inhaled corticosteroids in childhood asthma

Inhaled Corticosteroids inChildhood AsthmaGrowing Concerns

Kimberley A. Witzmann and Robert J. FinkDepartment of Allergy, Immunology, and Pulmonary Medicine, Children’s National MedicalCenter, George Washington University, Washington, DC, USA

Abstract Inhaled corticosteroids (ICS) are an established treatment for asthma in child-hood. Recent data bring to light growing concerns that ICS may have significanteffects on growth velocity in children. The Food and Drug Administration (FDA)recently convened a joint meeting to review these data, and to release new classlabelling for ICS that notes this potential adverse effect. Additional concerns regard-ing ICS are also discussed, including other potential adverse effects, difficulty ofuse, noncompliance, and patient and parental concerns with the safety of ICS.The aim of this article is as follows: to describe the rationale for the use of ICS

in children with asthma; to delineate the association of ICS with potential growthsuppression in children; to discuss recent FDA class labelling for use of ICS inchildren; to describe other potential long term effects of ICS in children; and todetail compliance issues in children with asthma treated with ICS.

REVIEW ARTICLE Drugs 2000; 59 Suppl. 1: 9-140012-6667/00/0001-0009/$25.00/0

© Adis International Limited. All rights reserved.

Asthma is currently the most common chronicdisease of childhood, affecting almost 5 millionchildren in the US. It is responsible for 5000 deathsannually,[1] with the highest mortality rates in thoseaged 15 to 24 years, and Blacks.[2] In 1991 andagain in 1997, the National Institutes of Health(NIH) released clinical practice guidelines for thediagnosis and management of asthma in responseto growing concerns that asthma was being under-treated. Goals for asthma therapy identified in theguidelines include preventing chronic symptomsand exacerbations, maintaining pulmonary func-tion and activity levels, meeting the expectationsof the patient and family, and providing optimalpharmacotherapy.[2]

1. Rationale for the Use of ICS

Optimal pharmacotherapy of asthma is difficultto achieve for a number of reasons. It is clear that

asthma is a chronic inflammatory disease and thatprevention is the best way to manage exacerba-tions. The Global Initiative for Asthma guidelines,which were issued in 1995, state that, ‘any asthmamore severe than mild, intermittent (FEV1 ≥ 80%predicted, intermittent symptoms less than onetime per week, and nighttime symptoms less thantwo times per month) is more effectively controlledby treatment to suppress and reverse the inflamma-tion than by treatment only of acute bronchocon-striction’.[3] These guidelines consider inhaledcorticosteroids (ICS) to be the most effective anti-inflammatory medication. In fact, worldwide, ICSare a mainstay of both adult and paediatric therapyfor moderate to severe asthma. The efficacy of ICShas been well documented, and many national andinternational treatment guidelines recommendtheir use as first-line therapy in all but mildasthma.[4-6] It is not necessary to argue the benefits

of ICS in asthma management, since these arewidely known and include the following: a de-crease in the need for oral corticosteroids; a de-crease in airway reactivity; a reduction in the fre-quency of acute exacerbations; and a reduction inthe need for concurrrent medications.[7] There is nodoubt that ICS decrease chronic inflammatorychanges in the lungs, and that, especially in adults,they do not seem to have significant adverse ef-fects on the hypothalamic-pituitary-adrenal (HPA)axis, or other serious systemic adverse effects.[8]In 1997 the NIH group recommended the use of

ICS in children with asthma to fight lung inflam-mation. Their rationale was that ICS were the mostpotent anti-inflammatory agents available and thatearly intervention with these drugs could improvecontrol of the disease process and lung function,and might prevent irreversible injury. They statedthat, ‘higher doses [of ICS] may be associated withpossible, but not predictable, growth retardation inchildren’.[2] They recommended that ICS be usedas first-line, anti-inflammatory therapy in childrenwith mild persistent, moderate, and severeasthma.[2] The potential risk of growth delay asso-ciated with ICS was felt to be justified by the over-all benefits of these drugs, which include an overalldecrease in morbidity from asthma, and becausethere was no better anti-inflammatory drug at thattime. However, since early 1997, because of theavailability of more data relevant to the adverseeffects of ICS together with growing patient andparental reservations, caregivers are increasinglyquestioning the use of ICS as a first-line agent.

2. Growth and ICS

During the last 30 years, a number of studieshave examined the effects of ICS on growth in chil-dren with asthma. Of approximately 53 publica-tions identified in a recent review,[9] 24 showedsuppressive effects on growth. These studies aresomewhat difficult to interpret, however, becauseof varying study designs, lack of blinding, varia-tions in dosage, concomitant use of systemic corti-costeroids, and no uniformity in the measurementof growth. In children, interpreting growth data is

difficult because there is a natural deceleration inthe growth rate prior to an acceleration in earlypuberty.[10] These expected velocity changes mayskew growth data in either direction, depending onthe age of the patients and the duration of the study.To avoid confounding, studies should focus ongirls aged <10 years and boys aged <12 years, priorto any change in Tanner staging, which indicatesthe onset of puberty. Most studies of growth veloc-ity have not recorded Tanner stages and, since thechildren’s ages have varied widely, it is difficult totease out what proportion of a change in growth isdue to a drug or due to puberty. Because of therecent increase in the use of ICS, studies have ex-amined these issues.Crowley and colleagues examined the effects of

ICS on growth in UK children.[11] They studied 56prepubertal children aged 4.4 to 11.7 years. After12months, 20% of children using inhaled budeson-ide (BUD), 50% of those using inhaled beclo-methasone dipropionate (BDP), and 70% of thoseusing an ICS in conjunction with systemic cortico-steroids had decreased growth velocities comparedwith controls. These data are somewhat difficult tointerpret because of the variety of ICS used, theirdosages, and the age of the children.In 1997, the Dutch Paediatric Asthma Study

Group published their initial findings comparingthe use of ICS versus inhaled salmeterol for longterm therapy. Although ICS were more effectivethan salmeterol, the group receiving ICS had sig-nificantly slower growth rates than those receivingsalmeterol.[12] The Canadian group led by Si-mons[13] compared BDP, salmeterol and placebo,and, during their 1-year study period, BDP pro-vided superior asthma control, but was associatedwith decreased linear growth in children. Heuckand colleagues[14] examined markers of collagenturnover and dosage effects in children usingICS, and found that twice-daily ICS suppressedthe lower leg growth rate, as well as collagenmarkers, when compared with once-daily morningtreatment. Unfortunately, this study did not in-clude a control group. These studies establish a

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© Adis International Limited. All rights reserved. Drugs 2000; 59 Suppl. 1

clear association between decreased growth rateand the use of ICS in children.

3. Variations between ICS

Some ICS seem to have a stronger suppressiveeffect on growth than others. MacKenzie et al.[15]compared inhaled fluticasone propionate (FP) 200μg/day with BDP 400 μg/day, and found that BDPsignificantly reduced lower leg growth, but thatlower doses of FP did not. They concluded that theeffect of early intervention with ICS on growth inchildren with asthma warrants further investiga-tion. The FluticasoneAsthma StudyGroup inMad-ison demonstrated that lower dosages of FP did notsignificantly change growth velocity when com-pared with controls, but that there was a downwardtrend. Children were treated with FP 50 or 100μg,or placebo twice daily. Themean (± standard error)height increase after 1 year was 6.15 ± 0.17cm inthe placebo group, 5.94 ± 0.16cm in the 50μggroup, and 5.73 ± 0.13cm in the 100μg group.[16]

4. Duration of Growth Velocity Changes

Since ICS do affect growth velocity, some stud-ies have examined the duration of these suppres-sive effects. Doull and colleagues[17] noted thatgrowth suppression was most marked in childrenduring the initial 6 weeks of treatment, was presentduring the first 18 weeks of treatment, but, there-after, growth rates were similar to those when thechildren were not receiving treatment. Saha etal.[18] examined catch-up growth after discontinu-ation of ICS in 30 children who had evidence ofgrowth suppression and who had received at least2 years of treatment with ICS. They found an in-crease in growth velocity in a majority of children,while 2 showed no change, and 3 continued to havedecreased growth velocity despite a change to non-steroidal medications.The effects of ICS on growth may not be per-

manent. A study from the Mayo Clinic comparedthe adult heights of children with asthma treatedwith corticosteroids, children with asthma nottreated with corticosteroids, and age- and gender-matched controls, and found no significant differ-

ences in the final adult height after correction formid-parental height.[19] Despite this hopeful out-come, however, many clinicians have concernsabout over-utilising ICS as first-line therapy for thetreatment of asthma in children.[20]

5. FDA Class Labelling

Concerns about the growth suppressive effectsof ICSwere brought into the spotlight when, in July1998, the Food and Drug Administration (FDA)convened a joint meeting of the Pulmonary andAllergy Drug Advisory Committee and the Endo-crine and Metabolic Drug Advisory Committee. Inthe Committees’ review of proprietary studies,they noted that ‘mean growth velocity decreased inactive treatment [phases] in all these studies’.[9]They also noted a trend toward decreasing growthvelocities with higher doses of ICS. StandardHPA-axis analyses were not predictive of lower growthvelocity in these patients.[9] As recommended bythe Advisory Committee, the FDA implementedICS class labelling in November 1998. The label-ling states, ‘controlled clinical studies have shownthat orally inhaled corticosteroids may cause a re-duction in growth velocity in pediatric patients’.They continue, ‘The long term effects of this re-duction in growth velocity associated with orallyinhaled corticosteroids, including impact on finaladult height, are unknown. The potential for "catchup" growth...has not been adequately studied... Thepotential growth effects of prolonged treatmentshould be weighed against the clinical benefits ob-tained and the availability of safe and effectivenon-corticosteroid treatment alternatives’.[21]

6. Other Potential Adverse Effects

In addition to potential growth suppressive ef-fects, there are other concerns regarding ICS. Twocommon adverse effects of ICS are thrush and dys-phonia. Thrush appears to be related to the dosageand frequency of use. The proper use of spacer de-vices and mouth rinsing after use decrease the in-cidence of thrush.[22] Dysphonia occurs in as manyas 20 to 30% of patients treated with ICS, but isnot ameliorated by the use of spacers. Although

ICS in Childhood Asthma 11


dysphonia resolves on discontinuation of therapy,typically it will recur with reintroduction of anICS.[22] Other adverse effects include decreasedbone mass,[23] a potential association with severeviral infections[24] and reduced collagen turnoverin children treated with ICS.[25] Ocular effects suchas cataract formation and ocular hypertension arenot seen in children; low to moderate ICS use hasnot significantly contributed to their developmentin adults.[10]

7. Compliance Issues with ICS

Noncompliance or poor compliance with ICS isanother concern regarding use of these drugs asfirst-line treatment. Milgrom and colleagues[26]found that more than 90% of patients in their studygroup exaggerated reports of ICS use, and thatcompliance was only 13% in those with exacerba-tions, compared with 68% in those patients who didnot experience exacerbations. Kelloway and col-leagues[27] also studied noncompliance withasthma medication, and found that 70% of patientstaking oral theophylline were compliant, comparedwith only approximately 30% of patients using in-haled therapies. Bender et al.[28] noted that patientsrarely took all their medications as prescribed, andfailed to take daily ICS on a median of 41.8% ofdays. They also noted that noncompliance waslinked to decreased knowledge of asthma and tofamily dysfunction. Celano and colleagues[29]found similar results in children from low in-come families; mean use of ICS was 44% of pre-scribed doses, and in half of the households therewere cigarette smokers. They also noted that 27%of children demonstrated metered-dose inhaler(MDI)/spacer technique that was likely to preventdrug delivery.The difficulty of teaching and learning proper

inhalation technique is a disadvantage of the use ofMDIs. In a study by Chapman,[30] it was found thatup to one-third of paediatric, teen, and adult pa-tients had inadequate inhaler technique. This wasalso reflected in a study by Van Beerendonk etal.,[31] who found that in a group of 316 adults89% made at least one mistake in MDI/spacer

technique. The most common errors were not con-tinuing to inhale once the medicine was dispensed(70%), and forgetting to exhale fully prior to inha-lation of the drug (66%). Despite initial educationin their use, not only is it difficult to use the propertechnique with theMDI/spacer apparatus, but com-pliance rates with these complicated devices arerather low as well. These difficulties can only in-crease when we take into account the multipleMDImedications with different instructions, and MDIversus dry powder inhaler (DPI) techniques.Parental concern is another reason for decreased

compliance with paediatric ICS use. A study fromSingapore in 1996 reported that 36% of parentswere opposed to ‘inhaler therapy’, or preferred oralmedications.[32] Reasons for parental reluctance touse ICS included fear of dependence, concernswith adverse effects and overdosage, and thechild’s dislike of inhaler devices. A more recentCanadian study published in 1998[33] demonstratedthat a large proportion of adult patients had mis-conceptions and fears regarding therapy with ICS,which reduced their willingness to use them. Morethan half the patients were concerned about usingICS on a regular basis and stated fears of adverseeffects on habitus and bone density, and decreasedefficacy over time. Two-thirds of these patients hadnot discussed their concerns with their physician.Another recent study conducted in an emergencydepartment examined parental attitudes. Adverseeffects of medications were a concern for 81% ofcompliant and 90% of noncompliant families.Doubts regarding usefulness were recorded in 34%and 54%, respectively, of compliant versus non-compliant families. Medications were forgottensome of the time by 42% of the children, and 53%actively avoided taking their asthma medicines.[34]By addressing issues of noncompliance, physicianscan facilitate more efficient targeting of behaviour-al interventions, which will result in better diseasecontrol and lower requirements for urgent inter-ventions.

12 Witzmann & Fink


8. Conclusions

ICS play a major role in the treatment of mod-erate to severe asthma in children, and are the beststudied class of drugs for controlling chronic air-way inflammation in children. ICS are a mainstayof our pharmacological armamentarium againstchildhood asthma, but their use is not without risk.There are many unresolved issues surrounding theuse of ICS, namely, adverse effects, complianceand safety. Especially in paediatrics, we need todevelop effective asthma treatment regimens thatare simple for the child and family members toutilise, that will not require frequent administra-tion at school (which might affect school perfor-mance), and that do not have potentially seriousadverse effects on growth velocity. This opens thedoor for other medications, especially those thatencourage improved adherence by being ‘user-friendly’, that are perceived as safe by parents, and,because they are compatible with the child’s andthe family’s lifestyle, pave the way for the futuremedical management of paediatric asthma into thetwenty-first century.

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ICS in Childhood Asthma 13


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Correspondence and offprints: Dr K.A. Witzmann, Depart-ment of Allergy, Immunology, and Pulmonary Medicine,Children’s National Medical Center, 111 Michigan Avenue,NW, Washington, DC 20010, USA.E-mail: [email protected]@cnmc.org

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inhaled corticosteroids in childhood asthma

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