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
1. Atopic status HMW allergens2. Prior sensitization to workplace
allergens3. Rhinitis precedes OA4. Smoking and non-smoking status5. Bronchial hyperresponsiveness6. Genes – HLA, snp
Epidemiology: susceptibility factors Platinum
Salts
Smokers Specific IgE
TCPA anhydride
Atopic Smokers Specific IgE
Lab animals
Atopic Smokers Specific IgE
Lab animals PST + 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
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
Other considerations?
• Nature and level of exposure is a key determinant of OA, but is clearly influenced by susceptibility factors intrinsic to individual workers
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.
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
44 mo. prospective study: Incidence and host determinants of probable OA in apprentice
exposed to lab animalsGautrin D et al. AJRCCM 2001
Incidence and host determinants of probable OA in apprentices exposed to lab
animalsGautrin D et al. AJRCCM 2001
Probable OA defined as: 1. ST + to occupational Ag2. 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)
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
BACKGROUND NOISE?
23 year follow-up study of 1,021 college freshmanSettipane et al. 1994
Initial classificatio
n
n Developed asthma
%
Allergic rhinitis
162 17 10.5
No allergic rhinitis
528 19 3.6
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
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 combinationsGSTM1 + NAT1 (OR 4.5) GSTM1 + NAT2 (OR 3.1)
Wikman, Piirila et al. Pharmacogenetics 2002
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?
Objective
Evaluate IL-4 R, IL-13 and CD14 promotor genotypes with diisocyanate asthma (DA) and non-DA phenotypes
IL-4 R Polymorphisms in Allergic Disease
1. IL-4Ra gene - chromosome 162. 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
CD141. CD14 pattern recognition receptor
for LPS macrophage activation Th1 polarization
2. CD14 promotor – 159 CT snp TT associated with ↑ s CD14
and reduced IgE CC - atopy
Methods1. 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)
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
Genetic studies
• Allelic combinations may help to discriminate DA from non-DA phenotypes
• Hypothesis– Diisocyanate asthma and allergic
asthma are genotypically distinct entities
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.
OA = Exposure + Host factors + Genotype