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Inhaled Corticosteroids and Asthma Control in Children: Assessing Impairment

and Risk
Gary Rachelefsky
Pediatrics 2009;123;353-366
DOI: 10.1542/peds.2007-3273

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/123/1/353

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly


publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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REVIEW ARTICLE

Inhaled Corticosteroids and Asthma Control in


Children: Assessing Impairment and Risk
Gary Rachelefsky, MD, FAAP

Executive Care Center for Asthma, Allergy, and Respiratory Diseases, Geffen School of Medicine at UCLA, Los Angeles, California

The author has indicated he has no financial relationships relevant to this article to disclose.

ABSTRACT
OBJECTIVE. To review the use of inhaled corticosteroids on asthma control in children by
using the new therapeutic paradigm outlined in the Expert Panel Report 3: Guidelines
for the Diagnosis and Management of Asthma. www.pediatrics.org/cgi/doi/10.1542/
peds.2007-3273
METHODS. A systematic review of the literature was performed by using the Medline doi:10.1542/peds.2007-3273
and Embase databases (January 1996 to October 2007). Key Words
asthma control, childhood asthma,
RESULTS. A total of 18 placebo-controlled, clinical trials in ⬎8000 children (aged 0 –17 impairment, inhaled corticosteroid,
years) with asthma met the criteria for evaluating monotherapy with inhaled corti- pediatric asthma, persistent asthma, risk
costeroids: 13 double-blind studies of inhaled corticosteroids versus placebo and 5 Abbreviations
controlled studies that compared inhaled corticosteroids to a nonsteroid antiinflam- EPR—Expert Panel report
ED— emergency department
matory agent. The findings can be summarized as follows: (1) Compared with
ICS—inhaled corticosteroid
placebo, inhaled corticosteroid treatment was associated with reductions in both the mAPI—modified Asthma Predictive Index
impairment and risk domains. (2) Improvements in impairment and risk observed OCS— oral corticosteroid
with inhaled corticosteroids were generally greater than those observed with non- FDA—Food and Drug Administration
BIS— budesonide inhalation suspension
steroid antiinflammatory comparator medications. (3) Inhaled corticosteroids were FP—fluticasone propionate
well tolerated. (4) Small reductions in growth rates were evident when compared DPI— dry powder inhaler
with placebo and/or comparator nonsteroid antiinflammatory medication use in the BDP— beclomethasone dipropionate
AE—adverse event
long-term (⬎1-year) studies, but when measured, the reductions diminished with CAMP—Childhood Asthma Management
time. Program
NED—nedocromil sodium
CONCLUSIONS. Treatment with inhaled corticosteroids improves the asthma-control do- SAB—short-acting bronchodilator
mains of impairment and risk in children. Differences in study protocols make FEV1—forced expiratory volume in 1
detailed comparisons difficult. Specific needs for additional trials include (1) more second
bid—twice daily
studies using appropriate indicators for impairment (eg, rescue-medication use; qd— once daily
symptoms scores; asthma/episode-free days) and risk (eg, forced expiratory volume START—Steroid Treatment as Regular
in 1 second in children who can perform spirometry; exacerbations requiring oral Therapy
prn—as needed
corticosteroids; urgent care usage) and (2) more studies evaluating adolescents; the SARE—severe asthma-related event
majority of the data reported were for children up to the age of 12 years, and data for LABA—long-acting bronchodilator
adolescents are often lost (either grouped with adults [eg, studies in patients ⱖ12 Accepted for publication Apr 16, 2008
years old] or not included [eg, studies of school-aged children ⱕ12 years old]). Address correspondence to Gary Rachelefsky,
Attention should be given to standardizing variables that will permit comparison of MD, FAAP, Executive Care Center for Asthma,
Allergy, and Respiratory Diseases, Geffen
outcomes between trials. Pediatrics 2009;123:353–366 School of Medicine at UCLA, 200 Medical
Plaza, Suite 140-17, Los Angeles, CA 90095.
E-mail: grachelefsky@mednet.ucla.edu

T HE NATIONAL HEART, Lung, and Blood Institute of the National Institutes of


Health recently released an update of the US asthma clinical practice guidelines,
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma1 (EPR3).
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2009 by the
American Academy of Pediatrics

This new document incorporates an evidence-based assessment of former guidelines


and current literature in revising the recommendations for practice.
The relative burden of asthma in relation to other chronic conditions remains high, particularly in children, despite
better understanding of asthma, improved approaches to treatment, and modest gains in asthma morbidity.2 The
prevalence of asthma in the United States is greater in children than in adults (8.9% vs 7.2%, 2005 data).3 Asthma
affects ⬎6.5 million children (0 –17 years old); ⬃1.4 million are ⬍5 years old.3 Children are more likely to have
suboptimally controlled asthma as demonstrated by exacerbations and use of urgent care services. The rates of
asthma exacerbations reported in 2005 for the previous 12 months were 5.2% and 3.9% for children and adults with
asthma, respectively.3 There were 103 emergency department (ED) visits per 10 000 children compared with 50 ED
visits per 10 000 adults; hospitalization rates were 27 per 10 000 children versus 14 per 10 000 adults. Children ⬍5
years old had the highest rates: 168 ED visits and 60 hospitalizations per 10 000 children.3 Asthma resulted in ⱖ1
missed day of school for almost 13 million children (5–17 years old) in 2003.3

PEDIATRICS Volume 123, Number 1, January 2009 353


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TABLE 1 Some Key Terms Used to Define the Patient With Asthma nary function, reduce the need for reliever medications,
Regardless of Age1 improve quality of life, enhance exercise tolerance, and
reduce hospitalizations.1 Thus, although early interven-
Term Definition
tion with ICSs for childhood asthma does not alter the
Severity The intrinsic intensity of asthma pathology, which is measured
natural history of asthma, these medications are impor-
most easily and directly before a patient starts long-term
tant for gaining and maintaining asthma control.1 How-
control therapy (ie, before a patient is being treated)
Control The degree to which the manifestations of asthma ever, no review to date has examined the effect of ICSs
(symptoms, functional impairments, risks of AEs) are on childhood asthma in terms of impairment and risk as
minimized and the goals of therapy are met defined in the EPR3. The purpose of this review is to
Impairment The frequency and intensity of symptoms and functional evaluate the data on ICSs in childhood asthma with
limitations that the patient is experiencing or has recently specific regard to the newly defined domains of risk and
experienced impairment.
Risk The likelihood of asthma exacerbations, progressive decline in
lung function (or, for children, reduced lung growth), or
adverse effects from medication METHODS
A systematic review of the literature was performed for
randomized, placebo-controlled studies that evaluated
monotherapy with ICSs in children. Searches of the
For most patients, asthma onset occurs early in life,
Medline and Embase databases (January 1996 to Octo-
and disease persistence is associated with recognizable
ber 2007) were performed by using the Medical Subject
risk factors including atopic disease, recurrent wheezing,
Headings (MeSH) terms asthma, beclomethasone dipro-
and a parental history of allergy and/or asthma. Evi-
pionate, budesonide, flunisolide, controlled clinical tri-
dence indicates that therapy with current antiinflamma-
als, fluticasone propionate, mometasone, randomized,
tory medications does not prevent progression of the
controlled trials, and triamcinolone acetonide and the
underlying disease.1 In contrast to previous guidelines
text words childhood asthma, pediatric asthma, persis-
that focused on reducing asthma severity, the new
tent asthma, and ICS. Searches were limited to human
guidelines target asthma control as the primary goal for
subjects aged 0 to 17 years and English-language litera-
management. Classifying asthma severity to initiate
ture.
treatment is differentiated from assessing asthma control
for ongoing monitoring, and both are broken down to
newly defined domains of impairment and risk to op- EFFICACY OF ICSs IN CHILDREN
erationalize therapeutic targets (Table 1).1 According to the new guidelines, “ICSs are the most
The goal of asthma therapy is to achieve asthma potent and consistently effective long-term control med-
control by reducing impairment and risk on the basis of ication for asthma” for adults and children.1 They are the
the criteria1 shown in Table 2. As in previous guidelines, only medications consistently shown to meet the goals
inhaled corticosteroids (ICSs) are the preferred class of of pharmacotherapy for asthma:
long-term controller medications to manage persistent ● control (ideally, prevent) asthma symptoms;
asthma in all age groups. Numerous studies in children
with asthma have established that ICSs improve pulmo- ● reverse airflow obstruction;
● improve quality of life; and
● decrease the number and severity of asthma exacer-
TABLE 2 Criteria for Achieving Asthma Control by Targeting the
bations (and associated urgent medical care).
Domains of Impairment and Risk1
Asthma-Control Criteria In the step-care approach to therapy, ICSs are the main-
Domain stay of treatment for all patients with persistent asthma
Reducing impairment Prevent chronic and troublesome symptoms (eg, (Fig 1, steps 2– 6). Treatment for adolescents (12–18
coughing or breathlessness in the daytime, years old) is the same as for adults; changes to the
nighttime, after exertion) algorithm are shown for children ⬍12 years old. Table 3
Infrequent use (ⱕ2 d/wk) of inhaled SAB for shows the currently available ICSs indicated for use in
quick relief of symptoms children in the United States.
Maintain (near) “normal” pulmonary function The broad action of ICSs on airway inflammation and
Maintain normal activity levels (including associated clinical markers in asthma is well documented
exercise, other physical activity, attendance at
and beyond the scope of this article.4–7
work or school)
Meet patients’ and families’ expectations of and
Most of the clinical benefits observed with ICS treat-
satisfaction with asthma care ment in children occur at low doses. However, similar to
Reducing risk Prevent recurrent exacerbations of asthma; adults, the dose response to ICSs in children may vary
minimize ED visits, urgent care visits, according to the clinical outcome (eg, improvement in
hospitalizations lung function, prevention of exacerbations) and patient
Prevent progressive loss of lung function (for characteristics. Children with more severe asthma may
children, prevent reduced lung growth) respond to higher doses, whereas those with mild or
Provide optimal pharmacotherapy with minimal moderate asthma usually show a plateauing of effect at
(ideally, no) adverse effects low and medium doses.8–11 Nonetheless, stepping up the

354 RACHELEFSKY
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A
Intermittent
Consult with asthma specialist if step 3 care or higher is required.
asthma
Consider consultation at step 2. •Step up if
STEP 6 needed
(first, check
STEP 5 adherence,
PREFERRED
STEP 4 High-dose ICS
environmental
control and
PREFERRED
comorbid
STEP 3 PREFERRED High-dose conditions)
ICS and
Medium-dose
STEP 2 PREFERRED ICS either
ASSESS
Medium-dose and montelukast CONTROL
STEP 1 PREFERRED ICS and or
either
Low-dose ICS either LABA Step down
PREFERRED montelukast
or if possible
SABA prn ALTERNATIVE or
LABA and
Montelukast or (and asthma is
LABA oral corti-
cromolyn well-controlled
costeroids at least 3
mo)

FOR ALL PATIENTS and AT ALL STEPS:


• Education and environmental control
• Quick-relief medication: SABA prn for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-min intervals as needed. Short course of oral corticosteroids may be needed.
• Caution: Increasing of β-agonist or use >2 times per wk for symptoms control indicates inadequate control and the need to step
up treatment.

B
Persistent asthma: daily medication
Intermittent
Consult with asthma specialist if step 4 care or higher is required.
asthma
Consider consultation at step 3. •Step up if
STEP 6 needed
(first, check
STEP 5 PREFERRED adherence,
STEP 4 High-dose ICS environmental
PREFERRED control and
High-dose ICS + LABAb
STEP 3 PREFERRED comorbid
+ LABAb + oral
Medium-dose conditions)
corticosteroid
PREFERRED ICS + LABA
STEP 2 and ASSESS
Medium-dose and
ICS omalizumab CONTROL
PREFERRED may be omalizumab
STEP 1 ALTERNATIVE may be
Low-dose ICS or medium-dose considered for
PREFERRED patients who considered for Step down
ICS + either patients who
ALTERNATIVE low-dose ICS LTRA or have allergiesc if possible
SABA prn have allergiesc
LTRA, + LABA, theophylllinea
cromolyn, LTRA, or (and asthma is
nedocromil or theophyllinea well-controlled
theophylline at least 3
mo)

FOR ALL PATIENTS and AT ALL STEPS:


• Education and environmental control
• Quick-relief medication: SABA prn for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-min intervals as needed. Short course of oral corticosteroids may be needed.
• Caution: Increasing of β-agonist or use >2 times per wk for symptoms control indicates inadequate control and the need to step
up treatment.

FIGURE 1
A, Stepwise approach for managing asthma in patients 0 to 4 years of age.1 B, Stepwise approach for managing asthma in patients ⱖ5 years of age.1 a Zileuton may be considered in
patients 7 to 12 years old; b alternative in patients 5 to 11 years old: high-dose ICS plus either leukotriene receptor antagonist (LTRA) or theophylline; c 12 years old or older. (Adapted
from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Institute of Health, 2007
[Tables 41a and 41b].)

ICS dose may provide added clinical benefit for some ments may be based on measurement of a simple bi-
children with mild or moderate asthma during exacer- omarker of airway inflammation in children; sputum
bations or seasonal increases in symptom severity (eg, to eosinophils and exhaled nitric oxide are being studied
allergens, respiratory viruses).1 This “flexible dose ap- but require further validation.16,17
proach” to treatment suggests that ICS therapy may be
increased temporarily in response to some index of USING ICSs IN INFANTS AND YOUNG CHILDREN (<5 YEARS
worsening asthma, usually an increase in symptoms, OLD)
nighttime awakenings, decrease in peak flow rate, or use As in older children and adults, the use of ICSs in infants
of rescue medications; it remains subject to continued and young children is directed toward symptom control,
study and discussion.12–15 In the future, such dose adjust- preventing exacerbations, and improving the child’s

PEDIATRICS Volume 123, Number 1, January 2009 355


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TABLE 3 Estimated Comparative Daily Dosages of ICSs in Children1
ICS Daily Dose
Low Medium High
For children aged 5–11 y
Beclomethasone hydrofluoroalkane, 40, 80 80–160 ␮g ⬎160–320 ␮g ⬎320 ␮g
␮g per puff
Budesonide DPI (Flexhaler), 90 180 ␮g per 180–360 ␮g ⬎360–720 ␮g ⬎720 ␮g
inhalation
Budesonide inhalation suspension for 0.5 mg 1.0 mg 2.0 mg
nebulization, 0.25, 0.5 mg
Flunisolide, 250 ␮g per puff 500–750 ␮g 1000–1250 ␮g ⬎1250 ␮g
Flunisolide hydrofluoroalkane, 80 ␮g per puff 160 ␮g 320 ␮g ⱖ640 ␮g
Fluticasone hydrofluoroalkane MDI, 44, 110, 88–176 ␮g ⬎176–352 ␮g ⬎352 ␮g
220 ␮g per puff
Fluticasone DPI, 50, 100, 250 ␮g/inhalation 100–200 ␮g ⬎200–400 ␮g ⬎400 ␮g
Triamcinolone acetonide, 75 ␮g per puff 300–600 ␮g ⬎600–900 ␮g ⬎900 ␮g
For children aged 0–4 y
BIS for nebulization, 0.25, 0.5 mga 0.25–0.5 mg ⬎0.5–1.0 mg ⬎1.0 mg
Fluticasone hydrofluoroalkane MDI, 44, 110, 176 ␮g ⬎176–352 ␮g ⬎352 ␮g
220 ␮g per puffa,b
Beclomethasone hydrofluoroalkane MDI, 40, 80 ␮g 160 ␮g 320 ␮g
80 ␮g per puffa,c
a Fluticasone is not FDA approved for children ⬍4 years of age. Budesonide nebulizer suspension is the only ICS with FDA-approved labeling for

children in this age bracket.


b For fluticasone hydrofluoroalkane, the dose should be divided 2 times daily; the dose is higher than for older children because of the lower
amount delivered by face mask.
c Beclomethasone hydrofluoroalkane is not FDA approved for children ⬍5 years of age, and it is not included in the EPR3 for this age group (unlike

fluticasone hydrofluoroalkane). However, the author noted that beclomethasone hydrofluoroalkane is sometimes used with a chamber and face
mask to treat asthma in these children. As for fluticasone hydrofluoroalkane, the dose should be divided 2 times daily, and the dose may be higher
than for older children because of the lower amount delivered by face mask.

(and family’s) quality of life. Treatment with ICSs should proved for children aged ⱖ5 years. Although not ap-
not be initiated or prolonged to alter the progression or proved for young children and there are no data
underlying severity of asthma.1 regarding dosing, efficacy, or safety in this population,
Data on the use of ICSs to treat asthma in young many pediatricians will use a diagnostic trial of any of
children, particularly infants, are limited. Most treat- these ICSs as they deem necessary. Figure 2 presents an
ment recommendations are based on expert opinion and algorithm for a diagnostic trial of ICSs in infants and
extrapolations from studies in older children and adults.1 young children.
The most common symptoms of asthma in this popula-
tion are wheeze and cough, which are frequently asso- SAFETY OF ICSs IN CHILDREN
ciated with other conditions.18–20 A diagnostic trial of Regardless of age, few patients report serious adverse
ICSs is recommended if asthma is suspected. events (AEs) with ICSs at the recommended dosages,
A predictive clinical index (the modified Asthma Pre- even with long-term use.23–26 Most clinical benefit with
dictive Index [mAPI]) to identify children ⱕ3 years old ICSs is achieved at relatively low doses, further reducing
who might be at high risk for developing asthma has the potential risk of AEs.1 Nonetheless, as for any regu-
been developed and validated on the basis of data from larly used medication, children should be monitored
the Tucson Children’s Respiratory Study.18,21 In pre- regularly for potential systemic AEs, particularly because
school-aged children a positive mAPI was associated some children may be more susceptible to the effects of
with ⱖ4 severe wheezing episodes requiring use of oral ICSs even at conventional doses. Suggestions for reduc-
corticosteroids (OCSs) in 12 months and increased hos- ing AEs associated with ICSs are shown in Table 5.
pitalizations and urgent care visits for asthma.21,22 The Data on potential adverse effects of low- or medium-
recommendation of the EPR3 regarding which young dose ICSs on the hypothalamic-pituitary-adrenal axis in
child is appropriate for ICS therapy builds on the mAPI children show rare events, which are usually clinically
(Table 4). insignificant.27,28
ICSs approved by the Food and Drug Administration Of greater concern has been the potential effect of
(FDA) in the United States for young children (ⱕ5 years ICSs on linear growth. Again, the available data for low-
old) include budesonide inhalation suspension (BIS), to medium-dose ICSs show a minimal effect on growth
which is approved for children as young as 12 months, velocity: a reduction of ⬃1 cm in the first year of treat-
and fluticasone propionate (FP) dry powder inhaler ment in some children. This decrease, when observed,
(DPI) and hydrofluoroalkane formulations, which are usually does not progress over time, and long-term stud-
approved for children as young as 4 years. Beclometha- ies have indicated that these children attain their full
sone dipropionate (BDP) hydrofluoroalkane is only ap- adult height.18,28–32 All children using ICSs should be

356 RACHELEFSKY
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TABLE 4 ICSs as Asthma Controller Therapy in Infants and Young may outweigh the potential small reduction in growth
Children1 velocity in these children (Table 6).1,18,32
Recommended for the Has had ⱖ4 episodes of wheezing in the past
child who: year that lasted ⬎1 d and affected sleep THE EFFECT OF ICSs ON THE DOMAINS OF IMPAIRMENT AND
and who has either 1 of the following: RISK IN CHILDREN
Parental history of asthma Eighteen randomized, placebo-controlled studies involv-
Physician’s diagnosis of atopic dermatitis ing ⬎8000 children (0 –17 years old) met the criteria for
Evidence of sensitization to aeroallergens
reviewing monotherapy with ICSs: 13 double-blind
or 2 of the following:
Evidence of sensitization to foods
studies of ICSs alone (Table 7) and 4 double-dummy
ⱖ4% peripheral blood eosinophilia studies comparing ICSs to a nonsteroid antiinflamma-
Wheezing apart from colds tory agent (Table 8). One study, the Childhood Asthma
Should be considered for Consistently requires symptomatic treatment Management Program (CAMP), was a double-blinded
the child who: ⬎2 d/wk for ⬎4 wk trial that compared nedocromil sodium (NED), budes-
Has had 2 exacerbations requiring systemic onide, and matched placebos and is included in Tables 7
corticosteroids within 6 mo and 8. Approximately 4900 children were exposed to
Has periods, or seasons, of previously ICSs in these studies.
documented risk In most of the studies, the children had mild or mod-
erate persistent asthma as defined by symptoms, use of
short-acting bronchodilator (SAB), and/or need for daily
monitored by stadiometry and, if possible, measured by asthma medications. At study entry all children were
the same person at each clinic visit.1 Although no specific using ⱖ1 asthma medication, an SAB with or without a
clinical cutoffs are provided in the EPR3, my approach in controller medication (ICSs, cromolyn sodium). For chil-
practice is to (1) reduce the ICS dose if there is slowing dren who were able to perform spirometry, baseline
of growth at the 3-month visit and the child’s asthma is forced expiratory volume in 1 second (FEV1) ranged
from 70% to ⬎90% predicted.
stable and (2) stop ICSs and consider changing the med-
Study duration was ⱖ12 weeks, and dosing frequency
ication or the device if the child is still not growing after
for ICSs was twice or less daily.
6 months. A reduction in growth velocity also results
from inadequate control of asthma.1 Table 6 summarizes
the evidence-based findings of the 2007 EPR3. Double-Blind, Placebo-Controlled Studies
For children with difficult-to-control asthma, who A total of 6700 children received placebo (n ⫽ 2696) or
require higher doses of ICSs, the use of adjunctive long- an ICS (n ⫽ 4004) for ⱖ12 weeks. The ICSs included
term control therapy is recommended to reduce the dose budesonide, 200 to 2000 ␮g/day (n ⫽ 2941), FP, 100 to
of ICSs and, thus, minimize possible dose-related long- 200 ␮g/day (n ⫽ 826), or BDP hydrofluoroalkane, 80 to
term effects on growth (Fig 1).1 High doses of ICSs ad- 160 ␮g/day (n ⫽ 237).
ministered for prolonged periods of time (eg, ⬎1 year), Three studies evaluated ⬎2 years of treatment with
particularly in combination with frequent courses of budesonide (n ⫽ 1951) or FP (n ⫽ 143).18,29,33 Five stud-
OCSs, may be associated with adverse growth effects. ies evaluated young children and/or infants (mean age:
However, the benefits of early intervention with ICSs ⬍5 years).18,34–37 The results were comparable to the

Diagnostic trial
with ICS
Unsatisfactory

Monitor child’s response to therapy


4–6 wk

Check medication
Positive response No clear positive technique,
FIGURE 2 suggested response adherence
(parents/caregivers)
Algorithm for a diagnostic trial of ICSs in infants and young chil-
dren (⬍5 years old) with suspected asthma.1
Monitor child’s response to therapy
12 wk
Satisfactory

Positive response
suggested Consider alternative
diagnoses/therapies

Careful step down to lowest


dose to maintain control

PEDIATRICS Volume 123, Number 1, January 2009 357


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TABLE 5 Suggestions for Reducing the Potential for Adverse Effects TABLE 6 Summary of ICSs and Linear Growth in Children Based on
of ICSs in Children1 the Opinion of the Expert Panel1
Use the lowest dose of ICS that maintains asthma control Summary Statements Supporting Findings
Use spacers or valved holding chambers with non–breath-activated metered- The potential risks of ICSs The efficacy of ICSs is sufficient to outweigh
dose inhaler to reduce local adverse effects are well balanced by concerns about growth (or other
Advise patients to rinse their mouths and spit after inhalation their benefits systemic effects)
Monitor growth Studies in which growth has been carefully
Control comorbid conditions (allergic rhinitis, sinusitis, obesity, gastroesophageal monitored suggest that the growth-
reflux disease) velocity effect of ICSs occurs in the first
Review age-appropriate dietary intake of calcium and exercise with the child’s several months of treatment and is
parents/caregivers generally small and nonprogressive
When considering an increase in ICS dose ICSs should be titrated to the lowest dose
Evaluate patient adherence that maintains good control of the
Assess inhaler technique child’s asthmaa
Review environmental factors (allergen and irritant triggers) that may Growth rates are highly Short-term evaluations may not be
contribute to asthma severity variable in children predictive of final adult height
Consider adding an LABA or leukotriene receptor antagonist to a low or Poorly controlled asthma may delay growth
medium dose of ICS rather than using a higher dose of ICS In general, children with asthma tend to
have longer periods of reduced growth
rates before puberty (boys more than
girls)
studies conducted in school-aged children (mean age: The potential for adverse Use of a low-to-medium dose of ICSs for
⬎5 years). effects of ICSs on children with mild or moderate
Treatment with ICSs clearly improved measures of linear growth seems persistent asthma may be associated
impairment. Benefits in the risk domain were also ob- to be dose dependent with a possible, but not predictable,
served, where reported. adverse effect on linear growth, which is
usually lost after 1 y
High doses of ICSs have greater potential
Impairment Domain for growth suppression
Significant improvements in symptoms with ICSs com- Use of high doses of ICSs for children who
pared with placebo were evident as mean reductions in have severe persistent asthma has
symptom scores and increased numbers of days free significantly less potential for an adverse
from asthma (symptoms) or “episode-free days.”18,29,33–43 effect on linear growth than use of OCSs
In young children (⬍30 months old), significantly less a No specific recommendations for clinical cutoffs are made in the EPR3. However, my approach

daytime and nighttime wheezing (P ⬍ .05 and P ⬍ .01, in practice is to (1) reduce the ICS dose if there is slowing of growth at the 3-month visit and the
respectively) were reported with BIS versus placebo, but child’s asthma is stable and (2) stop ICSs and consider changing the medication or the device if
the child is still not growing after 6 months.
the specific scores and/or between-treatment changes
were not provided.35 A similar population had significant
increases in the percentage of days without cough (P ⫽
.011) or wheeze (P ⫽ .002) when treated with FP.37 trial, a 3-year study in which budesonide was added to
Improvements in symptoms were maintained with long- the usual care of patients diagnosed with mild asthma
term treatment (ⱖ2 years).18,29,33 who had not regularly used ICSs.32,33 Added medica-
The symptom improvements were observed regard- tions were tracked, but changes in usual care medica-
less of the patient’s therapy before randomization. In tions were not.32,33
some studies, patients were allowed to use their regular Concomitant with fewer symptoms, ICS use was as-
asthma medications (including ICSs) up to the point of sociated with significant reductions in daily and/or as-
randomization; other studies were conducted in steroid- needed (prn) SAB.29,34,36–43 de Blic et al35 (1996) observed
naive patients or required a steroid-free run-in period a slightly shorter duration of nebulized albuterol in in-
before trial entry. In the studies reported by Baker et al34 fants treated with BIS compared with placebo, but the
(1999) and Peden et al41 (1998), children were permitted difference was not statistically significant. Although use
to use their regular asthma medications through the of prn SAB was not reported, young children treated
run-in period; in these studies, 31% and 45% of chil- with FP for 2 years required less added controller med-
dren used ICSs up to random assignment to BIS and ication (montelukast [P ⬍ .001] or additional FP [P ⬍
FP, respectively. Shapiro et al43 (2001) specifically .001]) than placebo-treated children.18 A similar trend
evaluated the ability of once-daily (qd) budesonide to was observed in older children treated with budesonide
maintain asthma control in children who had been for 3 years in the START trial; again, specific use of prn
previously receiving ICSs; all children used their SAB was not reported.33
maintenance ICSs up to random assignment, and 87% It is difficult to make comparisons between the stud-
were using ICSs twice daily (bid). In most studies, all ies regarding degree of symptom improvement because
controller medications were withdrawn before ran- of differences in populations and study design. Presum-
dom assignment. However, Chen et al33 (2006) re- ably, for the patients who used ICSs through the run-in
ported a subanalysis of data for 5- to 10-year-olds in period, any statistically significant between-treatment
the Steroid Treatment as Regular Therapy (START) differences resulted from deterioration of asthma control

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TABLE 7 Effect of ICSs on Impairment and Risk in Children With Asthma Evaluated in Double-Blind, Placebo-Controlled Studies
Study Study Design and Children Impairment Risk
Treatment
Study duration ⬍1 y
Baker et al34 (1999) DBPC, 12 wk N ⫽ 481, 6 mo to 8 y BIS: 0.25 mg qd/0.25 mg bid/ FEV1 (L/min; 33% could perform): BIS:
(mean: 4.7 y) 0.5 mg bid/1.0 mg qd 0.07/0.08/0.17 (P ⬍ .05)/0.11; Pl:
0.04
BIS 0.25 mg qd (n ⫽ 94); Moderate asthma (31% had DT symptom score: BIS: ⫺0.28/ Patients who discontinued treatment
0.25 mg bid (n ⫽ 99); used ICSs ⱖ2 mo) ⫺0.40 (P ⱕ .05)/⫺0.46 because of disease exacerbation
0.50 mg bid (n ⫽ 98); (P ⱕ .01)/⫺0.37(P ⱕ .05); (most required OCSs): BIS: 21%
1.0 mg qd (n ⫽ 95) Pl: ⫺0.19 (P ⱕ .011)/21% (P ⱕ .011)/19%
(P ⱕ .011)/31%; Pl: 39%
Pl (n ⫽ 95) FEV1 %Pred: 79.6 NT symptom score: BIS: ⫺0.28/ AE:
⫺0.49 (P ⱕ .001)/⫺0.42
(P ⱕ .01); Pl: ⫺0.13
Used meds until trial start Albuterol days/14 d: BIS: 4.4/ Corticotropin-stimulated cortisol: NS
(through a 2- to 3-wk BL) 5.2/4.9/4.4 (P ⱕ .01 for all);
Pl: 2.4
de Blic et al35 (1996) DBPC, 12 wk, BIS 1 mg bid N ⫽ 38, 6–30 mo (mean: BIS associated with less DT Children with ⱖ1 exacerbation: BIS:
(n ⫽ 20) 16.4–18.1 mo) wheeze (P ⬍ .05) and less 40% (P ⬍ .01); Pl: 83%
NT wheeze (P ⬍ .01) 关data
not provided兴
Pl (n ⫽ 18) Recurrent severe asthma (3 Median of total treatment time Children with no exacerbation: BIS:
exacerbations of during which nebulized SAB 55% (P ⬍ .05); Pl: 8%
dyspnea in 12 previous was needed: BIS: 5.2%; Pl: Median of total treatment time
mo; 1 exacerbation per 8.8% during which an OCS was needed:
month required steroids BIS: 0% (P ⬍ .05); Pl: 14.5%
for 3 mo before or
persistent symptom for
15 d before entry)
Hoekstra et al38 (1996) DBPC, 12 wk N ⫽ 34, 8–14 y (mean: Morning wheezing: FP: ⫺0.14 FEV1 averaged 9% higher with FP
10.8 y) (P ⫽ .006); Pl: ⫺0.08 (P ⫽ .0005) 关data not provided兴
FP 100 ␮g bid (n ⫽ 15); Pl Allergic asthma requiring Evening wheezing: FP: ⫺0.21 AE:
(n ⫽ 19) maintenance therapy, (P ⫽ .004); Pl: ⫺0.10
which was discontinued
4 wk before trial
FEV1 %Pred: 88–92 FP associated with less Urine cortisol: 57% lower with FP
albuterol (P ⬍ .05) 关data not (P ⫽ .009) but change within
provided兴 group from BL was NS
School absences: NS
Kemp et al36 (1999) DBPC, 12 wk N ⫽ 359, 6 mo–8 y (mean: BIS: 0.25/0.5/1.0 mg FEV1 (L/min, 36% could perform): BIS:
4.8 y) ⫺0.01/⫹0.03 (P ⫽ .044)/⫹0.03
(P ⫽ .033); Pl: ⫺0.07
BIS 0.25 mg qd (n ⫽ 91); Mild persistent asthma, DT symptom score: BIS: ⫺0.57/ AE:
0.5 mg qd (n ⫽ 83); 1.0 steroid naive ⫺0.46/⫺0.50 (P ⱕ .05 for
mg qd (n ⫽ 93) all); Pl: ⫺0.26
Pl (n ⫽ 92) FEV1 %Pred: 81.4 NT symptom score: BIS: ⫺0.49/ Corticotropin-stimulated cortisol: NS
⫺0.42/⫺0.42 (P ⱕ .05 for
all); Pl: ⫺0.16
albuterol days/14 d: BIS: ⫺6.3/
6.3/⫺6.0 (P ⱕ .038 for all);
Pl: ⫺4.2
LaForce et al (2000 DBPC, 12 wk ⫹ 52 wk OL N ⫽ 242, 4–11 y (mean: FP 200/100 ␮g FEV1 %Pred: FP: 6.5 (P ⱕ .05)/12.2
(39) extension 8.6 y) (P ⱕ .05); Pl: ⫺1.5
FP DPI 200 ␮g qd (n ⫽ Mild-to-moderate Awakenings night: FP: ⫺0.04/ FEV1 (L): FP: 0.13 (P ⱕ .05)/0.23 (P ⱕ
84); 100 ␮g bid (n ⫽ persistent asthma: 57% ⫺0.06 (P ⱕ .05); Pl: 0.04 .05); Pl: ⫺0.04
80) used ICSs or CROM, 43%
used only SAB before
study
Pl (n ⫽ 78) FEV1 %Pred: 70–73 Symptom score: FP: ⫺0.24 AE:
(P ⱕ .05)/⫺0.28 (P ⱕ .05);
Pl: ⫺0.01
2 wk BL on Pl only Albuterol puff per day: FP: Morning plasma cortisol: NS
⫺0.5/⫺0.7; Pl: 0

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TABLE 7 Continued
Study Study Design and Children Impairment Risk
Treatment
Nayak et al40 (2002) DBPC, 12 wk N ⫽ 353, 5–12 y (mean: BDP HFA 80/160 ␮g FEV1 % change (absolute): BDP: 13.3/
8.9–9.4 y) 14.5 (P ⱕ .01 for both); Pl: 5.7
BDP HFA 80 ␮g/d (n ⫽ Moderate, symptomatic Days free from asthma FEV1 %Pred: BDP: 9.2/10 (P ⱕ .01 for
120); 160 ␮g/d (n ⫽ asthma; SAB prn only symptom: BDP: 3.8%/3.9% both); Pl: 3.9
117) before study (P ⱕ .05); Pl: 3.9 %
Pl (n ⫽ 116) FEV1 %Pred: 71.0–72.3 BDP 160 ␮g associated with AE:
less daily SAB (P ⱕ .05) Morning plasma cortisol: NS
关data not provided兴
Peden et al41 (1998) DBPC, 12 wk N ⫽ 437, 4–11 y FP 50/100 ␮g FEV1 %change (absolute): FP: 15.77–
17.93 (P ⱕ .05 for all); Pl: 6.96
FP DPI 50␮g bid (n ⫽ Mild-to-moderate asthma: Symptom score: FP: ⫺0.36 to FEV1 %Pred: FP: 11.25–12.74 (P ⱕ .05
181); 100 ␮g bid (n ⫽ before study 45% used ⫺0.41 (P ⱕ .05 for all); Pl: for all); Pl: 4.72
170) (given by ICSs, 9% CROM, 46% SAB ⫺0.02
Diskhaler and Diskus) only
Pl (n ⫽ 86) FEV1 %Pred: 72–74 Awakenings per night: FP: AE:
⫺0.03 to ⫺0.06 (P ⱕ .05 for
all); Pl: 0.07
Treatment continued Albuterol puffs per day: FP: Morning plasma cortisol: NS
during 2-wk BL ⫺0.75 to ⫺1.04(P ⱕ .05 for Urine cortisol: NS
all); Pl: 0.08
Roorda et al37 (2001) DBPC, 12 wk (pooled data N ⫽ 305, 12–47 mo (mean: Significant improvements with Exacerbation-free patients: FP: 75%
from 2 studies) 28.5 mo) FP in children who had (P ⫽ .033); Pl: 64%
frequent symptoms:
FP 100 ␮g bid (n ⫽ 153) Documented history of Days and nights with no
recurrent wheeze or symptom: FP: 45 (P ⫽ .005);
asthma symptom; Pl: 25
symptom on at least 7 of
last 14 d of 4 wk RI (no
ICSs)
Pl (n ⫽ 152) Separated into 2 groups: Days with no cough: FP: 56%
those with symptoms (P ⫽ .011); Pl: 42%
ⱖ3 d/wk and ⱖ75% of Days with no wheeze: FP: 92%
RI days (n ⫽ 169) and (P ⫽ .002); Pl: 80%
those with less-frequent Days with no rescue meds: FP:
symptoms (n ⫽ 127) 80% (P ⫽ .048); Pl: 71%
Shapiro et al42 (1998) DBPC, 12 wk N ⫽ 178, 4–8 y (mean: BIS 0.25/0.5/1.0 mg FEV1 (L/min): BIS: 0.05/0.08 (P ⬍ .05)/
6.7 y) 0.07; Pl: ⫺0.01
BIS 0.25 mg bid (n ⫽ 47); Moderate-to-severe DT asthma score: BIS: ⫺0.45 Patients requiring OCSs: BIS: 11%/
0.5 mg bid (n ⫽ 42); asthma, maintained on (P ⱕ .05)/⫺0.53 (P ⱕ .01)/ 5%/18%; Pl: 36%
1.0 mg bid (n ⫽ 45) ICSs ⫺0.55 (P ⱕ .01);Pl ⫺0.11
Pl (n ⫽ 44) FEV1 %Pred: 79.6 NT asthma score: BIS: ⫺0.36/ AE:
⫺0.37/⫺0.36 (P ⱕ .05 for
all); Pl: ⫺0.08
2 wk BL on Pl only All doses of BIS were Corticotropin-stimulated cortisol: NS
associated with less use of
albuterol (P ⱕ .032) 关data
not provided兴
Shapiro et al (2001 DBPC, 12 wk N ⫽ 274, 6–17 y (mean: Budesonide 200/400 ␮g FEV1 %Pred: budesonide: 2.65 (P ⫽
(43) 12.1 y) .015)/3.29 (P ⫽ .005); Pl: ⫺1.49
Budesonide 200 ␮g qd Moderate-to-severe DT asthma score: budesonide:
(n ⫽ 90); 400 ␮g qd asthma, maintained on ⫺0.03/⫺0.12 (P ⱕ .001 for
(n ⫽ 93) ICSs ⱖ 16 wk both); Pl: 0.19
Pl (n ⫽ 91) FEV1 %Pred: 76.6–77.5 NT asthma score: budesonide:
⫺0.12/⫺0.11 (P ⬍ .001 for
both); Pl: 0.14
Used ICSs through BL up to Albuterol puff per day:
randomization to budesonide: ⫺0.69/⫺0.70
treatment (P ⬍ .001 for both); Pl: 0.39

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TABLE 7 Continued
Study Study Design and Children Impairment Risk
Treatment
Study duration ⱖ1 y
CAMP29 (2000) DBPC, 4–6 y N ⫽ 519, 5–12 y (mean: Symptom score: budesonide: FEV1: NS
(budesonide and 8.9 y) ⫺0.44 (P ⫽ .005); Pl: ⫺0.37
matching placebo Budesonide 200 ␮g bid Mild-to-moderate asthma Episode-free d/mo: No./100 child-years:
arms) (n ⫽ 311) (symptoms or SAB ⱖ2⫻ budesonide: 11.3 (P ⫽ .01);
/wk) Pl: 9.3
Pl (n ⫽ 208) FEV1 %Pred: 93.4–94.2 NT awakenings/mo: NS Prednisone course: budesonide: 70
(P ⬍ .001); Pl: 122
⬃38% used ICSs in 6 mo Albuterol puffs per week: Urgent care visits: budesonide: 12
before study; stopped all budesonide: ⫺7.4 (P ⬍ (P ⬍ .001); Pl: 22
asthma meds except prn .001); Pl: ⫺5.3 Hospitalizations: budesonide: 2.5
SAB ⬎28 d before (P ⫽ .04); Pl: 4.4
randomization AE:
Increase in height: budesonide: 22.7
cm (P ⫽ .005); Pl: 23.8 cm
Chen et al33 (2006); DBPC, 3 y followed by 2 y N ⫽ 1974, 5–10 y (mean: Subanalysis of 5–10 y: FEV1 %Pred (at 1 y/at 3 y): 5–10 y:
Pauwels et al32 OL 8.4 y); N ⫽ 1221, 11–17 y Symptom-free d/y: budesonide: 4.35/3.77; Pl: 2.12/
(2003); Weiss et al44 budesonide: 964 (P ⬍ .001); 2.48; 11–17 y: budesonide: 4.44/
(2006) START in Pl: 948 3.97; Pl: 2.91/3.54
early asthma Usual care ⫹ budesonide Mild, persistent asthma for Patients requiring intervention: Subanalysis of 5–10 y:
(pediatric arms) 200 ␮g qd (n ⫽ 1000, ⱖ3 mo and ⬍2 y before with other ICSs: budesonide:
5–10 y), budesonide entry 13.6% (P ⬍ .01); Pl: 24.8%;
400 ␮g qd (n ⫽ 640, FEV1 %Pred: 85%–85.5% with OCSs: budesonide:
11–17 y), Pl (n ⫽ 974, (for 5–10 y) 1.1%; Pl: 2.5%; with SAB:
5–10 y; 581, 11–17 y) No ICSs ⬎30 d budesonide: 60.9%; Pl: Hospitalizations: budesonide: 34; Pl:
65.9% 53
ED visits: budesonide: 18; Pl: 29
Hazard ratio for risk of an SARE: 0.60
(P ⫽ .012); risk reduction ⫽ 40%
AE:
Difference in growth rate per year vs
Pl: budesonide 200 ␮g (5–10 y):
⫺0.43 cm (P ⬍ .0001);
budesonide 400 ␮g (11–17 y):
⫺0.40 cm (P ⫽ .003)
Guilbert et al18 (2006) DBPC, 2 y followed by 1 y N ⫽ 285, 2–3 y (mean: 3 y) Episode-free days: FP: 93.2%; No./100 child-years:
without treatment Pl: 88.4% (P ⫽ .006)
Prevention of Early FP 88 ␮g bid (n ⫽ 143) At high risk for asthma Bronchodilator use: FP: 14.4 Exacerbations requiring OCSs: FP:
Asthma in Kids (⫹API); 66%–67% had d/y; Pl: 18.0 d/y 57.4 (P ⬍ .001); Pl: 89.4
(PEAK) ED visit for asthma
exacerbation and 10%
were hospitalized in
previous year
Pl (n ⫽ 142) ⱕ4 mo ICSs; no ICSs in Supplemental use of FP: FP: 8.3 Hospitalizations: FP: 1.05; Pl: 1.76
months before d/y (P ⬍ .001); Pl: 17.6 d/y
treatment (RI) Montelukast use: FP: 11.4 d/y AE:
(P ⬍ .001); Pl: 24.2 d/y Increase in height over 2 y: FP: 12.6
cm (P ⬍ .001); Pl: 13.7 cm
FEV1 is prebronchodilator; all outcomes are reported as “change from BL” unless otherwise indicated; significance is versus placebo unless otherwise indicated. BL indicates baseline; CROM,
cromolyn sodium; DBPC, double-blind, placebo-controlled; DT, daytime; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; NEB, nebulized; NS, not significant; NT, nighttime; OL, open label; Pl,
placebo; RI, run in; %Pred, percent predicted; API, Asthma Predictive Index.

in the placebo group rather than substantial increases in compared with placebo-treated children regardless of
asthma control with the ICSs. However, no subanalyses ICS use before random assignment.
were performed, leaving this to speculation. Two of the long-term studies included children who were
able to perform spirometry: CAMP and START. In both stud-
Risk Domain ies, ICS use was associated with slight improvements in FEV1
Eight of the ten 12-week studies reported pulmonary in the first year that gradually decreased throughout the treat-
function test results.34,36,38–43 In all cases, children treated ment period so that no significant between-treatment differ-
with ICSs had small but significant increases in FEV1 ences were evident at trial end.29,32,33

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TABLE 8 Effect of ICSs on Impairment and Risk in Children With Asthma Evaluated in Controlled Comparator Trials
Study Study Design and Treatment Children Impairment Risk
Study duration ⬍1 y
Ostrom et al45 (2005) DBDD, 12 wk N ⫽ 342, 6–12 y (mean: 9.1– DT asthma score: FP: ⫺0.81; FEV1 (change): FP: 10.62% (P ⫽ .002);
9.6 y) montelukast: ⫺0.75 montelukast: 4.60%
Montelukast 5 mg qd (n ⫽ 170) SAB use only before study NT asthma score: FP: ⫺0.4 (P ⬍ % patients with ⱖ10% improvement
.001); montelukast: ⫺0.19 in FEV1:
FP DPI 50 ␮g bid (n ⫽ 172) FEV1 %Pred: 75.4–76.4 Albuterol puffs per day: FP: BL FEV1 %Pred ⬎75%: FP: 35 (P ⬍
⫺1.43 (P ⫽ .018); .031); montelukast: 18
montelukast: ⫺1.23
NT albuterol use: FP: ⫺0.39 (P ⬍ BL FEV1 %Pred 65–75: FP: 65 (P ⫽
.001); montelukast: ⫺0.21 .007); montelukast: 42
Symptom-free days: FP: 37.7%; Patients who withdrew because of
montelukast: 31.3% asthma exacerbation: FP: 5.2%;
Rescue free days: FP: 45.1% (P ⫽ montelukast: 8.2%
.002); montelukast: 35%
Sorkness et al31 (2007) DBDD, 48 wk N ⫽ 285, 6–14 y (mean: 9.6– Pl vs montelukast: FEV1 %Pred: FP: 6.32 (P ⬍ .001); FP/
10.3 y) salmeterol: 3.62 (P ⫽ .01);
montelukast: ⫺0.58
Pediatric Asthma FP 100 ␮g bid (n ⫽ 96) Mild-to-moderate asthma; no Asthma-control days: FP: 64.2% Time to first prednisone burst
Controller Trial controller medications ⱖ2 (P ⫽ .004); FP/salmeterol: favored FP vs montelukast (P ⫽
(PACT) wk before randomization 59.6%; montelukast: 52.5% .002)
FP/salmeterol 100/50 ␮g AM ⫹ FEV1 %Pred: 96.8–97.8 Episode-free days: FP: 26.4% AE:
salmeterol 50 ␮g PM (n ⫽ 94) (P ⫽ .04); FP/salmeterol: 26.8%
Montelukast 5 mg PM (n ⫽ 95) (P ⫽ .032); montelukast: Increase in height: NS
17.8%
Szefler et al46 (2005); DMCO, 16 wk (2–8 wk N ⫽ 144, 6–17 y Asthma-control d/wk: FP: 5 (P ⬍ FEV1 % change (absolute): FP: 6.8
Zeiger et al47 treatment periods) .001); montelukast: 4.3 (P ⬍ .001); montelukast: 1.9
(2006) FP 100 ␮g bid Mild-to-moderate asthma, prn Albuterol puffs per week: FP: 3.1 No. of patients with exacerbations
SAB only before study (P ⫽ .031); montelukast: 4.4 requiring OCSs (treatment
Montelukast 5–10 mg qd PM FEV1 %Pred: 88–99 failures): FP: 2; montelukast: 10
(P ⫽ .019)
Study duration ⱖ1 y
CAMP29 (2000) DBPC, 4–6 y N ⫽ 1041, 5–12 y (mean: 8.9 y) Symptom score: budesonide: FEV1: NS
⫺0.44 (P ⫽ .005); NED: ⫺0.38;
Pl: ⫺0.37
Budesonide 200 ␮g bid (n ⫽ Mild-to-moderate asthma: Episode-free d/mo: budesonide: No./100 person-years:
311) symptoms or used SAB 11.3 (P ⫽ .01); NED: 9.3; Pl: 9.3
ⱖ2⫻/wk
NED 8 mg bid (n ⫽ 312) FEV1 %Pred: 93.4–94.2 Night awakenings per month: NS Prednisone course: budesonide: 70
(P ⬍ .001); NED: 102 (P ⫽ .01); Pl:
122
Matching Pl for budesonide/ ⬃38% used ICSs in 6 mo Albuterol puffs per week: Urgent care visits: budesonide: 12
NED (n ⫽ 208/210) before study; stopped meds budesonide: ⫺7.4 (P ⬍ .001); (P ⬍ .001); NED: 16 (P ⫽ .02); Pl:
22
except prn SAB ⬎28 d NED: ⫺6.7; Pl: ⫺5.3 Hospitalizations: budesonide: 2.5
before randomization (P ⫽ .04); NED: 4.3; Pl: 4.4
AE:
Increase in height: budesonide: 22.7
cm (P ⫽ .005); NED: 23.7; Pl: 23.8
cm
Garcia et al30 (2005) DBDD, 12 mo N ⫽ 994, 6–14 y (median: 9 y) Rescue-free days: FP: 25.2%; FEV1 %Pred: FP: 2.7 (P ⫽ .004);
Montelukast Study montelukast: 22.4% montelukast: 0.6
of Asthma in Montelukast 5 mg qd (n ⫽ 495) Mild, persistent asthma Days with SAB use: FP: ⫺25.4% FEV1 (L): FP: 0.30; montelukast: 0.27
Children (MOSAIC) FP DPI 100 ␮g bid (n ⫽ 499) FEV1 %Pred: 86.8 (P ⫽ .003); montelukast: Patients using OCSs: FP: 10.5% (P ⫽
⫺22.7% .001); montelukast: 17.8%
Asthma controller meds AE:
stopped during 4-wk RI Growth rate (cm/y): FP: 5.81 (P ⫽
.018); montelukast: 6.18
FEV1 is prebronchodilator; all outcomes are reported as “change from BL” unless otherwise indicated; significance is versus placebo unless otherwise indicated. BL indicates baseline; CO, cross-over;
DBPC, double-blind, placebo-controlled; DD, double dummy; DM, double masked; DT, daytime; MDI, metered dose inhaler; NS, not significant; NT, nighttime; Pl, placebo; RI, run in; %Pred, percent
predicted.

Five studies assessed exacerbations or worsening of courses of OCSs regardless of whether they were ⱖ5 or
asthma requiring a short course of OCSs.18,29,35,40,42 Chil- ⬍5 years old.18,29,35 Although significance was not noted,
dren treated with ICSs required significantly fewer 2 studies reported more OCSs for “worsening asthma” in

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school-aged children treated with placebo or usual care montelukast included a third group of children who
compared with budesonide.33,42 More infants and pre- were treated with the combination of FP and salmeterol,
schoolers (⬍48 months old) were “exacerbation-free” 100 ␮g/50 ␮g in the morning and salmeterol alone, 50
with FP treatment compared with placebo treatment ␮g, in the evening.31
(P ⫽ .033).37 Each trial was unique, which makes comparisons dif-
Nayak et al40 (2002) noted a trend toward later onset ficult. Treatment duration ranged from 12 weeks to 6
of “time to first exacerbation” with hydrofluoroalkane- years. The inhaled medications were given twice daily;
BDP, but statistical significance was not reached. The montelukast (tablet or sprinkles) was given once per
addition of qd budesonide to usual care was associated day, usually in the evening. All children were only using
with a significant increase in the time to first severe an SAB at random assignment.
asthma-related event (SARE) in children between 5 and Overall, treatment with ICSs improved measures
10 years of age in the START trial.33 The risk of an SARE of impairment and risk to a greater extent than the
decreased by 40% with the addition of budesonide to nonsteroid antiinflammatory medications.
usual care (hazard ratio: 0.60; P ⫽ .012).33
Children treated with budesonide had significantly Impairment Domain
fewer hospitalizations and urgent care visits than pla- Impairment was evaluated by symptom scores, episode-
cebo-treated children during the 4 to 6 years of the free days (or asthma-control days), and rescue-medica-
CAMP.29 Fewer hospitalizations were also reported dur- tion use. Compared with montelukast, FP-treated pa-
ing 2 years of FP, although statistical significance was not tients had more asthma-control days, episode-free days,
achieved.18 In the START trial, adding budesonide to and rescue-free days.30,31,45,46 Ostrom et al45 (2005) also
usual care was associated with a 50% reduction in hos- reported significant reductions in nighttime asthma
pitalizations and a 34% decrease in emergency visits symptoms (P ⬍ .001) and rescue albuterol use (P ⫽ .018)
over 3 years; statistical significance was approached but with FP compared with montelukast.
not achieved.33,44 Additional comparisons are difficult In the CAMP, both NED and budesonide improved
because of differences between studies in both design asthma symptoms, episode-free days, and albuterol use
and study population. compared with placebo treatment.29 Differences be-
All ICSs used in these studies were well tolerated, and tween the active treatments did not reach statistical sig-
there were no serious AEs related to any of the study nificance, but the clinical improvements were consis-
medications. Seven studies evaluated hypothalamic-pi- tently greater with budesonide; only budesonide
tuitary-adrenal axis function.34,36,38–41,43 No ICS-specific attained statistical significance compared with placebo.29
changes were observed except for a small decrease in
urinary cortisol reported in some children treated with
FP who had previously used ICSs.38 Risk Domain
No changes in growth with ICSs were reported in two The 5 studies included FEV1, and significant increases
12-week studies.34,35 However, small decreases in growth with the ICSs versus the nonsteroid antiinflammatory
with ICSs were reported in the 3 long-term studies.18,29,32 medication were evident in all except the CAMP.29–31,45–47
Compared with usual care alone, children treated with Improvements in asthma exacerbations favored FP
budesonide showed a reduction in growth of 0.43 cm/ over montelukast when measured as the time to first
year (P ⬍ .001) in the START trial regardless of dosing at prednisone burst (P ⫽ .002)31 or worsening of asthma
400 or 200 ␮g/day.32 In the CAMP, the mean increase in requiring a short course of OCSs (P ⫽ .019; P ⫽ .001).30,46
height was also lower (by 1.1 cm) with budesonide.29 Compared with placebo, both budesonide and NED sig-
The long-term study of FP showed a small but significant nificantly reduced the number of prednisone courses per
difference in height percentiles after 2 years (FP: 51.5%; 100 person-years and the number of asthma-related ur-
placebo: 56.4% [P ⬍ .001]).18 Where assessed, these gent care visits.29 The decreases were greater with budes-
changes in growth rates were predominant during the onide, but the differences were not statistically signifi-
first year of treatment, and all groups had similar rates of cant. Only budesonide significantly decreased the
growth at the end of the treatment periods.18,29 number of asthma-related hospitalizations.29
“Catch-up growth” was not evaluated. No other sys- All treatments in the comparator studies were well
temic effects were observed in these studies. tolerated, with no significant between-treatment differ-
ences for AEs and no serious AEs related to any of the
Controlled Comparisons With Nonsteroid Antiinflammatory study drugs. Small reductions in growth rates were ob-
Medications served with ICSs versus the comparator medications in
Five placebo-controlled studies comparing an ICS to a the 2 long-term studies.29–31 No other systemic effects
nonsteroid antiinflammatory medication are described were observed.
in Table 8.29–31,45–47 These studies included 2806 children:
1222 were exposed to ICSs (budesonide, 200 ␮g bid [n ⫽ SUMMARY
311]; FP, 50 –100 ␮g bid [n ⫽ 908]), and 1216 received Children with asthma remain a significant challenge,
comparator nonsteroid medications (NED, 8 mg bid [n ⫽ particularly as the relationship between early treatment
312]; montelukast, 5–10 mg qd [n ⫽ 904]). The CAMP of asthma symptoms and the development of adult dis-
included matching placebos for budesonide and NED ease is not yet clearly delineated. ICSs are recommended
(n ⫽ 418).29 In addition, 1 of the trials comparing FP and as the primary controller medication for children (as

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well as adults) with asthma. The efficacy and safety of rescue-medication use, daytime and nighttime symptom
ICSs to treat children has been well documented, al- scores, and asthma/episode-free days are recommended
though the data are more limited than for adults.1 When as indicators. For risk, FEV1 should be reported for chil-
used at indicated doses, ICSs are safe. However, efficacy dren who can perform spirometry; exacerbations that
with dose plateaus; thus, when a child is symptomatic, it require OCSs and urgent care usage are also suggested as
may be better to add another medication rather than indicators. Attention should be given to standardizing
increase the dose of ICSs beyond medium.1 Discussion of variables that can be used to compare outcomes between
what to add is beyond the scope of this article. The trials.
evidence reviewed in the EPR3 suggests that the addi- The majority of pediatric data are for children ⱕ12
tion of a long-acting bronchodilator (LABA) provides years; only 5 of the 18 studies included adolescents
greater asthma control than increasing the dose of ICSs (13–18 years old).30,31,38,43,46 Data for this population are
or adding a leukotriene modifier.1 However, adjunctive lost when assessing childhood asthma, either grouped
therapy for children between 5 and 11 years of age has with adults (eg, studies in patients ⱖ12 years old) or not
not been well studied, and data are lacking for younger included (eg, studies of school-aged children ⱕ12 years
children.1 The reader is directed to the EPR3,1 and other old). More studies are needed to evaluate whether diag-
resources for parents of children with asthma may be nosing asthma and starting therapy early affects the
helpful.48 course of the disease in adolescence. More information is
The National Asthma Education and Prevention Pro- also needed to assess how treatment can better meet the
gram guidelines continue to serve as a basis for treat- needs of the adolescent patient.
ment recommendations; the latest report describes a The evidence presented in this systematic retrieval
new paradigm targeting asthma control through the do- and review of the literature is not ranked, because this is
mains of impairment and risk.1 This systematic review the work of a single author and not a committee. How-
strengthens previous evidence (reported in the EPR2 ever, the studies chosen were separated according to
and clinical practice guidelines) supporting the safe and design: double-blind, placebo-controlled studies and
effective use of ICSs to treat children with asthma. In randomized, controlled, comparison trials. No nonran-
addition, the data provide new evidence linking ICS use domized trials or observational studies were included.
in children with asthma to improved asthma control as Thus, all of the data collected in this review would fall
now defined by the EPR3 according to the domains of into category A and B evidence according to the defini-
risk and impairment. Data from placebo-controlled stud- tions in the EPR3.1
ies confirm that treatment with ICSs improves both Asthma is a complex and heterogeneous disease.
domains in children (0 –17 years old).18,29–43,45–47 Many factors affect impairment and risk and influence
choice of therapy. Not addressed in this article but of
1. Compared with placebo, ICS treatment was associ- significant impact are adherence with treatment, envi-
ated with reductions in the impairment domain re- ronmental control, comorbid conditions, differences in
ported as symptoms scores, specific symptom epi- delivery devices, and penetration of medication into the
sodes, episode-free days (or asthma-control days), small airways. The reader is directed to the EPR3 for
rescue-free days, and/or rescue-medication use. additional information.1
2. Compared with placebo, ICS treatment was associ- In summary, the available data indicate that ICSs
ated with reductions in the risk domain evident as improve asthma control in children by reducing both
increased FEV1 (in children able to perform spirom- impairment and risk associated with the disease and
etry), fewer courses of OCSs, decreased exacerbation support current recommendations for treatment.
rates, and/or less use of urgent care services.
3. The reductions in the impairment and risk domains ACKNOWLEDGMENTS
observed with ICSs were generally greater than re- This work was funded partially by an unrestricted edu-
ductions observed with nonsteroid antiinflammatory cational grant from Teva Pharmaceuticals.
comparator medications. The expert research and technical support of Judith
4. ICSs were well tolerated in all studies. Farrar, PhD, is greatly appreciated; this publication
would not have been possible without her editorial as-
5. Small reductions in growth rates compared with pla- sistance.
cebo and/or comparator nonsteroid antiinflammatory
medications were evident in several long-term (⬎1-
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FRAUD CHARGES CAST DOUBT ON CLAIMS OF DNA DAMAGE FROM CELL PHONE
FIELDS

“The only 2 peer-reviewed scientific papers showing that electromagnetic


fields (EMFs) from cell phones can cause DNA breakage are at the center of
a misconduct controversy at the Medical University of Vienna (MUV). Critics
had argued that the data looked too good to be real, and in May a university
investigation agreed, concluding that data in both studies had been fabricated
and that the papers should be retracted.”
Science. August 29, 2008
Noted by JFL, MD

366 RACHELEFSKY
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Inhaled Corticosteroids and Asthma Control in Children: Assessing Impairment
and Risk
Gary Rachelefsky
Pediatrics 2009;123;353-366
DOI: 10.1542/peds.2007-3273
Updated Information including high-resolution figures, can be found at:
& Services http://www.pediatrics.org/cgi/content/full/123/1/353
References This article cites 45 articles, 16 of which you can access for free
at:
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