Inhaled corticosteroids in preschool asthmatic children Is it

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

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 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 n Inception No Asthma sio s re Persistent Asthma g o Pr Protection Asthma Initial Phase Re Exacerbation Intermittent asthma mis sio n 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 ICS? Inception No Asthma n sio s re Persistent Asthma g o Pr Protection Asthma Initial Phase Re Exacerbation Intermittent asthma mis sio n No Asthma

Rationale ICS have been reported to reduce symptoms in high-risk young children with intermittent wheezing 1, 2 1 Teper, Ped Pulm, 2004 2 Bisgaard, 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 -FEV 1 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 preasthma 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 3 rd 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 years 1 > 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 ER – No No cough or wheeze unscheduled clinic, urgent care, or hospital visits use of asthma medications 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 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 p=0. 83

Episode-free Days During the Entire Study Treatment 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-reactivity Higher FEV 1 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 P<0. 001

PEAK-ICS effect during treatment Supplementary Controller Use P<0. 001

ICS Effect on IOS Measures: Reactance at 5 Hz p=0. 008 p=0. 83

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)

ICS • • ICS improves asthma control Decrease hyper-reactivity Higher FEV 1 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)