Transcript The window of opportunity

How can we prevent
Prof. Dr. U. Wahn
U. Wahn
Department of Pediatric
Pneumology and Immunology
EPAAC Atopic Dermatitis Severity
(SCORAD)
Atopic Dermatitis Severity (SCORAD)
Scorad Score
40
30
Placebo
20
Lctz
10
0
0
1
3
6
9
Months
12
15
18
Specific IgE (kU/l)
Natural course of sIgE concentrations
100
Cow's milk
10
1
0
1
Specific IgE (kU/l)
100
2
3
5
2
3
5
Years
6
Birch
10
1
0
1
Years
6
(Kulig et al, JACI 1999)
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
80
non-atopic
Wheezing at school age (5–7 yrs):
atopic
70
60
50
40
30
20
10
0
1
MAS-90
2
3
4
5
6
7
8
Age (in years)
9
10
11
12
13
S. Illi et al., Lancet 2006
Early sensitisation and allergen exposure to perennial
allergens * and lung function at school age
160
not sensitised
sensitised / low exposure
p = 0.003
140
p = 0.018
p < 0.001
120
Mean + /– SD
sensitised / high exposure
p = 0.001
p = 0.020
p = 0.003
p = 0.025
100
80
60
40
20
0
FEV1 (% FVC)
MAS-90
FEV1 (% pred)
MEF75 (% pred)
MEF50 (% pred)
MEF25 (% pred)
* Sensitisation / exposure to mites and/or cats up to the age of 3 years
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
The child at risk for asthma
Candiates for preventive intervention
Parental
Phenotypes
Atopy/Asthma
Atopy/Asthma
Specific
GeneMutation
Infantile
Phenotypes
Specific
GeneMutation
AD
Wheeze
Food
Sensitization
Food
Sensitization
Perennial
aerosensitization
Perennial
aerosensitization
Persistent
asthma
in adolescene
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 breastfeeding 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
Cumulative Incidence of AD
%
25
KMF
eHF-M
pHF-M
eHF-C
20
15
*
10
*
5
*
*
*
*
0
0
1. Year
2. Year
*p < 0.05 für pHF-M and eHF-C vs KMF
3. Year
Populations with low susceptibility for atopy
Model
Population
Regionality
Farming
Former East
Germany
Lifestock Farming
Anthroposophy
Antropos. Pupils
Migration
Migrants
Proposed protective
factors
Common colds in infancy
Unpasteurized milk
endotoxin in dust
Infections ?
microbial flora?
avoidance of
vaccines/antibiotics?
???
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
BACTERIAL
MOLECULES
Modified LPS 5
ISS-ODN (CpG motifs)
4
PAMPs
Pathogen Associated Molecular Patterns (interaction with PRR)
Protective „farm-effect“
PARSIFAL study population
n=285/ 2086
Current farm exposure
Regular contact with farm animals ever
Farm milk consumption ever
Stable exposure in pregnancy
0.96 (0.63-1.46)
0.76 (0.51-1.15)
0.76 (0.52-1.11)
0.58 (0.39-0.86)
Atopic sensitisation
p=0.854
p=0.194
p=0.162
p=0.007
Ege. J. Allergy Clin. Immunol. 2006; 117: 817.
The effect of farm milk consumption on
asthma
Bieli Ch., JACI 2007; 120: 1308-1315
Intervention strategies:
The „protective factor“ concept
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
Mouse Model
LPS Aerosol
Day -21 -14 -7
Mother
0
Birth
LPS Aerosol
1
Offspring
OVA i.p.
25 28
42
OVA Aerosol
56 57 58 60
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.
Treatment phase of human intervention study
Bacterial lysates of
E. coli / Strept. faecalis p.o.
635 Infants
Atopic Background
Month of Life
1
AD
Placebo p.o.
2
3
4
5
6
7
 Primary outcome within treatment
phase

Effect of oral bacterial compounds on
 atopic eczema
 sensitisation to food allergens
Prebiotic, Probiotic and Synbiotic Food
Probiotics
Synbiotics
living bacteria
in the food
Prebiotics
neutral HMOS
(GOS/FOS)
% survival ?
activity ?
active
exogeneous
bacteria
excretion
promotion of
active endogeneous
beneficial bacteria
fermentation
in the colon
Prebiotic 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 Cumulative
after 1 year.
Incidence of Atopic Dermatitis (FAS)
12
p=0.0469
10
p=0.082
p=0.0153
(%)
8
6
p=0.0109
39
32
20
4
23
20
15
2
0
19
3
5
8
10
4
1
16
24
52
Weeks of life
Total Active (n=414)
Total Control (n=416)
Total Breast (n=300)
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)
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
Study Design
Allergens
Enrolment
(Cat, house dust mites, grass)
Endpoint
Assessment
Randomisation
(n=200)
(age 12 – 30 month)
Placebo
12 months of
oral application
(ITT/ PP)
Follow-up
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
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:
Sweden:
Finland:
Austria:
Germany:
A. Høst, S. Halken
C. Møller, S. Dreborg, H.A. Ferdousi
E. Valovirta
R. Urbanek, D. Koller
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. 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
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