Epidemiology

Risk Factors

OA results from complex interactions between environmental factors and individual susceptibility. The environmental and individual risk factors are summarized in Table 40-3, together with the level of evidence supporting their role. The intensity of exposure to sensitizing agents currently is the best-identified and the most important environmental risk factor for the development of OA. Characterization of the relationship between the level of exposure to occupational agents and the development of IgE sensitization and OA has been greatly enhanced by the use of personal sampling techniques, direct analytic methods for chemicals, and immunoassay techniques for the quantification of airborne protein allergens. Exposure-response relationships may be affected by the nature of the sensitizing agent, individual susceptibility, and timing of exposure. Some agents seem to be more potent than others in inducing sensitization; the dose-response relationship for IgE sensitization is steeper for the bakery enzyme alpha-amylase than for wheat allergens. Some evidence indicates that the exposure-response relationships are not linear for certain occupational agents (e.g., laboratory animals, wheat flour), thereby suggesting an unexplained protective effect of high-level exposures. The role of genetic susceptibility markers, such as certain human leukocyte antigen (HLA) class II alleles, may become more apparent at low levels of exposure to occupational agents. The timing of exposure also may play a role, because the frequency of onset of work-related asthma symptoms is consistently higher within the first 1 to 4 years of exposure to HMW agents, and exposure-response gradients are more clearly documented in this early period of exposure.

Table 40-3 Summary of Potential Risk Factors for Development of Occupational Asthma (OA)

HLA, human leukocyte antigen; HMW, high-molecular-weight; IgE, immunoglobulin E; IL-4RA, interleukin-4 receptor alpha chain; LMW, low-molecular-weight; TLR-4, Toll-like receptor-4.

* Glutathione S-transferase (GSTM) and N-acetyltransferase (NAT).

A number of studies indicate that exposure to cigarette smoke can increase the risk for IgE-mediated sensitization to some HMW and LMW agents, but the evidence supporting an association between smoking and the development of clinical OA is still very weak. The role of other environmental cofactors, such as non-respiratory routes of exposure and concomitant exposure to endotoxin and pollutants at work, remains largely uncertain.

Atopy has been consistently demonstrated as an important host risk factor for the development of IgE sensitization and OA, but only for HMW agents. Prospective cohort studies of workers entering exposure to occupational sensitizing agents have shown that the presence of rhinitis and nonspecific bronchial hyperresponsiveness at baseline is associated with an increased risk for subsequent IgE sensitization and development of OA.

With the advances in human genetics, research has been directed toward investigating the genetic basis of individual susceptibility to develop OA. Certain HLA class II molecules (i.e., HLA-DR, HLA-DQ, and HLA-DP alleles), which are involved in the presentation of processed antigens to T lymphocytes, were found to confer either susceptibility to or protection against OA due to various LMW and HMW occupational allergens (i.e., isocyanates, red cedar, acid anhydrides, platinum salts, natural rubber latex, and laboratory animals). Other evidence suggests that genes associated with T_H2 cell differentiation (i.e., polymorphism of the IL-4 receptor α chain, IL-13, and CD14 (C159T) genes) may play a role in the development of OA. Genes involved in the protection against oxidative stress, such as glutathione S-transferase (GST) and N-acetyltransferase (NAT), have been associated with an increased risk of isocyanate-induced OA (e.g., GSTM1-null genotype and slow N-acetylator phenotypes) or a protective effect (e.g., GSTP1*Val/Val allele). Overall, the currently available information indicates that the utility of genetic testing is limited for both diagnostic and preventive purposes. In addition, there is convincing evidence that a wide variety of environmental factors can interact with genetic determinants to affect disease susceptibility. For instance, a gene-environment interaction has been demonstrated in platinum refinery workers, in whom the relative risk of sensitization associated with the HLA-DR3 phenotype was more apparent at lower levels of exposure.

Pathophysiology

OA can be classified according to pathogenic mechanisms as either immunologically or nonimmunologically mediated. Immunologically mediated OA is characterized by a latency period that is necessary for acquiring sensitization, whereas nonimmunologically mediated OA has no latency period.

Immunologic, Non–immunoglobulin E–mediated Occupational Asthma

Many LMW agents, including diisocyanates and plicatic acid (responsible for red cedar asthma), have been shown to cause OA, yet specific IgE antibodies cannot be detected or are found in only a small percentage of affected persons. Specific IgG antibodies also are found and have been discovered to be significantly associated with the development of OA.

The significance of IgE and IgG antibodies in the pathogenesis of asthma is not clear. Bronchial biopsy specimens from patients with OA obtained at the time of diagnosis have shown activation of T lymphocytes, suggesting that T lymphocytes may play a direct role in mediating airway inflammation. This hypothesis has been substantiated by the finding of proliferation of peripheral blood lymphocytes when stimulated with the appropriate antigen in a proportion of affected persons with nickel-induced asthma and Western red cedar asthma. In isocyanate-induced asthma, an increase in CD8⁺ cells and in percentage of eosinophils was found in the peripheral blood of patients during a late asthmatic reaction induced by exposure testing. Cloning of T cells from bronchial biopsy specimens of these subjects showed that most of the clones exhibited CD8⁺ phenotype that produced IL-5, with very few clones producing IL-4. This finding provides supportive evidence that CD8⁺ cells may play a direct role in OA without the necessity of producing IgE antibodies.

Early asthmatic reactions induced by occupational allergens probably are associated with smooth muscle contraction and edema induced by inflammatory mediators such as histamine and leukotrienes but not cellular infiltration. Late asthmatic reactions are associated with influx of inflammatory cells. Although both asthma and OA have been identified as diseases in which eosinophilic inflammation plays a key role, the role of neutrophils has recently been examined. Induced sputum examination is a noninvasive means to assess cell profiles and currently is more often used as an interesting investigative tool. Eosinophilic and neutrophilic variants of OA have been found in the case of OA due to LMW agents, especially diisocyanates. Some LMW agents have pharmacologic properties that cause bronchoconstriction. For example, diisocyanates may block the β₂-adrenergic receptor. Diisocyanates and other occupational agents also may stimulate sensory nerves to release substance P and other peptides that have been shown to inhibit neutral endopeptidases necessary for the inactivation of neuropeptides. Neuropeptides affect many cells in the airways and may participate in airway inflammation by causing smooth muscle contraction, mucus production, and recruitment and activation of inflammatory cells. Thus, LMW occupational agents such as diisocyanates may have a variety of proinflammatory effects and induce asthma through more than one mechanism. An autopsy study of the lung of a person with isocyanate-induced asthma who died after reexposure showed denudation of airway epithelium, subepithelial fibrosis, infiltration of the lamina propria by leukocytes (mainly eosinophils), and diffuse mucous plugging of the bronchioles, similar to findings in persons who died from non-OA. Bronchial biopsy specimens of 18 patients with proven OA also have shown extensive epithelial desquamation, ciliary abnormalities of the epithelial cells, smooth muscle hyperplasia, and subepithelial fibrosis (Figure 40-2). The total cell count, eosinophils, and lymphocytes were increased compared with those in healthy control subjects.

Figure 40-2 Bronchial biopsy specimen from a patient who had occupational asthma caused by exposure to toluene diisocyanates. Even after removal from exposure, partial desquamation of the epithelium, thickened basement membrane, and some cellular infiltration are evident.

Nonimmunologic Occupational Asthma

OA resulting from nonimmunologic mechanisms is characterized by the absence of latency. The underlying mechanism of IrIA is not known. It has been postulated that the extensive denudation of the epithelium in these conditions leads to airway inflammation and airway hyperresponsiveness by several mechanisms, including loss of the epithelial cell–derived relaxing factors, exposure of the nerve endings leading to neurogenic inflammation, and nonspecific activation of mast cells with release of inflammatory mediators and cytokines (Figure 40-3). Secretion of growth factors for epithelial cells, smooth muscle, and fibroblasts may lead to airway remodeling. Sequential changes in the airways of a patient with IrIA have been described. In the acute phase of IrIA, rapid denudation of the mucosa with fibrinohemorrhagic exudate in the submucosa is followed by regeneration of the epithelium with proliferation of basal and parabasal cells and subepithelial edema (Figure 40-4). In the chronic phase of IrIA, marked thickening of the airway wall is seen (Figure 40-5). In a study of IrIA caused by multiple exposures to an irritant, inflammatory infiltrate with eosinophils and lymphocytes and diffuse deposition with collagen fibers were found. Similar sequential changes have been reproduced in animal models of IrIA.

Figure 40-3 Proposed pathophysiology of reactive airways dysfunction syndrome (RADS).

Figure 40-4 Bronchial biopsy specimen taken 3 days after an acute accidental inhalation of a high concentration of chlorine. This preparation shows almost complete desquamation of bronchial mucosa with fibrinohemorrhagic deposit. (Weigert-Masson stain.)

Figure 40-5 Bronchial biopsy specimen taken 2 years after an acute accidental inhalation of chlorine, showing severe desquamation of epithelial cells. Smooth muscle cells are surrounded by reticulocollagenic fibrous tissue. (Weigert-Masson stain.)

Clinical Features

OA induced by immunologic mechanisms is a form of asthma that is characterized by the clinical features of hypersensitivity: (1) work-related asthma symptoms develop only after an initial symptom-free period of exposure (i.e., the latency period), which is required to acquire the immunologic sensitization; (2) once OA is initiated, the asthmatic reactions tend to recur on reexposure to the causal agent at concentrations not affecting others who are similarly exposed; and (3) asthma affects only a proportion (usually a minority) of those exposed to the agent.

A typical history of OA includes the appearance or worsening of asthma symptoms at work and their disappearance or improvement away from work. This pattern frequently is obscured, however, because late asthmatic reactions can develop after the workshift, and asthma symptoms can be triggered by nonspecific stimuli outside the workplace. In addition, when affected workers continue to be exposed to the sensitizing agent, remission of symptoms in the evenings or during weekends tends to disappear, and much longer periods off work are necessary for improvement to take place. Thus, OA often remains unrecognized by affected workers and their physicians for long periods, the diagnosis usually being made 2 to 4 years after the onset of symptoms. The latency period typically is within 2 years of starting exposure to sensitizing agents, but OA may develop after much longer periods of exposure.

Some differences in the clinical presentation of subjects with OA caused by HMW and that implicating LMW agents have been noted, with isolated late or atypical asthmatic reactions more frequently observed after specific inhalation challenges with LMW agents. A majority of workers with OA also suffer from occupational rhinitis. Work-related rhinitis symptoms are more frequent and severe when HMW agents are involved. In those patients with associated rhinitis, work-related nasal symptoms frequently precede the onset of OA, especially with exposures to HMW agents.

The acute IrIA originally described by Brooks and colleagues in 1985 under the term reactive airways dysfunction syndrome is due to acute airway injury from accidental exposure to a high dose of irritants. In the typical clinical presentation, symptoms of asthma and airway obstruction or nonspecific bronchial hyperresponsiveness develop within a few hours after the acute exposure in a person without a history of respiratory disease, although sometimes the interval to symptom onset is longer. Certain features distinguish IrIA from allergic OA: At the time of the acute event, coughing generally is a predominant symptom. Thereafter, bronchial obstruction, if present, does not respond as well to bronchodilators, which may potentially be explained by the marked airway remodeling that has been documented in bronchial biopsy specimens from patients with IrIA.

Diagnosis

Confirmation of the diagnosis of OA by objective means is necessary for several reasons. The diagnosis of OA has considerable socioeconomic implications for the worker and his or her family; it typically means a change of job in most instances, with its financial and other consequences. Asthma is a common disease, and it has been estimated that up to 50% of workers are exposed at one time or another to agents with sensitizing or irritating properties. The combination of having asthma and working in an environment with an agent known to give rise to OA does not make the diagnosis of OA. An occupational cause should be suspected for all new cases of adult-onset asthma, especially in persons who report worsening of their asthma symptoms at work. A detailed occupational history including past and current exposure to possible causal agents in the workplace, possible episodes of accidental exposures to irritant material, work processes, and specific job duties should be obtained. In addition, the intensity, frequency, and peak concentrations of exposure in the workplace should be assessed qualitatively. Worksite-specific information, including material safety data sheets, also can be requested, although in some instances, the information is incomplete on all constituents of the product, especially those constituents with concentrations less than 1%. Computerized databases and published lists of agents and workplaces are useful. Walk-through visits of the workplace may be necessary. Industrial hygiene data and employee health records can be obtained as well. Open medical questionnaires should be regarded as fairly sensitive but not specific tools for diagnostic purposes. Temporal associations are not sufficient to diagnose work-related asthma.

A person with suspected OA is best evaluated by a specialist in this area of practice. The role of this specialist is to confirm the diagnosis of OA by objective means if possible and to assess for impairment or disability. A delay in referral may jeopardize the chance of confirming the diagnosis with objective measurements, because the subject may have left the workplace and have recovered, or the working conditions may have changed. In cases of OA, however, inhalation challenges with a specific agent generally remain positive even 2 years or more after cessation of exposure.

An algorithm for the clinical investigation of OA is shown in Figure 40-6. The advantages and pitfalls of the various tools in confirming the diagnosis of OA are listed in Table 40-4. The presence of sensitization to occupational agents can be detected either by skin testing or by radioallergosorbent test (RAST) or enzyme immunosorbent assay (ELISA) techniques. In patients with a compatible clinical history of OA and bronchial hyperresponsiveness, a positive result on a skin test or RAST probably has a diagnostic accuracy close to 80% in the case of HMW agents. Unfortunately, very few standardized testing materials are commercially available for skin tests or for RASTs in OA, and for most LMW agents, an IgE-mediated mechanism has not been confirmed

Figure 40-6 Clinical investigation of occupational asthma. IgE, immunoglobulin E.

(From Chan-Yeung M, Malo JL: Occupational asthma, N Engl J Med 333:107–112, 1995.)

Table 40-4 Advantages and Disadvantages of Diagnostic Methods in Occupational Asthma

From Chan-Yeung M, Malo JL: Occupational asthma, N Engl J Med 333:107–112, 1995.

For HMW agents, skin tests to detect immediate reactivity and measurements of specific IgE antibodies are important tools. The absence of nonspecific bronchial hyperresponsiveness in a subject at the end of 2 weeks of working under the usual conditions virtually excludes the diagnosis of asthma and OA. If nonspecific bronchial hyperresponsiveness is present, further testing is required. Spirometric measurements obtained before and after a work shift have not been found to be sensitive or specific. Two options (controlled exposure and PEF) can be considered for objective confirmation, depending on availability (see Figure 40-6). Exposure to the suspected agent under control conditions in a hospital laboratory can be done as originally described by Pepys and Hutchcroft in 1975. Attempts have been made to improve specific challenge tests by exposing subjects in the laboratory to low and stable levels of dry or wet aerosols and vapors to avoid nonspecific reactions. However, these tests can give false-negative results if an incorrect agent is used for testing or if the subject has been away from work for too long, although such occurrences are rare. In the latter instance, the subject should be instructed to return to the workplace, if feasible, and specific laboratory or worksite challenges should be repeated at a later time.

Burge and co-workers were the first to propose the use of serial measurement of peak expiratory flow (PEF) by use of portable devices in the diagnosis of OA. An example of serial PEF recording is shown in Figure 40-7. Although relatively good correlation has been found between the results of serial PEF monitoring and OA as confirmed by specific inhalation challenges in the laboratory, several limitations and pitfalls in PEF monitoring are recognized (see Table 40-4). When PEF monitoring is suggestive of OA and specific inhalation challenges in the laboratory are not possible or yield negative results, it is advisable to confirm OA by sending a technician to the workplace to record serial spirometric variables throughout a work shift. The use of computerized peak flowmeters is very helpful in overcoming some of the problems of PEF monitoring. Computerized programs to assess changes in PEF are currently available (e.g., OASYS [Occupational Asthma Expert System]). Combining PEF monitoring with serial assessments of nonallergic bronchial responsiveness can provide further objective evidence, although this approach does not add to the sensitivity and specificity of PEF monitoring alone. Finally, assessment of airway inflammation (percent eosinophils) in induced sputum has recently been found to be sensitive and specific in the diagnosis of OA. Such measurements improve the sensitivity and specificity of PEF monitoring. Assessing airway inflammation at work and away from work also can be done by assessing exhaled NO, but the reliability of this technique has not been demonstrated in the investigation of OA.

Figure 40-7 Pattern of changes in peak expiratory flows that suggest occupational asthma. The horizontal lines show the periods at work; the triangles illustrate the need for an inhaled bronchodilator.

(From Malo JL, Cote J, Cartier A, et al: How many times per day should peak expiratory flow rates be assessed when investigating occupational asthma? Thorax 48:1211–1217, 1993.)

The main diagnostic criteria for IrIA are (1) the report of at least one inhalational accident (dates, times); (2) the onset of symptoms generally within 24 hours; and (3) the presence of airway obstruction or hyperresponsiveness.

Clinical Course

Subjects with OA will deteriorate if they continue in the same job without protection. Fatalities in workers who continue to be exposed have been reported. A scheme of the progressive natural history of OA is shown in Figure 40-8. Most patients with OA improve but do not recover completely even several years after removal from exposure. Even those subjects apparently cured as indicated by clinical and functional assessments continue to show airway inflammation and remodeling on subsequently obtained bronchial biopsy specimens. Follow-up studies of various types of OA have shown that persons who became asymptomatic after leaving exposure had better lung function and a lower degree of nonallergic bronchial hyperresponsiveness at the time of diagnosis and a shorter duration of exposure after the onset of symptoms. These findings suggest that they were diagnosed at an earlier stage of the disease. Early diagnosis and removal from exposure are essential in ensuring recovery. Although symptoms subside and lung function improves within 1 year of leaving the job involving exposure, decrease in nonallergic bronchial hyperresponsiveness depends on the length of the interval from cessation of exposure. Specific IgE antibodies decrease even more slowly, with no plateau after 5 years as shown in persons with snow crab–induced asthma. It has been recommended that assessment of permanent respiratory impairment or disability take place after at least 2 years of cessation of exposure. The rate of decline in lung function of patients with OA with continuous exposure is higher than in patients without asthma. Moreover, specific bronchial reactivity to the offending occupational agents often persists after the person has left exposure for 2 or more years. Thus, it is not advisable for these patients to return to the same job after they became asymptomatic. Finally, although fewer follow-up studies are available, the outcome with IrIA seems similar to that with immunologic OA.

Figure 40-8 Natural history of asthma and occupational asthma. The boxes illustrate the steps; the modifying factors before each step are listed under the horizontal line. HLA, human leukocyte antigen.

(From Malo JL, Ghezzo H, D’Aguino C, et al: 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 90:937–943, 1992.)

A histologic basis for the persistence of symptoms and nonallergic bronchial hyperresponsiveness in patients with OA has been confirmed. Higher total cell count and eosinophils in bronchoalveolar lavage fluid were found in persons with Western red cedar asthma who did not recover than in those who recovered completely after removal from exposure. Saetta and co-workers in 1992 documented some reversal of airway wall remodeling (thickness of subepithelial fibrosis and number of subepithelial fibroblasts) in patients with toluene diisocyanate (TDI)-induced asthma 6 months after cessation of exposure, but no decrease in bronchial inflammation and in the degree of nonallergic bronchial hyperresponsiveness was seen. Signs of airway inflammation and remodeling may persist for intervals of 10 years or more after the cessation of exposure, even in apparently cured workers. The reasons for the persistence of symptoms and nonallergic bronchial hyperresponsiveness, as well as of airway inflammation and remodeling, after removal from exposure are not known.

Some researchers have explored the possibility of further improving clinical outcomes by combining the use of inhaled steroids to reduce the degree of airway inflammation with removal from exposure. Although more improvement in various clinical and functional parameters was shown by comparison with removal from exposure only, no case of cure from asthma was documented. Because most cases of IrIA occur in isolation, it is difficult to study the natural history in a series of such patients. However, the time course of improvement seems to follow the same pattern as for OA caused by sensitization. Cure in the first 2 to 3 years after the inhalational accident has been described in approximately 25% of persons who incurred the exposure, with the remainder still showing airway inflammation and remodeling many years after the inhalational accident.

Prevention

Primary prevention aims at reducing the risk of the development of immunologic sensitization to workplace agents and subsequent OA. In view of the strong evidence for an exposure-response relationship, primary preventive efforts should focus on the control of workplace exposures. Various interventions can be implemented to reduce exposure at the workplace, including the elimination of hazardous agents whenever feasible; the modification of sensitizing materials (e.g., encapsulation of detergent enzymes); the substitution of highly sensitizing agents by materials with lower asthmagenic potential (e.g., nonvolatile oligomers of diisocyanates, latex gloves with a lower content of powder and protein allergens); engineering changes to the workplace (e.g., improved ventilation, enclosure of industrial process); implementation of safer work practices; and the use of personal protective equipment. Such primary preventive strategies have been shown to be effective in reducing the incidence of OA resulting from enzymes in the detergent industry and from latex gloves in health care facilities.

Another approach is to identify susceptible persons at the time of preemployment examination and exclude them from employment or from high-risk jobs. Unfortunately, the currently identified markers of individual susceptibility (see Table 40-3) have a low positive predictive value for the development of OA. The high prevalence of these markers among the general population, compared with the relatively low risk of occupational sensitization, precludes such screening from being an effective strategy and would unduly exclude many workers in whom OA would never develop. Accordingly, primary prevention should be directed toward reducing exposure to low-enough levels to prevent the onset of asthma in all workers, irrespective of their individual susceptibility. Nevertheless, physicians caring for adolescents with asthma and allergic diseases may offer useful advice regarding careers in which their underlying atopic status increases the risks for work-related sensitization to HMW agents.

Secondary prevention involves the detection of the disease process at an early (preferably preclinical) stage to prevent the development of overt OA and to minimize long-term respiratory impairment by appropriate interventions, which usually involve removal of the worker from exposure. The rationale underlying secondary prevention is the consistent finding that the outcome of OA is better with early diagnosis and milder asthma at the time of removal from exposure. Reduction in the delay between the onset of respiratory and appropriate assessment and intervention could be achieved by increasing awareness of the disease among workers and health professionals. All workers with new-onset asthma or worsening of existing asthma should be interviewed to discover any temporal relationship between work exposure and their symptoms. In the field of occupational medicine, early identification of OA requires the implementation of periodic health surveillance programs in high-risk industries that may be based on questionnaires, spirometry, and identification of allergen-specific IgE when such tests are available and reliable. Surveillance programs should focus on the very first years of exposure, when the incidence of sensitization is highest. Growing evidence indicates that appropriately designed surveillance programs are effective in identifying OA in subjects with less severe asthma and a more favorable outcome.

Treatment

Workers with immunologic OA who remain exposed to the causal agent are likely to experience a worsening of asthma symptoms and nonspecific bronchial hyperresponsiveness, with an accelerated decline in FEV₁ over time. This adverse long-term outcome is not prevented by treatment with inhaled corticosteroids and long-acting β₂-agonists. Thus, the ideal treatment for patients with OA is complete removal from the causal exposure. Nevertheless, OA is associated with substantial long-term morbidity. Complete avoidance of exposure results in an overall improvement in asthma, but asthma symptoms and nonspecific bronchial hyperresponsiveness persist in approximately 70% of the patients with OA several years after removal from the offending environment.

Avoidance of exposure is associated with a substantial adverse socioeconomic impact, because maintaining the affected worker at the same job after elimination of the causal agent from the workplace or accommodation of the worker to an unexposed job often is not feasible.

Reduction in rather than complete avoidance of exposure to causal agents may lead to clinical improvement in terms of asthma symptoms and exacerbations and could be considered as an alternative to complete avoidance, in order to minimize the socioeconomic impact of OA when elimination of exposure is not feasible or when jobs that do not entail exposure are not available. Reducing a worker’s exposure can be implemented by various engineering measures (see earlier section, “Prevention”) or by relocation of the affected worker to a less exposed area or job in the same company. Nevertheless, the limited available evidence indicates that the option of exposure reduction is less beneficial than cessation of exposure, and that this approach requires careful medical monitoring of the subject to ensure early identification of asthma worsening.

Besides environmental interventions, the pharmacologic treatment of OA should follow the general recommendations for asthma as defined in the Global Initiative for Asthma (GINA) guidelines. Patients with OA should be thoroughly informed about the possibilities for compensation, and established cases should be reported to the appropriate public health authorities, according to national regulations. Patients should be considered as permanently and completely impaired for jobs involving exposure to the sensitizing agent that caused their OA. Evaluation for impairment and disability should take into account all of the special features of asthma and should be based on the level of airway obstruction, the degree of nonspecific bronchial hyperresponsiveness or airway reversibility, the minimum amount of medication required for maintaining control of asthma, and the effects of asthma on quality of life.

Data on the optimal management of IrIA are limited, because most cases occur in isolation. Some evidence from case series indicates that subjects with IrIA should benefit rapidly from treatment with oral and/or inhaled corticosteroids, although the dose and duration of treatment remain unknown. Unlike persons with immunologic OA, workers with acute IrIA may be able to continue in their usual jobs if the risk of accidental high-level exposures is prevented through engineering controls. Persons who develop IrIA may subsequently experience worsening of their asthma symptoms on exposure to irritants in the workplace, which may substantially reduce their capacity to work in polluted or dusty environments.

Controversies and Pitfalls

It is important to have objective evidence that the patient’s asthma is due to occupational exposure. Many pitfalls may be encountered in confirming the diagnosis of OA. Although lists of agents causing OA found in published articles and databases are useful to alert the physician, the absence of an agent on such lists does not exclude the possibility of OA, because new proteinaceous materials and chemicals are constantly being introduced into the marketplace. Patients often are asked to leave the job when the diagnosis is suspected. However, one of the objective tests for OA is serial monitoring of PEF by the patient for a period at work and a period away from work. Unless the patient has severe symptoms, it is best to obtain objective evidence first before recommending permanent removal from a specific workplace (i.e., job resignation). PEF monitoring also has limitations, as discussed previously. It should be done properly according to a protocol and with use of a logging device, or together with serial measurements of nonallergic bronchial hyperresponsiveness and airway inflammation. Specific challenge tests have been said to be the “gold standard” modality for diagnosis of OA. When a new agent is suspected, investigators often use several methods to confirm the diagnosis. Some evidence suggests that work-related asthma remains largely unrecognized and inappropriately investigated. A crucial step for enhancing the diagnosis of OA is to promote the prompt referral of workers suspected of having work-related asthma to specialists who have the expertise and facilities for conducting appropriate investigations. In addition, the relative cost and effectiveness of various diagnostic approaches should be further assessed.

Considerable controversy continues regarding whether exposure to a low level of irritant gases or fumes in the workplace or in the environment can actually induce asthma de novo. Despite a great deal that has been learned about OA over the past several years, many gaps remain in current knowledge. Future research priorities should include further improvement in diagnostic, surveillance methods, and control of exposures to prevent the development of the disease and curtail the psychosocioeconomic impact.