Multivariate analysis and data mining help predict asthma exacerbations.

BACKGROUND: Work-related asthma has become a highly prevalent occupational lung disorder. OBJECTIVE: Our study aims to evaluate occupational exposure as a predictor for asthma exacerbation. METHOD: We performed a retrospective evaluation of 584 consecutive patients diagnosed and treated for asthma between October 2017 and December 2019 in four clinics from Western Romania. We evaluated the enrolled patients for their asthma control level by employing the Asthma Control Test (ACT < 20 represents uncontrolled asthma), the medical record of asthma exacerbations, occupational exposure, and lung function (i.e. spirometry). Then, we used statistical and data mining methods to explore the most important predictors for asthma exacerbations. RESULTS: We identified essential predictors by calculating the odds ratios (OR) for the exacerbation in a logistic regression model. The average age was 45.42 ± 11.74 years (19-85 years), and 422 (72.26%) participants were females. 42.97% of participants had exacerbations in the past year, and 31.16% had a history of occupational exposure. In a multivariate model analysis adjusted for age and gender, the most important predictors for exacerbation were uncontrolled asthma (OR 4.79, p < .001), occupational exposure (OR 4.65, p < .001), and lung function impairment (FEV1 < 80%) (OR 1.15, p = .011). The ensemble machine learning experiments on combined patient features harnessed by our data mining approach reveal that the best predictor is professional exposure, followed by ACT. CONCLUSIONS: Machine learning ensemble methods and statistical analysis concordantly indicate that occupational exposure and ACT < 20 are strong predictors for asthma exacerbation.

Endotyping asthma related to 3 different work exposures.

BACKGROUND: Work exposures play a significant role in adult-onset asthma, but the mechanisms of work-related asthma are not fully elucidated. OBJECTIVE: We aimed to reveal the molecular mechanisms of work-related asthma associated with exposure to flour (flour asthma), isocyanate (isocyanate asthma), or welding fumes (welding asthma) and identify potential biomarkers that distinguish these groups from each other. METHODS: We used a combination of clinical tests, transcriptomic analysis, and associated pathway analyses to investigate the underlying disease mechanisms of the blood immune cells and the airway epithelium of 61 men. RESULTS: Compared with the healthy controls, the welding asthma patients had more differentially expressed genes than the flour asthma and isocyanate asthma patients, both in the airway epithelia and in the blood immune cells. In the airway epithelia, active inflammation was detected only in welding asthma patients. In contrast, many differentially expressed genes were detected in blood cells in all 3 asthma groups. Disease-related immune functions in blood cells, including leukocyte migration and inflammatory responses, and decreased expression of upstream cytokines such as TNF and IFN-γ were suppressed in all the asthma groups. In transcriptome-phenotype correlations, hyperresponsiveness (R ∼ |0.6|) had the highest clinical relevance and was associated with a set of exposure group-specific genes. Finally, biomarker subsets of only 5 genes specifically distinguished each of the asthma exposure groups. CONCLUSIONS: This study provides novel data on the molecular mechanisms underlying work-related asthma. We identified a set of 5 promising biomarkers in asthma related to flour, isocyanate, and welding fume exposure to be tested and clinically validated in future studies.

Novel approaches in occupational asthma diagnosis and management.

PURPOSE OF REVIEW: To describe the recent findings of the last 2 years on the epidemiology and phenotypes of occupational asthma, as well as new developments in its diagnosis and management. RECENT FINDINGS: Data from nine longitudinal studies showed a population attributable fraction for the occupational contribution to incident asthma of 16%. The main phenotypes of occupational asthma are: occupational asthma caused by high-molecular-weight (HMW) or low-molecular-weight (LMW) agents, irritant-induced asthma and occupational asthma-chronic obstructive pulmonary disease overlap. Among the variety of causative agents of occupational asthma, food-derived components are increasingly being reported, accounting for up to 25% cases of occupational asthma and/or occupational rhinitis. Recently, a specific inhalation challenge (SIC)-independent model has been developed to calculate the probability of occupational asthma diagnosis in workers exposed to HMW agents. In this model, work-specific sensitization, bronchial hyperresponsiveness, inhaled corticosteroid use, rhinoconjunctivitis and age 40 years or less were the most relevant predictive factors. Specific IgE measurements showed a pooled sensitivity of 0.74 and a specificity of 0.71 in the diagnosis of occupational asthma for HMW agents, while a lower sensitivity (0.28) and a higher specificity (0.89) was shown for LMW agents. Cessation of exposure to workplace sensitizers is the cornerstone of management of work-related conditions. SUMMARY: An early and precise diagnosis of occupational asthma is crucial, allowing appropriate management and implementation of preventive strategies.

Hospital Attendances and Acute Admissions Preceding a Diagnosis of Occupational Asthma.

PURPOSE: Occupational exposures are a common cause of adult-onset asthma; rapid removal from exposure to the causative agent offers the best chance of a good outcome. Despite this, occupational asthma (OA) is widely underdiagnosed. We aimed to see whether chances of diagnosis were missed during acute hospital attendances in the period between symptom onset and the diagnosis of OA. METHODS: Patients diagnosed with OA at the regional occupational lung disease service in Birmingham between 2007 and 2018 whose home address had a Birmingham postcode were included. Emergency department (ED) attendances and acute admission data were retrieved from acute hospitals in the Birmingham conurbation for the period between symptom onset and diagnosis. RESULTS: OA was diagnosed in 406 patients, 147 having a Birmingham postcode. Thirty-four percent (50/147) had acute hospital attendances to a Birmingham conurbation hospital preceding their diagnosis of OA, including 35 (24%) with respiratory illnesses, which resulted in referral for investigation of possible OA in 2/35. The median delay between symptom onset and diagnosis of OA was 30 months (IQR = 13-60) and between first hospital attendance with respiratory illness and diagnosis 12 months (IQR = 12-48, range 3-96 months) CONCLUSIONS: The chance to reduce the delay in the diagnosis of OA was missed in 33/35 patients admitted or seen in ED with respiratory symptoms in the period between symptom onset and diagnosis of OA. The diagnosis of OA was delayed by a median of 12 months by failure to ask about employment and work relationship of symptoms.

Severe Occupational Asthma: Insights From a Multicenter European Cohort.

BACKGROUND: Although sensitizer-induced occupational asthma (OA) accounts for an appreciable fraction of adult asthma, the severity of OA has received little attention. OBJECTIVE: The aim of this study was to characterize the burden and determinants of severe OA in a large multicenter cohort of subjects with OA. METHODS: This retrospective study included 997 subjects with OA ascertained by a positive specific inhalation challenge completed in 20 tertiary centers in 11 European countries during the period 2006 to 2015. Severe asthma was defined by a high level of treatment and any 1 of the following criteria: (1) daily need for a reliever medication, (2) 2 or more severe exacerbations in the previous year, or (3) airflow obstruction. RESULTS: Overall, 162 (16.2%; 95% CI, 14.0%-18.7%) subjects were classified as having severe OA. Multivariable logistic regression analysis revealed that severe OA was associated with persistent (vs reduced) exposure to the causal agent at work (odds ratio [OR], 2.78; 95% CI, 1.50-5.60); a longer duration of the disease (OR, 1.04; 95% CI, 1.00-1.07); a low level of education (OR, 2.69; 95% CI, 1.73-4.18); childhood asthma (OR, 2.92; 95% CI, 1.13-7.36); and sputum production (OR, 2.86; 95% CI, 1.87-4.38). In subjects removed from exposure, severe OA was associated only with sputum production (OR, 3.68; 95% CI, 1.87-7.40); a low education level (OR, 3.41; 95% CI, 1.72-6.80); and obesity (OR, 1.98; 95% CI, 0.97-3.97). CONCLUSIONS: This study indicates that a substantial proportion of subjects with OA experience severe asthma and identifies potentially modifiable risk factors for severe OA that should be targeted to reduce the adverse impacts of the disease.

Pyromellitic dianhydride (PMDA) may cause occupational asthma.

INTRODUCTION: Anhydrides are widely used as cross-linking agents in epoxy resins and alkyd production, for example, as coatings and adhesives in plastic products. Sensitisation to several anhydrides is known to cause occupational asthma. There are indications that the lesser known pyromellitic dianhydride (PMDA) can cause irritative respiratory symptoms and possibly asthma. We report three cases of workers from a plastic foil manufacturing plant, who developed asthma when exposed to PMDA during specific inhalation challenge (SIC). METHODS: SIC was performed over 2 days according to recommendations of European Respiratory Society. Lactose powder was used in control challenges and a mixture of 10% PMDA and 90% lactose powder in active challenges. RESULTS: All cases experienced a delayed decrease in forced expiratory flow in 1 s (FEV1) 4-12 hours after active challenge. FEV1 decreased by 19%, 15% and 16%, respectively. After 21 hours, FEV1 decreased by 24% in one worker. DISCUSSION: Respiratory symptoms after working hours may represent delayed work-related asthma. During SIC, the three patients developed lower respiratory symptoms and a delayed decrease in FEV1 which suggest sensitisation. The mechanism of anhydride-related asthma is not well understood. Anhydrides are known irritants and hence an irritative response cannot be excluded. The company improved ventilation and enforced the use of respiratory protection equipment, and finally phased out PMDA. Occupational workplace risk identification may help to identify exposures. SIC can contribute to improving working conditions, by identifying and confirming asthmogens in the environment.

Vitamin D Intake and Obesity in Occupational Asthma Patients and the Need for Supplementation.

BACKGROUND: Occupational asthma occurs in a significant number of adult unset forms of asthma. Even after exposure cessation, persistent asthma is frequent. Although recognized as important, nutrition, specifically vitamin D intake, was rarely evaluated in occupational asthma. OBJECTIVE: To assess the vitamin D intake in occupational asthma patients and the relation with body mass index, co-morbidities related to vitamin D deficit, lung function and quality of life. RESULTS: We found a reduced vitamin D intake in both irritant and allergic asthma, in obese and nonobese patients. The average intake in non-obese patients, although higher, did not reach statistical significance. We also found lower vitamin D intake in the mild asthma group versus the severe group, marginally reaching the significance level (p=0.056) at the median test. Regression analysis in asthma subpopulations revealed a different pattern of correlation, with a stronger relationship between the BMI and the impact score in irritant asthma and a closer link between vitamin D intake and symptoms score (p= 0.027) in the allergic asthma group. CONCLUSION: The relation between obesity and vitamin D on clinical scores and lung function seems to be different according to the asthma phenotype. However, our study supports the usefulness of nutritional interventions in all occupational asthma patients, targeting both the reduction of the fat mass and the achievement of the recommended daily intake of vitamin D. When analyzing the impact of the weight loss effect on asthma evolution, the vitamin D status should also be considered as an influencer.

Pracenje vrsnog ekspiratornog protoka u dijagnozi profesionalne astme.

Prema podacima iz Registra profesionalnih bolesti Hrvatskoga zavoda za zastitu zdravlja i sigurnost na radu, u posljednjih deset godina (2008. ‒ 2017.) prijavljeno je samo 20 slucajeva profesionalne astme od ukupno 2234 prijavljene profesionalne bolesti. To upucuje na znacajne nedostatke u prepoznavanju toga poremecaja u nasoj radnoj populaciji. Cilj ovoga rada bio je opisati standardnu metodu pracenja vrsnog ekspiratornog protoka zraka (eng. peak expiratory flow, PEF) i predloziti prakticnu smjernicu za koristenje te dijagnosticke metode u ambulantama medicine rada i sporta. Pracenje vrsnog ekspiratornog protoka zraka (PEF-monitoring) jednostavna je, jeftina, neinvazivna i pouzdana metoda za utvrdivanje funkcije disnog sustava u stvarnim uvjetima rada i radnog okolisa. Sadasnje smjernice preporucuju PEF-monitoring kao inicijalnu dijagnosticku metodu prilikom sumnje na profesionalnu astmu. Pozitivan test upozorava na povezanost promjene plucne funkcije s radnom izlozenoscu i vazan je dio dijagnostickoga procesa utvrdivanja profesionalne astme. Najveci je nedostatak te metode da se tim testom ne moze utvrditi uzrok astme, tj. on ne razlikuje profesionalnu astmu od astme pogorsane na radu, nema standardizirane metode za interpretaciju rezultata, a mjerenja provode sami radnici pa su moguce namjerne i nenamjerne manipulacije rezultatima mjerenja. U radu je predlozena prakticna smjernica za primjenu te metode u ambulantama medicine rada i sporta, s preporukama protokola mjerenja PEF-a, prikaza rezultata mjerenja i njihove interpretacije u sklopu dijagnosticiranja profesionalne astme.

Work-related asthma in a sample of subjects with established asthma.

OBJECTIVE: To assess the impact of occupational exposure to irritants or sensitizers on the occurrence, recrudescence and worsening of asthma and to identify unrecognized cases of work related asthma (WRA) including Work-Exacerbated Asthma (WEA) and Occupational Asthma (OA), in a general asthma clinic population sample. SETTING, DESIGN AND PARTICIPANTS: The study was a population-based cross sectional survey. 1289 asthmatic subjects (from 15 to 46 yrs old) living in a vast district of Tuscany (Italy) were identified from the Medical Reimbursement Register of the National Health System. 893 subjects agreed to take part in the study. Subjects who were currently working or had worked in past were classified in different categories of occupational risk exposure (No, Low or High) according to the italian standard classification for industries and job titles, associated with the judgment of occupational hygiene experts. RESULTS: 41% of subjects worked in industries and in job titles at risk for exposure to airway irritants and/or sensitizers, 48.6% reported an occupational exposure to gases, dust and fumes, more males than females. Prevalence of WEA and OA was higher in subjects who worked at higher risk exposure; these subjects reported a higher prevalence of markers of asthma severity (asthma control, level of treatment, FEV1) than subjects without WRA. Risk of WEA was significantly associated to female gender, older age, and self-reported exposure, while risk of OA was associated to job title with higher exposure risk to occupational asthmogens. CONCLUSIONS: Our study shows a high prevalence of WRA (especially WEA) associated with employment in industries and job titles at risk for airways sensitizers and/or irritants; data also support a role for occupational exposure in determining a poor asthma control and a higher level of asthma severity.

Incidence of Occupational Asthma and Exposure to Toluene Diisocyanate in the United States Toluene Diisocyanate Production Industry.

OBJECTIVE: This study examines asthma risk in facilities producing toluene diisocyanate (TDI). METHODS: A total of 197 workers were monitored from 2007 to 2012. TDI air concentrations were used to estimate exposures. RESULTS: The incidence of cases consistent with TDI-induced asthma was 0.009 per person-years (seven cases) or consistent with TDI-induced asthma or asthma indeterminate regarding work-relatedness was 0.012 (nine cases). Increased risk of cases consistent with TDI asthma was observed for cumulative (odds ratio [OR] = 2.08, 95% confidence interval [CI] 1.07 to 4.05) per logarithm parts per billion-years and peak TDI exposures (OR = 1.18, 95% CI 1.06 to 1.32) (logarithm parts per billion). There was a weak association with cumulative and peak exposures for decline of short-term forced expiratory volume in one second (FEV1). Asthma symptoms were associated with workers noticing an odor of TDI (OR 6.02; 95% CI 1.36 to 26.68). CONCLUSIONS: There is evidence that cumulative and peak exposures are associated with TDI-induced asthma.

Recommendations for a Clinical Decision Support System for Work-Related Asthma in Primary Care Settings.

OBJECTIVE: The aim of this study was to describe a recommended clinical decision support (CDS) approach for work-related asthma for incorporation in electronic health records (EHRs) for primary care health care providers. METHODS: Subject matter experts convened by the American Thoracic Society reviewed available guidelines and published literature to develop specific recommendations. RESULTS: It is important to recognize possible work-related asthma among persons with new-onset or worsening asthma. The work group recommends incorporating three simple questions about temporal relations between asthma symptoms and work in EHR systems and identified specific clinical conditions to trigger this intervention. Patients with positive responses to the three questions should have the asthma diagnosis documented and have further evaluation, education, and possible referral. CONCLUSION: An effective CDS system for improving recognition of work-related asthma may help reduce morbidity and mortality of asthma in adults.

Occupational asthma caused by an epoxy amine hardener.

We describe a 43-year-old epoxy floor layer who developed work-related asthma while exposed to an epoxy hardener based on isophorone diamine (IPDA). Challenge exposures to the curing of the epoxy resin system and subsequently to the polyfunctional amine hardener containing IPDA both elicited delayed asthmatic reactions. This report further indicates that exposure to epoxy hardeners containing polyfunctional amines should be considered as a potential cause of occupational asthma. Appropriate work hygiene measures should be implemented to minimize airborne exposure to these volatile compounds.

Comparison of Psychological, Quality of Life, Work-Limitation, and Socioeconomic Status Between Patients With Occupational Asthma and Work-Exacerbated Asthma.

OBJECTIVE: The aim of this study was to compare psychological status, quality of life (QoL), work limitation, and socioeconomic status between patients with occupational asthma (OA) and work-exacerbated asthma (WEA). METHODS: The following questionnaires were administered to participants: Beck anxiety and depression (II) inventories, Marks' Asthma Quality of Life Questionnaire, and Work Limitations Questionnaire. Cross-sectional analyses between OA and WEA subgroups were completed. RESULTS: There were 77 participants. WEA subjects had a trend to higher anxiety scores (OA = 9.2 ±â€Š8.0, WEA = 12.8 ±â€Š8.3, P = 0.07, Cohen d = 0.4). Depression scores trended higher for those with WEA (OA = 9.6 ±â€Š10.3, WEA = 13.4 ±â€Š13.5, P = 0.2, Cohen d = 0.3). QoL was comparable between groups. WEA subjects had fewer work limitations (N = 50, OA = 25.1 ±â€Š27.3, WEA = 20.6 ±â€Š24.4, P = 0.56, Cohen d = 0.3) and OA subjects were more likely to have reduced income. CONCLUSION: In a tertiary clinic, there were some modest differences for specific variables between OA and WEA subjects that may help inform management.

Distinct Clinical Phenotypes of Occupational Asthma due to Diisocyanates.

OBJECTIVE: To assess whether diisocyanate occupational asthma represents a unique phenotype. METHODS: We studied 187 patients with diagnosis of asthma due to diisocyanates confirmed by a positive specific inhalation challenge. The simplified algorithm from severe asthma research program (SARP) (Moore et al, 2010) was applied to classify patients into five clusters. RESULTS: Our patients were allocated in three of the five clusters described in common asthma, since the most severe Clusters (4 and 5) were not represented. Cluster 2 was the most populated, as in common asthma, and included the youngest patients with the shortest duration of exposure to the sensitizers. Cluster 3 included older men patients with worse lung function and longer occupational exposure. CONCLUSIONS: Diisocyanate asthma is a heterogeneous disease. Differences across clusters include demographic characteristics, lung function, and chronology of diisocyanate exposure.

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.

Developing a framework for assessing chemical respiratory sensitization: A workshop report.

Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, -omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non-immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment.