Definitions

• Occupational Asthma: new-onset asthma associated with a workplace exposure
  • However, workplace exposures also cause greater amount of “workplace-aggravated asthma” than actual “workplace-caused asthma”
• Work-Aggravated Asthma:
  • Sulfur Dioxide: highly water-soluble irritant gas found in many worksites
    • OSHA regulations require < 5 ppm over 8 hr period (has little effect at this level in normal subjects)
    • However, may cause symptomatic airflow limitation in pre-existing mild asthma within 5 min at levels as low as 0.5 ppm
    • Bronchoconstriction is not related to irritant properties of sulfur dioxide
  • Formaldehyde: highly irritating (causing eye/throat irritation), but does not aggravate asthma
  • Allergens (animal proteins encountered by lab workers, farmers, etc): well-known aggravators of pre-existing asthma (see Asthma), as well as triggers of occupational asthma
  • Tobacco Smoke Exposure: may aggravate asthma
  • Stress: may aggravate asthma
• Reactive Airways Dysfunction Syndrome (RADS): persistent airway reactivity occurring after a single, high-dose exposure
• Irritant-Induced Asthma (more generalized term, similar to RADS): persistent airway reactivity resulting from single or multiple exposures to non-specific irritant chemical (at concentration high enough to induce airway inflammation or injury)
  • UK SWORD data: Less than 10% of of reported inhalational injuries result in persistent asthma
  • Level of exposure is an important risk factor for irritant-induced asthma (in studies of glacial acetic acid spills, more exposure increased risk of developing asthma)
  • US SENSOR data: Exposure to irritant sensitizers are frequently reported as causes of new-onset asthma
  • Atopy/smoking are risk factors the development of irritant-induced asthma
• Organic Dust-Induced Airway Disease (due to exposure to organic dusts from cotton, flax, hemp, sisal, jute, and various grains): produces an asthma-like disorder (but not true asthma, due to lack of airway eosinophilia, less frequent airway hyperresponsiveness, tendency to develop chronic bronchitis, and chronic airflow limitation with chronic exposure)

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Epidemiology

• Occupational asthma is most common type of occupational lung disease in industrialized countries
• Occupational asthma accounts for 26% of all occupational lung disease cases in UK SWORD data, 52% of cases in British Columbia (due to high rates of western red cedar exposure), and 15% of cases in US (according to 1978 Social Security data)
• Occupational exposures cause between 8-21% of “asthma”/wheezing cases in population (depends on definition of “asthma” and definition of exposure)
• Highest Prevalence Rates of Occupational Asthma: platinum and proteolytic detergent industries

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Etiologic Agents

Low MW Chemicals (MW <5000 D)

• Isocyanates
  • Toluene Diisocyanate: polyurethane industry, insulators, laminators, roofers
    • Average latency before developing occupational asthma symptoms is 2 years
  • Diphenylmethane Diisocyanate: laminators, polyurethane foam industry
  • Hexamethylene Diisocyanate: painters, plastics industry
  • Naphthalene Diisocyanate: chemists, rubber workers
• Anhydrides
  • Trimellitic Anhydride (see Trimellitic Anhydride, [[Trimellitic Anhydride]]): chemical workers
  • Phthalic Anhydride (see Phthalic Anhydride, [[Phthalic Anhydride]]): paint industry, plastics industry
  • Hexahydrophthalic Anhydride: epoxy resin industry
  • Tetrachlorophthalic Anhydride: epoxy resin industry
• Metals
  • Chromium (see Chromium, [[Chromium]]): chrome platers, welders
  • Nickel (see Nickel, [[Nickel]]): nickel platers, welders
  • Cobalt (see Cobalt, [[Cobalt]]): tool grinders, diamond polishers
  • Platinum (see Platinum, [[Platinum]]): platinum refiners
  • Aluminum (see Aluminum, [[Aluminum]]): aluminum pot-room workers
• Drugs/Toxins
  • Benzyl PCN/Ampicillin/Sulfathiazole/Tetracycline/Psyllium/Methyldopa/Salbutamol/Piperazine Dihydrochloride: pharmaceutical industry
  • Chloramine Gas (see Chlorine, [[Chlorine]]): pharmaceutical industry, lab workers
  • Organophosphates (see Organophosphates, [[Organophosphates]]): farm workers, pesticide formulators, fumigators
• Other
  • Formaldehyde (see Formaldehyde, [[Formaldehyde]]): disinfectant, lab workers, embalmers, insulators, textile workers, paper and photographic industries, insulators
  • Glutaraldehyde (see Glutaraldehyde, [[Glutaraldehyde]]): hospital disinfection
  • Dimethylethanolamine (see Dimethylethanolamine, [[Dimethylethanolamine]]): paint sprayers
  • Ethylenediamine: rubber workers, photographic processors
  • Persulfate Salts: chemical workers, beauticians
  • Ethylene Oxide Gas (see Ethylene Oxide Gas, [[Ethylene Oxide Gas]]): hospital disinfection, medical sterilization
  • Pyrethrin: fumigators
  • Ammonium Thioglycolate: beauticians
  • Monoethanolamine: beauticians
  • Hexamethyleneamine: beauticians
  • Polyvinyl Chloride Vapor: neat wrappers
  • Aminoethylethanolamine: aluminum soldering

High MW Organic Materials (MW >5000 D)

• Animal Products
  • Domestic Animals: farmers, vets, meat processors
  • Birds: poultry breeders, bird fanciers
  • Bats/Mice/Guinea pigs: lab workers
  • Sea Squirt: oyster farmers
  • Fish Glue: bookbinders, postal workers
  • Silkworms: silk sericulturers
  • Grain Mites/Weevils: grain mill and storage workers, bakers
  • Prawns/Crabs: processors
• Plant Products
  • Buckwheat/Rye Flour: bakers
  • Wheat: farmers, grain handlers
  • Grain Dust: farmers, grain handlers, bakers
    • Average latency before developing occupational asthma symptoms is around 4.2 years
  • Hops: brewers
  • Tamarind Seeds: millers, spice processors
  • Castor Beans: farmers, castor bean workers
  • Coffee Beans: farmers, coffee bean workers
  • Wool: textile workers
  • Cotton/Flax/Hemp: textile workers
  • Latex from Natural Rubber: health care workers, food processors
• Vegetable Gums
  • Acacia/arabic: printing
  • Tragacanth: printing, food processing
  • Karaya: food processing
• Wood Dusts: carpenters, woodworkers, sawmill workers
  • Western Red Cedar
    • Causes occupational asthma in 5-24% of exposed workers/due to plicatic acid in wood
  • Cedar of Lebanon
  • Mahogany
  • California Redwood
  • Oak
  • Iroko
  • Boxwood
  • Cocabolla
  • Zebrawood
  • Mansonia
  • Mulberry
• Dyes
  • Anthraquinone: fabric dyeing
  • Carmine: cosmetics, dyeing
  • Paraphenyl Diamine: fur dyeing
  • Henna Extract: beauticians
  • Hexafix Brilliant Yellow/Drimaren Brilliant Blue/Cibachrome Brilliant Scarlet: dye manufacturers
• Fluxes
  • Colophony Soft-Core Solder: solderers, electrical workers
• Enzymes
  • Pancreatic Extracts/Flaviastase: pharmaceutical industry
  • Bacillus Subtilis: detergent manufacture
  • Papain: food processors
  • Trypsin: plastics industry, rubber workers
  • Bromelain/Pectinase: food processors

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Physiology

Types of Mechanisms

• Non-Sensitization-Type Mechanism (Non-Immunologic or Irritant-Induced): irrtant-induced epithelial damage -> local neurogenic airway inflammation -> macrophage activation and mast cell degranulation
  • Endotoxin Effects: cotton dust
  • Anticholinesterase Effect: organophosphate pesticides
  • Inflammatory Response: ammonia, chlorine
  • Irritant Response: dusts, fumes, vapors, cold
• Sensitization-Type Mechanism (Immunologic Type): involves T-cell orchestration of eosinophils, mast cells, epithelial cells, and neutrophils
  • Level of exposure is an important risk factor for sensitizer-type occupational asthma
  • Atopy: important risk factor for some types of IgE-mediated occupational asthma (psyllium workers, bakers, and lab animal handlers)
  • Smoking: important risk factor for some types of IgE-mediated occupational asthma (workers with exposure to platinum, acid anhydrides, snow crab, green coffee beans, and ispaghula)
  • Atopy/Smoking: these are NOT risk factors for the development of occupational asthma due to diisoocyanates and western red cedar
  • Genetic Risk Factors: HLA associations (both associated with and protective) have been described for occupational asthma due to platinum, acid anhydrides, western red cedar, diisocyanates, soybeans, and latex
  • High MW Compounds:
    • IgE-mediated (complete allergens, do not require interaction with any proteins): animal, plant, and bacterial proteins
  • Low MW Compounds:
    • IgE-mediated (haptens, require interaction with autologous or heterologous proteins): platinum, antibiotics
    • Unknown mechanism (not IgE-mediated): isocyanates, amines, acid anhydrides, western red cedar

Timing of Clinical Features

• Sensitizer-Induced Occupational Asthma: symptoms typically develop months-years after onset of exposure
  • Early airway response: occurs within minutes of inhalation (maximal bronchoconstriction within 30 min)
  • Late airway response: occurs within 4-8 hrs of inhalation
  • Dual airway response: involves both early and late responses
• IgE-Dependent Agents (typically high MW agents): may induce early or biphasic responses
• IgE-Independent Agents: may induce late or biphasic responses

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Diagnosis

• PFT’s: obstructive pattern during episodes
  • PFT’s may be normal between episodes
  • ”Cross-shift” Spirometry: may detect work-related changes in FEV1, but is insensitive for late asthmatic responses
    • Cross-Shift FEV1 Criteria: >10% decrease in FEV1 across a work shift is objective evidence of work-related bronchoconstriction
• Reversibility with Bronchodilators: positive by ATS criteria if >12% (or >200 ml) increase in FEV1 after bronchodilator
• Methacholine Challenge: may be useful in cases with normal spirometry
  –Best Test for Airway Reactivity: a negative methacholine challenge within 2 weeks of the last exposure makes occupational asthma very unlikely
• Peak Flow: may be useful, if measured QID and log is kept
  -A >20% diurnal variation in peak flow rates is suggestive, but a work-related pattern of decrease is probably the best criteria
  • Some concern about peak flow rates being too dependent on patient effort, but most believe them to have adequate sensitivity/specificity for the diagnosis of occupational asthma
• Bronchial Provocation Studies: rarely performed in US
  • Quebec studies indicate that these can be performed safely, if conducted in a controlled, monitored setting
• Skin Testing: useful to test for presence of atopy (which is a risk factor for high MW sensitizer-associated asthma)
  • Extracts Available For: flour, animal proteins, coffee
• IgE Antibodies: can be used to test for high MW sensitizers and some low MW sensitizers (like diisocyanates and acid anhydrides)
  • Anti-Toluene Diisocyanate IgE (by RAST): present in only 15-18% of cases (and signifiies only sensitization, but does not establish it as a cause of the occupational asthma)
    • Not commercially available
• CXR/Chest CT Patterns
  • Hyperinflation/flattening of diaphragms, bronchial wall thickening, mucus plugging, and fleeting infiltrates: may been seen during an exacerbation
  • Normal CXR: typical between exacerbations

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Clinical

Symptoms/Signs

• Exertional or Resting Dyspnea:
• Cough:
• Chest Tightness:
• Wheezing:
• Nocturnal Awakening: may occur in some cases (similar to asthma)
• Recurrent Work-Related “Bronchitis”: with cough and sputum
• Rhinoconjunctivitis: may accompany respiratory symptoms
  • With Low MW substances: rhinoconjunctivitis occurs concurrently with respiratory symptoms
  • With High MW substances: rhinoconjunctivitis occurs prior to development of respiratory symptoms (possible due to high MW substances invoking an IgE-mediated immune response)

Pattern of Symptoms

• Pattern of presentation in association with work is the best diagnostic feature (since many chemicals that cause occupational asthma have not been specifically identified and multiple causative agents may be simultaneously present)
• History is also useful to rule out an occupational cause, if one is not present
• Occasionally, a single exposure to an offending agent may result in repeated asthmatic reactions over several days
• Latency Period: in sensitizer-induced cases, symptoms usually do not develop immediately, but develop after some period of occupational exposure
  • Typical Latency for Platinum-Associated Occupational Asthma: around 17 days
  • Typical Latency for Toluene Diisocyanate-Associated Occupational Asthma: around 2 years
  • Typical Latency for Baker’s Occupational Asthma: around 4.2 years

Relationship of Symptoms to Work

• Symptoms that occur only at work
• Symptoms that improve on weekends/vacations
• Symptoms that occur regularly after the work shift (late asthmatic responses, 2-4 hrs later, may occur with some aeroallergens and toluene diisocyanate)
• Symptoms that progressively increase over the course of the work week
• Symptoms that improve after a change in work environment

ACCP 1995 Criteria

• History compatible with occupational asthma
• Presence of airflow limitation and its reversibility
• In the absence of airflow limitation, presence of non-specific airway responsiveness
• Demonstration of work-relatedness by objective means

NIOSH SENSOR Case-Classification Criteria

(work-related state-based surveillance program)

• Work-Aggravated Asthma: pre-existing asthma that was symptomatic and/or treated with asthma medications within the 2 years prior to entering the occupational setting associated with the patient’s asthma symptoms
• Reactive Airways Dysfunction Syndrome (RADS): new asthma symptoms that develop within 24 hrs after a one-time high level inhalation exposure (at work) to an irritant gas, fume, smoke, or vapor and that persist for at least 3 months
• Classic/Work-Induced Asthma
  • Workplace exposure to an agent previously associated with occupational asthma
  • Work-related changes in bronchial responsiveness as measured by serial non-specific inhalation challenge testing
  • Positive response to specific inhalation challenge testing with an agent to which the patient has been exposed at work

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Treatment

Removal from Exposure

(it may take weeks-years for symptoms/PFT’s/peak flow improvement)

• Sensitizer-Induced Occupational Asthma: complete removal from exposure is crucial, as even low-level exposure may trigger asthmatic episodes (including status asthmaticus)

  • Toluene diisocyanate can trigger asthmatic episodes at levels as low as parts per billion (cessation of toluene diisocyanate exposure: decreases airway mucosal inflammatory cells and subepithelial fibrosis)
  • Recovery: the majority of sensitizer-related cases (60% in Lemiere, 1996 study) never completely recover, but they generally improve over time after cessation of exposure
  • Risk factors for persistent asthma: duration of exposure, duration of symptoms before removal from exposure, and severity of symptoms at time of diagnosis
  • Early removal from exposure increases chances for recovery and decrease symptoms, it may not prevent persistent asthma
  • Continued exposure is associated with worsening of asthma
  • Spirometric improvement generally plateaus at about 1 year after cessation of exposure
  • Bronchial responsiveness generally plateaus at about 2 years after cessation of exposure

• Irritant-Induced Occupational Asthma: respiratory protection and/or engineering controls may be beneficial

  • Limited data about extent and time-course of recovery after cessation of exposure
  • In a study of pulp mill workers who were acutely “gassed”, a majority had increased nonspecific airway hyperresponsiveness 2 years later

Standard Asthma Treatment

• Inhaled steroids: shown to small, but significant, improvement in both low and high MW sensitizer-induced asthma (after withdrawal of exposure)
  • Better efficacy if used early, rather than late, in course of occupational asthma
  • Role on inhaled steroids in irritant-induced asthma is unclear

Prevention of Occupational Asthma

• Primary prevention: prevent exposures
  • Ex: engineering control (process enclosure, respirators, etc.)
• Secondary prevention: surveillance with early detection of asthma (so that duration and severity of asthma can be minimized)
  • Ex: paint-spraying industry (with exposure to diisocyanates)
  • Any case of occupational asthma should be considered a sentinel event: other at risk workers should also be screened (surveys, diurnal peak flows, spirometry, skin testing for high MW antigens, etc. by medical department) and exposure monitoring (air monitoring, etc. by industrial hygienists) should be instituted
• Tertiary prevention: appropriate healthcare and prevention of further exposure in those who have already been diagnosed

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Prognosis

Disability

• Occupational asthma may result in significant long-term disability and unemployment
• Rates of job loss and jon change are high
• 50% of patients have reduced income, when assessed 3 years after diagnosis is made
• ATS Scoring system for disability (assessed when disease has been optimally treated and stabilized), includes these factors:
  • Post-bronchodilator FEV1
  • Reversibility of FEV1 or degree of non-specific airway responsiveness
  • Minimum asthma medication needed for optimum control

Hospitalization Rates

• Occupational asthma patients have higher all-cause hospitalization rates, as compared to non-asthmatics (but have lower hospitalization rates than that of non-occupational asthma at tertiary care centers)

Quality of Life

• Occupational asthma patients have decreased QOL (with increased asthma symptoms, more activity limitation, and increased emotional dysfunction), as compared to non-occupational asthma
• Decreased QOL may be related to worsened asthma severity, loss of employment, need for job retraining, or need for early retirement

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References

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