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
Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from www.pediatrics.org by on March 14, 2010

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

Downloaded from www.pediatrics.org by on March 14, 2010
 TABLE 1 Some Key Terms Used to Define the Patient With Asthma
Regardless of Age1
Term Definition
Severity The intrinsic intensity of asthma pathology, which is measured
most easily and directly before a patient starts long-term
control therapy (ie, before a patient is being treated)
Control The degree to which the manifestations of asthma
(symptoms, functional impairments, risks of AEs) are
minimized and the goals of therapy are met
Impairment The frequency and intensity of symptoms and functional
limitations that the patient is experiencing or has recently
experienced
Risk The likelihood of asthma exacerbations, progressive decline in
lung function (or, for children, reduced lung growth), or
adverse effects from medication
For most patients, asthma onset occurs early in life,
and disease persistence is associated with recognizable
risk factors including atopic disease, recurrent wheezing,
and a parental history of allergy and/or asthma. Evi-
dence indicates that therapy with current antiinflamma-
tory medications does not prevent progression of the
underlying disease.1 In contrast to previous guidelines
that focused on reducing asthma severity, the new
guidelines target asthma control as the primary goal for
management. Classifying asthma severity to initiate
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-
erationalize therapeutic targets (Table 1).1
The goal of asthma therapy is to achieve asthma
control by reducing impairment and risk on the basis of
the criteria1 shown in Table 2. As in previous guidelines,
inhaled corticosteroids (ICSs) are the preferred class of
long-term controller medications to manage persistent
asthma in all age groups. Numerous studies in children
with asthma have established that ICSs improve pulmo-
TABLE 2 Criteria for Achieving Asthma Control by Targeting the
Domains of Impairment and Risk1
Asthma-Control Criteria
Domain
Reducing impairment Prevent chronic and troublesome symptoms (eg,
coughing or breathlessness in the daytime,
nighttime, after exertion)
Infrequent use (ⱕ2 d/wk) of inhaled SAB for
quick relief of symptoms
Maintain (near) “normal” pulmonary function
Maintain normal activity levels (including
exercise, other physical activity, attendance at
work or school)
Meet patients’ and families’ expectations of and
satisfaction with asthma care
Reducing risk Prevent recurrent exacerbations of asthma;
minimize ED visits, urgent care visits,
hospitalizations
Prevent progressive loss of lung function (for
children, prevent reduced lung growth)
Provide optimal pharmacotherapy with minimal
(ideally, no) adverse effects
354 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
nary function, reduce the need for reliever medications,
improve quality of life, enhance exercise tolerance, and
reduce hospitalizations.1 Thus, although early interven-
tion with ICSs for childhood asthma does not alter the
natural history of asthma, these medications are impor-
tant for gaining and maintaining asthma control.1 How-
ever, no review to date has examined the effect of ICSs
on childhood asthma in terms of impairment and risk as
defined in the EPR3. The purpose of this review is to
evaluate the data on ICSs in childhood asthma with
specific regard to the newly defined domains of risk and
impairment.
METHODS
A systematic review of the literature was performed for
randomized, placebo-controlled studies that evaluated
monotherapy with ICSs in children. Searches of the
Medline and Embase databases (January 1996 to Octo-
ber 2007) were performed by using the Medical Subject
Headings (MeSH) terms asthma, beclomethasone dipro-
pionate, budesonide, flunisolide, controlled clinical tri-
als, fluticasone propionate, mometasone, randomized,
controlled trials, and triamcinolone acetonide and the
text words childhood asthma, pediatric asthma, persis-
tent asthma, and ICS. Searches were limited to human
subjects aged 0 to 17 years and English-language litera-
ture.
EFFICACY OF ICSs IN CHILDREN
According to the new guidelines, “ICSs are the most
potent and consistently effective long-term control med-
ication for asthma” for adults and children.1 They are the
only medications consistently shown to meet the goals
of pharmacotherapy for asthma:
● control (ideally, prevent) asthma symptoms;
● reverse airflow obstruction;
● improve quality of life; and
● decrease the number and severity of asthma exacer-
bations (and associated urgent medical care).
In the step-care approach to therapy, ICSs are the main-
stay of treatment for all patients with persistent asthma
(Fig 1, steps 2– 6). Treatment for adolescents (12–18
years old) is the same as for adults; changes to the
algorithm are shown for children ⬍12 years old. Table 3
shows the currently available ICSs indicated for use in
children in the United States.
The broad action of ICSs on airway inflammation and
associated clinical markers in asthma is well documented
and beyond the scope of this article.4–7
Most of the clinical benefits observed with ICS treat-
ment in children occur at low doses. However, similar to
adults, the dose response to ICSs in children may vary
according to the clinical outcome (eg, improvement in
lung function, prevention of exacerbations) and patient
characteristics. Children with more severe asthma may
respond to higher doses, whereas those with mild or
moderate asthma usually show a plateauing of effect at
low and medium doses.8–11 Nonetheless, stepping up the
 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
children with mild or moderate asthma during exacer-
bations or seasonal increases in symptom severity (eg, to
allergens, respiratory viruses).1 This “flexible dose ap-
proach” to treatment suggests that ICS therapy may be
increased temporarily in response to some index of
worsening asthma, usually an increase in symptoms,
nighttime awakenings, decrease in peak flow rate, or use
of rescue medications; it remains subject to continued
study and discussion.12–15 In the future, such dose adjust-
ments may be based on measurement of a simple bi-
omarker of airway inflammation in children; sputum
eosinophils and exhaled nitric oxide are being studied
but require further validation.16,17
USING ICSs IN INFANTS AND YOUNG CHILDREN (<5 YEARS
OLD)
As in older children and adults, the use of ICSs in infants
and young children is directed toward symptom control,
preventing exacerbations, and improving the child’s

PEDIATRICS Volume 123, Number 1, January 2009 355

Downloaded from www.pediatrics.org by on March 14, 2010
 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
not be initiated or prolonged to alter the progression or
underlying severity of asthma.1
Data on the use of ICSs to treat asthma in young
children, particularly infants, are limited. Most treat-
ment recommendations are based on expert opinion and
extrapolations from studies in older children and adults.1
The most common symptoms of asthma in this popula-
tion are wheeze and cough, which are frequently asso-
ciated with other conditions.18–20 A diagnostic trial of
ICSs is recommended if asthma is suspected.
A predictive clinical index (the modified Asthma Pre-
dictive Index [mAPI]) to identify children ⱕ3 years old
who might be at high risk for developing asthma has
been developed and validated on the basis of data from
the Tucson Children’s Respiratory Study.18,21 In pre-
school-aged children a positive mAPI was associated
with ⱖ4 severe wheezing episodes requiring use of oral
corticosteroids (OCSs) in 12 months and increased hos-
pitalizations and urgent care visits for asthma.21,22 The
recommendation of the EPR3 regarding which young
child is appropriate for ICS therapy builds on the mAPI
(Table 4).
ICSs approved by the Food and Drug Administration
(FDA) in the United States for young children (ⱕ5 years
old) include budesonide inhalation suspension (BIS),
which is approved for children as young as 12 months,
and fluticasone propionate (FP) dry powder inhaler
(DPI) and hydrofluoroalkane formulations, which are
approved for children as young as 4 years. Beclometha-
sone dipropionate (BDP) hydrofluoroalkane is only ap-
proved for children aged ⱖ5 years. Although not ap-
proved for young children and there are no data
regarding dosing, efficacy, or safety in this population,
many pediatricians will use a diagnostic trial of any of
these ICSs as they deem necessary. Figure 2 presents an
algorithm for a diagnostic trial of ICSs in infants and
young children.
SAFETY OF ICSs IN CHILDREN
Regardless of age, few patients report serious adverse
events (AEs) with ICSs at the recommended dosages,
even with long-term use.23–26 Most clinical benefit with
ICSs is achieved at relatively low doses, further reducing
the potential risk of AEs.1 Nonetheless, as for any regu-
larly used medication, children should be monitored
regularly for potential systemic AEs, particularly because
some children may be more susceptible to the effects of
ICSs even at conventional doses. Suggestions for reduc-
ing AEs associated with ICSs are shown in Table 5.
Data on potential adverse effects of low- or medium-
dose ICSs on the hypothalamic-pituitary-adrenal axis in
children show rare events, which are usually clinically
insignificant.27,28
Of greater concern has been the potential effect of
ICSs on linear growth. Again, the available data for low-
to medium-dose ICSs show a minimal effect on growth
velocity: a reduction of ⬃1 cm in the first year of treat-
ment in some children. This decrease, when observed,
usually does not progress over time, and long-term stud-
ies have indicated that these children attain their full
adult height.18,28–32 All children using ICSs should be

356 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
 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

Downloaded from www.pediatrics.org by on March 14, 2010
 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,
respectively) were reported with BIS versus placebo, but
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
Improvements in symptoms were maintained with long-
term treatment (ⱖ2 years).18,29,33
The symptom improvements were observed regard-
less of the patient’s therapy before randomization. In
some studies, patients were allowed to use their regular
asthma medications (including ICSs) up to the point of
randomization; other studies were conducted in steroid-
naive patients or required a steroid-free run-in period
before trial entry. In the studies reported by Baker et al34
(1999) and Peden et al41 (1998), children were permitted
to use their regular asthma medications through the
run-in period; in these studies, 31% and 45% of chil-
dren used ICSs up to random assignment to BIS and
FP, respectively. Shapiro et al43 (2001) specifically
evaluated the ability of once-daily (qd) budesonide to
maintain asthma control in children who had been
previously receiving ICSs; all children used their
maintenance ICSs up to random assignment, and 87%
were using ICSs twice daily (bid). In most studies, all
controller medications were withdrawn before ran-
dom assignment. However, Chen et al33 (2006) re-
ported a subanalysis of data for 5- to 10-year-olds in
the Steroid Treatment as Regular Therapy (START)
in practice is to (1) reduce the ICS dose if there is slowing of growth at the 3-month visit and the
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.
trial, a 3-year study in which budesonide was added to
the usual care of patients diagnosed with mild asthma
who had not regularly used ICSs.32,33 Added medica-
tions were tracked, but changes in usual care medica-
tions were not.32,33
Concomitant with fewer symptoms, ICS use was as-
sociated with significant reductions in daily and/or as-
needed (prn) SAB.29,34,36–43 de Blic et al35 (1996) observed
a slightly shorter duration of nebulized albuterol in in-
fants treated with BIS compared with placebo, but the
difference was not statistically significant. Although use
of prn SAB was not reported, young children treated
with FP for 2 years required less added controller med-
ication (montelukast [P ⬍ .001] or additional FP [P ⬍
.001]) than placebo-treated children.18 A similar trend
was observed in older children treated with budesonide
for 3 years in the START trial; again, specific use of prn
SAB was not reported.33
It is difficult to make comparisons between the stud-
ies regarding degree of symptom improvement because
of differences in populations and study design. Presum-
ably, for the patients who used ICSs through the run-in
period, any statistically significant between-treatment
differences resulted from deterioration of asthma control

358 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
 TABLE 7 Effect of ICSs on Impairment and Risk in Children With Asthma Evaluated in Double-Blind, Placebo-Controlled Studies
Study Study Design and
Treatment
Study duration ⬍1 y
Baker et al34 (1999) DBPC, 12 wk
BIS 0.25 mg qd (n ⫽ 94);
0.25 mg bid (n ⫽ 99);
0.50 mg bid (n ⫽ 98);
1.0 mg qd (n ⫽ 95)
Pl (n ⫽ 95)
de Blic et al35 (1996) DBPC, 12 wk, BIS 1 mg bid
(n ⫽ 20)
Pl (n ⫽ 18)
Hoekstra et al38 (1996) DBPC, 12 wk
FP 100 ␮g bid (n ⫽ 15); Pl
(n ⫽ 19)
Kemp et al36 (1999) DBPC, 12 wk
BIS 0.25 mg qd (n ⫽ 91);
0.5 mg qd (n ⫽ 83); 1.0
mg qd (n ⫽ 93)
Pl (n ⫽ 92)
LaForce et al (2000 DBPC, 12 wk ⫹ 52 wk OL
(39) extension
FP DPI 200 ␮g qd (n ⫽
84); 100 ␮g bid (n ⫽
80)
Pl (n ⫽ 78)
Downloaded from www.pediatrics.org by on March 14, 2010
Children Impairment Risk
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
Moderate asthma (31% had DT symptom score: BIS: ⫺0.28/ Patients who discontinued treatment
used ICSs ⱖ2 mo) ⫺0.40 (P ⱕ .05)/⫺0.46 because of disease exacerbation
(P ⱕ .01)/⫺0.37(P ⱕ .05); (most required OCSs): BIS: 21%
Pl: ⫺0.19 (P ⱕ .011)/21% (P ⱕ .011)/19%
(P ⱕ .011)/31%; Pl: 39%
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
N ⫽ 38, 6–30 mo (mean: BIS associated with less DT Children with ⱖ1 exacerbation: BIS:
16.4–18.1 mo) wheeze (P ⬍ .05) and less 40% (P ⬍ .01); Pl: 83%
NT wheeze (P ⬍ .01) 关data
not provided兴
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)
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
Allergic asthma requiring Evening wheezing: FP: ⫺0.21 AE:
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
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
Mild persistent asthma, DT symptom score: BIS: ⫺0.57/ AE:
steroid naive ⫺0.46/⫺0.50 (P ⱕ .05 for
all); Pl: ⫺0.26
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
N ⫽ 242, 4–11 y (mean: FP 200/100 ␮g FEV1 %Pred: FP: 6.5 (P ⱕ .05)/12.2
8.6 y) (P ⱕ .05); Pl: ⫺1.5
Mild-to-moderate Awakenings night: FP: ⫺0.04/ FEV1 (L): FP: 0.13 (P ⱕ .05)/0.23 (P ⱕ
persistent asthma: 57% ⫺0.06 (P ⱕ .05); Pl: 0.04 .05); Pl: ⫺0.04
used ICSs or CROM, 43%
used only SAB before
study
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
PEDIATRICS Volume 123, Number 1, January 2009 359
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

360 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
 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
asthma control with the ICSs. However, no subanalyses
were performed, leaving this to speculation.
Risk Domain
Eight of the ten 12-week studies reported pulmonary
function test results.34,36,38–43 In all cases, children treated
with ICSs had small but significant increases in FEV1
compared with placebo-treated children regardless of
ICS use before random assignment.
Two of the long-term studies included children who were
able to perform spirometry: CAMP and START. In both stud-
ies, ICS use was associated with slight improvements in FEV1
in the first year that gradually decreased throughout the treat-
ment period so that no significant between-treatment differ-
ences were evident at trial end.29,32,33

PEDIATRICS Volume 123, Number 1, January 2009 361

Downloaded from www.pediatrics.org by on March 14, 2010
 TABLE 8 Effect of ICSs on Impairment and Risk in Children With Asthma Evaluated in Controlled Comparator Trials
Study Study Design and Treatment
Study duration ⬍1 y
Ostrom et al45 (2005) DBDD, 12 wk
Montelukast 5 mg qd (n ⫽ 170) SAB use only before study
FP DPI 50 ␮g bid (n ⫽ 172)
Sorkness et al31 (2007) DBDD, 48 wk
Pediatric Asthma FP 100 ␮g bid (n ⫽ 96)
Controller Trial
(PACT)
FP/salmeterol 100/50 ␮g AM ⫹
salmeterol 50 ␮g PM (n ⫽ 94)
Montelukast 5 mg PM (n ⫽ 95)
Szefler et al46 (2005); DMCO, 16 wk (2–8 wk
Zeiger et al47 treatment periods)
(2006) FP 100 ␮g bid
Montelukast 5–10 mg qd PM
Study duration ⱖ1 y
CAMP29 (2000) DBPC, 4–6 y
Budesonide 200 ␮g bid (n ⫽
311)
NED 8 mg bid (n ⫽ 312)
Matching Pl for budesonide/
NED (n ⫽ 208/210)
Garcia et al30 (2005) DBDD, 12 mo
Montelukast Study
of Asthma in Montelukast 5 mg qd (n ⫽ 495) Mild, persistent asthma
Children (MOSAIC) FP DPI 100 ␮g bid (n ⫽ 499)
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.
Children Impairment Risk
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%
NT asthma score: FP: ⫺0.4 (P ⬍ % patients with ⱖ10% improvement
.001); montelukast: ⫺0.19 in FEV1:
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%
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
Mild-to-moderate asthma; no Asthma-control days: FP: 64.2% Time to first prednisone burst
controller medications ⱖ2 (P ⫽ .004); FP/salmeterol: favored FP vs montelukast (P ⫽
wk before randomization 59.6%; montelukast: 52.5% .002)
FEV1 %Pred: 96.8–97.8 Episode-free days: FP: 26.4% AE:
(P ⫽ .04); FP/salmeterol: 26.8%
(P ⫽ .032); montelukast: Increase in height: NS
17.8%
N ⫽ 144, 6–17 y Asthma-control d/wk: FP: 5 (P ⬍ FEV1 % change (absolute): FP: 6.8
.001); montelukast: 4.3 (P ⬍ .001); montelukast: 1.9
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
FEV1 %Pred: 88–99 failures): FP: 2; montelukast: 10
(P ⫽ .019)
N ⫽ 1041, 5–12 y (mean: 8.9 y) Symptom score: budesonide: FEV1: NS
⫺0.44 (P ⫽ .005); NED: ⫺0.38;
Pl: ⫺0.37
Mild-to-moderate asthma: Episode-free d/mo: budesonide: No./100 person-years:
symptoms or used SAB 11.3 (P ⫽ .01); NED: 9.3; Pl: 9.3
ⱖ2⫻/wk
FEV1 %Pred: 93.4–94.2 Night awakenings per month: NS Prednisone course: budesonide: 70
(P ⬍ .001); NED: 102 (P ⫽ .01); Pl:
122
⬃38% used ICSs in 6 mo Albuterol puffs per week: Urgent care visits: budesonide: 12
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
N ⫽ 994, 6–14 y (median: 9 y) Rescue-free days: FP: 25.2%; FEV1 %Pred: FP: 2.7 (P ⫽ .004);
montelukast: 22.4% montelukast: 0.6
Days with SAB use: FP: ⫺25.4% FEV1 (L): FP: 0.30; montelukast: 0.27
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

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

362 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
school-aged children treated with placebo or usual care
compared with budesonide.33,42 More infants and pre-
schoolers (⬍48 months old) were “exacerbation-free”
with FP treatment compared with placebo treatment
(P ⫽ .033).37
Nayak et al40 (2002) noted a trend toward later onset
of “time to first exacerbation” with hydrofluoroalkane-
BDP, but statistical significance was not reached. The
addition of qd budesonide to usual care was associated
with a significant increase in the time to first severe
asthma-related event (SARE) in children between 5 and
10 years of age in the START trial.33 The risk of an SARE
decreased by 40% with the addition of budesonide to
usual care (hazard ratio: 0.60; P ⫽ .012).33
Children treated with budesonide had significantly
fewer hospitalizations and urgent care visits than pla-
cebo-treated children during the 4 to 6 years of the
CAMP.29 Fewer hospitalizations were also reported dur-
ing 2 years of FP, although statistical significance was not
achieved.18 In the START trial, adding budesonide to
usual care was associated with a 50% reduction in hos-
pitalizations and a 34% decrease in emergency visits
over 3 years; statistical significance was approached but
not achieved.33,44 Additional comparisons are difficult
because of differences between studies in both design
and study population.
All ICSs used in these studies were well tolerated, and
there were no serious AEs related to any of the study
medications. Seven studies evaluated hypothalamic-pi-
tuitary-adrenal axis function.34,36,38–41,43 No ICS-specific
changes were observed except for a small decrease in
urinary cortisol reported in some children treated with
FP who had previously used ICSs.38
No changes in growth with ICSs were reported in two
12-week studies.34,35 However, small decreases in growth
with ICSs were reported in the 3 long-term studies.18,29,32
Compared with usual care alone, children treated with
budesonide showed a reduction in growth of 0.43 cm/
year (P ⬍ .001) in the START trial regardless of dosing at
400 or 200 ␮g/day.32 In the CAMP, the mean increase in
height was also lower (by 1.1 cm) with budesonide.29
The long-term study of FP showed a small but significant
difference in height percentiles after 2 years (FP: 51.5%;
placebo: 56.4% [P ⬍ .001]).18 Where assessed, these
changes in growth rates were predominant during the
first year of treatment, and all groups had similar rates of
growth at the end of the treatment periods.18,29
“Catch-up growth” was not evaluated. No other sys-
temic effects were observed in these studies.
Controlled Comparisons With Nonsteroid Antiinflammatory
Medications
Five placebo-controlled studies comparing an ICS to a
nonsteroid antiinflammatory medication are described
in Table 8.29–31,45–47 These studies included 2806 children:
1222 were exposed to ICSs (budesonide, 200 ␮g bid [n ⫽
311]; FP, 50 –100 ␮g bid [n ⫽ 908]), and 1216 received
comparator nonsteroid medications (NED, 8 mg bid [n ⫽
312]; montelukast, 5–10 mg qd [n ⫽ 904]). The CAMP
included matching placebos for budesonide and NED
(n ⫽ 418).29 In addition, 1 of the trials comparing FP and
Downloaded from www.pediatrics.org by on March 14, 2010
montelukast included a third group of children who
were treated with the combination of FP and salmeterol,
100 ␮g/50 ␮g in the morning and salmeterol alone, 50
␮g, in the evening.31
Each trial was unique, which makes comparisons dif-
ficult. Treatment duration ranged from 12 weeks to 6
years. The inhaled medications were given twice daily;
montelukast (tablet or sprinkles) was given once per
day, usually in the evening. All children were only using
an SAB at random assignment.
Overall, treatment with ICSs improved measures
of impairment and risk to a greater extent than the
nonsteroid antiinflammatory medications.
Impairment Domain
Impairment was evaluated by symptom scores, episode-
free days (or asthma-control days), and rescue-medica-
tion use. Compared with montelukast, FP-treated pa-
tients had more asthma-control days, episode-free days,
and rescue-free days.30,31,45,46 Ostrom et al45 (2005) also
reported significant reductions in nighttime asthma
symptoms (P ⬍ .001) and rescue albuterol use (P ⫽ .018)
with FP compared with montelukast.
In the CAMP, both NED and budesonide improved
asthma symptoms, episode-free days, and albuterol use
compared with placebo treatment.29 Differences be-
tween the active treatments did not reach statistical sig-
nificance, but the clinical improvements were consis-
tently greater with budesonide; only budesonide
attained statistical significance compared with placebo.29
Risk Domain
The 5 studies included FEV1, and significant increases
with the ICSs versus the nonsteroid antiinflammatory
medication were evident in all except the CAMP.29–31,45–47
Improvements in asthma exacerbations favored FP
over montelukast when measured as the time to first
prednisone burst (P ⫽ .002)31 or worsening of asthma
requiring a short course of OCSs (P ⫽ .019; P ⫽ .001).30,46
Compared with placebo, both budesonide and NED sig-
nificantly reduced the number of prednisone courses per
100 person-years and the number of asthma-related ur-
gent care visits.29 The decreases were greater with budes-
onide, but the differences were not statistically signifi-
cant. Only budesonide significantly decreased the
number of asthma-related hospitalizations.29
All treatments in the comparator studies were well
tolerated, with no significant between-treatment differ-
ences for AEs and no serious AEs related to any of the
study drugs. Small reductions in growth rates were ob-
served with ICSs versus the comparator medications in
the 2 long-term studies.29–31 No other systemic effects
were observed.
SUMMARY
Children with asthma remain a significant challenge,
particularly as the relationship between early treatment
of asthma symptoms and the development of adult dis-
ease is not yet clearly delineated. ICSs are recommended
as the primary controller medication for children (as
PEDIATRICS Volume 123, Number 1, January 2009 363
well as adults) with asthma. The efficacy and safety of
ICSs to treat children has been well documented, al-
though the data are more limited than for adults.1 When
used at indicated doses, ICSs are safe. However, efficacy
with dose plateaus; thus, when a child is symptomatic, it
may be better to add another medication rather than
increase the dose of ICSs beyond medium.1 Discussion of
what to add is beyond the scope of this article. The
evidence reviewed in the EPR3 suggests that the addi-
tion of a long-acting bronchodilator (LABA) provides
greater asthma control than increasing the dose of ICSs
or adding a leukotriene modifier.1 However, adjunctive
therapy for children between 5 and 11 years of age has
not been well studied, and data are lacking for younger
children.1 The reader is directed to the EPR3,1 and other
resources for parents of children with asthma may be
helpful.48
The National Asthma Education and Prevention Pro-
gram guidelines continue to serve as a basis for treat-
ment recommendations; the latest report describes a
new paradigm targeting asthma control through the do-
mains of impairment and risk.1 This systematic review
strengthens previous evidence (reported in the EPR2
and clinical practice guidelines) supporting the safe and
effective use of ICSs to treat children with asthma. In
addition, the data provide new evidence linking ICS use
in children with asthma to improved asthma control as
now defined by the EPR3 according to the domains of
risk and impairment. Data from placebo-controlled stud-
ies confirm that treatment with ICSs improves both
domains in children (0 –17 years old).18,29–43,45–47
1. Compared with placebo, ICS treatment was associ-
ated with reductions in the impairment domain re-
ported as symptoms scores, specific symptom epi-
sodes, episode-free days (or asthma-control days),
rescue-free days, and/or rescue-medication use.
2. Compared with placebo, ICS treatment was associ-
ated with reductions in the risk domain evident as
increased FEV1 (in children able to perform spirom-
etry), fewer courses of OCSs, decreased exacerbation
rates, and/or less use of urgent care services.
3. The reductions in the impairment and risk domains
observed with ICSs were generally greater than re-
ductions observed with nonsteroid antiinflammatory
comparator medications.
4. ICSs were well tolerated in all studies.
5. Small reductions in growth rates compared with pla-
cebo and/or comparator nonsteroid antiinflammatory
medications were evident in several long-term (⬎1-
year) studies.18,29–32 These changes decreased with
time, and the clinical significance is unclear. Other
data suggest that asthmatic children treated with ICSs
attain their full adult height despite initial reductions
in growth rates.29,49
More in-depth comparisons are difficult to make because
of differences in study protocols.
Additional studies that use appropriate indicators for
impairment and risk are warranted. For impairment,
364 RACHELEFSKY
Downloaded from www.pediatrics.org by on March 14, 2010
rescue-medication use, daytime and nighttime symptom
scores, and asthma/episode-free days are recommended
as indicators. For risk, FEV1 should be reported for chil-
dren who can perform spirometry; exacerbations that
require OCSs and urgent care usage are also suggested as
indicators. Attention should be given to standardizing
variables that can be used to compare outcomes between
trials.
The majority of pediatric data are for children ⱕ12
years; only 5 of the 18 studies included adolescents
(13–18 years old).30,31,38,43,46 Data for this population are
lost when assessing childhood asthma, either grouped
with adults (eg, studies in patients ⱖ12 years old) or not
included (eg, studies of school-aged children ⱕ12 years
old). More studies are needed to evaluate whether diag-
nosing asthma and starting therapy early affects the
course of the disease in adolescence. More information is
also needed to assess how treatment can better meet the
needs of the adolescent patient.
The evidence presented in this systematic retrieval
and review of the literature is not ranked, because this is
the work of a single author and not a committee. How-
ever, the studies chosen were separated according to
design: double-blind, placebo-controlled studies and
randomized, controlled, comparison trials. No nonran-
domized trials or observational studies were included.
Thus, all of the data collected in this review would fall
into category A and B evidence according to the defini-
tions in the EPR3.1
Asthma is a complex and heterogeneous disease.
Many factors affect impairment and risk and influence
choice of therapy. Not addressed in this article but of
significant impact are adherence with treatment, envi-
ronmental control, comorbid conditions, differences in
delivery devices, and penetration of medication into the
small airways. The reader is directed to the EPR3 for
additional information.1
In summary, the available data indicate that ICSs
improve asthma control in children by reducing both
impairment and risk associated with the disease and
support current recommendations for treatment.
ACKNOWLEDGMENTS
This work was funded partially by an unrestricted edu-
cational grant from Teva Pharmaceuticals.
The expert research and technical support of Judith
Farrar, PhD, is greatly appreciated; this publication
would not have been possible without her editorial as-
sistance.
REFERENCES
1. National Asthma Education and Prevention Program. Expert
Panel Report 3: Guidelines for the Diagnosis and Management of
Asthma. Bethesda, MD: National Institutes of Health; 2007.
Available at: www.nhlbi.nih.gov/guidelines/asthma. Accessed
October 30, 2007
2. Centers for Disease Control and Prevention, National Center
for Health Statistics. Summary health statistics for U.S.
children: National Health Interview Survey, 2005. Available at:
www.cdc.gov/nchs/data/series/sr㛭10/sr10㛭231.pdf. Accessed
October 25, 2007
 3. Centers for Disease Control and Prevention, National Center
for Health Statistics. Asthma prevalence, health care use and
mortality: United States, 2003– 05. Available at: www.cdc.gov/
nchs/products/pubs/pubd/hestats/ashtma03-05/asthma03-05.
htm. Accessed October 25, 2007
4. Djukanović R, Wilson JW, Britten KM, et al. Effect of an
inhaled corticosteroid on airway inflammation and symptoms
in asthma. Am Rev Respir Dis. 1992;145(3):669 – 674
5. Leung TF, Wong GWK, Ko FWS, et al. Analysis of growth
factors and inflammatory cytokines in exhaled breath conden-
sate from asthmatic children. Int Arch Allergy Immunol. 2005;
137(1):66 –72
6. Jarjour NN, Wilson SJ, Koenig Sm, et al. Control of airway
inflammation maintained at a lower steroid dose with 100/50
microg of fluticasone propionate/salmeterol. J Allergy Clin Im-
munol. 2006;118(1):44 –52
7. Hauber H, Taha R, Bergeron C, Migounov V, Hamid Q, Oliv-
enstein R. Effects of hydrofluoroalkane and dry powder-
formulated corticosteroids on sputum inflammatory markers in
asthmatic patients. Can Respir J. 2006;13(2):73–78
8. Bousquet J, Ben Joseph R, Messonnier M, Alemao E, Gould
AL. A meta-analysis of the dose-response relationship of in-
haled corticosteroids in adolescents and adults with mild to
moderate persistent asthma. Clin Ther. 2002;24(1):1–20
9. Holt S, Suder A, Weatherall M, Cheng S, Shirtcliffe P, Beasley
R. Dose-response relation of inhaled fluticasone propionate in
adolescents and adults with asthma: meta-analysis. BMJ. 2001;
323(7307):253–256
10. Szefler SJ, Martin RJ, King TS, et al. Significant variability in
response to inhaled corticosteroids for persistent asthma. J
Allergy Clin Immunol. 2002;109(3):410 – 418
11. Masoli M, Weatherall M, Holt S, Beasley R. Systematic review
of the dose-response relation of inhaled fluticasone propionate.
Arch Dis Child. 2004;89(10):902–907
12. Aalbers R, Backer V, Kava TT, et al. Adjustable maintenance
dosing with budesonide/formoterol compared with fixed-dose
salmeterol/fluticasone in moderate to severe asthma. Curr Med
Res Opin. 2004;20(2):225–240
13. Boushey HA, Sorkness CA, King TS, et al. Daily versus as-
needed corticosteroids for mild persistent asthma. N Engl J Med.
2005;352(15):1519 –1528
14. Foresi A, Morelli MC, Catena E. Low-dose budesonide with the
addition of an increased dose during exacerbations is effective
in long-term asthma control. On behalf of the Italian Study
Group. Chest. 2000;117(2):440 – 446
15. Harrison TW, Oborne J, Newton S, Tattersfield AE. Doubling
the dose of inhaled corticosteroid to prevent asthma
exacerbations: randomised controlled trial. Lancet. 2004;
363(9405):271–275
16. Green RH, Brightling CE, McKenna S, et al. Asthma exacerba-
tions and sputum eosinophil counts: a randomized controlled
trial. Lancet. 2002;360(9347):1715–1721
17. Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR.
Use of exhaled nitric oxide measurements to guide treatment
in chronic asthma. N Engl J Med. 2005;352(21):2163–2173
18. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled
corticosteroids in preschool children at high risk for asthma.
N Engl J Med. 2006;354(19):1985–1997
19. Taussig LM, Wright AL, Holberg CJ, Halonen M, Morgan WJ,
Martinez FD. Tucson children’s respiratory study: 1980 to
present. J Allergy Clin Immunol. 2003;111(4):661– 675
20. Castro-Rodríguez JA, Holberg CJ, Wright AL, Martinez FD. A
clinical index to define risk of asthma in young children with
recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 pt
1):1403–1406
21. Guilbert TW, Morgan WJ, Zeiger RS, et al. Atopic characteris-
tics of children with recurrent wheezing at high risk for the
Downloaded from www.pediatrics.org by on March 14, 2010
development of childhood asthma. J Allergy Clin Immunol.
2004;114(6):1282–1287
22. Bacharier LB, Phillips BR, Bloomberg GR, et al. Severe inter-
mittent wheezing in preschool children: a distinct phenotype. J
Allergy Clin Immunol. 2007;119(3):604 – 610
23. Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of
fluticasone propionate with beclomethasone dipropionate in
moderate to severe asthma treated for one year. International
Study Group. Thorax. 1993;48(8):817– 823
24. Kamada AK, Szefler SJ, Martin RJ, et al. Issues in the use of
inhaled glucocorticoids. The Asthma Clinical Research Net-
work. Am J Respir Crit Care Med. 1996;153(6 pt 1):1739 –1748
25. Gustafsson P, Tsanakas J, Gold M, Primhak R, Radford M,
Gillies E. Comparison of the efficacy and safety of inhaled
fluticasone propionate 200 micrograms/day with inhaled be-
clomethasone dipropionate 400 micrograms/day in mild and
moderate asthma. Arch Dis Child. 1993;69(2):206 –211
26. van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiver-
man EJ, Pocock SJ, Kerrebijn KF. Effects of 22 months of
treatment with inhaled corticosteroids and/or beta2-agonists
on lung function, airway responsiveness, and symptoms in
children with asthma. The Dutch Chronic Non-specific Lung
Disease Study Group. Am Rev Respir Dis. 1992;146(3):547–554
27. Agertoft L, Pedersen S. Short-term knemometry and urine
cortisol excretion in children treated with fluticasone propi-
onate and budesonide: a dose response study. Eur Respir J.
1997;10(7):1507–1512
28. Turktas I, Ozkaya O, Ilknur B, Bideci A, Cinaz P. Safety of
inhaled corticosteroid therapy in young children with asthma.
Ann Allergy Asthma Immunol. 2001;86(6):649 – 654
29. Childhood Asthma Management Program Research Group.
Long-term effects of budesonide or nedocromil in children
with asthma. N Engl J Med. 2000;343(15):1054 –1063
30. Garcia Garcia ML, Wahn U, Gilles L, Swern A, Tozzi CA, Polos
P. Montelukast, compared with fluticasone, for control of
asthma among 6- to 14-year-old patients with mild asthma:
the MOSAIC study [published correction appears in Pediatrics.
2005;116(4):1058]. Pediatrics. 2005;116(2):360 –370
31. Sorkness CA, Lemanske RF, Mauger DT, et al. Long-term
comparison of 3 controller regimens for mild-moderate persis-
tent childhood asthma: the Pediatric Asthma Controller Trial. J
Allergy Clin Immunol. 2007;119(1):64 –72
32. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention
with budesonide in mild persistent asthma: a randomised,
double-blind trial. Lancet. 2003;361(9363):1071–1076
33. Chen YZ, Busse WW, Pedersen S, Tan W, Lamm CJ, O’Byrne
PM. Early intervention of recent onset mild persistent asthma
in children aged under 11 yrs: the Steroid Treatment as Regular
Therapy in Early Asthma (START) trial. Pediatr Allergy Immunol.
2006;17(suppl 17):7–13
34. Baker JW, Mellon M, Wald J, Welch M, Cruz-Rivera M, Wal-
ton-Bowen K. A multiple-dosing, placebo-controlled study of
budesonide inhalation suspension given once or twice daily for
treatment of persistent asthma in young children and infants.
Pediatrics. 1999;103(2):414 – 421
35. de Blic J, Tillie-Leblond I, Tonnei AB, Jaubert F, Scheinmann
P, Gosset P. Efficacy of nebulized budesonide in treatment of
severe infantile asthma: a double-blind study. J Allergy Clin
Immunol. 1996;98(1):14 –20
36. Kemp JP, Skoner DP, Szefler SJ, Walton-Bowen K, Cruz-
Rivera M, Smith JA. Once-daily budesonide inhalation suspen-
sion for the treatment of persistent asthma in infants and
young children. Ann Allergy Asthma Immunol. 1999;83(3):
231–239
37. Roorda RJ, Mezei G, Bisgaard H, Maden C. Response of pre-
school children with asthma symptoms to fluticasone propi-
onate. J Allergy Clin Immunol. 2001;108(4):540 –546
PEDIATRICS Volume 123, Number 1, January 2009 365
38. Hoekstra MO, Grol M, Bauman K, et al. Fluticasone propionate
in children with moderate asthma. Am J Respir Crit Care Med.
1996;154(4 pt 1):1039 –1044
39. LaForce CF, Pearlman DS, Ruff ME, et al. Efficacy and safety of
dry powder fluticasone propionate in children with persistent
asthma. Ann Allergy Asthma Immunol. 2000;85(5):407– 415
40. Nayak A, Lanier R, Weinstein S, Stanpone P, Welch M. Efficacy
and safety of beclomethasone dipropionate extrafine aerosol in
childhood asthma: a 12-week, randomized, double-blind pla-
cebo-controlled study. Chest. 2002;122(6):1956 –1965
41. Peden DB, Berger WE, Noonan MJ, et al. Inhaled fluticasone
propionate delivered by means of two different multidose pow-
der inhalers is effective and safe in a large pediatric population
with persistent asthma. J Allergy Clin Immunol. 1998;102(1):
32–38
42. Shapiro G, Mendelson L, Kraemer MJ, Cruz-Rivera M, Wal-
ton-Bowen K, Smith JA. Efficacy and safety of budesonide
inhalation suspension (Pulmicort Respules in young children
with inhaled steroid-dependent persistent asthma. J Allergy
Clin Immunol. 1998;102(5):789 –796
43. Shapiro GG, Mendelson LM, Pearlman DS. Once-daily budes-
onide inhalation powder (Pulmicort Turbuhaler) maintains
pulmonary function and symptoms of asthmatic children pre-
viously receiving inhaled corticosteroids. Ann Allergy Asthma
Immunol. 2001;86(6):633– 640
44. Weiss K, Buxton M, Andersson FL, Lamm CJ, Liljas B, Sullivan
SD. Cost-effectiveness of early intervention with once-daily
budesonide in children with mild persistent asthma: results
from the START study. Pediatr Allergy Immunol. 2006;17(suppl
17):21–27
45. Ostrom NK, Decotis BA, Lincourt WR, et al. Comparative
efficacy and safety of low-dose fluticasone propionate and
montelukast in children with persistent asthma. J Pediatr.
2005;147(2):213–220
46. Szefler SJ, Phillips BR, Martinez FD, et al. Characterization of
within-subject responses to fluticasone and montelukast in
childhood asthma. J Allergy Clin Immunol. 2005;115(2):
233–242
47. Zeiger RS, Szefler SJ, Phillips BR, et al. Response profiles to
fluticasone and montelukast in mild-to-moderate persistent
childhood asthma. J Allergy Clin Immunol. 2006;117(1):45–52
48. Rachelefsky G. Free Your Child From Asthma. New York, NY:
McGraw-Hill; 2006
49. Agertoft L, Pedersen S. Effect of long-term treatment with
inhaled budesonide on adult height in children with asthma.
N Engl J Med. 2000;343(15):1064 –1069

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
Downloaded from www.pediatrics.org by on March 14, 2010
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:
http://www.pediatrics.org/cgi/content/full/123/1/353#BIBL
Post-Publication One P3R has been posted to this article:
Peer Reviews (P3Rs) http://www.pediatrics.org/cgi/eletters/123/1/353
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Asthma
http://www.pediatrics.org/cgi/collection/asthma
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://www.pediatrics.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
http://www.pediatrics.org/misc/reprints.shtml

Downloaded from www.pediatrics.org by on March 14, 2010