 months) to the lowest dose needed to maintain good control of asthma ('Step down' approach). The concern, however, among some respiratory paediatricians is that children may be left on an unnecessarily high dose of inhaled corticosteroid for too long. It is essential that the dose is stepped down in the way described once control is achieved (i.e. the child has minimal symptoms, unrestricted activity, and sustained improvement in lung function without significant diurnal variation in peak expiratory flow).
Suboptimal control of background symptoms and lung function despite inhaled corticosteroid should not be an automatic indication for increasing the dose. Adherence to the prescribed regimen, and the child's inhaler technique should be checked, and possible correctable causes (e.g. exposure to allergen) sought. The diagnosis may need to be reviewed, and the responsiveness to corticosteroid checked. The dose-response curve for symptoms and lung function is relatively flat for all the inhaled corticosteroids, so increasing the dose may give little clinical benefit but could increase the risk of unwanted effects. In children already receiving a maximum licensed dose of inhaled corticosteroid, the addition of a long-acting β2-agonist may be as useful as increasing the dose of inhaled corticosteroid.38 However, in some children with severe asthma, regular treatment with a high dose of inhaled corticosteroid may be the only alternative to regular oral corticosteroid therapy.
Which inhaler device?
The inhaler device should be one that the child and the parents prefer and that the child is able to use. An MDI with a large-volume spacer is often a reasonable first choice in children because it does not require close co-ordination of actuation and breathing, minimises oropharyngeal deposition (and so local unwanted effects) and limits the amount of drug swallowed and absorbed. For drugs with low first-pass metabolism (i.e. BDP) this should reduce systemic availability. The dose of inhaled corticosteroid may need adjustment if the type of delivery device is changed. For instance, with the Turbohaler, only about half the dose of budesonide may be needed for equal efficacy to budesonide from an MDI plus spacer.39 In general, administration of corticosteroid via a nebuliser has few if any advantages over an MDI plus spacer (fitted with a face-mask where necessary) and is rarely indicated. Delivery systems for anti-asthma drugs, including CFC-free inhalers, will be reviewed more fully in a future article.
The main role of inhaled corticosteroid in childhood asthma is to control background symptoms and exacerbations in those with persistent or perennial wheezing. Inhaled corticosteroids are less helpful in viral episodic wheezing, where there are no interval symptoms. Data on long-term outcome are few, and it is not known whether earlier, rather than later, treatment with inhaled corticosteroid holds advantages. Despite differences in pharmacological potency, there seems little to choose between beclometasone dipropionate (BDP), budesonide and fluticasone propionate (FP) in terms of clinical efficacy.
Clinically apparent adverse effects are uncommon with inhaled corticosteroids when used in licensed doses. At such doses, any differences in systemic activity between BDP, budesonide and FP appear mainly subtle, detectable chiefly by surrogate measures such as knemometry. However, there is some evidence that BDP, in daily doses of 400µg, can slow statural growth in the medium term. While inhaled corticosteroids have not been shown to affect final adult height, it is important that growth is carefully monitored in any child receiving an inhaled corticosteroid. For children with severe asthma, who need to inhale high doses of corticosteroid, and for children with milder asthma, in whom the benefits of long-term inhaled corticosteroid therapy may be more marginal, much clearer evidence is needed on the ratio of safety to efficacy for each corticosteroid.
Children who need inhaled corticosteroids should use a delivery device that they prefer and can manage; a pressurised metered dose inhaler (MDI) with a large-volume spacer is often a good first choice. Once control of asthmatic symptoms and improvement in lung function have been achieved, the daily dose of inhaled corticosteroid should be reduced gradually to the lowest effective maintenance dose. Up to a daily maintenance dose of 400µg, BDP still seems a good choice. In the dose range 400-800µg daily, only budesonide is licensed; the equivalent dose of FP, while being as effective and safe, costs slightly more. Whichever corticosteroid is given, children needing high maintenance doses are probably best supervised by a paediatrician.
[M=meta-analysis; R=randomised controlled trial]
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