1. Inhaled corticosteroids in preschool asthmatic children
Inhaled corticosteroids in preschool asthmatic children. Is it really needed?? OR Can inhaled corticosteroids change the natural history of asthma??
Lea Bentur, MD
Pediatric Pulmonary Unit

2. 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

3. 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

4. Inhaled corticosteroids in preschool asthmatic children
Inhaled corticosteroids in preschool asthmatic children. Is it really needed??

5. 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
A significant public-health problem, asthma is the most common chronic disease of childhood.1 In addition, as many as 50 to 80% of children with asthma develop symptoms before they are five years of age.2 Asthma in these children is treated with the same medications as in adults. However, currently available therapies have troublesome limitations for children and new therapies that are effective, well-tolerated, and easily administered would be welcome advances.
The leukotriene receptor antagonist montelukast has been shown in previous clinical studies to be an effective and well-tolerated therapy for 6- to 14-year-old children with asthma.3 The slides in this presentation review key issues in the management of childhood asthma and present data for new, lower-dose formulations of montelukast developed for use in young (2–5 years of age)4 and older (6–14 years of age) children with chronic asthma.
Ref 1,
p 3A
Ref 2, pp 1A, 94A
Common
Medical
Knowledge
Ref 3, p 1186A
Ref 4,
pp 3A, 9B,
6A-F
Slide 1
REFERENCES
1. Boner AL, Martinati LC. Diagnosis of asthma in children and adolescents. Eur Respir Rev 1997; 7(40):3-7.
2. National Institutes of Health Guidelines for the Diagnosis and Management of Asthma. Expert Panel Report 2. NIH Publication No Bethesda, MD: National Institutes of Health, 1997.
3. Knorr B, Matz J, Bernstein JA et al for the Pediatric Montelukast Study Group. Montelukast for chronic asthma in 6- to 14-year-old children: A randomized, double-blind trial. JAMA 1998;279(15):
4. Knorr B, Franchi LM, Bisgaard H et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108(3):1-10.

7. Hypothetical representation of the natural history of asthma
Persistent
Asthma
Inception
Progression
Protection
Intermittent asthma
No Asthma
Asthma Initial Phase
Remission
Exacerbation
No Asthma

8. Persistent and intermittent asthma
Lower quality of life
Possible lower pulmonary function in adulthood

9. Key Issues Can we modify the natural history of asthma?
Can we modify lung function Levels in adult life?

10. Hypothetical Representation of the Natural History of Asthma
Persistent
Asthma
ICS?
Inception
Progression
Protection
Intermittent asthma
No Asthma
Asthma Initial Phase
Remission
Exacerbation
No Asthma

11. Rationale
ICS have been reported to reduce symptoms in high-risk young children with intermittent wheezing1,2
1Teper, Ped Pulm, Bisgaard, AJRCCM, 1999

12. Prevention of inflammation  prevention of airway remodeling??
Possible consequence of remodeling
Persistent asthma
Lung function decline
Fatal asthma
Normal Mucosa
Assessment of remodeling
Biopsy
Post 2 -FEV1
Persistent asthma
Episode free days
Airway Remodeling
Busse et al. NEJM 2000

13. 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:

14. 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.

15. 411 infants enrolled, 294 randomly assigned

16. 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

17. 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

18. 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 infection
We identified high risk children based on a modified asthma predictive index developed by Castro-Rodriguez using data from the Tucson CRS study.
Modified from: Castro-Rodriguez, AJRRCM, 2000

19. Interim Efficacy Tests
PEAK: Study Design
Screening/
Eligibility
Treatment
Observation
Run-in
Year 3
1 month
Years 1 & 2
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.)

20. 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

21. Episode-free days during the observation-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

22. Addition of Controllers
Persistent Symptoms OR
> 4 courses of oral steroids in 12 mos
Montelukast
Open label fluticasone
Without unmasking
Supplementary asthma medication was started in a blinded fashion based on symptom-based protocols. Singular 4 mg po QHS and fluticasone 110 mcg/puff 1 puff BID via metered-dose inhaler and Aerochamber and mask)
Other supplementary asthma medications
Taper after 2 months based on specific protocols

23. Study Population: Enrollment and Disposition
285 Randomized Participants
143 in ICS group
142 in placebo group
132 included in Year 1 & 2 analyses
131 included in Year 3 analysis
130 included in Year 1 & 2 analyses
125 included in Year 3 analysis
Cascade of enrollment. PEAK had excellent subject retention. Less than 10% of children were lost-to-followup between the fluticasone and placebo groups during the two-year treatment period and 12% during the observation-year.

24. ICS Effect on IOS Measures: Reactance at 5 Hz
Reactance at 5 Hz measure by IOS. Reactance at low frequencies reflects the elastic properties of the respiratory system and will be more negative in patients with small airway dysfunction. Here we see less absolute respiratory system reactance in the inhaled steroid group while on treatment which based on the literature may be a possible indicator of greater dynamic lung compliance. The two treatment groups are similar at the end of observation. Only 56% of children completed spirometry at both the end of treatment and end of observation and therefore is not presented here.
p=0.83

25. Episode-free Days During the Entire Study
Treatment
Observation
Episode-free days during the two-year treatment period. Fluticasone during the two-year treatment period, compared to placebo, significantly improved the proportion of episode-free days. Clear effect on treatment which disappeared off treatment. The proportion of episode days in the ICS group compared to the placebo group was 97% vs 96% at baseline, 96% vs. 89% at the end the treatment phase and 84% vs. 87% at the end of the observation year demonstrating increase in the frequency of asthma-like symptoms over time.

26. ICS probably do not prevent remodeling or change natural history
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

27. Inhaled corticosteroids in preschool asthmatic children
Inhaled corticosteroids in preschool asthmatic children. Is it really needed?? X

28. 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
שקף 15
מחקר CAMP עשה השוואה בין בודזונייד לנדוקרומיל לפלסבו ב 1,041 ילדים בגילאי 5 עד 12 שנים עם אסתמה קלה עד בינונית, ועקב אחרי מצב מחלתם במשך 4-6 שנים.
בנקודת הסיום העיקרית, שיעור השינוי של תפקודי הריאות FEV1, לא היה הבדל משמעותי בין הקבוצות הטיפוליות לבין פלסבו.
הילדים שטופלו עם פלסבו הראו ירידה קטנה, אך משמעותית, ביחס FEV1/FVC לפני שימוש במרחיבי סמפונות.
הילדים שטופלו עם בודזונייד הראו פחות רגישות יתר למטכולין בדרכי האוויר התחתונות, פחות אשפוזים, פחות ביקורים דחופים, ירידה גדולה יותר בצורך במרחיבי סמפונות, פחות שימוש בפרדניזון, ופחות ימים בהם היה צורך לטיפול נוסף באסתמה.
מסקנות: הטיפול עם בודזונייד לא שיפור את תפקודי הריאות, אך שיפר את רגישות היתר של דרכי האוויר והעניק שליטה טובה יותר במחלה לעומת פלסבו או נדוקרומיל
CAMP study. NEJM 2000; 343:

29. ICS Effect During Treatment Phase
Asthma Exacerbations
During the treatment period and compared to the placebo-group, the ICS-group had a 32.0% lower rate of systemic corticosteroid courses for exacerbations (p<0.001)
P<0.001

30. PEAK-ICS effect during treatment
Supplementary Controller Use
During the treatment period and compared to the placebo-group, the ICS-group had 52.8% less montelukast use (p<0.001), 53.0% less supplementary fluticasone use apart from study medication (p<0.001),
P<0.001
P<0.001

31. ICS Effect on IOS Measures: Reactance at 5 Hz
Reactance at 5 Hz measure by IOS. Reactance at low frequencies reflects the elastic properties of the respiratory system and will be more negative in patients with small airway dysfunction. Here we see less absolute respiratory system reactance in the inhaled steroid group while on treatment which based on the literature may be a possible indicator of greater dynamic lung compliance. The two treatment groups are similar at the end of observation. Only 56% of children completed spirometry at both the end of treatment and end of observation and therefore is not presented here.
p= p=0.83

32. Low Dose ICS Impacted Growth
Average height percentile:
End of Treatment:
ICS: 51.5%ile vs.
Placebo: 56.4%ile
(1.1 cm, p = )
End of observation:
ICS: 54.4%ile vs.
Placebo: 56.4%ile (0.7 cm ,p=0.03)
Height growth over 3 years. The mean increase in height from baseline in the fluticasone group was 1.1 cm less than in the placebo group at the end of the 24 month treatment period and 0.7 cm at the end of the observation-year.

33. 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

34.  ICS- No carry over effect
 Hypertension
 Diabetes
 Hypercholesterolemia
 CHF
 Connective tissue disorders
 Hypothyroidism
 Arrhythmia
No carry over effect

35. Chronic treatment in chronic diseases
Improvement in quality of life
Decrease fatality rate
Prevention of end target dysfunction

36. 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?

37. 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)