Diagnosis, Prevention and Treatment of Occupational Asthma

1. Diagnosis, Prevention and Treatment of Occupational Asthma Jonathan A. Bernstein, M.D. Professor of Medicine University of Cincinnati Department of Internal Medicine Division of Immunology/Allergy Section

2. Jonathan A. Bernstein, M.D.Disclosures Financial: Consultant to Flint Hills Resources Research: Flint Hills Resources Legal Consult/Expert Witness:Environmental related issues Organizational:AAAAI EORD interest section Gifts:None Other:Journal of Asthma Editor-in-Chief

3. Occupational asthma Definition “Occupational asthma is a form of work-related asthma characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation attributable to a particular exposure in the workplace and not due to stimuli encountered outside the workplace” Bernstein IL et al. Asthma in the workplace,2006.

4. Occupational Asthma: Significance Occupational exposures cause significant worsening in up to 15% of asthmatics. Estimated 15% of de novo adult asthma cases in U.S. are occupational asthma. Failure to diagnose and manage promptly can lead to long-term, irreversible sequelae. ATS Statement: Occupational contribution to the burden of airway disease. 167: 787-797, 2003.

5. Classification of Work-related Asthma Sensitizer induced occupational asthma High molecular weight Low molecular weight Unknown Irritant induced occupational asthma (RADS) Aggravation of pre-existing asthma by workplace exposures

6. Work-related asthma Inducers Inciters Irritants (moderate/high levels) Irritants (toxic levels) No latency Allergens/ sensitizers Latency Work-exacerbated asthma Irritant-induced occupational asthma Sensitizer-induced occupational asthma

7. Exposure in the workplace Irritants high levels allergens/sensitizers • Sensitization • IgE-dependent • IgE-independent OCCUPATIONAL ASTHMA

8. Etiologies of Occupational AsthmaHigh Molecular Weight Agents EXAMPLES: Flour - cereals Animal danders Latex Psyllium Crab processing Enzymes

9. Etiologies of Occupational AsthmaLow Molecular Weight Chemicals EXAMPLES: Isocyanates (HDI, MDI, TDI, IPDI) Woods (red cedar, exotic, sawmills) Antibiotics Glues (methacrylates, cyanoacrylates) Epoxies (anhydrides, amines...) Colophony Dyes

10. Isocyanates: Common Sensitizers In paints, adhesives, plastics, foams, polyurethane Putative mechanisms Specific IgE in minority, specific IgG as biomarker of other immunologic responses? Lymphocytes, eosinophils, neutrophils, mast cells Genetic influence HLA-DQ alleles

11. Occupational Asthma Induced By Sensitizing Agents Latent period of immunologic sensitization After sensitization, low levels may cause symptoms Sensitivity increases with continued exposure If IgE mediated, may correlate with skin tests, in vivo tests Usually only in minority of workers

12. Factors modifying risk for sensitizer induced Occupational Asthma Industrial factors Nature of occupational agent Molecular weight, reactivity Level of exposure (spills, etc) Duration of exposure Host factors Atopy Underlying bronchial hyperreactivity Genetic susceptibility Cigarette smoking in some

13. Onset of OA 1,0 0,8 0,6 0,4 0,2 0,0 0 10 20 30 40 Latency period – highly variable… Malo JL et al. JACI 1992; 90:937 Proportion of subjects without symptoms Isocyanates High molecular weight agents Western red cedar Years of exposure before onset of symptoms

14. Occupational Asthma Prevalence Western red cedar 5% Plastics industry 5% Animal breeders/handlers 6% Bakers 10-30% Metal refinery (platinum) 30-50%

15. Diverse industries associated with sensitizer induced Occupational Asthma Plastics and paint manufacturing Electronics, photography Welding, metal refining Health care, pharmaceutical manufacturing Saw mills, forestry Farming

16. Typical Physiologic Patterns of Response Perrin B, Cartier A, Ghezzo H, Grammer L, Harris K, Chan H et. Al. Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents. J Allergy Clin Immunol 1991; 87: 630-9.

17. Atypical patterns of response Perrin B, Cartier A, Ghezzo H, Grammer L, Harris K, Chan H et al. Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents. J Allergy Clin Immunol 1991; 87:630-9

18. Reactive Airways Dysfunction Syndrome (RADS) No previous history of asthma Acute, high level exposure to toxic/irritant Respiratory symptoms within 24 hrs of exposure Persistent respiratory symptoms, non-specific bronchial hyperreactivity Pulmonary function may be normal or show reversible obstruction: but obstruction less reversible than sensitizer induced asthma Eosinophilic infiltration not characteristic Worse outcome than sensitizer induced OA

19. Exacerbation of pre-existing asthma Reported in > 20% of asthmatics in 1° care settings. Asthma that preceded or started concurrently with the implicated work conditions, and worsened at work. Causes include typical asthma triggers such as dusts or fumes at work, cold air and exercise. If frequent or persistent, may mimic sensitizer OA. Document with objective tests, especially when work-related symptoms are frequent or prolonged, or sensitizer-induced OA is in the differential diagnosis. Management includes: optimizing asthma control. may require reducing work exposure to triggers (e.g. short-term use of respirators, or move to cleaner area.

20. Occupational History Current and previous jobs Employer, job names and descriptions, duration Specific exposures Adverse health effects Control measures Provision and use of personal protective equipment Work place practices (e.g. procedures to follow if a spill occurs) Engineering controls

21. Elements of the clinical history Circumstances of the onset of asthma symptoms Severity and persistence, clinical course of asthma Temporal relationships between exposures at work and disease exacerbation: Immediate (minutes), late (hours) or dual (both) Known triggers and intercurrent factors of asthma Identify risk factors: Atopy – Smoking habit Focused occupational/environmental history

22. Diagnostic Approach to Occupational Asthma Does the patient have asthma? History, physical examination Reversible airway obstruction (e.g. spirometry) Non-specific airway hyperreactivity If absent while symptomatic and at work, may rule out diagnosis Is the asthma caused by work or a non-occupational factor? History Objective testing

23. Does History Suggest Occupational Basis? Symptoms within months of job change? (though may also take years to develop.) New agent introduced in workplace? Are respirable agents in the workplace known to cause asthma? Symptoms relieved on weekends or vacations? Are other workers affected? Have workers left because of similar symptoms?

24. Additional Information About Suspected Work Exposures Information sources: employers, product manufacturers, labor unions. Material safety data sheet (MSDS) (Bernstein JA, Material safety data sheets: are they reliable in identifying human hazards? JACI 2002;110:35-8.) By law, employer must provide Identity of workplace agents and information about adverse health effects May be misleading Contacts for additional information Medical literature searches

25. Does History Suggest Non-Occupational Basis? No relation between work and symptoms Preexisting asthma / respiratory problems Upper respiratory infection at onset of symptoms Non-occupational allergies Smoking Medications (beta blockers, NSAIDs) Gastroesophageal reflux symptoms  Review medical records

26. Occupational Hygiene Assessment Occupational/industrial hygienists assess workplace environments. Identify relevant exposures. Measure concentrations to determine if suspect agents are present at harmful levels Recommend changes in the work environment (e.g. product substitution, improved ventilation).

27. Standards for Airborne Exposure OSHA Permissible Exposure Limits (PEL) Time-Weighted Averages (TWA) Short-Term Exposure Limits (STEL) Ceiling limits ACGIH Threshold Limit Values (TLV)

28. Beyond History: Testing for Occupational Asthma History alone insufficient for diagnosis Objective testing Work-related changes in peak flows (&/or NSBR) Immunologic testing for occupational allergens Controlled inhalation challenge with suspect agent

29. Immunologic assessment • Skin prick tests (occasionally ID) to HMW agents • In vitro tests • Measurements of specific IgE: RAST/CAP, ELISA • Immunoblotting, CRIE • Reagents: • Whole “natural” extracts (not standardized, potency?) • Purified allergens (e.g. enzymes, isolated proteins) • Recombinant allergens (e.g. latex allergens)

30. Sensitivity, Specificity, and Positive Predictive Values (PPV) of IgE for Predicting SPT and IC Dilutions PPV=positive predictive value; IC=intracutaneous a SPT+ IC = 0 if SPT=0 and IC=0, otherwise (SPT+ IC) > 0. b p-value <0.001 indicates a significant association between dilution category and IgE category. Note: Specific IgE values that were entered as “< ” were considered to be below the limit of detection (< LOD). Otherwise values were considered above the limit of detection (> LOD). • Bernstein JA, et.al. Is Trimellitic Anhydride Skin Testing a Sufficient Screening Tool for Selectively Identifying TMA-Exposed Workers With TMA-Specific Serum IgE Antibodies? JOEM 2011;53: 1122-7.

31. Results Cytokine responses for TMA exposed workers Non-Ab producers(n=7) IgG-Ab producers (n=7) * IgG-IgE-Ab producers (n=7) * % CD4+ cells * IFNγ IL-4 Treg • Ghosh D, et.al. Cytokine responses in TMA-Exposed Workers (Presented at the AAAAI, 2011). *p<.01

32. Monitoring of PEF & PC20:Objective confirmation of asthma exacerbations at work Cartier A, Malo JL, Forest F, Lafrance M, Pineau L, St-Aubin JJ et al. Occupational asthma in snow crab-processing workers. J Allergy Clin Immunol1984; 74:261-9

33. Indications for Controlled Challenge with Suspect Agent Diagnostic uncertainty Poor history, confounding factors, work related changes in peak flows unavailable or equivocal, unknown etiology, can’t return to work for monitoring Diagnostic dispute Physicians, employers, insurance companies, attorneys Research

34. Relative Contraindications for Specific Inhalation Challenge Inability of worker to hold asthma medications before challenge Unstable asthma and/or low FEV1 Severe underlying medical or psychological problem

35. Specific Inhalation Challenge in Occupational Asthma Most often, these tests are done on an outpatient basis. Multiple challenges required. Tests are time consuming and expensive. Informed consent and compliance needed. Not always available.

36. Interpretation of positive challenge A positive challenge is usually defined by a sustained fall in FEV1 of ≥ 20%, compared to the control mock exposure day. Other indices suggesting OA: 3.2-fold change in pre vs. post challenge PC20 Increase in eosinophils in post vs. pre challenge induced sputum.

37. Interpretation of negative challenge A negative challenge, however, does not entirely exclude the diagnosis of occupational asthma: Wrong agent (or sensitizing process not active) Loss of sensitization over time out of exposure Mixture of antigens at work not replicated in challenge Took medication that blocked the test (e.g. bronchodilators)

38. Purpose of Immunosurveillance Programs • To periodically evaluate the health of workers in the workplace • Monitor clinical symptoms • Monitor changes in lung function • Monitor changes in Chest x-rays (Berylliosis…) • Monitor specific antibody responses • Monitor lymphocytic responses (Berylliosis…) • Identification of workers demonstrating signs of sensitization and/or work related symptoms • Early removal from further exposure • Identify hazardous work conditions using group health information and environmental information • Implement appropriate interventions to prevent reoccurrences or new cases • Evaluation of the effectiveness of exposure controls

39. Medical Surveillance Methods • Itemized questionnaires • Respiratory responses to 22 irritants correlated with methacholine PC20 (Brooks SM, et.al. JACI 1990;85;17-26) • Spirometry • Testing for Nonspecific Bronchial Hyperresponsiveness • Methacholine, mannitol, histamine • Immunological tests • ELISAs (low and high molecular weight antigens) • Skin testing (enzymes, animal handlers, some LMW chemicals such as anhydrides and platinum salts)

40. Industries with Successful Immunosurveillance Programs • Diisocyanates • Two year longitudinal study of 243 workers exposed to diphenylmethylene diisocyanate (MDI) in a urethane mold plant surveyed workers annually with questionnaires, screening spirometry and MDI-HSA specific antibodies • Identification of 3 new cases of OA were identified; one of these workers had no respiratory symptoms and recognized only by screening spirometry • Removal from further exposure led to remission of asthma in all 3 cases after one year • Implementation of stricter control procedures and continuous ambient MDI exposure (Bernstein, D.I., et.al. JACI 1993; 92:387-96) • Enzymes • Proctor and Gamble developed a comprehensive immunosurveillance program that incorporated preclinical, analytical, clinical and hygiene assessments (Schweigert, M.K. et.al. Clin and Exp Allergy 2000; 30:1511-1518) • Acid Anhydrides • No cases of worker’s compensation or disability since 2007 • Bernstein JA, et.al. Is Trimellitic Anhydride Skin Testing a Sufficient Screening Tool for Selectively Identifying TMA-Exposed Workers With TMA-Specific Serum IgE Antibodies? JOEM 2011;53: 1122-7.

41. Limitations/Challenges of Immunosurveillance • Evidence supporting immunosurveillance is based on non-randomized studies • Validation of surveillance programs/methods is required • Demographic diversity (gender, race, age, smoking history, past medical history for allergies and asthma) • Difficult to identify risk factors for sensitization and disease • Individual variability of exposure • Difficult to correlate personal exposure with sensitization and disease • Lack of reliable immunologic biomarkers that can identify workers at risk for developing sensitization and the development of occupational respiratory symptoms

42. Occupational Asthma Management Reduce / avoid exposure in workplace. Removal of worker in some cases, particularly if sensitizer present. Surveillance measures: Periodic monitoring of work place exposures, spirometry, tests for immunologic sensitization. Medications. Address any non-occupational factors. The patient with OA should be considered a sentinel event in the workplace.

43. Occupational Asthma Prognosis Timely removal should result in improvement. Residual disease: Isocyanates, red cedar, snow crab, some irritants, other agents. Prognosis worse if: longer duration of exposure, greater severity / frequency of symptoms, airway obstruction or hyper-reactivity, dual bronchial responses.

44. Occupational asthma prognosis Restriction from exposure or removal from the job often has significant socioeconomic consequences for the worker: Loss of income Unemployment Higher medication costs in those remaining in exposure Be reasonably sure of the diagnosis and cause of OA before recommending job change.

45. Impairment and Disability from Occupational Asthma Assess 2 yrs after removal from exposure Respiratory impairment assessed by guidelines [ATS Guidelines ARRD 147: 1056-61, 1993.] Degree of airway obstruction, reversibility Airway hyperresponsiveness Medication requirements Disability Limitation in work tasks or activities of daily living, including future work restrictions

46. Occupational Asthma Summary Take into account your patient’s environment. Hippocrates, c. 400 B.C. To the question recommended by Hippocrates, one more should be added, “What occupation does he follow?” Ramazzini, 1713 A.D. History is key to suspecting OA Use objective measures to confirm diagnosis Focus on prevention

47. Acknowledgment • AAAAI • I.L. Bernstein, M.D. • Debajyoti Ghosh, Ph.D.

48. Third