Inhaled corticosteroids in
preschool asthmatic children.
Is it really needed??
OR
Can inhaled corticosteroids change
the natural history of asthma??
30.4.2002
Lea Bentur, MD
Pediatric Pulmonary Unit
‫השקה‬
Conclusions : Intermittent inhaled
corticosteroid therapy had no effect on
the progression from episodic to persistent
wheezing and no short-term benefit during
episodes of wheezing in the first three
years of life.
Bisgaard
Conclusions: In preschool children at high
risk for asthma, two years of inhaledcorticosteroid therapy did not change
the development of asthma symptoms or
lung function during a third treatmentfree year.
These findings do not provide support for
a subsequent disease-modifying effect of
inhaled corticosteroids after the
treatment is discontinued.
Martinez
Inhaled
corticosteroids in
preschool
asthmatic
children.
Is it really
needed??
Preschool Asthma

Most common chronic disease in childhood

Prevalence up to 32%
 Children and adults with persistent asthma
usually have their first symptoms before age 3
 Limited objective measures of treatment
efficacy
Slide 1
Hypothetical representation of the
natural history of asthma
Persistent
Asthma
Inception
No Asthma
Asthma Initial Phase
Exacerbation
Protection
Intermittent
asthma
No Asthma
Persistent and intermittent asthma
Lower quality of life
Possible lower pulmonary function in
adulthood
Key Issues
• Can we modify the natural history of
asthma?
• Can we modify lung function Levels in adult
life?
Hypothetical Representation of the
Natural History of Asthma
Persistent
Asthma
ICS?
Inception
No Asthma
Asthma Initial Phase
Exacerbation
Protection
Intermittent
asthma
No Asthma
Rationale
ICS have been reported to reduce
symptoms in high-risk young children
with intermittent wheezing1,2
1Teper, Ped Pulm, 2004 2Bisgaard, AJRCCM, 1999
Prevention of inflammation 
prevention of airway remodeling??
Normal Mucosa
Possible consequence of remodeling
– Persistent asthma
– Lung function decline
– Fatal asthma
Assessment of remodeling
Biopsy
Post 2 -FEV1
Persistent asthma
Airway Remodeling
Busse et al. NEJM 2000
Episode free days
CAMP Study
1041 children, 5-12 years
Followed 4-6 years
Budesonide / Nedocromil / Placebo
No effect of ICS on the natural course of
asthma in school aged children.
Due to the initiation of ICS after the
occurrence of critical injurious events??
N Engl J Med 2000;343:1054-63
Prevention of Asthma in Childhood (PAC)
Hypothesis : intermittent ICS treatment of
pre-asthma may prevent or delay progression
to persistent wheezing
• A cohort of infants whose mothers had
received a diagnosis of asthma.
• A double-blind, randomized, controlled trial
treatment with two-week courses of
budesonide (400 μg per day) or placebo,
initiated after a three-day episode of
wheezing.
411 infants enrolled, 294 randomly assigned
Limitation
• Pre-asthma group
• Heterogeneity of causes and response to
therapy in this age group
• Variability in definition of symptoms
• Starting therapy on the 3rd day
• Intermittent treatment
PEAK Trial
PEAK is investigating if inhaled corticosteroids
when initiated in preschool-aged children
at high risk for asthma,
can alter the natural history of asthma after
ICS are discontinued
Asthma Predictive Index- identifies children
(ages 2 & 3) that will have asthma-like
symptoms in school years1
> 4 wheezing episodes in the past year
(at least one must be MD diagnosed)
PLUS
– One major criteria
• Parent with asthma
• Atopic dermatitis
• Aero-allergen sensitivity
OR - Two minor criteria
Food sensitivity
 Peripheral eosinophilia (4%)
 Wheezing not related to
infection

Modified from: Castro-Rodriguez, AJRRCM, 2000
PEAK: Study Design
Screening/
Eligibility
Run-in
1 month
Treatment
Years 1 & 2
Observation
Year 3
Randomize Interim Efficacy Tests
• Randomized, multicenter, double-blind, parallel
group, placebo-controlled trial
• 285 two and three year olds at high-risk for asthma
• Fluticasone 44 g/puff or placebo (2 puffs b.i.d.)
Inclusion Criteria
•
•
•
•
•
•
•
Children 24-47 months of age
Positive asthma predictive index
At least 36 weeks at birth
No systemic illnesse
> 10% for height
< 4 months of inhaled corticosteroid
< 4 courses of systemic steroid in last year
PEAK: Primary Outcome
• Episode-free days during the
observation-year
– No cough or wheeze
– No unscheduled clinic, urgent care,
ER or hospital visits
– No use of asthma medications
No bronchodilator before exercise
Addition of Controllers
Persistent Symptoms OR
> 4 courses of oral steroids in 12 mos
Montelukast
Open label fluticasone
Other supplementary asthma medications
Taper after 2 months based
on specific protocols
Study Population:
Enrollment and Disposition
285 Randomized Participants
143 in ICS group
142 in placebo group
132
131
130
included in included in included in
Year 1 & 2 Year 3
Year 1 & 2
analyses
analysis
analyses
125
included in
Year 3
analysis
ICS Effect on IOS Measures:
Reactance at 5 Hz
End of
treatment
End of
observation
33
36
Placebo
ICS
39
42
45
p=0.83
Episode-free Days
During the Entire Study
Observation
Proportion of Episode-free Days
Treatment
†
1.00
†
†
0.95
0.90
0.85
0.80
†
0.75
ICS
Placebo
p<0.05
p<0.01
6
12
18
24
Months
30
36
Conclusions
• Two years of treatment with daily
ICS did not change the natural
history of asthma
• Changes in airway function
(remodeling?) occur early in life in
asthma, with little subsequent
further deterioration
ICS probably do not prevent
remodeling or change natural history
Inhaled corticosteroids in preschool
asthmatic children.
Is it really needed??
X
CAMP
Budesonide improves asthma control
Decrease hyper-reactivity
Higher FEV1 pre-bronchodialtor
Fewer hospitalizations (2.5 vs. 4.4)
Fewer urgent visits (12 vs. 22)
Less albuterol need
Fewer courses of prednisone
Less additional asthma medications
Small transient effect on growth
CAMP study. NEJM 2000; 343:1054-1063
ICS Effect During Treatment Phase
Asthma Exacerbations
100
80
Number
per 100
child years
60
Placebo
ICS
40
20
0
P<0.001
PEAK-ICS effect during treatment
Supplementary
Controller Use
28
21
Placebo
Days per
14
year
ICS
7
0
ICS
Montelukast
P<0.001
P<0.001
ICS Effect on IOS Measures:
Reactance at 5 Hz
End of
treatment
End of
observation
-0.33
-0.36
Placebo
ICS
-0.39
-0.42
-0.45
p=0.008
p=0.83
Growth since baseline (cm)
Low Dose ICS Impacted Growth
• Average height
percentile:
Placebo
ICS
p<0.01
20
15
– End of Treatment:
ICS: 51.5%ile vs.
Placebo: 56.4%ile
(1.1 cm, p = 0.0001)
10
– End of observation:
ICS: 54.4%ile vs.
Placebo: 56.4%ile
(0.7 cm ,p=0.03)
5
0
0
8
16
24 30 36
Months
ICS
•
•
•
•
•
•
•
•
ICS improves asthma control
Decrease hyper-reactivity
Higher FEV1 pre-bronchodialtor
Fewer hospitalizations
Fewer urgent visits
Less albuterol need
Fewer courses of prednisone
Less additional asthma medications
 Small transient effect on growth
 ICS- No carry over effect

ICS- No carry over effect
 Hypertension
 Diabetes
 Hypercholesterolemia
No carry over effect
 CHF
 Connective tissue disorders
 Hypothyroidism
 Arrhythmia
Chronic treatment in chronic diseases
• Improvement in quality of life
• Decrease fatality rate
• Prevention of end target dysfunction
Chronic treatment in asthma
• Improvement in quality of life!!
• Decrease fatality rate
• Prevention of end target dysfunction ?
Airway remodeling in childhood asthma
Non preventable?
Non existing?
Prophylactic Tx = insurance
(not cure)
• You have to pay (side effects) in order to be
insured
• You are insured as long as you pay
• Find the lowest cost for the best coverage
( low ICS, Singulair, combination therapy).
• Even if your premium (dose) is high, there is
still self deduction (exacerbations)