Jack Pepys

(1914-1996)

Father of Occupational Asthma

Professor of Clinical Immunology (1967-1979)Cardiothoracic Institute, Brompton Hospital

Achievements in research in occupational asthma

Western red cedar (Thuja plicata)

Toluene diisocyanates

Bronchial biopsy during LAR in a patient with RCA

Cells expressing activation markers in bronchial biopsies of patients with RCA, atopic asthma and normals

Reactive airways dysfunction syndrome: persistent asthma syndrome after high-

level irritant exposure Brooks et al. Chest 1985;88:376-384

Classification of Occupational asthma

Immunologic(with latency)

Nonimmunologic (without latency)

RADS or irritant- induced asthma

HMW compounds Laboratory animals Flour, detergent enzymes

IgE-dependent IgE-independent

LMW compoundsDiisocyanatesRed cedarColophony

Chlorine, acetic acid, acids, formalin, spray paints, isocyanates, metam sodium, bleaching agents

Development of diagnostic methods

1713 Ramazzini “What is your occupation?”

1832 Thackrah “…the scientific treatment of a malady requires a knowledge of its nature, and the nature is imperfectly understood without knowledge of the cause” Measurement of airflow obstruction by a “pulmometer” – early version of spirometer

1952 Colldahl BPT using common allergens

1963 Gelfand BPT using LMW agents

1969 Pepys Simulated work exposure testing - safe

and reproducible TDI - application of polyurethane varnish without and with TDI activator

Development of diagnostic methods

Types of asthmatic reaction

Development of diagnostic methods Malo et al - closed circuit for exposure tests, providing a

steady level of exposure

Flour

Serial monitoring of PEF in the diagnosis of OA Burge, Eur Respir J 1982

Use of induced sputum and measurement ofexhaled nitric oxide in the diagnosis of OA

Eosinophils in sputum before and during late asthmatic reaction

Exhaled nitric acid before and at 6 hr after methacholine challenge; before, 6 and 24 hrs after plicatic acid challenge in patients who had a positive late reaction

Natural history: Follow up studies of OA patients after removal from exposure

Agent N Duration of FU (yrs) Symptomatic (%) Year

Red cedar 38 0.5 - 4 39 1977

Red cedar 75 1 - 9 49 1982

Colophony 20 1.3 - 3.8 90 1982

Snow crab 31 0.5 - 2 61 1985

Snow crab 31 4.8 - 6 100 1988

Isocyanates 50 > 4 82 1987

Isocyanates 20 1 - 3 66 1984

Various 28 4 – 11 100 1989

Diagnosis 0-1 1-2 2-3 3-5 5-7 7-9 >9

0.25

0.5

1

2

4

8

16Ceased exposure

PC20

Years since diagnosis

PC20 of patients with red cedar asthma

0

10

20

30

40

50

60

Asymptomatic

Symptomatic

*

Macrophages

Lymphocytes

Neutrophils

Eosinophils

Epithelial Cells

Degenerated Cells

Cellular content of BAL of patients with red cedar asthma on follow up

*

*

Chan-Yeung et al. Clinical Allergy 1988

EosinophilEosinophil

Mast cellMast cell

Th2 cellTh2 cell

Airway inflammation and remodelling in asthmaAirway inflammation and remodelling in asthma

NeutrophilNeutrophil

MucusMucushypersecretionhypersecretionHyperplasiaHyperplasia

Macrophage/Macrophage/dendritic celldendritic cell

Plasma leakPlasma leak OedemaOedema

VasodilatationVasodilatationNew vesselsNew vessels

BronchoconstrictionBronchoconstrictionHypertrophy/hyperplasiaHypertrophy/hyperplasia

Cholinergic reflexCholinergic reflex

Epithelial ‘fragility’Epithelial ‘fragility’

SubepithelialSubepithelialfibrosisfibrosis

Sensory nerve Sensory nerve activationactivation

Nerve activationNerve activation

Cellular infiltrate Cellular infiltrate

Thoracic Medicineat the NHLI

Thoracic MedicineThoracic Medicineat theat the NHLI NHLI

0

2

4

6

8

10

12

0 1 2 3 4 5

Year in programme

%

Sensitization

Occupational rhinoconjunctivitis

Occupational asthma

Prospective study of apprentices of animal facilities (n = 417)

Gautrin et al AJRCCM: 2001

Determinants of sensitization and OA in apprentices exposed to laboratory animals

Determinants OR (95% CI)Sensitization

• Atopy 2.2 (1.4-3.9)

• Resp symptoms during pollen season 5.2 (1.7-11.0)

• > 53 hours of exposure to rodents 2.5 (1.3-4.8)

Occupational asthma

• Atopy to pets 4.1 (1.6-10.8)

• PC20 <32 mg/ml 2.5 (1.0-5.8)

• High FEV1 1.7 (1.3-2.2)

Gautrin et al ERJ 2002

STAGES: Rhinoconjunctivitis. Onset of airway inflammation onset of sensitization occupational end or diminution cure or persis- exposure asthma of exposure tence of asthma FACTORS: host markers: agent: level of duration of exposure; anti- genetic, nature, bronchial asthma severity inflammatory atopy, level of concentra- responsiveness at the time treatment bronchial res- tion, dura- of diagnosis compensation ponsiveness, tion of and smoking, exposure psychosocio- psychosocial others: economic impact viral infections pollutants, smoking EXPERTISE: basic, psychosocial, environmental, epidemiologic, clinical, R&D, evaluative

Malo 2003

Natural History of Occupational Asthma

Prevalence of occupational asthma by types of agent

Agents Prevalence (%)

Platinum refinery 54 (South Africa)

Colophony 22 (UK)

Various isocyanates 20 (Canada)

Isocyanates (production) 8.3 (US)

Spiramycin 19 (Canada)

Western red cedar 5.0 (Canada)

Attributable risk (AR) of work exposure for asthma by source of data

AR

Population-based studies 15 (2-20)

Medical practice data 9 (2-33)

Surveillance or registry data 4 (2-17)

Medicolegal data 5 (3-8)

Overall Median 10 (2-45)

Blanc and Toren 1999

Exposure-response relationships

Substance Lowest effective doseFlour 1-2.4 mg/m3

Fungal amylase 0.25 ng/m3

Red cedar dust 1 mg/m3

Natural rubber latex 0.6 ng/m3

Cow dander 1-29 ug/g dustRat urine 0.1 – 68 u/m3

Acid anhydride - TMA 0.82 mg/m3

Isocyanates 5-10 ppb

Baur et al. Clin Exp Allergy 1998

Genetic factors in occupational asthma

Accepted claims for diisocyanate-induced and other types of OA in Ontario, 1980-93

0

10

20

30

40

50

60

70

'80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93

Year

No

. ac

ce

pte

d c

laim

s

Diisocyanate OA

Non-diisocyanate-OA

Tarlo and Liss 2002

0

5

10

15

20

25

30

35

40

45

50

'85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99

Year

Num

ber

Incident reports

Clinic visit

Annual incidence of incident reports and allergy clinic visits of hospital staff relating to perceived NRL allergy

Prevention of OA

Structure of the occupational agent

Some agents are potent respiratory sensitizers:

• HMW – those with enzymatic activity eg. detergent enzymes

• LMW compounds – those with N=C=O eg. isocyanates