1. Diagnostic Strategies for Occupational Asthma Louis-Philippe Boulet, MD, FRCPC Institut de cardiologie et de pneumologie de l’Université Laval, Hôpital Laval Québec, Canada Université Laval

2. Synopsis  Definition  Mechanisms  Main causal agents  Diagnostic strategies  Conclusion

3. Prevalence of asthma Masoli M et coll. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469-78.

4. Epidemiology  Asthma : 5-10 % of occupational origin  Incidence of asthma may vary according to: – Type of agent – Duration and intensity of exposure – Risk factors Atopy Genetic factors (HLA) Smoking

5. Estimated prevalence of work related-asthma Mapp et al. AJRCCM 2006

6. “Occupational asthma is a disease characterized by variable airflow limitation and/or hyperresponsiveness and/or inflammation due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace.” - With a latency period: classical occupational asthma - Without latency period: irritant induced asthma & RADS Bernstein IL, Chan-Yeung M Malo JL, Bernstein DI. Asthma in the Workplace Marcel Dekker Inc., NY 1993 Occupational asthma

7. Asthma caused by workplace exposure (occupational asthma) After latency period Without latency period « Irritant-induced asthma » or « Reactive airways dysfunction syndrome » Asthma exacerbated by exposure at the workplace Variants of asthma e.g. non asthmatic eosinophilic bronchitis Asthma at the workplace

8. Risk factors, e.g. atopy, genetic markers, smoking, etc. exposure concentration, duration of exposure and nature of the sensitized agent; Other intercurrent factors: viral infection, exposure to pollutants, smoking, etc. sensitization Occupational asthma exposure total duration of exposure, duration of symptoms after exposure, severity of asthma at the time of diagnosis asthma or healing ??? baseline airway hyperreactivity Natural history of occupational asthma pharmacologic modulation development of airway inflammation

9. Pathogenesis  Immune mechanisms – Latency period – Mininal exposure can lead to a severe bronchospasm – Various mechanisms: mainly production of specific IgE  Non immune mechanisms

10. Source : Mapp CE, Boschetto P, Maestrelli P, Fabbri LM. Occupational Asthma. Am J Respir Crit Care Med. 2005

11. Low molecular weight agents

12. High molecular weight agents

13. Investigation Based on :  Medical & environmental history*  Specific bronchoprovocation test (in laboratory or at work)  Methacholine test  PEF at work and out of work  Skin prick test  Induced sputum * http://www.asmanet.com/asmapro/substances.htm

14. Diagnosis  History – Exposure Current or past work Description of tasks and agents at work – Symptoms Initially present at work May be accompanied by symptoms of rhino-conjunctivitis Some may also cause symptoms of alveolitis

15. Diagnosis  History – Symptoms Diagnosis may be difficult: –if the exposure is intermittent –if the patient has not recently been exposed –with progression of the disease (Fixed Airflow Limitation, severe asthma…) Latency period variable –Shorter with LMW agents (e.g. Isocyanates)

16. Diagnosis  Diagnosis – Confirm the presence of asthma – Establish the relationship between asthma and the workplace – Identify causal agent and subject’s response to this agent

17. Diagnosis  Diagnosis – Confirm the presence of asthma Significant response to bronchodilator (variable airway obstruction) OR Identification of airway hyperresponsiveness to a pharmacological agent (e.g. methacholine)

18. Diagnosis  Diagnosis – Establish the relationship between asthma and the workplace PEF Spirometry Repeated measurements of non allergic airway responsiveness at work and out of work Skin prick tests for certain agents (e.g. animal danders) Change in the eosinophil counts after exposure

19. Screening of occupational asthma High molecular weight agents Skin prick tests negative positive Methacholine test during time of work negativepositive referNo occupational asthma

20. Screening of occupational asthma Low molecular weight agents questionnaire and methacholine test during the time of work If both are positive, refer

21. Occupational asthma without latency period (“irritant-induced asthma”)  Diagnosis based on history : only one event sometimes repeated high exposure event

22. A diagnostic challenge…  Differential diagnosis with an exacerbation of preexisting asthma – Caused by exposure to irritants at the workplace – E.g. dust, smoke, … – Treatment is different: Can continue to work but with changes in the environment or the level of exposure Medication should be adjusted

23. Diagnosis and management of Occupational Asthma

24. Clinical investigation of Occupational Asthma

25. Investigation protocol

26. QUESTIONNAIRE Pattern of symptoms Positive predictive value: 63% Negative predictive value: 83%

27. PEF

28. PEF Circadian variation

29. Serial PC 20 methacholine tests  2 measures – End of holiday – End of working period  Suggestive of OA: – Improvement by 3.2X out of work – E.G.: 2 to 12 mg /ml

30. PC20 methacholine

31. Diagnosis – Identification of the causal agent Bronchoprovocation in specialized centres –HMW: can be done with increasing concentration over one day –LMW: may require many days with increasing doses as there are not always early responses Skin prick tests –Available for some proteinic agents –When negative: usually exclude OA

32. Specific bronchoprovocation test  « Gold-standard for the diagnosis of occupational asthma  If asthma is stable (FEV 1 >60-70% predicted and/or > 2 L)  Control day : – Exposure to a non specific irritant or a spontaneous variation of expiratory flows measurement – Fall in FEV 1 < 10%  Exposure days : – Controlled and increasing concentrations / time of exposure – Different methods for LMW and HMW substances – Positive if FEV 1 falls > 20% Vandenplas O, Malo JL. Inhalation challenges with agents causing occupational asthma. Eur Respir J. 1997

33. Specific Inhalation Challenge  Baseline FEV1  After each exposure period: – FEV1 and FVC at 30 sec and 10 min  After last inhalation, – Each 10-15 min x 1 hr then hourly for 7-8 h  PEF measures on return home in the evening  Monitor symptoms, sometimes DLCO and temperature (alveolitis?)

34. SIC - Early Response

35. SIC - Dual Response

36. SIC – Atypical Response

37. SIC – Very Late Response

38. Patterns of response to occupational agents  206 subjects  More frequent Late or Dual Responses with Low Molecular Weight substances  EAR more frequent un women and smokers % 0 10 20 30 40 50 60 70 80 EARLAR Dual Response Atypical Response HMW LMW * * * p < 0,0001

39. Role of induced sputum in the diagnosis of occupational asthma Lemière et al.  2000 : 15 subjets with OA Increase eosinophils after exposure (LMW > HMW) Early markers of exposure / sensitization ?  2001 : 41 subjets, 17 with positive BPT ↑ eosinophils + neutrophils with HMW + LMW Sputum eosinophilia and change in airway responsiveness could predict the response to occupational agents.  2004 : 49 subjets, 23 with positive BPT Sputum eosinophils is a valuable tool to support the diagnosis of OA

40. Occupational Asthma and Work- Exacerbated Asthma: Factors associated with time delay to diagnosis Occupational asthma -Male sex, unmarried, low education, lack of awareness of symptoms association with work, older age, sole income of the family and no knowledge of potential effects of occupational agents Work-exacerbated asthma - Lower household income, low education, absence of health and safety program at work, no union, lack of awareness of potential effects of occupational agents and of OA. Santos et al Chest 2007;131: 1768.

42. Conclusion  Occupational asthma is one of the main causes of respiratory diseases at work  It is important to make the diagnosis early to prevent long term consequence on lung function  Patient should be referred to the Workmen’s Compensation Board  Promotion of preventative strategies is important particularly for high-risk workers

43. Bronchial provocation test with occupational sensitizers