Diagnosis of Work-related Asthma

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

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

3. Guidelines and Statements • 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 • 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.

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   - 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. • 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 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: • Irritant-induced • Sensitizer-induced

7. OA? • 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

8. Differential diagnosis for WRA • Other asthma (non-occ) coincidentally worse while working • Non-asthma causes for asthma-like symptoms • GERD • 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] • Hyperventilation/anxiety • Eosinophilic bronchitis • - or any combination of these ± WRA

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

10. Sensitizer-induced OA DiagnosisValue of the history • Exposures, symptoms: start while working, improve w-ends/holidays off work PPV 63%, NPV 83% (Malo et al ’91) • Daily wheeze worse at work most sensitive (88%) • + itchy nose/eyes • + 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) • 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 • MSDS, WHIMIS: have limitations, incomplete information • 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 • History could be influenced by other factors • Management differs for OA vs. WEA • Early correct diagnosis of sensitizer-OA with removal from exposure leads to the best asthma prognosis • 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: • Confirm a diagnosis of asthma objectively • Review MSDS • Skin test where feasible • PEFR and Methacholine responses work and off work, considering possible confounding factors • Add induced sputum if available • Consider specific challenges if available, especially if the diagnosis is in doubt

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

17. Skin tests/ immunologic tests • Limited skin test extracts commercially available for occupational allergens • Few are standardized • Immunologic sensitization is more common than OA in exposed workers • 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. • 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

19. Evidence-based medicine Diagnosis and Management of OA (AHRQ ’05)

21. Beach J et al Chest 2007

22. 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 • at least 4x per day, several weeks at work and off work • requires careful patient instruction • needs compliance • effort-dependent • no generally accepted objective criteria for interpretation • 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 Working weeks Off work days Methacholine PC20 0.07mg/ml Methacholine PC20 11.6 mg/ml

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

26. PEFs • 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 • Record at least 2 weeks at work and 10 days off work

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

28. PEF 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) • 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)

29. PEFs • 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)

30. Methacholine challenges • Serial inhalation of increasing concentrations of nebulized methacholine • Spirometry pre- and post- each dose. • 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) • 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 • 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

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. • 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

34. Specific laboratory challenges • Labour-intensive and expensive • 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 • 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: • irritant exposure levels • uncontrolled asthma or unrelated exacerbation • False negative responses: • wrong “sensitizer” • insufficient exposure (concentration/duration), especially after a prolonged period away from exposure • 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 • Objective monitoring at work (e.g. hourly spirometry, preferably with laboratory quality equipment and personnel) • 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)

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. OA vs WEA Diagnosis

40. 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