Presenter Disclosures

2. Presenter Disclosures John E. Parker, M.D. The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months: “No relationships to disclose”

3. Non-Pneumoconiotic Effects Associated with Inorganic Dust Exposures& Boutique Lung Diseases John E. Parker, MD Pulmonary and Critical Care Medicine West Virginia University Morgantown, WV USA 11th Annual Congress Turkish Thoracic Society 2008 25 Nisan 2008

4. Objectives for Sunrise SeminarTTD 2008 Nisan • Review the broad spectrum of occupational lung diseases • Briefly discuss some general mechanisms of dust clearance, airway and lung injury and repair • Identify infectious, neoplastic, and systemic diseases associated with classic inorganic dust exposures • Review the impact of obstructive lung disease on dust exposed workers • Introduce some rare or boutique lung diseases • See some photographs of wildlife and the great outdoors

5. Occupational Lung Diseases • The Pneumoconioses • Asthma and Obstructive airways disease • Mixed Dust related lung injury • Hypersensitivity Pneumonitis • Granulomatous and other interstitial responses • Cancer of lung and pleura • Infectious lung diseases

6. Traditional Dust DiseasesBriefly, only for orientation purposes • The traditional pneumoconioses or dust diseases • These are the diseases we are not going to talk about at length this morning, but they deserve brief mention • The chest radiograph is key to the recognition or diagnostic evaluation of these diseases

7. Asbestosis • Radiographic shadows are ırregular (lınear or reticular) dominating the lower zones • Irregular shadows when seen wıth pleural abnormlıtıes are hıghly specıfıc for asbestos related dısease • CT scan shows peripheral lower zone septal thickening, honeycombing and fibrous bands

8. Advanced Silicosis

10. Attention to Dust Over-Exposures and to dust reduction and control impacts the burden of these diseases • Some data shows reduction of dust diseases • But they are stubborn adversaries and not going away quietly – as Saturday’s round table on silicosis in sandblasters will attest • Traditional medical therapy is not very good for these chronic diseases – we have antibiotics, influenza and pneumococcal vaccinations, bronchodilators, oxygen therapy, etc – but no agents for true cure • Dust control is the secret or “the vaccine” for controlling or eliminating these diseases

11. Silicosis deaths in 1968-2000 (USA)

12. Coal miners - CWP profusion 1/0 or greater, by year and tenure (USA)

13. Diego Rivera: El vendedor de flores( The heavy burden of dust diseases)

14. The Spectrum of Occupational Respiratory Disorders

15. Lung Injury Patterns • Airway injury • Parenchymal injury • Pleural injury • Neoplastic injury

16. How does the lung protect itself?Lung Protective Mechanisms • Cough reflex • Mucous layer • MC escalator • Macrophages • Neutrophils • Local immunoglobulins

19. Properties of the Agent Producing Lung Injury • Site of deposition and injury • Particle size, and aerodynamic diameter • Particle physical and biological properties and the resulting “toxicity” • Concentration of particles or gas (dose) • Clearance or retention of particles

20. Key Role of the Macrophage • An important scavenger cell • Especially critical in defense against infectious agents • Kills by phagocytosis -- bacteria and viruses • Presents antigenic fragments to the immune system • But in dust dıseases may inititiatee an inflammatory cascade or harmful cycle of ınjury and repaır • Injury of the airway and the parenchyma

21. Dust, Gas, Fume and Vapor Induced Lung Injury • Silica, Asbestos and Coal Mine Dusts are classic agents for activation of target cells • Inducing inflammation and injury via macrophage activation • Mediator production– cytokines, proteases, oxidants, and arachidonic acid metabolites • Injury can occur in the airway, interstitium, or the pleural with or without radiographic changes • Many agents inorganic dusts, fumes, gasses, mists, and vapors can injure the lung

22. Non-Pneumoconiotic Complications (I) of Silica Dust Exposures • Chronic Bronchitis and Airflow Obstruction (COPD) • Immune-Mediated Complications -Scleroderma and renal disease • Lung Cancer – controversial in silica but well established with asbestos exposure • Mycobacterial Infections, Nocardia ATS. Adverse Effects of Crystalline Silica Exposure. Am J Respir Crit Care Med 155:761-768, 1997.

23. Non-Pneumoconiotic Complications (II) of Asbestos Dust Exposures • Laryngeal cancer • Lung cancer and mesothelioma - well established with asbestos exposure • Retroperitoneal fibrosis with anuria and renal failure • Small airways disease and Airflow Obstruction Sauni R, Oksa P, Jarvenpaa R, Parker JE, Roto P. Asbestos Exposure, A Potential Cause of Retroperitoneal Fibrosis. Am J Ind Med 1998; 33:418-421. ATS. The Diagnosis and Initial Management of Nonmalignant Diseases related to Asbestos. Amer jour Res Crit Care Med 2004; 170:691-715

24. asbestos-related laryngeal cancer vocal cords 9

25. asbestos worker suffering from diffuse malignant pleural mesothelioma, (absolutely fatal)

26. Asbestos exposed roofer suffering from diffuse malignant peritoneal mesothelioma, ascities, not liver cirrhosis absolutely fatal

27. Non-Pneumoconiotic Complications (III) of Coal Dust Exposures • Chronic bronchitis • Emphysema • COPD • Small airways disease & airflow obstruction • Caplan’s syndrome CDC/NIOSH. Criteria for a Recommended Standard -Occupational Exposure to Respirable Coal Mine Dust. September 1995. DHHS (NIOSH) Publication No. 95‑106.

29. Strength of the evidence for COPD and dust exposures or mixed dust exposures – a bit of recent history and older history • Margaret Becklake published in Chest a wonderful and visionary article on OAD and Dust in 1985 • And a bıt of 150 year old hıstory - • Way back in the19th Century Public Health Leaders Were Quite Clear About the Role of the Dusty Trades: and Chronic Bronchitis wıth a publication by E. Headlam Greenhow, M.D. – heralding COPD and dust

30. COPD and Occupation from an Epidemiological Perspective Define COPD - how it is diagnosed and studied epidemiologically Cover key points in the 2003 American Thoracic Society statement on COPD and occupation Summarize data from other recent studies and address policy implications of body of evidence

31. Defining Chronic Obstructive Pulmonary Disease [COPD] • This is a modern construct or concept to lump rather than spit these disorders • It subsumes 3 main disease labels: • COPD, Emphysema, Chronic bronchitis • Each label is based on different criteria

32. COPD - Diagnosis • Based on lung function defined by: • Deficit,amount breathed out in 1 second [FEV1] • Or its ratio to the total breath [FEV1/FVC] • Cut-points use to define COPD vary: • FEV1/FVC < 70% [GOLD Stage I] • FEV1/FVC < 70% + FEV1 <80% predicted

33. Limitations for epidemiologic study • Many patients have no lung function data • Studies using lung function are expensive • Varying cut-points complicate comparison • Term is not widely used by lay public

34. Emphysema - Diagnosis • Definitive dısease is based on tissue (autopsy): • Destruction of functional lung gas exchange • Loss of airway support; ‘punched-out’ spaces • CT scanning “allows” diagnosis by x-ray • Loss of normal images of lung • Plain chest x-ray is inadequate to image

35. Limitationsin epidemiologic studies • Tissue is not usually available • CT scanning is expensive • CT’s cannot be done in field studies • Diagnosis is often given without either test

36. Chronic Bronchitis - Diagnosis • Based on reported symptoms • Productive cough x 3 months • Two consecutive years of symptoms • Standard questionnaire items • Developed by MRC, commonly used to define

37. Limitationsin epidemiologic • In clinical practice, often used imprecisely • In lay use, blurred with acute bronchitis • Only partly overlaps with PFT obstruction • Even less overlap with CT emphysema

38. Role of Cigarette Smoking • Leading risk factor established for COPD • Accounts for 80% of all cases of disease • 80%=smoking Population Attributable Risk • PAR%=disease stopped if risk eliminated

39. Impact of Smoking Role • Primary focus of prevention efforts; minimizing attention to other factors • PAR% allows overlapping risks [can be >100%] • Eliminating any risk factor can reduce disease • Diagnostic impacts • Reluctance to diagnose COPD in nonsmokers • Reluctance to diagnose asthma in smokers

40. Going Beyond Direct Smoking • If direct cigarette smoking doesn’t account for all COPD cases, what else matters? • What is the role of workplace exposures? • Is there a strong and plausible effect, consistent in multiple studies?

42. ATS Statement • Drafted in 2002, published in 2003; data through 1999 • Reviewed occupational links to asthma and to COPD • Concentrated on population attributable risk (PAR) % • Work hazard defined broadly - typically: “exposure to vapors, gas, dust, and fumes”

43. ATS Statement: Chronic Bronchitis • 8 epidemiological studies reviewed including > 38,000 subjects • U.S. (1987), France (1988), Poland (1990), Italy (1991), Norway (1991), China (1993), Holland (1994), Spain (1998) • PAR% for occupational dust/fume: Range = 4-24%, Median = 15%

44. ATS Statement: COPDBreathlessness (Effort Dyspnea) • 6 epidemiological studies reviewed including > 25,000 subjects • U.S. (1987), France (1988), Italy (1991), Norway (1991), China (1993), New Zealand (1997) • PAR% for occupational dust/fume: Range = 6-30%, Median = 13%

45. ATS Statement: COPD Airflow Obstruction (Spırometry Deficit) • 6 epidemiological studies reviewed including > 12,000 subjects • U.S. (1977,1987), Italy (1991), Norway (1991), Spain (1998), New Zealand (1997) • PAR% for occupational dust/fume: Range = 12-55%, Median = 18%

46. ATS Statement: Conclusion ‘ …occupational exposures account for a substantial proportion of the (i.e., from 10-20%) of either symptoms or functional impairment consistent with COPD…a value of 15% is a reasonable estimate of the occupational contribution to the population of the burden of COPD. ’

47. Since ATS Statement: COPD, I • Sweden, n >317,000. Work dust PAR% for COPD mortality = 11% (53%, non-smokers)[Bergdahl et al. Eur Respir J 2004; 31:1-5] • USA, n>9,000. At risk occupations PAR% for COPD by PFT criteria = 19% (31% nonsmokers) based on industry (15%; 27% by occupation) [Hnizdo et al. Am J Epidem 2002; 156:738-46] • USA, n=517 non-smokers. Gases, fumes, dust by self report. PAR% for COPD by PFTS = 30%.[Mak et al. Am J Med Sci 2001; 322:121-6.]

48. Since ATS Statement: COPD, II • Australia, n=1213, COPD by FEV1/FVC <80% PAR% = 37% (biologic dust); PAR%=8% (mineral); PAR%=27% (gases)[Matheson et al. Thorax 2005; 60:645-51] • Spain, n=497, self-reported exposure to VGDF, COPD by FEV1 + FEV1/FVC, OR=1.2 (PAR%*= 9%) [Non-smokers PAR% =42%][Jaen et. al. Environ Health 2006, 5:2] *PAR% calculated from data, not reported

49. Since ATS Statement: Chronic Bronchitis, I • Denmark, n >3,300 men only. Longitudinal chronic bronchitis risk: dust=1.5 (PAR*=4%); solvents=1.5 (PAR*=5%); work cold air =1.4 (PAR*=17%)[Suadicani et al. Occup Environ Med 2001; 58:160-164] • Denmark, n>3,700. Longitudinal VGDF risk for chronic bronchitis OR= 2.2 (PAR%* 16%).[Lange et al. Age Aging 2003; 32:636-642] • International (14 countries) n>13,000. Risk by VGDF for chronic bronchitis Current sm, OR=1.7 (PAR%*=24%); Ex-sm,OR=1.8 (PAR%*=26%); Non-smoker OR=1.3 (PAR%*=12%)[Zock et al. Am J Respir Crit Care Med 2001; 163:1572-77] • *PAR% calculated from data, not reported

50. Since ATS Statement: Chronic Bronchitis, II • Singapore, n >50,000. Chronic bronchitis risk: dusty trades v. all others =1.4 (PAR%*=6%); [LeVan et al. Am J Epi 2006; 163:1118-28] • Sweden, n=8,469. Chronic bronchitis: laborers v. all other OR= 1.4 (PAR%*=11%). [Montnemery et al. Respir Med 2001; soi:101.1053] • Netherlands, n=1906. Chronic bronchitis risk for mineral dust [JEM], OR =2.2 (PAR%* = 25%) [de Meer et. al. Environ Health 2004,3:6] *PAR% calculated from data, not reported