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Prof. Dr. U. Wahn How can we prevent U. Wahn Department of Pediatric Pneumology and Immunology.

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Presentation on theme: "Prof. Dr. U. Wahn How can we prevent U. Wahn Department of Pediatric Pneumology and Immunology."— Presentation transcript:

1 Prof. Dr. U. Wahn How can we prevent U. Wahn Department of Pediatric Pneumology and Immunology

2

3 EPAAC Atopic Dermatitis Severity (SCORAD)

4 Natural course of sIgE concentrations (Kulig et al, JACI 1999) Natural course of sIgE concentrations

5 Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at schoolage (5 – 7 yrs), stratified for atopy at schoolage MAS-90 Age (in years) Wheezing at school age (5–7 yrs): non-atopic atopic S. Illi et al., Lancet 2006

6 Early sensitisation and allergen exposure to perennial allergens * and lung function at school age * Sensitisation / exposure to mites and/or cats up to the age of 3 years MAS-90

7 Target Groups for prevention: The windows of opportunity  Primary Prevention (no clinical signs) in high risk or low risk infants (1 – 6 months)  Secondary prevention (6 – 36 months) in infants/young children with a) early wheeze b) atopic dermatitis c) sensitization to egg/milk d) early sensitization to indoor allergens e) combination of risk factors  Disease modification (school age) Children with SAR

8 Parental Phenotypes Infantile Phenotypes Atopy/Asthma ADWheeze Food Sensitization Perennial aero- sensitization Food Sensitization Perennial aero- sensitization Persistent asthma in adolescene Specific GeneMutation The child at risk for asthma Candiates for preventive intervention

9 Combining family history and early phenotypes with specific gene mutations may help to identify the child with persistant asthma within the first year of life Prediction instead of risk assessment!

10 Primary prevention Diet in early infancy - breast milk - hypoallergenic formulae (high risk!) - probiotics (lactobacilli) - prebiotic formula (low risk and high risk!) Avoidance of tobacco smoke exposure

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12 Saarinen UM et al. Prolonged breast- feeding as prophylaxis for atopic disease. Lancet 1979; 2: Saarinen UM et al. Breast-feeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old. Lancet 1995; 346:

13 van Odijk J et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature ( ) on the mode of early feeding in infancy and its impact on later atopic manifestations. Allergy 2003; 58:

14 Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: Three-year results of the German Infant Nutritional Intervention Study Andrea von Berg et al. J Allergy Clin Immunol, 2007;119:718-25

15 Cumulative Incidence of AD Cumulative Incidence of AD % *p < 0.05 für pHF-M and eHF-C vs KMF * * * * * *

16 ModelPopulationProposed protective factors RegionalityFormer East Germany Common colds in infancy FarmingLifestock FarmingUnpasteurized milk endotoxin in dust AnthroposophyAntropos. PupilsInfections ? microbial flora? avoidance of vaccines/antibiotics? MigrationMigrants??? Populations with low susceptibility for atopy

17 Prevalence of Hay Fever (A), Hay Fever Symptoms (B), and Atopic Sensitization (C) in Relation to Endotoxin-Load N Engl J Med 2002; 347 (12):869-77

18 BACTERIAL MOLECULES ISS-ODN (CpG motifs) 4 Modified LPS 5 PAMPs Pathogen Associated Molecular Patterns (interaction with PRR)

19 Protective „farm-effect“ Ege. J. Allergy Clin. Immunol. 2006; 117: 817. PARSIFAL study population n=285/ 2086 Atopic sensitisation Current farm exposure0.96 ( )p=0.854 Regular contact with farm animals ever0.76 ( )p=0.194 Farm milk consumption ever0.76 ( )p=0.162 Stable exposure in pregnancy0.58 ( )p=0.007

20 The effect of farm milk consumption on asthma Bieli Ch., JACI 2007; 120:

21 Intervention strategies: The „protective factor“ concept

22 “Probiotic Bacteria”: Lactobacilli & Bifidobacteria Rationale to increase gut “barrier” stimulate TH1 to suppress TH …..stimulate T reg & cytokines aspecific immunomodulation

23 Mouse Model  Prenatal initiation of exposure to LPS via the airways –inhibited allergen-mediated sensitisation and airway inflammatory responses in the offspring associated with increased expressions of –LPS receptors –Th1-controlling transcription factor T-bet Gerhold et al. J. Allergy Clin. Immunol. 2006; 118: 666. LPS Aerosol Day Mother Birth OVA i.p OVA Aerosol Offspring LPS Aerosol 4256 IgE  Eosinophilic AI  AR 

24 Treatment phase of human intervention study  Primary outcome within treatment phase  Effect of oral bacterial compounds on  atopic eczema  sensitisation to food allergens 635 Infants Atopic Background Bacterial lysates of E. coli / Strept. faecalis p.o Month of Life 6 AD Placebo p.o. 7

25 Synbiotics living bacteria in the food Probiotics % survival ? activity ? excretion active exogeneous bacteria neutral HMOS (GOS/FOS) Prebiotics fermentation in the colon promotion of active endogeneous beneficial bacteria Prebiotic, Probiotic and Synbiotic Food

26 Prebiotic prevention study team

27 Cumulative Incidence of Atopic Dermatitis Group differences develop slowly during study period. Development for BF infants delayed. As numbers are low, significance between formula groups is reached only after 1 year p= p=0.082 p= p=0.0109

28 Incidence of Atopic Dermatitis (MIP-Study) Time to first occurrence of AD significantly different between both formula groups according 2-sided logrank test: p= BF (n=20) Control (N=39) Prebiotic formula (N=23)

29 Prophylaxis of atopy and asthma in children Immune Tolerance Network (NIH) Inclusion criteria: Children 12 – 30 months of age (n=200) Atopic dermatitis, sensitisation to food No sensitisation to aeroallergens Positive family history for atopy/asthma Primary end points: Allergic sensitisation Secondary end points: Current asthma 3 years after the end of intervention

30 Enrolment Randomisation (n=200) (age 12 – 30 month) (Cat, house dust mites, grass) Allergens Placebo Endpoint Assessment (ITT/ PP) 12 months of oral application Follow-up Study Design

31 Helminth therapy for Crohn’s Disease Summers R. Gastroenterology, 2005;128: Trichuris suis eggs Joel Weinstock Randomized, DBPC trial in 54 patients with active colitis, randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks.

32 Trichuris Suis Ova Porcine whipworm; very similar to human whipworm, but does not reproduce in humans Eggs hatch, populate human gut for 2 – 3 weeks, then die Can be extracted from pathogen-free pigs Present in large numbers in farming communities

33 Trichuris Suis Ova Appears to help restore proper immune function in autoimmune disorders (Crohn‘s disease) Appears to have no side effects

34 THE PAT STUDY Denmark:A. Høst, S. Halken Sweden:C. Møller, S. Dreborg, H.A. Ferdousi Finland:E. Valovirta Austria:R. Urbanek, D. Koller Germany:U. Wahn, B. Niggemann ALK: S. Sparholt, H. Løwenstein, L. Jacobsen, Monitor: Lotte Askevig Statistics: Jannik Godt

35 Specific immunotherapy and asthma prevention in children Niggemann et al. Allergie 2006, 61, 855

36 Acknowledgement Berlin: S. Lau R. Nickel R. Bergmann C. Grüber P. Matricardi B. Niggemann T.Keil Partners: S. Illi E. von Mutius C.P. Bauer J. Forster V. Wahn W. Kamin EPAAC-Cohort: J.O. Warner A. Huret (Business Effisciences) EPAAC Board and study group MIPS-Cohort: J. Jelinek G. Boehm MIPS-study group ITN-Cohort: P. Holt P. Sly B. Bjorksten H. Sampson

37 Funding German Ministry of Education and Research (BMBF) German Research Foundation (DFG) Ga2len (EU-Network of Excellence, 7th framework program) Numico Research, Wageningen NL UCB Pharma

38 Statistical Method

39 Five-year follow-up on the PAT study Niggemann et al. Allergie 2006, 61, 855

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41 Ongoing studies for secondary prevention: Bacterial lysates Mucosal tolerance induction by aeroallergens


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