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*From the University of Toronto (Drs. Tarlo and Liss), Toronto, ON, Canada; the University of California San Francisco (Drs. Balmes and Blanc), San Francisco, CA; National Jewish Medical and Research Center (Drs. Balkissoon and Pacheco), Denver, CO; the University of Alberta (Drs. Beach and Rowe), Calgary, AB, Canada; the University of Rochester School of Medicine and Dentistry (Dr. Beckett), Rochester, NY; the University of Cincinnati (Dr. Bernstein), Cincinnati, OH; the University of South Florida (Dr. Brooks), Tampa, FL; Mayo Clinic (Dr. Cowl), Rochester, MN; the State University of New York (Dr. Daroowalla), Stony Brook, NY; the University of California, Los Angeles (Dr. Harber), Los Angeles, CA; the Université de Montréal (Dr. Lemiere), Montréal, QC, Canada; the Yale University School of Medicine (Dr. Redlich), New Haven, CT; and the American College of Chest Physicians (Ms. Heitzer), Northbrook, IL.
Correspondence to: Susan M. Tarlo, MBBS, FCCP, Toronto Western Hospital EW7-449, 399 Bathurst St, Toronto, ON, Canada M5T 2S8; e-mail: susan.tarlo{at}utoronto.ca
Abstract
Background:A previous American College of Chest Physicians Consensus Statement on asthma in the workplace was published in 1995. The current Consensus Statement updates the previous one based on additional research that has been published since then, including findings relevant to preventive measures and work-exacerbated asthma (WEA).
Methods:A panel of experts, including allergists, pulmonologists, and occupational medicine physicians, was convened to develop this Consensus Document on the diagnosis and management of work-related asthma (WRA), based in part on a systematic review, that was performed by the University of Alberta/Capital Health Evidence-Based Practice and was supplemented by additional published studies to 2007.
Results:The Consensus Document defined WRA to include occupational asthma (ie, asthma induced by sensitizer or irritant work exposures) and WEA (ie, preexisting or concurrent asthma worsened by work factors). The Consensus Document focuses on the diagnosis and management of WRA (including diagnostic tests, and work and compensation issues), as well as preventive measures. WRA should be considered in all individuals with new-onset or worsening asthma, and a careful occupational history should be obtained. Diagnostic tests such as serial peak flow recordings, methacholine challenge tests, immunologic tests, and specific inhalation challenge tests (if available), can increase diagnostic certainty. Since the prognosis is better with early diagnosis and appropriate intervention, effective preventive measures for other workers with exposure should be addressed.
Conclusions:The substantial prevalence of WRA supports consideration of the diagnosis in all who present with new-onset or worsening asthma, followed by appropriate investigations and intervention including consideration of other exposed workers.
Key Words: asthma • occupational lung • preventive medicine
Abbreviations: ACCP, American College of Chest Physicians • AHRQ, Agency for Healthcare Quality and Research • CE, cost effectiveness • EBC, exhaled breath condensate • ENO, exhaled nitric oxide • HHE, Health Hazard Evaluation • HMW, high molecular weight • HSA, human serum albumin • LMW, low molecular weight • MSDS, material safety data sheet • NIOSH, National Institute for Occupational Safety and Health • NPV, negative predictive value • NRL, natural rubber latex • OA, occupational asthma • OSHA, Occupational Safety and Health Administration • PC20, provocative concentration causing a 20% fall in FEV1 • PEFR, peak expiratory flow recording • PPV, positive predictive value • RADS, reactive airways dysfunction syndrome • RAST, radioallergosorbent test • RCT, randomized controlled trial • SIC, specific inhalation challenge • SPT, skin prick test • VCD, vocal cord dysfunction • WEA, work-exacerbated asthma • WRA, work-related asthma
Executive Summary
This Consensus Statement on the diagnosis and management of work-related asthma (WRA) has been developed by an expert panel of specialists in allergy, pulmonary medicine, and occupational medicine, which was impaneled at the request of the American College of Chest Physicians (ACCP) Health and Science Policy Committee, with the endorsement of the ACCP Board of Regents to update the earlier 1995 ACCP Consensus Statement: Assessment of Asthma in the Workplace.1 The initial aim was to develop formal recommendations using an evidence-based approach and including greater consideration of work-exacerbated asthma (WEA) than that in the previous Consensus Statement. However, by the nature of the topic, the citations captured through systematic review were limited in scope and number. Randomized controlled trials (RCTs) relevant to the diagnosis and treatment of WRA are not available and are not likely to be performed. A limited number of studies have compared various diagnostic tests for sensitizer-induced occupational asthma to the selected reference standard test, a specific inhalation challenge (SIC). Most of the published literature consists of clinical studies of patients in whom occupational asthma (OA) was diagnosed rather than cross-sectional or longitudinal cohort studies of exposed workers. The panel also considered additional studies, which were not included in the formal Agency for Healthcare Quality and Research (AHRQ) analysis, as well as later literature identified by an additional review of the literature into 2007. Therefore, due to the evidence considered for this document, this statement does not use the ACCP grading system (which relies heavily on RCT data),2 but rather is based on the best available evidence and has been arrived at by consensus among the panel members. This Consensus Document addresses WRA (Fig 1), which the panel defined as including OA (caused by work) as well as WEA (preexisting or concurrent asthma that is worsened by work factors). In addition to addressing the diagnosis and management of patients with WRA, this Consensus Statement also covers several other important topics, including the physician's role in promoting safer employment options and access to worker's compensation or other benefit systems, as well as the prevention of WRA. It is hoped that this document will assist health-care providers in the diagnosis and management of WRA. The advised approach is summarized in Figure 2. Since WRA is potentially largely preventable and is best diagnosed early in its course, this Consensus Document also addresses primary, secondary, and tertiary preventive measures for WRA. Additional practical materials are provided on the CHEST Web site (www.chestjournal.org). Consistent with the ACCP requirements for consensus statements, the panel does not use the term recommendation but instead "suggests" approaches based on panel consensus in light of the best available evidence.
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Introduction
WRA, which includes OA and WEA, presents a major health challenge with significant potential for acute morbidity, long-term disability, and adverse social and economic impacts.3 Since the 18th century, medical writers have noted links between certain trades and respiratory symptoms recognizable today as asthma. In the 20th century, the number of work-related causes of asthma (sensitizers) expanded substantially. By the mid-1980s, recognition grew4 that acute irritant exposure could cause asthma in an etiologic process that is distinct from that of sensitizers. Currently, hundreds of distinct causes of OA have been recognized.1,5–7 WEA has received less systematic study, yet has been recognized as a priority area for further research.8,9
The prevalence of WRA has not been well defined due in part to variable definitions, diagnostic criteria, and work settings, as well as limited surveillance data. It has become clear that WRA is a far more substantive component of adult asthma than has been appreciated from clinical case series, or from studies of individual worksites or single industries. Approximately 10 to 15% of cases of adult asthma are attributable to occupational factors, which is consistent with a role for work in initiating asthma.10–13 The incidence of OA has been difficult to measure with precision. OA surveillance data vary widely in case capture, underestimating the true extent of the problem. As much as 25% of adult asthmatic patients are estimated to have WRA, which would include WEA as well as OA.14 Consistent with this, in other studies3,15–17 of patients in whom WRA has been diagnosed, the proportion of patients with WEA ranges from about 10 to 50% of cases of WRA, although this may be as reflective of compensation practices as of true prevalence.
The magnitude of WRA is matched by the important opportunities for the primary prevention of new cases and the secondary and tertiary prevention of disease progression and disability. Prevention is intimately linked both to the diagnosis and treatment of disease. The diagnosis of a single case of OA among a group sharing similar exposures offers the possibility of preventing new asthma (ie, primary prevention) or the progression of subclinical illness to frank disease (ie, secondary prevention) in other workers. Moreover, the appropriate management of WRA involves the control of the specific factors responsible for disease onset or exacerbation/aggravation, thus avoiding a situation in which ongoing exposure causes disease progression (ie, tertiary prevention).
Clinical practice in the diagnosis and management of WRA differs from standard asthma care in several important ways. In addition, critical aspects of this subject can be unfamiliar or daunting, even to practitioners who are well versed in standard clinical asthma care. The goal of this review is to provide guidance to health-care providers, including those who treat adult asthma patients in primary care practice, those approaching this question from a pulmonary or allergy care perspective, and clinicians working in occupational health settings.
To meet this ambitious goal, we include topics that have not typically been emphasized in standard practice guidelines, such as WEA and preventive measures. A thorough occupational history is essential to the diagnosis of WRA, including the delineation of work-related exposures. General issues of evidence-based medicine and the diagnostic process have been well described.18 Because of the limitations to diagnostic testing, the pretest probability of WRA based on symptoms and the occupational history (and the related Bayesian analysis of posttest likelihood) warrants particular consideration. Bayesian issues are especially relevant here because the diagnosis of occupational disease often demands a different level of diagnostic certainty than that used in other fields of practice. In occupational practice, the attribution of etiology is frequently benchmarked against a "more-likely-than-not" (ie, > 50% likelihood) standard (eg, for workers compensation and medicolegal determinations) rather than achieving a higher level of certainty, as is typically desired in standard clinical practice.
We will also address a combination approach based on the results of several diagnostic modalities used together, as opposed to a linear algorithm restricted to a stepwise series of tests. Although such an integrative approach is not typically emphasized in practice guidelines, it is especially relevant to the evaluation of WRA because testing choices are often limited by factors such as occupational status, access to the workplace, and logistical access to certain diagnostic modalities.
Despite limitations in the relevant literature and in the accuracy of the diagnostic modalities available, there is a tremendous need for guidance on how to diagnose and manage patients with WRA. It is important to remember that the goal of this Consensus Document is to assist clinicians along a management pathway, rather than to prescribe a specific checklist that must be fulfilled in order to achieve a valid clinical decision. Keeping these limitations in mind, we believe that this document based on published literature and supplemented with clinical expert guidance will assist clinicians to diagnose and treat WRA.
Materials and Methods
In 1995, the ACCP published ACCP Consensus Statement: Assessment of Asthma in the Workplace.1 In 2005, the Health and Science Policy Committee of the ACCP chose to reexamine this topic. This new publication is intended to update and expand the previous review. The University of Alberta/Capital Health Evidence-Based Practice Center was commissioned to review the evidence in the areas of diagnosis and treatment of OA. An international panel of experts was convened to provide a document, synthesized from this evidence review and supplemented by an additional literature review, to inform pulmonary, occupational, allergy/immunology, and primary care practitioners on the diagnosis and management of WRA. Although initially intended to develop formal "evidence-based" guidelines, a Consensus Document has been developed as more fitting to the available published studies on WRA.
Panel Selection and Composition
Susan Tarlo, MBBS, FCCP, of the Department of Medicine at the University of Toronto (Toronto, ON, Canada) served as the Chair of this international panel of experts, representing a variety of specialties including pulmonary, occupational medicine, allergy, and clinical immunology. Many were members of ACCP; however, members of other organizations (eg, the American Thoracic Society; the Canadian Thoracic Society; the American Academy of Allergy, Asthma, & Immunology; the American College of Allergy, Asthma, & Immunology; and the Occupational and Environmental Medicine Association of Canada) were also invited to participate. The expert panel first met in August 2005 in Chicago, at which time they selected the final scope of the topics. Teleconference and e-mail communication supplemented that initial work.
Authors volunteered to draft sections of the document. The assignments were made by the steering committee based on known expertise and interest in the area; however, all committee participants reviewed the entire document, and contributed to discussion and consensus on the document and made suggestions. The proposals and suggestions in this document should not be used for performance measurement or for competency purposes, since they are not evidence based, as outlined by the ACCP Health and Science Policy Committee. This Consensus Document has been endorsed by the Canadian Thoracic Society and the Canadian Society of Allergy and Clinical Immunology.
Funding and Conflicts of Interest
Funding for the development of this document was supported by an educational grant from the Schering-Plough Corporation. No representatives from this company were granted the right of review nor were they allowed participation in any portion of the document development including participation on any conference calls or attendance at any meetings. The document authors were unaware of the origin of the funding and were not paid for their contributions.
The very stringent approach of the ACCP to the issue of potential or perceived conflicts of interest has created many firewalls to ensure that there are no influences from industry or other sources. This policy is available on the ACCP Web site (www.chestnet.org). All conflicts of interest within the preceding 5 years were required to be disclosed by all panelists, at all face-to-face meetings, the final conference, and prior to submission of the Consensus Document for publication. The most recent of these are documented in this published Consensus Document. Furthermore, the panel was instructed in this matter, verbally and in writing, prior to the deliberations of the final conference. Any disclosed memberships on speaker's bureaus; consultant fees, grants, and other research monies; and any fiduciary responsibilities to industry were provided to the full panel in writing at the beginning of the conference and at the time of submission of the Consensus Document for publication.
Scope of the Consensus
For the purposes of this document, we consider WRA to include asthma initiated by workplace exposures (ie, OA) as well as preexisting asthma made worse by work exposures (ie, WEA). Other respiratory conditions, such as industrial bronchitis, work-related chronic obstructive disease and emphysema, or "asthma-like" syndromes associated with certain occupational exposures, will not be subsumed within this document, even though they may share characteristics with WRA. Most of the published literature has addressed OA rather than WEA. Nonetheless, the panel determined that it should be included in the present document since WEA is considered to be a type of WRA, can be difficult to distinguish from OA, and does have an important impact on morbidity, work time loss, and job efficiency.
Evidence Review
The evidence review for this clinical practice guideline included a systematic review commissioned by ACCP through the AHRQ on the diagnosis and treatment of OA, as well as topic specific searches following the completion of the systematic review.11 In addition, the authors of specific sections of this document were encouraged to conduct searches and to supplement the evidence from knowledge of their topic area.
Formal systematic reviews performed by The University of Alberta/Capital Health Evidence-based Practice Center were focused on the diagnosis and management of OA. The diagnosis review focused on evidence from studies that reported an acceptable reference standard (usually an SIC19 or clinical consensus) compared to a single diagnostic test or some combination thereof. The management review focused on evidence from studies that included patients in whom OA had been diagnosed, and for whom clinical outcomes had been reported at follow-up. A detailed description of the methods used can be found at www.ahrq.gov. For the ACCP document, additional and updated information was obtained regarding the domains of clinical history, and primary and secondary prevention.
The Consensus Panel also derived supplemental data from peer-reviewed publications up to 2007 (identified through searches of standard databases, including the National Library of Medicine PubMed database). When available data were limited, inconclusive, or conflicting, the panel relied on a consensus-reaching process in order to develop its final suggestions.
Limitations of the Evidence
High-quality evidence is particularly problem ridden in WRA. First, for diagnostic tests there is no "gold standard" against which to determine sensitivity and specificity. Although SIC served as a "reference standard" for OA in the initial evidence-based literature review that we utilized,11 our Consensus Document is circumspect in comparing SIC testing to other diagnostic approaches for several reasons. OA is not a single disease, and diagnostic tests evaluated in one clinical setting, such as bakers' asthma, may not be applicable to other conditions, such as diisocyanate-induced asthma or irritant-induced OA. Additionally, several diagnostic approaches depend on the worker still being at the job in question, as well as the ability to remove the worker from work exposures for days to weeks during testing followed by a return to work, which is difficult to achieve in many real-world situations. Second, for treatment and management issues in patients with WRA, there have been few controlled clinical trials (as noted previously), and such trials are unlikely to be performed in the future. Thus, ecologic data, temporal trends, and case reports (which were excluded from the original evidence-based review) must be relied on to supplement traditional RCT evidence. Indeed, several of the suggestions ultimately reached in the Consensus Document are based on the strength and consistency of observational studies.
Methods of Consensus, Document Writing, and Validation
Throughout the process of development of the Consensus Document, expert consensus was reached whereby all panel members came to agreement, as follows: by panel discussions, including e-mail communications, conference calls, and two face-to-face meetings, which allowed any differing views to be expressed and modifications of wording to be made in order to achieve consensus. The writing groups and the executive committee of the panel extensively reviewed each section during the writing process, and the entire panel received each full draft for comments and discussion. A final conference provided an opportunity for the entire panel to review and discuss the document. Following final revisions and one final review by the executive committee and the full panel, the Consensus Document was reviewed and approved by the ACCP Health and Science Policy Committee, the ACCP Occupational Disease Network, and the ACCP Board of Regents. These reviews were performed prior to endorsement by the Canadian Thoracic Society and the Canadian Society of Allergy and Clinical Immunology. The document has not been field tested. Institutional research ethics board approval was not sought for this project, which consisted of the review of published data and achievement of expert consensus.
Disclaimer
The extracts of NRL mentioned in the Consensus Document that have been used for skin testing and treatment for allergy to NRL have not been approved in the United States for the purposes under discussion. In addition, for many of the occupational sensitizers discussed in the Consensus Document, there are no commercial and approved extracts in the United States for skin testing and/or treatment, many of which have only been used in research studies. There are commercially available mammalian epidermal extracts (eg, cat) that have been approved in the United States for the treatment of allergy confirmed by demonstration of specific IgE, but have not been specifically approved for indications of occupational allergy or occupational asthma. Foodallergens are not approved in the United States for immunotherapy. Omalizumab is currently approved in the United States for patients with asthma who fulfill certain criteria but is not currently approved in the United States for the treatment of specific occupational allergy or occupational asthma. The other medications that are discussed in this Consensus Document have been approved in the United States for general asthma treatment.
Definitions
The ACCP committee that composed this document has arrived at the following consensus definitions for WEA and OA. WRA is the broad term that refers to asthma that is exacerbated or induced by inhalation exposures in the workplace.20 The term WEA1,21–23 refers to asthma triggered by various work-related factors (eg, aeroallergens, irritants, or exercise) in workers who are known to have preexisting or concurrent asthma (ie, asthma that is occurring at the same time but is not caused by workplace exposures). Some differentiate between WEA and work-aggravated asthma, based on whether the worker returns to a prior asthma baseline (WEA) or not (work-aggravated asthma); but, this distinction is not widely accepted, and this Consensus Document will use the term WEA.
The term OA refers to de novo asthma or the recurrence of previously quiescent asthma (ie, asthma as a child or in the distant past that has been in remission) induced by either sensitization to a specific substance (eg, an inhaled protein [high-molecular-weight (HMW) protein of > 10 kd] or a chemical at work [low-molecular-weight (LMW) agent]), which is termed sensitizer-induced OA, or by exposure to an inhaled irritant at work, which is termed irritant-induced OA1 (Fig 1). OA due to a sensitizer presents with a latency period and includes those causative agents (proteins and some chemicals) for which sensitization can be demonstrated (typically by antigen-specific IgE) in most persons with asthma due to exposure to that agent. It also incorporates OA caused by those agents (usually reactive chemicals) for which an immunologic mechanism is strongly suspected, yet an antigen-specific immune response cannot easily be tested in most affected workers. This definition of OA is consistent with other definitions. It also encompasses irritant-induced asthma (with no apparent latency period).24–28 The most definitive form of irritant-induced asthma is reactive airways dysfunction syndrome (RADS), which describes an acute onset of asthma after a single, very high irritant exposure.4 Earlier definitions of OA typically referred only to sensitizer-induced asthma and not to irritant-induced asthma.
These definitions are interpreted with the understanding that WEA and OA are not mutually exclusive and may coexist in the same worker.1 In contrast to WEA, the onset of asthma due to work exposures in a person with a history of asthma as a child or in the distant past is considered more likely to be new-onset OA, not WEA, although the recurrent onset of asthma unrelated to work and subsequent WEA is also possible.
In summary, WRA encompasses both OA and WEA, which may coexist in individual workers (Fig 1). OA includes asthma caused by exposure to sensitizing agents and/or irritants in the workplace. A history of childhood asthma does not exclude the possibility that OA may develop after an appropriate workplace exposure. Studies on WEA and irritant-induced OA are limited compared to those on sensitizer-induced OA, leading to relative uncertainty regarding the definition, prevalence, diagnosis, and management of WEA and irritant-induced asthma.
General Asthma Considerations
Before considering specific aspects of WRA, it is helpful to review some features of general asthma, since the majority of patients with WRA will initially present to their physician with asthmatic symptoms. Furthermore, the diagnosis of WRA requires, first, that asthma be diagnosed; and, second, that the relationship with work be established. The possibility of WRA should be considered in all adult patients who are currently employed, and in those in whom asthma started or worsened during their working life.
The Global Initiative for Asthma29,30 describes asthma as a heterogeneous chronic inflammatory disorder of the airways associated with airway hyperresponsiveness and recurrent episodes of wheezing, dyspnea, chest tightness, or cough. Episodes are usually associated with variable airflow limitation that is often reversible, either spontaneously or with treatment. It must be appreciated, however, that these features are not specific for asthma (other respiratory disorders share some or all of them), and that there can be significant variability and heterogeneity in the clinical presentation of asthma. There are also several conditions that coexist with, exacerbate, or mimic asthma such as rhinosinusitis,31 gastroesophageal reflux disease,32,33 laryngopharyngeal reflux,34 paradoxical vocal fold motion disorder (also known as vocal cord dysfunction [VCD]),35,36 or chronic subacute infections by Mycoplasma or Chlamydia.37 The clinical evaluation of asthma patients requires a comprehensive history, a thorough physical examination, and pulmonary function testing. The history should detail any precipitating events, whether onset was in childhood or as an adult, and whether there is a personal history of allergies or a family history of asthma and allergies. The characterization of symptoms (eg, shortness of breath, chest tightness, cough, and/or wheezing); triggers in the home and work environment; and worsening by season, exercise, or night support the diagnosis and aid in the management of asthma.
A physical examination helps to assess the severity of airflow obstruction as well as signs of extrapulmonary disease (eg, nasal congestion or cardiac disease that may contribute to, or mimic, asthma symptoms). The principal physical finding in asthma is expiratory wheezing, but the absence of wheezing does not rule out asthma.
The assessment of asthma by history and physical examination may be misleading; thus, it is important to carry out pulmonary function testing. Measurements of airflow obstruction, its reversibility, and its variability are important in establishing the diagnosis of asthma.29 Spirometry and peak expiratory flow recordings (PEFRs) directly assess airflow obstruction. Reversible airflow obstruction is a key feature of asthma, but many asthmatic patients may have normal or near-normal pulmonary function, especially during nonexacerbation periods or due to treatment. In the case of OA, test results may be normal if the patient has not recently been exposed to the relevant work agent or is receiving asthma medications. While the accepted response to bronchodilator therapy in asthma patients is a > 12% and a > 200-mL improvement in FEV1,38 their absence does not rule out asthma.39 The measurement of variability in airflow limitation using a peak expiratory flowmeter over a 2-week period can also help to support a diagnosis of asthma. A diurnal variation in PEFRs of 
20% is considered to be a diagnostic criterion.40 In patients with symptoms consistent with asthma but normal lung function, the measurement of airway responsiveness to methacholine, histamine, or exercise challenge may help to establish the diagnosis of asthma. In the context of sensitizer-induced OA, such tests are preferably performed soon after a work exposure (ie, within 24 h after a typical exposure). Such challenge tests are sensitive for the diagnosis of asthma, but are not specific since airway hyperresponsiveness can be found with other conditions (eg, allergic rhinitis or bronchiectasis)41 or in the absence of any clinical condition. The absence of airway hyperresponsiveness on challenge testing has a fairly high negative predictive value (NPV) for current symptomatic asthma, and generally can be used to rule out active disease.42 As we will detail in a later section, however, there have been documented reports, although uncommon, of persons without nonspecific hyperresponsiveness who do respond to SIC with the workplace agent to which they have been sensitized. Ancillary laboratory studies such as skin-prick tests (SPTs), radioallergosorbent tests (RASTs), and measurements of total IgE levels provide evidence for an allergic response to environmental, workplace, and/or food allergens. The health-care provider should make the diagnosis of asthma with the combination of consistent symptoms and pulmonary function test findings because the consequences for the patient are considerable.
Differential Diagnostic Considerations
There are several reported conditions that manifest clinical presentations that can be mistaken for WRA or may coexist with WRA. These will be briefly reviewed before discussing methods of diagnosis of WRA. These alternative diagnostic possibilities can be differentiated from WRA through obtaining a careful history and conducting appropriate laboratory testing, and are important to identify since their management differs from that of WRA.
Asthma-Like Symptoms and Odor Triggers: A spectrum of clinical responses besides asthma may occur after irritant exposures. Irritant exposures can lead to an enhanced cough reflex,43,44 poorly defined illnesses, such as an increased awareness of irritants,45 and asthma-like symptoms with cognitive complaints similar to multiple chemical sensitivity/idiopathic environmental intolerance.46,47 A number of asthmatic patients have noted an enhanced response to odorants and irritants.48,49 Nonetheless, sensitivity to chemicals in the environment,46,47 which is defined as becoming ill after smelling chemical odors like perfume, has been reported in 15 to 30% of the general population.47 The term sensory hyperreactivity has been used to describe patients who complain of upper airway symptoms induced by scents and chemicals50 and show increase cough sensitivity by capsaicin challenge, but no increased responsiveness to methacholine.44,50
VCD: One of the most common clinical syndromes that mimics asthma is VCD, which is also included in the term irritable larynx syndrome or episodic paroxysmal laryngospasm.51 Vocal cord closure usually occurs on inspiration, causing airflow obstruction, wheezing, and occasionally stridor. About 10% of patients referred for refractory asthma experience VCD; an additional 33% of patients have VCD accompanying asthma. A temporal association between VCD onset and irritant exposure has been described.52 The mechanisms of VCD remain unknown, although underlying gastroesophageal reflux and psychogenic factors may contribute. Irritants, chemicals, certain odors, exercise, and methacholine challenge may precipitate attacks in VCD patients. A definitive VCD diagnosis requires visualization of the vocal cords via laryngoscopy, showing adduction of the anterior two thirds of the vocal cords during inspiration that may persist into expiration. Speech therapy and treatment of any underlying gastroesophageal reflux are the first lines of treatment for VCD.
Eosinophilic Bronchitis: Eosinophilic bronchitis is a term describing subjects with large numbers of eosinophils found on sputum examination and without evidence of asthma. A nonproductive cough, the absence of airway obstruction, and hyperresponsiveness characterize the clinical presentation, which has been reported in workers exposed to acrylates,53 latex,54 mushroom spores,55 and lysozyme.56
Diagnosis of WRA
The History in WRA
In every adult whose asthma begins or worsens while working, the possibility of WRA should be considered and evaluated. There is consistency in the published literature indicating that patients with WRA have a history supportive of the diagnosis, and this has been used as the basis for further investigations. Thus, a necessary first step in evaluating patients with asthma of working age is to obtain a detailed and accurate history. In addition to providing information about asthma symptoms, the history should identify any temporal relationships between asthma symptoms and work, and should detail information about work status and exposure characteristics. Although transient work-related aggravation/exacerbation of asthma is often diagnosed in asthmatic patients based on history alone (including history of exposure and reported medication needs), the history findings are generally not sufficient alone to diagnose other WRA. Thus, added objective tests should be performed, especially for detection of sensitizer-induced OA.
Respiratory symptoms present in WRA patients (ie, cough, wheeze, shortness of breath, and chest tightness) are identical to those present in non-OA patients. They may be accompanied by or preceded by symptoms of rhinitis and/or conjunctivitis. Specific inquiry should be made to determine any relationship between the workplace and symptoms. This is especially pertinent for sensitizer-induced OA and for WEA where an improvement in symptoms typically occurs during times away from work (eg, on weekends and during vacations) and worsens on days with regular or intermittent exposures at work. The following key questions should be asked of any patient with asthma starting or worsening during their working life:
Changes in work processes may entail exposure to a new agent to which the worker has not been previously exposed or to increased levels of exposure to an agent that was previously present. Sensitizing agents carry an increased risk of sensitization and OA, especially in the first few years of exposure, although this can occur after many years of ongoing contact. WEA could occur from a change in work area or process with increased exposure to conditions triggering asthma, but could also occur without a specific change at work if the underlying asthma worsens or is less well controlled than usual (ie, there is an increasing susceptibility to previously tolerated work conditions). As an example, a worker with asthma may have an exacerbation from cold air or sulfur dioxide exposure at work only when the worker has a concurrent respiratory viral infection and an associated worsening of underlying airway hyperresponsiveness.
An unusual exposure at work (eg, a spill or other high-level exposure) to a potentially irritant chemical or chemicals, especially within 24 h before the onset of the first asthma symptoms, raises the suspicion of irritant-induced asthma. Typically, symptoms are severe enough to require first aid or emergency treatment at that time. RADS is the most definitive form of irritant-induced asthma. The original diagnostic criteria for RADS (Table 1)4 include a single, massive exposure to an irritant gas, vapor, or fume with an immediate onset of asthma symptoms or within 24 h of the exposure. Cases that do not meet these stringent criteria (eg, where there is a lag of several days before the onset of symptoms, or when there is no single massive exposure but rather repeated exposures over days or weeks,25 less massive exposures, or a shorter duration of symptoms) are subsumed under a broader category of "irritant-induced asthma."57,58
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Additional work-related symptoms of allergic rhinitis increase the probability of sensitizer-induced OA, while work-related dysphonia (which is more consistent with VCD) has been negatively associated with OA.61 When compared with a SIC carried out in a compensation referral case series,61 false-positive diagnoses often occurred, both for OA and for asthma itself, when using history findings alone (34% of those with a positive history of asthma had no asthma based on objective test results). In that population, the presence of wheezing that was worse at work and nasal itching at work showed the greatest historical value for challenge-proven OA (positive predictive value [PPV], 0.89 and 0.53, respectively; NPV, 0.32 and 0.70, respectively; sensitivity, 0.40 and 0.48, respectively; specificity, 0.85 and 0.74, respectively). As would be expected, nasal itching was a more sensitive factor among those exposed to HMW sensitizers. Loss of voice at work carried a significant negative value. However, a model developed from this study was correctly predictive in only 42% of subjects, emphasizing the need for further investigations when the diagnosis is suspected. As with other clinical studies that include SIC, the population was confined to those in whom WRA was already suspected, and the predictive values and sensitivity/specificity have not been assessed as yet in a population of unselected asthmatic patients.
Exposures and Exposure Assessment
Although not subjected to evidence-based studies, a detailed work exposure history, enabling the determination of likely exposure to a known workplace sensitizer or irritant, can affect the pretest probability of WRA. The exposure history should focus particularly on exposures occurring at the time that asthma started or worsened at work. There are > 250 reported workplace sensitizers and multiple at-risk workplace settings. Many of these (based on reports in the published literature up to 2002) are listed on a Web site at www.asmanet.com (following links to OA, user guide); however, the absence of exposure to a previously identified sensitizer does not exclude OA. Examples of common jobs and specific agents are shown in Tables 2,62 3, and 4; agents are typically classified according to whether they are of HMW (usually protein) or LMW (small chemical). Multiple exposures can occur in the same work area, termed mixed environments, with both sensitizers and irritant exposures, which can interact to increase the risk of asthma. Common occupations reported in a North American report63 of WRA include teachers, farm workers, and construction workers.
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Commonly reported causes of irritant-induced OA include accidental spills or other high-level exposures to acids, chlorine or chlorine compounds, alkaline dusts, smoke (through inhalation), and aldehydes (Table 5). Diverse occupational exposures, populations, and host factors have been associated with an increased risk of WEA (Table 5). There have been differences between studies in asthmatic and comparison populations, those with disparate clinical and exposure data available, and those using variable diagnostic criteria, all of which are factors that can also hamper the comparison of studies.8,15,60,67–70 Several studies8,68,71 have suggested a healthy worker effect, where asthmatic patients avoid or leave workplaces with higher exposures to asthma triggers such as irritants, allergens, or extreme temperatures. Together, the findings of the available studies suggest that irritants are the most frequently reported workplace exposures for those with a history of WEA.15,60,69,70 Frequently, the reported exposures include mineral and inorganic dusts, chemicals, paints, temperature extremes, cleaning agents, second-hand cigarette smoke, and poor indoor air quality.15,60,67,69,70 Work exposure to common asthma triggers such as cold air, physical exertion, viral infections, and plant, mold, and animal allergens can also exacerbate asthma at work. WEA or WRA has been reported in a wide range of occupations and work settings, including cleaners, teachers, production, and service and construction workers.63,72,73
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1% presence in a chemical product ( 0.1% in Canada) be listed as hazardous ingredients. A note given to the patient can help to obtain MSDSs for products used by the patient or coworkers. MSDSs generically identify hazardous ingredients, provide cursory but important toxicologic information, and recommend safety and emergency procedures. OSHA requires the employer to maintain MSDSs onsite and to make them available to physicians and workers. A physician has the right to contact the employer or the supplier by telephone or written request for MSDS information. It is also possible to acquire MSDS information through the internet. Identification of the agent allows access to further in-depth information via standard textbooks and publications. If sensitizer OA is suspected, it may be necessary to request additional information from the product manufacturer or the workplace (always with the patient's permission). Sources of information about work exposures and MSDSs are given in Table 6. Knowledge of the major exposures seen in certain jobs or industries can also help to identify potential causative agents, as are shown in Tables 3 and 4, which are not intended to list all possible agents or occupations. Further exposure information is available from several publications.74–76
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The onset of asthma symptoms related to a sensitizer occurs after a latent period of exposure, which can range from weeks to years, in contrast to the onset of RADS, which typically begins within 24 h after a very high irritant exposure. The latency period for LMW sensitizers (eg, diisocyanates and plicatic acid) and for some HMW sensitizers (eg, laboratory animals) is typically within 2 years of ongoing exposure,7,79,80 while it is typically slightly longer for other HMW sensitizers such as flour or latex,7,81 although there is a wide range for both (up to 20 years after starting exposure). Once sensitizer-induced OA is present, the timing of worsened asthma symptoms in relation to work exposures can range from immediate (ie, within minutes of further exposure to the sensitizer), to late (ie, typically 4 to 8 h after exposure, and more common as an isolated late response when the sensitizer is an LMW agent), or as a dual response (ie, an immediate response followed by a late response, as illustrated in Fig 3). The association with work may be less obvious if an isolated late response occurs, such as asthma symptoms in the evening after work. Improvement away from work may not be evident for several days or longer away from exposure and therefore may be noted only during a holiday period.
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Atopic workers are in general more likely to have asthma than are nonatopic workers, and they are also more likely to experience WRA symptoms.10 The clinical features of those patients with WEA, such as severity or duration of symptoms, atopy, or medication use, are not consistently different from the clinical features of those patients classified with asthma not related to work or of those with OA.8,15,60,69,70 Thus, this does not reliably distinguish among these forms of asthma. Although the diagnosis of WEA is frequently made on the basis of history and exposure features, the possibility of OA in such patients also requires consideration and, when appropriate, additional diagnostic tests.
Influence of Pretest Probability From History on Posttest Probability of OA
Although the probability of OA from history cannot be accurately quantified, a typical history and consistent exposure could lead to a high pretest probability (eg, 70%) before additional investigations are performed. This pretest probability influences the posttest probability of OA after the performance of subsequent investigations such as methacholine challenge and/or the assessment of the relationship of specific IgE to a work allergen, when feasible (Fig 482). Conversely, a paucity of suggestive factors from history (eg, pretest probability of OA of around 15%) will result in a low posttest probability of OA, even when the results of other investigations are positive (Fig 4).
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Panel Consensus
Using a Combination Approach for Diagnosis
The tests described in the sections below supplement the initial medical and occupational history, physical examination, and pulmonary function tests.74,83,84 Objective testing is not pursued consistently in all cases of suspected sensitizer-induced OA, in part due to practical limitations, such as the availability of testing. A combination of objective measurements has been advised in previous Consensus Statements,1,74 and an aggregate of consistent objective findings, in addition to the asthma diagnosis and history, improves the diagnostic accuracy for sensitizer-induced OA.
Patients who have confirmed asthma, a temporal relationship of symptoms with workplace exposures, and appropriate work exposures typically have a high pretest probability for sensitizer-induced OA. Probability increases further with each additional positive diagnostic test result that supports a work relationship, and decreases with negative test results. The benefit derived from multiple tests to confirm or rule out sensitizer-induced OA depends to some degree on the pretest probability of the diagnosis. However, the use of multiple tests even in those with a high pretest probability can be useful. For example, if the test results are negative, they may suggest that sensitizer-induced OA is unlikely and may prevent a job change.11
Although used as a reference standard for comparison with other diagnostic tests, SICs are not widely available in North America (outside Quebec), may have false-positive or false-negative results, and have generally been considered only if other test results have been inconclusive or if other tests cannot be performed. Analyses of the added value of combination testing over single tests are very limited. The AHRQ review11 showed that when a single test of airway responsiveness was compared to the combination of airway responsiveness and a test for sensitization (either SPT or serology), there was an added benefit. The published studies included in the estimates involved HMW antigens and, when pooled, revealed an estimated sensitivity of 83% and a specificity of 100% (compared with the reference standard of SIC that was used by the AHRQ review) when the results of a single test for nonspecific airway responsiveness and a skin test to a workplace HMW agent to which the patient had exposure were positive. The likelihood ratio calculation with a combination of tests showed that in a population with a 50% pretest probability a combination of positive test results adds to the posttest probability of sensitizer-induced OA (Fig 4).
In a study85 of suspected sensitizer-induced OA patients, the addition of induced sputum cell counts showing an increase in sputum eosinophils during periods at work compared to away from work improved the specificity of serial PEFRs by 18 to 26%, using SIC as the reference standard. Sensitivity was increased 8% with a cutoff level for increased sputum eosinophils of 1%, but was reduced with a cutoff level of 2%. This test is of no value, however, if the patient does not produce sputum during induction or cannot take time off from being in the suspected work area.85–87
For the exclusion of sensitizer-induced OA, a negative diagnostic test result, even a negative SIC response, is not always sufficient, and further diagnostic testing may be indicated (eg, serial PEFRs with or without methacholine testing or equivalent when on and off work).1,88 The results of different tests may not be concordant, since all tests have potential false-positive and false-negative responses. The reasons include the following: intercurrent respiratory infections; medication changes; nonoccupational allergen exposures; variable exposures to the causative agent at work; and inadequate duration of time at work/off work to identify work-related changes in PEFRs. There can be a benefit from the repetition of such tests.
Most of the diagnostic tests providing objective evidence of work-relatedness are not relevant for those with suspected irritant-induced OA and are not included in the diagnostic criteria for that entity. They may be relevant, however, if it is suspected that the asthma-inducing exposure may also have caused sensitization (eg, from a spill of glutaraldehyde or diisocyanates).
WEA has been diagnosed most commonly by self-report of worsened asthma symptoms on the job in workers with preexisting asthma.15,60,70 The use of qualitative or quantitative workplace exposure assessment, or "objective indicators" of asthma exacerbations such as a greater use of asthma medications, physician or hospital visits, or worsened pulmonary function (as determined by PEFRs, spirometry, and nonspecific airway responsiveness) has, to date, not been systematically reported.
Objective investigations for WRA are most feasible when the patient is still working. Therefore, workers should be investigated soon after the diagnosis is suspected and should be advised to remain in the same job until the diagnosis has been investigated, unless this is considered to be unsafe (eg, in the presence of severe symptoms). Ideally, patients with suspected WRA should be referred soon after suspicion of the diagnosis to a physician with expertise in the assessment of such patients.89 A summary of the approach to diagnosis is included in Figure 2. Practical supplemental materials are also provided (www.chestjournal.org).
Panel Consensus
Work-Related Changes in Physiologic Tests
Serial PEFRs in the Diagnosis of WRA
Most published reports90 have examined lung function changes in patients with sensitizer-induced OA, and there are limited data on WEA. The use of "cross-shift" changes in lung function has had limited usefulness in diagnosing sensitizer-induced OA, probably in part due to late asthmatic responses occurring after the work shift.91–94 Peak flowmeters provide a compact and inexpensive index of airway caliber. Portable flow-sensing spirometers, which have been more recently introduced, allow the measurement of FEV1 and other indexes of airway caliber in a compact device,95,96 although at greater expense than peak expiratory flow meters.
The advantages of PEFRs include device portability and the more realistic exposures that occur at work compared with the limited exposure testing available with SIC. Most studies of lung function testing in the diagnosis of sensitizer-induced OA have compared serial PEFRs with either SIC or an "expert diagnosis" of OA. The sensitivity and specificity of a PEFR in comparison with SIC can be high, with pooled estimates suggesting approximately 64% sensitivity (95% confidence interval, 43 to 80%) and 77% specificity (95% confidence interval, 67 to 85%).11 Agreement of PEFRs with expert diagnosis has been reported,97 with sensitivity and specificity of up to 75% and 94%, respectively, and a positive test result has been reported98 to significantly influence expert opinion on the probability of sensitizer-induced OA.
Peak Flowmeter Considerations: Ideally, the peak flowmeter (or portable spirometer) should be simple, inexpensive, accurate, and reliable in use. Several peak flowmeters fit these characteristics. A patient should use the same type of peak flowmeter to reduce variability. Peak flowmeters may have a nonlinear response to changes in flow, and it is important to characterize the devices if possible.99 Peak expiratory flow can be recorded in a standard diary, which can also be used to collect information such as the frequency of symptoms, medication use, and specific tasks at work. A data logger is a useful addition and is increasingly available; by recording the measurements, it prevents the possibility of PEFRs being fabricated. Patients require a careful explanation of how to use the peak flowmeter, and there may be a learning effect during the first few days of use that can interfere with the interpretation.
Frequency and Duration of PEFRs: The optimal frequency and duration of PEFRs has not been fully established, although more frequent measurements over longer periods with good adherence to the test provide more information and increase sensitivity and specificity. One comparison of PEFRs made every 2 h with PEFRs made four times daily showed similar sensitivity and specificity in diagnosing sensitizer-induced OA,100 with measurements made less than four times a day being less effective. A minimum of four readings daily seems necessary, with there being a possible benefit of obtaining readings more frequently. PEFRs should be performed throughout the day while the patient is awake, on days off work and at work.
The optimum duration of PEFRs has not been established, although a duration of several weeks is customary.101,102 A prolonged period of testing is important as it may take several days or longer for workplace exposures to affect PEFR or for recovery to occur away from exposure. A recording period of 4 weeks, including a period of at least 1 week away from work, seems to be the minimum time necessary to reliably identify changes due to work (with optimally at least 2 weeks at work and 2 weeks off work). It may take repeated recording episodes to capture relevant exposures and changes in PEFRs. The absence of clear work-related changes does not exclude WRA (ie, sensitizer-induced OA or WEA).
Stability of Underlying Asthma and Use of Medication: The best time to identify changes in PEFRs from workplace exposures is when the patient with underlying asthma is as stable as possible. The use of long-acting bronchodilators or inhaled steroids may mask work-related changes, and a temporary switch to short-acting bronchodilators as needed or a reduced inhaled steroid dose may be required if PEFR monitoring is negative. Ideally, medication should remain unchanged throughout the recording period except for rescue medication, the use of which should be recorded. Intercurrent chest infections or exposure to asthma triggers away from work should be similarly recorded. Variable shift work may also cause problems in interpretation because of changes in the timing of diurnal rhythms of lung function.
Interpretation of Serial PEFRs:
No single universally accepted technique for evaluating the results of serial PEFRs has emerged. Usually, the best of triplicate recordings made at each time point is taken as the value for that time. The results can be plotted (Fig 5) then visually interpreted to determine whether there is a pattern of worsened PEFRs during work weeks compared with days or weeks off work; when undertaken by "experts," there is relatively good agreement with the SIC in diagnosing sensitizer-induced OA.103 The following various patterns can be seen: diurnal worsening during a work day that does not worsen progressively during the work week and improves on the weekend or other days off work; a diurnal pattern of worsening during the working day with the daily value before the work shift value falling progressively over the work week and worsening over successive weeks of work; and an intermittent fall in peak flows during working weeks with marked improvement after several days away from work. An alternative approach involves identifying asthma by the presence of significant diurnal variation in PEFRs (ie, a 20% fall in peak flow from maximum to minimum as the criterion) and then identifying the relative ratio of days with significant diurnal variation during work periods to the diurnal variation during days off work.104 For example, for a 5-day work week, a significant diurnal variation occurring on 10 of 15 working days, on only 2 of 6 days off work on weekends, and 2 of 14 days off work would be a positive response. This technique gave a sensitivity of 93% and a specificity of 90% in diagnosing sensitizer-induced OA among those persons from whom PEFRs could be fully interpreted.104 A more sophisticated method of analysis is based on a computer-generated discriminant analysis (OASYS-2; OASYS Research Group, Midland Thoracic Society; Birmingham, UK) that is commercially available and uses a different method of plotting results (Fig 6). It has also given reasonably good sensitivity and specificity of 75% and 94%, respectively, and relatively good agreement with the opinion of experts reading the plotted graphs (median 
value, 0.75).93,97
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Panel Consensus
Serial Measures of Airway Responsiveness in the Diagnosis of WRA
Statements and reviews for the diagnosis of sensitizer-induced OA74,83,88,107 have suggested that a methacholine or histamine challenge be performed toward the end of a work week and be repeated at the end of a period (usually 10 to 14 days) away from the exposure, and that a worsening of the provocative concentration of a substance causing a 20% fall in FEV1 (PC20) at work vs off work beyond the normal variability of the test (defined107 as a threefold or greater change in PC20) would provide additional evidence to support the diagnosis of sensitizer-induced OA.83 A smaller shift in PC20 would be less definitive in the diagnosis. The basis of this suggestion has been the observation that with exposure to a work sensitizer, a positive response is often associated with an increase in nonspecific airway hyperresponsiveness compared with preexposure results.108
Both methacholine and histamine inhalation challenge testing109–113 have been used in this manner. The tests should be performed using standard recommended protocols and methods114–121 supported by European and North American respiratory societies.120,122,123 Changes in airway hyperresponsiveness are best evaluated by comparing tests conducted in the same laboratory.
Patient-related factors that impact results include the actual degree of airway responsiveness as well as other factors. The failure to discontinue bronchodilator therapy for an adequate time interval before the test will reduce the measured responsiveness; the effects of current inhaled corticosteroids are less marked (a mean reduction of approximately one doubling dose).124 A respiratory infection within the 6 weeks prior to testing can increase airway responsiveness.125 Repeat tests are best compared when the baseline FEV1 is similar. Exposure within days to weeks before the test to a nonoccupational allergen to which the patient is sensitized can increase airway hyperresponsiveness.126,127 Gastroesophageal reflux disease may also impact the results.128 Such factors must be considered when evaluating changes in responsiveness during periods on and off work. In addition, workers with longstanding OA from a sensitizer to which they are still exposed may have airway remodeling and less acute improvement in airway responsiveness once removed from the work sensitizer. Such patients may have slow improvements in lung function over months or even years away from work.126,127
Although studies85,101 have found serial changes in methacholine or histamine responsiveness to be useful as part of the diagnosis of sensitizer-induced OA, few have assessed sensitivity and specificity in comparison to SIC. A study101 designed mainly to compare serial PEFRs with SIC reported a lower sensitivity and specificity of serial methacholine challenges. Another report85 noted serial methacholine challenges to be less sensitive and specific compared with SIC. The AHRQ review11 failed to identify sufficient evidence comparing serial measures
