1. Occupational Asthma : Who gets it? David I. Bernstein MD Professor of Medicine University of Cincinnati Allergy-Immunology Division

2. Factors traditionally associated with susceptibility to OA 1.Atopic status  HMW allergens 2.Prior sensitization to workplace allergens 3.Rhinitis  precedes OA 4.Smoking and non-smoking status 5.Bronchial hyperresponsiveness 6.Genes – HLA, snp

3. Epidemiology: susceptibility factors Platinum Salts Smokers  Specific IgE TCPA anhydride AtopicSmokers  Specific IgE Lab animals AtopicSmokers  Specific IgE Lab animalsPST + to pets PC20 ≤ 32  mg/ml Occupational asthma* red cedar, colophony Non-smoking  Occupational asthma *Gautrin et al. Am J Resp Crit Care Med 2000

4. Susceptibility: other considerations Pre-disposing host factors differ between chemicals and proteins Sensitization and OA may be modified or enhanced by: Air pollutants (e.g. oxidants, DEP) Workplace irritants Environment-gene interaction

5. Other considerations? Nature and level of exposure is a key determinant of OA, but is clearly influenced by susceptibility factors intrinsic to individual workers

6. Atopic-Exposure Interaction Heederik, D et al. JACI 1999 3 cross-sectional studies; 3 countries Laboratory animal workers exposed to rat urinary proteins; N=1,062 In non-atopic workers, sensitization rates increased with exposure Atopic workers exposed to low allergen levels had 3-fold higher sensitization rate vs. non-exposed atopics.

7. Other considerations? Prospective epidemiologic studies are optimal for defining risk –Minimizes self-selection and survival bias –Best defines the natural history of OA –Intrinsic limitation  case definitions do not establish the phenotype

8. 44 mo. prospective study: Incidence and host determinants of probable OA in apprentice exposed to lab animals Gautrin D et al. AJRCCM 2001

9. Incidence and host determinants of probable OA in apprentices exposed to lab animals Gautrin D et al. AJRCCM 2001 Probable OA defined as: 1.ST + to occupational Ag 2.  3.2 fold decrease in PC20 Probable OA in 28 pt (2.7% incidence) but only 29% report work ass. wheeze, SOB Probable OA vs workers absent criteria –SPT + to pets (RR-4.1), PC20  32; rhinitis with pet exposure (RR-2.4); low FEV1 (RR-0.58)

10. Occupational rhinoconjunctivitis: Prospective 44 mo. follow-up of 387 apprentices exposed to lab animals (Rodier et al JACI 2003) Probable OA* in 18/37 (48%) with Occ. Rhinitis** vs. 12/56 (21%) without Occ. rhinitis *Probable OA = 3.2 fold decrease PC20 + sensitization to  1 workplace allergen **Occ rhinitis = Sx at work + SPT positive

11. BACKGROUND NOISE? 23 year follow-up study of 1,021 college freshman Settipane et al. 1994 Initial classification n Developed asthma % Allergic rhinitis 1621710.5 No allergic rhinitis 528193.6

12. Chemicals and OA Smoking status –Platinum salts, acid anhydrides  IgE –Red cedar – protective effect? Stimulation of innate immunity (irritant, virus)  sensitization ? Genetic markers –HLA, MHC II –Anti-oxidant enzymes –Cytokine genes

13. Genetics: Diisocyanate asthma   HLA DQB1 0503;  DQB1 0501 Mapp - 2000 Clin Exp Allergy   Lack of GSTM1 (null genotype) associated with a 2x risk of DA, lack of sp. IgE, LAR  Piirila Pharmacogenetics 2001  NAT 1 allele (slow acetylation phenotype) associated with TDI asthma (8X risk) ; DA(2.5 risk)  DA associated with combinations GSTM1 + NAT1 (OR 4.5) GSTM1 + NAT2 (OR 3.1) Wikman, Piirila et al. Pharmacogenetics 2002

14. Genetic studies: issues 1.Can candidates be identified given limitations of worker populations? 2.Defining phenotypes? –Gold standard – specific challenge testing? –What are appropriate control groups? 3.Can findings be replicated in different background populations?

15. Objective Evaluate IL-4 R , IL-13 and CD14 promotor genotypes with diisocyanate asthma (DA) and non-DA phenotypes

16. IL-4 R Polymorphisms in Allergic Disease 1.IL-4Ra gene - chromosome 16 2.Arg variant allele at position 576  mutant allele - 9.3 RR of atopy Hershey et al. 1997 3.RR homozygosity (Q576R) associated with 8.2 RR of severe asthma (FEV1≤60%) Rosa-Rosa L et al. 1999

17. CD14 1.CD14 pattern recognition receptor for LPS  macrophage activation  Th1 polarization 2.CD14 promotor – 159 C  T snp  TT associated with ↑ s CD14 and reduced IgE  CC - atopy

18. Methods 1.Study population J-L Malo, A Cartier, J Coté, L-P Boulet, S Tarlo and NIOSH (M Luster, B Yucesoy) DA (challenge pos.) (n=56) Non-DA (challenge neg.) (n=51) 2.SNPs  TNF  (A308G), IL-1 , IL-1ß, TBF ß, IL-10  C159T, IL-4R  : Q576R, I75V, Glu400Ala, Cys431Arg, S503P and IL-13 promotor (R130Q)

19. Preliminary Results 1.No associations with individual alleles or IL4Ra haplotypes 2.Genotype combination of II(I75V), EE(E400A), QQ(Q576R), CC(C159T) 14% of confirmed DA (8/56) vs. 2% of non-DA (1/51) OR= 8.6, p<0.05

20. Genetic studies Allelic combinations may help to discriminate DA from non-DA phenotypes Hypothesis –Diisocyanate asthma and allergic asthma are genotypically distinct entities

21. Is it important to define susceptibility? 1.Restricting high risk workers (e.g atopic) may not be indicated due to low predictive value of risk factors. 2.Customize surveillance programs. 3.Design primary prevention strategies with the intent to prevent disease among most susceptible workers. 4.Host determinants OA due to small molecular weight agents are poorly defined.

22. OA = Exposure + Host factors + Genotype