Page 699 - Clinical Immunology_ Principles and Practice ( PDFDrive )

672 ParT fivE Allergic Diseases

occupational asthma. Certain human leukocyte antigen (HLA) dependence of allergic sensitization on concomitant TLR4
class II molecules (i.e., HLA-DR, HLA-DQ, and HLA-DP alleles) activation by endotoxin, although in high concentrations Th2-cell
were found to be factors that either placed subjects at risk of inflammation is inhibited. In addition, TRPA1 is activated by
OA or were protective against OA caused by various LMW and stimuli, such as cigarette smoke, chlorine, aldehydes, scents, and
HMW agents. Genes associated with Th2-cell differentiation may endogenous products of oxidative stress, and has been shown
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also play a role in the development of OA. Increased risks of to be essential for allergic “asthma” in a murine model. Con-
developing isocyanate-induced asthma may be associated with firmation of such mechanisms in humans is required.
genetic variations in transforming growth factor (TNF)-α,
TGF-β1, PTGS1(cyclooxygenase-1), and PTGS2 (cyclooxygenase-2) DIAGNOSIS AND MANAGEMENT OF
genes, as well as genes involved in the protection against oxidative OCCUPATIONAL ASTHMA
stress, such as glutathione-S-transferase and N-acetyltransferase.
Genome-wide association studies have identified genetic poly- Diagnosis of Occupational Asthma
morphisms in catenin α-3, α-T catenin (CTNNA3) associated Sensitizer-induced OA should be suspected in every worker
with isocyanate-induced asthma. Although some genetic markers exposed to potential sensitizers with new-onset asthma or with
seem to indicate susceptibility or a protective effect for developing asthma that has become difficult to control. The diagnosis of
OA, we are not yet ready to use these in clinical practice. 12 OA should not be discarded only on the basis of the time between
Pathophysiology. As is frequently the case, the genetic onset of asthma and the beginning of the occupational exposure,
polymorphisms identified do not lead to clear explanations of since approximately 20% of subjects with OA report having
the known pathophysiological processes but often appear to be childhood asthma or asthma onset before entering the workforce.
peripheral to the issue of excessive airway narrowing. Although Although some of them had a remission of their asthma before
genes associated with inflammatory processes and oxidative stress entering the workforce, many of them still experience asthma
are expressed in association with OA driven by HMW or LMW symptoms when entering the workforce. 15,16
agents, the precise mechanistic links await elucidation. Catenins The respiratory symptoms (e.g., dyspnea, chest tightness,
are linked to epithelial cell adhesion processes and differentiation wheezing, cough, and sputum production) are similar to those
and, as such, may affect epithelial responses to injury or inflam- encountered in non–work-related asthma, but in OA, their
mation. Allergens that trigger neutrophilic inflammation will occurrence is usually modulated by the work exposure. The
necessarily cause oxidative stress, as neutrophils are a rich source symptoms can start at the beginning of the work shift, toward
of reactive oxygen species and produce hypochlorite in high its end, or even after working hours, with remission or improve-
concentrations within the airway lumen. Prostaglandin synthesis ment during weekends and holidays. Rhinitis often precedes the
may also result in proinflammatory effects, vasodilation, and occurrence of the respiratory symptoms, especially with HMW
airway smooth muscle constriction. agents. A thorough clinical and occupational history must be
carefully recorded, but the diagnosis of OA cannot be made only
Environmental Factors on the basis of a compatible history, which has a low positive
Level of exposure. The level of exposure to sensitizers has predictive value. A comprehensive investigation should be
1
been well established as a strong predictor of the occurrence of performed to accurately diagnose OA. Fig. 49.2 summarizes the
OA and appears as the most important environmental risk factor different steps leading to a diagnosis of OA.
for developing OA. A dose–response relationship has been The investigation of OA should start as soon as the diagnosis
identified between the level of exposure to HMW agents and is suspected, as a long duration of exposure after the occurrence
the occurrence of IgE-mediated sensitization and OA. Such a of respiratory symptoms is associated with a poor prognosis.
dose–response relationship has also been documented for some Immunological assessment is particularly important for the
LMW agents, such as platinum salts, acid anhydrides, and diagnosis of HMW agents. Skin prick tests or serological assess-
isocyanates. 2 ment of specific IgE have a high sensitivity but a relatively poor
Tobacco smoke and irritants. Cigarette smoking may increase specificity, since they indicate sensitization, which is necessary
the risk of IgE-mediated sensitization to some HMW and but not sufficient for the disease. Unfortunately, immunological
LMW agents, although the association between smoking and tests are limited by the lack of standardized commercially available
the occurrence of OA is weak. The role of other environmental reagents for skin and in vitro tests for allergens implicated
cofactors, such as nonrespiratory routes of exposure and in OA.
concomitant exposure to endotoxin and pollutants at work, In any case, the diagnosis of asthma needs to be confirmed
remains largely uncertain. Exposure to pollutants augments in a worker who has a clinical and occupational history compatible
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the response to allergens. It is also possible that exposure to with OA, by documenting reversible airflow limitation and/or
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irritants in the workplace modifies the immunological response to AHR. Although the lack of AHR does not exclude the diagnosis
sensitizers. of OA in subjects who have been removed from exposure, in
Pathophysiology. Exposures in the workplace may be complex subjects that are still working a negative methacholine challenge
and do not only involve sensitizing substances. It is increasingly has a 95% negative predictive value for excluding the diagnosis
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recognized that nonimmunological stimuli, such as endotoxin, of OA. The work-relatedness of asthma should be assessed
cold, and irritants, activate the airway epithelium and sensory through serial measurements of peak expiratory flow (PEF) and/
nerves through Toll-like receptors (TLRs) and transient receptor or AHR at work and off work and/or specific inhalation challenges
potential (TRP) channels. The release of proinflammatory in the laboratory or at the workplace.
mediators may be predicted to evoke neutrophilic inflammation Specific inhalation challenge tests involve exposing the subject
directly but also favors eosinophilic inflammation by the release to the putative cause of OA in the laboratory and/or at the
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of mediators favoring Th2-cell differentiation or type II innate workplace. Although these tests are considered reference tests
lymphoid cell stimulation. Experimental models have shown a for diagnosing OA, they are only available in a small number of