HOW EFFECTIVE IS PREVENTION IN ASTHMA?

1. HOW EFFECTIVE IS PREVENTION IN ASTHMA? Dr. A. Füsun Kalpaklıoğlu

3. Environ ment Genetics Age Environmental Influences • Cigarette smoking in pregnancy increases the risk of wheezing in infancy • Allergen specific T-helper cell programming is initiated early in life and is driven by ubiquitos dietary and inhalant allergens • Early exposure to high levels of dietary allergens results in high zone tolerance • Exposure to low levels of inhalant allergens triggers low zone tolerance with weak Th1-like immunity or Th2 polarised response. • Some early respiratory infections, e.g. pertussis and RSV, may enhance IgE-sensitization • Relatively lack of early microbial exposure may enhance the development of allergic diseases. Genetics • The atopic constitution is a major risk factor for the development of IgE-sensitization • Individuals with a family history of atopy have an increased risk of developing allergic diseases • Double heredity means a four-fold, Single heredity means a two-fold risk to develop allergies • Target organ sensitivity is a familial trait • High IgE level in cord blood is specific for subsequent allergic disease but has a low sensitivity • Early signs of atopic eczema, and presence of IgE antibodies to inhalant allergens, are important risk factors for later respiratory allergy ADAM 33 gene

4. Allergens Microbes Infections Pollution Stress Cytokine response profile Environ ment Genetics Age Prevention of allergen-specific IgE response, sensitization Primary prevention Immune Response Atopy Th2 Th1 Prevention of asthma in sensitized individual Secondary prevention • Viral infections • Aeroallergens • Pollution Lower airway injury Prevention of the onset of symptoms in an asthmatic individual • Persistant inflammation • BHR • Remodelling • Lung maturation/differentiation Abnormal repair Tersiary prevention ASTHMA

5. CYTOKINE BALANCE ENVIRONMENT ENVIRONMENT

7. Breast-feeding • The association between infant feeding practices and subsequent atopy among children with a family history of asthma • A cohort of children with a family history of asthma in Sydney, Australia, was followed from birth to age 5 years. • In 516 children evaluated at age 5 years, there was no significant association between the duration of breastfeeding or timing of introduction of solid foods and protection against asthma or other allergic disease. • However, breastfeeding for 6 months or more and introduction of solid foods after 3 months were both associated with an increased risk of atopy at age 5 years. • Longer duration of breastfeeding and later introduction of solid foods did not prevent the onset of asthma. Mihrshahi S, CAPS Team. Clin Exper Allergy May 2007 Kull I, et al. JACI 2004;114:755-60.

8. The Link Between Housing & Health

9. NHLBI Report 2007

10. Effectiveness of the Mite Avoidance Intervention Asthma and Wheezing at Age 5 by Mite AvoidanceTreatment Marks et al, JACI 2006; 118:53

11. Asthma by Size of Alternaria Skin Test Responses at Age 6 in Tucson, AZ p<0.00001 % Asthma Alternaria Response

12. Hygiene Hypothesis; Lack of intense infections in industrialized countries owing to improved hygiene, vaccination, and use of antibiotics may alter the immune system such that it responds inappropriately to innocuous substances. (increased allergy/asthma)

13. Atopic disease is the price paid by some members of the white community [as opposed to native Americans in Saskatchewan, Canada] -Gerard JW, 1976

14. HYGIENE HYPOTHESIS

18. Inverse association of farm milk consumption with asthma and allergy in rural and suburban populations across Europe • Cross sectional multi-centre study (PARSIFAL) including 14 893 children aged 5–13 years from five European countries (2823 from farm families and 4606 attending Steiner Schools as well as 5440 farm reference and 2024 Steiner reference children). • Farm milk consumption ever in life showed a statistically significant inverse association with asthma. The associations were observed in all four subpopulations and independent of farm-related co-exposures. Other farm-produced products were not independently related to any allergy-related health outcome. Unpasteurized milk: health or hazard? Waser M, et al. Clin Exper AllergyMay 2007

19. Endotoxin Exposure and IgE Mediated Sensitization 1.0 0.8 0.6 Predicted probability for sensitisation P=0.005 0.4 0.2 0.0 1.0 2981 7.4 54.6 22000 162755 403.4 1.2x106 Endotoxin Load (EU/m2) Simpson et al, AJRCCM September 2006

20. Endotoxin in inner-city homes: Associations with wheeze and eczema Perzanowski M et al. JACI 2006;117:1082-9

21. Response to endotoxin increases with BMI Obesity&Asthma 1.Development in early life 2.Mechanical factors promote asthma 3.GER resulting from obesity induces asthma Alexis N et al. JACI 2006;117:1185-6

22. Data not to support the H.H. • Pets • Brussee JE et al.Allergen exposure at 3 m and • sensitization, wheeze and asthma at 4 y of age. • JACI 2005;115:946-52. • 4146 children from the Prevention and Incidence of Asthma and Mite Allergy study. • Early cat allergen exposure leads to persistent wheeze. • Early dog allergen exposure leads to persistent wheeze in children with maternal atopy.

23. Timing? Having cat before age 18 protects against adult asthma&atopy! de Meer Gea, et al. Jacı 2004;113:433-8.

24. Probiotics; beneficial microbes in the gut flora may promote maturation of the immune system away from proatopic state

25. Probiotics: Lactobacillus&Bifidobacterium Rautava S et al. JACI 2002;109:119-21

26. NHLBI Report 2007

27. ISLE OF WIGHT Arshad et al. JACI 2007;119:307-13

28. The Canadian Study: 2 years Becker, et al. JACI 2004;113:650-6

29. The Canadian Study: 7 years Chan-Yeung et al. JACI 2005;116:49-55

30. 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 Marks GB et al. JACI 2006;118:53-61

31. 成年人過敏性哮喘或鼻炎 哮喘/ 鼻炎/濕疹 鼻炎 喘嗚/ 哮喘 因食物引起的 過敏症狀 濕疹 誘發過敏 激發過程 連鎖過敏反應 (Allergy March) 若在嬰幼兒期間已誘發過敏感機制 (Sensitization)及出現過敏症狀， 他們在成長過程中可能會增加患上其他過敏症的風險 (Sarrinen U.M. & Kajosaari 1995; Bergmann RL et al. 1998 ; Host A 2001 ;Spergel JM & Paller AS 2003 ;Rhodes et al. 2001; Sampson H.A. 2003 ; Halken S 2004; Wickman M. 2005; Hahn E. & Bacharier L.B. 2005)

32. PEAK (Prevention of Early Asthma in Kids): Study Design Treatment Observation Screening/ Eligibility Run-in Year 3 1 month Years 1 & 2 Interim Efficacy Tests Randomize • Randomized, multicenter, double-blind, parallelgroup, 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.) Guilbert et al, NEJM 2006;354:1985

33. Episode-free Days During the Entire Study Observation Treatment Guilbert et al, NEJM 2006;354:1985

34. ICS Effect During Treatment Phase Asthma Exacerbations P<0.001 Guilbert et al, NEJM 2006;354:1985

35. ETAC EPAAC Warner JO et al. JACI 2001;108:929-37

36. Immunotherapy; Mechanisms IL-2 INF-g Th1 IMMUNE DEVIATION? ANERGY? BOTH? IT TCD4+ Th2 IL-4 IL-5 IL-9

37. IT: Prevention of New Sensitizations New sensitizations after 3 years: 55% SIT group vs 100% control group. Des Roches et al, JACI 1997 New sensitizations after 3 years: 25% SIT group vs 67% control group. Pajno et al, Clin Exp Allergy 2001 New sensitizations after 4 years 23% SIT group vs 68% control group. Purello D’Ambrosio et al, Clin Exp Allergy 2001

38. Specific immunotherapy prevents the development of asthma in children with allergic rhinitis (the PAT study) No asthma % Asthma 60 40 205 children with rhinitis age: 6-14 yrs grass or birch allergy 3 yrs immunotherapy 32 19 SIT CONTROL Moller C et al, JACI 2002 Niggemann et al, Allergy 2006;61:855-9

39. Asthma Treatment moderate persistent asthma intermittent asthma mild persistent asthma severe persistent asthma allergen avoidance pharmacotherapy immünotherapy

40. Reduce Exposure to Triggers

41. Encasing Mattress Halken S et al. JACI 2003;111:169-76

42. ARIA UPDATE

43. NHLBI Report 2007

44. NHLBI Report 2007

45. Asthma Treatment and Asthma Prevention: a Tale of 2 Parallel Pathways Martinez FD 2007, JACI, in press

48. Two (Provocative) Ideas • Asthma-related airway remodeling and deficits in lung function growth occur mainly during the preschool years; blocking the processes that cause these changes will drastically reduce persistent asthma • In children with mild (moderate?) persistent asthma, intermittent, SABA-linked controller therapy may be as effective as daily therapy with ICS, and will be much more acceptable for parents and children alike Martinez FD

49. Nature begins with the cause and ends with the experience; we need to operate in the reverse.-Leonardo da Vinci, 1512 THANK YOU!