Journal of Asthma, 45(S1):1–9, 2008Copyright C© 2008 Informa Healthcare USA, Inc.ISSN: 0277-0903 print / 1532-4303 onlineDOI: 10.1080/02770900802631361

ORIGINAL ARTICLE

Safety and Efficacy of Inhaled Corticosteroids (ICS)in Children with Asthma

MARIA A. PETRISKO,1 JONATHAN D. SKONER,2 AND DAVID P. SKONER, M.D.3,4,∗

1Duquesne University, Pittsburgh, Pennsylvania, USA2Juniata College, Huntingdon, Pennsylvania, USA

3Division of Allergy, Asthma and Immunology, Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA4Drexel University College of Medicine, Philadelphia, Pennsylvania, USA

Inhaled corticosteroids (ICS) are the guideline-preferred preventative therapy for persistent asthma of all severity levels and for all ages, includingchildren. While these drugs are unquestionably efficacious, concerns of adverse systemic effects limit patient compliance with treatment regimensand thus the attainable benefits. Suppression of bone growth, bone density, and HPA axis function, in addition to cataract formation and elevatedintraocular pressure/glaucoma, have been associated with ICS use. This review will focus on recent developments in the safety and efficacy of ICS ascompared to oral CS corticosteroids and the achievement of a balance between risk and benefit in optimizing ICS therapy.

Keywords inhaled corticosteroids, asthma, children, bone density, bone growth, hypothalamic pituitary adrenal axis, cataract, glaucoma, safety,efficacy.

INTRODUCTION

Inhaled corticosteroids (ICS) are recommended as the firstchoice of treatment for persistent asthma symptoms (1, 2).Specifically, ICS have been shown to improve lung func-tion and quality of life, reduce symptoms and exacerbationsresulting in emergency visits, hospitalizations, and death, de-crease the need for bronchodilator rescue and airway hyper-responsiveness, and control airway inflammation (3). Unfor-tunately, safety concerns often limit their use and, thus, theattainable benefits. While ICS definitely have an improvedsafety margin versus oral CS therapy, concerns about sideeffects remain (4). This review will provide an update on theefficacy and safety considerations of ICS and oral CS therapy.

EFFICACY CONSIDERATIONS

Recent studies have indicated that the response to ICS ther-apy varies, with as many as 30%–60% considered nonrespon-ders (5, 6). Such variability in response could be environ-mentally or genetically driven. Environmental factors mayinclude tobacco smoking (7) and obesity (8). Variation in thecorticotropin-releasing hormone receptor 1 was consistentlyassociated with enhanced response to ICS therapy in bothchildren and adults (9). Previously, it was believed that earlyuse of ICS therapy could modify the disease progression inasthma. However, a recent study in which ICS therapy wasused for 2 years in pre-school children did not support anylong-term disease modification by ICS at high risk for asthma.

SAFETY CONSIDERATIONS

Inhaled corticosteroids enter the blood via both the gas-trointestinal (GI) tract (swallowed portion) and lungs (inhaled

∗Corresponding author: David P. Skoner, Allegheny General Hospital,Allergy, Asthma and Immunology, 320 East North Avenue, Pittsburgh, PA15212. E-mail: dskoner@wpahs.org

portion), and are thus present to potentially cause systemicside effects. The majority of drug measured in the blood orig-inates from pulmonary absorption. Studies investigating thesafety effects of different ICS have numerous controllableand uncontrollable variables that must be considered in theevaluation of their methods and results. Duration of treat-ment, type of inhalation device, ages of patients, diseases orother afflictions of patients, and previous and concomitantexposure to oral corticosteroids (CS) are all factors that mustbe noted. Although it is difficult to set up a study while takingall of these factors into account, multiple studies have beendevised and performed in order to measure the safety effectsof ICS in children.

Hypothalamic Pituitary Adrenal (HPA) Axis EffectsExogenous CS entering the blood after inhalation can sup-

press the hypothalamic pituitary adrenal (HPA) axis. Sucheffects are much less for ICS than orally administered pred-nisolone (11). Although acute adrenal crisis appears to be arare event in individuals using ICS, smaller degrees of pertur-bation of the HPA axis have been reported for ICS. Dependingon the sensitivity of the test being used, such perturbationsmay even be clinically irrelevant. Based on the results of stud-ies showing an effect of intranasal CS on childhood growth, inthe absence of effects on the HPA axis (12), it is reasonable toconclude that HPA-axis function is a less sensitive indicatorof systemic bioavailability of inhaled and intranasal CS thanchildhood growth. Nonetheless, clear dose-response effectson HPA-axis function have been reported for all availableICS (13). Marked adrenal suppression was seen at high doses(more than 800 µg/day) of ICS, with greater adrenal suppres-sion observed with fluticasone propionate (FP) than with be-clomethasone dipropionate (BDP), budesonide (BUD), andtriamcinolone acetonide aqueous (TAA). However, at thelower doses typically used for treatment of children, verylittle effect was observed. In contrast, inhaled ciclesonide at

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doses up to 1280 mcg/day had no detectable effect on HPAaxis, despite the use of a very robust measure of function(mean serum cortisol area under the curve for 0 to 24 hr)(14).

In the United Kingdom Todd et al. (15) conducted a postalsurvey of 2912 pediatricians and endocrinologists. There wasa 24% (N = 709) response rate with 55 positive replies and33 cases met diagnostic criteria for acute adrenal crisis. In-terestingly, 91% (N = 30) of cases used the ICS FP, 3%(N = 1) used FP plus BUD, and 6% (N = 2) used BDP.However, at that time, FP was a novel ICS that was beingincreasingly used to replace many other ICS that had failedto provide adequate benefit. Moreover, when there was a sub-optimal response to a given dose of FP, doses were generallyescalated to higher than recommended doses. Thus, the higherfrequency observed with FP does not necessarily imply thatFP is the only ICS that is associated with adrenal crisis. Thisis likely a class effect provided by the administration of asufficient higher than recommended dose.

Ophthalmologic EffectsTreatment of asthma using oral CS for extended periods

of time, i.e., more than 1 year, has clinically been shownto cause detrimental ophthalmologic conditions of cataractand/or glaucoma with a suggested dosage dependency (16,17). The replacement of oral CS with ICS as the foremosttherapy in the treatment of asthma requires the understand-ing of ICS’s ability to potentially cause the same adverseophthalmologic side effects. Much of the available evidencesuggests that ICS have a decreased likelihood of producingsuch side effects (18).

Variables in ICS treatment, including factors of daily dose,cumulative treatment, duration of treatment, patient age, andpatient ethnic origin, are being examined to better understandthe relationship between ICS treatment and adverse ophthal-mologic side effects (19). According to Bielory (20), poste-rior subcapsular cataracts (PSC) are the most prevalent typesof cataracts found in asthmatics (up to 9%). It is believed thatCS binds to lens proteins, resulting in oxidation that leads tocataracts.

A controlled study by Agertoft et al. (21) attempted to dis-tinguish side-effect differences, if any, between oral CS andICS. The study showed that of 157 asthmatic children, 111 ofwhom received no previous CS treatment, treated daily with504 µg/day of BUD, there were no incidents of PSC forma-tion. Accordingly, Volovitz et al. (22) found no cataract for-mation after 3 to –5-year-long term, low-dose (200 mcg/day)treatment with inhaled BUD in children. Conversely, the BlueMountains Eye Study by Cumming et al. (23), showed a posi-tive correlation between cataract formation and inhaled BDP,independent of oral CS. These studies indicate that the use ofICS and their tendency to cause adverse side effects are onlypartly understood. The majority of evidence for treatment ofasthmatic children with short-term (less than 3 years)/low-dose ICS indicates a minimal risk. However, more long-termstudies at high dosages, and limiting variables mentionedpreviously, would be beneficial to better the understandingbetween ICS treatment and ocular side effects.

The relationship between ICS and glaucoma as a side ef-fect is less well understood. However, there are a few stud-

ies elucidating some possibilities. Factors that can increasepropensity for developing glaucoma include genetics, age,drug usage, structural irregularity, race, and sex. Garbe et al.(24) conducted a case-control study on an elderly populationin which they found no association between ICS treatmentand an elevated intraocular pressure at low-to-medium doses.However, they did find a positive correlation between highdose of ICS and glaucoma development in patients treatedfor 3 or more months. Furthermore, the Blue Mountains EyeStudy (25) determined a strong association between glau-coma and ICS in patients that had a family history of glau-coma, independent of simultaneous use of oral and ocularCS.

In conclusion, the ocular risks associated with ICS tend tobe minimal at short-term low-dose treatment, whereas high-dose ICS treatment requires more attention, with possiblesusceptibility to both cataract formation and ocular hyper-tension development. Those individuals with a propensity todevelop the above conditions deserve special considerationfor monitoring and treatment purposes.

Bone Density EffectsDuring the normal remodeling process of bones, osteo-

clasts resorb bone and osteoblasts build new bone so that bonemass could be maintained. Under the influence of exogenousCS, osteoblast function is suppressed and less bone is rebuiltthan resorbed. Consequently, bone mass can be diminishedand bone strength gets decreased, potentially increasing therisk of fractures. Studies have shown that oral CS affects bonemineral density (BMD) to a greater degree than ICS (26).However, Israel and colleagues (27) clearly showed a dose-dependent effect of the older ICS triamcinolone acetonide onBMD in premenopausal women.

Children normally accrue bone mass until adult bone massis attained by the age of 20–30 years. An earlier, small, cross-sectional study indicated that repeated short courses of oralCS in the treatment of asthma seemed to be reasonably safe,with no association with any lasting perturbation in bonemetabolism, bone mineralization, or adrenal function (28).Data from the larger Childhood Asthma Management Pro-gram (CAMP) study were reassuring, indicating that treat-ment with inhaled BUD 400 mcg/day for up to 5 years did notaffect BMD in children of 5–12 years of age with mild to mod-erate persistent asthma (29). However, 7-year follow-up datafrom the CAMP study clearly showed that oral CS bursts pro-duced a dose-dependent reduction in bone mineral accretionand an increase in risk for osteopenia in boys, but not in girls.In contrast, cumulative ICS use was associated with a smalldecrease in bone mineral accretion in boys, but not in girls, butno increased risk for osetopenia was observed (30). Impor-tantly, ICS have been shown to decrease the requirement fororal CS bursts by approximately 50%, which may indirectlycontribute to the overall safety profile of ICS. Furthermore,an increased risk of fracture was reported in children treatedwith as few as four short-term oral CS courses (Odds Ratio1.32) (31). In contrast, exposure to ICS did not materially in-crease the fracture risk in children or adolescents comparedwith nonexposed individuals in a population-based, nestedcase-control analysis from the United Kingdom-based Gen-eral Practice Research Database (32).

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OPTIMIZING INHALED CORTICOSTEROID THERAPY IN ASTHMATIC CHILDREN 3

FIGURE 1.—Timeline of growth studies in children with asthma.

Growth EffectsA. Introduction. Beginning in the 1980s and continuing

in1990s as well, numerous studies were published regardingthe effect of ICS on the growth of children with asthma (Fig-ure 1). The results of these studies indicated that there wasa correlation between the use of ICS and growth suppres-sion. This prompted the US Food and Drug Administration(FDA) to convene a meeting in 1998 to review the results ofthese studies. They concluded that the published studies wereflawed methodologically, but nonetheless showed that all ofthe marketed ICS had a little effect on the growth of children.Subsequently, in order to inform the public of ICS’s poten-tial for growth suppression in children, the FDA institutedclass labeling for all inhaled and intranasal CS. Moreover, in2001, the FDA published guidelines on the proper conduct ofgrowth studies to enhance uniformity in future study designand analysis (33). Since 2001, two growth studies have beenconducted in accordance with those guidelines (montelukastand ciclesonide, as described below).

The relative risk of growth suppression in pediatric patientsseems to be dependent on several factors regarding the na-ture of the drug therapy used in treatment. Figure 2 providesa graphical representation of this concept. Research has indi-cated that ICS have a lower risk than oral CS, and high dosesof ICS have a greater risk than low doses of ICS. In addition,progression in the pharmaceutical industry has allowed forthe development of newer drugs that demonstrate improve-ment in comparison to older drugs, thus further reducing risklevels.

B. Oral (Systemic) Versus Inhaled Corticosteroids. Con-sidering orally administered versus inhaled CS, oral CS ap-pears to have a greater risk. Oral, or systemic, CS were usedprevalently in the 1970s and 1980s, and have been associatedwith a variety of adverse consequences (34). In addition togrowth suppression, oral CS were found to cause HPA-axissuppression, cataract formation, dermal thinning, diabetes,Cushing’s syndrome, and muscle weakness. Therefore, as aconsequence of these findings and others, it has been deter-mined that ICS have a lower risk, and are therefore recom-mended as the first choice of treatment for persistent asthmasymptoms (1, 2).

C. High Versus Low-Dose Inhaled Corticosteroids. Al-though it has been determined that inhaled corticosteroidsare preferred to oral corticosteroids, a second aspect to con-sider in establishing a drug treatment with the lowest risk isICS dosage level. Both the efficacy and safety of ICS are dosedependent. The dose–response curve for efficacy is steep atlow to medium doses and flattens at high doses, while thatof safety is flat at low doses and steep at higher doses. Thus,the greatest degree of benefit is attained from relatively lowdoses, and increasing dosage usually does not prove moreeffective and incurs additional risk (35). Most of the adverseeffects of ICS on HPA axis, bones, and eyes have been ob-served at higher dose levels, with minimal or no effects atlower dose ranges.

Studies have shown that the relationship between ICS andgrowth suppression is dose dependent (36). In one of these

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FIGURE 2.—Relative levels of corticosteroid risk.

studies, it was determined that high doses of the BUD causeda significant suppression of growth velocity in children withmild to moderate asthma (37). In another study, higher dosesof BUD were also found to reduce growth rate in comparisonto combination therapy (38). Nevertheless, unlike other ad-verse effects of ICS, growth suppression in pediatric patientshas also been observed in instances of lower doses (39).Therefore, it is important to evaluate studies done at lowerdoses of different ICS in order to identify an ICS that exhibitsthe lowest risk involving growth suppression.

D. Newer versus older inhaled corticosteroids. Studiesindicated that older ICS, including triamcinolone acetonide(TAA; 40) and CFC-propelled beclomethasone dipropionate(CFC-BDP) (41–45; see Figure 3) demonstrated a larger de-gree of growth suppression than the newer ICS, such as flu-ticasone propionate (46, 47; FP; see Figure 4). Indeed, BDPcaused growth retardation ranging from 0.9 to 1.5 cm/year(Figure 3), while growth suppression caused by FP was ap-proximately 0.5 cm/year (Figure 4). An exception to this wasseen in the PEAK study, in which a larger effect size wasdetected in 2–3-year-old children treated with FP for twoyears (10). One possible reason for potential difference ineffect sizes is the high degree of GI bioavailability and lowdegree of hepatic first-pass metabolism of CFC-BDP versusthe newer agents. This is supported by findings from a studyemploying intranasal delivery in patients with allergic rhini-tis, whereby the older BDP decreased growth velocity byapproximately 1 cm/year (12), an effect not observed withthe use of newer agents (48, 49). Transitioning to HFA-BDPimproved the profile by reducing the GI deposition. However,lung deposition was increased with the new formulation, anda growth study found similar effects for the CFC and HFAformulations of BDP (45, Figure 3).

The effects of BUD on growth had been assessed by severalstudies (29, 50–53; see Figure 5). In fact, BUD is the most ex-tensively studied ICS with regard to the effects on childhoodgrowth. In particular, the findings of the START and CAMPstudies confirmed that it also caused slower growth velocityand lower mean height in the children that participated inthe investigation. (29, 54). In the CAMP study (29), BUDdemonstrated a mean growth velocity that was 1.1 cm/yearless than that of the placebo (Figure 5), mostly observed dur-ing the first year of therapy and not during subsequent yearsof continued treatment. Results of these investigations indi-cate that although the newer ICS (FP and BUD) show animprovement in relative risk for growth suppression in chil-dren in comparison to the older ICS (CFC-BDP and TAA),the risk nevertheless continues to exist.

Another newer ICS, mometasone furoate (MF), has alsobeen shown to have small negative effects on growth, al-though there are much more limited data available. In onestudy that involved large doses of dry powder formulationof MF (200 µg/day), it was discovered that MF did signifi-cantly reduce growth velocity in comparison to the placebo(55). However, no effect on growth with the 100 µg/day reg-imen was detected, possibly indicating that negative effectsof MF are also dose-dependent.

E. Newer studies conducted according to the FDA guid-ance. The FDA guidance (33) listed the following criticaldesign elements for the conduct of growth studies. Regardingthe population under study, the guidance recommended thefollowing measures: pre-pubertal, mild, persistent asthma (toavoid possible confounding by disease severity and oral CSuse), and comparable baseline demographics. Regarding thestudy design, the following steps were recommended: min-imum 1 year of treatment, inclusion of an untreated control

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OPTIMIZING INHALED CORTICOSTEROID THERAPY IN ASTHMATIC CHILDREN 5

FIGURE 3.—Beclomethasone dipropionate (BDP) key growth studies.

group, collection of baseline growth velocity data (at least 16weeks), inclusion of a follow-up period (at least 8 weeks),repeated stadiometer measurements, cortisol measurements,and measurement of pulmonary function. Regarding analy-sis, the following steps were recommended: primary analysisusing regression analysis of growth velocity and total lengthof 95% CI ≤ 0.5 cm and secondary analysis using shift analy-sis in growth velocity percentile, analysis of growth velocitypercentiles, and growth velocity during follow-up course.Two studies were conducted using design elements recom-mended in the FDA guidance, i.e., one using oral montelukastand the other using the ICS ciclesonide. Both were designedas primary safety studies, and not primarily designed to ex-amine efficacy.

In the montelukast growth study, children with mild per-sistent asthma were randomly placed on montelukast, BDP,or placebo, and it was observed that the mean growth veloc-ity was slower in the BDP group than either the placebo ormontelukast groups (56). No effect on pulmonary functionwas noted in this investigation.

In a more recent study published in 2008, the effects of theICS ciclesonide (CIC) on the growth of children were eval-uated in a multicenter, randomized, double blind, placebo-controlled investigation that adhered to the 2001 FDA guide-

lines (57). The study lasted 1 year, with a 6-month run-inperiod that preceded it, and incorporated 661 children rang-ing from 5.0 to 8.5 years of age with mild, persistent asthma.These children were randomly assigned to different treatmentgroups, and montelukast therapy was permitted, if needed, bythe participants. The results indicated that once-daily inhaledCIC (40 and 160 µg) during a period of 12 months had noclinically or statistically significant effects on growth veloc-ity in children, in comparison to the children in the placebogroup. This was true for both the high and low dosage. Thebiological properties of CIC seem to indicate why the drugperformed well in this study. Ciclesonide, which is activatedby esterases in the lungs, has low oral bioavailability, rapidelimination, and high plasma protein binding (58). The pos-sibility of an improved safety profile, which is suggested bythe above PK/PD parameters, is also supported by the resultsof a trial using a very robust test of the HPA-axis function,in which CIC at doses up to 1280 mcg/day had no detectableeffect (14).

F. Do we have a new ICS that does not affect growth?.Despite the favorable results of this study, its publication wasadmonished by Dr. Malozowski (59), who stated that thestudy gave “a false sense of safety and its conclusions should

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FIGURE 4.—Fluticasone propionate (FP) key growth studies.

be disregarded since there were no effects on any pulmonaryfunction or asthma-control benefit of ciclesonide when com-pared to the placebo.” However, the authors of the study main-tained that the results of the study must be considered correctunless proven invalid by an equally well-designed test mea-suring the same effects. Adherence by diary cards and canis-ter weights was excellent in this study. Adding blood drawsto measure systemic CIC levels to confirm adherence wouldhave raised the difficulty of conducting such a study andmay have deterred study participation. Furthermore, effectson pulmonary function are difficult to demonstrate in patientswith mild disease who could receive montelukast, if needed.

G. Summary. In summation, multiple studies havedemonstrated that ICS seem to cause a small degree of growthsuppression in children. This growth suppression is depen-dent upon different aspects of the drug treatment, as rep-resented by Figure 2. Research has shown that ICS havea lower risk than oral CS, and increasing ICS dosage usu-ally also increases risk without providing additional benefit.Newer ICS have a lower risk of growth suppression thanolder ones, and the ICS CIC revealed no discernable effecton growth in a very scientifically robust study, indicatingthat its “safety profile may serve to ease concerns regardinglong-term treatment” (57). Indeed, the relative risk levels for

growth suppression caused by CS use have decreased signif-icantly, and there appears to be the potential for this to riskto be eliminated altogether with the advent of the new ICSciclesonide.

BALANCING EFFICACY AND SAFETY

In conclusion, CS efficacy is unquestioned and unparal-leled for persistent asthma, but the benefits of therapy arenot as broad as once believed to be and the consistency ofresponse across individuals is not uniform. Safety has un-doubtedly improved with the transition from treatment withoral CS to that with ICS (Figure 6). However, risks continueto be present with the use of ICS, albeit to a small degree. Therisks, which are dose-dependent, are minimal for HPA axis,bone density, and eye effects at low to medium doses, butget clearly elevated at higher doses. In contrast, growth ef-fects have been observed even at the lower ICS doses. NewerICS have improved the safety profile, but have not altogethereliminated concerns. Such risks are easily managed throughthe monitoring of growth in children, the monitoring for othersystemic side effects of ICS at higher doses, and use of thelowest effective dosage of ICS with solid safety profiles (60).Also, minimizing the number, the dose, and the duration ofa given of oral CS burst (by using ICS) is desirable. In thatregard, a daily oral CS dose of 1 mg/kg was shown to be as

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OPTIMIZING INHALED CORTICOSTEROID THERAPY IN ASTHMATIC CHILDREN 7

FIGURE 5.—Budesonide (BUD) key growth studies.

effective as 2 mg/kg (61) and a 3 day duration of treatmentwas as effective as a 5 day treatment period (62). Further-more, clinicians should address “steroid phobia” proactivelywith parents to minimize effects on adherence.

FIGURE 6.—Summary.

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