Prevention of asthma in childhood Prof. Dr. U. Wahn Ulrich Wahn Department of Pediatric Pneumology and Immunology Cancun - 08.12.11 - Prevention of asthma in childhood

Possible opportunities Allergen avoidance Preventative Pharmakotherapy in high risk groups a) Cetirizin/Levocetiricin b) Desloratadin c) Pimecrolimus Spec. Immunotherapy in pollen allergic children SLIT in high risk infants Primary prevention by modification of infant nutrition

Allergen avoidace Dust mites Pets Novel tools

Prevalence of current wheeze from birth to age 13 years Wheezing at school age (5–7 years) Non-atopic Atopic Age (years) Illi S, et al. Lancet 2006

Early sensitization and allergen exposure to perennial allergens Early sensitization and allergen exposure to perennial allergens* and lung function at school age Not sensitized Sensitized/ low exposure Sensitized/ high exposure Mean±SD 160 140 120 100 80 60 40 20 p=0.003 p=0.020 p=0.018 p=0.001 p<0.001 p=0.003 p=0.025 FEV1 (% FVC) FEV1 (% 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

Parental smoking and sensitization 27,7 Adj. OR and 95%CI No atopic parents 1 atopic parent 2 atopic parents No atopic parents 1 atopic parent 2 atopic parents No atopic parents 1 atopic parent 2 atopic parents Only father smoked Mother smoked irregularly Mother smoked regularly T. Keil et al, Allergy Allergy. 2010 Apr;65(4):482-90

Laminar airflow systems Cancun - 08.12.11 - Prevention of asthma in childhood

Pharmacotherapeutic attempts Cetiricin/Levocetericin Desloratadin Pimecrolimus

36.5% 37.3% EPAAC™ : Percentage of Subjects Who Developed Asthma at the end of the 18 Month Treatment Period Levocetirizine (n=252) Placebo (n=252) 100 No significant differences between treatments 80 60 % of subjects who developed asthma At the end of the 18 month treatment period evaluation of the asthma development showed no significant difference in the % of subjects developing asthma between the two study groups. 40 36.5% 37.3% 20 Cancun - 08.12.11 - Prevention of asthma in childhood 15

Specific Immunotherapy in pollen allergic children

Clinical efficacy of immunotherapy Early effect reduction in symptoms/need for medication Progressive effect 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) Cancun - 08.12.11 - Prevention of asthma in childhood

Probability of New Onset of Wheeze in children with and without atopy Rochat et al, JACI 2010; 126: 1170-1175 Cancun - 08.12.11 - Prevention of asthma in childhood

The PAT study Cancun - 08.12.11 - Prevention of asthma in childhood

PAT Study Period SIT Follow up Follow up Maintenance dose: Grass: 20 µg Phl p5 Birch: 13 µg Bet v1 Follow up Follow up SIT AAAAI, 2006 In print, Allergy 2006 Möller et al. J Allergy Clin.Immunol. 2002;109:251-6. Cancun - 08.12.11 - Prevention of asthma in childhood

Demographic data at inclusion All included No asthma Asthma *** Number 208 (205)* 163 42 Mean age (range) 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 N=137 4.9(1 9)** N=34 Methacholin e PC 20 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 Cancun - 08.12.11 - Prevention of asthma in childhood

Patient flow Patients included 205 Control group 102 SIT group 103 Asthma: 42 Continued for 3 years as controls 94 Continued for 3 years on SIT 97 Asthma: 40 Follow up at 5 years 83 Follow up at 5 years 95 Asthma: 36 Follow up at 10 years 68 Follow up at 10 years 79 Asthma: 30 Total follow up at 10 years: 147

Conjunctival provocation test 3 P<0.001 P<0.001 P<0.001 P<0.001 P<0.05 2,5 2 Control Change from baseline 1,5 (2 x log SQ) Active 1 0,5 1 2 3 5 10 Year

Rhinitis: Change from baseline (Visual analogue scores) 30 P=0.01 P<0.001 P<0.0001 P<0.0001 P<0.05 15 Control Mean VAS Score Active -15 -30 1 2 3 5 10 Year Means adjusted for baseline difference

Development of asthma at 3 years N=151 (patients without asthma in season one) N=60 Odds-ratio = 2.52 (1.3 – 5.1) N=40 N=32 N=19 Cancun - 08.12.11 - Prevention of asthma in childhood

Development of asthma at 5 years N=142 (patients without asthma in season one) N=60 Odds-ratio = 2.68 (1.3 – 5.7) N=38 N=29 N=15 Cancun - 08.12.11 - Prevention of asthma in childhood

Development of asthma at 10 years N=117 (patients without asthma in season one) N=48 Odds-ratio = 2.48 (1.2 – 5.4) N=29 N=24 N=16

GAP-Study

Sublingual allergen application

SLIT in high risk infants

Recent evidence from high dose SLIT trials opens new avenues for early intervention studies in infants and young children

Onset pre-clinical early late clinical Number of Phl p molecules recognized by IgE in 79 children with SAR by time from the onset of symptoms Onset = 2,575 mol Years/mol = 4,1 confidential 10-15 kU/l IgE to g6 2.5 – 3 molecules to be adjusted by AGE AT ONSET!!! Component Resolved Prophylaxis CRP early simplified (es-CRT) (too) complex late CRT 1,4 2,1 3,0 4,0 4,2

Prophylaxis of atopy and asthma in children (ITN) 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 Cancun - 08.12.11 - Prevention of asthma in childhood

12 months of oral application Study Design Allergens (Cat, house dust mites, grass) Endpoint Assessment (ITT/ PP) Randomisation (n=200) (age 12 – 30 month) Enrolment Patient fulfilling the inclusion criteria were randomly assigned to one of the 4 treatment arms (SIT birch, SIT grass, Xolair+SIT birch or Xolair+SIT grass) Each patients randomly received active treatment i.e. SIT birch or grass In addition each patient randomly received Xolair or Xolair-placebo. The SIT titration was performed in accordance to ALK guidelines for 12 weeks followed by 24 weeks of combined treatment SIT+Xolair during both pollen seasons. Start of SIT treatement was 14 - 16 weeks prior to the expected start of birch pollen season. Start of Xolair treatment was scheduled 2 - 4 weeks prior to to the expected start of birch pollen season. Duration of birch + grass pollen season was expected to be 24 weeks in total. Placebo Follow-up 12 months of oral application Cancun - 08.12.11 - Prevention of asthma in childhood

The child at risk for asthma Parental Phenotypes Atopy/Asthma Atopy/Asthma Filaggrin Mutation Filaggrin Mutation AD Wheeze Infantile Phenotypes Food Sensitization Food Sensitization Perennial aero-sensitization Perennial aero-sensitization Persistent asthma in adolescene

What are the studies we need? Allergen-specific SLIT in young children at high risk for asthma with established sensitization to house dust mite Allergen-specific mucosal tolerance induction at high risk for asthma prior to aeroallergen sensitization Asthma prevention studies in established disease of the upper airways

Primary prevention by modifcation of infant nutrition

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 Cancun - 08.12.11 - Prevention of asthma in childhood