Occupational asthma induced by exposure to quinoa

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Serum Periostin Levels: A Potential Serologic Marker for Toluene Diisocyanate-Induced Occupational Asthma.

PURPOSE: Toluene diisocyanate (TDI) is a leading cause of occupational asthma (OA). Periostin is a matricellular protein implicated in type 2 immunity-driven asthma. Its pathogenic role in TDI-OA has not been completely elucidated. The present study was performed to investigate the role of periostin in TDI-OA. MATERIALS AND METHODS: Serum periostin levels were measured in subjects with TDI-OA, asymptomatic TDI-exposure controls (AECs), non-occupational asthmatics (NAs), and unexposed normal controls (NCs). To understand the mechanism by which TDI induces periostin production, primary small airway epithelial cells (SAECs) were cultured under stimulation of TDI and neutrophils from asthmatic patients. RESULTS: Fifty-three subjects with TDI-OA, 71 AECs, 67 NAs, and 83 NCs were enrolled. Serum periostin levels were significantly higher in TDI-OA subjects than in AECs (p=0.001), NAs (p<0.001), and NCs (p<0.001). In TDI-exposed subjects (TDI-OA and AEC), the PC20 methacholine levels were significantly lower in subjects with a higher periostin level than in those with a lower periostin level. TDI exposure did not increase periostin production directly by SAECs; however, periostin production increased significantly after co-culture with TDI and neutrophils, which was suppressed by an antioxidant. In addition, increased release of TGF-ß1 was noted from SAECs when exposed to TDI and neutrophils, which was also suppressed by an antioxidant. CONCLUSION: These results suggest that an increased periostin level may contribute to the progression of airway inflammation to remodeling in TDI-exposed workers. A high serum periostin level is a potential serologic marker of the phenotype of TDI-OA.

Role of clusterin/progranulin in toluene diisocyanate-induced occupational asthma.

Toluene diisocyanate (TDI) exposure induces oxidative stress and epithelial cell-derived inflammation, which affect the pathogenesis of TDI-induced occupational asthma (TDI-OA). Recent studies suggested a role for clusterin (CLU) and progranulin (PGRN) in oxidative stress-mediated airway inflammation. To evaluate CLU and PGRN involvement in airway inflammation in TDI-OA, we measured their serum levels in patients with TDI-OA, asymptomatic exposed controls (AECs), and unexposed healthy normal controls (NCs). Serum CLU and PGRN levels were significantly lower in the TDI-OA group than in the AEC and NC groups (P < 0.05). The sensitivity and specificity for predicting the TDI-OA phenotype were 72.4% and 53.4% when either CLU or PGRN levels were below the cutoff values (≤125 µg/mL and ≤68.4 ng/mL, respectively). If both parameters were below the cutoff levels, the sensitivity and specificity were 58.6% and 89.8%, respectively. To investigate CLU and PGRN function, we evaluated their production by human airway epithelial cells (HAECs) in response to TDI exposure and co-culturing with neutrophils. TDI-human serum albumin stimulation induced significant CLU/PGRN release from HAECs in a dose-dependent manner, which positively correlated with IL-8 and folliculin levels. Co-culturing with neutrophils significantly decreased CLU/PGRN production by HAECs. Intracellular ROS production in epithelial cells co-cultured with neutrophils tended to increase initially, but the ROS production decreased gradually at a higher ratio of neutrophils. Our results suggest that CLU and PGRN may be involved in TDI-OA pathogenesis by protecting against TDI-induced oxidative stress-mediated inflammation. The combined CLU/PGRN serum level may be used as a potential serological marker for identifying patients with TDI-OA among TDI-exposed workers.

Assessment of eosinophilic airway inflammation as a contribution to the diagnosis of occupational asthma.

BACKGROUND: Ascertaining the presence of asthma through the assessment of nonspecific bronchial hyperresponsiveness (NSBH) is a key step in the diagnosis of occupational asthma (OA). We aimed at investigating whether indices of airway inflammation including fractional exhaled nitric oxide (FeNO) and sputum eosinophils would be useful adjuncts to the measurement of NSBH in diagnosing OA defined as a positive specific inhalation challenge (SIC). METHODS: The study included 240 consecutive subjects with a suspicion of OA who completed a SIC, of whom 133 showed a positive response. The sensitivity, specificity, and predictive values of NSBH, and FeNO, as well as sputum eosinophil counts assessed at baseline of the SIC were determined. RESULTS: A concentration of histamine inducing a 20% decline in FEV1 (PC20 ) ≤16 mg/mL showed a sensitivity of 87% and a specificity of 36%. A FeNO level ≥25 ppb and a sputum eosinophil count ≥2% provided lower sensitivity rates (47% and 39%, respectively) than the PC20 value. Eight of the 17 subjects without baseline NSBH despite a positive SIC showed a sputum eosinophil count ≥2%, a FeNO level ≥25 ppb, or both outcomes. Combining either a PC20 value ≤16 mg/mL or a FeNO ≥25 ppb increased the sensitivity to 91%. Using either a PC20 ≤16 mg/mL or a sputum eosinophil count ≥1% increased the sensitivity to 94%. CONCLUSION: Adding the assessment of FeNO level and sputum eosinophils to NSBH improves the identification of subjects who may have OA and require further objective testing before excluding the possibility of OA.

Nasal protein profiles in work-related asthma caused by different exposures.

BACKGROUND: The mechanisms of work-related asthma (WRA) are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of WRA caused by different kind of exposures. METHODS: We collected nasal brush samples from 82 nonsmoking participants, including healthy controls and WRA patients exposed to (i) protein allergens, (ii) isocyanates and (iii) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two-dimensional difference gel electrophoresis, and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot. RESULTS: We detected an average of 2500 spots per protein gel. Altogether, 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls, exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen- and isocyanate-related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in galectin 10 and protein S100-A9 between the groups. CONCLUSIONS: Work-related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.

PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.

BACKGROUND: PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. OBJECTIVE: We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. METHODS: We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. RESULTS: There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (ß=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. CONCLUSIONS AND CLINICAL RELEVANCE: The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.

Comparison of biomarkers in serum and induced sputum of patients with occupational asthma and chronic obstructive pulmonary disease.

OBJECTIVES: Occupational asthma and chronic obstructive pulmonary disease (COPD) are associated with the airway inflammatory process. The aim of this study was to compare the sputum and serum markers of inflammation in patients with occupational asthma and COPD. METHODS: The study group included 20 patients with stable COPD, 24 patients with asthma, and 22 healthy subjects. Interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-9 levels in serum and induced sputum as well as fibrinogen and CRP in serum were determined in all the subjects. RESULTS: Higher concentrations of IL-1ß, IL-6, TNF-α, and MMP-9 in induced sputum and an increased concentration of acute-phase proteins in serum were observed in COPD patients compared with healthy subjects. Higher concentrations of IL-1ß and MMP-9 in induced sputum and a higher concentration of C-reactive protein (CRP) were detected in COPD patients than in asthmatic subjects. Never smokers with COPD had significantly higher levels of IL-1ß and MMP-9 in induced sputum than never smoker controls. There was no significant difference between the serum and sputum levels of cytokines and MMP-9 of never smokers and smokers with COPD. CONCLUSIONS: Higher concentrations of IL-1ß and MMP-9 in induced sputum and a higher concentration of CRP in serum allow distinguishing between biomarker profiles of COPD patients and asthmatic patients. Occupational exposure induces a systemic proinflammatory state with increased levels of acute-phase proteins in stable COPD patients. MMP-9 and IL-1ß concentrations are increased in induced sputum of never smokers with COPD, which is associated with occupational exposure.

Genetic variants in TNFα, TGFB1, PTGS1 and PTGS2 genes are associated with diisocyanate-induced asthma.

Diisocyanates are the most common cause of occupational asthma, but risk factors are not well defined. A case-control study was conducted to investigate whether genetic variants in inflammatory response genes (TNFα, IL1α, IL1ß, IL1RN, IL10, TGFB1, ADAM33, ALOX-5, PTGS1, PTGS2 and NAG-1/GDF15) are associated with increased susceptibility to diisocyanate asthma (DA). These genes were selected based on their role in asthmatic inflammatory processes and previously reported associations with asthma phenotypes. The main study population consisted of 237 Caucasian French Canadians from among a larger sample of 280 diisocyanate-exposed workers in two groups: workers with specific inhalation challenge (SIC) confirmed DA (DA(+), n = 95) and asymptomatic exposed workers (AW, n = 142). Genotyping was performed on genomic DNA, using a 5' nuclease PCR assay. After adjusting for potentially confounding variables of age, smoking status and duration of exposure, the PTGS1 rs5788 and TGFB1 rs1800469 single nucleotide polymorphisms (SNP) showed a protective effect under a dominant model (OR = 0.38; 95% CI = 0.17, 0.89 and OR = 0.38; 95% CI = 0.18, 0.74, respectively) while the TNFα rs1800629 SNP was associated with an increased risk of DA (OR = 2.08; 95% CI = 1.03, 4.17). Additionally, the PTGS2 rs20417 variant showed an association with increased risk of DA in a recessive genetic model (OR = 6.40; 95% CI = 1.06, 38.75). These results suggest that genetic variations in TNFα, TGFB1, PTGS1 and PTGS2 genes contribute to DA susceptibility.

Work-Related Asthma.

OBJECTIVE: Summarize developed evidence-based diagnostic and treatment guidelines for work-related asthma (WRA). METHODS: Comprehensive literature reviews conducted with article critiquing and grading. Guidelines developed by a multidisciplinary expert panel and peer-reviewed. RESULTS: Evidence supports spirometric testing as an essential early test. Serial peak expiratory flow rates measurement is moderately recommended for employees diagnosed with asthma to establish work-relatedness. Bronchial provocation testing is moderately recommended. IgE and skin prick testing for specific high-molecular weight (HMW) antigens are highly recommended. IgG testing for HMW antigens, IgE testing for low-molecular weight antigens, and nitric oxide testing for diagnosis are not recommended. Removal from exposure is associated with the highest probability of improvement, but may not lead to complete recovery. CONCLUSION: Quality evidence supports these clinical practice recommendations. The guidelines may be useful to providers who diagnose and/or treat WRA.

Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation.

BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2.

Prediction of chemical respiratory sensitizers using GARD, a novel in vitro assay based on a genomic biomarker signature.

BACKGROUND: Repeated exposure to certain low molecular weight (LMW) chemical compounds may result in development of allergic reactions in the skin or in the respiratory tract. In most cases, a certain LMW compound selectively sensitize the skin, giving rise to allergic contact dermatitis (ACD), or the respiratory tract, giving rise to occupational asthma (OA). To limit occurrence of allergic diseases, efforts are currently being made to develop predictive assays that accurately identify chemicals capable of inducing such reactions. However, while a few promising methods for prediction of skin sensitization have been described, to date no validated method, in vitro or in vivo, exists that is able to accurately classify chemicals as respiratory sensitizers. RESULTS: Recently, we presented the in vitro based Genomic Allergen Rapid Detection (GARD) assay as a novel testing strategy for classification of skin sensitizing chemicals based on measurement of a genomic biomarker signature. We have expanded the applicability domain of the GARD assay to classify also respiratory sensitizers by identifying a separate biomarker signature containing 389 differentially regulated genes for respiratory sensitizers in comparison to non-respiratory sensitizers. By using an independent data set in combination with supervised machine learning, we validated the assay, showing that the identified genomic biomarker is able to accurately classify respiratory sensitizers. CONCLUSIONS: We have identified a genomic biomarker signature for classification of respiratory sensitizers. Combining this newly identified biomarker signature with our previously identified biomarker signature for classification of skin sensitizers, we have developed a novel in vitro testing strategy with a potent ability to predict both skin and respiratory sensitization in the same sample.

The cardiac protein αT-catenin contributes to chemical-induced asthma.

Ten to 25% of adult asthma is occupational induced, a subtype caused by exposure to workplace chemicals. A recent genomewide association study identified single-nucleotide polymorphisms in the cardiac protein αT-catenin (αT-cat) that correlated with the incidence and severity of toluene diisocyanate (TDI) occupational asthma. αT-cat is a critical mediator of cell-cell adhesion and is predominantly expressed in cardiomyocytes, but its connection to asthma remains unknown. Therefore, we sought to determine the primary αT-cat-expressing cell type in the lung and its contribution to lung physiology in a murine model of TDI asthma. We show that αT-cat is expressed in lung within the cardiac sheath of pulmonary veins. Mechanically ventilated αT-cat knockout (KO) mice exhibit a significantly increased pressure-volume curve area compared with wild-type (WT) mice, suggesting that αT-cat loss affects lung hysteresis. Using a murine model of TDI asthma, we find that αT-cat KO mice show increased airway hyperresponsiveness to methacholine compared with WT mice. Bronchoalveolar lavage reveals only a mild macrophage-dominant inflammation that is not significantly different between WT and KO mice. These data suggest that αT-cat may contribute to asthma through a mechanism independent of inflammation and related to heart and pulmonary vein dysfunction.

Occupational asthma in seafood manufacturing and food allergy to seafood

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Occupational asthma and eosinophilic esophagitis in a patient with egg-bird syndrome

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Occupational asthma and dermatitis induced by eugenol in a cleaner

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Exhaled nitric oxide and screening for occupational asthma in two at-risk sectors: bakery and hairdressing.

BACKGROUND: Fractional exhaled nitric oxide (FENO) levels are increasingly being used in the diagnosis and management of asthma. However, this indicator has rarely been used to detect occupational asthma. OBJECTIVE: To examine non-invasive methods to estimate airway inflammation. METHODS: A nested case-control study was conducted among a retrospective cohort of young workers in the bakery, pastry-making and hairdressing industries. Subjects underwent a clinical examination during a medical visit. Blood samples were collected and FENO levels measured. Cases were subjects diagnosed as suffering from 'confirmed' or 'probable' occupational asthma. RESULTS: Of the 178 workers included in the study, 19 were cases. In univariate analysis, FENO was associated with case/control status, and height and smoking status. In a multiple linear regression model, case/control status (P < 0.001), height (P = 0.006) and smoking status (P < 0.001) remained independent risk factors for variations in FENO levels. Good or fair sensitivity of respectively around 80% and 70% can be achieved using low FENO thresholds (8.5 and 10.5 ppb, respectively). FENO >8.5 ppb and a positive clinical examination increases specificity without loss of sensitivity (to 80.5% and 79.0%, respectively). CONCLUSION: This study suggests that FENO measurements alone cannot be considered a useful screening test for occupational asthma. Further investigations are needed to investigate the use of combined FENO and questionnaire or repeated measures.

Human mesenchymal stem cells resolve airway inflammation, hyperreactivity, and histopathology in a mouse model of occupational asthma.

Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 × 10(6) cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the AP-injured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

Occupational asthma follow-up--which markers are elevated in exhaled breath condensate and plasma?

OBJECTIVES: To search for optimal markers in the exhaled breath condensate (EBC), plasma and urine that would reflect the activity/severity of occupational asthma (OA) after the withdrawal from the exposure to the allergen. MATERIAL AND METHODS: Markers of oxidative stress: 8-iso-prostaglandin F2α (8-isoprostane, 8-ISO), malondialdehyde (MDA), 4-hydroxy-trans-2-nonenale (HNE), cysteinyl leukotrienes (LT) and LTB4 were determined using liquid chromatography and mass spectrometry in 43 subjects with immunological OA (49.3 ± 11.8 years), removed from the exposure to the sensitizing agent 10.5 ± 6.5 years ago; and in 20 healthy subjects (49.0 ± 14.9 years). EBC was harvested both before and after the methacholine challenge test. In parallel, identical markers were collected in plasma and urine. The results were analyzed together with forced expiratory volume in one second (FEV1), blood eosinophils, immunoglobulin E (IgE) and eosinophilic cationic protein (ECP) and statistically evaluated (Spearman rank correlation rS, two- or one-sample t tests and alternatively Kruskal Wallis or pair Wilcoxon tests). RESULTS: Several parameters of lung functions were lower in the patients (FEV1% predicted, MEF25% and MEF50%, Rtot%, p < 0.001). Shorter time interval since the removal from the allergen exposure correlated with higher ECP (rS = 0.375) and lower FEV1%, MEF25% and MEF50% after methacholine challenge (rS = -0.404, -0.425 and -0.532, respectively). In the patients, IgE (p < 0.001) and ECP (p = 0.009) was increased compared to controls. In EBC, 8-ISO and cysteinyl LTs were elevated in the asthmatics initially and after the challenge. Initial 8-ISO in plasma correlated negatively with FEV1 (rS = -0.409) and with methacholine PD20 (rS = -0.474). 8-ISO in plasma after the challenge correlated with IgE (rS = 0.396). CONCLUSIONS: The improvement in OA is very slow and objective impairments persist years after removal from the exposure. Cysteinyl LTs and 8-ISO in EBC and 8-ISO in plasma might enrich the spectrum of useful objective tests for the follow-up of OA.

Fractional exhaled nitric oxide in the interpretation of specific inhalational challenge tests for occupational asthma.

PURPOSE: Fractional exhaled nitric oxide (FENO) measurements are recommended for the assessment of eosinophilic airway inflammation in asthma. Clinically relevant increases in FENO have been reported 24 h after positive specific inhalational challenge (SIC) tests in occupational asthma. We aimed to determine whether positive SICs could be discriminated from control tests, on the basis of change in FENO. METHODS: We reviewed all positive SICs to a variety of agents performed at our institution 2008-2012 and gathered data on age, sex, asthmatic response (immediate/dual/late), smoking status, inhaled corticosteroid usage, and FENO pre- and 24-h postcontrol and positive SIC from each worker. Changes in FENO after positive SICs were compared with control SICs from each worker, by using paired Student's t tests. RESULTS: In 16 workers, negative control challenges were associated with mean changes in FENO of 9 % (95 % CI -1.14 to 19.01) or 1.1 ppb (95 % CI -3.59 to 5.84); 2 of 16 (13 %) workers tested showed increases in FENO that were clinically relevant based on recent guidelines. Subsequent positive SICs were associated with mean changes in FENO of 7 % (95 % CI −15.73 to 29.6) or 2.1 ppb (95 % CI -6.07 to 10.19), which were not significantly different to controls; only 2 of 16 (13 %) workers had FENO changes that were clinically relevant. CONCLUSIONS: FENO changes above the upper confidence limits of ≥20 % or ≥6 ppb may be considered to be outside the range of normality. However, the majority of workers who had clearly positive SICs to common low molecular weight agents also had no statistically or clinically relevant increase in FENO. Therefore, change in FENO does not predict a positive SIC in this group.