New causes of immunologic occupational asthma 2014-2020.

PURPOSE OF REVIEW: The purpose of this review was to list all new confirmed cases of immunological occupational asthma (IOA) described between mid-2014 and April 2020. RECENT FINDINGS: Several new agents, both of high and low molecular weight, have been identified in the last 6 years as potential respiratory sensitizers being able to induce immunological occupational asthma. This review confirms that new causes of IOA are still identified regularly, particularly in subjects exposed to high molecular agents, in the food industry (farming, pest control, food processing), pharmaceutical industry (antibiotics, various drugs) and cosmetic environment (dyes, powders). SUMMARY: It stressed the need for clinicians to stay alert and suspect occupational asthma in any adult with new onset asthma or newly uncontrolled asthma.

Novel clinical scores for occupational asthma due to exposure to high-molecular-weight agents.

OBJECTIVE: Specific inhalation challenge (SIC) as the reference diagnostic test for occupational asthma (OA) is not widely available worldwide. We aimed to develop non-SIC-based models for OA. METHODS: Of 427 workers who were exposed to high-molecular-weight agents and referred to OA clinic at Montréal Sacré-Cœur Hospital between 1983 and 2016, we analysed 160 workers who completed non-specific bronchial hyper-responsiveness (NSBHR) tests and still worked 1 month before SIC. OA was defined as positive SIC. Logistic regression models were developed. The accuracy of the models was quantified using calibration and discrimination measures. Their internal validity was evaluated with bootstrapping procedures. The final models were translated into clinical scores and stratified into probability groups. RESULTS: The final model, which included age ≤40 years, rhinoconjunctivitis, inhaled corticosteroid use, agent type, NSBHR, and work-specific sensitisation had a reasonable internal validity. The area under the receiver operating characteristics curve (AUC) was 0.91 (95% CI 0.86 to 0.95), statistically significantly higher than the combination of positive NSBHR and work-specific sensitisation (AUC=0.84). The top 70% of the clinical scores (ie, the high probability group) showed a significantly higher sensitivity (96.4%vs86.9%) and negative predictive value (93.6%vs84.1%) than the combination of positive NSBHR and work-specific sensitisation (p value <0.001). CONCLUSIONS: We developed novel scores for OA induced by high-molecular-weight agents with excellent discrimination. It could be helpful for secondary-care physicians who have access to pulmonary function test and allergy testing in identifying subjects at a high risk of having OA and in deciding on appropriate referral to a tertiary centre.

Association Between Depression, Lung Function, and Inflammatory Markers in Patients with Asthma and Occupational Asthma.

OBJECTIVE: Depression is associated with autonomic and immune dysregulation, yet this remains poorly explored in asthma. We assessed associations between depressive disorder, lung function, and inflammatory markers in patients under investigation for occupational asthma (OA). METHODS: One hundred twelve patients under investigation for OA (60% men) underwent a psychiatric interview to assess depressive disorder, and spirometry, a methacholine test, sputum induction, and specific inhalation challenge (SIC) to assess OA. Blood and sputum inflammatory markers were assessed. RESULTS: There was a statistically significant association between depressive disorder (P = 0.0195) and forced expiratory volume in 1 second (FEV1) responses, with the drop in FEV1 post-SIC smaller in patients with OA and depression, versus OA with no depression (P < 0.001). CONCLUSION: The presence of depressive disorder may influence FEV1 in patients with OA, which may be via autonomic pathways. However, further studies are warranted in order to determine the mechanisms that underlie these effects.

Development of a graphical tool to measure medication adherence in asthma patients: A mixed-methods pilot study.

OBJECTIVES: ( 1 ) To develop Med-Resp, a graphical tool based on prescription refills to measure adherence and use of asthma medications; ( 2 ) To test the feasibility of implementing Med-Resp in a hospital outpatient asthma clinic; ( 3 ) To explore the effectiveness of Med-Resp to improve medication adherence to asthma controller medications. METHODS: A sequential exploratory design was used: ( 1 ) Prototype design in collaboration with respiratory physicians and patients via focus groups; ( 2 ) Med-Resp creation based on algorithms developed and applied to prescription refills data recorded in the drug claims database reMed; ( 3 ) Feasibility assessment of the implementation of Med-Resp in the outpatient asthma clinic; and ( 4 ) Exploration of the effectiveness of Med-Resp through a pre-post design. RESULTS: A total of 29 patients and six respiratory physicians participated in this pilot study. The tool was highly appreciated by the participants, while the majority believed that Med-Resp has the potential to enhance physician-patient communication and aid in treatment decisions. The feasibility of implementing Med-Resp in clinical practice was demonstrated. However, we did not observe an increase in medication adherence in the six months following its implementation. CONCLUSION: In the clinical setting, the use of prescription refills data may constitute a non-invasive and objective measure of medication adherence. This study highlights the importance of providing clinicians with objective and easily interpretable measures of medication adherence and use in routine clinical practice. Med-Resp has the potential to become implemented on a larger scale if integrated in electronic medical records.

Genetic variants with gene regulatory effects are associated with diisocyanate-induced asthma.

BACKGROUND: Isocyanates are major causes of occupational asthma, but susceptibility and mechanisms of diisocyanate-induced asthma (DA) remain uncertain. OBJECTIVE: The aim of this study was to identify DA-associated functional genetic variants through next-generation sequencing (NGS), bioinformatics, and functional assays. METHODS: NGS was performed in 91 workers with DA. Fourteen loci with known DA-associated single nucleotide polymorphisms (SNPs) were sequenced and compared with data from 238 unexposed subjects. Ranking of DA-associated SNPs based on their likelihood to affect gene regulatory mechanisms in the lung yielded 21 prioritized SNPs. Risk and nonrisk oligonucleotides were tested for binding of nuclear extracts from A549, BEAS-2B, and IMR-90 lung cell lines by using electrophoretic mobility shift assays. DNA constructs were cloned into a pGL3 promoter vector for luciferase gene reporter assays. RESULTS: NGS detected 130 risk variants associated with DA (3.1 × 10-6 to 6.21 × 10-4), 129 of which were located in noncoding regions. The 21 SNPs prioritized by using functional genomic data sets were in or proximal to 5 genes: cadherin 17 (CDH17; n = 10), activating transcription factor 3 (ATF3; n = 7), family with sequence similarity, member A (FAM71A; n = 2), tachykinin receptor 1 (TACR1; n = 1), and zinc finger and BTB domain-containing protein 16 (ZBTB16; n = 1). Electrophoretic mobility shift assays detected allele-dependent nuclear protein binding in A549 cells for 8 of 21 variants. In the luciferase assay 4 of the 21 SNPs exhibited allele-dependent changes in gene expression. DNA affinity precipitation and mass spectroscopy of rs147978008 revealed allele-dependent binding of H1 histones, which was confirmed by using Western blotting. CONCLUSIONS: We identified 5 DA-associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824 and rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed nonrisk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation.

An Official American Thoracic Society Workshop Report: Presentations and Discussion of the Sixth Jack Pepys Workshop on Asthma in the Workplace.

The Sixth Jack Pepys Workshop on Asthma in the Workplace focused on six key themes regarding the recognition and assessment of work-related asthma and airway diseases: (1) cleaning agents and disinfectants (including in swimming pools) as irritants and sensitizers: how to evaluate types of bronchial reactions and reduce risks; (2) population-based studies of occupational obstructive diseases: use of databanks, advantages and pitfalls, what strategies to deal with biases and confounding?; (3) damp environments, dilapidated buildings, recycling processes, and molds, an increasing problem: mechanisms, how to assess causality and diagnosis; (4) diagnosis of occupational asthma and rhinitis: how useful are recombinant allergens (component-resolved diagnosis), metabolomics, and other new tests?; (5) how does exposure to gas, dust, and fumes enhance sensitization and asthma?; and (6) how to determine probability of occupational causality in chronic obstructive pulmonary disease: epidemiological and clinical, confirmation, and compensation aspects. A summary of the presentations and discussion is provided in this proceedings document. Increased knowledge has been gained in each topic over the past few years, but there remain aspects of controversy and uncertainty requiring further research.

Diagnostic Accuracy of Inflammatory Markers for Diagnosing Occupational Asthma.

BACKGROUND: The assessment of airway responsiveness and inflammation is key to the investigation of occupational asthma (OA). OBJECTIVE: We sought to assess and compare the diagnostic accuracies of the blood and sputum eosinophil counts and the methacholine challenge for the diagnosis of OA. METHODS: We conducted a retrospective study assessing 618 patients who underwent specific inhalation challenges (SICs) for symptoms suggestive of OA between 2000 and 2015. A sputum induction and a methacholine challenge were performed before and after SICs. Blood samples were collected in all subjects before the SICs and in 100 subjects before and after SICs. The diagnostic accuracies of blood and sputum eosinophil counts and methacholine challenge were calculated for diagnosing OA. RESULTS: The change in blood eosinophil count failed to differentiate workers with positive and negative SICs. The change in sputum eosinophil counts induced by the exposure to the offending agent had the highest diagnostic accuracy (receiver operating characteristic area under the curve: 86% [95% confidence interval: 0.8-0.9, P < .001]) for diagnosing OA compared with changes in concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 second (PC20) and blood eosinophils. Combining a 2-fold or greater decrease in PC20 or a 3% or greater increase in sputum eosinophil count achieved a sensitivity of 84% and a specificity of 74% with a negative predictive value of 91% for the diagnosis of OA. CONCLUSIONS: Blood eosinophil counts do not appear to be an effective aid for diagnosing OA. The performance of both sputum cell count analysis and a methacholine challenge before and after exposure to the offending agent may represent an effective alternative in diagnosing OA when SICs are unavailable.

Review of Diagnostic Challenges in Occupational Asthma.

PURPOSE OF REVIEW: Occupational asthma (OA) is one of the most frequent occupational diseases and its diagnosis is often difficult. This review summarizes its current diagnostic challenges. RECENT FINDINGS: OA is associated with significant health and socio-economic burden. It is underdiagnosed and physicians need to adopt a stepwise approach to confirm the diagnosis. Although early removal from exposure to the offending agent is associated with a better prognosis, physicians should try to confirm the diagnosis of work-related asthma before taking a worker off work. A proper occupational and medical history is very important but is not enough to make the diagnosis of OA. Objective evidence of work-related asthma is required and this represents a serious challenge to most physicians. Measurement of non-specific bronchial responsiveness (NSBR) and spirometry may confirm the diagnosis of asthma but do not confirm the diagnosis of OA. Serial monitoring of peak expiratory flows (PEF), NSBR, and airway inflammation at and off work may confirm the diagnosis of OA but are often difficult to perform. Confirming sensitization by skin prick tests or specific IgE may help to support the diagnosis of OA. Specific inhalation challenges (SIC) in the lab or at work are considered the reference standard but are of limited access. Medical surveillance programs along with primary prevention (reducing exposure) may help to reduce the burden of OA, but the ideal program has yet to be defined. The diagnostic workup of OA remains a challenge and needs a rigorous stepwise evaluation.

Impact of Panic Attacks on Bronchoconstriction and Subjective Distress in Asthma Patients With and Without Panic Disorder.

OBJECTIVE: Panic disorder (PD) is common among asthma patients and is associated with worse asthma outcomes. This may occur because of psychophysiological factors or cognitive/affective factors. This study evaluated the impact of panic attacks (PAs) on bronchoconstriction and subjective distress in people who have asthma with and without PD. METHODS: A total of 25 asthma patients (15 with PD who had a PA [PD/PA], 10 without PD who did not have a PA [no PD/no PA]) were recruited from an outpatient clinic. They underwent a panic challenge (one vital capacity inhalation of 35% carbon dioxide [CO2]) and completed the Panic Symptom Scale, the Subjective Distress Visual Analogue Scale, and the Borg Scale before and after CO2. Forced expiratory volume in 1 second was assessed pre- and post-CO2; respiratory (i.e., CO2 production, minute ventilation, tidal volume) was continuously recorded, and physiological measures (i.e., systolic and diastolic blood pressure [SBP/DBP]) were recorded every 2 minutes. RESULTS: Analyses adjusting for age, sex, and provocative concentration of methacholine revealed no significant differences between groups in forced expiratory volume in 1 second change after CO2 inhalation (F(1, 23) < 0.01, p = .961). However, patients with PD/PA reported more panic (F(1, 22) = 18.10, p < .001), anxiety (F(1, 22) = 21.93, p < .001), worry (F(1, 22) = 26.31, p < .001), and dyspnea (F(1,22) = 4.68, p = .042) and exhibited higher levels of CO2 production (F(1, 2843) = 5.89, p = .015), minute ventilation (F(1, 2844) = 4.48, p = .034), and tidal volume (F(1, 2844) = 4.62, p = .032) after the CO2 challenge, compared with patients with no PD/no PA. CONCLUSIONS: Results, presented as hypothesis generating, suggest that asthma patients with PD/PA exhibit increased panic-like anxiety, breathlessness, and a respiratory pattern consistent with hyperventilation that was not linked to statistically significant drops in bronchoconstriction.

Prospective Impact of Psychiatric Disorders on Employment Status and Health Care Use in Patients Investigated for Occupational Asthma.

OBJECTIVE: We previously reported high rates (34%) of psychiatric disorders (PSY) in patients evaluated for occupational asthma (OA). We determined the impact of PSY on employment status and health care use 12 to 18 months later. METHODS: One hundred ninety-six patients underwent clinical and psychiatric interviews on the day of their OA evaluation. Patients were re-contacted 12to 18 months later to assess employment status and health care use. RESULTS: Results indicated that patients with a PSY at baseline were less likely to be employed (adjusted odds ratio = 2.88; 95% confidence interval = 1.29 to 6.44) irrespective of final medical diagnosis (including OA), and had higher rates of emergency visits (35% vs 19%, P = 0.04). CONCLUSION: Psychiatric morbidity is common in this population and associated with lower employment rates and greater use of emergency services. Greater efforts should be made to assess and treat PSY in this population.

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.

Predictive value of nonspecific bronchial responsiveness in occupational asthma.

BACKGROUND: The diagnosis of occupational asthma (OA) can be challenging and needs a stepwise approach. However, the predictive value of the methacholine challenge has never been addressed specifically in this context. OBJECTIVE: We sought to evaluate the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in OA. METHODS: A Canadian database was used to review 1012 cases of workers referred for a suspicion of OA between 1983 and 2011 and having had a specific inhalation challenge. We calculated the sensitivity, specificity, and positive and negative predictive values of methacholine challenges at baseline of the specific inhalation challenge, at the workplace, and outside work. RESULTS: At baseline, the methacholine challenge showed an overall sensitivity of 80.2% and a specificity of 47.1%, with positive and negative predictive values of 36.5% and 86.3%, respectively. Among the 430 subjects who were still working, the baseline measures displayed a sensitivity of 95.4%, a specificity of 40.1%, and positive and negative predictive values of 41.1% and 95.2%, respectively. Among the 582 subjects tested outside work, the baseline measures demonstrated a sensitivity and specificity of 66.7% and 52%, respectively, and positive and negative predictive values of 31.9% and 82.2%, respectively. When considering all subjects tested by a methacholine challenge at least once while at work (479), the sensitivity, specificity, and positive and negative predictive values were 98.1%, 39.1%, and 44.0% and 97.7%, respectively. CONCLUSION: A negative methacholine challenge in a patient still exposed to the causative agent at work makes the diagnosis of OA very unlikely.

N-Acetyltransferase 2 Genotypes Are Associated With Diisocyanate-Induced Asthma.

OBJECTIVE: To investigate whether genetic variants of N-acetyltransferase (NAT) genes are associated with diisocyanate asthma (DA). METHODS: The study population consisted of 354 diisocyanate-exposed workers. Genotyping was performed using a 5'-nuclease polymerase chain reaction assay. RESULTS: The NAT2 rs2410556 and NAT2 rs4271002 variants were significantly associated with DA in the univariate analysis. In the first logistic regression model comparing DA+ and asymptomatic worker groups, the rs2410556 (P = 0.004) and rs4271002 (P < 0.001) single nucleotide polymorphisms and the genotype combination, NAT2 rs4271002*NAT1 rs11777998, showed associations with DA risk (P = 0.014). In the second model comparing DA+ and DA- groups, NAT2 rs4271002 variant and the combined genotype, NAT1 rs8190845*NAT2 rs13277605, were significantly associated with DA risk (P = 0.022, P = 0.036, respectively). CONCLUSIONS: These findings suggest that variations in the NAT2 gene and their interactions contribute to DA susceptibility.

Investigation of occupational asthma: Do clinicians fail to identify relevant occupational exposures?

BACKGROUND: Specific inhalation challenges (SIC) enable the identification of the agent responsible of occupational asthma (OA). A clinician may fail to identify a specific agent in the workplace, which may potentially lead to a misdiagnosis. The expert assessment method performed by an occupational hygienist has been used to evaluate occupational exposures in epidemiological studies. OBJECTIVE: The broad aim of the present study was to evaluate the contribution of an expert assessment performed by an occupational hygienist to the diagnosis of OA. The specific aim was to compare workplace exposures identified by an occupational hygienist and by chest physicians in subjects with positive SICs and subjects with asthma, but with a negative SIC. METHODS: SICs were performed in 120 cases: 67 were positive and 53 were negative. A clinician assessed occupational exposures to sensitizers during a routine clinical evaluation preceding the performance of the SIC. An expert assessment of occupational exposures was performed by an occupational hygienist blind to the result of the SIC. RESULTS: The occupational hygienist identified the causal agent in 96.7% of the 61 cases of positive SIC. In 33 (62.3%) cases of negative SICs, the occupational hygienist identified ≥1 sensitizing agent(s) that had not been identified by the clinician. CONCLUSION: The hygienist identified the causal agent in almost all subjects with OA. In contrast, the clinician failed to identify potential exposures to sensitizers in >60% of the negative SIC subjects, which may have resulted in some subjects being misdiagnosed as not having OA.

Do asthma patients with panic disorder really have worse asthma? A comparison of physiological and psychological responses to a methacholine challenge.

BACKGROUND: Panic disorder (PD) has been linked to worse asthma outcomes. Some suggest that asthmatics with PD have worse underlying asthma; others argue that worse outcomes are a result of their tendency to over-report symptoms. This study aimed to measure physiological and psychological responses to a simulated asthma attack (methacholine challenge test: MCT) in asthmatics with and without PD. METHODS: Asthmatics with (n = 19) and without (n = 20) PD were recruited to undergo a MCT. Patients completed subjective symptom questionnaires (Panic Symptom Scale, Borg Scale) before and after a MCT. Physiological measures including heart rate (HR), and systolic and diastolic blood pressure (SBP/DBP) were also recorded. RESULTS: Analyses, adjusting for age and sex, revealed no difference in methacholine concentration required to induce a 20% drop in forced expiratory volume in one second (FEV1: F = 0.21, p = .652). However, PD patients reported worse subjective symptoms, including greater ratings of dyspnea (F = 8.81, p = .006) and anxiety (F = 9.44, p = .004), although they exhibited lower levels of physiological arousal (i.e., HR, SBP/DBP). An interaction effect also indicated that PD, relative to non-PD, patients reported more panic symptoms post-MCT (F = 5.05, p = .031). CONCLUSIONS: Asthmatics with PD report higher levels of subjective distress, despite exhibiting lower levels of physiological arousal, with no evidence of greater airway responsiveness. Results suggest that worse outcomes in PD patients may be more likely due to a catastrophization of bodily symptoms, rather than worse underlying asthma. Interventions designed to educate patients on how to distinguish and manage anxiety in the context of asthma are needed.

An official American Thoracic Society Workshop Report: presentations and discussion of the fifth Jack Pepys Workshop on Asthma in the Workplace. Comparisons between asthma in the workplace and non-work-related asthma.

The fifth Jack Pepys Workshop on Asthma in the Workplace focused on the similarities and differences of work-related asthma (WRA) and non-work-related asthma (non-WRA). WRA includes occupational asthma (OA) and work-exacerbated asthma (WEA). There are few biological differences in the mechanisms of sensitization to environmental and occupational allergens. Non-WRA and OA, when due to high-molecular-weight agents, are both IgE mediated; it is uncertain whether OA due to low-molecular-weight agents is also IgE mediated. Risk factors for OA include female sex, a history of upper airway symptoms, and a history of bronchial hyperresponsiveness. Atopy is a risk factor for OA due to high-molecular-weight agents, and exposure to cleaning agents is a risk factor for both OA and non-WRA. WEA is important among workers with preexisting asthma and may overlap with irritant-induced asthma, a type of OA. Induced sputum cytology can confirm airway inflammation, but specific inhalation challenge is the reference standard diagnostic test. Inhalation challenges are relatively safe, with the most severe reactions occurring with low-molecular-weight agents. Indirect health care costs account for about 50% of total asthma costs. Workers with poor asthma control (WRA or non-WRA) are less likely to be employed. Income loss is a major contributor to the indirect costs of WRA. Overall, asthma outcomes probably are worse for adult-onset than for childhood-onset asthma but better for OA than adult-onset non-WRA. Important aspects of management of OA are rapid and proper confirmation of the diagnosis and reduction of exposure to sensitizers or irritants at work and home.

New causes of immunologic occupational asthma, 2012-2014.

PURPOSE OF REVIEW: The objective of this study was to review all new causes of well documented immunologic occupational asthma (IOA) published in the English and French medical literature between January 2012 and mid-2014. RECENT FINDINGS: Ten case reports of new causes of IOA were reported during that period. The diagnosis was either confirmed by specific inhalation challenges (n = 5) or a combination of peak expiratory flow monitoring at and off work, confirmation of specific sensitisation, and asthma (n = 3). These involved both high (mites contaminating cured ham, various enzymes used as detergents and food additives, aquarium fish food, and orange allergens) and low-molecular-weight agents (spruce wood dust, a biocide, and an halogenated platinum compound used in cytotoxic drugs). Furthermore, eight studies reported cases of IOA with agents already known as airway sensitizers but in working environments that were unusual and reported for the first time. SUMMARY: There are more than 400 known causes of IOA and the list grows continuously with the development of new technologies and better recognition of the diagnosis by physicians. IgE-mediated sensitization was confirmed in all new cases involving high-molecular-weight agents and in two of the three new cases involving low-molecular-weight agents. Symptoms of rhinitis were often associated with both types of agents. Physicians should stay alert and suspect occupational asthma in any adult with new-onset asthma or with newly uncontrolled asthma.