Occupational asthma: Pathogenesis - UFPR...eosinophilic bronchitis) [1]. Occupational asthma is a disease characterized by variable airflow limitation, airway hyperresponsiveness,

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Occupational asthma: PathogenesisAuthors: David I Bernstein, MD, Louis-Philippe Boulet, MD, André Cartier, MDSection Editor: Peter J Barnes, DM, DSc, FRCP, FRSDeputy Editor: Helen Hollingsworth, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2019. | This topic last updated: Mar 13, 2019.

INTRODUCTION

The label "asthma in the workplace" encompasses several entities: (1) asthma exacerbated atwork by various environmental conditions; (2) occupational asthma; and (3) variants (eg,eosinophilic bronchitis) [1]. Occupational asthma is a disease characterized by variable airflowlimitation, airway hyperresponsiveness, and inflammation resulting from an inciting agent onlyfound in the workplace [2].

The pathogenesis and pathology of occupational asthma will be reviewed here. Issues related toother aspects of occupational asthma are discussed separately. (See "Occupational asthma:Definitions, epidemiology, causes, and risk factors" and "Occupational asthma: Clinical features,evaluation, and diagnosis" and "Reactive airways dysfunction syndrome and irritant-inducedasthma".)

TYPES

Two main types of occupational asthma have been recognized [1,3]:

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Immunologically mediated. This type includes IgE and nonIgE-mediated responses followingchronic exposure and respiratory sensitization to high or low molecular weight agents.

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Nonimmunologic, irritant-mediated, also called irritant-induced asthma. This type includesreactive airways dysfunction syndrome (RADS) caused by a single high level exposure to anirritant, irritant-induced asthma caused by multiple high level exposures to an irritant, andpossibly asthma caused by chronic lower level of exposure, although the latter iscontroversial. (See "Reactive airways dysfunction syndrome and irritant-induced asthma".)

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Some occupational agents, such as diisocyanates, may induce asthma through more than onemechanism. As an example, asthma may develop in subjects after a diisocyanate spill by causingacute airway injury and reactive airways dysfunction syndrome (RADS), while in others,respiratory sensitization to diisocyanate develops with lower levels of exposure. Exposure to highlevels of diisocyanates causing irritant-induced occupational asthma can also promote thedevelopment of immunologic occupational asthma caused by diisocyanates. (See "Reactiveairways dysfunction syndrome and irritant-induced asthma".)

The various types of occupational asthma may include different phenotypes or endotypes [4]. Asan example, in an analysis of 187 patients with diisocyanate asthma, different clusters werepopulated, similar to common asthma, with the largest cluster including the youngest patients withthe shortest duration of exposure to the sensitizers, while another cluster included older malepatients with worse lung function and longer occupational exposure [5]. This suggests thatoccupational asthma (as probably many others) is phenotypically heterogeneous. More researchshould be done to characterize the phenotypes/endotypes of occupational asthma.

This variation in features among patients with occupational asthma is supported by aninternational study of 1167 subjects with occupational asthma to high (n = 544) and low (n = 623)molecular weight agents, confirmed by specific inhalation challenges [6]. Multivariate logisticregression analysis showed significant associations between occupational asthma caused by highmolecular weight agents and work-related rhinitis, conjunctivitis, atopy, and early asthmaticreactions. By contrast, occupational asthma to low molecular agents was associated with chesttightness at work, daily sputum production, and late asthmatic reactions. Although assessed in alower proportion of subjects, baseline sputum inflammatory profiles were similar in the two groups,but occupational asthma caused by high molecular weight agents showed higher baseline bloodeosinophils and a greater postchallenge increase in fractional nitric oxide. Postchallenge, a higherproportion of subjects with occupational asthma to high molecular weight agents showed a switchfrom a paucigranulocytic to an eosinophilic pattern in their sputum.

PATHOLOGY

In the case of immunologically mediated occupational asthma, the pathology in the airways at thetime of exposure is similar to that seen in patients with nonoccupational asthma (see"Pathogenesis of asthma", section on 'Airway inflammation'). Nonimmunologic irritant mediatedoccupational asthma is discussed elsewhere. (See "Reactive airways dysfunction syndrome andirritant-induced asthma".)

The pathologic abnormalities associated with occupational asthma persist for weeks to years aftercessation of exposure. One study examined the bronchial biopsies of 18 subjects withoccupational asthma after cessation of exposure for a period of 3 to 24 weeks [7]. Eleven subjectshad disease due to exposure to high molecular weight compounds, and seven to low molecular





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weight (LMW) compounds. Extensive epithelial desquamation, epithelial cell ciliary abnormalities,smooth muscle hyperplasia, and subepithelial fibrosis were found, and the numbers of totalinflammatory cells, eosinophils, and lymphocytes were increased compared to healthy controls(picture 1). Similar findings were described in reports of subjects with isocyanate- and Western redcedar-related asthma [8,9]. Animal models have suggested that profibrotic cytokines such asinterleukin (IL)-13, can be involved in these changes although a direct toxicity of some agentsagainst epithelial cells can be involved in the remodelling process [10,11].

Subjects with isocyanate-induced asthma show a reduction in subepithelial fibrosis, butinflammatory cell infiltration of the airways after removal from exposure can persist for a periodranging from 5 to 21 months [12]. The course of airway hyperresponsiveness parallels that ofairway inflammation, suggesting that airway inflammation contributes to the persistence ofhyperresponsiveness. It is possible that inflammatory and remodeling airway changes precede thedevelopment of clinical features of occupational asthma, as shown in asthma induced by commonallergens, but this remains to be further documented [13].

Persistent airway inflammation and remodeling exists even in subjects whose occupationalasthma is presumed to be cured. In an observational study, 133 subjects with occupational asthmawere evaluated at a mean of nine years after cessation of the exposure [14]. Among those fromwhom induced sputum was obtained (n = 84), eosinophils were increased (≥2 percent) in 18percent, including 3 of the 20 subjects who were considered cured, based on resolution ofsymptoms, no need for respiratory medication, normal airway caliber, and nonallergic airwayresponsiveness. Neutrophils were increased (≥61 percent of cells in induced sputum) in 45percent (including nine of those considered cured). Furthermore, 10 of the subjects consideredcured, who had no evidence of bronchial eosinophilia on induced sputum, underwentbronchoscopy with bronchial biopsies at a mean of 14 years after cessation of exposure.Compared to controls, subjects with prior occupational asthma had more transforming growthfactor (TGF)-beta1 and eosinophil cationic protein (ECP) positive cells, increased subepithelialfibrosis, and decreased distance between the epithelium and airway smooth muscle [15]. Thesefindings suggest that permanent inflammatory and structural changes persist many years afterstopping exposure to a respiratory sensitizer. The reason for the persistence of eosinophilicinflammatory changes many years after stopping exposure is unknown.

Acute changes in the airways of subjects with reactive airways dysfunction syndrome (RADS) orirritant-induced asthma consist of rapid denudation of the mucosa with fibrinohemorrhagic exudateand swelling in the submucosa (picture 2) [16]. This is followed by regeneration of the epitheliumwith proliferation of basal and parabasal cells and persistent subepithelial edema [16]. Similarfindings have been described in an animal model of RADS due to chlorine exposure [17,18].Furthermore, bronchial biopsies from subjects with persistent asthma symptoms two yearsfollowing chlorine-induced RADS show a thickened basement membrane with reticulocollagenicfibrosis of the bronchial wall (picture 3) [19]. In irritant-induced asthma due to multiple exposures

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to an irritant, an inflammatory infiltrate with eosinophils and lymphocytes is found, as well asdiffuse deposition with collagen fibers [20]. Even many years after the inhalational accident,induced sputum can show increased levels of mediators involved in inflammation and airwayremodeling [21]. (See "Reactive airways dysfunction syndrome and irritant-induced asthma".)

Evidence of eosinophilic and neutrophilic inflammation and also airway remodeling can persist forseveral years following acute irritant-induced asthma. Ten subjects with irritant-induced asthma(mean interval of 10.9 years, minimum of 4 years, since the inhalational accident) underwentbronchoscopy followed by bronchoalveolar lavage and bronchial biopsies [22]. The mostsignificant difference in tissue morphometry was the increase in basement membrane thickness insubjects with irritant-induced asthma compared with the healthy controls and subjects with mildasthma. The detachment of epithelium was increased in subjects with irritant-induced asthma,although not significantly so. Also, the number of TGF-beta1 positive cells and ECP positive cellswas increased by comparison with normal controls and comparable to subjects with commonasthma. Finally, the levels of cells (neutrophils and eosinophils) and of several mediators thatreflect an inflammatory and remodeling effect were significantly higher in the bronchoalveolarlavage than in normal controls and comparable or even higher than in subjects with commonasthma.

GENETICS

Genetic loci associated with non-occupational asthma have been investigated as susceptibilitymarkers for occupational asthma, primarily in workers with diisocyanate asthma [3]:

The human leukocyte antigen (HLA) system, which is synonymous with the majorhistocompatibility complex (MHC), encodes a variety of cell surface markers, antigen-presentingmolecules, and other proteins involved in immune function. Studies of genes involved inimmunoregulation have shown associations between HLA Class II antigens and various types ofoccupational asthma [23]. Several examples of HLA associates (eg, DR3, DQ5, DQA1, DQB1,DR1) have been described in the case of workers exposed to diisocyanates, Western red cedar,platinum salts, laboratory animals, and anhydrides [24]. In a study of 140 diisocyanate-exposedworkers, diisocyanate asthma was associated with HLA Class I (HLA-B and HLA-E) and Class IIsingle nucleotide polymorphisms (SNPs), not identified in prior studies [25]. The associations withHLA antigens have biological implications in that they provide evidence for a specificimmunological response and for T cell involvement in the development of occupational asthmacaused by low molecular weight compounds.

Innate immunity and immunoregulation●

Th2-cell differentiation●

Epithelial biology and mucosal immunity●

Lung function (airway hyperresponsiveness), airway remodeling, and disease severity●











Several studies support a role for antioxidant genes, such as the glutathione S-transferases (eg,GSTP1 and GSTM1) and N-acetyltransferase (NAT1, NAT2), in the development of occupationalasthma [25,26]. As examples:

Associations have also been found for other genes (eg, toll-like receptors, IL-4 receptor, IL-13,CD14, neurokinin 2 receptor, alpha-catenin) in patients with occupational asthma due todiisocyanates [31-33]. An association between diisocyanate asthma and two linked alpha-cateningene variants was identified by GWAS and confirmed in a second worker population [34,35]. Inaddition, genetic variations in tumor necrosis factor (TNF)-alpha, transforming growth factor(TGF)-beta1, prostaglandin-endoperoxide synthase (PTGS) 1, and PTGS2 are associated withdiisocyanate asthma susceptibility [36].

Work-related exposure to occupational chemicals could result in epigenetic modification of specificgenes associated with airway inflammation. The interferon (IFN)-gamma gene promoter regionwas significantly hyper-methylated in a study of workers with diisocyanate asthma in comparisonto asymptomatic workers, suggesting that epigenetic effects could play an important mechanisticrole [37].

Gene-environment interactions are difficult to study in the workplace. A cross-sectional studyperformed in laboratory animal workers demonstrated that those workers with high endotoxinexposure and a known CD14 endotoxin responsive genotype had significantly lower forcedexpiratory volume in one second (FEV ), suggesting that workers with the latter genotype are atgreatest risk [38].

An unbiased genome wide association study followed by next generation sequencing of workerswith diisocyanate asthma identified five disease-associated variants (proximal to ATF3, cadherin

Glutathione S-transferases belong to a family of enzymes that detoxify chemical substancesin the body. The GSTM1 null genotype is associated with an approximately two fold increasedrisk of diisocyanate-induced asthma [27]. In addition, GSTM1 null and GSTM3 AA genotypesare significantly related to late asthmatic reactions induced by diisocyanates [27]. On theother hand, homozygosity for the GSTP1*Val allele may provide a protective effect againstasthma in workers exposed to isocyanate [3,27].

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NAT1 also helps to metabolize drugs and chemicals. The slow acetylator genotype increasesthe risk of asthma in workers exposed to toluene diisocyanate (TDI) [3,28]. NAT2 SNPs andSNP combinations have been associated with a higher likelihood of diisocyanate asthma[28,29].

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Genetic variants in manganese superoxide dismutase (SOD2) and microsomal epoxidehydrolase (EPHX1) and their interactions may contribute to development of diisocyanateasthma [30].

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17, FAM71A, and TACR1 genes) with gene regulatory effects [39]. Such an approach could helpelucidate novel pathogenic mechanisms in the future.

IMMUNOLOGIC MECHANISMS

Agents that induce occupational asthma by immunologic mechanisms are characterized by alatency period between exposure and the development of symptoms. Immunologic occupationalasthma affects only a small proportion of exposed subjects, but in these patients exposure to aminute quantity of the offending agent can lead to a severe asthmatic reaction. While somecompounds, mostly metal salts and those containing protein, induce asthma through theproduction of specific IgE antibodies, the immunologic mechanism(s) that pertain to other agents(most chemicals) have not been identified.

Specific IgE-mediated responses to work-place sensitizers are considered to be involved in themajority of cases of occupational asthma, particularly when caused by high-molecular-weightagents [40]. Low molecular weight agents are, however, more likely to cause non-IgE-mediateddisease. In this regard, bronchial biopsies obtained after inhalation challenge with diisocyanatesdid not reveal an expression of messenger RNA for IgE ε (epsilon) chains or interleukin (IL)-4,suggesting that IgE is not usually involved in this type of OA [41].

T lymphocytes appear to play a major role in the pathophysiology of occupational asthma. Whencausative agents are inhaled, antigen-presenting cells collect and process the antigen, and thenmigrate to regional lymph nodes where the antigen is presented to T helper cells, which areresponsible for the initiation of the immune response. In a series of nonsmoking patients withoccupational asthma, a triple-color immunohistofluorescence labelling technique was used oncryosections of bronchial samples to demonstrate a significantly increased bronchial density ofregulatory T cells, effector T cells, proliferative T cells, and activated CD8+ T cells [42]. (See "Theadaptive cellular immune response: T cells and cytokines".)

The most common route of exposure in occupational asthma is inhalational. However, skinexposure has also been incriminated in the onset of sensitization to diisocyanates [43].

IgE-mediated — High molecular weight (HMW) agents (eg, latex, animal proteins, and flour) actas complete antigens and induce the production of specific IgE antibodies. Certain low molecularweight (LMW) occupational agents, including platinum salts, trimellitic anhydride, and other acidanhydrides, can also induce specific IgE antibodies, probably by acting as haptens and bindingwith proteins to form functional antigens (table 1). Several human leukocyte antigen (HLA)associations have been described, but the results have not been convincingly reproduced [23].

Regardless of the characteristics of the inciting antigen, reactions between specific IgE antibodiesand antigens lead to a cascade of events that results in an influx of inflammatory cells into theairway and the release of inflammatory mediators.





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Inhalational challenge with culprit antigens in sensitized individuals generally results in an isolatedearly reaction, although inhalation challenge may sometimes result in a late reaction or a biphasicreaction (figure 1) [44,45]:

Specific inhalation challenges can also cause atypical temporal patterns of airflow limitation [45].Although occupational asthma due to high-molecular-weight agents is frequently if not alwaysassociated with increased levels of serum specific IgE antibodies, this test alone should not beconsidered as confirming the disease. Confirming the effect of exposure to the agent on airwayfunction should always be recommended for diagnostic purposes [46].

Detection of IgE — The ability to detect specific IgE antibodies in patients with occupationalasthma to low molecular weight agents may be technically difficult [47,48]. Specific IgE antibodiesto toluene diisocyanate (TDI) have been reported in 0 to 50 percent of workers with TDI inducedasthma [49]. This variation has been attributed to several factors:

Workers with the AA genotype of the 46 A>G polymorphism of the beta 2-adrenergic receptorgene (ADRB2) who were exposed to TDI had significantly higher serum levels of TDI-albumin-specific IgE than those with GG genotype, suggesting that ADRB2 polymorphism may affect IgE-specific sensitization to TDI [53].

An isolated early asthmatic reaction occurs within a few minutes after an inhalation challenge,reaches it maximum within one-half hour, and subsides within 1 to 1.5 hours.

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A late reaction occurs four to six hours after a challenge, reaches maximal intensity withineight to ten hours, and subsides after 24 to 48 hours.

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A biphasic reaction is a combination of an early and a late reaction.●

The short half-life of the specific IgE antibodies to TDI of about two days [50].●

The appearance of new antigenic determinants after the binding of specific IgE to TDI-humanalbumin conjugate [51].

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Use of different carrier proteins. As an example, human serum albumin is sometimes used forconjugation with TDI, while keratin, which is found in the lungs and skin, has been found toconjugate with hexamethylene diisocyanate in studies using human epithelial cell lines andendobronchial biopsy samples [52]. Whether the TDI-keratin conjugate would give a higherproportion of specific IgE antibodies in patients with TDI induced asthma remains to be seen.

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The different methods of conjugation of the haptenic low molecular weight antigen with acarrier and the methods of assay [52].

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Pathogenic mechanisms other than IgE mediation are causing occupational asthma. (See'Non-IgE mediated reactions' below.)

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Non-IgE mediated reactions — Many LMW agents can induce occupational asthma after a latentperiod (eg, acid anhydrides, certain metals, diisocyanates), suggestive of immunologic mediation.Some LMW agents produce pathogenic IgE via conjugation with a hapten (see 'IgE-mediated'above). However, many LMW agents are NOT associated with production of specific IgE. Theexact nature of the non-IgE immunologic mechanisms remains unclear.

The ability of a LMW agent to induce asthma may depend upon its chemical structure [54,55]. Asexamples, certain transitional metals form coordination complexes that may chelate humanproteins (eg, chromium, cobalt, nickel, platinum), and some organic substances have two or morereactive chemical groups (eg, amines, cyanates) that are highly reactive with humanmacromolecules. The agents with two or more reactive chemical groups, also known asbifunctional bases, (eg, diisocyanate) have a much higher propensity to induce asthma than thosewith a single reactive group, also known as a monofunctional base (eg, monoisocyanates) [55].

Evidence against IgE mediation — Evidence against IgE mediation in occupational asthmainduced by LMW agents includes the following observations: affected workers are typicallynonatopic, the pattern of airflow limitation following inhalational challenge is different from that ofIgE-mediated occupational asthma, and the IgE molecules identified lack the ability to causepassive sensitization.

Specific inhalation challenge tests with LMW agents generally induce an isolated late asthmaticreaction or a biphasic reaction, rather than the predominantly early reaction of IgE-mediatedoccupational asthma [45]. Atypical reactions are often observed with LMW agents (figure 2): aprogressive type with onset during or minutes after exposure, progressing to a maximum reactionfive to six hours later, a continuous asthmatic reaction with no remission between the early and thelate phases (square-waved), and a prolonged immediate reaction. (See "Bronchoprovocationtesting", section on 'Antigen challenge'.)

Patients with occupational asthma due to non-IgE mediated reactions may produce IgE antibodiesthat are reflective of prior exposure, rather than being integral to disease pathogenesis. As anexample, Western red cedar-related asthma, caused by sensitization to the LMW agent plicaticacid, results in production of IgE antibodies to plicatic acid in approximately 20 percent of affectedsubjects [56]. However, these antibodies do not passively sensitize human lung fragments [56,57].Based on the high proportion of patients without evidence of specific IgE production and the lackof passive sensitization, it is likely that non-IgE mechanisms are responsible for the majority ofplicatic acid-induced occupational asthma.

In contrast, among workers with suspected diisocyanate-induced asthma, having a higher level ofspecific IgE to diisocyanates is highly specific for identifying those affected with occupationalasthma as confirmed by specific inhalation challenges [50].





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Evidence for cell mediated responses — Most studies have found that cellular mediatedimmunological mechanisms contribute to the pathogenesis of non-IgE mediated immunologic (lowmolecular weight antigen) occupational asthma. Bronchial biopsies from subjects withdiisocyanate and red cedar-related asthma show large numbers of activated T lymphocytesadjacent to bronchi, suggesting that these cells play a direct role in mediating airway inflammation[8,9].

Diisocyanate-induced asthma, a non-IgE mediated disease in most instances, appears to beassociated with increased recruitment and activation of pulmonary lymphocytes:

Other evidence that T lymphocytes play a role in occupational asthma induced by LMWcompounds comes from studies of peripheral blood cells obtained from patients with occupationalasthma due to various LMW agents.

Monocyte chemoattractant protein-1, a T cell chemoattractant, is elaborated in increasedamounts by peripheral blood mononuclear cells from patients with occupational asthma dueto diisocyanates [58]. Among workers exposed to diisocyanate, production of monocytechemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells in response tostimulation with diisocyanate-human serum albumin (DIISO-HSA) was more sensitive andspecific for diisocyanate-induced asthma than serum levels of specific IgE [58].

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When bronchial biopsy specimens were obtained by fiberoptic bronchoscopy 24 hours afterdiisocyanate inhalational challenge, bronchial recruitment of IL-5, CD25 (soluble IL-2receptor), and CD4 positive cells was noted in patients with diisocyanate-induced asthma[41].

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In contrast to most studies that suggest mediation by CD4 T cells, one study of bronchialbiopsies from patients with diisocyanate-induced asthma found that the majority of T cellsexhibited the CD8 phenotype and produced IFN-gamma and IL-5, with very few clonesproducing IL-4 [59]. However, there was evidence of an eosinophilic involvement.

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In another study, bronchial biopsies of workers with occupational asthma to methylenediphenyl diisocyanate (MDI) demonstrated an increase in eosinophil cationic protein andincreased basophil release of histamine [60]. Sputum eosinophil counts correlated with IL-8and MMP-9 levels.

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In patients with asthma associated with Western red cedar, nickel, or cobalt, proliferation ofperipheral blood lymphocytes occurs following incubation with the appropriate antigen,suggesting the presence of a cell-mediated hypersensitivity reaction [61,62].

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In diisocyanate-induced asthma, CD8-positive T lymphocytes and eosinophils are increasedin the peripheral blood of subjects during late asthmatic reactions induced by challenge withthe agent [63].

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Specific IgG antibodies — Exposure to occupational allergens can induce specific IgGresponses, and specific IgG antibodies may play a role in low molecular weight agent-inducedoccupational asthma, although their exact role is unknown. As an example, specific IgG antibodieshave been identified in patients with occupational asthma due to diisocyanates [58]. However, theymay represent an immunological response to current or past exposure and may not be directlyrelated to the pathogenic mechanisms in diisocyanate-induced asthma [65].

Animal models — Animal models have been developed to examine the physiopathology ofimmunologic occupational asthma [66]. Unique effector mechanisms may exist for differentantigens or types of antigens (haptens versus protein antigens) [67]. The species, strain, age,dose of allergen, and routes of sensitization and challenge may influence the model. Effectormechanisms may also differ depending on the asthmatic reaction being considered (ie, airwayobstruction or eosinophil infiltration).

Data from animal models support a role for Th2 lymphocytes and their cytokines in some forms ofoccupational asthma [68,69]. As an example, T regulator lymphocytes (Tregs) isolated from TDI-sensitized mice, were significantly more suppressive than those from nonsensitized controls,supporting a role for Tregs in TDI sensitization [70]. When Tregs were depleted beforesensitization, the sensitization response was enhanced.

NONIMMUNOLOGIC MECHANISMS

Agents that induce asthma by nonimmunologic mechanisms are characterized by the absence ofa latency period. Three mechanisms may explain the development of symptoms in these patients:

Platinum salt sensitization in patients with asthma due to platinum salts is associated with anexpansion of T-lymphocytes bearing specific T cell receptors (TCRs: Vb21.3, Vb11 and Va2a)[64]. Furthermore, stimulation of peripheral blood mononuclear cells with sodiumhexachloroplatinate leads to increases in expression of certain specific TCRs.

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Subjects without any prior respiratory difficulties develop symptoms of asthma within a fewhours of acute, high level irritant exposure, and may have evidence of nonspecific airwayhyperresponsiveness for more than three months. Acute airway injury from accidentalexposure to high dose of irritants such as chlorine, ammonia, smoke, or acetic acid may leadto reactive airways dysfunction syndrome (RADS). Furthermore, the development of irritant-induced asthma due to diisocyanates may promote sensitization to these compounds [71,72].(See "Reactive airways dysfunction syndrome and irritant-induced asthma".)

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The underlying mechanism of RADS is not known, but it has been postulated that extensivedenudation of the epithelium results in airway inflammation because of a loss of epithelialderived relaxing factors, exposure of the nerve endings leading to neurogenic inflammation,and nonspecific activation of mast cells with release of inflammatory mediators and cytokines












The role of long-term irritant exposure at work in the development of asthma remains to beelucidated, but some observations suggest an effect of such exposure in work-related asthma.The proposed underlying mechanisms include oxidative stress, neurogenic inflammation, and dualirritant and adjuvant effects [77].

In regard to occupational asthma induced by exposure to laboratory animals, exposure toendotoxins is associated with a higher prevalence of wheezing, but not with asthma, as assessedwith mannitol challenge or self-reported asthma [78].

Some agents can induce asthma through both immunological and nonimmunologicalmechanisms. Diisocyanate is the best example. Toluene diisocyanate-induced asthma (throughsensitization) has been reported in individuals who have previously been heavily exposed during achemical spill [72,79]. While the immune system plays an important role in occupational asthma,inflammation may be a secondary response rather than the underlying cause of pathogenesis.Multiple mechanisms involving airway epithelial injury and repair, structural remodeling, oxidativestress, and neurogenic factors may also contribute to the pathogenesis [65].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regionsaround the world are provided separately. (See "Society guideline links: Occupational asthma".)

SUMMARY

[73]. Epithelial damage may also result in the marked airway remodeling observed in thesepatients, particularly the intense subepithelial fibrosis which is probably responsible for thereduced reversibility of airflow obstruction observed in this condition [19].

Some low molecular weight agents have pharmacologic properties that may causebronchoconstriction. As examples, diisocyanates may block beta-2 adrenergic receptors, andplicatic acid in high concentrations may activate complement [71,74].

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Diisocyanates and other occupational agents may stimulate sensory nerves to releasesubstance P and other neuropeptides and may inhibit the neutral endopeptidases thatnormally inactivate these substances [75]. Neuropeptides affect a variety of cells in theairways, resulting in cough, smooth muscle contraction, and mucus production [76].

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Occupational asthma is a disease characterized by variable airflow limitation, airwayhyperresponsiveness, and inflammation resulting from exposures to agents present in theworkplace. (See 'Introduction' above.)

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ACKNOWLEDGMENT

The editorial staff at UpToDate would like to acknowledge Moira Chan Yeung, MD and Jean-LucMalo, MD, who contributed to an earlier version of this topic review.

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REFERENCES

1. Bernstein, IL, Chan-Yeung, et al. Asthma in the workplace, 3rd, Taylor and Francis, New York 2006.

Two main types of occupational asthma have been recognized: immunologically mediated(with or without evidence of participation of IgE), and nonimmunologic, irritant mediated. (See'Types' above.)

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In the case of immunologically mediated occupational asthma, the pathology in the airways issimilar to that seen in patients with nonoccupational asthma. The pathologic changes maypersist for weeks to years after cessation of exposure. For nonimmunological occupationalasthma, there is a predominance of denudation of epithelium in the acute phase with a long-term increase in basement membrane thickness. (See 'Pathology' above.)

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High molecular weight agents (eg, animal proteins and flour) act as complete antigens andinduce the production of specific IgE antibodies, which are felt to play a key role in diseasepathogenesis, similar to that of common inhalant allergens (eg, dust mite) in allergic asthma.(See 'Immunologic mechanisms' above.)

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Certain low molecular weight occupational agents, including platinum salts, trimelliticanhydride, and other acid anhydrides, also induce specific IgE antibodies, probably by actingas haptens, binding with proteins to form functional antigens. Most low molecular weightagents may also cause occupational asthma through non-IgE mediated mechanisms. (See'Immunologic mechanisms' above.)

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Occupational asthma due to exposure to irritants (eg, chlorine, ammonia, smoke) may resultfrom nonimmunologic mechanisms such as denudation of the airway epithelium, direct beta-2adrenergic receptor inhibition, or elaboration of substance P by injured sensory nerves.Nonimmunologic occupational asthma is characterized by the absence of a latency periodand by exposure to a high level of the irritant agent. (See 'Nonimmunologic mechanisms'above and "Reactive airways dysfunction syndrome and irritant-induced asthma".)

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2. Malo JL, Chan-Yeung M, Bernstein DI. Asthma in the Workplace, 4th ed, CRC Press, BocaRaton, FL 2013.

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GRAPHICS

Occupational asthma

Bronchial biopsy of a patient with occupational asthma after removal fromexposure, showing partial desquamation of the epithelium, thickened basementmembrane, and some cellular infiltration.

Courtesy of Lemiere, C, Malo, JL, Boulet, M.

Graphic 60266 Version 1.0

Normal lung

Low power photomicrograph of normal lung tissue shows open alveoli withthin, capillary- containing interstitial spaces. An artery (A) is identifiable byits thick, muscular wall; the accompanying bronchus (B) contains mucoidmaterial and is lined by columnar respiratory epithelial cells.

Courtesy of Steven E Weinberger, MD.




Irritant-induced asthma

Bronchial biopsy taken three days after acute accidental inhalation of highconcentration of chlorine showing almost complete desquamation of bronchialmucosa (upper part) with fibrinohemorrhagic deposits (dark pink) andinflammatory influx of neutrophils (dark purple spots in the middle and upperportions). Normal smooth muscle is shown in the lower portion. Weigert-Massonstain.



Normal lung






Irritant-induced asthma

Bronchial biopsy taken two years after an acute accidental inhalation of chlorineshowing severe desquamation of epithelial cells. Smooth muscle cells aresurrounded by reticulocollagenic fibrous tissue seen in the center part of thefigure. Weigert-Masson trichrome stain.



Normal lung






Major causes of occupational asthma and rhinitis

Occupation at risk

Low molecular weight chemicals

Isocyanates (eg, toluene diisocyanate, diphenylmethanediisocyanate, hexamethylene diisocyanate, naphthalenediisocyanate)

Polyurethane workers, roofers, insulators,painters

Anhydrides (eg, trimellitic anhydride, phthalic anhydride) Manufacturers of paint, plastics, epoxy resins

Metals (eg, chromic acid, potassium dichromate, nickel sulfate,vanadium, platinum salts)

Platers, welders, metal and chemical workers

Drugs (eg, beta-lactam agents, opiates, other) Pharmaceutical workers, farm workers, healthprofessionals

Wood dust (eg, Western red cedar, maple, oak, exotic woods) Carpenters, woodworkers

Dyes and bleaches (eg, anthraquinone, carmine, henna extract,persulfate, reactive dyes)

Fabric and fur dyers, hairdressers

Amines (eg, chloramine, quaternary amines) Chemists, cleaners, plastic manufacturers

Glues and resins (eg, acrylates, epoxy) Plastic manufacturers

Miscellaneous (eg, formaldehyde, glutaraldehyde, ethyleneoxide, pyrethrin, polyvinyl chloride vapor)

Laboratory workers, textile workers, paintsprayers, health professionals

High molecular weight organic materials

Animal proteins (eg, domestic and laboratory animals, fish andseafood)

Farmers, veterinarians, poultry processors,fish and seafood processors

Flours and cereals Bakers, food processors, dock workers

Enzymes (eg, pancreatic extracts, papain, trypsin, Bacillussubtilis, bromelain, pectinase, amylase, lipase)

Bakers, food processors, pharmaceuticalworkers, plastic workers, detergentmanufacturers

Plant proteins (eg, wheat, grain dust, coffee beans, tobaccodust, cotton, tea, latex, psyllium, various flours)

Bakers, farmers, food and plant processors,health professionals, textile workers




Inhalation challenge testing

Types of specific asthmatic reactions after specific inhalation challenge testing:immediate, early late, isolated late, and dual (immediate and late). Mean andstandard deviation of percent change in FEV1 (ordinate) are shown as a functionof time (abscissa) from the challenge test.

From Perrin et al, J Allergy Clin Immunol 1991;87:630.




Inhalation challenge testing

Atypical asthmatic reactions after specific inhalation challenge testing.

From Perrin et al, J Allergy Clin Immunol 1991; 87:630.




Contributor Disclosures

David I Bernstein, MD Grant/Research/Clinical Trial Support: Glaxo; Astra Zeneca; Pearl; Novartis;Genentech; Glenmark; Gossamer; Leo; Merck; Nerre; Aimmune [Clinical trials of asthma therapies, newCOPD drugs, new forms of immunotherapy, biologics for treatment of asthma or hives]. Consultant/AdvisoryBoards: Glaxo [Anti-IL5 for asthma]; ALK America [Sublingual immunotherapy]; Gerson-Lehman; GuidepointGlobal. Louis-Philippe Boulet, MD Grant/Research/Clinical Trial Support: AstraZeneca [Asthma(Benralizumab)]; GlaxoSmithKline [Asthma (FF/UMEC/VI, GSK3772847)]; Novartis [Asthma (CSJ117)];Sanofi [Asthma (Dupilumab)]; Boston Scientific [Asthma (Bronchial Thermoplasty)]; Hoffman La Roche[Asthma]; Takeda [Asthma]; Boehringer Ingelheim [Asthma (Bi-671800 ED)]. Speaker’s Bureau: AstraZeneca[Asthma (Benralizumab)]; GlaxoSmithKline [Asthma (FF/UMEC/VI)]. Consultant/Advisory Boards:AstraZeneca [Asthma (Benralizumab)]; Novartis [Asthma (CSJ117)]. André Cartier, MD Speaker’s Bureau:Merck Frosst Canada; Boehringer-Ingelheim Canada; IC-EBM Canada [Asthma]; GSK Canada [Asthma(Mepolizumab, Fluticasone/vilanterol, Umeclidinium, Umeclidinium/vilanterol)]. Consultant/Advisory Boards:AZ Canada; Teva Canada; GSK Canada [Asthma (Mepolizumab, Fluticasone/vilanterol, Umeclidinium,Umeclidinium/vilanterol)]; Sanofi Genzyme Canada [Asthma (Benralizumab, reslizumab, mepolizumab,dupilumab)]. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca[Asthma, COPD (Symbicort)]; Novartis [COPD (Indacaterol)]; Boehringer [COPD (Tiotropium, olodaterol)];Chiesi [Asthma, COPD (Foster)]. Speaker's Bureau: AstraZeneca [Asthma (Symbicort)]; Novartis [COPD(Indacaterol, glucopyrolate, Ultibro)]; Boehringer [COPD (Tiotropium, olodaterol)]; Chiesi [Asthma (Foster)].Consultant/Advisory Board: AstraZeneca [Asthma, COPD]; Novartis [COPD]; Boehringer [COPD]; Teva[COPD]; Pieris [Asthma]. Helen Hollingsworth, MD Nothing to disclose

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Occupational asthma: Pathogenesis - UFPR...eosinophilic bronchitis) [1]. Occupational asthma is a disease characterized by variable airflow limitation, airway hyperresponsiveness,