Asthma in The Workplace 2016

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BOOK CHAPTER
Asthma in the Workplace

Catherine Lemière MD, MSc and Olivier Vandenplas MD, PhD
Murray and Nadel's Textbook of Respiratory Medicine, 72, 1295-1306.e3
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 (f0010) ). 2
Figure 72-1
Categorization of work-related asthma into subsets based on the cause and timing of the asthma.
Several definitions of OA have been proposed. The most recent has been published in the latest American
College of Chest Physicians Consensus statement on WRA 3 : “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 irritant-induced OA.”
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
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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 8 9 10 11 12 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 WEA 2 and consists of four criteria:
▪ 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.
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 population-based surveys. A pooled analysis of data published up until 2007 indicated that
17.6% of all adult-onset asthma is attributable to workplace exposures. 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 19 20 21 22 23 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.
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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 (t0010) ). HMW agents are (glyco)proteins from
plant and animal origins. LMW agents include chemicals, metals, and wood dusts. The intrinsic
characteristics of occupational agents that determine their sensitizing potential remain largely uncertain.
However, LMW agents causing OA are typically highly reactive electrophilic compounds that are capable of
combining with hydroxyl, amino, and thiol functionalities on airway proteins. Quantitative structure-
activity relationship models have identified a number of reactive groups that are associated with a high risk
of respiratory sensitization (e.g., isocyanate [N = C = O], carbonyl [C = O], and amine [NH 2 ]), particularly
when two or more groups are present within the same molecule. 28
Table 72-1
Principal Agents Causing Occupational Asthma
Agent Occupation/Industry
HIGH-MOLECULAR-WEIGHT AGENTS
Cereals, Wheat, rye, barley, buckwheat Flour mills, bakers, pastry makers
flour
Latex Proteins from the Hevea tree Health care workers, laboratory technicians
Animals Mice, rats, cows, seafood Laboratory workers, farmers, seafood

processing
Enzymes α-Amylase, maxatase, alcalase, papain, Baking product production, bakers,

bromelain, pancreatin detergent production, pharmaceutical
industry, food industry
LOW-MOLECULAR-WEIGHT AGENTS
Isocyanates Toluene diisocyanate (TDI), methylene Polyurethane production, plastic industry,

diphenyl-diisocyanate (MDI), hexamethylene insulation, molding, spray painting
diisocyanate (HDI)
Metals Chromium, nickel, cobalt, platinum Metal refinery, metal alloy production,
electroplating, welding
Biocides Formaldehyde, glutaraldehyde, quaternary Health care workers, cleaners

ammonium compounds
Persulfate Hair bleach Hairdressers

salts
Acrylates Cyanoacrylates, methacrylates, di- and tri- Adhesives, dental and orthopedic materials,
acrylates sculptured fingernails, printing inks, paints
and coatings
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Agent Occupation/Industry
Acid Phthalic, trimellitic, maleic, Epoxy resin workers

anhydrides tetrachlorophthalic anhydrides
Reactive Reactive black 5, pyrazolone derivatives, Textile workers, food industry workers
dyes vinyl sulphones, carmine,
Woods Red cedar, iroko, obeche, oak, and others Sawmill workers, carpenters, cabinet and
furniture makers
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 19 20 21 22 23 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-cedar-induced asthma. 35 Furthermore, a specific-
inhalation challenge (SIC) test induced a mixed Th2/Th1 response in which CD8 + cells were the main
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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 (t0015) ). 29
Table 72-2
Potential Risk Factors for the Development of Occupational Asthma
Risk Factor Evidence Agents/Settings
ENVIRONMENTAL FACTORS
High level of exposure Strong HMW agents
Moderate LMW agents: platinum salts, acid anhydrides, isocyanates
Cigarette smoking Moderate (For IgE sensitization) Laboratory animals, snow crab,
prawn, salmon, psyllium, green coffee, enzymes, acid
anhydrides, platinum, reactive dyes
Weak (For clinical OA) Laboratory animals, enzymes
Skin exposure Weak Isocyanates
HOST-RELATED FACTORS
Atopy Strong HMW agents
Weak LMW agents: platinum, acid anhydrides
Genetic markers
HLA class II alleles Moderate LMW agents: isocyanates, red cedar, acid anhydrides,
platinum salts
HMW agents: laboratory animals, latex
Antioxidant enzymes * Moderate Isocyanates

(hl0000179)
SNPs of α-T catenin Moderate Isocyanates
TLR4 polymorphisms Weak Laboratory animals
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Risk Factor Evidence Agents/Settings
IL-4 receptor alpha and IL13 Weak Isocyanates

polymorphisms
Preexisting nonspecific bronchial Moderate HMW agents (laboratory animals, flour, latex)
hyperresponsiveness
Work-related rhinitis Strong Laboratory animals
Gender (female) Weak Snow crab processors
HMW, high-molecular-weight; IL, interleukin; LMW, low-molecular-weight; OA, occupational asthma; SNPs, single
nucleotide polymorphisms; TLR4, Toll-like receptor-4.
* Glutathione-S-transferase and N-acetyltransferase.
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 hyperresponsiveness 40 41
and rhinitis 41 42 before entering exposure to HMW occupational agents is an independent risk factor for
subsequent IgE 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
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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-S-transferase (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 (f0015) . 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 (t0020) .
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.
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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 ▪ Simple, low cost.

bronchial hyperresponsiveness
▪ 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.
Immunologic tests ▪ 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.
PEF monitoring ▪ 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.
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Diagnostic Tests Advantages and Limitations
Specific-inhalation challenges in ▪ Confirmation of the diagnosis of OA when the test is positive.

the laboratory
▪ False-negative tests are possible.
▪ Costly.
▪ Available in a small number of centers worldwide.
Specific-inhalation challenges at ▪ Exclude diagnosis if negative when performed in the usual work
the workplace conditions.
▪ Requires usual work conditions.
▪ Costly.
Noninvasive measures of airway Sputum cell counts

inflammation ▪ 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
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
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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 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 (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 (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
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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 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 Sensitizer-Induced Asthma

According to recent systematic reviews of the existing data, the complete avoidance of exposure to the causal
agent remains the optimal treatment of immunologic OA. 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 IgE-
dependent 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 wood 63 ). However, whether immunotherapy can alter the course of OA in the long term remains to be
determined. Further studies need to be conducted before immunotherapy can be recommended for the
treatment of OA to HMW agents.
A few case reports provided some suggestion that treatment with the anti-IgE omalizumab could improve
asthma control in subjects with flour-induced OA, who remain exposed to the causal work environment,
although further prospective investigations are required in subjects who choose to continue exposure. 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
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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
(t0015) ) 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
asthma 79 80 and with a higher health care resource utilization 81 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
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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
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 87 88
A 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 new-onset 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 91 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
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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 (t0025) ). 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.
Table 72-4
Examples of Exposures Causing Acute Irritant-Induced 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
Acids Acetic, hydrochloric, hydrofluoric, hydrobromic acids
Alkali Ammonia, calcium oxide (lime), hydrazine
Biocides Formalin, ethylene oxide, fumigating agents, insecticides (sodium

methyldithiocarbamate, dichlorvos)
Halogenated Bromochlorodifluoromethane (fire extinguisher), trifluoromethane, chlorofluorocarbons

derivatives (CFC, thermal degradation products of freons), uranium hexafluoride, hydrogen and
carbonyl fluoride
Solvents Perchloroethylene
Fumes Diesel exhaust, paint fumes, urea fumes, fire smoke, iodine compounds (iodine and
aluminium iodide, hydrogen iodide), diethylaminoethanol (corrosion inhibitor)
Sprays Paints (not specified), floor sealant (aromatic hydrocarbons)
Dusts World Trade Center alkaline dust, calcium oxide (lime)
Potential Isocyanates, phthalic anhydride

sensitizers
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
100 101 Two studies provided information on the long-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
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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 sensitizer-induced 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.
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 (t0030) ). 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
irritant-induced 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.
Table 72-5
Diagnostic Criteria for the Reactive Airways Dysfunction Syndrome (i.e., Acute Onset Irritant-induced Asthma)
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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.
There are some clinical features that clearly distinguish acute IIA from sensitizer-induced OA. Unlike
sensitizer-induced 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 asthma 9 ); (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
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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 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
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 self-reports 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
17 of 35 5/20/2018, 5:13 PM
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 Work-Exacerbated 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 America 120 121 122 123 124 125 126 127 128 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 stress 121 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 FEV 1 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 hyper-
responsiveness 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
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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. 135 136 137
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 colleagues 139 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 colleagues 137 found that after adjusting for age, asthma control, and FEV 1 , 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 colleagues 140 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
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Table 72-6 (t0035) summarizes demographic, clinical, functional, and inflammatory differences between
subjects with WEA and subjects with NWRA or OA.
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- Compared with Adults with Occupational
Related Asthma Asthma
Gender Similar 135 138 or predominance of men in Similar 81 or greater number of women
subjects with WEA 81 in subjects with WEA 139
Age Older 135 138 Similar or younger 139
Race More nonwhite 135 More nonwhite 139
Education Less 135 N/A
Smoking habits More likely to have smoked cigarettes 135 More smokers 81
Asthma severity More asthma exacerbations requiring Same number of asthma exacerbations
emergency department visits or requiring emergency department visits or
hospitalizations in workers with WEA, 81 hospitalizations 137
More days with asthma symptoms, more Greater need of ICS in subjects with
severe asthma based on self-report 135 WEA 137
Functional Similar FEV 1 , PC 20 81 Less PEF variability when at work in

characteristics subjects with WEA compared with OA
133
PC 20 may be lower in subjects with

WEA 140
Airway Neutrophilic inflammation inconsistently Less likely to have eosinophilic airway

inflammation found depending on the study 51 52 inflammation 52 137
ICS, inhaled corticosteroids; OA, occupational asthma; PEF, peak expiratory flow rate.
Socioeconomic Impact of Work-Exacerbated 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. 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.
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If one examines all of WRA, the 2001 and 2002 data from Breton and colleagues 142 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 colleagues 81 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.
21 of 35 5/20/2018, 5:13 PM
▪ 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.
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 2012; 21: pp.
125-139.
Baur X, Sigsgaard T, Aasen TB, et. al., ERS Task Force on the Management of Work-Related Asthma:
Guidelines for the management of work-related asthma. Eur Respir J 2012; 39: pp. 529-545.
Beach J, Russell K, Blitz S, et. al.: A systematic review of the diagnosis of occupational asthma. Chest 2007;
131: pp. 569-578.
Brooks SM, Bernstein IL: Irritant-induced airway disorders. Immunol Allergy Clin North Am 2011; 31: pp.
747-768.
Henneberger PK, Redlich CA, Callahan DB, et. al.: An official American Thoracic Society statement: work-
exacerbated asthma. Am J Respir Crit Care Med 2011; 184: pp. 368-378.
Tarlo SM, Balmes J, Balkissoon R, et. al.: Diagnosis and management of work-related asthma: American
College of Chest Physicians consensus statement. Chest 2008; 134: pp. 1S-41S.
Vandenplas O, Dressel H, Nowak D, et. al.: What is the optimal management option for occupational
asthma?. Eur Respir Rev 2012; 21: pp. 97-104.
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Asthma in the Workplace- ClinicalKey https://www-clinicalkey-com.dbproxy.umfiasi.ro/#!/content/book/3-s2.0...

Asthma in the Workplace

▪ Workplace exposures or conditions that can exacerbate asthma exist.

▪ Occupational asthma (asthma caused by a specific, identified workplace exposure) is unlikely.

Sensitizer-Induced Occupational Asthma

Animals Mice, rats, cows, seafood Laboratory workers, farmers, seafood

Enzymes α-Amylase, maxatase, alcalase, papain, Baking product production, bakers,

Isocyanates Toluene diisocyanate (TDI), methylene Polyurethane production, plastic industry,

Biocides Formaldehyde, glutaraldehyde, quaternary Health care workers, cleaners

Persulfate Hair bleach Hairdressers

Acid Phthalic, trimellitic, maleic, Epoxy resin workers

Immunologic, non–IgE mediated

Neutrophils are also likely to be involved in isocyanate-induced asthma as shown by an increase in

Risk Factor Evidence Agents/Settings

High level of exposure Strong HMW agents

Moderate LMW agents: platinum salts, acid anhydrides, isocyanates

Weak (For clinical OA) Laboratory animals, enzymes

Skin exposure Weak Isocyanates

Atopy Strong HMW agents

Weak LMW agents: platinum, acid anhydrides

Antioxidant enzymes * Moderate Isocyanates

SNPs of α-T catenin Moderate Isocyanates

TLR4 polymorphisms Weak Laboratory animals

Risk Factor Evidence Agents/Settings

IL-4 receptor alpha and IL13 Weak Isocyanates

Work-related rhinitis Strong Laboratory animals

Gender (female) Weak Snow crab processors

* Glutathione-S-transferase and N-acetyltransferase.

Diagnostic Tests Advantages and Limitations

Assessment of nonspecific ▪ Simple, low cost.

▪ Low specificity for diagnosis of OA. The absence of airway

Immunologic tests ▪ Easy to perform, low cost.

▪ Measurement of specific IgE available for some LMW agents

▪ Lack of standardization for the majority of occupational allergens

▪ Can identify the sensitization but not necessarily the disease.

PEF monitoring ▪ 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

▪ No standardized method for interpreting the results.

▪ Interpretation of the results requires experience.

Diagnostic Tests Advantages and Limitations

Specific-inhalation challenges in ▪ Confirmation of the diagnosis of OA when the test is positive.

▪ Available in a small number of centers worldwide.

▪ Requires usual work conditions.

Noninvasive measures of airway Sputum cell counts

▪ Bring additional evidence to the diagnosis of OA

▪ Not widely available

▪ Does not confirm or exclude the diagnosis of OA by itself

▪ Affected by many different factors

Outcome and Management of Sensitizer-Induced Asthma

Acids Acetic, hydrochloric, hydrofluoric, hydrobromic acids

Alkali Ammonia, calcium oxide (lime), hydrazine

Biocides Formalin, ethylene oxide, fumigating agents, insecticides (sodium

Halogenated Bromochlorodifluoromethane (fire extinguisher), trifluoromethane, chlorofluorocarbons

Sprays Paints (not specified), floor sealant (aromatic hydrocarbons)

Dusts World Trade Center alkaline dust, calcium oxide (lime)

Potential Isocyanates, phthalic anhydride

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

Outcome and Treatment