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

TTS 2006, Kemer-Antalya, 20.04.2006 Symposium FEMTOS Recent advances in thoracic diseases

Recent advances in occupational lung diseases

Benoit Nemery, MD, PhDLung Toxicology Research Unit

Occupational Medicine

and Pneumology

K.U.Leuven – Belgium

ben.nemery@med.kuleuven.be

• 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

“Common” respiratory diseases and occupation

• Respiratory infections

• COPD

• Asthma

• Lung cancer

Respiratory infections and work

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)

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

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%)

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

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

Fouchier et al. PNAS 2004; 101: 1356-61

Fatal pneumonia in previously healthy 57 y-old veterinarian

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 (?)

Asthma and COPD

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)

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.

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

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 %

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 ?

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!)

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

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

TLV-STEL

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). AJRCCM 2003, 168, 2-3

Bronchial hyperreactivity PC20 ≤ 8 mg/ml

Banauch et al. AJRCCM 2003; 168: 54-62

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

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

Ardystil syndrome

“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)

Ardystil syndrome

Moya et al. (Lancet, 1994, 344, 498-502)

“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)

Ardystil syndrome

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

A

A

Ardystil syndrome

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

Ardystil syndrome

27%

66%

23%

71%

FVC FVC

Ould Kadi et al. (Eur. Respir. J. 1999, 13, 940-941)

“Flock worker’s lung”

“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

Flock worker’s lung - HRCT

Kern et al. Ann. Int. Med. 1998, 129, 261-72

Pt. 4 Pt. 8 Pt. 2

Nylon flock microfibres

NIOSH HETA 96-0093

Scanning electron microscopy of bulk nylon fiber ends

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.

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

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

Atis S. et al. ERJ, 2005, 25, 110-7

TNF- IL-8

Popcorn worker’s lung

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 ?

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

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 ppmCH3- C - C - CH3

O O

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

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)

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

Popcorn worker’s lung

Akpinar-Elci et al.

Eur Respir J. 2004, 24, 298-302

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)

« ... considerable efforts

are needed to improve the

diagnosis and reporting of

occupational diseases. »

Thank you for your attention

ben.nemery@med.kuleuven.be

Bernardino Ramazzini(Carpi, Modena, 4 Oct.1633 -

Padova, 5 Nov.1714)

De Morbis Artificum PRÆFATIO

Multa sunt quae medicus ad aegrotum Multa sunt quae medicus ad aegrotum accedens, ab aegro ipso seu accedens, ab aegro ipso seu assendentibus, sciscitari debet ex divini assendentibus, sciscitari debet ex divini Praeceptoris oraculo. Praeceptoris oraculo. Cum ad aegrotum Cum ad aegrotum deveneris, interrogare oportet quae deveneris, interrogare oportet quae patiatur, et ex qua causa, et quot jam patiatur, et ex qua causa, et quot jam diebus, et an venter secedat, et quo victu diebus, et an venter secedat, et quo victu utatur, utatur, verba sunt HIPPOCRATIS in verba sunt HIPPOCRATIS in librolibro De Affectionibus; De Affectionibus; liceat quoque liceat quoque interrogationem hanc adjicereinterrogationem hanc adjicere: : et quam et quam artem exerceatartem exerceat..

There are many things that a doctor, on his first visit to a patient, ought to find out, either from the patient or from those present. For so runs the oracle of our inspired teacher: “When you come to a patient’s house, you should ask him what sort of pains he has, what caused them, how many days he has been ill, whether his bowels are working and what sort of food he eats.” So says Hippocrates in his work Affections. I may venture to add one more question: “What occupation does he follow?”