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

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 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 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. 97-4051. 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): 1181-1186. 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.

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

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 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

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.)

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 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 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

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.

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

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.

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

Inhaled corticosteroids in preschool asthmatic children 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 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; 343:1054-1063

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

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

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=0.008 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) 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.

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)