Occupational asthma: Clinical features, evaluation, and diagnosis

INTRODUCTION — Occupational asthma (OA) is a form of work-related asthma characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation attributable to exposures in the workplace and not due to stimuli encountered outside the workplace [1]. Work-exacerbated asthma (also known as work-aggravated asthma) is defined as preexisting or concurrent asthma that subjectively worsens in the workplace.

The clinical features, evaluation, and diagnosis of suspected sensitizer-induced OA will be reviewed here. The pathophysiology, epidemiology, causes, risk factors, and management of OA and reactive airways dysfunction syndrome are discussed separately. (See "Occupational asthma: Pathogenesis" and "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Occupational asthma: Management, prognosis, and prevention" and "Overview of occupational and environmental health" and "Irritant-induced asthma".)

CLINICAL FEATURES

Lower respiratory symptoms — The typical symptoms of OA are the same as nonoccupational asthma and include cough, sputum production, dyspnea, wheeze, and chest tightness. (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Clinical features'.)

Some patients report a pattern of increased symptoms while at work or within several hours of the completion of a work shift and improvement on weekends or during vacations, but this is variable. (See 'Time course' below.)

Once sensitized, workers exposed to high molecular weight (HMW) agents are more likely to report early (eg, within an hour of workplace exposure) asthmatic reactions [2,3]. In contrast, workers exposed to low molecular weight (LMW) agents are more likely to experience late asthmatic reactions, chest tightness at work, daily sputum production, and a higher risk of severe exacerbations [3]. The delay in symptom onset with LMW agents may reflect mediation by a non-immunoglobulin E (IgE) mechanism. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Causative agents'.)

Extrapulmonary symptoms — Certain patterns of extrapulmonary symptoms are strongly associated with OA, although they are not sufficiently specific to secure a diagnosis or cause of OA.

●Rhinoconjunctivitis – Symptoms of work-related rhinoconjunctivitis (itchy eyes, tearing, sneezing, nasal congestion, rhinorrhea) often precede symptoms of OA caused by HMW proteinaceous agents [3-7], or may accompany symptoms of OA caused by other HMW agents and the LMW agents [8]. In general, workers with HMW-inducer OA are more likely to report occupational rhinitis (odds ratio [OR] 4.79, 95% CI 3.28-7.12) or conjunctivitis (OR 2.13, 95% CI 1.52-2.98), compared with those with LMW-inducer OA, and their symptoms are often more severe. (See "Occupational rhinitis".)

The report of work-related wheezing, nasal symptoms, and ocular itching substantially increases the likelihood of OA, especially among workers exposed to HMW agents [8]. However, these symptoms are not predictive in subjects exposed to LMW agents. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Causative agents'.)

●Allergic contact dermatitis – Several agents that cause OA (eg, diisocyanates, epoxies, rubber accelerant chemicals in latex, or cleaning agents) have been associated with allergic contact dermatitis [9-16]. However, the occurrence of contact dermatitis is generally not predictive of OA [17]. (See "Common allergens in allergic contact dermatitis" and "Clinical features and diagnosis of allergic contact dermatitis".)

An exception comes from a study of adolescent car painting apprentices (exposed to diisocyanates) in which occupational dermatitis was predictive of work-related asthma symptoms [9]. Cobalt exposure has also been associated with the combination of OA and contact dermatitis [14].

●Urticaria – Work-related urticaria on exposed body parts is sometimes seen with exposure to HMW agents such as latex, mammalian proteins from furry animals, or crustaceans (eg, crab) and may suggest an IgE-mediated process, but there are no studies looking at its predictive value for the development of OA. (See "Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history".)

●Hoarseness – Questionnaires are poorly specific in diagnosing OA. However, among symptoms reported by workers referred for possible OA, wheezing, nasal, and ocular itching at work were positively, and loss of voice negatively, associated with the presence of OA in the case of HMW, but not LMW agents [8].

Physical examination — The physical examination in OA is generally nonspecific and may be normal during office visits away from the occupational exposure. Widespread, high-pitched wheezes are characteristic of asthma, heard most commonly on expiration, but sometimes also during inspiration. However, the presence or absence of wheezing on physical examination is a poor predictor of the presence or severity of OA. (See "Asthma in adolescents and adults: Evaluation and diagnosis" and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Physical findings'.)

Patients with OA may also have pale, swollen nasal mucosa, suggesting concomitant occupational rhinitis [18]. (See "Occupational rhinitis".)

Rarely, an erythematous, eczematous rash (consistent with allergic contact dermatitis) or urticarial rash may be present on skin exposed to the sensitizing agent in the workplace. (See "Clinical features and diagnosis of allergic contact dermatitis".)

EVALUATION — OA should be suspected in every adult with new onset asthma, as OA accounts for approximately 10 to 16 percent of adult onset asthma with some between study variability [19-21]. Patients with reappearance of childhood asthma and deteriorating asthma control on stable therapy should also be screened for OA [22]. For all patients, the evaluation begins with an occupational history, focused on known or potential sensitizing agents. Our approach to testing combines complementary tests, as individual tests have limitations when viewed in isolation. The approach differs if patients are still working and exposed to causative substances (algorithm 1) or are no longer working (algorithm 2). (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Epidemiology'.)

Occupational history — The onset of symptoms relative to exposure varies and a work-related association may not be spontaneously reported by the patient. Thus, the clinical history in patients with possible OA should include detailed questioning about the job description and potential exposures to causal agents, in addition to the routine evaluation of adult-onset asthma (table 1) [23,24]. The clinical history, while important, is not sufficient to confirm or exclude the diagnosis of OA [25-27]. (See "Asthma in adolescents and adults: Evaluation and diagnosis".)

Exposures — All adults with asthma should be questioned not only about their current occupation and exposures, but also about their previous occupations and exposures (table 2). Once the patient’s occupation is ascertained, the potential associated exposures can be evaluated in greater detail. Asking about exposure to vapors, gas, fumes, or dust may help the patient’s recall [28].

As examples, the job description of "engineer" or "clerk" does not yield a full account of the actual exposures in the workplace. Further questioning may reveal indirect exposure to a sensitizing agent depending upon the particular work environment (eg, a work station adjacent to the paint booth in an auto body shop, desk near the site of the flood in an office building, work space adjacent to packaging area in epoxy paint factory). Janitorial and healthcare work may involve use of amines or bleach in cleaning. Exposure to cigarette smoke (active or passive) can occur in many occupations and may trigger symptoms on an irritant basis.

●Occupation-specific exposures – Certain industries or professions are associated with greater contact with agents that have a high potential for provoking OA [29]. As examples, nurses may be exposed to psyllium, chlorhexidine, pharmaceutical products, enzymes, glutaraldehyde, or formaldehyde, while spray painters may be exposed to diisocyanates, acrylates, and various amines (table 2). A description of the more common causative agents and their associated occupations is provided separately. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Causative agents'.)

Additional information on agents that cause OA is available at https://reptox.cnesst.gouv.qc.ca/en/occupational-asthma/Pages/occupational-asthma.aspx.

●Safety data sheet (SDS) – When OA is suspected, but the exact cause is unclear, it is important to obtain a list of the potential causative agents used by the worker or in the workplace. If the names of the chemicals in the workplace are not known, the worker can obtain the SDS from the employer. In the United States, the Occupational Safety and Health Administration (OSHA) requires that suppliers include a SDS with each shipment of an industrial material or chemical, and workers are entitled to receive copies of these sheets.

Importantly, one should not depend entirely upon the information present in safety data sheets, because regulations stipulate that materials present in concentrations less than 1 percent need not be reported and high molecular weight (HMW) compounds from animal and plant sources are typically omitted [30]. In addition, careful review is needed in case an alternate name for a chemical of interest is used, such as urethane or polyester instead of diisocyanate.

●Nonspecific irritants – Asking about exposure to nonspecific irritants (eg, environmental tobacco smoke, strong fumes, extremes of temperature and humidity) is important as all types of asthma can be worsened by exposure to nonspecific irritants at work, a condition that is labeled work-exacerbated asthma [31]. This sensitivity to nonspecific irritants is particularly likely among patients who are exposed to chemical products such as ammonia, engine-exhaust fuel, aerosols and solvents [32], have severe airway (bronchial) hyperresponsiveness, and/or are undertreated with medication. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Definitions'.)

Few studies have investigated non-allergic irritant-induced asthma in which multiple irritant exposures at low concentrations appear to induce asthma in the absence of pre-existing asthma [33]. Since there is no specific testing that can prove that asthma has been caused by repetitive exposure to an irritant agent, it is often difficult to establish the diagnosis of irritant-induced asthma with certainty. However, epidemiologic studies suggest that some jobs, like cleaning and pulp mill work that are associated with exposure to high concentration of irritants, are associated with an increasing risk for the occurrence of asthma [34]. Irritant-induced asthma is discussed separately. (See "Irritant-induced asthma".)

Time course — The natural history of immune-mediated OA is characterized by the following progression (figure 1):

●Onset of exposure

●Sensitization

●Onset of upper and lower airway inflammation

●Clinical disease

●Cessation or persistence of exposure

●Cure, improvement, or persistence of asthma

The latency period between the onset of exposure and the onset of symptoms is highly variable in OA, ranging from months to years. The latency period may vary according to the type of agent, being shorter with exposure to low molecular weight (LMW) agents, such as diisocyanates and plicatic acid (Western red cedar), than with HMW agents (table 2) [3,35].

As an example, among 1179 OA patients, those exposed to HMW agents developed symptoms after a median of eight years of exposure compared with 5.1 years for those exposed to LMW agents [3]. The latency period also varies between HMW agents; sensitization to laboratory animals occurs more commonly and rapidly than sensitization to flour [4].

A pattern of increased symptoms while at work or within several hours of the completion of a shift, and a definite improvement on weekends or during vacations, is common in OA, but documenting this feature is not necessarily helpful. In a series of 162 patients referred for evaluation of possible OA, 88 percent of patients with confirmed OA stated that their symptoms improved during holidays, while 76 percent of patients without OA reported a similar improvement [25]. In addition, the absence of this pattern does not exclude the possibility of OA.

Workers with more advanced OA and those who are only away from work for brief intervals are less likely to report this classic pattern, possibly due to insufficient time away from work to allow improvement or a combination of early and late phase reactions that leads to persistent symptoms. (See "Pathogenesis of asthma", section on 'Early and late phase reactions'.)

Furthermore, workers may not be exposed to the etiologic agent every day, and intermittent exposures make it difficult to relate symptoms to work.

Atopy — The possibility of pre-existing asthma and atopy (genetic predilection to produce specific immunoglobulin E (IgE) following exposure to allergens) should be explored in all patients with suspected occupational asthma. Thus, we ask patients about prior symptoms suggestive of asthma, allergic rhinitis, and atopic dermatitis. This information can help determine whether the patient has new onset disease or a pre-existing process that has worsened. (See "The relationship between IgE and allergic disease".)

While atopy is an important individual risk factor for OA induced by HMW agents [36], atopy by itself has a poor positive predictive value for the presence of OA.

●Only approximately one-third of atopic subjects developed rhinoconjunctivitis or asthma symptoms in the five years following onset of exposure to laboratory animals [37].

●Because atopy is present in almost 50 percent of young adults, it alone does not satisfactorily predict the development of OA.

●Furthermore, pre-existing asthma is not a predisposing factor for immunologic OA.

Skin and immunologic testing — Skin tests and immunoassays for serum specific IgE (ssIgE) have several roles in the evaluation of OA: they can identify sensitization to potential culprit allergens (when available); they can be used to identify sensitivity to common (nonoccupational) aeroallergens that can contribute to symptoms; and newer molecular methods may eventually improve the ability of testing to relate specific epitope sensitivity to the likelihood of disease.

The presence of immediate skin test reactivity or ssIgE reflects specific sensitization, but a positive result can be found in some patients without symptoms of asthma or rhinoconjunctivitis. Therefore, it is important to document objective evidence of physiological changes (eg, airflow obstruction, airway hyperresponsiveness, and/or increased sputum eosinophils) related to exposure, in addition to skin test reactivity or positive testing for specific IgE.

●Skin prick test to common aeroallergens – Skin testing with a panel of common aeroallergens is often performed to identify nonoccupational allergens (eg, pets, pollen, dust mite) that may be contributing to the patient’s asthma. (See "Overview of skin testing for IgE-mediated allergic disease".)

●Skin testing to potential culprit allergens – Skin test reagents for documenting hypersensitivity are only available for a few occupational agents. Extracts of HMW antigens, such as plant material (wheat), mold (Alternaria, Cladosporium), and animal proteins (laboratory animals, insects), have a sensitivity of 0.74 (95% CI 0.66-0.80) and a specificity of 0.71 (95% CI 0.63-0.77), while extracts of LMW agents have a much lower sensitivity and are less commonly available [38,39].

Skin testing can be performed with extracts of HMW agents made in the clinic using material provided by the worker, but these extracts are not standardized and are not very specific or sensitive.

Negative skin prick tests with HMW allergens (eg, relevant cereals, mites, and enzymes in a baker) virtually exclude the possibility that OA is caused by that specific antigen, provided that the skin testing extract reflects the actual exposure and is of the correct concentration to elicit a response [19,27]. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Combined exposures'.)

●Serum specific IgE antibodies – In vitro immunoassay for IgE antibodies to occupational sensitizers is available for a limited number of HMW agents (eg, animal danders, latex, wheat) and LMW chemical-protein conjugates (eg, diisocyanates), but these are not standardized or not always commercially available [19]. When positive, they support but do not confirm the diagnosis of OA to that agent; furthermore, the sensitivity of this testing is low, particularly with LMW agents. (See "Overview of in vitro allergy tests", section on 'Immunoassays for allergen-specific IgE'.)

Some LMW agents, such as platinum salts and trimellitic or phthalic anhydride, can be developed for skin testing, but these are usually not standardized and the sensitivity of testing is low (table 2).

●Recombinant allergens and component resolved diagnosis – Component resolved diagnosis is an emerging molecular method for the diagnosis of OA and rhinitis [40-43]. It utilizes purified recombinant allergens to identify sensitization and characterize the specific allergens involved. It appears that IgE to certain allergenic moieties is more likely to be associated with a severe response than IgE to other moieties. As examples, gliadin-omega-5 is likely to be associated with more severe wheat allergy, and specific IgE antibodies to latex Hev b and Hev b 6.01 are strongly associated with positive specific inhalation challenge [40,41]. (See "Grain allergy: Clinical features, diagnosis, and management", section on 'IgE-mediated presentations'.)

Pulmonary function tests — Baseline spirometry before and after bronchodilator should be obtained in virtually all patients with suspected OA. If airflow limitation is not present, the next step is either nonspecific bronchoprovocation testing or serial peak flow or spirometry at work and at home. For patients who are no longer working, nonspecific bronchoprovocation is used to document the presence or absence of airway hyperresponsiveness.

Spirometry before and after bronchodilator — Baseline spirometry before and after bronchodilator is used to determine the presence and severity of any airflow limitation [44]. The results of spirometry determine the most appropriate next test and are useful as a baseline for future assessments.

In a subject with airflow obstruction (ie, a ratio of forced expiratory volume in one second [FEV₁]/forced vital capacity [FVC] below the lower limit of normal), the next step is to assess reversibility with inhaled bronchodilator. The presence of a significant increase in FEV₁ (10 percent of predicted value) after inhaling a bronchodilator supports the diagnosis of asthma. (See "Pulmonary function testing in asthma", section on 'Bronchodilator responses'.)

Restrictive physiology in the absence of airflow limitation suggests that the patient’s symptoms may have an alternate etiology. Further evaluation usually includes full pulmonary function testing and radiographic imaging. (See "Overview of pulmonary function testing in adults", section on 'Restrictive ventilatory defect'.)

Nonspecific bronchoprovocation challenge — In the absence of airflow limitation at baseline, the next step is to assess nonspecific airway (bronchial) responsiveness, a characteristic feature of asthma [45]. Typically, a pharmacologic agent, such as methacholine or histamine, is used. (See "Bronchoprovocation testing".)

If the FEV₁ does not decrease by 20 percent with a methacholine dose of 16 mg/mL or less, the test excludes significant airway hyperresponsiveness [46]. Absence of airway hyperresponsiveness could be due to lack of recent exposure to the sensitizing agent in a worker who has been away from work, but virtually rules out occupational asthma in a worker who has continued to work and is symptomatic. For patients who have been away from the workplace and have negative initial bronchoprovocation testing, repeat bronchoprovocation testing after an exposure to the causative agent (in the laboratory or at work) may then reveal airway hyperresponsiveness. (See 'Advanced testing' below.)

Serial peak expiratory flow measurement — Serial measurement of peak expiratory flow (PEF) can be useful in the investigation and assessment of OA by demonstrating work-associated airflow limitation (eg, a decrease in peak flow by ≥20 percent at work compared with values at home) [47-49]. Serial PEF is sometimes used to confirm a diagnosis of asthma by demonstrating variable airflow limitation, but spirometry pre and post bronchodilator is preferred. (See 'Spirometry before and after bronchodilator' above.)

The subject is instructed on the proper use of the peak flow meter and asked to monitor his or her PEF a minimum of four times per day for a period of at least two weeks at work and during a similar period away from work (for a total monitoring time of at least three weeks) [20,50]. The period of testing at work should be shortened if the patient develops pronounced airway obstruction or has severe symptoms. The normal degree of PEF variation is <15 percent, whereas variability ≥20 percent associated with workplace exposure supports OA. Diagnostically, multiple methods may be used to compare peak flow changes between days on and off work; some centers use a computerized quantitative approach [22]. (See "Peak expiratory flow monitoring in asthma".)

A number of potential problems are inherent to serial PEF monitoring, including the variable reproducibility of readings, compliance and honesty of subjects, interpretation of results, and sensitivity and specificity compared with specific inhalation challenges [20]. Newer portable peak flow meters store values electronically or online, enabling identification of falsified patient logs, although variable patient effort remains a problem. Interpretation of graphs of serial PEF measurements can be carried out by using a computer program called OASYS, although other diagnostic approaches may be used [51,52]. Ideally, monitoring of PEF should be combined with monitoring of nonspecific bronchial (airway) responsiveness (NSBR) at and off work (see below). When there is discrepancy between changes in PEF and NSBR, further testing such as specific inhalation challenges may be required.

Serial spirometry at work — Spirometry provides more detailed information about airflow and more reliable results than PEF monitoring [53], but serial spirometry has limited utility in evaluating OA. The spirometric parameter that is most reliable is the FEV₁; changes in the FVC and forced expiratory flow at 25 to 75 percent of vital capacity are less reliable. A decrease in workplace FEV₁ ≥15 percent compared with home FEV₁ is considered positive. (See "Office spirometry", section on 'Interpretation'.)

Serial spirometry can be used to identify changes in airflow limitation in and away from the workplace, similar to the procedure for serial PEF monitoring [53]. However, unsupervised serial FEV₁ monitoring at and off work has not proven to be as reliable as serial PEF measurement [54]. Furthermore, portable spirometers are more expensive than PEF meters and the technical training more complex for the worker.

Comparisons between data from exposure and nonexposure days can support (or refute) work-related exacerbations of asthma. However, a single measurement of FEV₁ when the subject is at work and repeating once away from work (eg, pre and post shift) does not have sufficient sensitivity nor specificity to detect a relationship between work and asthma [55-57].

Periodic spirometry measurements can be used for workplace surveillance when occupational exposures place workers at risk for OA [44,53]. Typically, measurements are repeated at one to two year intervals, although periodic spirometry alone is not considered a sensitive tool for identifying new cases [58].

Advanced testing — For patients with a positive exposure history to a known inducer of OA, but nondiagnostic results from the above evaluation, additional tests (largely performed in specialized centers) may be useful (algorithm 1 and algorithm 2). Sputum eosinophil counts are time-consuming and require experienced laboratory personnel.

Airway inflammation — Identifying increased airway inflammation with noninvasive tests, such as sputum eosinophil counts and fractional concentration of exhaled nitric oxide (FE_NO), at the end of a period at work or following laboratory challenge can provide supportive evidence of airway inflammation and, thus, indirect evidence of OA [59].

●Sputum cell counts – Asthmatic airway inflammation may be characterized by the presence of eosinophils in induced sputum samples, especially in HMW induced OA; neutrophils may also be involved, especially in more severe asthma. Either eosinophilic or neutrophilic inflammation can be predominant, the latter being more common in OA induced by LMW agents (table 2) [60-62].

For patients who do not spontaneously raise sputum, inhalation of hypertonic saline can be used to induce sputum, ideally 7 to 24 hours after exposure [63,64]. Typically, a sample of induced sputum is obtained at the end of the work day, after two weeks of work, and compared with a sample from the same time after a day at home, after two weeks off work. Inhalation of albuterol prior to sputum induction will inhibit airway obstruction induced by the hypertonic saline. One common method is to provide seven minutes of nebulization of increasing doses of saline solution (eg, 3, 4, and 5 percent) until sputum can be obtained. We use the Diff-Quik stain which is based upon a modification of the Wright Giemsa stain, although the Wright and Hansel stains are alternatives. The nonsquamous cell differential counts are expressed as a percentage of the total nonsquamous cell counts. This test is only available at specialized centers.

The presence of eosinophils in induced sputum (≥2 percent) suggests that either asthma or eosinophilic bronchitis is present. Eosinophilic bronchitis can be occupationally induced and cause cough and sputum production in the absence of airway hyperresponsiveness [65-67]. (See 'Nonspecific bronchoprovocation challenge' above and "Evaluation and treatment of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis' and "Causes and epidemiology of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

The use of sputum eosinophil counts in the diagnosis of OA was compared with PEF monitoring in a case series of 49 patients with suspected OA who were evaluated during two weeks at work and two weeks away [59]. The combination of work-related decreases in PEF and a greater than 1 percent increase in sputum eosinophils after two weeks at work increased both the sensitivity and specificity of OA diagnosis, compared with PEF monitoring alone. In a separate study, a 3 percent increase in sputum eosinophils following specific inhalation challenge had a positive predictive value of 75 percent for specific bronchial reactivity to occupational agents [68].

In the presence of normal airway caliber and responsiveness and no change in PEF at work, a normal induced sputum cell content in a symptomatic patient with current workplace exposure to a known OA sensitizer excludes OA and further specific testing is not needed.

●Exhaled nitric oxide – The FE_NO generally correlates with sputum eosinophilia, but studies examining a role in the diagnosis of OA are conflicting [69-73], and the value of FE_NO in the investigation of OA remains to be established [70,74]. (See "Exhaled nitric oxide analysis and applications".)

The measurement of FE_NO is appealing because it provides immediate results. However, it is sensitive to confounding factors, such as smoking, atopy, and treatment with inhaled glucocorticoids. The increase in FE_NO is not uniform among subjects who experience a positive asthmatic reaction during specific inhalation challenge [69,75]. Among patients with a positive specific inhalation challenge to an occupational agent, a greater increase in FE_NO is observed among those with sensitivity to a HMW agent than a LMW agent [76]. The use of FE_NO may be more useful in patients exposed to HMW agents, where an IgE-dependent reaction is involved, than in patients exposed to LMW agents [76].

While a positive SIC is often associated with increased FE_NO, FE_NO cannot invalidate or confirm a diagnosis of OA [77].

Variation in nonspecific bronchial responsiveness — Increased nonspecific bronchial (airway) responsiveness (NSBR) can last for years in patients with established OA; in milder OA, it resolves much more quickly, but will last for at least a day or two. Thus, NSBR can be measured after two or more weeks away from work and again after workplace exposure to obtain more objective evidence of an occupational cause of symptoms and airflow limitation [20]. This testing is particularly helpful when the baseline spirometry and initial testing of NSBR are normal.

Airway hyperresponsiveness is usually assessed with direct challenges using methacholine or histamine, but indirect challenges using mannitol may also be helpful in assessing patients with occupational asthma, especially to appreciate the severity of their disease [78]. (See "Bronchoprovocation testing", section on 'Pharmacologic challenge'.)

When assessing changes in bronchoprovocation before and after workplace or laboratory exposure, a change of 3.2-fold (eg, 16 mg/mL to 4 mg/mL) in the concentration of methacholine or histamine that causes a 20 percent fall in FEV₁ is considered clinically significant [79].

When a symptomatic subject is tested within 24 hours of exposure to the suspected work sensitizer, the absence of increased NSBR virtually excludes OA [80]. As an exception, normal responsiveness has been shown in a very few instances, generally in workers who experience an isolated immediate reaction, without delayed bronchoconstriction several hours later. On the other hand, absence from work for several days or longer has been associated with a falsely negative methacholine inhalation challenge [81,82]. If bronchoprovocation testing is negative, but OA is still strongly suspected clinically, skin or immunoassay testing may provide evidence of sensitization. For confirmation of OA in this setting, specific inhalation challenge with the relevant agent is needed. (See 'Specific inhalation challenge' below.)

●Nonasthmatic eosinophilic bronchitis – When nonspecific bronchoprovocation challenge testing is negative despite ongoing exposure, induced sputum may be assessed to identify occupational nonasthmatic eosinophilic bronchitis as a cause of the patient’s symptoms [65]. (See 'Airway inflammation' above and "Evaluation and treatment of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis' and "Causes and epidemiology of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

●Surveillance – Surveillance of asymptomatic workers is generally performed by the workplace. Nonspecific bronchoprovocation challenge is one of the potential tools used to assess development of sensitization. In asymptomatic workers who are undergoing surveillance because of known exposure to an occupational sensitizer, an increase in NSBR and sputum eosinophil numbers after antigen exposure may precede the onset of asthmatic reactions and provide an early and sensitive marker of an abnormal airway response to inhalation of occupational agents [83,84]. (See 'Airway inflammation' above.)

Specific inhalation challenge — Specific inhalation challenge (SIC; also called specific bronchoprovocation challenge) with specific occupational agents is performed in specialized centers [85]. The number of available centers is small [86,87]. Specific bronchoprovocation challenge involves exposing subjects to occupational agents in a hospital laboratory or, occasionally, at work [88]. When these tests are carried out in a hospital laboratory, low doses of the occupational agent are used to avoid a nonspecific irritant effect. Dose response curves are constructed in which the dose (concentration multiplied by duration) is progressively increased and compared with lung function changes. A control test without exposure (or with exposure to a control substance mimicking the suspected agent) is always performed on a separate day [89,90]. (See "Bronchoprovocation testing", section on 'Antigen challenge'.)

In general, specific bronchoprovocation challenges are carried out if other tests are inconclusive, rather than being used for routine diagnosis [86,91]. For example, they can be performed in patients with documented airway hyperresponsiveness when skin or immunoassay testing is not available and results of serial peak expiratory flow or spirometry measurements are unclear about whether asthma is occupationally induced.

In the case of high molecular weight agents, specific bronchoprovocation testing can be carried out in a single day, because an immediate reaction that is maximal during the first hour following exposure is expected. LMW agents often cause nonimmediate or late reactions and therefore require daily challenges of escalating doses of the agent on sequential days.

If airflow obstruction is not induced by inhalation of the specific agent, assessment of NSBR is carried out toward the end of the challenge day or at 24 hours after inhalation. An increase in NSBR, sputum eosinophils, or exhaled nitric oxide after specific antigen challenge supports the likelihood that the patient has OA or nonasthmatic eosinophilic bronchitis due to that agent. A negative specific bronchoprovocation challenge in the laboratory may not exclude entirely the diagnosis of OA as the worker may have become “desensitized” or the wrong agent may have been used [91]. If possible, the worker should return to work and be reassessed if symptoms develop [88].

Specific inhalation challenges appear safe especially when the exposure to LMW agents is spread over a few days with a short exposure on the first day (eg, one to four minutes), as recommended [92]. When the challenge to LMW agents was performed on a single day only, 3 percent of the patients tested experienced a severe asthmatic reaction requiring repeated administration of a short acting beta-2 agonist and oral or systemic glucocorticoids [93].

Imaging — A chest radiograph is often obtained in adults who present with new onset or work-related dyspnea to exclude causes of dyspnea and cough other than OA. The chest radiograph in OA may be normal or may show hyperinflation. High-resolution computed tomography (HRCT) is usually not needed for the evaluation of a patient with suspected OA, unless an unexplained abnormality is noted on the plain chest radiograph.

A possible exception is when a worker has known exposure to agents that cause both OA and hypersensitivity pneumonitis (eg, acid anhydrides, isocyanates). In that setting and when there is suspicion of hypersensitivity pneumonitis, an HRCT scan, combined with pulmonary function testing, may help in differentiating between these possibilities. (See 'Confirmation of asthma' below and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'High resolution computed tomography' and "Imaging of occupational lung diseases".)

DIAGNOSIS — The diagnosis of OA is based upon the following:

●Evidence of reversible airflow limitation (ie, asthma)

●A combination of exposure to a sensitizing agent at work (table 2) and the presence of latency, (ie, the time course of symptom onset relative to start of a particular workplace exposure)

●Specific testing that establishes an occupational contribution (algorithm 1 and algorithm 2).

Confirmation of asthma — The first step in evaluating a patient with suspected OA is to confirm that the patient indeed has asthma. The diagnosis of asthma based on history alone may not be accurate, and therefore pulmonary function testing is warranted, starting with assessment of spirometry pre and post bronchodilator. (See 'Pulmonary function tests' above and "Pulmonary function testing in asthma" and "Asthma in adolescents and adults: Evaluation and diagnosis".)

Asthma is confirmed in one of the following ways:

●Reversible airflow limitation demonstrated with spirometry pre and post bronchodilator. (See 'Spirometry before and after bronchodilator' above.)

●For patients with normal baseline spirometry, positive nonspecific bronchoprovocation challenge confirms asthma. If the testing is negative in a symptomatic patient who has ongoing exposure in the workplace, OA is unlikely. However, if bronchoprovocation challenge is negative in a patient who is not working, it remains possible that nonspecific airway (bronchial) hyperresponsiveness has waned in the absence of exposure. If the patient is able to return to work, bronchoprovocation challenge should be repeated. (See 'Nonspecific bronchoprovocation challenge' above.)

●Demonstration of variable airflow limitation by serial measurement of peak expiratory flow (PEF) or spirometry in and away from the workplace can be helpful but is less reliable for a firm diagnosis of asthma. (See 'Serial peak expiratory flow measurement' above and 'Serial spirometry at work' above.)

Establishing occupational relationship — For those patients who have a clear diagnosis of asthma, the next step is to establish that an occupational agent is causing the worker’s asthma and, when possible, to identify the causative agent. Given the important implications of establishing the diagnosis for both health and employment, it is best to establish the workplace association prior to initiation of maintenance treatment or workplace adaptations [22]. Several tests are available to determine whether a given patient's symptoms are due to OA and whether a particular occupational exposure is the inciting agent [20]. Stepwise schemes have been proposed for the diagnosis of OA using these various methods [94]. The exact order and combination of testing depends on whether the patient still has workplace exposure or not and the availability of testing (algorithm 1 and algorithm 2).

Patients who are working — For patients who continue to work or can return to the workplace, serial testing of PEF during and away from workplace exposures is a standard and widely available method for identifying OA. Skin testing and immunoassays to agents known to cause OA have limited availability, but should be performed if available. When positive in a patient with known exposure to that agent and objective evidence of asthma, the likelihood of OA is high. However, a positive allergy test is not diagnostic of OA, and a negative reaction does not exclude OA. Combining nonspecific bronchial responsiveness (NSBR) monitoring with serial PEF monitoring at and away from work improves the accuracy of the diagnosis.

Where available, combining monitoring of NSBR and induced sputum analysis with PEF measured at and away from work can further increase the accuracy of testing. (See 'Serial peak expiratory flow measurement' above and 'Serial spirometry at work' above and 'Airway inflammation' above.)

●Confident diagnosis of OA – Decreases in PEF noted at work and significant reduction in NSBR away from work. An increase in eosinophils (>1 to 2 percent) at the end of the workday relative to a sample from the same time of day at home helps support the diagnosis. Absence of change in sputum eosinophils does not negate the diagnosis.

●OA likely, but not definite – Work-related decreases in PEF without a work-related change in NSBR or increase in sputum eosinophils. If a definite diagnosis of OA is necessary in such a patient, referral to a center that could perform specific inhalation challenge to the presumed culprit agent would be required. Of note, a positive SIC is required for a diagnosis of OA in Canada, but not in the United States. (See 'Specific inhalation challenge' above.)

●OA unlikely – Absence of a work-related decrease in PEF, absence of NSBR changes at and off work, and absence of an increase in sputum eosinophils. If strong clinical suspicion for OA remains, referral to a center that offers specific bronchoprovocation challenge can provide a definitive result. (See 'Specific inhalation challenge' above.)

Patients who are not working — A definitive diagnosis of OA can be more difficult to make in patients who no longer have workplace exposure, because nonspecific bronchial hyperresponsiveness (NSBH) tends to wane the longer the person is away from the workplace and serial lung function monitoring cannot be performed. The initial steps are to assess skin testing or immunoassays for evidence of sensitization to potential causes of OA (where available) and confirm objective evidence of asthma based on spirometry pre and post bronchodilator or nonspecific bronchoprovocation challenge.

●Likely diagnosis of OA – Positive skin test or immunoassay and objective evidence of asthma. Resolution of asthma symptoms away from the workplace lends further support to the diagnosis.

●Sensitization without current evidence of OA – Positive skin test or immunoassay, but normal spirometry and a negative bronchoprovocation challenge. As the person is no longer working, NSBH may have resolved. Specific inhalation challenge, possibly followed by repeat nonspecific bronchoprovocation challenge, may help establish the diagnosis. (See 'Advanced testing' above.)

●Confirmation of asthma, but diagnosis of OA unclear – Negative skin test or immunoassay, but objective confirmation of asthma. Definitive diagnosis of OA would require a positive specific bronchoprovocation challenge. In the absence of specific inhalation challenge, a likely diagnosis of OA would depend on whether the history of asthma onset, exposure to a causative agent, and improvement away from the workplace strongly suggest OA. (See 'Advanced testing' above.)

●OA unlikely – Skin test or immunoassay and nonspecific bronchoprovocation challenge are negative. Any current symptoms would be unlikely due to OA. A small possibility remains that the patient’s workplace symptoms were due to OA, but the NSBH resolved after the person left the workplace (if several weeks have elapsed). The only way to make a definitive diagnosis would be via specific bronchoprovocation challenge, possibly followed by repeat nonspecific bronchoprovocation challenge. (See 'Advanced testing' above.)

DIFFERENTIAL DIAGNOSIS — A number of disease processes have symptoms that mimic OA, such as asthma due to nonoccupational causes, chronic obstructive pulmonary disease (COPD), nonasthmatic eosinophilic bronchitis, work-related irritable larynx syndrome, upper respiratory tract irritation, hyperventilation syndrome, occupational rhinitis, hypersensitivity pneumonitis, and bronchiolitis obliterans. Certain distinguishing features can help to differentiate OA from the other diagnoses. The evaluation and diagnosis of asthma and occupational rhinitis are discussed separately. (See "Asthma in adolescents and adults: Evaluation and diagnosis" and "Occupational rhinitis" and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Differential diagnosis'.)

●COPD – Workers can develop COPD due to personal or workplace exposure to tobacco smoke, irritants such as coal mine dust, and other pollutants. A careful history can elicit the intensity and duration of these exposures. Spirometry will typically show a substantial component of irreversible airflow obstruction in patients with COPD. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Spirometry'.)

●Occupational Asthma and COPD Overlap (OACO) – Asthma and COPD may exist concurrently in some workers, and the syndrome presents with airflow obstruction not fully reversible with bronchodilator treatment. In a comparison of workers with OACO versus OA, those with OACO tended to be older, were exposed to the triggering agent for a longer period of time, were more frequently exposed to LMW agents, were treated with higher doses of inhaled glucocorticoids, and were less atopic [95,96]. (See "Asthma and COPD overlap (ACO)".)

●Nonasthmatic eosinophilic bronchitis (NAEB) – NAEB due to occupational exposure differs from OA by the absence of airway hyperresponsiveness and airflow obstruction. Sputum cell count analysis shows a significant increase in the percentage of eosinophils when the patient is exposed to the occupational agent to which they are sensitized, with a significant decrease after removal from exposure. (See "Evaluation and treatment of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis' and "Causes and epidemiology of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

●Work-related irritable larynx syndrome – Work-related irritable larynx syndrome refers to hyperkinetic laryngeal symptoms triggered by sensory stimuli in the workplace, such as odors and irritants [97]. This syndrome includes inducible laryngeal obstruction (ILO; also known as paradoxical vocal fold motion or vocal cord dysfunction), dysphonia due to laryngeal muscle tension (also known as muscle tension dysphonia), globus (ie, sensation of tension in the throat or neck), and chronic cough. In a case series of workers with work-related irritable larynx, dysphonia was present in 86 percent and chronic cough in 76 percent [97].

ILO can mimic asthma and OA, and can also coexist with these diagnoses [98]. Typically, the diagnosis of ILO is suspected when the patient has noisy, high-pitched breathing sounds (stridor), loudest above the throat and less audible through the chest wall, dysphonia, and an abnormal inspiratory flow volume curve, and does not respond as expected to treatment with an inhaled bronchodilator. Ascertaining the diagnosis requires the visualization of paradoxical motion of the vocal folds or supraglottic narrowing during symptoms. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Flow-volume loops", section on 'Variable extrathoracic obstruction'.)

●Hyperventilation syndrome – Hyperventilation syndrome is frequently misdiagnosed as asthma [25,99]. It is characterized by a variety of somatic symptoms induced by physiologically inappropriate hyperventilation and usually reproduced in whole or in part by voluntary hyperventilation. (See "Hyperventilation syndrome in adults".)

●Hypersensitivity pneumonitis – A number of the same antigens that cause OA can also cause hypersensitivity pneumonitis. Unlike OA, hypersensitivity pneumonitis is typically associated with a restrictive ventilatory defect and interstitial opacities on radiographic imaging. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on 'Etiologic agents'.)

●Bronchiolitis obliterans – Bronchiolitis obliterans presents with dyspnea and cough; airflow limitation on spirometry, when present, is typically not reversible. Silo filler’s disease due to inhalation of high concentrations of nitrogen dioxide is a classic example of bronchiolitis obliterans. Bronchiolitis obliterans has also been reported in popcorn workers and as a rare manifestation in nylon flock workers [100,101]. (See "Overview of bronchiolar disorders in adults", section on 'Cessation of culprit drugs and exposures' and "Flock worker's lung".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occupational asthma".)

SUMMARY AND RECOMMENDATIONS

●Definition – Occupational asthma (OA) is characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation attributable to a particular occupational exposure and not due to stimuli encountered outside the workplace. (See 'Introduction' above.)

●Clinical features – The typical symptoms of OA are the same as nonoccupational asthma and include cough, sputum production, dyspnea, wheeze, and chest tightness. Some patients report a pattern of increased symptoms while at work or within several hours of the completion of a shift and improvement on weekends or during vacations. Patients may also have symptoms of work-related rhinoconjunctivitis that precede or accompany the onset of OA. (See 'Clinical features' above.)

●Evaluation – A stepwise testing approach based on whether or not the patient continues to work can be useful to reach a diagnosis of OA (algorithm 1 and algorithm 2).

•Occupational history – Although insufficient on its own to confirm or exclude the diagnosis, a work history is an essential component of the evaluation of OA. It should generally include current and previous job titles, job descriptions, known exposures, and also any exposures to unidentified vapors, gas, fumes, or dust (table 2 and table 1). (See 'Occupational history' above.)

In general, the latency period from initial exposure to onset of symptoms (sensitization) is shorter with low molecular weight (LMW) agents than with high molecular weight (HMW) agents (table 2). However, onset of symptoms on a given day typically occurs faster with HMW agents than LMW agents. (See 'Occupational history' above.)

For HMW agents, work-related wheezing and nasal symptoms suggest OA. For LMW agents, no specific symptom question accurately predicts OA. (See 'Occupational history' above.)

•Skin and immunologic testing – When available, skin test reactivity or immunoassay for specific immunoglobulin E (IgE) can identify sensitization to known occupational sensitizers. (See 'Establishing occupational relationship' above and 'Skin and immunologic testing' above.)

•Confirmation of asthma – The evaluation of suspected OA generally requires tests to confirm asthma and determine whether a particular occupational exposure is the inciting agent. (See 'Diagnosis' above.)

-Initial testing includes spirometry before and after bronchodilator to determine the presence, severity, and reversibility of any airflow limitation. (See 'Spirometry before and after bronchodilator' above and 'Confirmation of asthma' above.)

-In the absence of airflow limitation, a nonspecific bronchoprovocation challenge (eg, methacholine) is helpful to confirm or exclude current asthma. For patients who have ongoing work exposure and are symptomatic, a negative bronchoprovocation challenge makes OA unlikely. (See 'Nonspecific bronchoprovocation challenge' above and 'Confirmation of asthma' above.)

•Establishing an occupational relationship – For patients who meet objective criteria for asthma and continue to work, monitoring of peak expiratory flow (PEF) or nonspecific bronchial responsiveness (if available) during and away from workplace exposures is useful to assess a workplace contribution. (See 'Establishing occupational relationship' above and 'Serial peak expiratory flow measurement' above.)

-In those with symptoms and ongoing workplace exposures, absence of nonspecific bronchial responsiveness, lack of sputum eosinophilia, and negative PEF monitoring in combination virtually excludes the possibility of OA. (See 'Variation in nonspecific bronchial responsiveness' above.)

For patients with adult-onset asthma and suspected OA, but uncertainty about the provocative agent, specific bronchoprovocation testing at the workplace may be helpful. Such testing is only available in specialized centers. (See 'Specific inhalation challenge' above and "Bronchoprovocation testing", section on 'Antigen challenge'.)

●Differential diagnosis

•Occupational nonasthmatic eosinophilic bronchitis (NAEB) – Occupational NAEB is an infrequent cause of occupational respiratory symptoms without bronchial hyperresponsiveness. (See 'Airway inflammation' above and 'Differential diagnosis' above.)

•Other allergic and pulmonary diseases – Other diseases that share features with OA include: asthma due to nonoccupational causes, chronic obstructive pulmonary disease (COPD), hyperventilation syndrome, upper respiratory tract irritation, occupational rhinitis, hypersensitivity pneumonitis, and bronchiolitis obliterans. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Moira Chan-Yeung, MD, Jean-Luc Malo, MD, André Cartier, MD, and Louis-Philippe Boulet, MD, who contributed to earlier versions of this topic review.