Epidemiologic Aspects

Estimates of the frequency of OA have been derived from various sources, including cross-sectional and longitudinal studies of high-risk workforces, occupational disease registries, voluntary notification programs, and population-based surveys. A pooled analysis of data published up until 2007 indicated that 17.6% of all adult-onset asthma is attributable to workplace exposures.

Cross-sectional surveys of workforces exposed to sensitizing agents reported highly variable prevalence rates of OA, but these estimates are largely affected by the criteria used to identify the disease and selection biases. Prospective cohort studies reported incidence rates ranging from 1.8 to 4.1 cases of OA per 100 person-years among workers exposed to laboratory animals, wheat flour, and latex gloves. Incidence rates derived from notification schemes and compensation statistics in various countries ranged from 24 to 174 new cases per million active workers per year. Differences from one country to another may result from geographic differences in industrial activities, as well as the heterogeneity in diagnostic criteria and data collection procedures.

The European Community Respiratory Health Survey II provided higher estimates of 250 to 478 incident cases of work-attributable asthma per million people per year. These data suggest that the disease remains largely unrecognized, although population surveys are affected by the lack of confirmation of OA through objective tests.

Causal Agents

A large number of substances (>400) used at work can cause immunologically mediated OA. They are usually categorized into HMW and LMW agents ( Table 72-1 ). HMW agents are (glyco)proteins from plant and animal origins. LMW agents include chemicals, metals, and wood dusts. The intrinsic characteristics of occupational agents that determine their sensitizing potential remain largely uncertain. However, LMW agents causing OA are typically highly reactive electrophilic compounds that are capable of combining with hydroxyl, amino, and thiol functionalities on airway proteins. Quantitative structure-activity relationship models have identified a number of reactive groups that are associated with a high risk of respiratory sensitization (e.g., isocyanate [N = C = O], carbonyl [C = O], and amine [NH ₂ ]), particularly when two or more groups are present within the same molecule.

Actually, a handful of agents (i.e., flour, diisocyanates, latex, persulfate salts, aldehydes, animals, wood dusts, metals, enzymes) usually account for the majority (50% to 90%) of reported cases of OA. Nevertheless, the distribution of causal agents may vary widely across geographic areas, depending on the pattern of industrial activities. The highest incidence of OA is seen in bakers and pastry makers, other food processors, spray painters, hairdressers, wood workers, health care workers, cleaners, farmers, laboratory technicians, and welders.

Pathophysiology

The pathophysiology of sensitizer-induced OA often involves an immunoglobulin E (IgE)-dependent mechanism. This mechanism is encountered mainly with HMW agents. Although specific IgE has also been encountered in OA due to LMW agents (e.g., platinum salts, trimellitic anhydride, other acid anhydrides), the production of specific IgE antibodies or the upregulation of IgE receptors has not been identified in the majority of cases of OA induced by LMW agents.

Risk Factors

OA results from the complex interaction between environmental and individual susceptibility factors ( Table 72-2 ).

Diagnosis

The diagnosis of OA is difficult to establish. A comprehensive and integrated approach including the assessment of occupational history, clinical symptoms, and functional and inflammatory characteristics at baseline and in response to exposure to occupational agents needs to be undertaken in order to achieve an accurate diagnosis. This approach is summarized in Figure 72-2 . Each step of the investigation has substantial limitations that may be attenuated by the combination of several tests. The validity of the different diagnostic tests and their practical limitations and advantages are summarized in Table 72-3 .

Diagnostic approach in the investigation of sensitizer-induced occupational asthma. OA, occupational asthma; PEF, peak expiratory flow rates; SIC, specific inhalation challenge.

OA should be suspected in every adult with new-onset asthma. Although the respiratory symptoms (e.g. wheezing, dyspnea, chest tightness, cough, and sputum production) are similar to those encountered in non-WRA (NWRA), in OA, their appearance and severity is usually modulated by the work exposure. The symptoms can start at the beginning of the work shift or toward its end or even after working hours with remission or improvement during weekends and holidays. Rhinitis is associated with respiratory symptoms in the majority of cases of OA and often precedes the respiratory symptoms, especially with exposure to HMW agents. Although a thorough clinical and occupational history must be carefully recorded, the diagnosis of OA cannot be made only on the basis of a compatible history, which has a low positive predictive value.

A good occupational history must detail not only the current employment and exposure but also the past employments and exposures. The work history (current and past employments), the symptoms (nature and temporal relationship to work), as well as the potential risk factors, need to be recorded. The substances to which the worker is potentially exposed at work can be checked against a comprehensive list of agents recognized as causing OA, and the person’s employment can be searched on the list of at-risk occupations. Material safety data (MSD) sheets can be requested from the workplace and may be of help in clarifying the presence of a workplace sensitizer. If the content of the causal agent is less than 1%, it may not be listed in the MSD. If available, the occupational health record and the industrial hygiene record from the company should also be reviewed. A list of agents responsible for OA can be found at:

http://www.asthme.csst.qc.ca/document/Info_Gen/AgenProf/Bernstein/BernsteinAng.htm .

A list of occupations in which the exposure to those agents is encountered can be found at:

http://www.asthme.csst.qc.ca/document/Info_Med/IdCauses/Bernstein/Occupational Asthma-Agents by occupation.pdf.

Once the history has been obtained, the diagnosis of asthma should be confirmed by documenting reversible airflow limitation and/or airway hyperresponsiveness. However, the lack of airway hyperresponsiveness does not exclude the diagnosis of OA in subjects who have been removed from exposure. Immunologic testing is useful in demonstrating a sensitization of the worker to the suspected agent. Although the negative predictive value of these tests is high in the case of HMW, they are limited by the lack of standardized commercially available reagents for skin and in vitro tests. Skin-prick tests are seldom useful when LMW agents are suspected.

The work-relatedness of asthma should be assessed through serial measurements of peak expiratory flow (PEF) and/or nonspecific bronchial hyperresponsiveness at work and off work and/or specific inhalation challenges in the laboratory or at the workplace.

Assessing airway responsiveness is an important step in the investigation of OA. It may confirm not only the diagnosis of asthma but also the improvement of airway responsiveness after a period away from work, which may support the diagnosis of OA. However, additional studies assessing the predictive positive and negative values of serial measures of nonspecific bronchial hyperresponsiveness at and away from work for diagnosing OA are required to know the diagnostic performance of this test. Nonetheless, normal airway responsiveness after a period at work at which time the workers experience their respiratory symptoms makes the diagnoses of OA and asthma improbable. In this case, an alternative diagnosis should be investigated.

As said, a serial measurement of PEF at work and away from work has been found to be useful in confirming OA. The minimum period of PEF monitoring should be 2 weeks at work with a significant exposure to the suspected causative agent and a similar period away from work, unless significant changes are recorded earlier at work. Asthma treatment should be kept constant throughout the period of monitoring. However, similarly to common asthma, compliance with PEF monitoring has been shown to be poor and the results may be falsified if an electronic PEF meter is not used.

SIC tests consist of exposing the subjects to the suspected occupational agent in the laboratory and/or at the workplace. These tests are considered to be the reference tests, but they are time consuming and require specialized facilities available in only a few centers. Specific-challenge tests are useful when (1) the diagnosis of OA remains in doubt after serial monitoring of PEF or airway responsiveness; (2) a patient clearly has OA, but the causal agent needs to be identified; (3) a new agent is suspected of causing OA; and (4) the patient cannot be returned to the incriminated workplace. A false-negative response may be obtained if the wrong agent is used or if the exposure conditions are not comparable with those in the workplace. SICs have been shown to be safe and induce rarely severe asthmatic reactions requiring administration of systemic steroids.

Noninvasive measures of airway inflammation are increasingly used during the investigation of OA. There is evidence that OA is associated with an increase in the sputum eosinophil percentage during periods at work and a decrease after removal from exposure. In settings where this tool is available, it may complement the current investigation of OA. Although the measurement of fractional exhaled nitric oxide (FeNO) is easier to obtain than sputum cell counts, the current evidence does not show a clear benefit of using FeNO in the investigation of OA. The interpretation of an increased FeNO is more difficult than sputum differential cell counts due to its lack of specificity, as well as the potential confounding factors that may influence the results. However, recent evidence shows a high specificity of this test in subjects exposed to HMW agents. Whether the monitoring of FeNO should be used in some phenotypes of OA remains to be determined. Making an accurate diagnosis of OA is crucial due to the significant social and financial consequences associated with this diagnosis.

Outcome and Management of Sensitizer-Induced Asthma

According to recent systematic reviews of the existing data, the complete avoidance of exposure to the causal agent remains the optimal treatment of immunologic OA. Although a reduction of exposure to the agent can be considered as an alternative option, the limited available evidence indicates that this option is less beneficial than complete cessation of exposure because it is associated with a lower likelihood of asthma improvement and a higher risk of worsening.

Immunotherapy has only been tested in workers with allergy and/or OA to HMW agents for which an IgE-dependent reaction has been demonstrated. Immunotherapy has been mainly tested in health care workers allergic to latex. Although immunotherapy can reduce cutaneous and respiratory symptoms in health care workers allergic to latex, this treatment can induce systemic reactions in a large number of treated subjects. Small or uncontrolled studies have reported an improvement of allergic and respiratory symptoms after immunotherapy to some selected agents (cereal, sea squirt, laboratory animal, and wood ). However, whether immunotherapy can alter the course of OA in the long term remains to be determined. Further studies need to be conducted before immunotherapy can be recommended for the treatment of OA to HMW agents.

A few case reports provided some suggestion that treatment with the anti-IgE omalizumab could improve asthma control in subjects with flour-induced OA, who remain exposed to the causal work environment, although further prospective investigations are required in subjects who choose to continue exposure.

Clinicians should be aware that OA is not always reversible after cessation of exposure to the sensitizing agent. Asthma symptoms and airway hyperresponsiveness (AHR) persist in approximately 70% of the patients with OA several years after removal from the offending environment. Besides environmental interventions, the pharmacologic treatment of OA should follow the clinical practice guidelines for asthma.

Primary prevention aims at preventing the development of immunologic sensitization to workplace agents and subsequent OA. Primary preventive strategies should focus on the control of workplace exposures because there is strong evidence supporting a dose-response relationship between the level of exposure to sensitizing agents and the development of OA. The control of exposure can be achieved through a panel of measures that include the elimination of agents with a known sensitizing potential whenever feasible: (1) the modification of sensitizing materials (e.g., encapsulation of detergent enzymes); (2) the substitution of highly sensitizing agents by materials with lower asthmagenic potential (e.g., nonvolatile oligomers of diisocyanates, latex gloves with a lower content in powder and protein allergens); (3) engineering changes to the workplace (e.g., exhaust ventilation, enclosure of industrial processes); (4) information and education of workers and employers on safe work practices; and (5) the use of personal protective equipment for specific tasks. Another approach is to identify susceptible individuals at the time of preemployment examination and exclude them from employment or from high-risk jobs. This strategy is inefficient and unduly discriminating because the currently identified markers of individual susceptibility (see Table 72-2 ) offer only a low positive predictive value for the development of OA, especially when these markers, such as atopy, are highly prevalent in the general population. 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 of sensitizer-induced OA involves the detection of the disease process at an early (preferably preclinical) stage to modify the disease process through appropriate interventions to eliminate exposure. The rationale underlying secondary prevention is the consistent finding that the outcome of OA is better with an early diagnosis and milder disease at the time of removal from exposure. Increasing awareness of the disease among workers and health professionals is a key step to enhance the recognition of OA because the condition still remains underdiagnosed and inappropriately investigated. There is recent evidence that appropriately designed surveillance programs are effective in identifying OA in subjects with less severe asthma and a more favorable outcome.

A few observational studies and historical data indicate that prevention is effective in reducing the incidence of OA and occupational rhinitis caused by natural rubber latex in health care workers, enzymes in the detergent industry, flour, laboratory animals, and isocyanates. However, available data do not distinguish the relative effect of the diverse components of prevention strategies because they are usually implemented as multicomponent programs targeting education, control of exposure, and medical surveillance.

Socioeconomic Impact

Studies worldwide have shown that OA is associated with substantial financial consequences for affected workers and society as a whole. There is growing evidence that WRA is associated with more severe asthma and with a higher health care resource utilization as compared with asthma unrelated to work. In addition, OA generates higher indirect costs than nonoccupational asthma because the former condition most often requires job changes to either avoid or reduce exposure to the causative agent. Follow-up studies of workers with OA have consistently documented that the condition is associated with a high rate of prolonged unemployment, ranging from 18% to 69%, and a reduction in work-derived income in 44% to 74% of affected workers. A poorer socioeconomic outcome is associated with the need for a complete avoidance of exposure to the sensitizing agent, a lower level of education, an older age, and lack of effective job retraining programs.

Because the specific bronchial hyperreactivity to occupational agents almost never completely disappears, workers with OA should be considered as permanently and completely disabled for jobs involving exposure to the sensitizing agent that caused their OA. They 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. Evaluation of physiologic impairment should take into account the characteristic features of asthma and should be based on the level of airway obstruction, the degree of nonspecific bronchial hyperresponsiveness, and the intensity of medication required for controlling asthma.