Investigation of occupational asthma

1. Hôpital du Sacré-Cœur de Montréal Investigation of occupational asthma Catherine Lemiere MD, MSc Associate Professor, University of Montreal Sacré-Cœur Hospital, Montreal Université de Montréal

2. Investigation of occupational asthma • History • Diagnosis of asthma • Skin tests and serology • Monitoring of PEF and PC20 off and at work • Specific inhalation challenges • Monitoring of airway inflammation

3. Chan-Yeung & Malo; NEJM, 1995

4. History

5. What questions should be asked to a worker with possible OA? • The questionnaire include questions regarding: • Type of work and work shift, agent that the worker identifies as responsible for his/her symptoms. 2) Nature of symptoms: • respiratory • systemic • nasal • ocular • cutaneous 3) Temporal relationship between symptoms and occupational exposure (at the beginning or at the end of exposure, persistence after the work shift) 4) Importance of symptoms at work, on weekends, on holidays. Berstein et al. Asthma in the workplace 1999

6. Clinical history Occupational asthma * • Final Diagnosis • OA (n=75) • Asthma without OA • (n=54) • No asthma, No OA • (n=33) Very probable-prob Uncertain Improbable-No 65 6 4 25 19 10 14 10 9 Negative and positive predictive value of 83 & 63% • A history of asthma at work, even in the presence of a known sensitizer, does not confirm the diagnosis of occupational asthma * Malo JL et al. Am Rev Respir Dis 1991; 143:528-532

7. Diagnosis of asthma

8. Diagnosis of asthma • Reversible airflow limitation: improvement in FEV1 >12% and et > 180ml post-ß2 agonist. • PC20 methacholine/histamine * • A negative PC20 does not exclude the diagnosis ofoccupational asthma in a worker off work, but makes it unlikely in a symptomatic workerstill at work PC20 : concentration of meth./hist. Inducing a 20% fall in FEV1

9. Skin tests & serology

10. Skin prick tests ± IgE/IgG ... • valid for HMWC & rarely for LMWC • requires good allergen extracts a positive test confirms sensitization but not occupational asthma Neg. pred. value: 76% 89% Pos. pred. value: 69% 54%

11. PEF Monitoring

13. False negative Poor compliance in PEF monitoring stored recorded correspondence between recorded and reported values: 52% Malo JL et al, JACI 1995

14. True negative Compliance may be good… stored recorded Malo JL et al, JACI 1995

15. Non-invasivemonitoring of airway inflammation: Use of induced sputum

16. p= 0.9 p<0.001 p=0.1 p=0.006 5.0 64.0 L L 4.0 8.0 m , / V g 1 E m F 3.0 1.0 , 0 C 2 P 2.0 0.12 1.0 0.015 Work At Off At Off At Off At Off p=0.6 p=0.007 p=0.2 p=0.01 10000 100 % , s l L i / h g p µ 10 1000 o , n P i C s o E E 100 1.0 0.1 10 Lemière C et al. Eur Respir J, 1999; 13: 482-8

17. The vast majority of subjects with occupational asthma show an increase in sputum eosinophils after exposure to the offending agent which is not the case in subjects without OA 3.00 2.40 1.80 Sputum eosinophils, 106/ml 1.20 0.60 0.0 B E B E B E Negative SIC Positive SIC Asthma without OA LLemiere et al J Allergy Clin Immunol. 2001; 107: 1063-8

18. Inflammatory and functional changes in subjects with and without OA * p <0.05 (Girard et al, ARJCCM 2004)

19. Sensitivity and specificity of different diagnostic strategies compared to SIC 1 0.9 0.8 PEF 0.7 PEF/Sputum (1% cutoff) 0.6 Sensitivity PEF/sputum (2% cutoff) 0.5 0.4 0.3 0.2 0.1 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1- Specificity (Girard et al, ARJCCM 2004)

20. Specific inhalation challenges (SIC) The reference test to confirm the diagnosis of occupational asthma

21. SIC - advantages • Safe • Fast, easy to perform and allow gradual exposure, avoiding too severe reactions (safer than return to work in some cases) • Allow identification of the responsible agent • Can be done on an out-patient basis

22. SIC – restrictions & precautions • Exposure may induce life-threatening asthma • Done under close supervision of an expert physician • Requires well trained and responsible technicians • Resuscitation material readily available • Need for a control day and PC20 assessment

23. Flour Methods- realistic exposure

24. Flour Dust generator – safe & controlled exposure

25. SIC - procedure • Control day to ensure that spirometry is stable • (lactose, diluent…), from 8:00 to 16:00, PC20 at end of day • Progressive and careful exposure • In one day if positive skin tests (HMWC) • On several days for LMWC (1-4, 30 & 120 min) • FEV1 q. 10 min. X 1 h., q. 30 min. X 1 h., then hourly for a total of 8 hours (+ FVC, T°) • PC20 at end of tests

26. SIC - In the workplace • Less controlled exposure • Process involved may not be active • More difficult to exclude irritant effect • FEV1 at 30-60 min. interval + FVC + T° • Combine if possible with monitoring of PC20 • Positive test = Fall in FEV1> 20% - confirms the diagnosis of OA

27. SIC - at work - indications • No known sensitizer • Unable to reproduce work condition in the lab • Too many potential sensitizers • To "exclude" asthma at work (legal issues…) • Requires trained personnel... • no previous history of severe asthma at work

28. Typical patterns of response

29. Eosinophilic Bronchitis Diagnosis and Treatment

30. Eosinophilic bronchitis • Sputum eosinophilia can be observed in subjects without airflow limitation or airway responsiveness. (Gibson et al. Lancet 1989:1346-8) • This has been described in chronic cough and labeled eosinophilic bronchitis. • Chronic cough with eosinophilic bronchitis is controlled with ICS. (Gibson PG et al. 1994 Clin Exp Allergy 1994; 127-32).

31. CAUSES OF ISOLATED CHRONIC COUGH (n = 91) Primary Cause of Cough No. of Patients (%) Rhinitis 20 (24%) Asthma 16 (17.6%) Postviral 12 (13.2%) Eosinophilic bronchitis 12 (13.2%) Gastroesophageal reflux 7 (7.7%) Unexplained 6 (6.6%) COPD 6 (6.6%) Bronchiectasis 5 (5.5%) ACE inhibitor-induced cough 4 (4.4%) Lung cancer 2 (2.2%) Cryptogenic fibrosing alveolitis 1 (1.1%) Brightling et al. Am. J. Respir. Crit. Care Med., 1999; 160: 406-10

32. Occupational eosinophilic bronchitis • Three subjects referred for possible OA • Exposed to low-molecular weight agents • cyanoacrylates • isocyanates (MDI) • Platinum salts

33. Clinical characteristics Smoking Treatment Symptoms Age, Sex Atopy Agent y (pack/y) at work IS: 200µg/d - 1 50 F - Ex(15) C,S,D , Cyano 2 agonist ; W,CT acrylates $ IS:1000µg/d 2 64 M - No C,S,D , MDI 2 agonist ; W,CT $ 3 44 M A 24 0 C,S Platinum salts

34. Functional and inflammatory characteristics Status FEV ,L VC,L PC , TCC Eos Neu 1 20 (% pred ) (% pred ) mg/ml x10 6 /ml % % 1 At W 2.3(100) 3.0(111) 24 1 13 16.3 Off W 2.5(108) 3.1(114) >64 1.3 0 26.7 2 At W 2.6(76) 4.0(92) 16 15.7 11 79 Off W 2.8(82) 4.2(97) 25 7.8 0.8 80.4 3 At W 3.8(90) 5.8(111) 57 2 27 26.3 Off W 4.0(95) 5.3(103) >64 1.3 0.5 19

35. Normal Control Glue Inhalation Test values Inhalation 30 min exposure Test 7 h after 24 h after 7 h after Chest symptoms + ++ + Nose symptoms 0 0 0 Treatment 0 0 0 FEV , L (% pred ) 2.2 2.4 (105) 2.4 (103) 2.6 (114) 1 VC , L (% pred ) 2.7 3.3 (120) ND 3.3 (120) PC , mg/ml >16 >64 ND >64 20 Induced sputum TCC , 10 6 /ml : <4.5 2.7 3 1.4 Neutrophils, %: <35 28.7 65.5 54.2 Eosinophils, % <2 0 5.8 5 Metachromatic cells %: <0.07 0 1.5 0.26 9 /L <0.4 0.2 ND 0.4 Blood eosinophils ,10 Lemière C et al. J Allergy Clin Immunol 1997; 100:852-3

36. Yacoub MR et al Allergy, 60 2005 1542

37. Diagnostic criteria for occupational eosinophilic bronchitis Quirce: Curr Opin Allergy Clin Immunol, Volume 4(2).April 2004.87-91

38. Conclusions • The diagnosis of OA is often difficult to make. • A comprehensive investigation needs to be performed. The diagnosis of OA must rely on respiratory function changes induced by the exposure to the suspected occupational agent. • History alone is not sufficient to make a diagnosis of OA.