Transcript Approaches to the Diagnosis and Management of

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
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
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.
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.
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
Work-related asthma
Inducers
Inciters
Irritants
(moderate/high
levels)
Workexacerbated
asthma
Irritants
(toxic levels)
No latency
Allergens/
sensitizers
Latency
Irritant-induced
Sensitizer-induced
occupational asthma
occupational
asthma
Exposure in the
workplace
Irritants
high levels
allergens/sensitizers
Sensitization
• IgE-dependent
• IgE-independent
OCCUPATIONAL ASTHMA
Etiologies of Occupational Asthma
High Molecular Weight Agents
EXAMPLES:
 Flour - cereals
 Animal danders
 Latex
 Psyllium
 Crab processing
 Enzymes
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: 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
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
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
Proportion of subjects without symptoms
Onset of OA
Latency period – highly variable…
1,0
Malo JL et al. JACI 1992; 90:937
0,8
0,6
0,4
Isocyanates
High molecular weight agents
0,2
Western red cedar
0,0
0
10
20
30
40
Years of exposure before onset of symptoms
Occupational Asthma Prevalence
•
•
•
•
•
Western red cedar
Plastics industry
Animal breeders/handlers
Bakers
Metal refinery (platinum)
5%
5%
6%
10-30%
30-50%
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
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.
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
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
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.
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
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
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 nonoccupational factor?
– History
– Objective testing
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?
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
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
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).
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)
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
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)
Sensitivity, Specificity, and Positive Predictive Values (PPV) of IgE
for Predicting SPT and IC Dilutions
IgE > 0.1
Dilution
Dilution
Level
Total
Responses
N
%Total
Sensitivity
Specificity
PPV*
pvalueb
SPT
0
31
3
9.7%
88.9%
90.3%
72.7% <0.001
SPT+
Dermal a
>0
0
>0
9
29
11
8
1
10
89.9%
3.4%
90.9%
90.9%
96.7%
90.9% <0.001
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.
Results
Cytokine responses for TMA exposed workers
40
Non-Ab producers (n=7)
IgG-Ab producers (n=7)
IgG-IgE-Ab producers (n=7)
% CD4+ cells
35
30
*
25
*
20
15
10
*
5
0
IFNγ
IL-4
Ghosh D, et.al. Cytokine responses in TMAExposed Workers (Presented at the AAAAI, 2011).
Treg
*p<.01
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 crabprocessing workers. J Allergy Clin Immunol1984; 74:261-9
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
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
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.
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.
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)
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
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)
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.
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
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.
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.
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.
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
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
Acknowledgment
• AAAAI
• I.L. Bernstein, M.D.
• Debajyoti Ghosh, Ph.D.
Third