Occupational lung disease: when should I think of it and why is it important?

Exposure to toxic inhalants in the workplace has the potential to cause (in susceptible individuals) almost any major type of lung disease, such as asthma, COPD and interstitial lung diseases. Patients with occupational lung disease will often present to or will be managed by respiratory specialists without training in occupational respiratory medicine, and patients (or their clinicians) may not identify a link between their disease and their current or a past job. Without an awareness of the range of different occupational lung diseases that exist, their similarity to their non-occupational counterparts, and without directed questioning, these conditions may go unidentified. Patients with occupational lung diseases are often in lower paid work and are disproportionally affected by health inequality. Both clinical and socioeconomic outcomes generally improve if cases are identified early. This allows appropriate advice to be given about the risks of ongoing exposure, clinical management, occupational mobility and, in some cases, eligibility for legal compensation. As respiratory professionals, it is important that these cases are not missed, and if needed, are discussed with a physician with specialised expertise. Here we describe some of the most common occupational lung diseases and outline the diagnostic and treatment approach.

Transcriptomic Profiling of Adult-Onset Asthma Related to Damp and Moldy Buildings and Idiopathic Environmental Intolerance.

A subset of adult-onset asthma patients attribute their symptoms to damp and moldy buildings. Symptoms of idiopathic environmental intolerance (IEI) may resemble asthma and these two entities overlap. We aimed to evaluate if a distinct clinical subtype of asthma related to damp and moldy buildings can be identified, to unravel its corresponding pathomechanistic gene signatures, and to investigate potential molecular similarities with IEI. Fifty female adult-onset asthma patients were categorized based on exposure to building dampness and molds during disease initiation. IEI patients (n = 17) and healthy subjects (n = 21) were also included yielding 88 study subjects. IEI was scored with the Quick Environmental Exposure and Sensitivity Inventory (QEESI) questionnaire. Inflammation was evaluated by blood cell type profiling and cytokine measurements. Disease mechanisms were investigated via gene set variation analysis of RNA from nasal biopsies and peripheral blood mononuclear cells. Nasal biopsy gene expression and plasma cytokine profiles suggested airway and systemic inflammation in asthma without exposure to dampness (AND). Similar evidence of inflammation was absent in patients with dampness-and-mold-related asthma (AAD). Gene expression signatures revealed a greater degree of similarity between IEI and dampness-related asthma than between IEI patients and asthma not associated to dampness and mold. Blood cell transcriptome of IEI subjects showed strong suppression of immune cell activation, migration, and movement. QEESI scores correlated to blood cell gene expression of all study subjects. Transcriptomic analysis revealed clear pathomechanisms for AND but not AAD patients. Furthermore, we found a distinct molecular pathological profile in nasal and blood immune cells of IEI subjects, including several differentially expressed genes that were also identified in AAD samples, suggesting IEI-type mechanisms.

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.

Asthma onset after exposure to fluorinated hydrocarbons in the presence of combustion.

Fluorinated hydrocarbons, which can thermally degrade into toxic hydrofluoric acid, are widely used as, for example, cooling agents in refrigerators and air conditioning systems and as medical aerosol propellants. Hydrofluoric acid is a known causative agent of irritant-induced asthma. We report on two patients with asthma initiation shortly after exposure to fluorinated hydrocarbon-based cooling agents while welding or smoking cigarettes in a confined space. Both cases developed respiratory symptoms and headache and later demonstrated nonspecific bronchial hyperresponsiveness. In follow-up, asthma was persistent and responded poorly to asthma medication. Exposure to the fluorinated hydrocarbons themselves is unlikely to have caused asthma due to their low toxicity. Instead, exposure to small amounts of hydrofluoric acid via the thermal degradation of the fluorinated hydrocarbons was considered the most likely cause of asthma onset. This is supported by the typical clinical picture of irritant-induced asthma and acute symptoms resembling hydrofluoric acid poisoning. When fluorinated hydrocarbons are used in the presence of combustion, thermal degradation may lead to the formation of hydrofluoric acid. In confined spaces, this exposure may induce asthma via irritation. Welding, smoking, and other sources of combustion in confined spaces may be a risk in workplaces and other places in which fluorinated hydrocarbons are used.

Occupational contact urticaria and protein contact dermatitis: causes and concomitant airway diseases.

BACKGROUND: Contact urticaria (CU) and protein contact dermatitis (PCD) are mainly induced by an immediate, IgE-mediated immunological mechanism. Immediate sensitization is also linked to asthma and/or allergic rhinitis. OBJECTIVES: To report causes of work-induced CU and PCD, and to evaluate the occurrence of concomitant airway diseases. METHODS: We retrospectively reviewed the patient files of cases diagnosed with CU or PCD at the Finnish Institute of Occupational Health during 1995-2011. We obtained data on occupation, exposures, clinical and immunological test results, and diagnosed occupational skin and respiratory diseases. RESULTS: Altogether, 291 cases of occupational CU or PCD were diagnosed during the study period. The most common causes were flour, cow dander, natural rubber latex and acid anhydrides. Concomitant occupational asthma caused by the same agent as the skin disease was detected in 60 patients (21%), and occupational rhinitis was detected in 111 patients (38%). CONCLUSIONS: Almost half of the patients (46%) with occupational CU and PCD had concomitant occupational airway disease. Patients with CU/PCD should always be asked about respiratory symptoms, and preventive measures at the workplace should include protection of both the skin and the airways.

Epithelial proteome profiling suggests the essential role of interferon-inducible proteins in patients with allergic rhinitis.

BACKGROUND: Seasonal allergic rhinitis (SAR) caused by intermittent exposure to seasonal pollen causes itching, nasal congestion, and repeated sneezing, with profound effects on quality of life, work productivity, and school performance. Although both the genotype and environmental factors can contribute to the immunologic basis of allergic reactions, the molecular underpinnings associated with the pathogenesis of allergic rhinitis are not entirely clear. METHODS: To address these questions, nasal epithelial brushings were collected from 29 patients with SAR and 31 control subjects during and after the pollen season. We then implemented an orbitrap-based, bottom-up, label-free quantitative proteomics approach, followed by multivariate analyses to identify differentially abundant (DA) proteins among the 4 sample groups. RESULTS: We identified a total of 133 DA proteins for which the most significantly overrepresented functional category was found to be interferon 1 signaling. Two proteins, cystatin 1 and myeloblastin, the former of which protects against protease activity of allergens and the latter with a role in epithelial barrier function, were DA in patients with SAR and control subjects, irrespective of season. Moreover, interferon-inducible protein with tetratricopeptide repeats 1, cystatin 1, and interferon-inducible protein with tetratricopeptide repeats 3 were found to be differentially regulated between patients with SAR and control subjects, with inverse abundance dynamics during the transition from fall to spring. CONCLUSION: We identified type 1 interferon-regulated proteins as biomarkers in patients with SAR, potentially playing an important role in its pathogenesis. Moreover, when compared with patients with SAR, healthy subjects exhibit an antagonistic proteomic response across seasons, which might prove to be a therapeutic target for disease prevention.

Occupational lung diseases: from old and novel exposures to effective preventive strategies.

Occupational exposure is an important, global cause of respiratory disease. Unlike many other non-communicable lung diseases, the proximal causes of many occupational lung diseases are well understood and they should be amenable to control with use of established and effective approaches. Therefore, the risks arising from exposure to silica and asbestos are well known, as are the means of their prevention. Although the incidence of occupational lung disease has decreased in many countries, in parts of the world undergoing rapid economic transition and population growth-often with large informal and unregulated workforces-occupational exposures continue to impose a heavy burden of disease. The incidence of interstitial and malignant lung diseases remains unacceptably high because control measures are not implemented or exposures arise in novel ways. With the advent of innovative technologies, new threats are continually introduced to the workplace (eg, indium compounds and vicinal diketones). In developed countries, work-related asthma is the commonest occupational lung disease of short latency. Although generic control measures to reduce the risk of developing or exacerbating asthma are well recognised, there is still uncertainty, for example, with regards to the management of workers who develop asthma but remain in the same job. In this Review, we provide recommendations for research, surveillance, and other action for reducing the burden of occupational lung diseases.

Level of Fatty Acid Binding Protein 5 (FABP5) Is Increased in Sputum of Allergic Asthmatics and Links to Airway Remodeling and Inflammation.

BACKGROUND: The inflammatory processes in the upper and lower airways in allergic rhinitis and asthma are similar. Induced sputum and nasal lavage fluid provide a non-invasive way to examine proteins involved in airway inflammation in these conditions. OBJECTIVES: We conducted proteomic analyses of sputum and nasal lavage fluid samples to reveal differences in protein abundances and compositions between the asthma and rhinitis patients and to investigate potential underlying mechanisms. METHODS: Induced sputum and nasal lavage fluid samples were collected from 172 subjects with 1) allergic rhinitis, 2) asthma combined with allergic rhinitis, 3) nonallergic rhinitis and 4) healthy controls. Proteome changes in 21 sputum samples were analysed with two-dimensional difference gel electrophoresis (2D-DIGE), and the found differentially regulated proteins identified with mass spectrometry. Immunological validation of identified proteins in the sputum and nasal lavage fluid samples was performed with Western blot and ELISA. RESULTS: Altogether 31 different proteins were identified in the sputum proteome analysis, most of these were found also in the nasal lavage fluid. Fatty acid binding protein 5 (FABP5) was up-regulated in the sputum of asthmatics. Immunological validation in the whole study population confirmed the higher abundance levels of FABP5 in asthmatic subjects in both the sputum and nasal lavage fluid samples. In addition, the vascular endothelial growth factor (VEGF) level was increased in the nasal lavage fluid of asthmatics and there were positive correlations between FABP5 and VEGF levels (r=0.660, p<0.001) and concentrations of FABP5 and cysteinyl leukotriene (CysLT) (r=0.535, p<0.001) in the nasal lavage fluid. CONCLUSIONS: FABP5 may contribute to the airway remodeling and inflammation in asthma by fine-tuning the levels of CysLTs, which induce VEGF production.

Prick testing with chemicals in the diagnosis of occupational contact urticaria and respiratory diseases.

BACKGROUND: Little is known about the use of prick tests with chemicals in diagnosing occupational diseases. OBJECTIVE: To evaluate the use of prick tests in the diagnosis of occupational contact urticaria, asthma and rhinitis caused by chemicals (undertaken at the Finnish Institute of Occupational Health). MATERIAL AND METHODS: We retrospectively reviewed the patient and test files for the period 1 January 1991 to 31 May 2011. Prick tests were performed with chemical solutions and human serum albumin (HSA)-chemical conjugates. RESULTS: Positive prick test reactions to isocyanate-HSA conjugates were associated with isocyanate-specific IgE in all 20 patients, and 17 patients had a relevant occupational disease. Positive reactions to chloramine-T-HSA conjugates in 10 patients also indicated the presence of specific IgE, although occupational diseases were not always diagnosed. Eleven of 17 patients with positive reactions to persulfate solutions were diagnosed with an occupational disease. Methacrylates, colophonium-related substances, amine hardeners, ethanolamines, glutaraldehyde, glyoxal, pyrocatechol and ammonium thioglycolate did not elicit any relevant prick test reactions. No generalized reactions were detected. CONCLUSION: Prick tests can be safely used for diagnosing contact urticaria, asthma and rhinitis caused by isocyanates, chloramine-T, persulfates, and chlorhexidine, but the results should be carefully interpreted and related to clinical symptoms and other diagnostic tests.

MicroRNA profiles in nasal mucosa of patients with allergic and nonallergic rhinitis and asthma.

BACKGROUND: Rhinitis and asthma commonly coexist and are often regarded as "unified airways disease." Evidence exists that microRNAs are important in controlling inflammatory processes, but little is known about their role in airway inflammation. The present study evaluated the inflammatory profiles of patients with allergic rhinitis (AR), with and without concomitant asthma, and of patients with nonallergic rhinitis (NAR). METHODS: We analyzed inflammatory cells, cytokines, and microRNAs from nasal biopsies and measured nasal nitric oxide (nNO) levels in 159 young adult subjects subdivided into 4 groups: (1) AR; (2) AR+asthma; (3) NAR; and (4) controls. RESULTS: We observed the upregulation of T-helper 2 (Th2) cytokines and the trend of elevation of nNO levels in AR patients compared to controls. Subjects with current AR symptoms had increased levels of miR-155, miR-205, and miR-498, but reduced levels of let-7e. In addition, patients with positive skin prick test (SPT) reactions exhibited increased miR-155 and miR-205 expression and a decreased level of let-7e, compared to subjects with negative SPT findings. Concomitant asthma had little effect on the inflammatory profile of AR. No significant changes in inflammatory markers were found in NAR patients compared to healthy controls. CONCLUSION: Our results suggest that microRNAs miR-155, miR-205, miR-498, and let-7e may be important in the allergic inflammation present in nasal mucosa. Regarding NAR, our findings support the view that mechanisms other than inflammation are pivotal.

Positive exercise test and obstructive spirometry in young male conscripts associated with persistent asthma 20 years later.

BACKGROUND: Asthma often begins in childhood or early adulthood and is a common disease among conscripts. The identification of long-term predictive factors for persistent asthma may lead to improved treatment opportunities and better disease control. OBJECTIVE: Our aim was to study the prognostic factors of the severity of asthma among 40-year-old male conscripts whose asthma began in youth. METHODS: We studied 119 conscripts who were referred to the Central Military Hospital during 1987-1990 due to asthma and who attended a follow-up visit approximately 20 years later. Asthma severity was evaluated during military service according to the medical records, and 20 years later during a follow-up visit using Global Initiative for Asthma guidelines. We used the results of lung function and allergy tests at baseline as predictors of current persistent asthma. RESULTS: Compared with baseline, asthma was less severe at follow-up: 11.8% of subjects were in remission, 42.0% had intermittent asthma, 10.9% had mild persistent asthma, and 35.3% had moderate/severe persistent asthma (p < .001). In multivariate models, a positive exercise test at baseline yielded an odds ratio (OR) of 3.2 (95% CI 1.0-9.8, p = .046), a decreased FEV1/FVC % predicted an OR of 4.0 (95% CI 1.7-9.3, p = .002), and a decreased FEF50% % predicted an OR of 2.8 (95% CI 1.3-6.4, p = .012) for current persistent asthma. CONCLUSIONS: About half of the men had persistent asthma at the 20-year follow-up. Positive exercise tests and obstructive spirometry results were related to the persistence of asthma and may be useful long-term prognostic factors for asthma severity.

[Peak expiratory flow monitoring--the basis for diagnosing occupational asthma--guidelines by the Finnish Expert Group on Occupational Lung Diseases]. / Ammattikeuhkosairauksien asiantuntijaryhmän (AKAR) suositus. PEF-työpaikkaseuranta--ammattiastma-diagnostiikan perusta.

Occupational exposures can cause adult-onset asthma. Early diagnosis and early avoidance of further exposure to causative agent improves the prognosis of occupational asthma. Occupational and primary care health services have an important role in the identification of new cases of occupational asthma. For the diagnosis of occupational asthma, serial peak expiratory flow (PEF) measurements should be performed in an early stage. Although it requires an effort from the patient, high quality recordings offer the best approach to assess the relationship between workplace exposure and respiratory symptoms. Good guidance and performance of serial PEF measurements in primary care is recommended and is worth the effort.

[Specific challenge tests in occupational asthma--guidelines by the Finnish Expert Group on Occupational Lung Diseases]. / Ammattikeuhkosairauksien asiantuntijaryhmän (AKAR) suositus. Hengitysteiden spesifiset altistuskokeet ammattiastman osoittamisessa.

In a specific inhalation challenge (SIC) test the patient inhales an occupational agent in controlled environment and the subsequent asthmatic reaction is monitored. SIC is considered as the reference standard when confirming the diagnosis of sensitizer-induced occupational asthma. However, SIC is not always needed for the diagnosis; in many cases the causal relationship between an occupational agent and asthma can be shown also with serial peak flow measurements and specific immunologic testing. SIC is invaluable in identifying new occupational airway sensitizers. This is essential for preventing occupational asthma in the future.

Reduced work ability in middle-aged men with asthma from youth--a 20-year follow-up.

We studied, whether asthma diagnosed in childhood or early adulthood affects work ability 20 years later. We used Finnish Defence Force registers, 1986-1990, to select: (1) conscripts with asthma to represent a mild/moderate asthma group (n=485), (2) asthmatics who were exempted from military service to represent a relatively severe asthma group (n=393) and (3) a control group (n 1500) without asthma. A questionnaire consisting of validated questions on asthma and work ability was sent out in 2009. A total of 54% of the men in the first study group, 44% of those in the second study group and 44% of the controls answered. The mean age of the participants was 41 (range 37-51). Self-assessed current work ability compared with lifetime best had decreased in 28.9% of the first asthma group, in 31.1% of the second asthma group, and in 19.7% of the controls (p = 0.0007). Current smoking (OR 2.5), only basic education (OR 2.6), being a manual worker (OR 2.7) and current severe asthma (OR 3.8) associated most strongly with decreased work ability among the asthmatics. Both mild and more severe asthma at the age of around 20 seems to be associated with reduced work ability in 40-year-old males.