inhaled corticosteroids in childhood asthma

Pediatr Drugs 2003; 5 (6): 351-361LEADING ARTICLE 1174-5878/03/0006-0351/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Inhaled Corticosteroids in Childhood AsthmaLong-Term Effects on Growth and Adrenocortical Function

Alessandro Salvatoni, Elena Piantanida, Luana Nosetti and Luigi Nespoli

Pediatric Clinic, University of Insubria, Varese, Italy

Inhaled corticosteroids (ICS) are the most potent of all the available inhaled treatments, and are effectiveAbstractmedications for long-term control of asthma. However, their use in children is limited by the risk of systemic

adverse effects. Although results reported in the literature on the adverse effects of ICS are conflicting and often

restricted to a small number of cases with a limited follow-up, most of them show an early decrease in growth

velocity without significant influence on final adult height. Partial adrenal suppression has also been demonstra-

ted in children treated with ICS for more than 2 months.

Only children with mild persistent, moderate, or severe asthma not controlled by non-corticosteroid drugs

should be treated with ICS for long periods. The dose of ICS must be individually adjusted to minimize the

possible adverse effects on growth, and all children with asthma receiving long-term treatment with ICS must be

regularly evaluated for growth impairment, which may necessitate dose reduction or drug replacement.

In recent years, a consensus has been achieved for controlling predict. The relationship of age at onset to prognosis is uncertain;

persistent asthma in childhood with the long-term treatment of most severely affected children have an onset of wheezing during

inhaled corticosteroids. Although the currently available inhaled the first year of life. These children may have growth retardation

corticosteroids should have minor systemic adverse effects, it is unrelated to corticosteroid treatment (although ultimate height

not yet well established whether long-term inhaled corticosteroid attainment is usually normal), chest deformity, and persistent

treatment could influence growth and adrenal function. In this abnormalities on pulmonary function testing.article we review the more recent papers on this topic. Manifestations of airway obstruction in asthma are a result of

bronchoconstriction, mucosal edema, cellular infiltration, and1. Asthma: Definition, Epidemiology

hypersecretion of mucus. These effects are a result of variousand Pathophysiology

allergic and nonspecific stimuli, including dust mites, pollens,

moulds, cockroach, cat or dog allergens, vegetable proteins, viralAsthma is defined as a ‘chronic, diffuse, inflammatory disorderinfections, cigarettes, air pollutants, cold air, exercise, etc.of the airways characterized by recurrent episodes of wheezing,

breathlessness, chest tightness, and coughing, associated with All these different stimuli can lead to the release of differentobstruction and hyperactivity of the airways to various stimuli, and types of mediators from local mucosal mast cells, i.e. histamine,a high degree of reversibility of the obstructive process’.[1] leukotrienes C4, D4 and E4, and platelet-activating factors that

Recent epidemiologic studies performed in the US and differ- initiate bronchoconstriction, edema, and immune response. The

ent European countries by the Centers for Disease Control and early immune response results in bronchoconstriction, is treatable

Prevention, document an increasing rate of asthma in the last 20 with β2-adrenoreceptor agonists, and may be preventable by mast

years.[2] Eighty to 90% of all cases of asthma are diagnosed by the cell-stabilizing agents (sodium cromoglycate or nedocromil). The

age of 6 years.[3] The course and severity of asthma are difficult to late inflammatory reaction, occurring 6–8 hours later, is character-

352 Salvatoni et al.

ized by eosinophilic and neutrophilic infiltration and airway 2.2 Pharmacodynamic and Pharmacokinetic Properties

hyper-responsiveness. This process can be treated and prevented

by corticosteroids, or prevented by sodium cromoglycate, Pharmacodynamic and pharmacokinetic properties of cortico-nedocromil or leukotriene inhibitors. Taking into account these steroids are largely dependent on their chemical and physicalconsiderations, treatment should be targeted to interrupt the pro- properties. They must have great receptor affinity, high anti-cess that leads to the activation of the immune system and prevents inflammatory action and, for the swallowed part of the drug, afunctional changes. rapid first-pass hepatic metabolism, to avoid high systemic bio-

Anti-inflammatory drugs are used for the long-term treatment availability.[7]

of mild persistent asthma. In particular, inhaled corticosteroidsOne of the most important aspects to be considered is their

(ICS) are the most potent of all the available inhaled treatments,lipophilic property. In fact, lipophilicity influences the rate of

and are consistently effective medications for long-term control ofabsorption in the lung. Fluticasone propionate and beclometha-

asthma (see table I).[4]

sone (the most lipophilic agents) have a distribution time of

several hours, while budesonide and flunisolide have a distribution2. Inhaled Corticosteroid (ICS) Therapytime of just several minutes. The latter also have a large volume of

The increased recognition of the important role of inflamma- distribution at steady-state. It has been postulated that lipophiliction in asthma, and the efficacy of corticosteroids in reducing agents can adhere better to the mucosa of the airways and prolonginflammation, has led to increased use of corticosteroids in the their topical action, reducing their systemic bioavailability andearly treatment of asthma. increasing their anti-inflammatory action.[8] Of course, because of

their lipophilicity and prolonged elimination half-life, lipophilic2.1 Mechanism of Action

agents may have increased systemic adverse effects, and for this

reason, the general approach is to use lower doses of the moreCorticosteroids have been shown to reduce airway hyper-re-lipophilic and more potent ICS.[9] Systemic bioavailability is thesponsiveness, improve lung function and asthma symptoms, andsum of inhaled drug absorbed across the airway mucosa and thereduce structural changes in the airways.[6] Corticosteroids act byswallowed part that escapes hepatic inactivation. A consistent partcontrolling the synthesis of several proteins. They act at specificof the portion of ICS deposited in the lung, ranging from 10–50%,receptors, localized in the cytoplasm of sensitive cells of variousis absorbed in the systemic circulation, the remaining 50–90%tissues, and form a corticosteroid-receptor complex. This complexbeing swallowed and absorbed at the gastrointestinal level. Thisthen undergoes modification and moves into the nucleus, where it

percentage may be greater in children because of the greaterbinds with chromatin and enhances specific gene transcription (see

proportion of drug swallowed, and is responsible for variablefigure 1).

Table I. Classifications of asthma severity and suggested treatment for long-term control[5]

Severity of asthma Symptoms Long-term control

Step 1: Mild intermittent Symptoms ≤2 times a week Not needed

Night-time symptoms ≤2 times a month

Step 2: Mild persistent Symptoms more than twice a week, but less than Sodium cromoglycate or nedocromil

once a day Either ICS (low dose) or montelukast (patients ≥6yrs

Night-time symptoms more than twice a month of age)

Step 3: Moderate persistent Daily, with exacerbations two or more times a week ICS (medium to high dose) + long-acting inhaled

Limited physical activity during exacerbations β2-agonists (for night-time control of symptoms)

Night-time symptoms more than once a week

Step 4: Severe persistent Continual, with limited physical activity ICS (high dose), and long-acting inhaled β2-agonists

Frequent and corticosteroid tablets (make repeated attempts to

maintain control with high dose ICS)

ICS = inhaled corticosteroids.

© Adis Data Information BV 2003. All rights reserved. Pediatr Drugs 2003; 5 (6)

Inhaled Corticosteroids: Growth and Adrenal Function 353

device used. This variation can be much smaller for the less potent

ICS, with higher oral and lower pulmonary availability. However,

it must be pointed out that in young children, independent of the

inhalation device, the proportion of the drug that is actually

inhaled is always smaller than in adolescents and adults. A further

factor influencing the proportion of the drug inhaled is obviously

the severity of the bronchial constriction.

2.3 Adverse Effects

When oral corticosteroids were first used in the treatment of

asthma in 1949–1950, long-term therapy resulted in adverse ef-

fects similar to those observed by Cushing in 1932. They could

suppress the hypothalamic-pituitary-adrenal (HPA) axis, and of

particular concern was the potential for growth retardation in those

children who received long-term corticosteroid therapy. It is worth

noting that, following this concern, the US FDA now requires

warning labels on the potential reduction in linear growth in

children treated with inhaled and intranasal corticosteroids.

ICS, a new class of drug with a rapid first-pass hepatic metabol-

ism, were introduced to avoid the adverse effects of long-term oral

corticosteroid treatment. They displayed more topical efficacy,

and were effective in the treatment of childhood asthma. However,

DNA

R

CS

CSRR

CS

hsp90

hsp9

0

mRNA

Protein

Fig. 1. Mechanism of action of corticosteroids. Binding of corticosteroids totheir receptor causes a dissociation of a phosphorylated protein of 90 kDain the citosol. This protein has been identified as a heat-shock protein(hsp90). It is presumed that the release of this protein plays an importantpart in the transformation of the receptor, enabling the hormone-receptorcomplex to proceed to its nuclear destination and interact with DNA. Hor-mone binding to the receptor induces dissociation of hsp90 from the recep-tor, causing a conformational (allosteric) change in the molecule whichallows DNA binding, gene activation, and mRNA transcription. The anti-inflammatory action of corticosteroids is mediated by down- or up-regula-tion of the synthesis of different proteins in different tissues. This is amultiform action, involving both inhibition of specific chemical mediators(enzymes, cytokines, adhesion proteins, regulation proteins) and modula-tion of the inflammation cell component. CS = corticosteroid; mRNA =messenger RNA; R = receptor.

systemic effects are also described for ICS, because of the system-

ically absorbed portion.[15] Thus, despite these remarkable bene-systemic effects resulting from differences in first-pass hepaticfits, there are also risks and adverse reactions,[9] which are dose-inactivation.dependent. Generally, a good therapeutic response in children can

There are many differences in bioavailability and lipophilicitybe achieved with beclomethasone dosages of 200–400 μg/day in a

among corticosteroids.[10] In the liver, fluticasone propionate istwice daily dosage regimen. However, sometimes children may

inactivated approximately 99%, budesonide 90%, and triamci-require higher dosages to better control severe symptoms. Adverse

nolone 80%, while beclomethasone dipropionate is not completely effects seem to be more likely with dosages of beclomethasoneinactivated in the hepatic first pass (60–70%), and an active ≥400 μg/day.[16]

metabolite is formed that has a similar potency.[11] Although the Different inhalation techniques (such as chambers, inhalers, orpotent ICS fluticasone propionate seems to have a superior tolera- spacers) can influence the portion of inhaled drug, and thusbility profile because of strong hepatic inactivation, the proportion systemic bioavailability. A further variable, which can influenceof drug absorbed from the lung can cause significant systemic the pulmonary and systemic bioavailability of ICS, is the gradualeffects. The potency, half-life, oral, and pulmonary availability, replacement of metered-dose inhalers containing chlorofluoro-and inhaled proportion by different devices of the most common carbons (CFC) with CFC-free preparations.[17]

ICS have been reported in table II. An ICS with a very low oral The studies on adverse effects of ICS on growth report conflict-availability and very high potency and pulmonary availability, ing results. Therefore, this is still an open point of discussion, alsosuch as fluticasone propionate, may have a wide variation in its considering that there is a tendency towards early and long-term

systemic availability, depending on the efficiency of the inhalation use of ICS in the treatment of asthma.



3.2 Effects of Asthma on Growth

Before considering whether or not ICS affect growth, several

aspects must be considered. To begin with, children with asthma

have been reported to have shorter stature, smaller increase in

height for age (slower height velocity), and a different pattern of

growth, than children without asthma, irrespective of the use of

corticosteroids. The first studies showing the different growth

pattern in children with severe asthma were published approxi-

mately 50 years ago.[21] Several factors are probably responsible

for growth failure, i.e. chronic hypoxia, recurrent infections lead-

ing to under-nutrition and dystrophy, impaired lung function, and

probably also sleep disturbances and long-term stress. In children

with asthma, growth retardation is usually associated with delayed

sexual and skeletal maturation.

Tinan and Russell[22] showed that in children with asthma not

treated with corticosteroids, height is strictly related to lung func-

tion and the severity of the disease. However, in 1997 Silverstein

et al.[15] retrospectively studied a cohort of 153 patients with

asthma who had attained their adult height. The height of these

patients was not statistically different from that of non-asthmatic

people, suggesting that, overall, asthma does not have an impor-

tant effect on attained adult height.

This aspect is extremely important and more studies need to be

conducted because it can be a confounding factor when analyzing

the effect of ICS on final height.

Table II. Comparison of the pharmacodynamic and pharmacokinetic

properties of the four most common inhaled corticosteroids[12-14]

Corticosteroid Potencya Type of device Half-life Oral

(h) availability

(%)

Beclomethasone 0.4 MDI 6.3–7.4 30–40

dipropionate

MDI + spacer

Nebulizer

Flunisolide 1.8 MDI 1.5–2 6.7–20

MDI + spacer

Nebulizer

Budesonide 9.4 MDI 2.3 10–11

MDI + spacer

DPIb

Nebulizer

Fluticasone 18 MDI 14.4 <1

propionate MDI + spacer

DPIc

Nebulizer

a Binding affinity to corticosteroid receptors in vitro relative to

dexamethasone.

b Turbohaler® (the use of tradenames is for product identification

purposes only and does not imply endorsement).

c Diskhaler®.

DPI = dry powder inhaler; MDI = metered-dose inhaler.

3.3 How Corticosteroids Influence Growth3. Growth

There are several pathways through which corticosteroid ex-

cess influences growth.3.1 Normal GrowthFirstly, it seems that corticosteroids directly influence GH

secretion by an increased hypothalamic somatostatin secretion thatThe normal height velocity pattern is characterized by a dra-

inhibits pituitary GH secretion. Corticosteroids most likely act bymatic fall in the first 2 years of life from 25 to 6 cm/year, and a

down-regulating the GH receptor and reducing insulin-like growthfurther sudden rise during puberty called ‘peak height velocity’ factor 1 activity through a modulation of insulin-binding protein.(PHV). Prepubertal growth is influenced by thyroid hormones and In addition, corticosteroids also interfere with other hormones;

they inhibit new connective tissue synthesis and reduce productiongrowth hormone (GH). The pubertal PHV is under the control of

of adrenal androgens, which enhance the GH action during asexual hormones, mainly estrogens, which stimulate GH secretion,growth spurt at puberty.[18]

and is particularly susceptible to the systemic effects of ICS whichAlthough the different mechanisms by which corticosteroids

interfere with pubertal hormonal changes.[18,19] However, the latteraffect growth have been identified, it is difficult to perform a

point has not been generally accepted; in fact, Agertoft and Peder- complete and detailed study on the influence of ICS on growth.sen[20] showed that growth before puberty is more susceptible to ‘Normal growth’ is indeed the result of many different factors,

the action of ICS. such as genetic background, tempo of puberty, individual patterns



of puberty, etc. All these factors are confounding parameters the evening may influence the nocturnal secretory pattern of

which must be taken into account. growth hormone to a greater extent than a morning dose.[27]

Recent studies have demonstrated that, generally, ICS are wellFurthermore, children with severe asthma could have an im-

tolerated at the recommended conventional dosages (see table III),paired final height as a result of the combination of corticosteroid

although impaired growth velocity has been reported in sometherapy and asthma itself. We assume that children with mild

children receiving conventional dosages.[19,28] However, it isasthma have more patent airways than those with severe asthma;

sometimes necessary to use higher dosages of ICS, and there areconsequently drug deposition and absorption may be higher, with

several studies reporting that this is not completely risk-free.[29,30]subsequent higher systemic effects.

A recent meta-analysis[31] suggested that a moderate dosage ofThe effect on growth of recurrent oral administration of cortico-inhaled beclomethasone significantly decreases the linear growthsteroids, such as methylprednisolone, for uncontrolled asthma,velocity of children with mild to moderate asthma, as does fluti-must also be taken into account when we compare the efficacy andcasone propionate, although there are few studies on this drug.adverse effects of ICS. Finally, in relation to the placebo-control-These results are in contrast with those reported in a previousled trials, the fact that the children treated with placebo or non-meta-analysis.[32]

corticosteroid drugs have mild asthma in contrast to childrenDuring the past decade it has been shown that uninterruptedtreated with ICS who have, in most cases, moderate or severe

treatment with beclomethasone 400 μg/day can reduce growthasthma, must be considered as a possible bias. Thus, it is useful torates in prepubertal children.[28] It has also been demonstrated thatconsider the different aspects that may influence the effects of ICSbeclomethasone was statistically more effective in reducing air-on growth, and critically evaluate these parameters when decidingway hyper-responsiveness than either salmeterol or placebo; how-to use these drugs in the long-term management of asthma.ever, linear growth in children who received beclomethasone was

significantly less than in children treated with salmeterol or place-3.4 Long-Term Effects of ICS

bo.[28] Other studies have confirmed this reduction of approximate-

ly 1.5 cm/year in the growth of prepubertal children treated withConsidering the normal circadian rhythm of cortisol and GH beclomethasone 400 μg/day.[34,35] However, in a former study,[36]

secretion, with a peak secretion of growth hormone during the no statistically significant differences were found between beclo-night coincidental with the minimum of cortisol levels, it seems methasone and budesonide in the dosage range of 400–1000 μg/that the risk of adverse effects on growth occurs when exogenous day. In patients receiving either beclomethasone or budesonidecorticosteroids exceed the endogenous production of cortisol.[18]

400 μg/day, doubling the dose did not produce clinical benefits,Thus, it is quite obvious that the time of administration of ICS, as and a further increase in dose did not improve asthma control, butdemonstrated for oral corticosteroids, may influence the negative increased the risk of adverse effects.[36] The effects of dosages ofeffect on growth, with a single morning dose being best tolerat-

ed.[23-25]

Clinical experience has suggested that once daily administra-

tion in the morning is better than twice daily, because the possibili-

ty of growth suppression may increase with administration fre-

quency. Findings from a study using once daily intranasal budeso-

nide versus a twice daily regimen appear to support this

hypothesis.[26] Furthermore, results of a study that compared in-

haled budesonide 800μg once daily in the morning and 400μg

twice daily confirm that once daily morning administration of

budesonide reduces the risks of adverse effects on growth. This is

probably because of the interaction of ICS with the hormonal

circadian rhythm and GH suppression. Considering that the bio-

logic half-life of budesonide is approximately 2–4 hours, 400μg in

Table III. Inhaled corticosteroid dosages recommended by the American

Academy of Allergy, Asthma, and Immunology for long-term control of

asthma (reproduced from the American Academy of Allergy, Asthma, and

Immunology,[33] with permission)

Generic name (formulation) Dosage (μg/day)

Low Medium High

Beclomethasone dipropionate 84–336 336–672 >672

(MDI)

Budesonide (DPI) 200 200–400 >400

Flunisolide (MDI) 500–750 1000–1250 >1250

Fluticasone propionate (DPI) 100–200 200–500 >500

Fluticasone propionate (MDI) 88–176 176–440 >440

DPI = dry powder inhaler; MDI = metered-dose inhaler.



ICS higher than 2000 μg/day are virtually unknown. In patients treatment. In particular, Doull et al.[34] noted a 1cm reduction in

whose asthma is not controlled with recommended dosages, strate- growth during 7 months of treatment with beclomethasone, with-

gies must be considered for increasing compliance and use of more out a significant catch-up growth during a washout period of 4

efficient inhalation techniques. months. In a second study, the same authors showed that the

reduction in growth velocity was limited to the first 18 weeks ofIn the last 20 years many studies have been published to try totreatment.[41] Unlike the above study, Tinkelman et al.[19] found noclarify whether ICS do actually affect growth, and if so, whether itdifference in growth velocity suppression in the first 6 months, andis a persistent or transient impairment (see table IV).between 6 and 12 months, in children treated with beclometha-A high volume of literature published during the past decadesone.has confirmed a dose-related inhibition of growth in short- and

Simons[28] showed that the majority of growth delay occursintermediate-term studies; however, long-term studies, defined aswithin the first 3 months of ICS therapy, with growth velocitystudies of treatment lasting >12 months, have shown no negativesimilar to that of the placebo group after this period. This meanseffects on final height.that if growth delay is confined to the first 3 months of therapy, theTwo important studies have been conducted on the long-termimplications for growth in long-term therapy are less significant.effects of ICS on linear growth.[20,39] The first one is the ChildhoodThe negative impact of ICS on growth velocity during the firstAsthma Management Program (CAMP) in which linear growthyear of treatment was also confirmed by a meta-analysis per-was examined in 1041 children aged between 5 and 12 years withformed by Sharek and Bergman,[31] who concluded that childrenmild to moderate asthma. Children were randomized to receivewith mild to moderate asthma using beclomethasone show abudesonide (200μg), nedocromil, or placebo twice daily for 4–6decreased linear growth velocity of about –1.51 cm/year. In addi-years (mean 4.3 years). The budesonide group demonstrated ation, the new molecule fluticasone propionate was analyzed and itsignificant decrease in growth velocity during the first year, with arevealed a modest statistically significant decrease in linearmean height increase during the whole study period of 1.1cm lessgrowth when compared with placebo (–0.43 cm/year).than that observed in the placebo group (22.7 versus 23.8cm; p =

In a recent 52-week study, Skoner et al.[30] showed a signifi-0.005). The difference in growth velocity between the two groups

cantly lower growth velocity in children with mild persistentdid not increase beyond the first year and, by the end of the study,

asthma treated with budesonide via nebulizer, compared withthe growth velocity was similar for all groups.[39] In the second

children receiving conventional non-corticosteroid treatment. Astudy, the mean difference between target height (calculated on the

similar difference was not observed in the other two groups ofbasis of parental height) and adult height attained in 211 children

children with more severe asthma treated with budesonide, ortreated with budesonide (average dosage 412 μg/day) for 9.2 years

receiving conventional treatment with corticosteroids. The au-was not different from that observed in 18 patients with asthma

thors’ interpretation of the results is that children with less severewho were not treated with ICS, and 51 healthy control individuals.

asthma ‘may have greater intrapulmonary deposition, and thusIn agreement with the former study, a growth reduction was

absorption, or be more sensitive to the effects of ICS’. However, itobserved during the first year of treatment, and the extent was

must be pointed out that all groups receiving treatment with ICSsignificantly related to age, with a more pronounced reduction in

had lower growth velocity than children treated without ICS;younger children.[20] Norjavara et al.[40] confirmed that long-term

therefore, we cannot see in this study any evidence that childrenICS treatment for asthma does not reduce adult height, by showing

with mild asthma are at greater risk of adverse effects.[30]that the introduction of ICS in Sweden has not changed the mean

difference in height between Swedish conscripts with and without Beyond these studies, a meta-analysis demonstrated that thereasthma. Moreover, in 1997 Silverstein et al.,[15] in a retrospective is a tendency, albeit small, for ICS to be associated with thestudy concerning a cohort of 153 patients with asthma who had impairment of final height in children with asthma.[32] However,attained their adult height, showed that patients with asthma who this effect was small and, therefore, it would not be confirmed byreceived corticosteroid treatment attained similar adult height to relatively few conflicting studies. Moreover, final growth impair-that of patients who had never been treated with corticosteroids. ment was limited to children also treated occasionally with sys-

Further studies that focused on shorter periods of treatment temic corticosteroids (methylprednisolone or prednisone), and the

confirm that ICS can impair growth velocity in the first year of reduction in linear growth during short-term ICS treatment was, in


Inhaled C

orticosteroids: G

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Table IV. Summary of the main studies of adverse effects on growth of long-term inhaled corticosteroid treatment in children with asthma

No. of Mean age (range) Drug/dosage Study period (y) Conclusions Reference

patients [years]

52 9.6 (4–13) Budesonide 200 μg/day 1 No effects of budesonide on growth 37

195 11.9 (6–16) Beclomethasone 400 μg/day 1 Growth velocity suppression in children treated with 19

beclomethasone

216 6.2 (3–11) Budesonide 430–710 μg/day 3–6 No overall significant effect of budesonide vs run-in 38

without corticosteroids or control children

153 6.1 (± 4.8)a Unspecified 23 Use of corticosteroids in childhood: no effect on adult 15

height

241 9.3 (± 2.4)a Beclomethasone 400 μg/day 1 Beclomethasone group: linear growth was 1.44cm less 28

than children receiving salmeterol

67 10.5 (6–16) Beclomethasone 400 μg/day 1 Growth slower in beclomethasone group (–0.28 SD) 35

compared with salmeterol group (–0.03 SD) [p =

0.001]

268 8 (4.0–11.9) Fluticasone propionate 100–200 μg/ 1 Children treated with fluticasone propionate grew at 18

day rates similar to those in the placebo group

2355 (1–15) Unspecified 4 Children treated with high doses of inhaled 29

corticosteroids were shorter on average than the

reference population

325 Prepubescent Fluticasone propionate 100–200 μg/ 1 Children treated with fluticasone propionate had growth 10

day similar to the placebo group

211 8.7 (3–13) Budesonide 110–877 μg/day 9.2 Long-term treatment with budesonide did not influence 20

final adult height

1041 (5–12) Budesonide 400 μg/day 4–6 The mean height increase in children treated with 39

budesonide was 1.1cm less than in the placebo group

670 5 (0.5–8) Budesonide 500–2000 μg/day 1 Children with mild persistent asthma, treated with 30

budesonide 1 mg/day, compared with those in

conventional asthma therapy without inhaled

corticosteroids, had a decrease in growth rate of 0.8

cm/year

a Standard deviation.


most cases, counterbalanced by a catch-up growth in the long-term Static tests include measurement of cortisol levels in the morn-

period leading to normal final height. Finally, from this meta- ing, the circadian rhythm of cortisol, and free urine cortisol excre-analysis it emerged that there is no correlation between dose and tion. Dynamic tests measure the adrenal response after stimulus.growth retardation within the recommended doses (table III).[32]

The corticotrophin (ACTH) test (standard or low dose) evaluates

the adrenal reserve, while insulin and metyrapone tests evaluate4. Hypothalamic-Pituitary-Adrenal (HPA) Axis the integrity of the whole HPA axis, both the adrenal and pituitary

functions.[45-48]

The systemic activity of ICS is determined by several factors,

including corticosteroid receptor potency, receptor binding affini-4.2 HPA Axis and Corticosteroids

ty, plasma elimination half-life, lipophilicity, and systemic tissue

retention.In patients treated with oral corticosteroids, the subsequent useUse of ICS for long periods and at high doses may cause HPA

of ICS results in a slow recovery in HPA function, lasting, in someaxis suppression. This is a result of long-term negative feedbackcases, more than 3 years.[40,49] There are several studies showingexerted on corticotropin, and a subsequent reduction in adrenalvariable adrenal suppression in children treated with ICS (tablecortisol production. There are many conflicting results in theVI). According to these studies, fluticasone propionate (200–1250literature on the effects of ICS on the HPA axis; this is because ofμg/24h) always causes measurable suppression of overnightdifferent methods in the study of HPA function.12-hour urinary cortisol output or corticotrophin-stimulated plas-

ma cortisol,[50,51] while adrenal suppression by budesonide and4.1 Evaluation of HPA Axis Functionbeclomethasone is lower and inconsistent.

There are many standardized methods of evaluating the integri- The greater systemic activity of fluticasone propionate can bety of the HPA axis, both in a static and dynamic condition (see explained by its pharmacology. In fact it is generally accepted thattable V). fluticasone propionate is at least twice as potent as budesonide.

This is because fluticasone propionate has a higher lipophilicity

and a longer corticosteroid/receptor complex half-life than

budesonide.[54]

The absence of significant dose-related suppression of urinary

cortisol with budesonide has been demonstrated in two pediatric

studies, with dosages ranging from 200–800 μg/day.[47,55]

A recent study which used a more sensitive test for adrenal

suppression, the low-dose adrenocorticotrophin test, showed that

children with asthma treated with inhaled fluticasone propionate

or budesonide had a significantly lower mean stimulated concen-

tration of serum cortisol than patients treated with sodium cromog-

lycate.[44] In this study, the adrenal suppression was associated

with growth retardation only in patients treated with ICS for >6

months.

Although biochemical asymptomatic HPA axis suppression has

been shown during ICS treatment, severe hypoglycemia resulting

from adrenal insufficiency has only been reported in two pre-

school children receiving inhaled fluticasone propionate treatment

at a dosage of 780 μg/m2/day.[56]

Table V. Static and dynamic tests for the assessment of adrenal

function[42-44]

Test Reference values

Plasma cortisol level 0800h: 138–635 mmol/L

1600h: 83–413 mmol/L

2000h: ≤50% of 0800h

Urine free cortisol (24h urine Child: 5.5–74 mmol/24h

collection) Adolescent: 14–152 mmol/24h

Corticotrophin (ACTH) test Plasma cortisol increment of 200

(tetracosactide [cosyntropin] 250μg mmol/L, or a level of 500 mmol/L

IV, blood samples taken 30 and 60 at any time during the test

minutes after injection)

Low-dose corticotrophin (ACTH) test Plasma cortisol increment of 200

(tetracosactide 0.5 μg/1.73 m2 body mmol/L, or a level of 500 mmol/L

surface IV, blood samples taken 30 at any time during the test

and 60 minutes after injection)

Insulin-induced hypoglycemia (0.1 Cortisol ≥550 mmol/L (blood

U/kg regular insulin IV, blood glucose must fall to 1.9 mmol/L

glucose and plasma cortisol level during test)

measured 30 and 45 minutes after

injection)



Table VI. Summary of the main studies measuring adrenal suppression with inhaled corticosteroid treatment in children with asthma

Drug Delivery device Dosage Adrenal assessment Adrenal suppression Reference

(mg/24h) (no. of patients) (%)

Beclomethasone MDI 0.2–1.0 UCC (60) 32 52

Spacer 0.2–1.0 UCC (60) NS 52

DPI/spacer 0.6–2.0 Corticotrophin test (28) 13 53

MDI 0.2–0.8 UCC (30) 36 47

MDI 0.2–0.8 Corticotrophin test (30) NS 47

Budesonide Spacer 0.4–1.25 UFC (10) NS 51

Spacer 0.4–1.25 UCC (10) NS 51

DPI/spacer 0.8–2.4 Corticotrophin test (49) 14 53

MDI 0.2–0.8 UCC (30) NS 47

MDI 0.2–0.8 Corticotrophin test (30) NS 47

DPI 0.4–0.8 Corticotrophin test (12) 15 44

MDI/spacer 0.2 Corticotrophin test; UCC (15) NS 54

MDI/spacer 0.2–0.8 UCC (15) NS 55

Fluticasone propionate Spacer 0.4–1.25 UFC (10) 71 51

Spacer 0.4–1.25 UCC (10) 74 51

DPI 0.2–0.5 Corticotrophin test (11) 23 44

DPI = dry powder inhaler; MDI = metered-dose inhaler; NS = not significant; UCC = urinary cortisol/creatinine ratio; UFC = urine free cortisol.

5. Conclusions among patients probably because of variations in susceptibility,

severity of asthma, compliance, type of inhalation device, and typeAsthma is a chronic disease that affects an estimated 4.8 million of adrenal function assessment.

people in the US, with an elevated morbidity and social cost. On the basis of these findings, and in agreement with most ofStudies over the past 15 years have demonstrated that treatment the current literature, we can conclude the following:with inhaled and systemic corticosteroids reduce mortality, mor- • long-term treatment with ICS in children with asthma should bebidity, and severity of asthma attacks.[57] Therefore, ICS are now limited to patients with mild persistent, moderate, or severerecommended for the treatment of children with asthma. Despite asthma not controlled by other non-corticosteroid drugs, suchclear benefits there are also risks in the use of ICS. as cromones and/or β2-agonists

The long-term use (>6 months) of ICS for the treatment of • the dose of ICS must be individually adjusted to minimize thechildren with asthma can temporarily decrease growth velocity by possible adverse effects on growth0.43–1.5 cm/year. Final height is probably not influenced by this • all children with asthma receiving long-term treatment withtemporary decrease in growth velocity. However, most of the data ICS must be regularly evaluated for growth impairment, whichavailable on the final height of children treated early and for long may necessitate dose reduction or discontinuation of the treat-periods with ICS, are retrospective and, consequently, not fully ment depending on clinical symptoms.reliable. The only prospective study is that of Agertoft and Peder-

sen,[20] in which they studied 211 children treated with budesonideAcknowledgements

who attained adult height. Their results confirmed that children

with asthma who received long-term treatment with budesonide We acknowledge Mrs Catriona Cameron for her revision of the Englishattained normal adult height. The hypothalamic-pituitary-adrenal text. The authors have provided no information on sources of funding or on

conflicts of interest directly relevant to the content of this review.axis can be partially suppressed by ICS, with a wide difference



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