prof. dr. u. wahn prevention of asthma in childhood ulrich wahn department of pediatric pneumology...
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Prof. Dr. U. Wahn
Prevention of asthma in Prevention of asthma in childhoodchildhood
Ulrich Wahn
Department of Pediatric Pneumology and Immunology
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Possible opportunities
• Allergen avoidance• Preventative Pharmakotherapy in high risk
groups a) Cetirizin/Levocetiricinb) Desloratadinc) Pimecrolimus
• Spec. Immunotherapy in pollen allergic children
• SLIT in high risk infants• Primary prevention by modification of
infant nutrition
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Allergen avoidace
• Dust mites
• Pets
• Novel tools
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Sensitisation to House Dust Stratified by Highestand Lowest Quartiles of House-Dust-Mite
Exposure at Age 6 Months
1 6
1 4
1 2
1 0
8
6
4
2
00 1 2 3 4 5 6 7
A ge (years )
F irs t quart ile(<0 .002-0 .032 g /g )
F ourth quart ile(0 .981-240 g /g )
Pro
po
rtio
n (%
) o
f ch
ildre
nse
nsi
tise
d to
mite
s
p< 0 .01
p< 0 .001
p< 0 .0001
Lau e t a l, La nce t 2000 ;356 :1392-7
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Prevalence of current wheeze from Prevalence of current wheeze from birth to age 13 yearsbirth to age 13 years
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7 8 9 10 11 12 13
Age (years)
Wheezing at school age (5–7 years)
Illi S, et al. Lancet 2006
Non-atopic Atopic
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Early sensitization and allergenEarly sensitization and allergenexposure to perennial allergens* andexposure to perennial allergens* and
lung function at school agelung function at school age
p=0.020
p=0.003
FEV1
(% FVC)
p=0.018
p=0.003
p=0.001
p=0.025
p<0.001
Not sensitized Sensitized/low exposure
Sensitized/high exposure
Mean±SD160
140
120
100
80
60
40
20
0FEV1
(% predicted)MEF75
(% predicted)MEF50
(% predicted)MEF25
(% predicted)FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; MEF = maximal expiratory flow *Sensitization/exposure to mites and/or cats up to the age of 3 years
Illi S, et al. Lancet 2006
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Parental smoking and sensitizationParental smoking and sensitization
27,7
Mother smoked regularly
Mother smoked irregularly
Only father smoked
Adj. OR and 95%CI
1 atopic parent
No atopic parents
2 atopic parents
0,8
1,71,3
1
2,9
1,1
1,8
7
1,2
0
10
1 atopic parent
No atopic parents
2 atopic parents
1 atopic parent
No atopic parents
2 atopic parents
T. Keil et al, Allergy Allergy. 2010 Apr;65(4):482-90
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Laminar airflow systems Laminar airflow systems
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Pharmacotherapeutic attempts
• Cetiricin/Levocetericin• Desloratadin• Pimecrolimus
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EPAAC™ : Percentage of Subjects Who Developed Asthma
at the end of the 18 Month Treatment Period
% o
f su
bjec
ts w
ho d
evel
oped
as
thm
a
0
20
40
60
80
100
Placebo (n=252)Levocetirizine (n=252)
No significant differences between treatments
37.3%36.5%
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Specific Immunotherapy in Specific Immunotherapy in pollen allergic childrenpollen allergic children
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Clinical efficacy of immunotherapyClinical efficacy of immunotherapy
• Early effect– reduction in symptoms/need for medication
• Progressive effect– reduction in symptoms/need for medication– reduction in hyperresponsiveness/late phase response
• Persistent effect– long-term reduced symptoms/need for medication– long-term reduced hyperresponsiveness/late phase
response
• Preventive effect– prevention of new sensitivities and exacerbation of
disease (rhinitis into asthma)
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Probability of New Onset of Wheeze in Probability of New Onset of Wheeze in children with and without atopychildren with and without atopy
Rochat et al, JACI 2010; 126: 1170-1175
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The PAT studyThe PAT study
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1 2 3 5 10
SIT
Follow up Follow up
Möller et al. J Allergy Clin.Immunol. 2002;109:251-6.
Maintenance dose: Grass: 20 µg Phl p5Birch: 13 µg Bet v1
PAT Study Period
In print, Allergy 2006 AAAAI, 2006
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Demographic data at inclusionDemographic data at inclusion
All included No asthma Asthma ***
Number 208 (205)* 163 42
Mean age (range) 10.7 (6-15) 10.7 (6-15) 10.6 (6-14)
Sex M/F 138/70 (137/68)* 108/55 29/13
Mean years with
hay fever (range)
4.7(1-15)**
N=171
4.6(1-15)**
N=137
4.9(1-9)**
N=34
Methacholine PC20
Mean (range)
10.8 (0.03-16)
12.2 (0.16-16)
5.1 (0.03-16)
Control/SIT f. 3 years 94/97 72/79 22/18
* Three patients dropped out of before baseline monitoring season (0 – season)** Only patients with reliable information’s included*** Mild seasonal asthma during first season before randomization
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Patients included205
Control group102
SIT group103
Continued for 3 years as controls
94
Continued for 3 years on SIT
97
Patient flowPatient flow
Follow up at 5 years83
Follow up at 5 years 95
Follow up at 10 years68
Follow up at 10 years 79
Asthma: 42
Asthma: 40
Asthma: 36
Asthma: 30
Total follow up at 10 years: 147
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P<0.001 P<0.001 P<0.001
1 2 3 5
P<0.001
Conjunctival provocation testConjunctival provocation testC
ha
ng
e f
rom
ba
se
lin
e (
2 x
lo
g S
Q)
P<0.05
100
0,5
1
1,5
2
2,5
3
Year
Control
Active
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Rhinitis: Rhinitis: Change from baseline Change from baseline
(Visual analogue scores)(Visual analogue scores)
P=0.01 P<0.001 P<0.0001 P<0.0001
1 2 3 5 10
P<0.05
Means adjusted for baseline difference
-30
-15
0
15
30
Year
Mea
n V
AS
Sco
re
Control
Active
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Development of asthma at 3 yearsDevelopment of asthma at 3 yearsN=151 (patients without asthma in season one)N=151 (patients without asthma in season one)
0102030405060708090
100
SIT Control
% o
f p
tt.
No asthma Asthma
N=60
N=19
N=40
N=32
Odds-ratio = 2.52(1.3 – 5.1)
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0102030405060708090
100
SIT Control
% o
f p
tt.
No asthma Asthma
N=60
N=15
N=38
N=29
Odds-ratio = 2.68(1.3 – 5.7)
Development of asthma at 5 yearsDevelopment of asthma at 5 yearsN=142 (patients without asthma in season one)N=142 (patients without asthma in season one)
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0102030405060708090
100
SIT Control
% o
f p
tt.
No asthma Asthma
N=48
N=16
N=29
N=24
Odds-ratio = 2.48(1.2 – 5.4)
Development of asthma at 10 yearsDevelopment of asthma at 10 yearsN=117 (patients without asthma in season one)N=117 (patients without asthma in season one)
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GAP-StudyGAP-Study
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Sublingual allergen applicationSublingual allergen application
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SLIT in high risk infantsSLIT in high risk infants
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Recent evidence from high dose SLIT trials opens new avenues for early intervention studies in infants and
young children
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3,0 4,0 4,22,11,4
Onset = 2,575 molYears/mol = 4,1
to be adjusted by AGE AT ONSET!!!
Titolo del grafico
y = 0,2448x + 2,575
R2 = 0,8899
0
1
2
3
4
5
6
-9 -6 -3 0 3 6 9 12
Number of Phl p molecules recognized by IgE in 79 children with SARby time from the onset of symptoms
pre-clinical clinicallateearlyOnset
ComponentResolved
ProphylaxisCRP
early simplified(es-CRT)
(too) complexlate CRT
confidential
10-15 kU/lIgE to g6
2.5 – 3 molecules
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Prophylaxis of atopy Prophylaxis of atopy and asthma in children (ITN)and asthma in children (ITN)
• Inclusion criteria:Children 12 – 30 months of age (n=200)Atopic dermatitis, sensitisation to food No sensitisation to aeroallergensPositive family history for atopy/asthma
• Primary end points:Allergic sensitisation
• Secondary end points:Current asthma 3 years after the end of intervention
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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
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Parental Phenotypes
Infantile Phenotypes
Atopy/Asthma Atopy/Asthma
AD Wheeze
Food Sensitization
Perennial aero-
sensitization
Food Sensitization
Perennial aero-
sensitization
Persistent asthma
in adolescene
Filaggrin Mutation
Filaggrin Mutation
The child at risk for asthmaThe child at risk for asthma
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What are the studies we What are the studies we need?need?
1. Allergen-specific SLIT in young children at high risk for asthma with established sensitization to house dust mite
2. Allergen-specific mucosal tolerance induction at high risk for asthma prior to aeroallergen sensitization
3. Asthma prevention studies in established disease of the upper airways
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Primary prevention by Primary prevention by modifcation of infant nutritionmodifcation of infant nutrition
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Conclusion
• Asthma prevention: challenge for pediatric allergist
• Asthma prediction in high risk infants possible• Results of allergen avoidance strategies and
pharmacotherapeutic interventions not very encouraging
• Primary prevention in infance not sucessful• Immunotherapeutic interventions probably more
promissing