Benoit Nemery, MD, PhD Lung Toxicology Research Unit Occupational Medicine and Pneumology

1. TTS 2006, Kemer-Antalya, 20.04.2006 Symposium FEMTOS Recent advances in thoracic diseasesRecent advances in occupational lung diseases Benoit Nemery, MD, PhD Lung Toxicology Research Unit Occupational Medicine and Pneumology K.U.Leuven – Belgium ben.nemery@med.kuleuven.be

2. Acute inhalation injuries • Occupational infections • Occupational asthma • Chronic obstructive pulmonary disease • Interstitial lung diseases • Pneumoconioses (silicosis, CWP, asbestosis, …) • Berylliosis, hard-metal/cobalt lung disease, other metals, … • Extrinsic allergic alveolitis • Other occupational ILD (Ardystil s., flock worker’s, …) • Bronchopulmonary cancer • Pleural disease

3. “Common” respiratory diseases and occupation • Respiratory infections • COPD • Asthma • Lung cancer

4. Respiratory infections and work

5. Pneumonia and occupation • Coggon et al. Lobar pneumonia: an occupational disease in welders. Lancet, 1994, 41-43 • Excess mortality (SMR 182-157) from pneumonia in metal-working occupations (welders) (< 65 y) • Coggon et al. Exposure to metal fume and infectious pneumonia. Am J Epidemiol 2003, 157, 227-33 • 1996-1999, 11 hospitals in West-Midlands, UK • 525 cases of CAP / 1,122 controls • Occupational exposure in past 6 months? • Exposure to metal fumes: adjusted O.R. 1.6 • Recent exposure to Fe: adj O.R. 2.3 (lobar pneumonia)

6. SARS and occupation • The first pandemic of the 21st century was, in part, an occupational disease • Contact with wild animals (zoonosis) • Contact with affected patients • Health care workers (21% of all reported cases) • Household members (« para-occupational ») • Transportation (personnel, passengers) • Laboratory workers

7. SARS and health care workers • Health care workers represented 21% of worldwide reported cases • China 1002 / 5327 (19%) • Hong Kong 326 / 1755 (19%) • Canada 109 / 251 (43%)

8. Avian Influenza A • 2003: outbreak of fowl plague in commercial poultry farms in The Netherlands (& Belgium) • Highly pathogenic avian influenza A virus H7N7 • 30,000,000 chickens killed • « Human transmission of this virus is low » yet, clinical disease (mainly conjunctivitis, also flu-like disease) occurred in 453 persons handling infected poultry / estimated 4,500 exposed persons • Farmers + family, cullers, veterinarians • + medical and laboratory personnel

9. Koopmans et al. Lancet 2004; 363: 587-93

10. Fouchier et al. PNAS 2004; 101: 1356-61 Fatal pneumonia in previously healthy 57 y-old veterinarian

11. Avian influenza A • Since 2003: outbreaks of avian influenza A (H5N1) in Vietnam & Far East → rest of Asia & Europe • Fatal infections children & adults • Mainly if close contact with poultry • Some person-to-person transmission (?)

12. Asthma and COPD

13. Asthma and COPD • [Balmes J. (chair) et al.]American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003, 167, 787-797 • Literature-based estimation of population attributable risk (PAR) for asthma and COPD due to occupational exposures • COPD: approximately 15% • Chronic bronchitis: median 19% (8 studies) • Lung function impairment: median 19% (5 studies) • Asthma: median 15% (21 studies)

14. Asthma and occupation If asthma is “severe”, then there is a high likelihood of exposure to known causes of occupational asthma * * Le Moual N. et al. Asthma severity and exposure to occupational asthmogens.Am J Respir Crit Care Med 2005, 172, 440-5.

15. Asthma risk by occupation • Karjalainen et al.AJRCCM 2001, 164, 565-8 • 3 cohorts of all employed Finns (25 - 59 y) without preexisting asthma in 1985, 1990, 1995 • followed for incident asthma for 4 years • 49,575 incident cases of adult asthma in Finland • 1.65 (M) - 2.47 (F) / 1,000 / year • 2,464 cases of recognized occupational asthma

16. Asthma risk by occupation • Karjalainen et al. • attributable fraction of occupation for adult-onset asthma (controls = administrative w.): • 29 % (men) - 17 % (women) • not confounded by smoking • known sectors (agriculture, manufacture, services) and occupations (bakers, …), but also less known jobs (cleaners, …) • share of recognised cases of OA << 50 %

17. Asthma and cleaning agents • Higher risk of asthma in female cleaners • Zock et al. SJWEH 2001; 27: 76-81: P.R. 1.7 • Karjalainen et al. ERJ 2002; 19: 90-5: R.R. 1.50 • Medina-Ramón et al. Thorax 2003; 58: 950-4: O.R. 1.46 • “hidden sensitizers”? • Quaternary ammonium cpds (disinfectants / preservatives) • Isothiazolinones (preservatives) • Ethanol amines (wax-removal agents) • d-Limonene, terpenes (perfumes) • exposure to irritants and sprays ?

18. Asthma and cleaning agents Medina-Ramón et al. OEM 2005, 62, 598-606 • (Nested) case-control study of female cleaners (30-65 y) • 40 cases (asthma or chronic bronchitis) – 155 controls • Higher risk of asthma if use of bleach (dose-related) • Higher risk of asthma if reported inhalation incident (frequent!)

19. Medina-Ramón et al. OEM 2005, 62, 598-606

20. TLV-STEL Medina-Ramón et al. OEM 2005, 62, 598-606

21. Asthma after inhalation injury (RADS) Banauch GI et al. Persistent hyperreactivity and reactive airway dysfunction in firefighters at the World Trade Center. Am J Respir Crit Care Med 2003; 168: 54-62 + Nemery B. (Editorial). AJRCCM2003, 168, 2-3

22. Bronchial hyperreactivity PC20≤ 8 mg/ml Banauch et al. AJRCCM 2003; 168: 54-62

23. RADS at WTC • RADS = « bronchial hyperreactivity with respiratory symptoms at 6 months » • 17/83 (20%) of highly exposed • 3/40 (8%) of moderately exposed • all nonsmokers, except one • no evidence of clinically severe initial injury • occurrence of RADS predicted only by hyperreactivity at 1 or 3 months

24. European Lung White Book • Acute inhalation injuries • Occupational infections • Occupational asthma • Chronic obstructive pulmonary disease • Interstitial lung diseases • Pneumoconioses (silicosis, CWP, asbestosis, …) • Berylliosis, hard-metal/cobalt lung disease, … • Extrinsic allergic alveolitis • Other occupational ILD (Ardystil, flock worker’s, …) • Bronchopulmonary cancer • Pleural disease

25. Ardystil syndrome

26. “Ardystil syndrome” (1) • early 1992 - Alcoi (Valencia, Spain): outbreak of interstitial lung disease in textile printing factories using air-spraying Moya et al. (Lancet, 1994, 344, 498-502) • survey of 257 workers from 8 factories • on the basis of chest x-ray & lung biopsy: 22 cases of organising pneumonia(~ BOOP) (6 fatal)

27. Ardystil syndrome • Moya et al. (Lancet, 1994, 344, 498-502)

28. “Ardystil syndrome” (2) • late 1992 - Tlemcen (Oran, Algeria): • 5 cases of interstitial lung disease (1 fatal) among 12 textile printing workers • air-spraying with products from Spain Ould Kadi et al. (Lancet, 1994, 343, 962-3)

29. Ardystil syndrome A A Ould Kadi et al. [Lancet, 1994, 343, 962-3]

30. Ardystil syndrome Ould Kadi et al. [Lancet, 1994, 343, 962-3]

31. FVC FVC 27% 23% 66% 71% Ardystil syndrome Ould Kadi et al. (Eur. Respir. J. 1999, 13, 940-941)

32. “Flock worker’s lung”

33. “Nylon flock worker’s lung” • 1994-96: D. Kern: 2 cases of ILD (35y, 28y) in textile workers from a nylon flocking plant, RI • 1990-91: 5 cases of ILD in plant from same company in Ontario: “mycotoxicosis” (Lougheed et al. Chest 1995, 108, 1196-200) • further case-finding Kern et al. (Ann. Int. Med. 1998, 129, 261-272) • hygiene study & survey of workforce (NIOSH) Health Hazard Evaluation Report 96-0093, April 1998

34. Flock worker’s lung - HRCT Pt. 8 Pt. 4 Pt. 2 Kern et al. Ann. Int. Med. 1998, 129, 261-72

35. Nylon flock microfibres Scanning electron microscopy of bulk nylon fiber ends NIOSH HETA 96-0093

36. Flock worker’s lung • Barroso et al. Polyethylene flock-associated interstitial lung disease in a Spanish female. Eur Respir J 2002, 20:1610-2. • Atis S. et al. The respiratory effects of occupational polypropylene flock exposure. Eur Respir J 2005, 25, 110-117.

37. Atis S. et al. ERJ, 2005, 25, 110-7 • Cross-sectional survey, polypropylene plant, Turkey • 50 workers exposed to polypropylene flock (32.2 y) – 45 non-exposed controls (33.9 y) • Questionnaire • Spirometry & DLco • Chest x-ray and HRCT (10 subjects with low DLco) • Serum TNF- and IL-8 • Dust measurements and microscopy of flock

38. Atis S. et al. ERJ, 2005, 25, 110-7 • No abnormal chest x-ray • HRCT in 10 subjects with low DLco: suggestive of (mild) ILD or bronchiolitis

39. Atis S. et al. ERJ, 2005, 25, 110-7 TNF- IL-8

40. Popcorn worker’s lung

41. Popcorn worker’s lung • May 2000: • report of 8 persons with severe airway obstruction (bronchiolitis obliterans) • all employed 1993-2000 at microwave-popcorn plant in Missouri: • 4 worked in flavor-mixing room • 4 worked in packaging areas only • no reported incident or apparent overexposure • mostly nonsmokers • cause ?

42. Popcorn worker’s lung • Kreiss et al. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med. 2002, 347, 330-8. • Survey of current workers (n=117/135) • Questionnaire & spirometry • Exposure characterization

43. O O CH3- C - C - CH3 Popcorn worker’s lung • Kreiss et al.N Engl J Med. 2002, 347, 330-8. • air samples in mixing room: > 100 volatile compounds predominant compound: diacetyl = 2,3-butanedione • mixing room: 32 ppm, packaging: 2 ppm, maintenance & QC < 1 ppm • other areas: < 0.25 ppm

44. Popcorn worker’s lung • Kreiss et al.N Engl J Med. 2002, 347, 330-8. • overall (compared to NHANESIII) • chronic cough & dyspnea: x 2.6 • MD-diagnosed asthma & chronic bronchitis: x 2 • airway obstruction: x 3.3 (x 10.8 in nonsmokers) • higher risk if direct exposure to microwave-popcorn production (compared to other areas) • FEV1 decrease // with cumulative exposure (quartiles) • no confounding by smoking

45. Popcorn worker’s lung • Hubbs et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol. 2002,185,128-35. • Rats exposed for 6h to vapors of butter flavoring • necropsy after 24 h • necrosuppurative rhinitis + multifocal, necrotizing bronchitis (diacetyl = 203-371 ppm)

46. Popcorn worker’s lung • Akpinar-Elci et al. Bronchiolitis obliterans syndrome in popcorn production workers. Eur Respir J. 2004,24, 298-302. • 9 cases (27-51 y; 1-17 y in popcorn industry) • 3 never smokers, five ex-smokers, 1 smoker • FEV1 14 – 67% pred • HRCT bronchial wall thickening, air trapping • Lung biopsy: constrictive bronchiolitis • Stabilisation after leaving employment

47. Popcorn worker’s lung Akpinar-Elci et al. Eur Respir J. 2004, 24, 298-302

48. Other microwave popcorn plants • Kanwal et al. JOEM 2006, 48, 149-157 • Cross-sectional study in 6 plants (n=708) • Respiratory symptoms and airways obstruction related to exposure to oil and flavorings (mixers)

49. « ... considerable efforts are needed to improve the diagnosis and reporting of occupational diseases. »

50. Thank you for your attention ben.nemery@med.kuleuven.be