Prof. Dr. U. Wahn

How can we preventHow can we prevent

U. Wahn

Department of Pediatric Pneumology and Immunology

EPAAC Atopic Dermatitis Severity (SCORAD)

Atopic Dermatitis Severity (SCORAD)

0

10

20

30

40

0 1 3 6 9 12 15 18

Months

Sc

ora

d S

co

re

Placebo

Lctz

0

1

10

100

1 2 3 5 6

Sp

ecif

ic I

gE

(kU

/l)

Years

Cow's milk

0

1

10

100

1 2 3 5 6

Sp

ec

ific

IgE

(k

U/l)

Years

Birch

Natural course of sIgE concentrations

(Kulig et al, JACI 1999)

Natural course of sIgE concentrationsNatural course of sIgE concentrations

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

0

10

20

30

40

50

60

70

80

1 2 3 4 5 6 7 8 9 10 11 12 13

Age (in years)

Wheezing at school age (5–7 yrs): non-atopic atopic

S. Illi et al., Lancet 2006

Early sensitisation and allergen exposure to perennial

allergens * and lung function at school age

0

20

40

60

80

100

120

140

160

FEV1 (% pred) MEF75 (% pred) MEF50 (% pred) MEF25 (% pred)

p = 0.020

p = 0.003

FEV1 (% FVC)

p = 0.018

p = 0.003

p = 0.001

p = 0.025

p < 0.001

not sensitised sensitised / low exposure sensitised / high exposure

Mea

n +

/–

SD

* Sensitisation / exposure to mites and/or cats up to the age of 3 yearsMAS-90

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

Parental Phenotypes

Infantile Phenotypes

Atopy/Asthma Atopy/Asthma

AD Wheeze

Food Sensitization

Perennial aero-

sensitization

Food Sensitization

Perennial aero-

sensitization

Persistent asthma

in adolescene

SpecificGeneMutation

SpecificGeneMutation

The child at risk for asthma The child at risk for asthma Candiates for preventive interventionCandiates for preventive intervention

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!

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

Saarinen UM et al. Prolonged breast-feeding as prophylaxis for atopic disease.

Lancet 1979; 2:163-166

Saarinen UM et al. Breast-feeding as prophylaxis against atopic disease:

prospective follow-up study until 17 years old.

Lancet 1995; 346:1065-1069

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

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

0

5

10

15

20

25

0 1. Year 2. Year 3. Year

KMF pHF-MeHF-M eHF-C

Cumulative Incidence of ADCumulative Incidence of AD

%

*p < 0.05 für pHF-M and eHF-C vs KMF

*

*

*

*

**

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

Prevalence of Hay Fever (A), Hay Fever Symptoms (B), and Prevalence of Hay Fever (A), Hay Fever Symptoms (B), and Atopic Sensitization (C) in Relation to Endotoxin-LoadAtopic Sensitization (C) in Relation to Endotoxin-Load

N Engl J Med 2002; 347 (12):869-77

BACTERIAL MOLECULES

ISS-ODN (CpG motifs)

4

Modified LPS 5

PAMPs

Pathogen Associated Molecular Patterns (interaction with PRR)

Protective „farm-effect“Protective „farm-effect“

Ege. J. Allergy Clin. Immunol. 2006; 117: 817.

PARSIFAL study population n=285/ 2086 Atopic sensitisation

Current farm exposure 0.96 (0.63-1.46) p=0.854Regular contact with farm animals ever 0.76 (0.51-1.15) p=0.194Farm milk consumption ever 0.76 (0.52-1.11) p=0.162Stable exposure in pregnancy 0.58 (0.39-0.86) p=0.007

The effect of farm milk consumption on The effect of farm milk consumption on asthmaasthma

Bieli Ch., JACI 2007; 120: 1308-1315

Intervention strategies: The „protective factor“ concept

“Probiotic Bacteria”: Lactobacilli & Bifidobacteria

Rationale

1995-98 to increase gut “barrier”

1999-2000 stimulate TH1 to suppress TH2

2000-….. stimulate T reg & cytokines

aspecific immunomodulation

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-betGerhold et al. J. Allergy Clin. Immunol. 2006; 118: 666.

LPS Aerosol

-7-14-21 0DayMother

Birth

OVA i.p.

605758

OVA Aerosol

Offspring

1 25 28

LPS Aerosol

42 56

IgE Eosinophilic AI

AR

Treatment phase of human intervention studyTreatment phase of human intervention study

Primary outcome within treatment phase

Effect of oral bacterial compounds on

atopic eczema

sensitisation to food allergens

635 InfantsAtopic Background

Bacterial lysates of E. coli / Strept. faecalis p.o.

1 2 3 4 5Month of Life 6

ADPlacebo p.o.

7

Synbiotics

living bacteriain 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

Prebiotic prevention study teamPrebiotic prevention study team

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.

0

2

4

6

8

10

12

8 16 24 52

Weeks of life

(%)

Total Active (n=414) Total Control (n=416) Total Breast (n=300)

35

1

15

20

4

19

32

10

23

39

20

p=0.0469

p=0.082

p=0.0153

p=0.0109

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

BF (n=20)

Control(N=39)

Prebiotic formula(N=23)

Prophylaxis of atopy and asthma Prophylaxis of atopy and asthma in childrenin children

Immune Tolerance Network (NIH)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

Enrolment Randomisation(n=200)

(age 12 – 30 month)

(Cat, house dust mites, grass)Allergens

Placebo

EndpointAssessment

(ITT/ PP)

12 months of oral application

Follow-up

Study DesignStudy Design

Helminth therapy for Crohn’s Disease

Summers R. Gastroenterology, 2005;128:825-832

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.

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

Trichuris Suis Ova

• Appears to help restore proper immune function in autoimmune disorders (Crohn‘s disease)

• Appears to have no side effects

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

Specific immunotherapy and asthma prevention in children

Niggemann et al. Allergie 2006, 61, 855

Acknowledgement

Berlin:S. LauR. NickelR. BergmannC. GrüberP. MatricardiB. NiggemannT.Keil

Partners:S. IlliE. von MutiusC.P. BauerJ. ForsterV. WahnW. Kamin

EPAAC-Cohort:J.O. WarnerA. Huret (Business Effisciences)EPAAC Board and study group

MIPS-Cohort:J. JelinekG. BoehmMIPS-study group

ITN-Cohort:P. HoltP. SlyB. BjorkstenH. Sampson

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