COMMENTARY

Drug Safety 9 (I): 9-20, 1993 0114-5916/93/0007-0009/$06.00/0 © Adis International Limited. All rights reserved. DRS1180

Inhaled Corticosteroids in Children Is There a 'Safe' Dosage? Attilio L. Boner and Giorgio L. Piacentini Department of Paediatrics, University of Verona, Verona, Italy

Contents 9 10 11 JJ 12 12 12 13 /5

15 16 16 16

Summary

Summary I. Activity and Metabolism of Inhjlled Corticosteroids 2. The Changing Role of Inhaled Steroids in the Treatment of Asthma in Children 3. Tolerability of Inhaled Steroids 3.1 Topical Adverse Effects 3.2 Systemic Effects 3.2.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression 3.2.2 Effects on Growth 3.2.3 Bone Metabolism 3.2.4 Other Systemic Adverse Effects 4. Use of a Spacer Device to Reduce Adverse Effects 5. Nebulised Corticosteroids in Infants 6. How Much is 'Safe' in Children?

Inhaled corticosteroids are effective for the treatment of asthma. Because of the appreciation of the importance of airway inflammation in the pathogenesis of the disease, these drugs are being used more frequently not only in severe but also in moderate asthma. Treatment rarely has to be stopped because of topical adverse effects since oropharyngeal candidiasis and dysphonia are uncommon in children. However, paediatricians need to remain alert for the possibility of systemic .adverse effects. With sensitive techniques, dose-dependent adrenal suppression has been documented in children treated with inhaled steroids but generally this effect has no clinical relevance. Although suppression of short term growth velocity has been reported, long term studies have shown that when growth impairment occurs in a child with asthma it is more likely to reflect poor asthma control than the administration of inhaled corticosteroids. Calcium supplementation may be necessary in children with asthma treated with inhaled steroids since this treatment may cause reduction in osteocalcin, a marker of osteoblast activity and bone formation. Other systemic adverse effects have been reported in case reports. The use of a large spacer device has been shown to reduce the incidence of both topical and systemic adverse effects from inhaled steroids and their use should be encouraged. In any child with asthma who really needs inhaled steroids, the lowest dose possible should be prescribed; however, the mistake of prescribing doses too low to be therapeutically effective should be avoided.

Drug Safety 9 (I) 1993

IO

Asthma, as recently defined by an international committee, is 'a chronic inflammatory disorder of the airways in which many cells play a role, including mast cells and eosinophils. In susceptible individuals this inflammation causes symptoms which are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment, and causes an associated increase in airway responsiveness to a variety of stimuli' [National Heart, Lung and Blood Institute (NHLBI) 1992]. The key aspect of this new definition is the pivotal role of inflammation in asthma. This is clear for adults, and probably holds true for infants and children. Although precise data in this age group are scanty it has been shown that children with asthma in remission demonstrate pathological findings similar to those who die of status asthmaticus (Cutz et al. 1978). Moreover, in children with stable asthma there is a correlation between airway hyperresponsiveness and eosinophil counts in bronchoalveolar lavage fluids (Ferguson & Wong 1989). Glucocorticoids have been shown to be the most potent anti-inflammatory agents available for the treatment of asthma and they are now highlighted as the treatment of choice for patients with persistent asthma both in adults (NHLBI 1992) and children (Warner et al. 1989a, 1992). Because of the concern over potential adverse effects of systemic steroids, preparations that could be administered by inhalation and which had fewer systemic reactions were developed.

1. Activity and Metabolism of Inhaled Steroids The properties of an ideal inhaled glucocorticoid that are associated with a favourable ratio of pulmonary vs systemic activity are: (a) potent glucocorticoid activity at the local site of application (i.e. high affinity for glucocorticoid receptors); (b) low systemic bioavailability of the swallowed portion of the dose (i.e. poor absorption); and (c) rapid metabolic clearance of the bioactive glucocorticoid that reaches the systemic circulation (i.e. short

plasma half-life). Among the potent glucocorticoids with desirable topical activity are beclomethasone (propionate), triamcinolone (acetonide), flunisolide, budesonide and fluticasone (propionate). Although the pharmacokinetics of each of these steroids are known, relatively less is known for triamcinolone. In respiratory airways, both beclomethasone dipropionate as an intact compound and its first hydrolysis product (beclomethasone monopropionate) act as potent glucocorticoids. When absorbed into the systemic circulation these compounds are biotransformed in the liver to beclomethasone which has much lower glucocorticoid activity (Martin et al. 1974). Budesonide is metabolically stable at the site of application where no biotransformation occurs; it is first inactivated by oxidative biotransformation in the liver (Brattsand et al. 1982). In a similar manner, systemic flunisolide (Chaplin et al. 1980) and fluticasone (Phillips 1990) are rapidly metabolised in the liver by extensive first-pass metabolism to water soluble conjugates which are relatively inactive in the case of flunisolide and completely inactive in the case of fluticasone. Thus, when absorbed into the systemic circulation, the concentration of inhaled steroids is reduced first by dilution and then by the high firstpass metabolism in the liver. The relative potency of different glucocorticoids for inhalation therapy is shown in tables I and II.

Table I. Relative potency of various glucocorticoids for inhalation therapy after topical and oral administration to mice (after Brattsand et al. 1982) Steroid

TAIP (inhibition of ear oedema formation)

Budesonide Beclomethasone Triamcinolone Flunisolide

1 0.4 0.3 0.7

SP (thymus involution)

TAIP/SP

3.5 5.3 12.8

0.1 0.06 0.05

Abbreviations: TAIP = topical anti-inflammatory potency; SP = systemic potency.

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Inhaled Corticosteroids in Children

Table II. Potency of fluticasone and beclomethasone compared with fluocinolone acetonide (after Phillips 1990) Steroid

Fluocinolone Beclomethasone Fluticasone

TAIP

100 21 91

Systemic HPA axis inhibitory potency8 100

49

TAIP: HPA potency ratio

1

0.4 91

a Calculated from the measured reduction of stress-induced plasma corticosterone levels. Abbreviations: TAIP = topical anti-inflammatory potency; HPA = hypothalamus-pituitary-adrenal.

As can be seen, budesonide and fluticasone appear to have a higher topical to systemic potency, on the basis of comparative studies in animal models, than beclomethasone, triamcinolone and flunisolide, which in contrast show similar topical to systemic ratios with decreased potency (Brattsand et al. 1982; Phillips 1990). Any speculation about the comparative efficacy and toxicity of different preparations must, however, rely on clinical trials in patients with asthma. In children with asthma, budesonide has been shown to have at least the same antiasthma tic effect as beclomethasone (Baran 1987) with better systemic tolerability when using higher doses of both compounds (Pedersen & Fuglsong 1988). In clinical studies in children, fluticasone has been found to be approximately twice as effective as beclomethasone (Boner 1992) with less systemic activity (Pedersen 1992). The theoretical advantages of fluticasone will need to be evaluated critically in long term studies. In clinical trials it has been shown that a daily dose of 400~g of beclomethasone is comparable with 5 to IOmg of oral prednisone in the control of asthma (Clark 1980). Flunisolide I mgjday equates with an average of 9 mgjday of oral prednisone without causing serious local or systemic adverse effects (Slavin et al. 1980), and 400~g of budesonide has the same effect in patients with asthma as IOmg of prednisolone (Rosenhall et al. 1982).

2. The Changing Role of Inhaled Steroids in the Treatment of Asthma in Children The observation in adult patients that inflammatory changes are present even in those with mild asthma (Lozewics et al. 1988; Wardlaw et al. 1988) and that these changes may be responsible for bronchial hyper-responsiveness has led to the use of inhaled steroids as first-line therapy for asthma (Haahtela et al. 1991). In several clinical studies (described in Barnes 1990; Kerrebijn 1990) it has been shown that bronchial hyper-responsiveness is reduced by inhaled steroids. Since the magnitude of these effects is fairly small, particularly in adult patients, it has been suggested that effective antiinflammatory regimens with these drugs should be initiated earlier in the course of disease and may be useful in children with asthma to prevent the decline in lung function and persistent bronchial hyper-responsiveness seen in adults with poorly controlled asthma (Barnes 1990). However, more information about the role of inflammation in children with mild asthma and the clinical relevance of adverse effects of inhaled steroids is needed before these drugs can be unequivocally recommended for long term management of children who are not generally considered candidates for glucocorticoid treatment (Larsen 1992; NHLBI 1992; Warner et al. I 989a, 1992). The beneficial and adverse effects of inhaled steroids are both dose related. Product information regarding maximum dosage guidelines for children with inhaled glucocorticoids are reported in table III. This does not necessarily mean that adverse effects will not occur at these dosages; however, a clear distinction should be made between statistically significant changes and clinically relevant adverse effects when evaluating the safety of inhaled corticosteroid preparations (Konig 1988).

3. Tolerability of Inhaled Steroids Dose-response curves for benefits and risks of inhaled steroids are not well established, and these drugs are often prescribed in doses that are spoken

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Table III. Maximum recommended paediatric doses from pro-

3.2 Systemic Effects

duct guidelines for glucocorticoid preparations Steroid

Dose administered

Inhalations/ day

(ltg/inhalation) Beclomethasone MOl 42 100 dry powder Triamcinolone 100 Flunisolide 250 Budesonide MOl 50 dry powder Fluticasone MOl dry powder

Abbreviations: MOl

Daily dosage (mg/day)

10 4 12 4

0.42 0.4 1.2 1.0

100 100 200

8 4 4 2

0.4 0.4 0.4 0.4

25 50 50 100

8 4 4 2

0.2 0.2 0.2 0.2

= metered dose inhaler.

of as 'low dose' «800/Lg) or 'high dose' in a rather generic way (Geddes 1992). Even low doses exert small but measurable systemic adverse effects which may not represent meaningful clinical effects by themselves, but which could be predictive markers of adverse effects. Therefore, the lowest dose possible should be prescribed, avoiding, however, the mistake of prescribing doses too low to be therapeutically effective (Stead & Cooke 1989). 3.1 Topical Adverse Effects Oropharyngeal candidiasis occurs in 1% of children receiving inhaled steroids, and its incidence apparently is not always related to the dose, the use of either a metered dose inhaler or powder inhaler, and the frequency of doses (Show & Edmunds 1986). Dysphonia resulting from reversible laryngeal myopathy and consequent bilateral adductor vocal cord deformity is less common (Dickson et al. 1973; Godfrey & Konig 1974; Gwynn & Morrison Smith 1974; Kerrebijn 1976). Therefore, treatment rarely has to be stopped because of candidiasis and dysphonia.

3.2.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression Controversy exists as to whether recommended doses of inhaled steroids can lead to suppression of the HPA axis. Studies investigating the efficacy and safety of inhaled steroids in children have most often demonstrated no change in baseline plasma cortisol levels and normal adrenal responses to adrenocorticotrophic hormone (ACTH) and metyrapone after long term treatment with beclomethasone or budesonide in doses up to 800/Lg daily (Baran 1987; Bhan et al. 1980, Bisgaard et al. 1988; Dickson et al. 1973; Francis 1976; Godfrey & Konig 1974; Goldstein & Konig 1983; Kerrebijn 1976; Kjellman et al. 1982; Klein et al. 1977; Meltzer et al. 1985; Pedersen 1988; Prahl et al. 1987a; Russell et al. 1989; Springer et al. 1987; Varsano et al. 1990). Further, treatment with 0.5mg of flunisolide aerosol twice a day for periods of 2 months (Meltzer et al. 1982; Piacentini et al. 1990) or 12 weeks (Shapiro et al. 1981) was not associated with any evidence of adrenal suppression. No significant changes in plasma cortisol levels were observed in adults treated with triamcinolone in doses of 1600/Lg daily (half a dose is available at the mouthpiece) for up to 1 year (Bernstein et al. 1982) or in children with a dosage of 400 /Lyday for 8 weeks (Sly et al. 1978). There was no evidence ofHPA axis suppression in children treated with fluticasone 200/Lg daily (Gustaffson & Tsanakas 1992). However, some suppression was observed in an individual patient treated with 400/Lg of beclomethasone daily (Springer et al. 1987) and an additive effect on the HPA axis was shown when 400 to 800 /Lyday of beclomethasone was administered together with alternate-day prednisone at doses of 20 to 40mg (Wyatt et al. 1978). Nocturnal cortisol secretion and adrenal function, when evaluated by cosyntropin stimulation, were reduced in children treated with beclomethasone 300 to 1000 /Lg/day (Law et al. 1986; Vaz et al. 1982). Although there is no clear-cut threshold for suppression of the HPA axis the dose of inhaled

Inhaled Corticosteroids in Children

steroid appears to be a critical determinant, and dose-dependent adrenal suppression has been documented in children treated with 400 to 2000llg of beclomethasone daily (Law et at. 1986; Prahl et at. 1987; Priftis et at. 1990; Vaz et at. 1982). An endocrine assessment has been therefore suggested for dosages exceeding 400 llg/m 2jday (Priftis et at. 1990). Evaluation techniques for adrenal function do not appear to be sensitive enough to detect subtle changes in HPA function resulting from inhaled steroid therapy (Kamada et at. 1992). It has been recently recommended, therefore, that 24-hour urinary free cortisol and single-dose metyrapone test at 0600h should be used to assess the effects of inhaled steroids on the HPA axis since the short tetracosactrin test may not be sufficiently sensitive (Holt et at. 1990). Because of the dynamic nature of the HPA axis, evaluation of adrenal function from single plasma concentration assays is difficult, and the measurement of plasma cortisol integrated concentrations over 24 hours has recently been suggested as a sensitive test of adrenal function (Law et at. 1986). This method has provided evidence that even relatively low dosages of inhaled steroids (200 to 450 Ilgjday of beclomethasone) may cause a reduction in the normal physiological secretion of cortisol (Phillip et at. 1992). Adequate data comparing the HPA axisinhibiting effects of different steroids are available only for beclomethasone and budesonide. In children, beclomethasone and budesonide have been compared for their effects on the HPA axis in 6 studies. Two studies (Springer et at. 1987; Warner et at. 1989b) showed that both drugs may cause mild adrenal suppression when given in a dose of 200llg twice daily. Another concluded that doses up to 2000 Ilg/ 1.73m 2 daily can be administered by pressurised aerosol with little risk of adrenal suppression (Prahl et al. 1987a). Two other studies indicate that adrenal suppression may be less marked with budesonide compared with beclomethasone (Bisgaard et at. 1988; Pedersen & Fuglsong 1988). In both of these studies, however, the differences were small and of doubtful long term clinical significance. A recent study, although dem-

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onstrating no significant differences between beclomethasone and budesonide when the patients were considered as a group, did show varying interpatient sensitivity between the 2 inhaled steroid preparations when single patient evaluations were performed (Prahl 1991). These differences may reflect the interindividual biological variation of the activity of the different enzymatic pathways through which different inhaled steroids are metabolised. The clinical significance of the effects of the inhaled steroids on the HPA axis has been considered by several reviewers (Douglass & Bowes 1990; Geddes 1992; Greenberger 1992; Kamada et al. 1992; Kerrebijn 1990; Konig 1988; Larsen 1992; Szefler 1991; Stead & Cooke 1989; Van Asperen et at. 1992). Collectively, these authors conclude that the systemic effects of inhaled steroids on the HPA axis may not have meaningful clinical effects as demonstrated by the recovery of the HPA axis when patients were switched from systemic to inhaled steroids (Kershnar et at. 1978; Spitzer et at. 1976). The worsening in these patients of other atopic disorders (hay fever, eczema) with discontinuation of their oral steroids suggests no clinically demonstrable systemic effect of the inhaled treatment. Further, it is possible that the modest reduction of endogenous plasma cortisol concentrations is compensated by the presence of the exogenous steroid that caused this reduction; moreover, there have been no case reports of Addisonian crises in patients receiving inhaled corticosteroids. The drop in blood eosinophils which commonly occurs and is taken as evidence of a systemic effect may more likely be the result of a therapeutic suppression of eosinophil-induced inflammation by inhaled steroids (Reed 1990). 3.2.2 Effects on Growth An important incompletely resolved clinical issue is whether the mild degree of adrenal suppression observed in some studies is sufficient to cause diminished growth in children. Growth retardation in severe childhood asthma was first described by Cohen et at. in 1940, long before the discovery of steroids and the subsequent introduc-

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tion of inhaled steroids in 1972 (Morrow Brown et al. 1972). Subsequently, the growth retardation seen in children with asthma was shown to be related both to the severity of the disease (Dawson et al. 1969; McNicol & Williams 1973) as well as to long term treatment with systemic steroids (Falliers et al. 1963; Spock 1965). The effect of inhaled steroid treatment on linear growth, however, is controversial. In a recent cross-sectional study, growth retardation was described in children with asthma ranging in age between 8.3 and 13.1 years treated with beclomethasone 200 to 800 JLg/day (mean 15 JLg/kg/day) [Littlewood et al. 1988]. Other studies have reported a dose-related suppression of short term growth velocity of the lower leg in children with asthma treated with inhaled budesonide 200 to 800 JLg/day for periods of 18 days (Wolthers & Pedersen 1991) and 8 consecutive weeks (Wolthers & Pedersen 1992a), and in children followed for two 4-week periods of treatment with beclomethas0ne 200JLg and then 400JLg daily (McKenzie & Wales 1991). A further study of short term linear growth over 2 weeks found growth was significantly greater with fluticasone 200 JLg/day than with either beclomethasone 400 JLg/day or beclomethasone 800 JLg/day (Wolthers & Pedersen 1992b). Six other cases of growth suppression after treatment with beclomethasone at doses ranging from 300 to 1000JLg daily have been attributed to individual variation in responsivity to steroid therapy as well as to overtreatment due to inappropriate escalation of the dose or to simultaneous introduction of intranasal steroids (Wales et al. 1991). Growth impairment and Cushingoid appearance with evidence of adrenal suppression was described in a 14-year-old prepubertal boy treated with beclomethasone 200JLg twice daily (Priftis et al. 1991). Similar adverse effects were reported in an 8-year-old girl who was receiving inhaled triamcinolone (Hollman & Allexn 1988). Apart from these case reports of unexpected adverse effects to even small doses of inhaled steroids, the assessment of growth in children treated with inhaled steroids is rather complex. First of all,

Drug Safety 9 (1) 1993

children with chronic asthma have a tendency for delay in the onset of puberty, with a subsequent physiological deceleration of growth velocity (Balfour-Lynn 1986). Therefore, conflicting reports of an association between growth retardation and asthma itself or asthma treatment are influenced by the age at which the children were first studied. Studies evaluating children below 10 years of age have found no growth retardation whereas those examining older children (10 to 15 years of age) have revealed a definite association. It has been shown, for example, that in children receiving up to beclomethasone 600 JLg/day before puberty and 400 JLg/day during puberty for a mean of 5.8 years, growth in height was inhibited by delayed puberty in 45%, but all the children later regained their predicted height (Balfour-Lynn 1986). Recently, no evidence was found that administration ofbudesonide or beclomethasone at a median dosage of 800 JLg/day (range 200 to 1600 JLg/ day) for a mean duration of 2.7 years (range 1 to 5.1 years) has an adverse effect on growth in prepubertal children (Ninon & Russel 1992). In this study the linear growth of children with poorly controlled asthma was significantly slower than in those whose asthma was well controlled. Such a finding was observed both before and after starting inhaled steroid, confirming the results of previous long term studies (Godfrey & Konig 1974; Godfrey et al. 1978; Graff-Lonnevig & Kraepelien 1979; Kerrebijn 1976; Nassif et al. 1987) which showed that when growth impairment occurs in a child with asthma it is more likely to reflect poor asthma control than the administration of inhaled steroids. Further, the significance of the suppression of short term growth velocity of the lower leg in children with asthma treated with inhaled steroids (McKenzie & Wales 1991; Walthers & Pedersen 1991, 1992a,b) is questionable (Crowley & Brook 1989) since extrapolations of changes in linear height velocity over longer periods are shown to be associated with enormous errors (Hermanussen & Burmeister 1989). It was observed, for example, that if the results obtained after a short time are extrapolated to years, height would fall from the fif-

Inhaled Corticosteroids in Children

tieth to the twenty-fifth or third centile, respectively, in children treated with 200 or 800J,Lg budesonide daily (Starr 1991). However, effects of such magnitude are not seen in clinical practice, nor have they been confirmed in long term clinical studies (Godfrey et al. 1978; Godfrey & Konig 1974; Graff-Lonnevig & Kraepelien 1979; Kerrebijn 1976; Nassif et al. 1987). However, even if the majority of studies demonstrate no effect on growth, this parameter should be carefully monitored, since some patients, dependent perhaps on rare idiosyncratic sensitivity, may exhibit some growth retardation. However, as previously observed (Crowley & Brook 1991), 'short stature can be disadvantageous but is rarely fatal', while there is ample evidence ofundertreatment of asthma in children resulting in increased morbidity, absence from school and mortality (Burney 1986; Henderson et al. 1981; Speight et al. 1983). Furthermore, in the majority of the paediatric population a dose of 200 to 400 J,Lgjday beclomethasone or budesonide is most unlikely to show impairment in growth velocity, and higher doses are seldom required for good asthma control.

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of treatment compared with placebo baseline (Pedersen 1992). The only data available in growing children treated with inhaled beclomethasone (mean daily dose 627J,Lg or 20 J.Lg/kg/day) for 25 months did not show any difference in serum osteocalcin levels, bone mineral density and content compared with children with asthma who were not treated with corticosteroids (Konig et al. 1991). Despite these reassuring data, calcium supplementation may be necessary in such children treated with inhaled steroids. A supplementation of calcium early in life has been associated with a more positive calcium balance and with a greater bone mass in later life (Johnston et al. 1992). This is particularly important in light of studies showing the possible persistence of asthma in adult life as well as recent surveys which have shown that dietary calcium intake of adolescents is considerably lower than recommended (Caroll et al. 1983; Nationwide Food Consumption Survey 1980).

3.2.3 Bone Metabolism Inhaled steroids have recently been reported to cause a reduction in serum osteocalcin, a marker of osteoblast activity and bone formation. Recent studies in adult patients have shown no changes in osteocalcin levels with dosages of budesonide lower than 800 J,Lg/day and decreasing levels at higher dosages up to 3200 J,Lg/day (Hodsman et al. 1991; Jennings et al. 1991). Beclomethasone has been shown to have an inhibitory effect at dosages of 2000 J,Lg/day (Ali et al. 1991; Pouw et al. 1991). The effects, therefore, appear to be dose related and to be greater with beclomethasone than with budesonide (Toogood & Hodsman 1991); these observations need to be confirmed by direct com-

3.2.4 Other Systemic Adverse Effects Posterior transient bilateral subcapsular cataracts have been reported in a child taking inhaled beclomethasone 400 J,Lg/day, but the combination of a 3-week course of oral prednisolone in the recent past is likely to have been at least in part responsible for this reaction (Kewley 1980). The metabolic effects of inhaled budesonide using initially high (800 J.Lg/m 2/day for I month) and subsequently lower dosages (400 J.Lg/m 2/day for 4 months) were evaluated in children with asthma. Serum high density lipoprotein (HDL) cholesterol increased significantly after the high dosage and declined significantly with dosage reduction (Turpeinen et al. 1991). The same pattern was observed for the ratio of serum insulin to blood glucose. There were no significant changes in the ratio of HDL to total cholesterol, suggesting that the risk

parative studies (Geddes 1992). No data are cur-

of cardiovascular disease would not be increased.

rently available for flunisolide or triamcinolone. A study with fluticasone 200 J.Lg/day in children showed no change in osteocalcin, urinary hydroxyproline or parathyroid hormone following 2 weeks

Moreover, with the low budesonide dosage the elevated serum HDL levels were reduced to levels that were not different from baseline (Turpeinen et al. 1991). It is uncertain whether these effects would

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Drug Safety 9 (1) 1993

be observed in children treated with lower doses of inhaled corticosteroids. A case of manic psychosis has been reported in a 5-year-old girl receiving 200JLg of inhaled budesonide daily. The psychosis resolved when the dosage was reduced to 100 JLgjday (Lewis & Cochrane 1983). Another 4 cases of behavioural disturbances following the use of inhaled budesonide in doses of 800 to 1200JLg daily have been described in young children. These effects appear to be dose- and drugrelated since they disappear with the reduction of the dose and/or changing to beclomethasone (Connet & Lenney 1991). Other theoretical adverse effects such as 'reactivation' tuberculosis, rubeola pneumonia in nonimmune individuals and bronchial mucosal atrophy have not been observed (Greenberger 1992).

4. Use of a Spacer Device to Reduce Adverse Effects The use oflarge volume (750ml) spacer devices increases the deposition in the lung of pressurised aerosols to approximately 20% and at the same time reduces oropharyngeal deposition to about 16% (Newman et al. 1984). These devices thus double the deposition of the aerosol in the lung and reduce oropharyngeal deposition by a factor of about 5, 50% of the dose being retained within the spacer itself. Net deposition of corticosteroids on oropharyngeal and bronchial mucosa is, therefore, significantly reduced and a smaller amount of the drug will reach the systemic circulation (Newman et al. 1984). This may explain their effect in reducing topical (Salzman & Pyszczynski 1988) and systemic adverse effects both in children (Prahl & Jensen 1987b) and adult patients (Brown et al. 1990; Farrer et al. 1990; Selroos & Halma 1991) although a reduction in systemic adverse effects has not been observed using devices without a I-way valve (Toogood et al. 1984). In order to reduce adverse effects from inhaled corticosteroids it seems reasonable, therefore, to use large volume devices with a I-way valve. These devices with attached face masks, appear

likely to deliver significantly greater quantities of aerosol also to infants (Everard et al. 1992).

5. Nebulised Corticosteroids in Infants The efficacy of inhaled steroids for the treatment of wheezing following bronchiolitis in infants and for the management of asthma in preschool children has been the subject of recent investigations (Bisgaard et al. 1990; Carlsen et al. 1988; Field et al. 1982; Noble et al. 1992; Webb et al. 1986; Wilson & Silverman 1990). Possible benefits have been observed in most of these studies; however, the differences in dose, mode of delivery, duration of treatment and concomitant medications make comparisons of these different therapeutic regimens difficult. Adrenal inhibition was evaluated in a double-blind, crossover trial comparing budesonide (400 JLg/day) and beclomethasone (400 JLgjday) [Field et al. 1982]. The results of this study showed no differences in the short tetracosactrin test before and after a total of 2 months of treatment with the 2 drug regimens. However, further studies are necessary in order to better evaluate the safety of the use of inhaled steroids in early infancy.

6. How Much is 'Safe' in Children? The real question is: does this child with asthma need inhaled steroids for the control of their disease? If the answer is yes, then the safest dose is the lowest one which effectively controls symptoms (Warner et al. I 989a, 1992). Inhaled steroids are generally effective at low dosages; usually 200 to 400 JLgjday of beclomethasone or budesonide. For these 2 steroids there are sufficient data to conclude that at these doses there is relative sparing from adverse effects on the HPA axis and growth (Warner et al. 1992). There are some patients, however, who are particularly susceptible to even small doses of inhaled steroid due to peculiar individual pharmacokinetic patterns (Hollman & Allexn 1988; Priftis et al. 1991). These case reports should not lead to a withdrawal of these highly effective drugs for the treatment of children with moderate to sev-

Inhaled Corticosteroids in Children

ere asthma. They should, however, alert the physician to maintain an appropriate follow-up of all patients, and to allow reduction of the dose to the minimum which maintains good control and possibly to switch to sodium cromoglycate (cromolyn sodium), a drug virtually free from adverse effects. In order to facilitate disease control and switch to safer drugs for all children with asthma, the avoidance of relevant allergens should be recommended and allergen avoidance should be the primary 'anti-inflammatory' treatment for asthma (Platts-Mills 1992). Inhaled steroids should not be withheld when moderate (>600 /Lg/day) to high dosage (>800 /Lg/ day) therapy is indicated by the severity of the disease. In these patients appropriate monitoring of growth, adrenal function and ophthalmological slit lamp examinations for cataract formation should be performed yearly, and ACTH stimulation may be appropriate before major surgical procedures (Kamada et al. 1992). These patients as well as children below 3 years of age should be referred to a specialist for assessment and management of their disease when this therapeutic option is indicated (Van Asperen et al. 1992; Warner et al. 1989a, 1992). Long term studies will be needed before these drugs can be recommended for long term management of children with mild disease (Mellis & Woolcock 1992; Murphy & Kelly 1992). The development of glucocorticoids with improved topical potency will increase the margin of safety and the indications of their use in children with asthma.

Acknowledgement We wish to thank Professor l.A. Bellanti for his review of the manuscript and his helpful suggestions.

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Correspondence and reprints: Dr A.L. Boner, Universita degii Studi di Verona, Clinica Pediatrica, Policlinico Borgo Roma, 37134 Verona, Italy.