Vivi Schlünssen

Guidelines for the management of work-related asthma

Work-related asthma, which includes occupational asthma and work-aggravated asthma, has become one of the most prevalent occupational lung diseases. These guidelines aim to upgrade occupational health standards, contribute importantly to transnational legal harmonisation and reduce the high socio-economic burden caused by this disorder. A systematic literature search related to five key questions was performed: diagnostics; risk factors; outcome of management options; medical screening and surveillance; controlling exposure for primary prevention. Each of the 1,329 retrieved papers was reviewed by two experts, followed by Scottish Intercollegiate Guidelines Network grading, and formulation of statements graded according to the Royal College of General Practitioners’ three-star system. Recommendations were made on the basis of the evidence-based statements, which comprise the following major evidence-based strategic points. 1) A comprehensive diagnostic approach considering the individual specific aspects is recommended. 2) Early recognition and diagnosis is necessary for timely and appropriate preventative measures. 3) A stratified medical screening strategy and surveillance programme should be applied to at-risk workers. 4) Whenever possible, removing exposure to the causative agent should be achieved, as it leads to the best health outcome. If this is not possible, reduction is the second best option, whereas respirators are of limited value. 5) Exposure elimination should be the preferred primary prevention approach.

Occupational chronic obstructive pulmonary disease: a systematic literature review

OBJECTIVE Occupational-attributable chronic obstructive pulmonary disease (COPD) presents a substantial health challenge. Focusing on spirometric criteria for airflow obstruction, this review of occupational COPD includes both population-wide and industry-specific exposures. METHODS We used PubMed and Embase to identify relevant original epidemiological peer-reviewed articles, supplemented with citations identified from references in key review articles. This yielded 4528 citations. Articles were excluded for lack of lung function measurement, insufficient occupational exposure classification, lack of either external or internal referents, non-accounting of age or smoking effect, or major analytic inadequacies preventing interpretation of findings. A structured data extraction sheet was used for the remaining 147 articles. Final inclusion was based on a positive qualitative Scottish Intercollegiate Guidelines Network (SIGN) score (≥2+) for study quality, yielding 25 population-wide and 34 industry/occupation-specific studies, 15 on inorganic and 19 on organic dust exposure, respectively. RESULTS There was a consistent and predominantly significant association between occupational exposures and COPD in 22 of 25 population-based studies, 12 of 15 studies with an inorganic/mineral dust exposure, and 17 of 19 studies on organic exposure, even though the studies varied in design, populations, and the use of measures of exposure and outcome. A nearly uniform pattern of a dose-response relationship between various exposures and COPD was found, adding to the evidence that occupational exposures from vapors, gas, dust, and fumes are risk factors for COPD. CONCLUSION There is strong and consistent evidence to support a causal association between multiple categories of occupational exposure and COPD, both within and across industry groups.

Prenatal maternal stress and atopic diseases in the child: a systematic review of observational human studies

A growing number of studies suggest that maternal stress during pregnancy promotes atopic disorders in the offspring. This is the first systematic review to address prenatal maternal stress (PNMS) and the subsequent risk of atopy‐related outcomes in the child.

Airborne Fungal and Bacterial Components in PM1 Dust from Biofuel Plants

Fungi grown in pure cultures produce DNA- or RNA-containing particles smaller than spore size (<1.5 μm). High exposures to fungi and bacteria are observed at biofuel plants. Airborne cultivable bacteria are often described to be present in clusters or associated with larger particles with an aerodynamic diameter (dae) of 2–8 μm. In this study, we investigate whether airborne fungal components smaller than spore size are present in bioaerosols in working areas at biofuel plants. Furthermore, we measure the exposure to bacteria and fungal components in airborne particulate matter (PM) with a D50 of 1 μm (called PM1 dust). PM1 was sampled using Triplex cyclones at a working area at 14 Danish biofuel plants. Millipore cassettes were used to sample ‘total dust’. The PM1 particles (29 samples) were analysed for content of 11 different components and the total dust was analysed for cultivable fungi, N-acetyl-β-D-glucosaminidase (NAGase), and (1 → 3)-β-D-glucans. In the 29 PM1 samples, cultivable fungi were found in six samples and with a median concentration below detection level. Using microscopy, fungal spores were identified in 22 samples. The components NAGase and (1 → 3)-β-D-glucans, which are mainly associated with fungi, were present in all PM1 samples. Thermophilic actinomycetes were present in 23 of the 29 PM1 samples [average = 739 colony-forming units (CFU) m−3]. Cultivable and ‘total bacteria’ were found in average concentrations of, respectively, 249 CFU m−3 and 1.8 × 105 m−3. DNA- and RNA-containing particles of different lengths were counted by microscopy and revealed a high concentration of particles with a length of 0.5–1.5 μm and only few particles >1.5 μm. The number of cultivable fungi and β-glucan in the total dust correlated significantly with the number of DNA/RNA-containing particles with lengths of between 1.0 and 1.5 μm, with DNA/RNA-containing particles >1.5 μm, and with other fungal components in PM1 dust. Airborne β-glucan and NAGase were found in PM1 samples where no cultivable fungi were present, and β-glucan and NAGase were found in higher concentrations per fungal spore in PM1 dust than in total dust. This indicates that fungal particles smaller than fungal spore size are present in the air at the plants. Furthermore, many bacteria, including actinomycetes, were present in PM1 dust. Only 0.2% of the bacteria in PM1 dust were cultivable.

K- ras mutations in sinonasal cancers in relation to wood dust exposure

BackgroundCancer in the sinonasal tract is rare, but persons who have been occupationally exposed to wood dust have a substantially increased risk. It has been estimated that approximately 3.6 million workers are exposed to inhalable wood dust in EU. In previous small studies of this cancer, ras mutations were suggested to be related to wood dust exposure, but these studies were too limited to detect statistically significant associations.MethodsWe examined 174 cases of sinonasal cancer diagnosed in Denmark in the period from 1991 to 2001. To ensure uniformity, all histological diagnoses were carefully reviewed pathologically before inclusion. Paraffin embedded tumour samples from 58 adenocarcinomas, 109 squamous cell carcinomas and 7 other carcinomas were analysed for K-ras codon 12, 13 and 61 point mutations by restriction fragment length polymorphisms and direct sequencing. Information on occupational exposure to wood dust and to potential confounders was obtained from telephone interviews and from registry data.ResultsAmong the patients in this study, exposure to wood dust was associated with a 21-fold increased risk of having an adenocarcinoma than a squamous cell carcinoma compared to unexposed [OR = 21.0, CI = 8.0–55.0]. K-ras was mutated in 13% of the adenocarcinomas (seven patients) and in 1% of squamous cell carcinomas (one patient). Of these eight mutations, five mutations were located in the codon 12. The exact sequence change of remaining three could not be identified unambiguously. Among the five identified mutations, the G→A transition was the most common, and it was present in tumour tissue from two wood dust exposed adenocarcinoma patients and one patient with unknown exposure. Previously published studies of sinonasal cancer also identify the GGT → GAT transition as the most common and often related to wood dust exposure.ConclusionPatients exposed to wood dust seemed more likely to develop adenocarcinoma compared to squamous cell carcinomas. K-ras mutations were detected in 13% of adenocarcinomas. In this study and previously published studies of sinonasal cancer the found K-ras mutations, were almost exclusively G → A transitions. In conclusion, our study, based on a large representative collection of human SNC tumours, indicates that K-ras mutations are relatively infrequent, and most commonly occur in adenocarcinomas. Wood dust exposure alone was not found to be explanatory for the G→A mutations, but combination of exposure to tobacco, wood dust, and possibly other occupational agents may be a more likely explanation. Overall, the study suggests a limited role for K-ras mutations in development of sinonasal cancer.

The management of work-related asthma guidelines: a broader perspective

The aim of the European Respiratory Society work-related asthma guidelines is to present the management and prevention options of work-related asthma and their effectiveness. Work-related asthma accounts for 5–25% of all adult asthma cases and is responsible for a significant socioeconomic burden. Several hundred occupational agents, mainly allergens but also irritants and substances with unknown pathological mechanisms, have been identified as causing work-related asthma. The essential message of these guidelines is that the management of work-related asthma can be considerably optimised based on the present knowledge of causes, risk factors, pathomechanisms, and realistic and effective interventions. To reach this goal we urgently require greatly intensified primary preventive measures and improved case management. There is now a substantial body of evidence supporting the implementation of comprehensive medical surveillance programmes for workers at risk. Those workers who fail surveillance programmes need to be referred to a clinician who can confirm or exclude an occupational cause. Once work-related asthma is confirmed, a revised risk assessment in the workplace is needed to prevent further cases. These new guidelines confirm and extend already existing statements and recommendations. We hope that these guidelines will initiate the much-needed research that is required to fill the gaps in our knowledge and to initiate substantial improvements in preventative measures.

Sensitisation to common allergens and respiratory symptoms in endotoxin exposed workers: a pooled analysis

Objective To test the hypotheses that current endotoxin exposure is inversely associated with allergic sensitisation and positively associated with non-allergic respiratory diseases in four occupationally exposed populations using a standardised analytical approach. Methods Data were pooled from four epidemiological studies including 3883 Dutch and Danish employees in veterinary medicine, agriculture and power plants using biofuel. Endotoxin exposure was estimated by quantitative job-exposure matrices specific for the study populations. Dose–response relationships between exposure, IgE-mediated sensitisation to common allergens and self-reported health symptoms were assessed using logistic regression and generalised additive modelling. Adjustments were made for study, age, sex, atopic predisposition, smoking habit and farm childhood. Heterogeneity was assessed by analysis stratified by study. Results Current endotoxin exposure was dose-dependently associated with a reduced prevalence of allergic sensitisation (ORs of 0.92, 0.81 and 0.66 for low mediate, high mediate and high exposure) and hay fever (ORs of 1.16, 0.81 and 0.58). Endotoxin exposure was a risk factor for organic dust toxic syndrome, and levels above 100 EU/m3 significantly increased the risk of chronic bronchitis (p<0.0001). Stratification by farm childhood showed no effect modification except for allergic sensitisation. Only among workers without a farm childhood, endotoxin exposure was inversely associated with allergic sensitisation. Heterogeneity was primarily present for biofuel workers. Conclusions Occupational endotoxin exposure has a protective effect on allergic sensitisation and hay fever but increases the risk for organic dust toxic syndrome and chronic bronchitis. Endotoxins protective effects are most clearly observed among agricultural workers.

Indices of asthma among atopic and non-atopic woodworkers

Aims: To investigate the relation between wood dust exposure and different indices of asthma among woodworkers and non-exposed subjects. Methods: A total of 302 woodworkers and 71 non-exposed subjects answered a respiratory health questionnaire, underwent a non-specific bronchial provocation test using the Yan method, and received a skin prick test with 12 common inhalant allergens. Subgroups performed repeated peak flow monitoring and underwent a reversibility test. A total of 347 dust measurements among 234 woodworkers were performed with passive dust monitors. Results: The overall geometric mean (geometric standard deviation) exposure to inhalable dust was 0.96 (2.02) mg/m3. There was a tendency to increased risk of asthma among atopic woodworkers compared to atopic non-exposed subjects, with ORs between 3.0 (0.8–11.9) (symptomatic BHR) and 1.3 (0.5–4.2) (work related symptoms). In woodworkers, asthma was associated with atopy, with ORs between 7.4 (2.8–19.7) (symptomatic BHR) and 4.2 (2.4–7.7) (asthma symptoms). Asthma was related to dust level, most pronounced for symptomatic BHR among atopics, with OR 22.9 (1.0–523.6) for the highest compared to the lowest dust level. For work related asthma symptoms the association with dust level was seen only for non-atopics. Conclusions: Wood dust exposure was associated with asthma, despite a low dust level compared to other studies. Atopy was an important effect modifier in the association between asthma and wood dust exposure.

Contribution of host factors and workplace exposure to the outcome of occupational asthma.

The outcome of occupational asthma after diagnosis is often poor. The identification of factors associated with a worse outcome may help in the management of the disease, determining its prognosis and assessing the permanent impairment attributable to occupational exposure. The aim of this systematic review was to provide the available evidence from the medical literature to answer the question: “What is the contribution of host factors and workplace exposure to the risk of a bad outcome of occupational asthma?” A systematic literature search was conducted in March 2010. We retrieved 177 abstracts. Of these, 67 were assessed as potentially relevant. After full text evaluation, 35 articles that were actually relevant for the question were included in the analysis. The information obtained was sufficient to establish that older age, high-molecular-weight agents, impaired lung function and longer duration of exposure to the offending agent at the time of diagnosis had a negative role on the outcome of occupational asthma. Atopy and smoking at diagnosis did not seem to influence the outcome of occupational asthma. A limited number of studies considered sex and the pattern of asthmatic reaction on specific inhalation challenge and their findings were contradictory.

Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer

The causal role of work‐related exposure to wood dust in the development of sinonasal cancer has long been established by numerous epidemiologic studies. To study molecular changes in these tumors, we analyzed TP53 gene mutations in 358 sinonasal cancer cases with or without occupational exposure to wood dust, using capillary electrophoresis single‐strand conformation polymorphism analysis and direct sequencing. A significant association between wood‐dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0–31.6]. TP53 mutations occurred in all histologies, with an overall frequency of 77%. TP53 mutation positive status was most common in adenocarcinoma (OR 2.0, 95% CI, 1.1–3.7; compared with squamous cell carcinoma), and mutation positivity showed an overall, nonsignificant association with wood‐dust exposure (OR 1.6, 95% CI, 0.8–3.1). Risk of TP53 mutation was significantly increased in association with duration (≥24 years, OR 5.1, 95% CI, 1.5–17.1), average level (>2 mg/m3; OR 3.6, 95% CI, 1.2–10.8) and cumulative level (≥30 mg/m3 × years; OR 3.5, 95% CI, 1.2–10.7) of wood‐dust exposure; adjustment for formaldehyde affected the ORs only slightly. Smoking did not influence the occurrence of TP53 mutation; however, it was associated with multiple mutations (p = 0.03). As far as we are aware, this is the first study to demonstrate a high prevalence of TP53 mutation‐positive cases in a large collection of sinonasal cancers with data on occupational exposure. Our results indicate that mutational mechanisms, in particular TP53 mutations, are associated with work‐related exposure to wood dust in sinonasal cancer.