Can We Prevent Asthma? Fernando D. Martinez, M.D. Arizona Respiratory Center The University of Arizona
What Do We Mean by Prevention? A strategy for primary prevention is one that, acting before the disease process ever starts, blocks its inception Primary prevention requires knowledge about the basic mechanisms that cause the disease A strategy of secondary prevention, acting at the first phases of the disease process, blocks and/or reverses its progression
Hypothetical Representation of the Natural History of Asthma Persistent Asthma n o i ss e gr o Pr
Inception
No Asthma
Initial Phase of Asthma
Triggers
Protection
Re mi ssi on
Intermittent Asthma
No Asthma
Allergen Exposure
Genetic Predisposition to Allergies Sensitization Genetic Predisposition to Asthma Asthma
Allergy, No Asthma
Exposure to Dust Mites and Asthma Lau and coworkers assessed concentrations of dust mites allergens in the homes of >900 children during the first year of life They subsequently followed exposed children and assessed allergic sensitization to mites and incidence of asthma up to age 7 Lau et al, Lancet 2000, 356:1392
Asthma Symptoms by House Dust Mite Sensitization
Lau et al, Lancet 2000, 356:1392
Asthma and BHR by Type of Sensitization
Illi et al, JACI 2001; 108:709
Asthma Symptoms and HDM Sensitization by Exposure
Lau et al, Lancet 2000, 356:1392
The Childhood Asthma Prevention Study (CAPS), Sidney Australia Established in 1997 Primary aims were to test whether in children at high risk of allergic disease the incidence of allergy and asthma at age 5 years could be reduced by the implementation of interventions directed at avoidance of HDM allergens, diet supplementation with omega-3 fatty acids, or a combination of these 2 interventions Mihrshahi et al, JACI 2003;111:162-8
Mihrshahi et al, JACI 2003;111:162-8
Effectiveness of the Mite Avoidance Intervention
Outcomes at Age 5 Years
Marks et al, JACI 2006; 118:53-61.
Conclusions: Primary Prevention Two randomized mite avoidance trials (Sydney and Manchester) showed no beneficial effect on asthmarelated outcomes measured in the early school years These results question the hypothesis that exposure to allergens causes the type of chronic asthma associated with early life sensitization
Hypothetical Representation of the Natural History of Asthma Persistent Asthma n o i ss e gr o Pr
Inception
No Asthma
Initial Phase of Asthma
Triggers
Protection
Re mi ssi on
Intermittent Asthma
No Asthma
Hypothetical Representation of the Natural History of Asthma ICS? Inception
No Asthma
n o i s es r og r P Protection
Asthma Initial Phase
Exacerbation
Re mi ssi on
Chronic Asthma
Asthma, Not Chronic
No Asthma
CAMP Study Design Children with “mild to moderate asthma” (symptoms or use of Albuterol ≥2 times weekly or daily use of asthma medication) Treated for 4-6 years with Budesonide 200 µg bid (N=311) or Nedocromil 8 mg bid (N=312) or matching placebo Primary outcome: mean change % predicted post bronchodilator FEV1 4-6 years after initiation of treatment N Engl J Med 2000;343:1054-63
Lung Function in the CAMP Study
N Engl J Med 2000;343:1054-63
What Is The PEAK Trial? PEAK is investigating if inhaled corticosteroids (ICS), when initiated in preschool-aged children at high risk for asthma, can alter the natural history of asthma after ICS are discontinued
Childhood Asthma Research and Education Network (CARE) Clinical Centers Denver: National Jewish Medical & Research Center Madison: University of Wisconsin San Diego: University of California Kaiser Permanente California St. Louis: Washington University Tucson: University of Arizona Data Coordinating Center Hershey: Penn State University NIH Funding Agency Bethesda, MD: NHLBI
Rationale Asthma Predictive Index identifies high-risk children that will have continuation of asthmalike symptoms in school years1. ICS have been reported to reduce symptoms in high-risk young children with intermittent wheezing2,3. No effect after discontinuation of ICS on the natural course of asthma in school aged children may be due to the initiation of ICS after the occurrence of critical injurious events4. 1Castro-Rodriguez,
AJRCCM, 2000 2Teper, Ped Pulm, 2004
3Bisgaard,
AJRCCM, 1999 4CAMP Research Group, NEJM, 2000
PEAK: Study Design Screening/ Eligibility Run-in 1 month
Treatment Years 1 & 2
Randomize
Observation Year 3
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 µg/puff or placebo (2 puffs b.i.d.) Guilbert et al, NEJM 354:19; 2006
Inclusion Criteria Children 24-47 months of age Positive asthma predictive index At least 36 weeks at birth No systemic illnesses apart from asthma or allergic rhinitis > 10% for height < 4 months of inhaled corticosteroid and < 4 courses of systemic steroid in last year
Asthma Predictive Index Identify high risk children (ages 2 & 3): > 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 Atopic dermatitis Aero-allergen sensitivity
Food sensitivity • Peripheral eosinophilia (≥4%) • Wheezing not related to infection •
Modified from: Castro-Rodriguez, AJRRCM, 2000
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 including bronchodilator pre-treatment 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 132 included in Year 1 & 2 analyses
131 included in Year 3 analysis
142 in placebo group 130 included in Year 1 & 2 analyses
125 included in Year 3 analysis
Episode-free Days During the Entire Study Observation
Proportion of Episode-free Days
Treatment †
1.00
†
†
0.95 0.90 0.85 0.80 0.75
†
ICS Placebo p<0.05 p<0.01
6
12
18 24 Months
30
36
ICS Effect During Treatment Phase Asthma Exacerbations 100 80 Number per 100 child 60 years
Placebo ICS
40 20 0
P<0.001
ICS Effect During Treatment Phase Supplementary Controller Use 28 21
Placebo
Days per 14 year
ICS
7 0
ICS
P<0.001
Montelukast
P<0.001
ICS Effect on IOS Measures: Reactance at 5 Hz End of treatment
End of observation
-0.33 -0.36
Placebo ICS
-0.39 -0.42 -0.45
p=0.008
p=0.83
Growth since baseline (cm)
Low Dose ICS Impacted Growth Average height percentile:
Placebo ICS p<0.01
20 15
End of Treatment: ICS: 51.5%ile versus Placebo: 56.4%ile
10
(p = 0.0001)
5 0
0
8
16
24 30 36
Months
End of observation: ICS: 54.4%ile versus Placebo: 56.4%ile (p=0.03)
Conclusions Daily ICS are effective in preventing exacerbations and controlling symptoms in 23 yr olds at high risk for asthma However, two years of treatment with daily ICS did not change the natural history of asthma in these same children These findings question a central role of ICSsensitive inflammation in the persistence and progression of asthma