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.

Occupations and exposure events in acute and subacute irritant-induced asthma.

BACKGROUND: Exposures leading to irritant-induced asthma (IIA) are poorly documented. METHODS: We retrospectively screened the medical records of patients with IIA diagnosed in an occupational medicine clinic during 2000-2018. We classified the cases into acute (onset after single exposure) and subacute (onset after multiple exposures) IIA. We analysed in detail, occupations, causative agents and their air levels in the workplace, exposure events and the root causes of high exposure. RESULTS: Altogether 69 patients were diagnosed with IIA, 30 with acute and 39 with subacute IIA. The most common occupational groups were industrial operators (n=23, 33%), metal and machinery workers (n=16, 11%) and construction workers (n=12, 8%). Among industrial operators significantly more cases had subacute IIA than acute IIA (p=0.002). Forty cases (57%) were attributable to some type of corrosive acidic or alkaline chemical. Acute IIA followed accidents at work in different types of occupation, while subacute IIA was typical among industrial operators performing their normal work tasks under poor work hygiene conditions. The most common root cause was lack of information or false guidance in acute IIA (n=11, 36%) and neglect of workplace hygiene measures in subacute IIA (n=29, 74%). CONCLUSIONS: Accidents are the main causes of acute IIA, whereas subacute IIA can develop in normal work in risk trades with poor work hygiene. Airborne strong acids or bases seem to be the most important causative agents of acute and subacute IIA. The different risk profiles of acute and subacute IIA should be considered in the prevention and identification of the cases.

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.

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.

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.

3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)- benzoic acid: a new cause of sensitiser induced occupational asthma, rhinitis and urticaria.

OBJECTIVES: 3-(Bromomethyl)-2-chloro-4-(methylsulfonyl)-benzoic acid (BCMBA) has not previously been identified as a respiratory sensitiser. We detected two cases who presented respiratory and urticaria symptoms related to BCMBA and had positive skin prick tests to the agent. Subsequently, we conducted outbreak investigations at the BCMBA-producing factory and performed clinical examinations to confirm occupational diseases. METHODS: The outbreak investigations included observations of work processes, assessment of exposure, a medical survey with a questionnaire and skin prick tests with 0.5% BCMBA water solution on 85 exposed workers and 9 unexposed workers. We used specific inhalation or nasal challenge and open skin application test to investigate BCMBA-related occupational asthma, rhinitis and contact urticaria. RESULTS: We identified nine workers with respiratory and/or skin symptoms and positive skin prick tests to BCMBA in a chemical factory. A survey among chemical factory workers indicated a BCMBA-related sensitisation rate of 8% among all exposed workers; the rate was highest (25%) among production workers in the production hall. Sensitisation was detected only in workers with the estimated highest exposure levels. Six cases of occupational asthma, rhinitis and/or contact urticaria caused by BCMBA were confirmed with challenge tests. Asthma-provoking doses in specific inhalation challenges were very low (0.03% or 0.3% BCMBA in lactose). CONCLUSIONS: We identified a new low molecular weight agent causing occupational asthma, rhinitis and contact urticaria. A typical clinical picture of allergic diseases and positive skin prick tests suggest underlying IgE-mediated disease mechanisms. Stringent exposure control measures are needed in order to prevent BCMBA-related diseases.

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 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.

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.

Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement.

This consensus statement provides practical recommendations for specific inhalation challenge (SIC) in the diagnosis of occupational asthma. They are derived from a systematic literature search, a census of active European centres, a Delphi conference and expert consensus. This article details each step of a SIC, including safety requirements, techniques for delivering agents, and methods for assessing and interpreting bronchial responses. The limitations of the procedure are also discussed. Testing should only be carried out in hospitals where physicians and healthcare professionals have appropriate expertise. Tests should always include a control challenge, a gradual increase of exposure to the suspected agent, and close monitoring of the patient during the challenge and for at least 6 h afterwards. In expert centres, excessive reactions provoked by SIC are rare. A positive response is defined by a fall in forced expiratory volume in 1 s ≥ 15% from baseline. Equivocal reactions can sometimes be clarified by finding changes in nonspecific bronchial responsiveness, sputum eosinophils or exhaled nitric oxide. The sensitivity and specificity of SIC are high but not easily quantified, as the method is usually used as the reference standard for the diagnosis of occupational asthma.

Altered microRNA expression of nasal mucosa in long-term asthma and allergic rhinitis.

BACKGROUND: Asthma and allergic rhinitis (AR) commonly coexist and can be taken as manifestations of one syndrome. Evidence exists that microRNAs (miRNAs) are important in controlling inflammatory processes and they are considered promising biomarkers. However, little is known about the differences in miRNA expression in patients with chronic allergic airway disease. This study evaluated the inflammatory and miRNA profiles of the nasal mucosa of patients with long-term asthma with and without AR. METHODS: We analyzed inflammatory cells, cytokines, and miRNAs in nasal biopsies and measured exhaled and nasal nitric oxide levels during the nonpollen season in 117 middle-aged men who had suffered mainly from allergic asthma for approximately 20 years and also in 33 healthy controls. RESULTS: The differences in the number of nasal eosinophils and cytokine expression levels were modest in nasal biopsies taken from asthmatics. Downregulation of miR-18a, miR-126, let-7e, miR-155, and miR-224 and upregulation of miR-498, miR-187, miR-874, miR-143, and miR-886-3p were observed in asthmatic patients in comparison to controls. The differences in miRNA expression were mainly similar in asthmatics with and without AR. With regard to asthma severity, a trend of increased miRNA expression in persistent asthma was seen, whereas the downregulation of certain miRNAs was most distinct in nonpersistent-asthma patients. CONCLUSIONS: Differences in miRNA expression in the nasal mucosa of subjects with long-term asthma and AR can be seen also when no markers of Th2-type inflammation are detected. Asthma severity had only a minor impact on miRNA expression.

Occupational asthma, rhinitis, and contact urticaria caused by oxidative hair dyes in hairdressers.

BACKGROUND: Oxidative hair dyes commonly contain paraphenylene diamine (PPD) and its derivatives, a well-known cause of delayed hypersensitivity among both consumers and hairdressers. They are also considered possible causes of occupational respiratory diseases. Despite the widespread use of hair dyes, there are only a few reports of asthma, rhinitis, and contact urticaria caused by PPD and related compounds. OBJECTIVE: To characterize patients with occupational asthma, rhinitis, or contact urticaria associated with oxidative hair dyes and to evaluate the diagnostic methods. METHODS: We reviewed the patient files of the Finnish Institute of Occupational Health for the period January 1, 2001, through May 31, 2011, to identify patients diagnosed as having asthma, rhinitis, or contact urticaria associated with oxidative hair dyes. The diagnoses of asthma and rhinitis were based on specific inhalation challenges with hair dye products. Skin prick tests were performed with hair dye ingredients as hapten conjugates of human serum albumin and with hair dye products and ingredients as is. Open skin tests confirmed the diagnosis of contact urticaria. RESULTS: We describe 11 hairdressers with occupational asthma (5 cases), rhinitis (5 cases), and contact urticaria (3 cases) due to hair dyes. Of the 52 specific inhalation challenges performed, 9 (17%) had positive results. One patient who experienced an anaphylactic reaction when having her own hair dyed had positive skin prick test results to PPD and toluene-2,5-diamine sulfate. CONCLUSION: Hairdressers are at risk for occupational asthma, rhinitis, and contact urticaria due to oxidative hair dyes. Skin prick testing may be insensitive for detecting immediate hypersensitivity to PPD and related compounds.

[Work aggravated asthma]. / Tyon pahentama astma.

One out of five working persons with asthma has work-related respiratory symptoms. When exploring the symptoms of a working-age patient it is essential to survey the job description and working conditions. Early intervention in the factors aggravating the respiratory symptoms will decrease morbidity, maintain working capacity and improve the quality of life. Occupational health service and the employer play a central role in identifying and decreasing the exposure factors in the working environment as well as in patient guidance for asthma therapy and protecting from the stimuli. The working capacity of an asthmatic person can be improved by applying vocational rehabilitation.

[Irritant-induced asthma]. / Ärsytyksen aiheuttama astma.

Irritant-induced asthma is a rare disease, usually being caused by an accidental or other exceptionally strong exposure to substances irritating the respiratory passages. High-dose inhaled corticosteroid medication is immediately started at the emergency call service. If severe exposure is suspected, it is important to monitor the patient at least for a couple of days in hospital. Immediately after the acute stage diagnostic investigations are carried out, including a metacholine or histamine challenge test, since demonstration of airway hyperreactivity is of diagnostic and prognostic significance. The asthma may remain permanent.

Long-term outcome of occupational asthma with different etiology.

PURPOSE OF REVIEW: This review summarizes the recent literature on the long-term outcome of sensitizer-induced and irritant-induced occupational asthma. RECENT FINDINGS: Recent studies of sensitizer-induced occupational asthma show that after the offending exposure has ceased, most patients report at least partial relief of symptoms. However, in the long term, the diagnosis may negatively impact their careers, incomes, and quality of life. The studies also offer new insights into diisocyanate-induced occupational asthma phenotypes and asthma remission rates. One third of these cases were in remission in long-term after reduction or cessation of exposure. The long-term prognosis of irritant-induced occupational asthma was demonstrated to be poorer than sensitizer-induced occupational asthma. Older age, low fractional exhaled nitric oxide levels and uncontrolled asthma at the time of diagnosis predicted uncontrolled asthma in the long term in patients with irritant and low-molecular-weight sensitizer induced occupational asthma. SUMMARY: Recent studies provide further evidence of the long-term outcome of different occupational asthma phenotypes and the factors that affect them. These findings help us identify patients at risk of poor asthma outcomes, who need close monitoring and support. It should also be borne in mind that occupational asthma diagnosis may have wider-ranging negative impacts on patients' lives.

Long-Term Impairment From Irritant-Induced Occupational Asthma.

OBJECTIVE: The aim of the study is to assess the long-term physical condition, health-related quality of life, employment, and work ability of irritant-induced asthma (IIA) patients. METHODS: Forty-three IIA patients completed a follow-up questionnaire a median of eight (interquartile range 4-11) years after asthma diagnosis. We compared their results with those of 43 low-molecular-weight (LMW) sensitizer-induced occupational asthma (OA) patients and those of 206 adult-onset asthmatics in the general population. RESULTS: Of the IIA patients, 40% reported depressive symptoms. Of the <65-year-olds, 56% were employed, of whom 39% assessed their work ability as limited. IIA patients had more difficulty climbing several flights of stairs than LMW-induced OA patients (70% vs 47%, OR = 4.83 95% CI: 1.51-15.47). Most of the IIA patients' outcomes were inferior to those of the adult-onset asthmatics in the general population. CONCLUSIONS: IIA prognosis appeared poor but resembled that of LMW-induced OA.