1. Asma na Infância Renato T. Stein, M.D. Pontifícia Universidade Católica Porto Alegre, Brazil

2. Respiratory System Development n More vulnerable (irritants/virus, pollutants) in the first years u Higher surface area-to-volume ratio (infants breath more air relative to body weight than older children) u Smaller airways: more deposition of particulate matter u Major lung growth period (50-70% alveoli formed after birth up to ~18 months old)

3. Infant Pulmonary Function: Prematures Reduced Lung Function in Healthy Preterm Infants in the First Months of Life Friedrich L, Stein RT, Jones MH et al. Am. J. Respir. Crit. Care Med. 2006 FVC

4. Infant Pulmonary Function: Prematures Friedrich L et al. Am. J. Respir. Crit. Care Med. 2006 FEF 25-75

5. Pulmonary Growth in Premature Infants Friedrich L, Jones MH et al.. AJRCCM 2007

6. Impact on Lung Development Allergens, pollutants, air toxics Acute severe Viral Infections

7. Different “Asthma” Phenotypes

8. Transient Wheezing by Early Lung Function % Transient Wheezing p<0.0001 Quartiles of V’max FRC at 2 months

9. Persistent Wheezing by Early Lung Function % Persistent Wheezing n.s. Quartiles of V’max FRC at 2 months

10. Lung Function over Time by Classification at Recruitment in the Melbourne Study

11. Sears et al, NEJM 349:1414 (2003)

12. FEV 1 by Age in Asthmatics and Smokers (Busselton, Australia) James et al, AJRCCM 2005, 171:109

13. Lung Function at Ages 1, 6, 11 and 16 Years in the Tucson Study Morgan WJ et al. AJRCCM 2005

14. Hypothetical Representation of the Natural History of Asthma Asthma Initial Phase Inception Exacerbation Progression No Asthma PersistentAsthma Asthma, Not Persistent No Asthma Protection Remission

15. Hypothetical Representation of the Natural History of Asthma Asthma Initial Phase Inception Exacerbation Progression No Asthma ChronicAsthma Asthma, Not Chronic No Asthma Protection Remission ICS?

16. CAMP Study Design n Children with “mild to moderate asthma” (symptoms or use of Albuterol  2 times weekly or daily use of asthma medication) n Treated for 4-6 years with Budesonide 200  g bid (N=311) or Nedocromil 8 mg bid (N=312) or matching placebo n Primary outcome: mean change % predicted post bronchodilator FEV1 4-6 years after initiation of treatment N Engl J Med 2000;343:1054-63

17. Lung Function in the CAMP Study N Engl J Med 2000;343:1054-63

18. What Is The PEAK Trial? PEAK investigated 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 Guilbert TW et al. NEJM 2006

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

20. Episode-free Days During the Entire Study TreatmentObservation Guilbert TW et al. NEJM 2006)

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

22. ICS Effect on IOS (impulse oscillometry) Measures: Reactance at 5 Hz p=0.008 p=0.83 * Greater dynamic lung compliance

23. Conclusions n Changes in airway function (remodeling?) occur early in life in asthma, with little subsequent further deterioration n Daily ICS are effective in preventing exacerbations and controlling symptoms in 2-3 yr olds at high risk for asthma n However, two years of treatment with daily ICS did not change the natural history of asthma in these same children

24. Asthma Phenotypes Stein R et al. Thorax 1997

25. Southern Brazil Study: Risk factors for Wheeze and Asthma Pereira M et al. ERJ 2007 Risk increases > 50X for children with both Bronchiolitis and Ascaris

26. 80 60 40 20 0 Sputum eosinophils x 10 5 cells/g *** Atopic asthma Non-atopic asthma No atopy/ no asthma

27. IS Neutrophil concentration in asthma phenotypes Pizzichini MM, et al. 2008

28. IMMATURE IMMUNE SYSTEM Slow TH1 Th2-driven Immunity Allergen exposure Airway Inflammation Altered Aw Function/BHR ASTHMASASTHMAS LRTI/ Bronchiolitis Airway Inflammation Altered Aw Function/BHR Intensification & low clearance ALLERGIC PATHWAY NON-ATOPIC/VIRUS PATHWAY Environment Genetic Predisposition Genetic Predisposition