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