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Management of paediatric respiratory allergy

Speaker: Ulrich Wahn

29 September 2012


Ulrich Wahn

Management of Pediatric Respiratory Allergy Prof. Dr. U. Wahn Ulrich Wahn CharitĂŠ, Berlin, Germany


Disclosures: Ulrich Wahn, Charite, Berlin, Germany • Lecture Fee: Allergopharma, Stallergenes, ALK-Abello, MSD, Danone, Novartis • Industry-sponsored grant: Danone, Hipp, Symbiopharm, FAES • Consultancy: ALK-Abello, Danone, MSD


Period Prevalence

Prevalence of atopic eczema during the last 12 months according to age and sex

Male

Male

Female

Female

Age (years)


Period Prevalence

Prevalence of asthma during the last 12 Results months according to age and sex

Male Female

Age (years)


Prevalence of specific allergic sensitization measured in serum (n=612) Aeroallergens

Prevalence (95% CI)

Prevalence (95% CI)

Foods

Age (years)

Age (years)

-o- Timothy grass -o- Dust mites -o- Birch -o- Cat -o- Dog

-o- Cows milk -o- Hens egg -o- Soy -o-Wheat


Prevalence of current wheeze from birth to age 13 years in children with any wheezing episode at school age (5–7 years), stratified for atopy Wheezing at school age (5–7 years)

80

Non-atopic

Atopic

70 60 50 40 30 20 10 0 1

2

3

4

5

6

7

8

9

10

11

12

13

Age (years) Illi S, et al. Lancet 2006


Intermittent and Persistent AR in Children Children With 1 or 2 Allergic Parents (n = 218)

50 40 30 8

20 10 0

1 2 3

1 5 2

2 4 1

2 2 1

3

4

5

6

7

4 2 2

6 4 3

5 2

6 2 1

7

8

9

10

6

6

15

6 2

6 1

1

11

12

13

Children with AR symptoms (%)

Children with AR symptoms (%)

Children Without Allergic Parents (n = 218)

Age in years

Age in years Intermittent AR Persistent AR (mild) Persistent AR (severe) Keil et al. PAI 2010;21:962-9.


Incidence of asthma in children with or without atopic manifestations

Rochat et al, JACI 2010


Early sensitization to grass pollen allergens and probability to be symptom free during consecutive seasons 1.00 0.90 0.80

p <0.001

Probability (%)

0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 0

1

2

3

4

5

6

7

8

9

10

11

years of follow up Number at risk igegrass3y = 0- 439 439 428 420 414 402 394 384 368 355 332 Grass pollen IgE igegrass3y = 1 37 37 29 22 19 13 12 12 12 12 12 Grass pollen IgE+ Grass pollen IgE -

Grass pollen IgE +

Hatzler et al, JACI, 2012

0 0


Current strategies in Allergology

• • • •

Allergen avoidance Pharmacotherapy Immunotherapy Prevention/Tolerance induction


The Sun, 29.11.11

17


Nocturnal temperatue controlled laminar airflow for treating atopic asthma: a randomised controlled trial Boyle et al. Thorax 2011;200665

18


Aim of Antiallergic Pharmacotherapy • Rhinitis: 8-20% reduction of seasonal symptoms • Asthma: Reduction of number of exacerbations, improved control • Atopic dermatitis: Control until spontaneous improvement • Urticaria: 100 % control of symptoms (!)


Antihistamines ± INS For SAR Baseline TSS

Mean Reduction (±SD) in TSS

0 -1

14.3

14.2

14.4

14.6

MFNS

MFNS

Loratadine

Placebo

+

-2

Loratadine

-16%

-3

-23%

-4 -5

-6

-32%† -35%*

-2.7 (±4.2)

-3.8 (±4.2)

-4.8 (±4.7)

-5.4 (±4.8)

*P<0.01 vs loratadine and placebo vs loratadine and P<0.01 vs placebo

†P=0.03

Anolik et al. Ann Allergy Asthma Immunol. 2008;100:264-271


Rationale for Anti-IgE IgM

APC

Anti-IgE

IgG

Clinical effects

B-cell

IgE

T-cell

B-cell Mast cell Basophil Eosinophil? Macrophage?


Seasonal Variation of wheeze in asthmatic children with or without omalizumab Days with symptoms

Number of exacerbations

Dose of topical steroids during study period Busse WW, NEJM, 2011;364: 1005-1015


Allergic airway disease

Multiple Allergies

Monospecific Allergy

Trees Trees

Grasses

Ragweed

Active Vaccination (SLIT/SCIT)

+ Grasses

+ Ragweed

• Anti-IgE? • Combination of anti-IgE and SIT


SYMPTOM /MEDICATION SCORE (grass pollen season) P<0.001*

1

P=0.032*

Symptom load (median)

0.89

P=0.001*

0.8

0.61

0.6 0.49

0.4 0.26 0.2

0

n=54 SIT birch + Placebo

n=55 SIT birch + Omalizumab

n=59 n=53 SIT grass + SIT grass + Omalizumab Placebo * = Wilcoxon test (2-sided)


Specific Allergen Immunotherapy 1. SIT has disease modifying potential. 2. The PAT-study suggests, that the incidence of allergen induced seasonal asthma can be reduced by SIT. 3. High Dose SLIT offers new options for mucosal tolerance induction studies including studies for primary and secondary prevention of allergen induced asthma.


Dialogue with PDCO/EMA Guidelines for the clinical development of products for spec. immunotherapy should be amended and adapted for the specific needs of children.


Patient Education is essential! Effects of educational programs have been evaluated for: â&#x20AC;˘ Pediatric Asthma â&#x20AC;˘ Atopic dermatitis in Children


PGD2, its receptors and allergic inflammation CRTH2 agonists

DP1 agonists

PGD2

PGD2

PGJ2

PGJ2

D12 PGJ2

D12 PGJ2

15-deoxyD12,14PGJ2

15-deoxyD12,14PGJ2

9a, 11b PGF2

9a, 11b PGF2

PGF2a

PGF2a

DK-PGD2 D12 PGD2 15-deoxy D12,14PGD2 11-dehydroTXB2 Kostensis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol. Med. 2006, 12: 148-158


Human monoclonal antibody that binds to the IL-4 receptor alpha subunit (IL-4RÎą), which is a component of both IL-4R Type I & Type II and IL-13R Type II. Ultimately this blocks IL-4 and IL-13 binding & receptor activation

REGN688/ SAR231893

Namita G: Chatila 2004)

(


Exposure to microbes?


Sublingual allergen application


Claims for Specific Immunotherapy (EMA- Guideline 2009)

1. Treatment of allergic symptoms: Efficacy in the first pollen season. 2. Sustained clinical effect: Maintenance of significant and clinically relevant efficacy during two to three treatment years. 3. Long-term efficacy and disease modifying effect: Sustained significant and clinically relevant efficacy in post treatment years. 4. Curing allergy: Sustained absence of allergic symptoms in post treatment years. Where is prevention???


Strategies for Asthma Treatment and Prevention Infection resistance

Upper respiratory infection

Local inflammation

Episodic moderate intensity airway inflammation

Lower respiratory infection

Asthma risk

Myeloid cells: activation/trafficking

Bone marrow amplification Perennial aeroallergen sensitation

Continuos exposure

Persistant lowlevel airway inflammation

FcĆ?- enhanced inflammation

Asthma risk

TH-2 cell trafficking

Atopic sensitization: prevention; reversal Immunoprophylaxis

SCIT SLIT

Holt PG, Sly PD, Nature Med 2012


Synbiotics

Ulrich Wahn  
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