Lea Bentur, MD Pediatric Pulmonary Unit

1. 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. 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

7. Hypothetical representation of the natural history of asthma Persistent Asthma Progression Inception 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? Progression Inception 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, 20042Bisgaard, 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;343:1054-63

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 criteriaOR - Two minor criteria • Parent with asthma Food sensitivity • Atopic dermatitis  Peripheral eosinophilia (4%) • Aero-allergen sensitivity  Wheezing not related to infection Modified from: Castro-Rodriguez, AJRRCM, 2000

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

24. ICS Effect on IOS Measures:Reactance at 5 Hz p=0.83

25. Observation Treatment Episode-free Days During the Entire Study

26. 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. 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 CAMP study. NEJM 2000; 343:1054-1063

29. ICS Effect During Treatment Phase Asthma Exacerbations P<0.001

30. PEAK-ICS effect during treatment Supplementary Controller Use P<0.001 P<0.001

31. ICS Effect on IOS Measures:Reactance at 5 Hz p=0.008 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 = 0.0001) • End of observation: ICS: 54.4%ile vs. Placebo: 56.4%ile (0.7 cm ,p=0.03)

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)