Is Early Exposure to Allergens Protective? Adnan Custovic MSc DM MD PhD Professor of Allergy North West Lung Centre Manchester, UK

Is Early Exposure to Allergens Protective? Adnan Custovic MSc DM MD PhD Professor of Allergy North West Lung Centre Manchester, UK

Highest Sensitisation Rate With Moderate Dose Antigen Exposure Anti-KLH IgE detected Anti-KLH IgG>20U/ml 0.1 mcg 10 mcg KLH Dose Group 1000 mcg 100,000 mcg Riedl MA et al, J Immunol 2005; 174:7440-5

Interrelationship of Exposure, Atopic Status and Frequency of Sensitization to Cockroach Allergen 70 60 69 63 55 Percent Positive CR Skin Test Eggleston et al JACI 1998;102:363-70 50 40 30 20 10 0 39 22 15 8+ 2 to 8 42 31 1 to 2 Blag1 Allergen (U/gm) 0 22 0 14 0 30 5+ 1 to 4 Total Positive Skin Test

Paradoxical Effects Of Exposure To Domestic Animals Decreased sensitization to cat amongst cat owners Hesselmar, Bjorksten et al Roost et al Sporik et al Custovic et al Sweden CEA 1999 ECRHS JACI 1999 USA Thorax 1999 UK JACI 2002 Production of IgG and IgG4 (without IgE): Platts-Mills et al Lancet 2001 Erwin et al JACI 2003 Non-specific effects on other allergens: Ownby et al* USA JAMA 2002 Perzanowski et al Sweden AJRCCM 2002 * More than one animal.

Decreased Risk of Sensitisation to Cat With High Exposure to Cat Allergen Number of Children 25 20 15 10 5 Sensitisated to Cat Allergen IgG 125 0 0.69 (n=37) 0.7-1.69 (n=38) 1.7-4.39 (n=38) 4.4-22.9 (n=37) 23-106 (n=38) 106-3840 (n=38) µg Fel d 1/g Platts Mills et al, Lancet 2001

Decreased Risk of Sensitisation to Cat With High Exposure to Cat Allergen 25 20 % sensitized to cat 15 10 5 Custovic et al. 0 <0.05 0.05-0.34 0.341-0.48 0.481-0.72 0.721-1.13 1.131-1.92 1.921-7.20 7.201-44.00 44.01-151 >151 J Allergy Clin Immunol 2001; 108: 537-9 Fel d 1 (mcg/g) M a n c h e s t e r A s t h n m a a d A l l e r g y S t u d y

PARSIFAL: Prevalence of Mite Sensitization by Tertiles of Der 1 Levels Schram-Bijkerk at al, Allergy 2006; 61: 640-7

% 50 45 40 35 30 25 20 15 10 5 0 Additive Exposure to Indoor Allergens and Sensitisation in 2200 Adults 0 1 2 3 4 5 6 7 8 Additive exposure category Sensitized to dust mite Asthma Custovic et al, JACI 2003;111:402-7

Additive Exposure to Indoor Allergens and Sensitisation in 2200 Adults 25 % 20 15 10 Sensitized to cat Sensitized to dog 5 0 0 1 2 3 4 5 6 7 8 Additive exposure category Custovic et al, JACI 2003;111:402-7

Allergen Exposure, Sensitisation and Wheeze Ashford cohort (Cullinan( et al, Thorax 2004; 59: 855 861) 861) No significant relationships between Der p 1 and Fel d 1 and either sensitisation or wheeze Exposure-response response relationships for both allergens and for each outcome rose steeply at low levels and were attenuated at high levels These patterns were modified by paternal atopy and by birth order No linear relationships between early allergen exposure and the induction of childhood respiratory allergy

Allergen Exposure, Sensitisation and Wheeze PIAMA PIAMA (Brussee et al, JACI 2005; 115: 946-52) Der p 1 and Fel d 1 exposure in infancy associated with an increased risk of sensitization at age 4 years Borderline associations between Fel d 1 exposure and persistent wheeze (all subjects) & between Can f 1 exposure and persistent wheeze (children with non-atopic mother) Indication of a positive association between Der p 1 and physician-diagnosed asthma (children with atopic mother)

AMICS and PIAMA: Differences in the Effect of Allergen Exposure

Sensitisation to House Dust Stratified by Highest and Lowest Quartiles of House-Dust-Mite Exposure at Age 6 Months Proportion (% ) of children sensitised to m ites 16 14 12 10 Lau et al, Lancet 2000;356:1392-7 8 6 4 2 0 First quartile (<0.002-0.032 g/g) Fourth quartile (0.981-240 g/g) 0 1 2 3 4 5 6 7 Age (years) p<0.001 p<0.01 p<0.0001

Mite Allergen Exposure Increases the Risk of Specific Sensitisation 1.0 Predicted probability for mite sensitisation.8.6.4.2 HR MR 0.0 0 7.4 2 54.5 4 403.4 6 2980 8 Cummulative Der p 1 exposure (mcg) LR M a n c h e s t e r A s t h n m a a d A l l e r g y S t u d y

WHAT CAN WE LEARN FROM INTERVENTION STUDIES?

Hypothetical Scenarios on the Outcomes of Environmental Control % sensitised Allergen exposure

Isle of Wight Study: At 8 Years Reduction in Respiratory Symptoms and Atopy Current wheeze OR 0.26 (0.07-0.96) 0.96) Nocturnal cough OR 0.22 (0.06-0.83) 0.83) Asthma (wheeze+bhr) OR 0.11 (0.01-1.02) 1.02) Sensitisation OR 0.21 (0.07-0.62) 0.62) Mite sensitivity OR 0.08 (0.02-0.39) 0.39) 0.01 0.1 1 P=0.04 P=0.02 P=0.05 P=0.04 P=0.002 Arshad SH et al, Thorax 2003;58:489-93

Age Three Years: Effect of Environmental Control on Sensitisation (IgE) 30 25 P<0.05 P=1.00 P=1.00 % 20 15 10 Control, n=49 Active, n=73 5 0 Dust mite Cat Dog Woodcock et al, AJRCCM 2004; 170: 433-9 M a n c h e s t e r A s t h n m a a d A l l e r g y S t u d y

CD 14 Promoter Polymorphism, Endotoxin Exposure and Sensitization 1.0 Predicted probability for for sensitisation 0.8 0.6 0.4 0.2.2 P=0.004 P=0.2 P=0.7 CC CT 0.0 0.0 1.0 0 7.4 2 54.6 4 6 8 10 12 14 403.4 2981 22000 162755 1.2x10 6 TT Ln total Endotoxin endotoxin Load recovered (EU/m(EU/m2) 2 ) Simpson et al, AJRCCM 2006;174:386-92 M a n c h e s t e r A s t a a h m n d A l l e r g y S t u d y

Endotoxin and Der p 1 Exposure and Probability for Mite Sensitisation in Children With CD14-159 CC Genotype Simpson et al, AJRCCM 2006;174:386-92 M a n c h e s t e r A s t a a h m n d A l l e r g y S t u d y

Allergen Sensitisation, Exposure and Lung Function at Age 3 Years 1.35 sr aw (kpa/s) 1.3 1.25 1.2 1.15 1.1 1.05 1 P=0.005 Not Sensitised Not exposed (n=114) Not Sensitised Exposed (n=282) Sensitised Not exposed (n=53) Sensitised Exposed (n=49) Lowe at al, Arch Ped Adolesc Med 2004; 158: 996-1001 M a n c h e s t e r A s t a a h m n d A l l e r g y S t u d y

Allergen Sensitisation and Exposure at 3 Years and Lung Function at Age 7 Years Illi at al, Lancet 2006; 368: 763-7

Conclusions Exposure to sensitising allergen increases asthma severity amongst allergic asthmatics The relationship between allergen exposure and the development of IgE- mediated sensitisation and the symptoms of allergic disease is complex Individual susceptibility critical in determining the effect of environmental exposures

Conclusions What is the effect of high early allergen exposure on the development of sensitisation? Increases the risk Protects Does not matter } Depending on allergen and individual susceptibility The selection of subjects for primary prevention and the treatment using environmental control needs to be refined Identify genetic polymorphisms which confer an increase in risk This will results in tailor made approaches for individuals