Jack Pepys (1914-1996) Father of Occupational Asthma

1. Jack Pepys (1914-1996) Father of Occupational Asthma Professor of Clinical Immunology (1967-1979) Cardiothoracic Institute, Brompton Hospital

2. Achievements in research in occupational asthma

3. Toluene diisocyanates Western red cedar(Thuja plicata)

4. Bronchial biopsy during LAR in a patient with RCA Cells expressing activation markers in bronchial biopsies of patients with RCA, atopic asthma and normals

5. Reactive airways dysfunction syndrome: persistent asthma syndrome after high-level irritant exposure Brooks et al. Chest 1985;88:376-384

6. Classification of Occupational asthma Immunologic (with latency) Nonimmunologic (without latency) IgE-dependent IgE-independent RADS or irritant- induced asthma HMW compoundsLaboratory animals Flour, detergent enzymes LMW compounds Diisocyanates Red cedar Colophony Chlorine, acetic acid, acids, formalin, spray paints, isocyanates, metam sodium, bleaching agents

7. Development of diagnostic methods 1713Ramazzini “What is your occupation?” • 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 • Colldahl BPT using common allergens • Gelfand BPT using LMW agents

8. Development of diagnostic methods Types of asthmatic reaction • Pepys • Simulated work exposure testing - safe and reproducible • TDI - application of polyurethane • varnish without and with TDI • activator

9. Flour Development of diagnostic methods Malo et al - closed circuit for exposure tests, providing a steady level of exposure

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

11. Use of induced sputum and measurement of exhaled nitric oxide in the diagnosis of OA 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 Eosinophils in sputum before and during late asthmatic reaction

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

13. PC20 of patients with red cedar asthma Ceased exposure 16 8 4 PC20 2 1 0.5 0.25 Diagnosis 0-1 1-2 2-3 3-5 5-7 7-9 >9 Years since diagnosis

14. Cellular content of BAL of patients with red cedar asthma on follow up * * Macrophages Neutrophils Epithelial Cells Lymphocytes Eosinophils Degenerated Cells Chan-Yeung et al. Clinical Allergy 1988

15. Airway inflammation and remodelling in asthma Macrophage/ dendritic cell Mast cell Th2 cell Neutrophil Eosinophil Epithelial ‘fragility’ Nerve activation Subepithelial fibrosis Plasma leak Oedema Sensory nerve activation Cellular infiltrate Vasodilatation New vessels Mucus hypersecretion Hyperplasia Cholinergic reflex Bronchoconstriction Hypertrophy/hyperplasia

16. Prospective study of apprentices of animal facilities (n = 417) Sensitization % Occupational rhinoconjunctivitis Occupational asthma Year in programme Gautrin et al AJRCCM: 2001

17. 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

18. Natural History of Occupational Asthma Malo 2003

19. Prevalence of occupational asthma by types of agent AgentsPrevalence (%) 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)

20. 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

21. Exposure-response relationships SubstanceLowest effective dose Flour 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 dust Rat urine 0.1 – 68 u/m3 Acid anhydride - TMA 0.82 mg/m3 Isocyanates 5-10 ppb Baur et al. Clin Exp Allergy 1998

22. Genetic factors in occupational asthma

23. Accepted claims for diisocyanate-induced and other types of OA in Ontario, 1980-93 Prevention of OA Annual incidence of incident reports and allergy clinic visits of hospital staff relating to perceived NRL allergy Tarlo and Liss 2002

24. 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