Are high- and low-molecular-weight sensitizing agents associated with different clinical phenotypes of occupational asthma?

BACKGROUND: High-molecular-weight (HMW) proteins and low-molecular-weight (LMW) chemicals can cause occupational asthma (OA) although few studies have thoroughly compared the clinical, physiological, and inflammatory patterns associated with these different types of agents. The aim of this study was to determine whether OA induced by HMW and LMW agents shows distinct phenotypic profiles. METHODS: Clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge response to HMW (n = 544) and LMW (n = 635) agents. RESULTS: Multivariate logistic regression analysis showed significant associations between OA caused by HMW agents and work-related rhinitis (OR [95% CI]: 4.79 [3.28-7.12]), conjunctivitis (2.13 [1.52-2.98]), atopy (1.49 [1.09-2.05]), and early asthmatic reactions (2.86 [1.98-4.16]). By contrast, OA due to LMW agents was associated with chest tightness at work (2.22 [1.59-3.03]), daily sputum (1.69 [1.19-2.38]), and late asthmatic reactions (1.52 [1.09-2.08]). Furthermore, OA caused by HMW agents showed a higher risk of airflow limitation (1.76 [1.07-2.91]), whereas OA due to LMW agents exhibited a higher risk of severe exacerbations (1.32 [1.01-1.69]). There were no differences between the two types of agents in the baseline sputum inflammatory profiles, but OA caused by HMW agents showed higher baseline blood eosinophilia and a greater postchallenge increase in fractional nitric oxide. CONCLUSION: This large cohort study describes distinct phenotypic profiles in OA caused by HMW and LMW agents. There is a need to further explore differences in underlying pathophysiological pathways and outcome after environmental interventions.

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.

Are allergen batch differences and the use of double skin prick test important?

BACKGROUND: Skin prick tests (SPT) are widely used both in clinical diagnostics and in research. The standardization of allergen extracts is well documented to be crucial for the validity of SPT, whereas less emphasis has been placed on reproducibility and the SPT procedure itself. The objectives of this study are to clarify how the double skin prick test procedure influence the sensitivity and specificity of the test and to analyse the differences in weal size in skin prick tests between two batches of allergen extracts from the same vendor. METHODS: The association between rhinitis and SPT was assessed among 1135 persons from a general population sample. SPT was performed twice with 10 common aeroallergens. In a subsample of 90 persons SPT was performed simultaneously with five of the allergens using different batches. RESULTS: Thirty percent had at least one positive SPT. Among asthmatics this number was 62%. Only minor differences were seen between the sizes of two weals from the same batch. A second SPT with the same batch did not change the association between rhinitis and sensitization. When performing SPT with two different batches disagreement was observed in 2% (Birch) to 11% (Cat) of the subjects. CONCLUSIONS: Performing SPT twice with the same allergen batch does not enhance the validity of the test, and value of double testing can be questioned. Considerable differences in SPT response with different batches from the same manufacturer were observed. Thus inter batch differences in allergen extracts might be a source of variability.

Asthma from the patient's perspective.

BACKGROUND: Asthma is a chronic disease with considerable burden on health and economy. Despite growing knowledge about causes and treatment, many patients have uncontrolled asthma, activity and social limitations and reduced quality of life (QOL). Coping with asthma could be developed in a social and scientific context and influenced by personal experience. OBJECTIVE: To investigate the asthmatic's perspective on asthma and how coping mechanisms with this disease were influenced by health professionals and networks. METHODS: Asthma and QOL questionnaires were sent to 1191 individuals, who had participated in a population-based clinical study in 2004. Of the 7271 responders (72.7%), 10 chronic asthmatics (4 males and 6 females) with different asthma severity grades were recruited to in-depth interviews. The results were interpreted according to selected theories, especially Antonovsky's salutogenic theory on how comprehensibility, manageability and meaningfulness contribute to sense of coherence and successful coping with stressor/disease. RESULTS AND CONCLUSION: Asthma comprehensibility was limited by both the lack of structured information about asthma diagnosis, treatment and prognosis and insufficient follow-up. The informants experimented with what worked and developed individual ways to accomplish satisfactory management. They adjusted their own medication and sometimes stopped prophylactic medicine as they did not detect an immediate effect. Many informants put their asthma into perspective, comparing it to what could have been worse. The unnoticeable development of asthma had probably triggered a gradual adaptation making it more complex for asthmatics to estimate severity. This together with their relative view of asthma might have led to gradual and uncritical accept of bothersome symptoms and reduced the need to seek professional advice or make important changes, e.g. eliminating exposure to irritating agents at work. Avoidance was a recurrent phenomenon as the asthmatics tended to drop physical activities with others instead of improving treatment. Several stated that they did not like to flash their asthma. They had concerns about being labelled as 'inadequate'. Physicians are urged to consider these tendencies and underlying the some of the mechanisms of 'living with asthma' in order to achieve proper asthma treatment and insure their patients' wellbeing.

The Relationship Between Potential Occupational Sensitizing Exposures and Asthma: An Overview of Systematic Reviews.

OBJECTIVES: The aim was to identify, appraise, and synthesize the scientific evidence of the relationship between potential occupational sensitizing exposures and the development of asthma based on systematic reviews. METHODS: The study was conducted as an overview of systematic reviews. A systematic literature search was conducted for systematic reviews published up to 9 February 2020. Eligibility study criteria included persons in or above the working age, potential occupational sensitizing exposures, and outcomes defined as asthma. Potential occupational sensitizing exposures were divided into 23 main groups comprising both subgroups and specific exposures. Two reviewers independently selected studies, extracted study data, assessed study quality, and evaluated confidence in study results and level of evidence of the relationship between potential occupational sensitizing exposures and asthma. RESULTS: Twenty-seven systematic reviews were included covering 1242 studies and 486 potential occupational sensitizing exposures. Overall confidence in study results was rated high in three systematic reviews, moderate in seven reviews, and low in 17 reviews. Strong evidence for the main group of wood dusts and moderate evidence for main groups of mites and fish was found. For subgroups/specific exposures, strong evidence was found for toluene diisocyanates, Aspergillus, Cladosporium, Penicillium, and work tasks involving exposure to laboratory animals, whereas moderate evidence was found for 52 subgroups/specific exposures. CONCLUSIONS: This overview identified hundreds of potential occupational sensitizing exposures suspected to cause asthma and evaluated the level of evidence for each exposure. Strong evidence was found for wood dust in general and for toluene diisocyanates, Aspergillus, Cladosporium, Penicillium, and work tasks involving exposure to laboratory animals.

Consequences of asthma on job absenteeism and job retention.

AIMS: Various social and economic effects are associated with asthma. This quantitative study describes the effects of current asthma on work life evaluated from the number of weeks receiving transfer incomes. METHODS: The study population comprised 7,241 persons answering the ECRHS II screening questionnaire, which was sent to a random age and gender stratified sample of 10,000 persons aged 20 to 44 years. Participants with current asthma were identified by positive answers to a set of validated questions. Transfer incomes for a five-year period were registered from a study-independent national database, which collects all public administered transfer incomes in Denmark. The numbers of weeks receiving unemployment, welfare, sick-leave and disability benefits were identified for each participant and differences between asthmatics and non-asthmatics were analyzed. RESULTS: Asthmatics had significantly more annual weeks receiving welfare (36.6 vs. 20.7, p=0.00), sick leave (9.2 vs. 6.6, p=0.00) and disability (19.3 vs. 11.4, p=0.00) benefits than non-asthmatics. Adult-onset asthmatics had increased prevalence rate ratios for disability of 2.40 (95% confidence interval 1.70-3.40). Blue collar work significantly increased the probability of all public transfer incomes. CONCLUSIONS: Current asthma makes it harder to keep a job. Adult-onset asthmatics and blue collar workers are particularly affected.

[Isocyanate-induced asthma].

Isocyanates are often found in workplaces in e.g., glue, paint, plastics and foam products. Asthma caused by isocyanates is one of the most common forms of occupational asthma, though it is difficult to diagnose, as described in this review. It is not possible to demonstrate sensitisation with available allergy tests. A certain diagnosis can only be made with the help of specific bronchial provocation, which is performed at three centres in Denmark. A correct diagnosis is important, as it helps provide optimal treatment as well as alerting the employer, that improvements are needed at the workplace.

Historical Asbestos Measurements in Denmark-A National Database.

OBJECTIVES: Due to the long lag-time for health outcomes, historical asbestos exposure measurements are valuable to support assessments of associated occupational health effects, and also to assess time trends and effects of preventive measures. METHODS: Different sources of stored data were collated, assessed and refined to create a harmonized database on historical asbestos fibre concentrations measured in specific work tasks and different industries. The final database contains 9236 asbestos measurements from Danish workplaces collected from 1971 to 1997. RESULTS: The geometric mean of asbestos concentrations in different occupations and tasks ranged from 0.003 to 35 fibres cm-3. Highest concentrations were registered during handling of asbestos products in the construction services during the period 1981-1997. Although all the measured asbestos exposures without the use of respiratory equipment by the worker in the period of 1971-1997 exceeded the current 8-h time-weighted average exposure limit of 0.1 fibres cm-3, the majority of samples collected in the earlier period of 1971 to 1980 did not exceed the exposure limit of 2 fibres cm-3, which was in place at the time. All exposure data obtained from 1980 and onwards were found to be one seventh of the mean fibre concentrations in the previous measurement period. The impact of time shows a clear exponentially decreasing trend-line. CONCLUSIONS: Despite limitations in coverage of different occupations and tasks associated with the inventoried historical asbestos measurements, the data are helpful to identify specific work scenarios within an industry, where relatively high asbestos exposure levels may still occur or have occurred from 1971 to 1997.

Phenotyping Occupational Asthma Caused by Acrylates in a Multicenter Cohort Study.

BACKGROUND: While acrylates are well-known skin sensitizers, they are not classified as respiratory sensitizers although several cases of acrylate-induced occupational asthma (OA) have been reported. OBJECTIVE: To evaluate the characteristics of acrylate-induced OA in a large series of cases and compare those with OA induced by other low-molecular-weight (LMW) agents. METHODS: Jobs and exposures, clinical and functional characteristics, and markers of airway inflammation were analyzed in an international, multicenter, retrospective cohort of subjects with OA ascertained by a positive inhalation challenge to acrylates (n = 55) or other LMW agents (n = 418) including isocyanates (n = 125). RESULTS: Acrylate-containing glues were the most prevalent products, and industrial manufacturing, dental work, and beauty care were typical occupations causing OA. Work-related rhinitis was more common in acrylate-than in isocyanate-induced asthma (P < .001). The increase in postchallenge fractional exhaled nitric oxide was significantly greater in acrylate-induced OA (26.0; 8.2 to 38.0 parts per billion [ppb]) than in OA induced by other LMW agents (3.0; -1.0 to 10.0 ppb; P < .001) or isocyanates (5.0; 2.0 to 16.0 ppb; P = .010). Multivariable models confirmed that OA induced by acrylates was significantly and independently associated with a postchallenge increase in fractional exhaled nitric oxide (≥17.5 ppb). CONCLUSIONS: Acrylate-induced OA shows specific characteristics, concomitant work-related rhinitis, and exposure-related increases in fractional exhaled nitric oxide, suggesting that acrylates may induce asthma through different immunologic mechanisms compared with mechanisms through which other LMW agents may induce asthma. Our findings reinforce the need for a reevaluation of the hazard classification of acrylates, and further investigation of the pathophysiological mechanisms underlying their respiratory sensitizing potential.

Sex determines the influence of smoking and gene polymorphism on glutathione peroxidase activity in erythrocytes.

OBJECTIVE: Glutathione peroxidase 1 (GPX1) is one of the major oxidative enzymes. Our aim was to characterize factors influencing its activity and to determine whether or not the activity is associated with asthma. MATERIAL AND METHODS: Serum selenium concentration was measured, GPX1 polymorphisms were genotyped and smoking history was obtained in a Danish population-derived case-base cohort of 1,191 subjects designed to evaluate risk factors for asthma. GPX1 activity was measured in 134 male and 164 female subjects equally distributed according to genotype of GPX1. Among these subjects, 82 (28 %) had doctor-diagnosed asthma. RESULTS: The average serum selenium concentration was too low for optimal enzyme activity (mean (SE), 83.4 (0.76) ng/mL). GPX1 activity in men was lower than in women, 52.6 (0.66) and 56.4 (0.59) U/g protein, respectively (p<0.001). In men, activity was positively associated with serum selenium concentration (p = 0.005) and negatively associated with both active smoking (p = 0.009) and exposure to environmental tobacco smoke (p = 0.02). In women, activity was associated with genotypes with 59.2 (1.4), 56.0 (1.4) and 54.2 (1.4) U/g protein in the homozygote wild-type, the heterozygote and the homozygote variant type, respectively (p = 0.001). Doctor-diagnosed asthma was unrelated to GPX1 activity in either sex. CONCLUSION: Determinants for activity in the oxidative enzyme GPX1 show marked differences between the sexes, but the activity is not associated with asthma. Sex ought to be taken into consideration when analysing the activity of the enzyme.

Coordinated and tailored work rehabilitation: a randomized controlled trial with economic evaluation undertaken with workers on sick leave due to musculoskeletal disorders.

INTRODUCTION: In Denmark, the magnitude and impact of work disability on the individual worker and society has prompted the development of a new "coordinated and tailored work rehabilitation" (CTWR) approach. The aim of this study was to compare the effects of CTWR with conventional case management (CCM) on return-to-work of workers on sick leave due to musculoskeletal disorders (MSDs). METHODS: The study was a randomized controlled trial with economic evaluation undertaken with workers on sick leave for 4-12 weeks due to MSDs. CTWR consists of a work disability screening by an interdisciplinary team followed by the collaborative development of a RTW plan. The primary outcome variable was registered cumulative sickness absence hours during 12 months follow-up. Secondary outcomes were work status as well as pain intensity and functional disability, measured at baseline, 3 and 12 months follow-up. The economic evaluation (intervention costs, productivity loss, and health care utilization costs) was based on administrative data derived from national registries. RESULTS: For the time intervals 0-6 months, 6-12 months, and the entire follow-up period, the number of sickness absence hours was significantly lower in the CTWR group as compared to the control group. The total costs saved in CTWR participants compared to controls were estimated at US $ 1,366 per person at 6 months follow-up and US $ 10,666 per person at 12 months follow-up. CONCLUSIONS: Workers on sick leave for 4-12 weeks due to MSD who underwent "CTWR" by an interdisciplinary team had fewer sickness absence hours than controls. The economic evaluation showed that-in terms of productivity loss-CTWR seems to be cost saving for the society.

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.

[Work-up of asbestosis and estimation of asbestos exposure in an occupational context].

Asbestosis is interstitial lung fibrosis due to inhalation of asbestos fibres. Up to the ban of import in 1986, 0.7 mil tons had been used in Denmark. The diagnosis of asbestosis is a challenge because of long latency time and very few national occupational asbestos measurements. The cornerstone of exposure assessment is a thorough occupational history, investigation of asbestos content in products used, search for possible and relevant measurements of asbestos fibres in the air, and results of lung biopsies, if present. Although no definite lower limit of exposure can be defined, a cumulated exposure of > 10 fibre-years is a relevant measure for exposure defining the disease, as one fibre-year equals one asbestos fibre/cm3 air/occupational year.

Risk factors for incident asthma and COPD in a cohort of young adults.

INTRODUCTION: The aim of the study was to describe potential shared risk factors for incident asthma and COPD in a population-based, 9-year follow-up study. METHODS: From a cohort of 1191 individuals, aged 20-44, who participated in baseline survey including spirometry, bronchial challenge, and skin prick test (SPT) 742 subjects (62%) were reexamined at follow-up in 2012-2014. RESULTS: A total of 27 incident cases of asthma and 22 cases of COPD were identified at follow-up corresponding to an incidence rate of 5.8 (95% CI 3.9-8.4) and 3.5 (2.2-5.3) per 1000 person years, respectively. Among the identified COPD cases a total of 12 were Asthma-COPD Overlap Syndrome (ACOS). Atopy defined by positive SPT was a risk factor for asthma in males (OR 7.54; 95% CI 1.24-45.90), whereas risk factors in females were nasal allergy (3.81; 1.20-12.11), FEV1 <100% predicted (3.96; 1.07-14.62) and parental asthma (3.06; 1.00-9.40). Risk factors for COPD in males were bronchial hyperresponsiveness (23.13; 1.41-380.50) and FEV1 <100% predicted (all male cases had FEV1 <100% predicted) and in females current smoking (3.34; 1.16-9.59) and asthma at baseline (5.21; 1.48-18.34). CONCLUSIONS: No shared risk factors for incident asthma and COPD were found. Despite low power when stratifying by sex risk factors for incident asthma and COPD emphasize considerable gender differences.

[Asbestosis and pleural plaques].

Asbestos was used in numerous products until its total ban in Denmark in 1988. The prevalence of asbestosis and pleural plaques does not yet appear to be falling. Unfortunately the statistics are unreliable due to errors in the Danish translation of the ICD-10 codes of the disease. In this review, clinical and radiologic diagnostic criteria of asbestosis and pleural plaques and recommendations for follow-up of patients are described. Typical changes on a high-resolution CT scan combined with relevant asbestos exposure is essential for the diagnosis. Asbestosis and pleural plaques are both notifiable in Denmark.

Determinants of persistent asthma in young adults.

Objective: The aim of the study was to evaluate determinants for the prognosis of asthma in a population-based cohort of young adults. Design: The study was a nine-year clinical follow up of 239 asthmatic subjects from an enriched population-based sample of 1,191 young adults, aged 20-44 years, who participated in an interviewer-administered questionnaire and clinical examination at baseline in 2003-2006. From the interview, an asthma score was generated as the simple sum of affirmative answers to five main asthma-like symptoms in order to analyse symptoms of asthma as a continuum. The clinical examination comprised spirometry, bronchial challenge or bronchodilation, and skin prick test. Results: Among the 239 individuals with asthma at baseline 164 (69%) had persistent asthma at follow up, while 68 (28%) achieved remission of asthma and seven (3%) were diagnosed with COPD solely. Determinants for persistent asthma were use of medication for breathing within the last 12 months: Short-acting beta-adrenoceptor agonists (SABA) only (OR 3.39; 95%CI: 1.47-7.82) and inhaled corticosteroids (ICS) and/or long-acting beta-adrenoceptor agonists (LABA) (8.95; 3.87-20.69). Stratified by age of onset determinants for persistence in individuals with early-onset asthma (age less than 16 years) were FEV1 below predicted (7.12; 1.61-31.50), asthma score at baseline (2.06; 1.15-3.68) and use of ICS and/or LABA within 12 months (9.87; 1.95-49.98). In individuals with late-onset asthma the determinant was use of ICS and/or LABA within 12 months (6.84; 2.09-22.37). Conclusions: Pulmonary function below predicted, severity of disease expressed by asthma score and use of ICS and/or LABA were all determinants for persistent early-onset asthma, whereas only use of ICS and/or LABA was a determinant in late-onset asthma. A high asthma score indicated insufficient disease control in a substantial proportion of these young adults.

A systematic review of occupational exposure to coal dust and the risk of interstitial lung diseases.

Objective: Exposure to coal dust can cause interstitial lung disease (ILD), but whether this is due to pure coal or to the contents of quartz in coal is less clear. Here, we systematically reviewed the relation between 'pure coal' and ILD. Methods: In a systematic review based on PRISMA criteria 2945 articles were identified. Strict eligibility criteria, which evaluated the 'pure coal effect', led to the inclusion of only nine studies. Results: Among these nine studies six studies indicated an independent effect of the non-quartz part of coal on the development and progression of ILD, two did not demonstrate an effect and one was inconclusive. Conclusions: Although an independent effect of non-quartz coal dust on the development of ILD is supported, due to methodological limitations the evidence is limited and further evidence is needed.

[Specific bronchial and nasal provocations with work-related allergens]. / Specifikke bronkiale og nasale provokationer for erhvervsallergener.

Specific inhalation challenge (SIC) is the golden standard for identifying specific causes of work-related asthma and rhinoconjunctivitis. Few centres offer SIC as it requires experience, resources and acute treatment facilities. Prior to SIC treatment should be carefully reduced. A control challenge is performed on a separate day. Many new asthma causes have been identified with SIC. SIC provides the basis for optimal treatment and advice.

Systemic sarcoidosis mimicking malignant metastatic disease.

We present a case of systemic sarcoidosis involving the liver, pancreas, lungs, mediastinal and intraabdominal lymph nodes and bones. Multiple organ system manifestations mimicked malignant metastatic disease. The diagnosis was established with clinical, radiological, and pathological findings after neoplasm was ruled out by pathological tests. The patient showed rapid symptom remission with systemic steroid treatment.