30.4.2002ה ש ק ה

Lea Bentur, MD

Pediatric Pulmonary Unit

Inhaled corticosteroids in preschool asthmatic children.

Is it really needed??OR

Can inhaled corticosteroids change

the natural history of asthma??

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 inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third treatment-free 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

Asthma Initial PhaseAsthma Initial Phase

InceptionInception

ExacerbationExacerbation

Progre

ssio

n

No AsthmaNo Asthma

PersistentPersistentAsthmaAsthma

Intermittent Intermittent asthma asthma

No AsthmaNo Asthma

Protection

Remission

Persistent and intermittent asthma

Lower quality of life Possible lower pulmonary function

in adulthood

• Can we modify the natural history of asthma?

• Can we modify lung function Levels in adult life?

Key IssuesKey Issues

Hypothetical Representation of the

Natural History of Asthma

Asthma Initial PhaseAsthma Initial Phase

InceptionInception

ExacerbationExacerbation

Progre

ssio

n

No AsthmaNo Asthma

PersistentPersistentAsthmaAsthma

Intermittent Intermittent asthma asthma

No AsthmaNo Asthma

Protection

Remission

ICS?ICS?

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

Airway Remodeling

Busse et al. NEJM 2000

Possible consequence of remodeling – Persistent asthma – Lung function decline – Fatal asthma

Assessment of remodeling

Biopsy

Post 2 -FEV1

Persistent asthma

Episode free days

CAMP Study

N Engl J Med 2000;343:1054-63

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??

1041 children, 5-12 yearsFollowed 4-6 yearsBudesonide / Nedocromil / Placebo

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 OR - Two minor

criteria• Parent with asthma Food sensitivity• Atopic dermatitis Peripheral

eosinophilia (4%) • Aero-allergen sensitivity Wheezing not related to

infectionModified from: Castro-Rodriguez, AJRRCM, 2000

• Randomized, multicenter, double-blind, parallelgroup, 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.)

Year 3Year 3

Screening/Screening/Eligibility Eligibility Run-inRun-in

Interim Efficacy Tests

PEAK: Study Design

Years 1 & 2Years 1 & 21 month1 month

Randomize

Treatment Treatment Observation Observation

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

•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

PEAK: Primary Outcome

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 Participants285 Randomized Participants

143 in ICS 143 in ICS groupgroup

142 in placebo 142 in placebo groupgroup

132 132 included included in Year 1 in Year 1

& 2 & 2 analysesanalyses

131 131 included included in Year 3 in Year 3 analysisanalysis

130 130 included included in Year 1 in Year 1

& 2 & 2 analysesanalyses

125 125 included included in Year 3 in Year 3 analysisanalysis

ICS Effect on IOS Measures:Reactance at 5 Hz

p=0.83

0.75

0.80

0.85

0.90

0.95

1.00

6 12 18 24 30 36

† † †

†

ICSPlacebop<0.05p<0.01

Pro

po

rtio

n o

f E

pis

od

e-f

ree

Da

ys

Months

Episode-free Days During the Entire Study

Treatment Treatment Observation Observation

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-reactivityHigher FEV1 pre-bronchodialtor

Fewer hospitalizations (2.5 vs. 4.4) Fewer urgent visits (12 vs. 22)Less albuterol needFewer courses of prednisoneLess additional asthma medications

Small transient effect on growth

CAMP study. NEJM 2000; 343:1054-1063

0

20

40

60

80

100

Number per 100

child yearsPlacebo

ICS

ICS Effect During Treatment Phase

P<0.001

Asthma Exacerbations

PEAK-ICS effect during treatment

0

7

14

21

28

ICS Montelukast

Days per year

Placebo

ICS

P<0.001 P<0.001

Supplementary Controller Use

ICS Effect on IOS Measures:Reactance at 5 Hz

-0.45

-0.42

-0.39

-0.36

-0.33

End oftreatment

End ofobservation

PlaceboICS

p=0.008 p=0.83

• Average height percentile:

– End of Treatment:

ICS: 51.5%ile vs.Placebo: 56.4%ile (1.1 cm, p = 0.0001)

– End of observation: ICS: 54.4%ile vs. Placebo: 56.4%ile

(0.7 cm ,p=0.03)

Low Dose ICS Impacted Growth

Months

Gro

wth

sin

ce b

asel

ine

(cm

)

0

5

10

15

20

0 8 16 24 30 36

PlaceboICSp<0.01

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

CHF

Connective tissue disorders

Hypothyroidism

Arrhythmia

No carry over effect

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)