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”
Occupational asthma is a disease characterized by variable airflow limitation and/or airway inflammation and/or nonspecific bronchial hyperresponsiveness due to causes and conditions which are attributable to a particular occupational environment and not to stimuli encountered outside the workplace.
Two types of OA are distinguished:
Immunological OA, that is characterized by a latency period (interval between onset of exposure and symptoms)
Non-immunological OA, that occurs after single or multiple exposures to irritants at high concentrations.
Bernstein IL et al. Asthma in the workplace, 2006. 3

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: , 2003.
Up to 15% of all asthmatic patients have significant worsening of their asthma because of occupational exposures that trigger transient bronchospasm. Although de novo occupational asthma (asthma that would never have developed without workplace exposure) is estimated to be about 2-5% of all cases of bronchial asthma in the U.S., failure to diagnose and manage these cases in a timely manner can lead to long-term, irreversible sequelae. 4

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 5

6. Irritants (moderate/high levels)
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 6

7. Exposure in the workplace
Irritants
high levels
allergens/sensitizers
Occupational asthma is usually due to an allergic response to high or low molecular weight antigens, either through the interaction with specific IgE antibodies or by IgE-independent immunologic mechanisms.
These allergic events lead to chronic and acute airway inflammation.
Less commonly, occupational asthma can result from high level irritant exposures at work.
Sensitization
IgE-dependent
IgE-independent
OCCUPATIONAL ASTHMA 7

8. Etiologies of Occupational Asthma High Molecular Weight Agents
EXAMPLES:
Flour - cereals
Animal danders
Latex
Psyllium
Crab processing
Enzymes
Some causes of occupational asthma are listed here and the importance will vary in different settings. 8

9. Etiologies of Occupational Asthma Low Molecular Weight Chemicals
EXAMPLES:
Isocyanates (HDI, MDI, TDI, IPDI)
Woods (red cedar, exotic, sawmills)
Antibiotics
Glues (methacrylates, cyanoacrylates)
Epoxies (anhydrides, amines...)
Colophony
Dyes
Isocyanates are highly reactive chemicals used as hardeners in various industries and represent ± 25% of cases of occupational asthma in US. 9

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
Isocyanate compounds such as TDI, MDI, and HDI, used in paints (particularly automobile paints), adhesives plastics, foams, and polyurethane, are leading causes of occupational asthma. Asthma from toluene diisocyanate (TDI) is clinically similar to allergic occupational asthma in many respects: a low concentration of TDI can cause asthma in susceptible workers, a latent period is necessary for sensitization, typically only a small number of exposed workers are affected, and after sensitization develops, minimal exposures will produce bronchospasm that previously would not have produced symptoms.
Studies of occupational asthma from isocyanates implicate multiple potential mechanisms, and demonstrate that the pathogenesis of occupational asthma may be more complex than asthma from non-occupational allergens such as house dust mites, pollens and animal danders. In contrast to classical IgE-mediated allergic occupational asthma, most studies of isocyanate asthma show poor correlation between bronchospastic responses to isocyanates and the presence of specific IgE antibodies. Non-IgE immunologic mechanisms have been implicated by several lines of evidence. For some isocyanates such as MDI and HDI, levels of IgG antibodies to isocyanate-protein conjugates best correlate with specific bronchial reactivity. However, these IgG antibodies are thought unlikely to be pathogenic, but rather are biomarkers for other incompletely understood immune responses that are pathogenic. Isocyanate asthma has also been associated with CD8+ clones that produce IL-5, an increased number of activated CD25+ T cells, lymphocyte proliferation in response to isocyanates, activated eosinophils, neutrophils and mast cells in the airway.
In addition, susceptibility and resistance to isocyanate asthma has been associated with different HLA-DQ alleles, implying that genetics may influence susceptibility to isocyanate asthma. 10

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
Most de novo occupational asthma is thought to be caused by sensitization mechanisms which often involve IgE allergic antibody responses. Typically, occupational asthma from sensitizers appears only after repeated exposures over months to years (latent period of sensitization); low, non-irritant levels not sensed by healthy individuals may cause symptoms; sensitivity increases with continued exposure; and symptoms often correlate with levels of IgE antibodies, as measured by skin testing or in vitro tests. Usually only a minority of exposed workers are affected. 11

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
This slide illustrates some of the multiple factors that are known to modify the risk of occupational asthma.
Higher molecular weight, protein agents are more likely to sensitize than are low molecular weight agents. However, some low molecular agents such as trimellitic anhydride (TMA) can readily react with airway proteins (e.g., albumin) to form hapten-protein conjugates that induce IgE antibody-mediated occupational asthma.
Some low molecular agents such as isocyanates, red cedar and various acrylates are also very potent sensitizers.
High level of exposures, particularly spills have been associated with an increase prevalence of occupational asthma.
In addition, longer period of exposure to sensitizing agents are more likely to result in occupational asthma.
Host factors may also influence development of occupational asthma, although their effect may vary according to the type of occupational exposure. Atopic individuals generally are more likely to develop asthma and specific IgE antibodies from high molecular weight (>1000 daltons) agents (e.g. latex, flour), but not from most low molecular weight occupational agents with a few notable exceptions (eg. Platinum salts). Individuals with pre-existing bronchial hyperreactivity may be more susceptible to developing occupational asthma from some agents but generally not to low molecular weights chemicals. Cigarette smokers are more likely to develop asthma from some occupational agents. 12

13. Onset of OA Latency period – highly variable…
Malo JL et al. JACI 1992; 90:937
0,0
0,2
0,4
0,6
0,8
1,0
Proportion of subjects without symptoms
Isocyanates
As illustrated in this slide (taken from Malo JL, Ghezzo H, D'Aquino C, L'Archevêque J, Cartier A, Chan-Yeung M. Natural history of occupational asthma: relevance of type of agent and other factors in the rate of development of symptoms in affected subjects. J Allergy Clin Immunol 1992; 90:937-44), symptoms of asthma may begin years after start of exposure although they often start in the first year. Chest symptoms beginning within days of starting a new job is not suggestive of occupational asthma unless there is a history of acute exposure to a toxic agent (RADS) or if the worker has been exposed previously before to the sensitizing agent.
High molecular weight agents
Western red cedar 40 30 20 10
Years of exposure before onset of symptoms 13

14. Occupational Asthma Prevalence
Western red cedar 5%
Plastics industry 5%
Animal breeders/handlers 6%
Bakers %
Metal refinery (platinum) 30-50%
The incidence of occupational asthma varies among occupations. Historically, workers manufacturing toluene diisocyanate (TDI) have become clinically sensitized at a rate of approximately five percent. On the other hand, bakers exposed to flour dust develop asthma at a rate of approximately ten to twenty percent. The reasons for these discrepancies are not clear, but they are probably the result of the sensitizing potential of the agent and the duration and degree of exposure to antigenic respirable materials in the workplace. With reduction of exposure levels through work place modification and employee protection, the prevalence of occupational asthma in some work places has been significantly reduced. 14

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
Among the many work environments where asthma occurs are plastics and paint manufacturing, electronics, photography, welding, metal refining, health related industries, hair salons, antibiotic and cosmetic manufacturing, saw mills, forestry, food processing and farming. Familiarization with the myriad of such agents that can cause occupational asthma is necessary to recognize potential exposures that may be causing occupational asthma. One must keep in mind that the list of sensitizing agents is continuously growing and that an occupational etiology must always be sought in adult-onset asthma. 15

16. Examples of Agents Causing Occupational Asthma
Family Examples
Metal Platinum, chrome, nickel
Vegetable/plant dusts Grain, bean, gum, latex, psyllium
Pharmaceuticals Antibiotics, cimetidine
Industrial chemicals Isocyanates, anhydrides
Enzymes Laundry detergents, pancreatic enzymes
Animal products Animal allergens
This slide lists the general families of agents causing occupational asthma in the column to your left. These include metal dusts, materials of vegetable or plant origin, pharmaceuticals, industrial chemicals, enzymes, and animal products. 16

17. Typical Physiologic Patterns of Response
As with non-occupational allergens such as molds, pollens and house dust, occupational sensitizers may cause early and dual (immediate and late) responses. However, low molecular weight occupational sensitizers are prone to cause isolated late responses without immediate responses. This must be borne in mind when assessing the temporal history between work exposure and development of respiratory symptoms.
Figure from 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.
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: 17

18. Atypical patterns of response
Some atypical patterns of bronchial responses to occupational challenges have also been described, particularly with low molecular chemicals such as red cedar and isocyanates.
Figure from 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.
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

19. 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
The reactive airways dysfunction syndrome (RADS) is the term which refers to the development of cough, wheezing and dyspnea after an acute, single exposure to a high level of an irritant agent such as ammonia or fumes (often in a workplace accident) in a patient without a prior history of airway disease. Patients develop symptoms within 24 hours of exposure and have bronchial hyperreactivity (e.g. to methacholine, cold air or exercise) that may persist for years after exposure. Results of pulmonary function tests may be normal or show reversible (often partly irreversible) air flow obstruction. Compared to patients with occupational asthma developing after a latency period, patients with RADS evaluated in the chronic stage have airway obstruction that is less reversible after inhalation of beta agonists, and have airways with more subepithelial thickening with fibrosis. Bronchial biopsies from RADS patients typically show epithelial desquamation and lymphocytic infiltrates, but not an increased number of eosinophils, a feature generally present in asthma.
See: Brooks SM, Weiss MA, Bernstein IL. Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 1985; 88: 19

20. 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

21. Occupational History Current and previous jobs Specific exposures
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
As part of the assessment of whether the history suggests occupational asthma, physicians need to obtain information about the patient's present and previous jobs. In some cases, exposures to materials at previous jobs may have sensitized the worker to an agent encountered in the current job. Accordingly, information should include specific information about jobs (employer, official job designation, actual job tasks, duration), specific exposures including adjacent work activity that may lead to adverse health effects, and control measures (e.g. ventilation, respiratory protection). When obtaining a worker’s history about job exposures, the worker may only know a slang name or trade name about a material used in the work place. Further information may therefore be required in order to determine the actual chemical composition of work place materials. 21

22. 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
Several important questions should be included in the history, such as: cirmcumstances of the onset of asthma symptoms, severity and persistence of asthma, the clinical course of the disease, and the
temporal relationships between exposures at work and disease exacerbation, that may occur within minutes of the onset of exposure at work (immediate asthmatic responses) or after several hours (late asthmatic responses) or both (dual asthmatic responses).
The medical history should also identify known triggers of asthma and intercurrent factors, as well as risk factors.
Atopic subjects and smokers are at a higher risk of OA due to high molecular weight agents. Tobacco smoke seems to act sinergistically with atopy to increase the risk of the disease.
Of course, the clinical history must include a focused occupational and environmental history, that in many instances may be sufficient to identify relevant exposures.
OA should be suspected in every adult with new-onset asthma
“Worsening of asthma symptoms on working days compared to weekends or holidays”
Clinical history has been found to have high sensitivity but low specificity
Consider co-morbidities: rhinitis, conjunctivitis, contact urticaria, dermatitis, food allergy... 22

23. 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
In approaching the diagnostic work up for occupational asthma, two basic questions must be answered. First, does the patient have asthma? If so, the second question is whether the asthma is caused or triggered by the work place, or by some other explanation.
The answer to the first question, whether asthma is present, is based upon the history of respiratory symptoms, physical examination and objective findings such as spirometric evidence of reversible airway obstruction. If this information fails to establish a diagnosis of asthma, assessment of bronchial hyperreactivity using non-specific challenge techniques (e.g., methacholine, eucapneic voluntary hyperventilation) can be helpful. If there is no evidence of non-specific bronchial hyperreactivity, particularly if testing is performed when the patient is having continuing exposure to suspect occupational agents, a diagnosis of asthma (and thereby occupational asthma) can essentially be ruled out. However, in workers who have stopped exposure to their sensitizing agent, a normal methacholine challenge does not rule out the diagnosis of occupational asthma. Indeed, in these subjects with occupational asthma, return to work or specific challenges may be associated with increased bronchial reactivity in the asthmatic range.
The answer to the second question, whether the asthma is caused or aggravated by occupational factors, is often more complex. To determine this, a combination of history and special objective assessments must be used. 23

24. 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?
In obtaining a history during the evaluation of a patient with suspected occupational asthma, it is important to know whether or not symptoms began within months of a job change, suggesting some new allergen or irritant in the new workplace environment. Likewise, one should determine if any new respirable agents have been introduced into the workplace and whether they are known to cause asthma, particularly when an individual who has been working in a certain work position for a long period suddenly develops asthma. Relief of symptoms on weekends or vacations while away from the workplace environment can also be a diagnostic clue (but not very specific), although one must be mindful that late phase responses may cause symptoms to persist over weekends away from the workplace. A thorough knowledge of the respirable agents present in the particular workplace environment, which can often be obtained in part by examination of material safety data sheets, is also of great value. Finally, information should be obtained about other workers who are possibly affected, including individuals who may have left the workplace environment because of symptoms. If one neglects to do this, one may fail to recognize that only a “survivor population” remains in the work place, leading to an underestimation about the causal importance of the work place exposures.   24

25. 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
By law, employers and manufacturers are required to disclose information that may help physicians care for persons with work-related health problems. Employers should have information on the chemical and physical agents used in their own work places and should be able to provide chemical and/or trade names. This information is essential, especially when a worker is able to provide only a slang name for a material being encountered in the work place.
By U.S. Federal Law, an employer is required to provide copies of relevant material safety data sheets (MSDS) to an employee, his or her representative or the patient's physician. A MSDS lists the identity of workplace agents that have potential health hazards including trade names for a product, chemical names for potentially hazardous constituents, and known information about adverse health effects, recommended exposure limits, and whether special protective work place measures should be used. A MSDS also lists contact information so that a physician may phone or write a product manufacturer for additional information. Although a MSDS may list helpful information, information may be incomplete, particularly about certain chemical components and their sensitization potential. For example, a MSDS may list a chemical component as a trade secret without identifying its chemical identity. In such cases, a manufacturer may disclose additional information if a physician contacts the manufacturer. As another example, MSDS lists are often incomplete because sensitizers in low concentrations (e.g. <1%) are often not reported although they may be highly relevant (see Bernstein JA. Material safety data sheets: are they reliable in identifying human hazards? J Allergy Clin Immunol 2002; 110(1):35-8.
Accordingly, health providers should not rely on MSDSs as the sole source of information. Labor unions should also not be overlooked as sources of information on toxic exposures. If the work place is unionized or a larger employer is involved, union officers, shop stewards, or health and safety committee members may be able to provide MSDSs, exposure data, medical information, and information about whether other workers reported adverse health effects. Searches of the medical literature may be needed to supplement this information.  25

26. 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
In the assessment of whether occupational asthma is present, it is important to determine whether there are alternative or confounding non-occupational explanations for asthma. Questions as follow may assist in this assessment.
Is there a poor relationship between acute work place exposure and symptoms?
Were there previous respiratory problems before work place exposure, such as prolonged wheezing, coughing after previous respiratory infections (suggesting preexisting asthma)? One must keep in mind however that the pre-existence of asthma does not exclude the diagnosis of occupational asthma.
Was there an upper respiratory infection at onset of symptoms (a common first presentation for adult-onset, non-occupational asthma)?
Are there non-occupational allergic factors (e.g. pets, symptoms with house dust or mold exposure, seasonal variation of symptoms coinciding with aeroallergen pollen seasons)?
Is there a smoking history that could predispose to COPD which could explain the symptoms of the worker?
Is there a family history of asthma or allergies?
Is there a family history of alpha 1-antitrypsin deficiency (that could predispose to COPD)?
Is there a history of recreational drug use? (e.g. heroin insufflation can cause asthma exacerbations, smoking crack cocaine can cause other lung disease, and injected drugs can cause talc pneumoconiosis that may complicate pulmonary status).
Are medications being used that could precipitate asthma (e.g. aspirin, non-steroidal anti-inflammatory drugs, beta blockers)?
Does the patient have a history of gastroesphogeal reflux symptoms?
Review of medical records may provide information about pre-existing respiratory problems and documentation when respiratory problems associated with work exposure first occurred. 26

27. 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).
Occupational/industrial hygienists can be consulted who can review work place environments. They can help identify agents in the work place capable of causing occupational asthma, perform tests to determine if suspect agents are present at harmful levels, and recommend specific changes in the work environment to reduce exposure (e.g. improved ventilation). They can also identify which sensitizing agents are found in the workplace as the worker is often unaware of his exposure. Exposure does not have to be above TLV limits (see next slide) to be hazardous to the workers as toxic are different from sensitizing levels. After an employer is notified that a worker may have occupational asthma, larger employers may have their own occupational/industrial hygienists who can conduct an investigation. For smaller employers, an employers’ workers compensation insurance carrier will often retain the services of an occupational hygienist so that the work place can be assessed for health hazards. 27

28. 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)
Governmental regulatory agencies and trade organizations have developed a variety of exposure limits values that may be cited in material safety data sheets and other sources. Threshold Limit Values (TLVs) of the American Conference of Government Industrial Hygienists (ACGIH) refer to airborne concentrations of substances below which it is believed that workers may repeatedly be exposed, day after day, without adverse effect. TLVs are recommendations and do not carry the weight of law.
Time-Weighted Averages (TWAs) consider that short term levels of airborne exposure may vary over a work shift, but the average levels of exposure should not exceed certain levels. By convention, exposure below TWA levels should not present any health hazard to a normal worker exposed for 8 working hours, 5 days a week. Because acute, short term exposure to relatively high concentrations of an agent might cause airway irritation or chronic disease, Short-Term Exposure Limits (STEL) or ceiling limits have also been developed. In an occupational hygiene evaluation of a work place, it could be found that although time-weighted average exposure limits are not being exceeded, short term exposure limits or ceiling limits are being exceeded that could present risk to a worker and explain respiratory symptoms from occupational exposure.
The Occupational Safety and Health Administration (OSHA) of the U.S. federal government establishes Permissible Exposure Limits (PELs) for many substances with TWA, STEL or ceiling limits as appropriate. These may vary slightly from recommendations established by the ACGIH.
As stated earlier, these safety limits are different from those which would protect workers from sensitization and symptoms once sensitized. There is currently no safety limits determined for sensitization although some attempts have been made. (See Baur X. Are we closer to developing threshold limit values for allergens in the workplace? Ann Allergy Asthma Immunol 2003; 90(5 Suppl 2):11-8.) 28

29. 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
Reliance upon history alone is an unsatisfactory means for diagnosing occupational asthma, as studies have shown that this will frequently lead to a misdiagnosis of occupational asthma when it is not present, or less commonly, a failure to diagnose occupational asthma when it is present. Indeed, One must keep in mind that, although the questionnaire is very sensitive, it is poorly specific, its positive predictive value being only 63% while its negative predictive value is 83% ( cf. Malo J.L., Ghezzo H., L'Archeveque J., Lagier F., Perrin B., and Cartier A. Is the clinical history a satisfactory means of diagnosing occupational asthma? Am Rev Respir Dis 1991:143; )
If the patient is still working in the work place, work related changes in peak flows can confirm a diagnosis of occupational asthma. Repeated and significant (≥ 20%) falls in peak flow values with work place exposure support the diagnosis of occupational asthma. PEF monitoring can be coupled with monitoring of non specific bronchial responsiveness to methacholine which can increase its sensitivity and specificity. Pre and post-shift changes in FEV1 have not been shown to be adequately sensitive or specific.
When occupational asthma from an agent that causes IgE mediated sensitivity is suspected, immediate-type skin testing with appropriate materials may establish sensitization but this does not confirm the diagnosis of occupational asthma. In vitro tests for specific IgE (e.g. RAST) may be useful but are generally less sensitive, and the predictive diagnostic value of some commercially available tests has not been established. For some isocyanates, specific IgG antibody levels correlate better with documented bronchospasm from isocyanate exposure than do specific IgE levels, even though specific IgG antibodies are not thought to be pathogenetic. However, positive in vivo or in vitro tests for immunologic sensitization only support, but do not by themselves prove the existence of occupational asthma.
Although the diagnosis of occupational asthma may often be made on the basis of the evidence just discussed, a positive controlled inhalation challenge to the specific agent from the work environment is considered the “reference standard” for diagnosis. These challenges are done either in the lab or in the workplace with close monitoring of spirometry by a technician over a work-shift period. In these instances, monitoring of spirometry on a control day (either with or without a sham exposure) is essential to rule out spontaneous diurnal variation of spirometry. 29

30. 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)
Skin prick testing is commonly used to identify sensitization to HMW allergens because it is safe, specific and more sensitive than most in vitro assays. Skin testing is not adequate to assess the response to LMW antigens, with the exception of platinum salts.
It is also possible to use in vitro tests for the detection of allergen-specific IgE antibodies, such as the radioallergosorbent test (RAST) or ELISA. Sometimes it is possible to perform more detailed immunologic studies, such as electrophoretic methods in combination with immunoblotting, or crossed radioimmuno-electrophoresis, that allow identification and characterization of the allergenic components.
Few occupational allergen extracts are commercially available for skin testing, most of which are not standardized, and may not be of the adequate potency. Sensitization to clinically irrelevant allergenic components and cross-reactivity with common aeroallergens may hamper the reliability of these tests.
In some cases, purified or recombinant allergens may be used, which might help to overcome these problems. 30

31. Sensitivity, Specificity, and Positive Predictive Values (PPV) of IgE for Predicting SPT and IC Dilutions
Dilution
Level
Total Responses
IgE > 0.1
Sensitivity
Specificity
PPV*
p-valueb N
%Total
SPT 31 3
9.7%
88.9%
90.3%
72.7%
<0.001
>0 9 8
89.9%
SPT+ Dermal a 29 1
3.4%
90.9%
96.7% 11 10
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:

32. Cytokine responses for TMA exposed workers
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

33. Monitoring of PEF & PC20: Objective confirmation of asthma exacerbations at work
Ideally, measurements of PEF should be performed for at least two weeks, every two hours, at work and off work. Because peak flow measurements are effort dependent and usually performed without medical observation (making it possible for a worker to record falsely low peak flow measurements in order to support allegations of occupational asthma), and as they are less sensitive to changes in airway caliber than FEV1, they are less reliable than work-related changes in spirometry. However, use of newer peak flow devices that record all peak flow efforts and the time these are performed can improve the reliability of peak flow monitoring. Reproducible triplicate efforts performed within several minutes are consistent with good patient effort. This slide illustrates the case of a crab processing worker who upon return to work showed significant changes in PEF associated with an increase in bronchial reactivity as assessed by an histamine bronchial challenge, the concentration of histamine causing a 20% fall in FEV1 (or PC20) falling upon return to work while the FEV1 recorded in the clinic had not changed. Taken from 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 Immunol 1984; 74:261-9.
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

34. 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
There are three indications for performance of a controlled inhalation challenge: diagnostic uncertainty, diagnostic dispute and research. If the individual gives a poor history, if there are multiple other confounding variables, or if work related changes in spirometry or peak flows are unavailable or uncertain, specific inhalation challenge testing is considered the “reference standard” to establish a definite cause-and-effect relationship between exposure to an inhaled substance and production of symptoms. Likewise, if physicians, employers, plaintiff and defense attorneys disagree on whether or not a worker actually has occupational asthma and should or should not be compensated, a challenge test may help by demonstrating whether the individual develops bronchospasm in response to exposure to sub-irritant levels of the suspect occupational agent.  
In research, controlled inhalation challenges with a suspect occupational agent may be useful in characterizing the potential for adverse health effects of that agent, and establishing exposure limits. 34

35. 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
There are several relative contraindications for performing specific inhalation challenge.
Ideally, bronchodilators or anti-inflammatory medications should be held prior to challenge, although this may be impossible if patients have more severe asthma. If asthma medications are not held for an appropriate interval before challenge, a bronchial response may be blunted, leading to a false negative challenge. The appropriate interval for holding asthma medications before each challenge varies. For example, short-acting inhaled beta agonists should be held for at least 8 hours prior to challenge, whereas long acting beta-2 agonist or anticholinergic and sustained release theophyllline preparations should be held for 48 hours prior to challenge. In many instances, it may be necessary to continue inhaled corticosteroids on the challenge days to avoid loss of asthma control. In these cases, the total dose may be given at the end of the day. Although the bronchial response may be blunted, it is unlikely that the response will be completely abolished.
Patients with unstable asthma and/or those with spirometric measurement showing evidence of a large degree of airway obstruction (FEV1 < 1.5 L) should not be challenged because of the risk of inducing severe bronchospasm and the difficulty interpreting changes in lung function after challenge.
Patients who have severe medical illnesses or psychological problems that would prevent their cooperation with a challenge (e.g. claustrophobia) generally should not be challenged. 35

36. 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.
In performing controlled inhalation challenges for a suspect occupational agent, a number of practical considerations must be followed. In most cases, hospital admission is not necessary. A series of challenges using steadily increasing exposure doses is necessary if any particular agent is to be proved relevant to the disorder under investigation. Because incremental increases generally are on the order of two to five times of the previous dose, four or even more challenges may be required along with one or more control tests.
When performed under close medical supervision, by experienced technicians and in specialized centers, specific inhalation tests are safe and fast. However, they may induce a life-threatening bronchospasm and adequate resuscitative material should be immediately available. They are also more expensive than simple monitoring of PEF. A worker should give informed consent, understanding the risks, rationale and time requirements for specific challenge testing.
In certain circumstances, specific challenges are done in the workplace with serial monitoring of spirometry at work by a technician. These tests are often indicated when the sensitizing agent at work is unknown, if the working environment cannot be reproduced in the laboratory or if there are too many potential sensitizers. 36

37. 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.
A positive challenge (defined by a sustained fall in FEV1 ≥ 20% as compared to a control mock day) confirms the diagnosis of occupational asthma. If the exposure induced the usual symptoms presented by the subject but if there were no significant changes in FEV1, the diagnosis of occupational asthma is less likely, and other diagnoses such as hyperventilation syndrome should be considered. Other measures considered to confirm the diagnosis of occupational asthma include ≥3-fold decrease post challenge in the concentration of methacholine that elicits a 20% fall in the FEV1, or the appearance of eosinophils in sputum induced post challenge compared to baseline pre-challenge. 37

38. 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)
However, a negative challenge does not entirely exclude the diagnosis of occupational asthma if exposure did not reproduce the worker’s symptoms. Indeed, the worker may have been exposed to the wrong agent (or the sensitizing process at work may not have be active on the challenge day), he may have lost his specific sensitivity particularly if exposure at work has been stopped for a long period. In such instances, monitoring of methacholine bronchial responsiveness after the challenge may show an increase in non specific bronchial responsiveness and a further exposure may then induce a positive response. Alternatively, return to work may be associated with recurrence of symptoms in a few days or weeks. Finally, the worker may have taken medication not allowed during the test. 38

39. 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

40. 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)

41. 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: )
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:

42. 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

43. 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.
In some cases where irritants are involved, a worker with occupational asthma may return to work if there is sufficient modification of the environment to reduce exposure (e.g. by increased ventilation, use of protective gear) and if surveillance measures are followed (e.g. air monitoring to verify low exposure levels and pulmonary function testing to assure no decline of respiratory status after exposure to the modified workplace). When a worker has developed occupational asthma to a sensitizer, even low levels of exposures may be intolerable and the worker should be removed from the work place in order to prevent increased sensitization and more serious disease. In work place environments that have significant potential for causing occupational asthma, medical surveillance of all workers on a periodic basis (e.g. every 6-12 months) can help identify workers who have developed evidence of early sensitization or occupational respiratory disease. Depending on the assessed risk, the worker may need to be reassigned to a different work environment to prevent further sensitization and significant clinical disease.
Although anti-inflammatory and bronchodilator medications used in other forms of asthma are also useful in occupational asthma, the focus of management should always be on avoidance and reduction of harmful occupational exposures.
Reduction or elimination of non-occupational factors in a worker’s asthma should also be pursued. For example, avoidance measures to reduce exposure to concomitant non-occupational allergens of significance (e.g. house dust mite, pets) also should be instituted, as this may help reduce airway hyperreactivity and thereby susceptibility to exposure to work place agents.
Consider the possibility that other exposed workers may have occupational asthma – see Tarlo S.M., Boulet L.P., Cartier A., Cockcroft D., Côté J., Hargreave F.E., Holness L., Liss G., Malo J.L., and Chan-Yeung M. Canadian Thoracic Society. Guidelines for occupational asthma. Can Respir J 1998:5 (4); . 43

44. 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.
After development of occupational asthma, early removal from the offending environment usually should either result in marked improvement or resolution of asthma; if no improvement occurs, the diagnosis of occupational asthma should be questioned and non-occupational causes should be reconsidered. Nonetheless, occupational asthma from some agents (e.g. isocyanates, Western red cedar, colophony, snow crab) and even some irritants has been reported to result in persistent abnormalities in lung function for years after removal from the work environment. Factors reported to be associated with a worse prognosis include greater length of exposure, greater duration of symptoms, greater severity and frequency of attacks, greater airway obstruction or hyper-reactivity at time of diagnosis, and presence of dual bronchial responses. 44

45. 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

46. Impairment and Disability from Occupational Asthma
Assess 2 yrs after removal from exposure
Respiratory impairment assessed by guidelines [ATS Guidelines ARRD 147: , 1993.]
Degree of airway obstruction, reversibility
Airway hyperresponsiveness
Medication requirements
Disability
Limitation in work tasks or activities of daily living, including future work restrictions
In the evaluation of occupational asthma, a physician may be asked to rate respiratory impairment for legal determination of workers compensation. Assessment of permanent impairment/disability from occupational asthma should be carried out 2 years after the removal from causal occupational exposure when improvement has been shown to plateau.
Impairment is defined as a functional abnormality resulting from a medical condition. Based upon the degree of abnormality of both physiologic and clinical parameters, several published guidelines are used for rating the degree of respiratory impairment from asthma. Factors to be assessed include the level of airflow reduction as assessed by post-bronchodilator FEV1; the degree of airway hyper-responsiveness or reversibility of abnormal FEV1 with bronchodilator; and the minimum amount of medication required to maintain control of asthma (or best results), an amount which if reduced leads to exacerbation of symptoms and reduced lung function.
Disability is a term used to indicate the total effect of impairment on a patient's life. An assessment of disability from asthma includes consideration of any limitation in the ability to perform work tasks or activities of daily living because of respiratory status, including a need for future work restrictions.
Whatever published guidelines are used, a physician should express an opinion whether the rating underestimates or overestimates impairment/disability for an individual. 46

47. 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
Several millennia ago, Hippocrates said that physicians should take into account the environments in which their patients live. Several hundred years ago, Bernadino Ramazzini, the father of occupational medicine, added to the words of Hippocrates by advocating that the physician take one more point into account, namely what is the occupation of his patient. In the case of occupational asthma, taking an occupational history is of great importance in suspecting the diagnosis and initiating appropriate objective evaluation and intervention. Intervention should be focused on reducing or avoiding harmful work place exposures so that permanent lung impairment and need for chronic medical treatment are avoided. 47

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

49. Third
In my unbiased opinion, this is the definitive text on OA, Asthma in workplace, now in its 2nd edition
co-edited by Names
and authors that makes up a list of who’s who in the field