1. Diagnosis of Work-related Asthma Susan M Tarlo, MB BS, FRCP(C) Professor, Dept Medicine, and Dalla Lana School of Public Health University of Toronto, Respiratory Division, Toronto Western Hospital

2. These groupings are not mutually exclusive; e.g. OA can be followed by WEA Chest 2008

3. Guidelines and Statements Assessment of Asthma in the Workplace, an ACCP Consensus Statement. Chest 1995;108:1084-117. Assessment of Asthma in the Workplace, an ACCP Consensus Statement. Chest 1995;108:1084-117. CTS Guidelines on Occupational Asthma. Can Resp J 1998;5:289-300 CTS Guidelines on Occupational Asthma. Can Resp J 1998;5:289-300 British Thoracic Society, Standards of Care for Occupational Asthma. Thorax 2008;63:240-50. British Thoracic Society, Standards of Care for Occupational Asthma. Thorax 2008;63:240-50. Diagnosis and Management of Work-related Asthma. ACCP Consensus Statement. Chest 2008;134:1S-41S. Diagnosis and Management of Work-related Asthma. ACCP Consensus Statement. Chest 2008;134:1S-41S.

4. Consensus Document Diagnosis and Management of Work-related Asthma. ACCP Consensus Statement. Chest 2008;134:1S-41S. http:/www.chestjournal.org/cgi/content/abstract /134/3_suppl/1S http:/www.chestjournal.org/cgi/content/abstract /134/3_suppl/1S - Based on an AHRQ evidence-based review, (Agency for Healthcare Quality and Research) 2005, supplemented by recent literature review to Dec 2006 and by panel consensus - Based on an AHRQ evidence-based review, (Agency for Healthcare Quality and Research) 2005, supplemented by recent literature review to Dec 2006 and by panel consensus

5. WEA Work-related worsening of asthma that started before the job or began incidentally. Work-related worsening of asthma that started before the job or began incidentally. Common (up to 25% of working asthmatics) Common (up to 25% of working asthmatics) May be transient and diagnosed on history or may occur daily at work and may mimic occupational asthma, requiring similar investigations May be transient and diagnosed on history or may occur daily at work and may mimic occupational asthma, requiring similar investigations May be due to expected asthma triggers such as dusts or temperature extremes, or to common allergens that may be in the workplace. May be due to expected asthma triggers such as dusts or temperature extremes, or to common allergens that may be in the workplace.

6. OA OA= Asthma due to causes and conditions which are attributable to a particular workplace environment and not to stimuli encountered outside the workplace: OA= Asthma due to causes and conditions which are attributable to a particular workplace environment and not to stimuli encountered outside the workplace: Irritant-induced Irritant-induced Sensitizer-induced Sensitizer-induced

7. OA? Some WRA does not clearly fit the definitions Some WRA does not clearly fit the definitions – previous childhood asthma recurring from sensitization to a specific work agent - existing asthma that worsens at work from sensitization to a specific work agent Clinical implications of these are as for OA but may/may not be included in compensation definitions Clinical implications of these are as for OA but may/may not be included in compensation definitions

8. Differential diagnosis for WRA Other asthma (non-occ) coincidentally worse while working Other asthma (non-occ) coincidentally worse while working Non-asthma causes for asthma-like symptoms Non-asthma causes for asthma-like symptoms GERD GERD Upper airway cough syndrome (post nasal drip) Upper airway cough syndrome (post nasal drip) Irritable larynx syndromes (WILS) – Hoy et al Occupational Medicine 2010; 60:546-51 [30 cases vs 90 WRA] Irritable larynx syndromes (WILS) – Hoy et al Occupational Medicine 2010; 60:546-51 [30 cases vs 90 WRA] Hyperventilation/anxiety Hyperventilation/anxiety Eosinophilic bronchitis Eosinophilic bronchitis - or any combination of these ± WRA - or any combination of these ± WRA

9. OA - Irritant-induced (Reactive Airways Dysfunction Syndrome) About 7% of all OA: from a high irritant exposure About 7% of all OA: from a high irritant exposure Onset typically within 24 h of exposure Onset typically within 24 h of exposure New symptoms of asthma, persist >3mo New symptoms of asthma, persist >3mo Exposure expected to be a high level irritant Exposure expected to be a high level irritant Asthma confirmed: PFTs / methacholine responses Asthma confirmed: PFTs / methacholine responses documented absence of previous respiratory disease documented absence of previous respiratory disease No specific diagnostic test available No specific diagnostic test available Most certain = RADS, less certain if criteria not all met Most certain = RADS, less certain if criteria not all met

10. Sensitizer-induced OA Diagnosis Value of the history Exposures, symptoms: start while working, improve w- ends/holidays off work Exposures, symptoms: start while working, improve w- ends/holidays off work PPV 63%, PPV 63%, NPV 83% (Malo et al ’91) NPV 83% (Malo et al ’91) Daily wheeze worse at work most sensitive (88%) Daily wheeze worse at work most sensitive (88%) + itchy nose/eyes + itchy nose/eyes + lack of hoarseness, + lack of hoarseness, - predicted 74% of high MWt OA (Vandenplas et al ERJ ’05) Nevertheless overall ~50% of specific challenges are negative even when OA suspected, emphasizing need for objective tests.

11. Exposure history for sensitizer- induced OA HMWt almost any airborne protein (plant, animal, fish, fungal, insect, enzymes) HMWt almost any airborne protein (plant, animal, fish, fungal, insect, enzymes) LMWt many reactive chemicals, especially with double bonds and 2 or more reactive side chains LMWt many reactive chemicals, especially with double bonds and 2 or more reactive side chains Seed M, Agius R. Further validation of computer- based prediction of chemical asthma hazard. Occup Med (Lond) 2010; 60:115-20.

12. Exposure assessment Patient’s history: often limited Patient’s history: often limited MSDS, WHIMIS: have limitations, incomplete information MSDS, WHIMIS: have limitations, incomplete information Occupational hygienist assessment: company hygienist, independent private assessment or public health/government agency, e.g MOL, NIOSH Occupational hygienist assessment: company hygienist, independent private assessment or public health/government agency, e.g MOL, NIOSH

14. Why objective tests are necessary to diagnose OA 1. History could be influenced by other factors 2. Management differs for OA vs. WEA 3. Early correct diagnosis of sensitizer-OA with removal from exposure leads to the best asthma prognosis 4. Objective diagnosis may lead to changes to prevent sensitization and OA in other workers

15. Diagnostic recommendations (from ACCP Consensus 2008) In patients with a hx of possible OA: In patients with a hx of possible OA: Confirm a diagnosis of asthma objectively Confirm a diagnosis of asthma objectively Review MSDS Review MSDS Skin test where feasible Skin test where feasible PEFR and Methacholine responses work and off work, considering possible confounding factors PEFR and Methacholine responses work and off work, considering possible confounding factors Add induced sputum if available Add induced sputum if available Consider specific challenges if available, especially if the diagnosis is in doubt Consider specific challenges if available, especially if the diagnosis is in doubt

16. Objective diagnosis of asthma FEV1 pre/post bronchodilator FEV1 pre/post bronchodilator Methacholine/histamine challenge Methacholine/histamine challenge sensitive for asthma if patient is still working and symptomatic sensitive for asthma if patient is still working and symptomatic positive findings do not confirm a work relationship positive findings do not confirm a work relationship negative findings do not exclude OA if not recently exposure to the sensitizer negative findings do not exclude OA if not recently exposure to the sensitizer occasional reports of normal responsiveness in diisocyanate-OA occasional reports of normal responsiveness in diisocyanate-OA

17. Skin tests/ immunologic tests Limited skin test extracts commercially available for occupational allergens Limited skin test extracts commercially available for occupational allergens Few are standardized Few are standardized Immunologic sensitization is more common than OA in exposed workers Immunologic sensitization is more common than OA in exposed workers Skin tests are unhelpful for most low-molecular-weight sensitizers Skin tests are unhelpful for most low-molecular-weight sensitizers

18. In-vitro immunologic tests In-vitro immunologic tests only reliable in a few centres. In-vitro immunologic tests only reliable in a few centres. Generally less diagnostic value than skin tests for high molecular weight sensitizers, eg natural rubber latex Generally less diagnostic value than skin tests for high molecular weight sensitizers, eg natural rubber latex Limited sensitivity/specificity for low molecular-weight sensitizers at present, eg diisocyanates Limited sensitivity/specificity for low molecular-weight sensitizers at present, eg diisocyanates

19. Evidence-based medicine Diagnosis and Management of OA (AHRQ ’05) HMWtSensitivitySpecificity Methacholine79%51% Specific IgE (skin/serum) 81/ 73% 60 / 79% Both61%83% LMWt Methacholine67%64% Specific IgE (skin/serum) 73 / 31% (very select studies, often not feasible) 86 /89% (often not feasible)

21. Beach J et al Chest 2007

23. Objective documentation of work-related changes in asthma Serial peak expiratory peak flow monitoring (PEF) with sx and med diary Serial peak expiratory peak flow monitoring (PEF) with sx and med diary at least 4x per day, several weeks at work and off work at least 4x per day, several weeks at work and off work requires careful patient instruction requires careful patient instruction needs compliance needs compliance effort-dependent effort-dependent no generally accepted objective criteria for interpretation no generally accepted objective criteria for interpretation by themselves, positive results do not distinguish OA from work-exacerbated asthma by themselves, positive results do not distinguish OA from work-exacerbated asthma

24. A 42 year old polyurethane foam worker PEFR (L/min), 4 x per day Off work Working weeks Methacholine PC20 0.07mg/ml Methacholine PC20 11.6 mg/ml days

25. A 50 year old dry cleaner Methacholine PC20 0.03 mg/mlMethacholine PC20 0.02 mg/ml Working weeksOff work days PEFR (L/min), 4 x per day

26. PEFs Also record symptoms and prn medication use. Also record symptoms and prn medication use. Keep regular meds stable at the lowest dose to adequately control symptoms but not to mask PEF changes Keep regular meds stable at the lowest dose to adequately control symptoms but not to mask PEF changes Record at least 2 weeks at work and 10 days off work Record at least 2 weeks at work and 10 days off work

27. PEF interpretation confounders Inadequate technique Inadequate technique Poor compliance with recordings Poor compliance with recordings Fabrication of results Fabrication of results Intercurrent cold or non-occupational exposure to asthma triggers Intercurrent cold or non-occupational exposure to asthma triggers Work exposures not representative of those causing symptoms Work exposures not representative of those causing symptoms Changes masked by medications Changes masked by medications Any of these may need further repeat PEFS

28. PEF Interpretation Expert visual interpretation Expert visual interpretation Formula e.g. ≥20% variability from maximum occurring relatively more frequently working days vs off work (93% sens 77% specificity when variability >1 day) (Liss, Tarlo ’91) Formula e.g. ≥20% variability from maximum occurring relatively more frequently working days vs off work (93% sens 77% specificity when variability >1 day) (Liss, Tarlo ’91) OASYS: 2-hourly PEFs analyzed to score 1-4, a cut-off 2.5 for OA: 75% sensitivity, 94% specificity (www.occupationalasthma.com) OASYS: 2-hourly PEFs analyzed to score 1-4, a cut-off 2.5 for OA: 75% sensitivity, 94% specificity (www.occupationalasthma.com) ABC (area between the curves) uses OASYS2 for curves work days vs days off work with readings >6 times per day, reported 72% sensitive, 100% specific at ABC 15 L/min/hour (Moore VC et al Chest, 2009; 135: 307- 14) ABC (area between the curves) uses OASYS2 for curves work days vs days off work with readings >6 times per day, reported 72% sensitive, 100% specific at ABC 15 L/min/hour (Moore VC et al Chest, 2009; 135: 307- 14)

29. PEFs Electronic spirometers allow assessment of compliance but expensive (~$500) Electronic spirometers allow assessment of compliance but expensive (~$500) Despite problems with compliance, a recent systematic review showed 61% had interpretable recordings and of those, a pooled sensitivity for OA 82%, specificity 88% (Moore et al Ann Resp Med ’10) Despite problems with compliance, a recent systematic review showed 61% had interpretable recordings and of those, a pooled sensitivity for OA 82%, specificity 88% (Moore et al Ann Resp Med ’10)

30. Methacholine challenges Serial inhalation of increasing concentrations of nebulized methacholine Serial inhalation of increasing concentrations of nebulized methacholine Spirometry pre- and post- each dose. Spirometry pre- and post- each dose. Test is stopped with at least a 20% drop in FEV1 Test is stopped with at least a 20% drop in FEV1 PC20 calculated (lower = more hyper- responsive, cut-off 8mg/ml, borderline 4- 16mg/ml) PC20 calculated (lower = more hyper- responsive, cut-off 8mg/ml, borderline 4- 16mg/ml) A ≥3-fold worsening in PC20 at work is significant A ≥3-fold worsening in PC20 at work is significant

31. Methacholine challenge A single test is useful to diagnose asthma – with current asthma symptoms/exposures A single test is useful to diagnose asthma – with current asthma symptoms/exposures Paired tests (one at the end of a work week and one after a period off work) is useful to assess work-related changes (e.g. OA) Paired tests (one at the end of a work week and one after a period off work) is useful to assess work-related changes (e.g. OA) Confounders: lab technique, intercurrent colds or other non-occupational exposures, insufficient time away from work exposure Confounders: lab technique, intercurrent colds or other non-occupational exposures, insufficient time away from work exposure

32. Peak flows and methacholine responses

33. Combinations of tests A combination of investigations has been advocated in OA guidelines/consensus statements, as far as is feasible. A combination of investigations has been advocated in OA guidelines/consensus statements, as far as is feasible. However, skin tests/immunologic tests often cannot be performed, patients often cannot adequately comply with PEFRs, and methacholine/histamine challenges may require travelling a long distance for the tests. However, skin tests/immunologic tests often cannot be performed, patients often cannot adequately comply with PEFRs, and methacholine/histamine challenges may require travelling a long distance for the tests. Despite recommendations, patients may have stopped work before assessment and be unwilling/unable to return on a trial basis Despite recommendations, patients may have stopped work before assessment and be unwilling/unable to return on a trial basis

34. Specific laboratory challenges Labour-intensive and expensive Labour-intensive and expensive Require specialized facilities with exposure- monitoring as well as prolonged response- monitoring Require specialized facilities with exposure- monitoring as well as prolonged response- monitoring Although referred to as a “gold standard”, there can be false positive and false negative responses Although referred to as a “gold standard”, there can be false positive and false negative responses In some countries, medicolegal concerns regarding positive responses have also limited use In some countries, medicolegal concerns regarding positive responses have also limited use

35. Laboratory challenges

36. Limitations to specific challenge interpretations (? how frequent) False positive: False positive: irritant exposure levels irritant exposure levels uncontrolled asthma or unrelated exacerbation uncontrolled asthma or unrelated exacerbation False negative responses: False negative responses: wrong “sensitizer” wrong “sensitizer” insufficient exposure (concentration/duration), especially after a prolonged period away from exposure insufficient exposure (concentration/duration), especially after a prolonged period away from exposure failure to monitor for late responses or airway responsiveness changes failure to monitor for late responses or airway responsiveness changes

37. Workplace challenge Open challenge in suspected work area compared with an expected unexposed area Open challenge in suspected work area compared with an expected unexposed area Objective monitoring at work (e.g. hourly spirometry, preferably with laboratory quality equipment and personnel) Objective monitoring at work (e.g. hourly spirometry, preferably with laboratory quality equipment and personnel) Expensive, employer may not permit access, exposures not blinded Expensive, employer may not permit access, exposures not blinded Most effective for hospital workers who can have the tests on-site in the PFT lab (including methacholine tests) Most effective for hospital workers who can have the tests on-site in the PFT lab (including methacholine tests)

38. Induced sputum eosinophilia as a diagnostic test (Girard et al AJRCCM ’04) Induced sputum working and off work (Confounders include inhaled steroid use, URIs and co- incidental allergen exposures)

39. Immunologic tests for Diisocyanate- OA Vapor phase TDI-HSA vs. liquid phase conjugates in ELISA for specific IgE antibodies showed much greater sensitivity for OA, (Ye et al JACI ’06) Vapor phase TDI-HSA vs. liquid phase conjugates in ELISA for specific IgE antibodies showed much greater sensitivity for OA, (Ye et al JACI ’06) 44% vs 17% 44% vs 17% HDI-HSA vapor phase 55% OA positive vs. 1.5% healthy controls (Wisnewski, JACI 2004) HDI-HSA vapor phase 55% OA positive vs. 1.5% healthy controls (Wisnewski, JACI 2004) Currently still only available in research labs (commercial tests have poor reliability)

40. OA vs WEA Diagnosis OAWEA Asthma history No preceding asthma Preceding asthma Work sensitizer +- Objective asthma ++ PEF worse with work ++ Methacholine PC20 better off work ++/- Sputum eos increase with work +/-+/- Work agent immunologic tests + if feasible - Specific challenge +-

41. Diagnostic Summary In patients with a hx of possible OA: Confirm an objective diagnosis of asthma Review MSDS / exposures Skin test where feasible PEFR and Methacholine responses work and off work, considering possible confounding factors Consider specific challenges if diagnosis is in doubt Consider addition of induced sputum if available A combination of tests is most useful