Historically, one of the most common occupational hazards has been airway injury. It is surprising, therefore, that it remains an under-recognized event. One reason may be that airway injuries vary greatly in severity--from increases in reported respiratory symptom frequency such as rhinitis in workers in industries associated with wood dust to frank pulmonary edema and even death in individual patients (e.g., silo workers exposed to high concentrations of NO₂. Most commonly these injuries present as well-recognized symptom complexes such as asthma or bronchitis.

The difficulty facing the physician who suspects an occupational airway disease is to sort out whether the illness is truly related to workplace exposure. This Cyberounds^® conference hopes to provide you with information helpful to making this sort of determination.

What Are Airway Diseases?

Airway diseases associated with occupational exposures result in a number of different clinical syndromes each with unique characteristics (see Table 1).

While each of these syndromes is clearly defined and suitable for diagnosis, a central issue in classification revolves around the question of sensitization.

Industrial Bronchitis

Similar to its non-occupational counterpart, chronic bronchitis is defined by chronic cough and expectoration resulting from exposure to irritant gases, fumes or dusts usually at relatively low concentrations for long periods of time. This is a non-immunologic illness without a latency period and not reflecting specific sensitivity to a single agent. While cigarette smoking is often a confounding variable in assessing an individual worker with chronic bronchitis(1) epidemiologic studies from a number of industries indicate the independent effect of these symptoms, particularly when contrasting smoking and non-smoking workers.(2) This issue will be covered in our next Cyberounds^®.

Reactive Airway Dysfunction Syndrome (RADS)

RADS is characterized by chronic airway obstruction and irritability, frequently resulting from a single exposure to high concentrations of gases, vapors or fumes.(3) Despite the relatively short exposure involved, abnormalities, particularly airway hyperreactivity, may persist for years. No sensitization appears to be involved.

Bronchiolitis Obliterans

Bronchiolitis obliterans is a well characterized inflammatory response of the terminal airways. Such inflammation results from a usually massive exposure to irritant gases which penetrate to the lower airways (e.g., nitrogen dioxide).(4) Characteristically after initial, relatively mild symptoms of mucous membrane irritation, pulmonary edema follows in an explosive manner. If the patient survives, bronchiolitis obliterans may develop. Resolution can occur but frequently there is persistent chronic obstructive lung disease.

Occupational Asthma

Occupational asthma has generally been defined in the narrow sense(5) of airway sensitivity to a specific occupational agent; sensitization usually follows an initial exposure period. Once established, the disease is uniquely and consistently triggered by the sensitizing agent; however, as with usual asthma, the airway is generally irritable and also responds excessively to challenge with non-specific stimulants. Early removal from the offending agent may abort the disease, however, once established, hyperreactivity frequently persists even though the worker is removed from the sensitizer.

A less restrictive definition of occupational asthma(6) suggests that it represents airway obstruction, usually reversible, caused by the inhalation of substances or materials that a worker manufactures or uses directly or that are incidentally present at the work site. For example, in the textile industry byssinosis and chronic broncitis are the result of non-immunologic airway reactions. Such a definition includes processes that are both immunologic and nonimmunologic. In principle such a definition would include individuals with pre-existing asthma whose disease is exacerbated by the workplace.

Finally, as with its more general counterpart, chronic obstructive pulmonary disease (COPD), occupational airway disease does not always fit conveniently into one of the above four categories. Overlap syndromes with elements of bronchitis, reversible bronchospasm and irreversible chronic airway obstruction may combine in any single individual, and may vary with time.

Prevalence

Asthma is a very common disease of the airways affecting up to as many as 10.6% of the general population.(7) An average of 15 days per year are lost from work or school because of this disease. Since the 1980s, a gradual increase in the morbidity and mortality of this disease has been noted in the U.S. and other countries. Although generally considered reversible, growing evidence from prospective epidemiologic studies suggests that chronic asthma can be associated with progressive lung function impairment.(8) Prevalences similar to those of asthma among adults have been documented for the symptoms of chronic bronchitis in population studies.(9) Nonspecific respiratory symptoms, such as cough and wheeze, are very common in the general population(10) but have been documented to be much more frequent (two to three times more so) in selected dusty industries.(11),(12),(13),(14),(15)

The prevalence of occupational airway disease is unknown. Some general conclusions can be made. One can expect the prevalence of bronchitic symptoms found among workers to rise with the dustiness of the industry. In a recent analysis from the Harvard Six City Study the prevalence of bronchitis was stratified by the presence or absence of persistent wheeze or asthma by the annual PM 15 level (particulate matter less than 15 um in diameter). There was a significant trend of increasing bronchitis with increasing PM 15 levels.(16)

More specifically, a study by Korn looking at occupational exposures found increasing prevalences of most respiratory symptoms (e.g., chronic cough, phlegm, persistent wheeze, dyspnea and lung faction impairment) associated with increasing exposures to gases, fumes and dust in the workplace.(17) Finally, a recent survey by Schwartz et al examining 534 patients in a Primary Care Clinic over a three month period indicated that nearly 75% of those patients reported prior occupational exposure to at least one potentially toxic agent and over 30% claimed exposure to at least four such agents.

Estimates of the prevalence of occupationally-attributable asthma among new cases of diagnosed asthma have ranged from 2-15%.(19),(20),(21) These prevalence data must be viewed in the context of individual agents where cases may vary from idiosyncratic to very frequent. For example, it has been estimated that some 5% of workers exposed to western red cedar dust develop occupational asthma,(22) whereas up to 45% of workers exposed to proteolytic enzymes may develop occupationally related asthma.(23)

Etiology and Mechanisms

Agents causing (or associated with) occupational airway diseases have been divided into three categories (see Table 2).

The clinical syndromes associated with exposure to gases and fumes tend to involve exacerbation of pre-existing asthma or RADS. Gases and fumes have well characterized irritant effects which are usually dose related, non-sensitizing and more irritating to susceptible individuals (e.g., asthmatics).(24)

Not all gases which irritate mucous membranes are equally dangerous to the airways. For example, formaldehyde is potentially far more irritating to the mucous membranes of the eyes and nose than SO₂ or NO₂, yet it has little or no airway effect at usual occupational levels,(25) although sensitization may occur.(26) Gases such as formaldehyde which are highly soluble and are maximally absorbed in the upper airways may not reach the lower airways in concentrations great enough to cause damage or irritation. The solubility of the gas and its ability to reach the lower airway is felt to be an important factor in promoting airway effects.

Low molecular weight compounds known to induce occupational asthma have been arbitrarily defined as having a molecular weight of less than 1000 daltons. These agents are in general simple organic molecules (e.g., isocyanates), drugs (e.g., antibiotics) or metals (e.g., platinum) used in a wide variety of industries (see Table 3a).

Examples which have been extensively studied include platinum salts,(27) acid anhydrides,(28),(29) such as trimellitic anhydride and tetrachlorophthalic anhydride, isocyanates,(30),(31) plicatic acid(32) and antibiotics.(33),(34)

In many instances it is known that these agents act by causing a classic immunologic sensitization by acting as haptens (e.g., acid anhydridres and platinum salts). For others, however, the immunologic mechanism, although suspected, has not been fully characterized (e.g., isocyanates and western red cedar). Pre-existing atopy does not appear to be a risk factor for development of disease with these agents.

Large molecular weight agents are in general proteins, peptides or polysaccharides of plant or animal origin (see Table 3b) which elicit classic humoral sensitivity via IgE or occasionally IgG antibodies. The affected individuals frequently exhibit general signs of atopy such as pre-existing allergic rhinitis or eczema. When exposed to these agents either in the natural setting or in a challenge situation the sensitized individual experiences immediate or biphasic (dual) reactions, the latter characterized by the onset of delayed airway obstruction a number of hours following challenge.

The mechanism of disease involved in asthma due to high molecu lar weight compounds is felt to be identical with asthma due to common allergens such as house dust or pollens. In such patients specific IgE antibodies develop following repeated exposure and lead to an interaction with antigen on the surface of immunoactive cells (e.g., mast cells). This in turn leads to the release of both preformed mediators (e.g., histamine, eosinophil chemotactic factor) as well as de-novo synthesized mediators (e.g., prostaglandins, leukotrienes).(35) By contrast the mechanism involved in airway disease attributable to low molecular weight agents involves inflammation(36),(37) and the role of classic IgE mediated disease is uncertain since these antibodies are not invariably associated with disease.(38),(39)

In addition to the above agents and mechanisms certain host characteristics are felt to be important in the development of occupational lung disease. The major host factors involved in pathogenesis and exacerbation are listed in Table 4.

The way in which these factors may interact with a disease mechanism are listed in Table 5.

In our next Cyberounds^® we will discuss a general approach to diagnosing occupational airway diseases and will examine in detail the problems faced worldwide by textile workers.