A Systematic Review of the Diagnosis of Occupational Asthma

doi:10.1378/chest.06-0492

Chest

Volume 131, Issue 2, February 2007, Pages 569-578

https://doi.org/10.1378/chest.06-0492 Get rights and content

Abstract

Background:This study systematically reviews literature regarding the diagnosis of occupational asthma (OA) and compares specific inhalation challenge (SIC) testing with alternative tests.

Methods:Electronic databases and trials registries were searched; additional references were identified from bibliographic searches of included studies, hand searches of conferences, and author contacts. Various study designs (clinical trials, cohorts, cross-sectional, or case series) were included involving workers with suspected OA. All diagnostic tests were compared to a “reference standard,” and two researchers independently extracted 2 × 2 data. Pooled sensitivities and specificities (95% confidence intervals [CIs]) were derived.

Results:Seventy-seven studies were included. For high molecular weight (HMW) agents, the nonspecific bronchial provocation (NSBP) test, skin-prick test (SPT), and serum-specific IgE had sensitivities > 73% when compared to SIC. Specificity was highest for specific IgE vs SIC (79.0%; 95% CI, 50.5 to 93.3%). The highest sensitivity among low molecular weight asthmagens occurred between combined NSBP and SPT vs SIC (100%; 95% CI, 74.1 to 100%). When compared to SIC, specific IgE and SPT had similar specificities (88.9%; 95% CI, 84.7 to 92.1%; and 86.2%; 95% CI, 77.4 to 91.9%, respectively). For HMW agents, high specificity was demonstrated for positive NSBP tests and SPTs alone (82.5%; 95% CI, 54.0 to 95.0%) or when combined with specific IgE (74.3%; 95% CI, 45.0 to 91.0%) vs SIC. Sensitivity was somewhat lower (60.6% and 65.2%, respectively).

Conclusions:In appropriate clinical situations when SIC is not available, the combination of a NSBP test with a specific SPT or specific IgE may be an appropriate alternative to SIC in diagnosing OA. While positive results of single NSBP test, specific SPT, or serum-specific IgE testing would increase the likelihood of OA, a negative result could not exclude OA.

Section snippets

Materials and Methods

A detailed description of the methods can be found at http://www.ahrq.gov/clinic/epcix.htm. A condensed version is presented below.

Search Strategy

The search strategy and complete reference list of included studies are available on the Agency for Healthcare Research and Quality (AHRQ) Web site cited above. The literature search resulted in 7,112 studies, and 487 unique citations were identified as potentially relevant. Seventy-seven studies were ultimately included; exclusions are shown inFigure 1.

Description of Included Studies

The 77 unique cohorts that were included in the diagnosis review are described inTable 1. SIC was the most commonly cited reference standard;

Single NSBP Test vs SIC

Thirty-nine studies compared the sensitivity and specificity of single NSBP test to SIC. Among the 10 studies examining HMW workplace exposures, the pooled estimate for sensitivity was 79.3% (95% CI, 67.7 to 87.6%) and for specificity was 51.3% (95% CI, 35.2 to 67.2%). The sensitivity/specificity pairs are plotted inFigure 2,top left,A. Twenty-four studies reported sufficient data that we could estimate both sensitivity and specificity among patients exposed to LMW agents. The pooled estimate

Discussion

There are a number of diagnostic tests available to clinicians to assist in the diagnosis of OA; however, varying test efficiency, availability, safety profiles, and cost limit their application. For example, of 235 patients with a diagnosis of OA in Ontario, only 43 patients (18%) underwent SICs and 41 patients (17%) underwent SPTs to a work agent; whereas OA in 94 patients (40%) was diagnosed by serial peak expiratory flows (PEFs), 84 patients (36%) underwent an NSBP (methacholine) challenge

Conclusions

Despite limited availability, lack of standardized protocols, and recognized possibilities of false-positive and false-negative results, SIC has been used as the main reference standard for the diagnosis of OA in research publications. In isolation, none of the other diagnostic tests yielded a sufficiently high combination of sensitivity and specificity that they could replace SIC. In the absence of SIC, NSBP testing is probably a pragmatic and readily available alternative test that can be of

Acknowledgments

We thank the American College of Chest Physicians for sponsoring this research through the AHRQ. We are grateful to members of our technical expert panel (Drs. Dilini Vethanayagam, Richard Jones, David Muir) and Capital Health Evidence Based Practice Centre staff (Dr. Terry Klassen, Ms. Lisa Hartling) for providing input on the direction and scope of the review. We appreciate Ms. Ellen Crumley's expertise in conducting the literature search. We thank Ms. Natasha Wiebe and Ms. Marlene Dorgan for

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Occupational allergic respiratory diseases represent a significant public health concern due to their high prevalence and their long-term respiratory health consequences. More than 400 occupational agents from many different workplaces can induce occupational asthma (OA) or occupational rhinitis (OR). Although the allergic reaction to many high-molecular agents is immunoglobulin E (IgE)–mediated, many aspects of the pathophysiology of OA and OR caused by low-molecular-weight agents remain poorly understood.
Although the diagnosis of OA should be established early with the highest level of accuracy to avoid unwarranted socio-economic costs, the process to make such a diagnosis can be cumbersome. A negative methacholine/histamine challenge test performed while the patient is working can reasonably exclude the diagnosis of OA. Very positive skin-prick tests or high titers of specific IgE to the suspected agent have a high positive predictive value for the diagnosis of OA in asthmatic subjects with a suggestive history of OA. Outside of these scenarios, relationship between work and asthma needs to be assessed by performing serial measurements of peak expiratory flow (PEF) and/or assessments of airway responsiveness and/or noninvasive measures of airway inflammation at work and off work and/or specific inhalation challenge (SIC) tests in the laboratory or at the workplace.
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Occupational Asthma Caused by Quaternary Ammonium Compounds: A Multicenter Cohort Study
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Citation Excerpt :
However, these between-center differences in procedures are unlikely to have affected the findings because the collection and interpretation of data were standardized for the whole cohort. Although, the reference method for establishing a diagnosis of OA,36,37 BPT, is not thoroughly standardized, the centers participating in this cohort conformed to the main methodologic requirements for safety and reliability issued by the European Respiratory Society, and airway responses to challenges exposures were interpreted using uniform criteria.25 Another limitation arises from the lack of quantitative assessment of exposure to QACs at the workplace and during BPTs.
Quaternary ammonium compounds (QACs) are used extensively for cleaning and disinfection and have been documented in scattered reports as a cause of occupational asthma (OA) through bronchoprovocation tests (BPTs).
To examine the clinical, functional, and inflammatory profile of QAC-induced OA compared with OA caused by other low–molecular weight (LMW) agents.
The study was conducted in a retrospective multicenter cohort of 871 subjects with OA ascertained by a positive BPT. Subjects with QAC-induced OA (n = 22) were identified based on a positive BPT to QACs after exclusion of those challenged with cleaning products or disinfectants that contained other potential respiratory sensitizers. They were compared with 289 subjects with OA caused by other LMW agents.
Most subjects with QAC-induced OA were working in the health care sector (n = 14). A twofold or greater increase in the postchallenge level of nonspecific bronchial hyperresponsiveness was recorded in eight of 11 subjects with QAC-induced OA (72.7%) and in 49.7% of those with OA caused by other LMW agents. Although sputum assessment was available in only eight subjects with QAC-induced OA, they showed a significantly greater median (interquartile) increase in sputum eosinophils (18.1% [range, 12.1% to 21.1%]) compared with those with OA caused by other LMW agents (2.0% [range, 0% to 5.2%]; P < .001).
This study indicates that QAC-induced OA is associated with a highly eosinophilic pattern of airway response and provides further evidence supporting the sensitizing potential of QACs. The findings highlight the heterogeneous nature of the pathobiologic pathways involved in OA caused by LMW agents.
Assessment and Management of Occupational Asthma
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Citation Excerpt :
These data indicate that the presence of sIgE against LMW agents when available, such as isocyanates or acid anhydrides, is associated with a high likelihood of a positive SIC result, but a very low sensitivity and poor performance for ruling out a diagnosis of OA. More importantly in the context of a stepwise diagnostic approach, available data indicate that combining a positive SPT or sIgE test result with the presence of NSBH increases the specificity and PPV of each test alone (Table II).26,28 Therefore, a positive SPT or sIgE test result to either HMW or LMW agents may be regarded as an alternative to SIC in establishing a diagnosis of probable OA in subjects with documented NSBH.28
Exposures at work can give rise to different phenotypes of “work-related asthma.” The focus of this review is on the diagnosis and management of sensitizer-induced occupational asthma (OA) caused by either a high- or low-molecular-weight agent encountered in the workplace. The diagnosis of OA remains a challenge for the clinician because there is no simple test with a sufficiently high level of accuracy. Instead, the diagnostic process combines different procedures in a stepwise manner. These procedures include a detailed clinical history, immunologic testing, measurement of lung function parameters and airway inflammatory markers, as well as various methods that relate changes in these functional and inflammatory indices to workplace exposure. Their diagnostic performances, alone and in combination, are critically reviewed and summarized into evidence-based key messages. A working diagnostic algorithm is proposed that can be adapted to the suspected agent, purpose of diagnosis, and available resources. Current information on the management options of OA is summarized to provide pragmatic guidance to clinicians who have to advise their patients with OA.
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There is convincing evidence that tight relationships between the upper and lower airways also apply to the workplace context. Most patients with occupational asthma (OA) also suffer from occupational rhinitis (OR), although OR is 2 to 3 times more common than OA. OR most often precedes the development of OA, especially when high-molecular-weight protein agents are involved, and longitudinal cohort studies have confirmed that OR is associated with an increased risk for the development of OA. The level of exposure to sensitizing agents at the workplace is the most important determinant for the development of IgE-mediated sensitization and OR. Atopy is a risk factor for the development of IgE-mediated sensitization only to high-molecular-weight agents. In workers with work-related rhinitis symptoms, documentation of IgE-mediated sensitization to a workplace agent via skin prick testing or serum specific IgE confirms a diagnosis of probable OR, whereas specific nasal provocation testing in the laboratory remains the reference method to establish a definite diagnosis of OR. Complete avoidance of exposure to the causal agent is the most effective therapeutic option for controlling work-related nasal symptoms and preventing the development of OA. If complete elimination of exposure is expected to induce meaningful adverse socioeconomic consequences, reduction of exposure can be considered as an alternative approach, but it is important to consider the individual risk factors for the development of OA to implement a more personalized management of OR.
Japanese guidelines for occupational allergic diseases 2020
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Occupational allergic diseases are likely to worsen or become intractable as a result of continuous exposure to high concentrations of causative allergens. These are socioeconomically important diseases that can lead to work interruptions for patients and potentially job loss. We published the first guideline for managing occupational allergic diseases in Japan. The original document was published in Japanese in 2013, and the following year (2014) it was published in English. This guideline consists of six chapters about occupational asthma, occupational allergic rhinitis, occupational skin diseases, hypersensitivity pneumonitis, occupational anaphylaxis shock, and the legal aspects of these diseases. Providing general doctors with the knowledge to make evidence-based diagnoses and to understand the occupational allergic disease treatment policies, was a breakthrough in allergic disease treatment.
Due to the discovery of new occupational allergens and the accumulation of additional evidence, we published a revised version of our original article in 2016, and it was published in English in 2017. In addition to including new knowledge of allergens and evidence, the 2016 revision contains a “Flowchart to Diagnosis” for the convenience of general doctors.
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Dr. Beach participated in writing the proposal, provided methodologic and content expertise, and participated in writing and editing the manuscript. Ms. Russell planned, oversaw, and participated in all steps of the systematic review process and in writing and editing the proposal and manuscript. Ms. Blitz performed all statistical analysis, participated in most steps of the systematic review process, and participated in writing and editing the manuscript. Ms. Hooton and Ms. Spooner participated in most steps of the systematic review process and in editing the manuscript. Drs. Lemiere and Tarlo participated in editing the proposal, provided content expertise, and participated in editing the manuscript. Dr. Rowe participated in writing the proposal, provided methodologic and content expertise, and participated in writing and editing the manuscript.

This study was supported by the AHRQ.

The investigating authors acknowledge the following financial support: Dr. Beach is supported by the Faculty of Medicine and Dentistry at the University of Alberta, Edmonton, Alberta; and Dr. Rowe is supported by the Canadian Institutes of Health Research, Canada Research Chairs Program.

The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Special FeatureA Systematic Review of the Diagnosis of Occupational Asthma

Abstract

Section snippets

Materials and Methods

Search Strategy

Description of Included Studies

Single NSBP Test vs SIC

Discussion

Conclusions

Acknowledgments

Am J Med

Chest

Chest

J Allergy Clin Immunol

Occupational airway sensitizers: an overview on the respective literature.

Am J Ind Med

Occupational asthma.

N Engl J Med

Special Feature
A Systematic Review of the Diagnosis of Occupational Asthma