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Prevention of Atopic Diseases in Children: Strategies and Interventions

This study explores preventive strategies for atopic diseases in children, including primary prevention in high-risk infants, secondary prevention in infants with early wheeze or atopic dermatitis, and disease modification in school-aged children. It highlights the role of breastfeeding, diet, probiotics, and avoidance of tobacco smoke exposure. The study also examines the impact of certain factors such as regionality, farming, microbial flora, and migration on atopic disease prevalence.

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Prevention of Atopic Diseases in Children: Strategies and Interventions

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

  2. EPAAC Atopic Dermatitis Severity (SCORAD)

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

  4. 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 non-atopic Wheezing at school age (5–7 yrs): atopic Age (in years) S. Illi et al., Lancet 2006 MAS-90

  5. 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

  6. Target Groups for prevention:The windows of opportunity PrimaryPrevention (no clinical signs) in highrisk or low risk infants (1 – 6 months) Secondaryprevention (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 Diseasemodification (school age) Children with SAR

  7. The child at risk for asthma Candiates for preventive intervention Parental Phenotypes Atopy/Asthma Atopy/Asthma SpecificGeneMutation SpecificGeneMutation AD Wheeze InfantilePhenotypes Food Sensitization Food Sensitization Perennial aero-sensitization Perennial aero-sensitization Persistent asthmain adolescene

  8. 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!

  9. 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

  10. Saarinen UM et al. Prolonged breast-feeding as prophylaxis for atopic disease.Lancet 1979; 2:163-166Saarinen UM et al. Breast-feeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old.Lancet 1995; 346:1065-1069

  11. van Odijk J et al. Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966-2001) on the mode of early feeding in infancy and its impact on later atopic manifestations.Allergy 2003; 58:833-843

  12. 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

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

  14. Model Population Proposed protective factors Regionality Former East Germany Common colds in infancy Farming Lifestock Farming Unpasteurized milkendotoxin in dust Anthroposophy Antropos. Pupils Infections ?microbial flora? avoidance of vaccines/antibiotics? Migration Migrants ??? Populations with low susceptibility for atopy

  15. 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

  16. 5 Modified LPS ISS-ODN (CpG motifs) 4 BACTERIAL MOLECULES PAMPs Pathogen Associated Molecular Patterns (interaction with PRR)

  17. Protective „farm-effect“ PARSIFAL study population n=285/ 2086 Atopic sensitisation Current farm exposure 0.96 (0.63-1.46) p=0.854 Regular contact with farm animals ever 0.76 (0.51-1.15) p=0.194 Farm milk consumption ever 0.76 (0.52-1.11) p=0.162 Stable exposure in pregnancy0.58 (0.39-0.86) p=0.007 Ege. J. Allergy Clin. Immunol. 2006; 117: 817.

  18. The effect of farm milk consumption on asthma Bieli Ch., JACI 2007; 120: 1308-1315

  19. Intervention strategies:The „protective factor“ concept

  20. Rationale 1995-98 to increase gut “barrier” 1999-2000 stimulate TH1 to suppress TH2 2000-….. stimulate T reg & cytokines aspecific immunomodulation “Probiotic Bacteria”: Lactobacilli & Bifidobacteria

  21. Mouse Model LPS Aerosol LPS Aerosol OVA i.p. OVA Aerosol Day -21 -14 -7 0 1 25 28 42 56 57 58 60 Mother Offspring Birth IgE  Eosinophilic AI AR  • 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.

  22. Treatment phase of human intervention study Bacterial lysates of E. coli / Strept. faecalisp.o. AD 635 Infants Atopic Background Placebop.o. • Primary outcome within treatment phase • Effect of oral bacterial compounds on 1 2 3 4 5 6 7 Month of Life • atopic eczema • sensitisation to food allergens

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

  24. Prebiotic prevention study team

  25. p=0.0469 p=0.082 p=0.0153 p=0.0109 39 32 20 23 20 19 15 10 5 4 3 1 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.

  26. Incidence of Atopic Dermatitis (MIP-Study) Time to first occurrence of AD significantly different between both formula groups according 2-sided logrank test:p=0.0411 Control(N=39) BF (n=20) Prebiotic formula(N=23)

  27. Prophylaxis of atopy and asthma in childrenImmune 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

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

  29. Helminth therapy for Crohn’s Disease 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. Joel Weinstock Trichuris suis eggs Summers R. Gastroenterology, 2005;128:825-832

  30. 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

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

  32. 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

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

  34. Acknowledgement Berlin:S. LauR. NickelR. BergmannC. GrüberP. MatricardiB. NiggemannT.KeilPartners:S. IlliE. von MutiusC.P. BauerJ. ForsterV. WahnW. Kamin EPAAC-Cohort:J.O. WarnerA. Huret (Business Effisciences)EPAAC Board and study groupMIPS-Cohort:J. JelinekG. BoehmMIPS-study group ITN-Cohort:P. HoltP. SlyB. BjorkstenH. Sampson

  35. 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

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