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Occupational Asthma : Who gets it?

Occupational Asthma : Who gets it?. David I. Bernstein MD Professor of Medicine University of Cincinnati Allergy-Immunology Division. Factors traditionally associated with susceptibility to OA. Atopic status  HMW allergens Prior sensitization to workplace allergens

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Occupational Asthma : Who gets it?

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  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 • Atopic status  HMW allergens • Prior sensitization to workplace allergens • Rhinitis  precedes OA • Smoking and non-smoking status • Bronchial hyperresponsiveness • Genes – HLA, snp

  3. Epidemiology: susceptibility factors *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 InteractionHeederik, 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 animalsGautrin D et al. AJRCCM 2001

  9. Incidence and host determinants of probable OA in apprentices exposed to lab animalsGautrin D et al. AJRCCM 2001 Probable OA defined as: • ST + to occupational Ag •  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:Prospective44 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 freshmanSettipane et al. 1994

  12. Chemicalsand 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 0501Mapp - 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 • Can candidates be identified given limitations of worker populations? • Defining phenotypes? • Gold standard – specific challenge testing? • What are appropriate control groups? • Can findings be replicated in different background populations?

  15. ObjectiveEvaluate 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 • IL-4Ra gene - chromosome 16 • Arg variant allele at position 576  mutant allele - 9.3 RR of atopy Hershey et al. 1997 • RR homozygosity (Q576R) associated with 8.2 RR of severe asthma (FEV1≤60%) Rosa-Rosa L et al. 1999

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

  18. Methods • 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) • 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 • No associations with individual alleles or IL4Ra haplotypes • 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? • Restricting high risk workers (e.g atopic) may not be indicated due to low predictive value of risk factors. • Customize surveillance programs. • Design primary prevention strategies with the intent to prevent disease among most susceptible workers. • Host determinants OA due to small molecular weight agents are poorly defined.

  22. OA = Exposure + Host factors + Genotype

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