Asthma in the Workplace

SECTION 

M

ENVIRONMENTAL AND OCCUPATIONAL HAZARDS

72

ASTHMA IN THE WORKPLACE CATHERINE LEMIÈRE, MD, MSc • OLIVIER VANDENPLAS, MD, PhD

INTRODUCTION SENSITIZER-INDUCED OCCUPATIONAL ASTHMA Epidemiologic Aspects Causal Agents Pathophysiology Risk Factors Diagnosis Outcome and Management of SensitizerInduced Asthma Socioeconomic Impact

IRRITANT-INDUCED ASTHMA Epidemiologic Aspects Pathophysiology Risk Factors Diagnosis Outcome and Treatment Prevention WORK-EXACERBATED ASTHMA Epidemiologic Aspects Pathophysiology

INTRODUCTION Work-related asthma (WRA) is a major public health concern due to its high prevalence and societal burden. WRA is a broad term indicating that asthma is worsened by the workplace.1 WRA encompasses occupational asthma (OA), which is asthma caused by a specific agent at the workplace and work-exacerbated asthma (WEA), which corresponds to asthma exacerbated by nonspecific stimuli at the workplace but not caused by it (Fig. 72-1).2 Several definitions of OA have been proposed. The most recent has been published in the latest American College of Chest Physicians Consensus statement on WRA3: “Occupational asthma refers to de novo asthma or the recurrence of previously quiescent asthma (i.e., asthma as a child or in the distant past that has been in remission) induced by either sensitization to a specific substance (e.g., an inhaled protein [high-molecular-weight (HMW) protein of > 10 kd] or a chemical [low-molecular-weight (LMW) agent]), at work, which is termed sensitizer-induced OA, or by exposure to an inhaled irritant at work, which is termed irritantinduced OA.”

Work Exposures Associated with Work-Exacerbated Asthma Diagnosis of Work-Exacerbated Asthma Differentiating Work-Exacerbated Asthma from Non–Work-Related Asthma or Occupational Asthma Socioeconomic Impact of WorkExacerbated Asthma

Sensitizer-induced OA has also been defined as “asthma with a latency period,” suggesting the presence of an underlying immunologic mechanism responsible for a latency period from the beginning of the occupational exposure to the onset of asthma symptoms.4 Irritant-induced (occupational) asthma (IIA), also called “OA without a latency period” or “nonimmunologic OA,”5 encompasses a wide spectrum of asthma phenotypes related to irritant mechanisms, as opposed to OA caused by immunologic mechanisms. The rapid onset of asthma within a few hours after a single exposure to high levels of irritant substances (i.e., acute-onset IIA or reactive airways dysfunction syndrome (RADS)6 is the best typified phenotype of IIA, whereas for other clinical phenotypes (e.g., “low-dose reactive airways dysfunction syndrome,” “not-so-sudden IIA,” or “IIA with latency”)7-13,13a the causal relationship with workplace irritant exposures remains uncertain. WEA has received growing attention during the past decade. The latest definition of WEA has been proposed by the American Thoracic Society Task Force on WEA2 and consists of four criteria: 1295

1296 PART 3  •  Clinical Respiratory Medicine

There is preexisting or concurrent asthma. The onset of asthma may have predated current employment or happened first while at the worksite of interest but was not caused by specific exposures within that workplace. ■ An increased frequency of asthma symptoms, medication use, or health care utilization is temporally associated with work. Medical test results may document more frequent abnormalities. ■ Workplace exposures or conditions that can exacerbate asthma exist. ■ Occupational asthma (asthma caused by a specific, identified workplace exposure) is unlikely. ■

In spite of these clear definitions, differentiating those conditions is often difficult in clinical practice. An accurate diagnosis is crucial because the diagnosis of this condition can result in a change of career and/or some financial compensation. This chapter reviews the epidemiology, pathophysiology, diagnosis, management, prevention, and socioeconomic impacts of sensitizer-induced OA, IIA, and WEA. Work-related asthma New-onset asthma directly caused by Occupational exposure to asthma workplace agent Sensitizerinduced

Workexacerbated asthma

Irritantinduced

Latency period of several weeks to decades

Preexisting or concurrent asthma aggravated by workplace exposure to irritants

Single or multiple high-level exposures to irritants

Figure 72-1  Categorization of work-related asthma into subsets based on the cause and timing of the asthma.

SENSITIZER-INDUCED OCCUPATIONAL ASTHMA 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 populationbased surveys. A pooled analysis of data published up until 2007 indicated that 17.6% of all adult-onset asthma is attributable to workplace exposures.14 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,15 wheat flour,16 and latex gloves.17 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.18-24 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.25,26 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.27 They are usually categorized into HMW and LMW agents (Table 72-1). HMW

Table 72-1  Principal Agents Causing Occupational Asthma Agent

Occupation/Industry

HIGH-MOLECULAR-WEIGHT AGENTS Cereals, flour Wheat, rye, barley, buckwheat Latex Proteins from the Hevea tree Animals Mice, rats, cows, seafood Enzymes α-Amylase, maxatase, alcalase, papain, bromelain, pancreatin

Flour mills, bakers, pastry makers Health care workers, laboratory technicians Laboratory workers, farmers, seafood processing Baking product production, bakers, detergent production, pharmaceutical industry, food industry

LOW-MOLECULAR-WEIGHT AGENTS Isocyanates Toluene diisocyanate (TDI), methylene diphenyldiisocyanate (MDI), hexamethylene diisocyanate (HDI) Metals Chromium, nickel, cobalt, platinum Biocides Formaldehyde, glutaraldehyde, quaternary ammonium compounds Persulfate salts Hair bleach Acrylates Cyanoacrylates, methacrylates, di- and tri-acrylates Acid anhydrides Reactive dyes Woods

Phthalic, trimellitic, maleic, tetrachlorophthalic anhydrides Reactive black 5, pyrazolone derivatives, vinyl sulphones, carmine, Red cedar, iroko, obeche, oak, and others

Polyurethane production, plastic industry, insulation, molding, spray painting Metal refinery, metal alloy production, electroplating, welding Health care workers, cleaners Hairdressers Adhesives, dental and orthopedic materials, sculptured fingernails, printing inks, paints and coatings Epoxy resin workers Textile workers, food industry workers Sawmill workers, carpenters, cabinet and furniture makers

72  •  Asthma in the Workplace 1297

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 [NH2]), particularly when two or more groups are present within the same molecule.28 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.24,29 Nevertheless, the distribution of causal agents may vary widely across geographic areas, depending on the pattern of industrial activities.18-24 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.30

Immunologic, IgE-mediated The pathophysiology of OA induced by IgE-dependent agents is similar to allergic asthma unrelated to work. HMW agents act as complete antigens and induce the production of specific IgE antibodies, whereas the LMW occupational agents that are likely to induce specific IgE antibodies do so by acting as haptens and binding with proteins to form functional antigens. The role of specific IgE is still controversial in isocyanate-induced asthma.31 The presence of specific IgE to isocyanates seems a good predictor of isocyanate-induced OA (specificity 89% to 100%),3 whereas specific IgG seems to be mostly associated with exposure to isocyanates.32 However, whether isocyanate-induced asthma is an IgE-mediated disease is still a matter of debate.31 Immunologic, non–IgE mediated Cell-mediated reactions are likely to play an important role in OA due to LMW agents. Although the predominant immune response to chemical respiratory allergens may be of the type 2 T helper (Th2) type, other cells may play important support or regulatory roles. CD4- and CD8-positive T cells and different cytokines such as interleukin (IL)-1, IL-4, IL-5, IL-6, and IL-15 have been found in biopsies,33 bronchoalveolar lavage (BAL), and the sputum of patients with isocyanate-induced asthma.32 Neutrophils are also likely to

be involved in isocyanate-induced asthma as shown by an increase in myeloperoxidase and IL-8 after exposure to toluene diisocyanate (TDI).34 A mixed Th1/Th2 cytokine production has been observed in subjects with red-cedarinduced asthma.35 Furthermore, a specific-inhalation challenge (SIC) test induced a mixed Th2/Th1 response in which CD8+ cells were the main producers of interferon (IFN)-gamma.36 There is evidence that isocyanates can stimulate human innate immune responses by up-regulating immune pattern-recognition receptors of monocytes and increasing the chemokines that regulate monocyte/macrophage trafficking (macrophage migration inhibitory factor [MIF], monocyte chemoattractant protein-1 [MCP-1]).37 Furthermore, repetitive antigenic stimulation of diisocyanate asthmatic peripheral blood mononuclear cells induced the synthesis of tumor necrosis factor (TNF)-α, and MCP-1,38 but not IL-4 or IL-5.30

RISK FACTORS OA results from the complex interaction between environmental and individual susceptibility factors (Table 72-2).29

Environmental Factors The intensity of exposure to sensitizing agents is currently the best identified and the most important environmental risk factor for the development of OA. There is strong evidence supporting a dose-response relationship between the level of exposure to HMW agents and the development of IgE-mediated sensitization and OA. Such a dose-response relationship has also been documented for some LMW agents, such as platinum salts, acid anhydrides, and isocyanates. Noteworthy, exposure-response relationships may be affected by individual susceptibility factors and the timing of exposure. For instance, the role of genetic susceptibility markers, such as certain HLA class II alleles, may become more apparent at low levels of exposure to occupational agents.39 The incidence of WRA 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.15 A number of studies indicate that cigarette smoking can increase the risk of 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 weak. The role of other environmental cofactors, such as nonrespiratory routes of exposure and concomitant exposure to endotoxin and pollutants at work, remains largely uncertain. Host-Related Factors Atopy has been consistently demonstrated as an important host risk factor for the development of IgE sensitization and OA, but only for HMW agents. Preexposure sensitization to common allergens that are structurally related to workplace allergens, such as exposure to pets in laboratory animal workers, could be a stronger risk factor for OA than atopy. Prospective cohort studies suggested that the presence of nonspecific bronchial hyperresponsiveness40,41 and rhinitis41,42 before entering exposure to HMW occupational agents is an independent risk factor for subsequent IgE

1298 PART 3  •  Clinical Respiratory Medicine Table 72-2  Potential Risk Factors for the Development of Occupational Asthma Risk Factor

Evidence

Agents/Settings

Cigarette smoking

Strong Moderate Moderate

Skin exposure

Weak Weak

HMW agents LMW agents: platinum salts, acid anhydrides, isocyanates (For IgE sensitization) Laboratory animals, snow crab, prawn, salmon, psyllium, green coffee, enzymes, acid anhydrides, platinum, reactive dyes (For clinical OA) Laboratory animals, enzymes Isocyanates

Strong Weak

HMW agents LMW agents: platinum, acid anhydrides

Genetic markers   HLA class II alleles

Moderate

  Antioxidant enzymes*   SNPs of α-T catenin   TLR4 polymorphisms   IL-4 receptor alpha and IL13 polymorphisms Preexisting nonspecific bronchial hyperresponsiveness Work-related rhinitis Gender (female)

Moderate Moderate Weak Weak Moderate Strong Weak

LMW agents: isocyanates, red cedar, acid anhydrides, platinum salts HMW agents: laboratory animals, latex Isocyanates Isocyanates Laboratory animals Isocyanates HMW agents (laboratory animals, flour, latex) Laboratory animals Snow crab processors

ENVIRONMENTAL FACTORS High level of exposure

HOST-RELATED FACTORS Atopy

*Glutathione-S-transferase and N-acetyltransferase. HMW, high-molecular-weight; IL, interleukin; LMW, low-molecular-weight; OA, occupational asthma; SNPs, single nucleotide polymorphisms; TLR4, Toll-like receptor-4.

sensitization to these allergens. On the other hand, there is strong evidence that the development of occupational rhinitis during exposure is associated with an increased risk for the development of OA.43,44 However, the proportion of subjects with occupational rhinitis who will develop OA remains unknown. Among workers exposed to laboratory animals, the predictive value of work-related nasal symptoms on the subsequent development of probable OA was only 11.4% over a follow-up period of 30 to 42 months. 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 or protection against OA due to various LMW and HMW occupational allergens.45 There is also some suggestion that genes associated with Th2-cell differentiation (i.e., polymorphism of the IL-4 receptor alpha-chain, IL13, and CD14 [C159T] genes) could play a role in the development of OA. Genes involved in the protection against oxidative stress, such as glutathione-Stransferase (GST) and N-acetyltransferase (NAT), have been associated with an increased risk of isocyanate-induced OA (i.e., GSTM1 null genotype and slow N-acetylator phenotypes) or a protective effect (i.e., GSTP1*Val/Val allele). Overall, the currently available information indicates that genetic markers have a low predictive value in identifying susceptible workers. In addition, there is convincing evidence that a wide variety of environmental factors can interact with genetic determinants to affect disease susceptibility.

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.46 The validity of the different diagnostic tests and their practical limitations and advantages are summarized in Table 72-3. 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.47 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.48 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.3 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

72  •  Asthma in the Workplace 1299

Work and clinical history compatible with sensitizer-induced OA Asthma diagnosis (reversible airflow limitation and/or airway hyperresponsiveness)  immunologic testing if possible

No evidence of asthma

Patient at work with asthma-like symptoms

No asthma Investigate alternative conditions (e.g., rhinitis, hyperventilation, vocal cord dysfunction, etc.)

Asthma

Patient off work

Patient at work

Consider return to work

Impossible

SIC in the laboratory if available

Possible Performance of serial monitoring of PEF  methacholine challenge , sputum eosinophil counts at and off from work and/or SIC in the laboratory and/or at the workplace if available

Negative

Positive

Negative

Sensitizer-induced occupational asthma unlikely

Sensitizer-induced occupational asthma

Non–work-related asthma

Figure 72-2  Diagnostic approach in the investigation of sensitizer-induced occupational asthma. OA, occupational asthma; PEF, peak expiratory flow rates; SIC, specific inhalation challenge.

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.3 As said, a serial measurement of PEF at work and away from work has been found to be useful in confirming OA.48 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.49 SIC tests consist of exposing the subjects to the suspected occupational agent in the laboratory and/or at the workplace.50,50a 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

1300 PART 3  •  Clinical Respiratory Medicine Table 72-3  Advantages and Limitations of the Diagnostic Tests Used in the Investigation of Occupational Asthma Diagnostic Tests

Advantages and Limitations

Assessment of nonspecific bronchial hyperresponsiveness

Simple, low cost. Confirms the diagnosis of asthma. ■ Low specificity for diagnosis of OA. The absence of airway hyperresponsiveness does not exclude the diagnosis of OA in subjects who have been removed from the workplace. ■ Easy to perform, low cost. ■ Commercial extracts are available (skin prick tests or specific IgE for HMW agents). ■ Measurement of specific IgE available for some LMW agents (anhydrides, acids, isocyanates, aldehydes), but low sensitivity. ■ Lack of standardization for the majority of occupational allergens except for latex. ■ Can identify the sensitization but not necessarily the disease. ■ Low cost. ■ Requires the workers’ collaboration. ■ Low adherence (<60%). ■ Possible falsification of results. ■ Requires 2 weeks at and away from work, which is not always possible. ■ Impossible to perform when the worker has been removed from work. ■ No standardized method for interpreting the results. ■ Interpretation of the results requires experience. ■ Confirmation of the diagnosis of OA when the test is positive. ■ False-negative tests are possible. ■ Costly. ■ Available in a small number of centers worldwide. ■ Exclude diagnosis if negative when performed in the usual work conditions. ■ Requires usual work conditions. ■ Costly. Sputum cell counts ■ Impossible to falsify ■ Bring additional evidence to the diagnosis of OA ■ Costly ■ Not widely available ■ Does not confirm or exclude the diagnosis of OA by itself Exhaled NO ■ Easy to perform ■ Inconsistent results ■ Difficult to interpret ■ Affected by many different factors

Immunologic tests

PEF monitoring

Specific-inhalation challenges in the laboratory

Specific-inhalation challenges at the workplace Noninvasive measures of airway inflammation

■ ■

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.50b 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.51,52 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.53 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.54 Whether the monitoring of FeNO should be used in some phenotypes of OA remains to be determined.54 Making an accurate diagnosis of OA is crucial due to the significant social and financial consequences associated with this diagnosis.

OUTCOME AND MANAGEMENT OF SENSITIZERINDUCED 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.55,56 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.57 Immunotherapy has only been tested in workers with allergy and/or OA to HMW agents for which an IgEdependent reaction has been demonstrated. Immunotherapy has been mainly tested in health care workers allergic to latex.58 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.59 Small or uncontrolled studies have reported an improvement of allergic and respiratory symptoms after immunotherapy to some selected agents (cereal,60 sea squirt,61 laboratory animal,62 and wood63). However, whether immunotherapy can alter the

72  •  Asthma in the Workplace 1301

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.3 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.64 Besides environmental interventions, the pharmacologic treatment of OA should follow the clinical practice guidelines for asthma.65 Primary prevention aims at preventing the development of immunologic sensitization to workplace agents and subsequent OA.3,66 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.67,68 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.3 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.69 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.64,70 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.71 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.72 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,73 enzymes in the detergent industry,74 flour,75 laboratory animals,76 and isocyanates.72 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.77,78 There is growing evidence that WRA is associated with more severe asthma79,80 and with a higher health care resource utilization81 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.82 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.83 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.83 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.84 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.3

IRRITANT-INDUCED ASTHMA EPIDEMIOLOGIC ASPECTS Surveillance programs conducted in various countries indicated that RADS and IIA account for 5% to 18% of all reported cases of WRA.85 However, few population-based surveys have addressed the impact of acute inhalation incidents on the global burden of asthma. The longitudinal part of the European Community Respiratory Health Survey found that reported acute inhalation incidents were associated with a higher risk of new-onset asthma.26 Several cross-sectional studies revealed that asthmatic individuals more often report a history of a single high-level exposure to irritant cleaning products than healthy controls.86-88 A

1302 PART 3  •  Clinical Respiratory Medicine

longitudinal study of rescue and recovery workers exposed to high levels of alkaline dust during and after the World Trade Center disaster showed an increased risk of newonset asthma in the follow-up period of 5 to 6 years, particularly in the first months after exposure.89 Longitudinal workforce-based studies have documented an increased risk of asthma among workers with repeated exposures to high levels of chlorine, ozone, and sulphur dioxide in metal production and pulp mill workers.90-92 Exposures to high levels of irritants in the workplace are called “gassings” and are often recalled by workers in epidemiologic studies. Few epidemiologic studies have supported the role of repeated and/or chronic exposure to lower levels of irritant compounds at work in the development of asthma, with the exception of workers exposed to cleaning agents.93 In these populations, the frequent use of chlorine bleach and ammonia has been associated with an increased risk of asthma.86,94 A spectrum of exposures to irritant agents are likely to induce different clinical presentations of asthma ranging from RADS, when subjects are exposed to high concentrations of irritants agents, to “low-dose reactive airways dysfunction syndrome,” “not-so-sudden IIA,” or “IIA with latency” when subjects are exposed to irritants at lower concentrations. However, “low-level” irritant-induced asthma cannot currently be reliably diagnosed in the individual worker.

PATHOPHYSIOLOGY Several factors may influence the pulmonary responses to irritants, such as the intensity of exposure, physical properties (e.g., vapor pressure, solubility), and the chemical reactivity.95 Although many irritants are odorous and pungent, it is worth remarking that odor is not related to toxicity. The resulting biologic effect will depend on the depositing of the irritant in the upper and/or lower airways. Water-soluble irritants and particles with an aerodynamic diameter larger than 5 µm are predominantly deposited in the upper respiratory tract and proximal airways. Water-insoluble agents and particles of 0.5 to 5 µm can reach the distal airways and alveoli, often without causing much sensory irritation (see Chapters 11 and 75). The development of acute IIA has been associated with a wide variety of high-level exposures to irritant fumes, gases, sprays, or even dusts (Table 72-4).96 Typically, the exposure is caused by spills of volatile compounds, accidental releases of irritants under pressure, accidental fire with release of complex mixtures of thermal degradation products, or inadvertent reduction of the air ventilation rate in a confined space.95 The nature and concentrations of inhaled irritants generated during workplace exposure incidents are most often unavailable. Inhaled irritants provoke epithelial cell damage and persistent inflammatory response and airway remodeling, although the precise pathophysiologic mechanisms leading to persistent asthma remain largely speculative.95 Bronchial biopsy samples obtained after a high-level exposure to irritants revealed marked epithelial desquamation, inflammatory changes with predominance of lymphocytes, airway remodeling, and collagen deposition in the bronchial wall.97,98 Similar changes have been described in animal models.99-101 Two studies provided information on the long-

Table 72-4  Examples of Exposures Causing Acute IrritantInduced Asthma Exposure

Examples

Gases

Chlorine (e.g., released by mixing sodium hypochlorite with acids), chloramines (released by mixing sodium hypochlorite with ammonia), sulfur dioxide, nitrogen oxides, dimethyl sulfate Acetic, hydrochloric, hydrofluoric, hydrobromic acids Ammonia, calcium oxide (lime), hydrazine Formalin, ethylene oxide, fumigating agents, insecticides (sodium methyldithiocarbamate, dichlorvos) Bromochlorodifluoromethane (fire extinguisher), trifluoromethane, chlorofluorocarbons (CFC, thermal degradation products of freons), uranium hexafluoride, hydrogen and carbonyl fluoride Perchloroethylene Diesel exhaust, paint fumes, urea fumes, fire smoke, iodine compounds (iodine and aluminium iodide, hydrogen iodide), diethylaminoethanol (corrosion inhibitor) Paints (not specified), floor sealant (aromatic hydrocarbons) World Trade Center alkaline dust, calcium oxide (lime) Isocyanates, phthalic anhydride

Acids Alkali Biocides

Halogenated derivatives

Solvents Fumes

Sprays Dusts Potential sensitizers

term outcome of airway inflammation and remodeling in a large series of subjects with acute IIA.98,102 Both showed an inflammatory profile similar to what has been described in sensitizer-induced OA after removal from exposure, with an increase of eosinophils in some patients or neutrophils in others. However, in patients with IIA, subepithelial fibrosis was more prominent than in those with sensitizer-induced asthma. Altogether, in IIA, the pathologic changes observed during the acute phase are consistent with an acute toxic injury, whereas the long-term phase is similar to sensitizerinduced OA.

RISK FACTORS The environmental and host factors that determine the initiation and persistence of IIA remain largely unknown. A relationship between the level of exposure assessed qualitatively by industrial hygienists and the prevalence of nonspecific bronchial hyperresponsiveness has been documented in subjects who had been exposed to a spill of acetic acid.103 In a follow-up survey of pulp mill workers exposed to high levels of chlorine, the severity of gassing incidents, as evidenced by hospital emergency department visits, was a more significant risk factor for the persistence of nonspecific bronchial hyperresponsiveness than was the number of incidents.104 The development of IIA did not appear to be associated with smoking and atopy.103,104 Among the World Trade Center rescue and cleaning workers, the main risk factors for the development of a respiratory disease were the presence on the site during the first 48 hours and the duration of exposure during rescue and cleaning.105 Smoking was a predisposing or an additive risk factor, whereas atopy was identified as a risk factor for upper, but not for lower, airway disease.

72  •  Asthma in the Workplace 1303

Table 72-5  Diagnostic Criteria for the Reactive Airways Dysfunction Syndrome (i.e., Acute Onset Irritant-induced Asthma) 1. Absence of preexisting asthma symptomatology or a history of asthma in remission 2. Onset of asthma symptoms after a single specific inhalational exposure or accident 3. Exposure to an irritant vapor, gas, fume, or smoke in high concentration 4. Onset of asthma symptoms within minutes to hours and less than 24 hours after the exposure 5. Presence of airflow limitation with a significant bronchodilator response or nonspecific bronchial hyperresponsiveness to histamine/methacholine 6. Exclusion of other pulmonary disorders that can explain the symptoms or simulate asthma Adapted from Brooks SM, Weiss MA, Bernstein IL: Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest 88(3):376–384, 1985; Brooks SM, Bernstein IL: Irritant-induced airway disorders. Immunol Allergy Clin North Am. Nov31(4):747–768, 2011; Tarlo SM, Balmes J, Balkissoon R, et al: Diagnosis and management of work-related asthma: American College of Chest Physicians Consensus Statement. Chest 134(3 Suppl):1S–41S, 2008.

DIAGNOSIS RADS (i.e., acute IIA) is characterized by the onset of asthma symptoms within 24 hours after a single, most often accidental, high-level exposure to a wide variety of irritant substances in subjects without preexisting asthma. Brooks and coworkers proposed stringent clinical and functional criteria for the diagnosis of this condition (Table 72-5).3,6 The presence of asthma should be substantiated by spirometry demonstrating airflow limitation with a significant bronchodilator response or nonspecific bronchial hyperresponsiveness to methacholine or histamine. Conditions with similar clinical manifestations, such as irritantinduced vocal cord dysfunction, should be carefully considered.3 The causal role of the workplace exposure can be documented with a reasonable level of confidence by the strong temporal association between an inhalation accident and the rapid onset of asthma symptoms. Such cases should be considered as “definite” IIA. Nevertheless, the World Trade Center tragedy brought new insights by suggesting that asthma can develop insidiously over a few months after a massive exposure to a complex mixture of alkaline dust and combustion products.106,107 In subjects who reported multiple high-level exposures to irritants, though less clearly massive than in RADS, the causal relationship can be supported by the documentation of repeated symptomatic inhalation accidents requiring medical care or reports to first aid units or occupational health services. These subjects should be regarded as having “probable” IIA. There are some clinical features that clearly distinguish acute IIA from sensitizer-induced OA. Unlike sensitizerinduced OA, acute IIA does not require a latency period of exposure before the appearance of asthma, but an apparent latency period can be present in IIA that develops after multiple high-level exposures. Subjects with IIA do not develop WRA symptoms after reexposure to low concentrations of the irritant that initiated the symptoms because they are not “sensitized” to the offending agent. However, subjects with acute IIA may experience WRA symptoms because

their nonspecific bronchial hyperresponsiveness makes them more susceptible to irritant stimuli at work. The development of specific bronchial hypersensitivity has been documented after a single, intense exposure to some LMW chemicals.108 Conversely, known sensitizers can induce IIA when inhaled at high concentrations.109,110 In such instances, specific inhalation challenges with the suspected agent may be useful in distinguishing IIA from sensitizer-induced-OA. In the clinical reports that described the onset of asthma after repeated, often daily exposure to “moderate” levels of respiratory irritants at work, the evidence supporting the work-relatedness of asthma was weak and relied on the following findings: (1) a history of adult onset of asthma (or even the reactivation of a previously quiescent asthma9); (2) a history of repeated exposure to irritants; and (3) the absence of an identified sensitizer in the subject’s working environment. Distinguishing IIA attributed to repeated, moderate level exposures from coincidental asthma that is not work-related is elusive on a clinical basis. The possibility of “chronic/delayed-onset IIA” can only be inferred from epidemiologic studies documenting an increased risk of adult-onset asthma in certain occupations that are associated with frequent “moderate/excessive” exposures to irritant compounds.

OUTCOME AND TREATMENT The few available data on the outcome of IIA indicate that it is quite similar to what has been described in subjects with sensitizer-induced OA after avoidance of exposure to the causal agent. Nonspecific bronchial hyperresponsiveness can improve over several years after an acute symptomatic inhalation accident.104,111 On the long term, however, about three quarters of subjects with acute IIA show persistent nonspecific bronchial hyperresponsiveness and require treatment with inhaled corticosteroids.112 Limited data exist on the management of IIA, and they are mainly related to case reports of acute IIA.113 There is some evidence that subjects with IIA benefit rapidly from treatment with oral and/or inhaled corticosteroids, although the dose and duration of treatment remains unknown. Unlike workers with sensitizer-induced OA, those with acute IIA may be able to continue in their usual jobs with appropriate asthma management, although they may subsequently experience worsening of their asthma symptoms on exposure to irritants at work, which may substantially reduce their capacity to work in polluted or dusty environments. The management of IIA may be further complicated by associated disorders, such as chronic rhinitis, perceived intolerance to multiple chemicals, and posttraumatic stress syndrome, which can result from an accidental exposure to irritant substances at work.89,112,114

PREVENTION Prevention of IIA should be primarily aimed at eliminating the risk of high-level exposures that can cause asthma. Such strategies should be directed toward the control of exposures to safe levels by occupational hygiene measures such as containment and adequate ventilation. Continuous monitoring of airborne concentrations of potential

1304 PART 3  •  Clinical Respiratory Medicine

respiratory irritants and alarm systems to detect peak exposures may be appropriate in some settings. An important component of prevention is the implementation of workers’ educational programs on safe handling of chemicals, effective use of personal protective equipment, and measures to take in the event of an accident at work.

WORK-EXACERBATED ASTHMA EPIDEMIOLOGIC ASPECTS The prevalence of WEA reported in the literature varies according to the definition and the type of settings (clinical vs. epidemiologic) in which the WEA was assessed. Twelve studies have provided overall estimates of prevalence of WEA. These studies were conducted in the general population or in general health care settings in seven countries. The definition of asthma was not consistent and included physician-diagnosed asthma as determined from selfreports or medical records, or diagnosis based on an objective measurement of pulmonary function.115,116 Some of the studies reported prevalence as a percentage of all adults with asthma, and others as a percentage of all working adults with asthma. The prevalence of WEA from these 12 studies ranged from 13% to 58%, with a median of 21.5%. In the study where WEA was diagnosed according to changes in PEF between periods at and away from work, the prevalence of WEA was 14% in asthmatic workers.117 The most recent systematic review of the literature estimates that 21.5% of the cases of asthma are exacerbated by conditions at the workplace.2 Therefore, although the prevalence varies quite widely from one study to another due to the definition and the population of interest, the prevalence of WEA can be estimated to be around 20% of the adult asthma population, which constitutes a substantial proportion of the whole asthmatic population.

PATHOPHYSIOLOGY The pathophysiology of WEA is likely to be largely dependent on the type of triggers inducing asthma exacerbations. There is no reason to believe that the pathophysiology of WEA is different from the pathophysiology of asthma exacerbations observed in NWRA when the triggers are common allergens. When triggers consist of irritant agents, it is likely that the pathophysiology resembles what is seen in IIA. An airway epithelium injury is likely to play a pivotal role, and the injury intensity of the epithelial layer may be correlated with the respiratory function impairment as demonstrated in New York firefighters who intervened on 9/11.118 In murine models of chlorine exposure, oxidative stress plays a pivotal role in the pathogenesis of this condition and the administration of antioxidants can mitigate the epithelial damage.119 As shown in the animal models of chlorine exposure, the extent of the damage is likely to depend on the dose of the irritant agent inhaled.

WORK EXPOSURES ASSOCIATED WITH WORKEXACERBATED ASTHMA The identification of exposures associated with WEA has been reported either in studies that recorded the agents to

which the subjects with WEA were exposed in clinical settings, surveillance programs, or worker compensation programs or by using a risk-set approach, testing associations between occupational exposures and WEA while controlling for potential confounders. The studies assessing individual cases of WEA were performed mainly in North America120-128 or Europe.129 The most commonly described agents were chemicals, dust, smoke, paints, and cleaning products. Although less frequently encountered than these agents, physical factors such as exercise,128 temperature,120 or emotional stress121 have also been reported to be associated with WEA.

DIAGNOSIS OF WORK-EXACERBATED ASTHMA WEA should be suspected in all patients whose asthma is difficult to control, in patients who complain of a worsening of their symptoms, or in those who require an increase of their asthma medication when at work.3 Before establishing a diagnosis of WEA, the diagnosis of asthma needs to be confirmed by objective measures. Most asthma guidelines recommend the performance of spirometry, both prebronchodilator and postbronchodilator in order to show a FEV1 reversibility of 12% with an absolute increase of at least 200 mL.130 In the absence of a reversible airflow limitation, the measurement of airway hyperresponsiveness can confirm the diagnosis of asthma. The lack of objective confirmation of the diagnosis of asthma can lead to misdiagnosis in 30% of cases.131 Furthermore, nonspecific respiratory symptoms are frequent and can mimic asthma in workers exposed to a dusty or irritant environment.132 The diagnosis of WEA relies on the demonstration of (1) a relationship between asthma exacerbations and occupational exposures or (2) poor asthma control during periods at work, along with (3) the determination that OA is unlikely. Asthma exacerbations or loss of asthma control can be documented by a change in the frequency and severity of asthma symptoms or by the need for an increase in asthma medications. Asthma exacerbations can also be documented by the need for emergency visits or hospitalizations or by changes in respiratory function at work. Serial PEF monitoring can show increased variability during periods at work compared with periods away from work.133 Identifying the factors that trigger asthma symptoms is important to not only confirm the diagnosis of WEA but also decrease or remove the adverse environmental conditions at the workplace. Identifying multiple triggers is common because the workers are frequently exposed to several agents concomitantly. Although there are limited data concerning the management of WEA, professional organizations have advised minimizing exposures at work and optimizing standard medical management for asthma (e.g., pharmacologic treatment, avoidance of symptom triggers).3,134 Although there is clear evidence that a persistent exposure to the occupational agent that caused their asthma is detrimental for workers with OA,55 the impact of continuing exposure to triggers for WEA has not been well studied and thus is unknown at this time. There is limited evidence that workers with OA may have a greater improvement in their lung function and asthma control than subjects with WEA when removed from exposure.135-137

72  •  Asthma in the Workplace 1305

DIFFERENTIATING WORK-EXACERBATED ASTHMA FROM NON–WORK-RELATED ASTHMA OR OCCUPATIONAL ASTHMA A few studies have compared workers with WEA to adults with NWRA. The clinical characteristics of workers with WEA did not differ greatly from adults with NWRA. Some studies reported that workers with WEA tended to be older,135,138 while others found an increased proportion of smokers in subjects with WEA.81 No specific risk factors have been clearly identified for WEA. Workers with WEA are often difficult to differentiate from asthmatic subjects with OA, especially in cases who report a new onset of asthma while in the current workplace. The studies that compared subjects with WEA and OA report discrepant findings that can be explained by the different populations studied (general population vs. tertiary clinics). On the basis of U.S. cases that fulfilled the surveillance case definitions set by the Sentinel Event Notification System for Occupational Risks (SENSOR), Goe and colleagues139 found that subjects with WEA were more likely to be female, young, nonwhite, and nonsmokers. These findings were not confirmed in the studies where WEA cases were from a referral clinic and defined by a worsening of asthma symptoms when at work and a negative SIC to the suspected agent(s).52,140 Lemière and colleagues137 found that after adjusting for age, asthma control, and FEV1, the diagnosis of WEA was associated with more frequent prescriptions of inhaled corticosteroids, a noneosinophilic phenotype, and a trend toward a higher proportion of smokers than the diagnosis of OA. The timing of the onset of asthma with respect to the start of employment at the workplace does not necessarily differentiate WEA from OA; for example, Larbanois and colleagues140 defined WEA by the presence of WRA symptoms and a negative SIC and showed that only 7% of the 71 WEA subjects had asthma before employment. Also, onset of asthma before employment in the workplace of interest does not preclude the diagnosis of OA. Workers with previously diagnosed asthma can become sensitized to a new

agent at their workplace and develop OA. An increase in asthma symptoms or severity is usually noticed at this time. In both WEA and OA, there is a worsening of asthma symptoms when at work with an improvement when removed from exposure. Serial PEF monitoring can show a greater variability during periods at work compared with periods away from work in both types of cases, and the PEF variability is greater in subjects with OA than with WEA.133 However, in clinical practice, the difference in the magnitude of PEF variability does not allow differentiating WEA from OA. SIC testing can be performed to diagnose OA, with a positive result considered indicative of OA. Although there can be false-negative tests, a negative SIC favors the diagnosis of WEA. In several clinical studies, the definition of OA and WEA relied on the positivity or negativity, respectively, of SIC.52 However, those tests are not available in the majority of settings. An eosinophilic phenotype is more frequently found in subjects with OA compared with WEA. Workers with OA usually show an increase in eosinophilic inflammation when exposed to the agents to which they are sensitized. In contrast, workers with WEA had no increase in eosinophilic inflammation when at work compared with periods away from work or during exposure to the suspected agents in the laboratory.52 Table 72-6 summarizes demographic, clinical, functional, and inflammatory differences between subjects with WEA and subjects with NWRA or OA.

SOCIOECONOMIC IMPACT OF WORKEXACERBATED ASTHMA WRA has a major impact on workers and society as a whole. The workers tend to experience asthma symptoms interfering with their work productivity and causing absenteeism. Although there are no current data on absenteeism in subjects with WEA while at work, the cost related to reduced workforce participation, restrictions in job duties, loss of work days (“absenteeism”), or decreased effectiveness while at work (“presenteeism”) is likely to be substantial.

Table 72-6  Characteristics of Work-Exacerbated Asthma (WEA) in Comparison with Non–Work-Related Asthma and Occupational Asthma Characteristics

Compared with Adults with Non–Work-Related Asthma 135,138

Gender

Similar

Age Race Education Smoking habits Asthma severity

Older135,138 More nonwhite135 Less135 More likely to have smoked cigarettes135 More asthma exacerbations requiring emergency department visits or hospitalizations in workers with WEA,81 More days with asthma symptoms, more severe asthma based on self-report135 Similar FEV1, PC2081

Functional characteristics

Airway inflammation

or predominance of men in subjects with WEA

81

Neutrophilic inflammation inconsistently found depending on the study51,52

ICS, inhaled corticosteroids; OA, occupational asthma; PEF, peak expiratory flow rate.

Compared with Adults with Occupational Asthma Similar81 or greater number of women in subjects with WEA139 Similar or younger139 More nonwhite139 N/A More smokers81 Same number of asthma exacerbations requiring emergency department visits or hospitalizations137 Greater need of ICS in subjects with WEA137 Less PEF variability when at work in subjects with WEA compared with OA133 PC20 may be lower in subjects with WEA140 Less likely to have eosinophilic airway inflammation52,137

1306 PART 3  •  Clinical Respiratory Medicine

Presenteeism is the term used to describe employees who are physically present at their jobs but experience decreased productivity because of illness or other barriers to performance. Unproductive workers who are present at work seem to represent even higher costs than those who are absent.141 In addition to the decreased work productivity, the workers have to seek medical care, go to the emergency department, or be hospitalized. If one examines all of WRA, the 2001 and 2002 data from Breton and colleagues142 showed that the subjects who reported suffering from WRA in the United States were 4.8 times more likely to report having an asthma exacerbation, 4.8 times more likely to visit the emergency department at least once, and 2.5 times more likely to visit their physician for an asthma exacerbation in the previous 12 months compared with individuals with NWRA. Lemière and colleagues81 confirmed those data showing that 341 subjects with WRA followed in a tertiary Canadian clinic had more visits to the clinic for asthma (4.1 vs. 1.2 P < 0.05) and hospitalizations for asthma (0.04 vs. 0.008 P < 0.05) during the year preceding their diagnosis than 381 subjects with NWRA. In a recent cohort study of subjects with WRA followed in two Quebec tertiary clinics, Lemière and colleagues showed that the health care–related costs were similar between WEA and OA but 10-fold greater than the costs related to NWRA in the year preceding the assessment of those subjects in tertiary clinics.137 Although the cost of OA decreased significantly after the diagnosis was made and the patients were removed from exposure, the cost of WEA following the diagnosis did not decrease significantly. In the few studies in which the work disruption of subjects with WEA was evaluated, it was reported to be similar to OA.136,140 There is a high rate of unemployment in workers with WEA (30% to 50%),140,143 which is equivalent to subjects with OA. Job changes are frequent in subjects affected with WEA. The reduction in earnings seems to be similar in WEA and OA.140 Overall, WEA exerts a large socioeconomic impact on workers and society by using a large amount of health care resources and inducing substantial disruption of work.

Key Points The workplace environment can lead to the development of different types of work-related asthma (WRA), including occupational asthma (i.e., asthma caused by work through either immunologic [sensitizer induced] or nonimmunologic [irritant induced] mechanisms) and work-exacerbated asthma (i.e., preexisting or coincident asthma exacerbated by nonspecific stimuli at work). ■ WRA represents a significant public health concern due to the high-prevalence, long-term respiratory ■

health consequences, and socioeconomic consequences for affected workers and society. ■ For subjects with sensitizer-induced occupational asthma, the recommended treatment is complete avoidance of the causal agent, although the rate of recovery is low, especially when the diagnosis is delayed. ■ The diagnosis of sensitizer-induced occupational asthma should be established with the highest level of accuracy by performing a comprehensive investigation in order to avoid unwarranted removal from exposure. ■ Unlike those with sensitizer-induced occupational asthma, subjects with irritant-induced occupational asthma do not develop work-related asthma symptoms after reexposure to low concentrations of the irritant that initiated the symptoms. ■ Irritant-induced asthma is characterized by early onset after exposure; however, irritant-induced asthma can also develop insidiously over a few months after a massive exposure to a complex mixture of alkaline dust and combustion products, as shown in the World Trade Center disaster. ■ Work-exacerbated asthma (WEA) should be suspected in all patients whose asthma is difficult to control and in patients who complain of a worsening of their symptoms or who require an increase of their asthma medication when at work. ■ Workers with WEA are often difficult to differentiate from asthmatic subjects with occupational asthma, especially in cases who report a new onset of asthma while in the current workplace. Complete reference list available at ExpertConsult.

Key Readings Baur X, Aasen TB, Burge PS, et al: ERS Task Force on the Management of Work-Related Asthma: the management of work-related asthma guidelines: a broader perspective. Eur Respir Rev 21(124):125–139, 2012. Baur X, Sigsgaard T, Aasen TB, et al: ERS Task Force on the Management of Work-Related Asthma. Guidelines for the management of workrelated asthma. Eur Respir J 39(3):529–545, 2012. Beach J, Russell K, Blitz S, et al: A systematic review of the diagnosis of occupational asthma. Chest 131:569–578, 2007. Brooks SM, Bernstein IL: Irritant-induced airway disorders. Immunol Allergy Clin North Am 31(4):747–768, 2011. Henneberger PK, Redlich CA, Callahan DB, et al: An official American Thoracic Society statement: work-exacerbated asthma. Am J Respir Crit Care Med 184(3):368–378, 2011. Tarlo SM, Balmes J, Balkissoon R, et al: Diagnosis and management of work-related asthma: American College of Chest Physicians consensus statement. Chest 134(3 Suppl):1S–41S, 2008. Vandenplas O, Dressel H, Nowak D, et al: What is the optimal management option for occupational asthma? Eur Respir Rev 21(124):97–104, 2012.

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