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.

Occupational IgE-mediated psyllium allergy in contemporary gluten-free and vegan baking: A case of allergic rhinitis.

Psyllium (from Plantago ovata; ispaghula) is used as a dietary supplement and is supplied in the form of husk, granules, capsules, or powder. Consumers using psyllium-containing laxatives, healthcare workers handling these, and pharmaceutical workers in laxative-manufacturing plants are known to be at risk of sensitization and subsequent rhinitis, asthma, contact urticaria, and even anaphylaxis. To our knowledge, the case we present here is the first of baker's immunoglobulin E (IgE)-mediated occupational allergy due to psyllium exposure. Our patient, a 24-year-old female baker with no previous allergies, was referred to our clinic with suspected occupational rhinitis. After 1 year of baking with cereal flour or gluten-free flour-mix, she began to suffer from rhino-conjunctival symptoms during workdays. Skin prick tests with agents from the patient's workplace revealed allergies not only to wheat and rye flours but also to psyllium, with a remarkable 10 mm wheal. Subsequently, nasal provocation tests confirmed occupational allergic rhinitis to psyllium. We also found work-related sensitization to buckwheat, which she used in gluten-free baking. Due to the increased prevalence of celiac disease and the popularity of gluten-free and vegan food, psyllium has recently become a common ingredient in baking, used as a substitute for gluten or eggs. Bakers handle allergens such as these in high concentrations and this may lie behind the emergence of respiratory and dermal symptoms. It is essential to consider new or recenlty introduced materials as possible allergens if it is suspected that a baker has work-related respiratory or allergic symptoms.

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.

Do aggravating rhinologic symptoms at work indicate occupational exposure? A cross-sectional outpatient clinic study.

BACKGROUND: Air impurities can exacerbate or cause rhinologic diseases. However, only a few studies have assessed rhinologic patients' symptoms at work. OBJECTIVE: This study surveys the impact of work on rhinology clinic patients' quality of life in relation to work-related respiratory exposures. In addition, we surveyed patients' sick leave periods. METHODS: We recruited adult employed rhinology patients referred to the otorhinolaryngology clinic. A total of 177 patients were included. We collected data on patients' medical history, rhinologic disease-specific and generic quality of life, current or most recent job title, a description of current work, nasal symptoms, possible worked-related symptom triggers and sick leave periods during the preceding year. RESULTS: In total, 101 (57.1%) patients reported exacerbated rhinologic symptoms at work and reported more severe rhinologic disease and a lower disease-specific quality of life compared to non-work-related rhinologic patients (P = 0.008). A minority, 24.3% of our patients were exposed to any specific occupational respiratory sensitizer or irritant at work. The mean sick leave period due to rhinologic disease was 7.7 days per year. CONCLUSIONS: Exposure to specific occupational sensitizers or irritants did not associate with increasing symptoms at work or quality of life amongst our patients. Most rhinology patients reported exacerbated symptoms at work. They appeared to be more symptomatic than the rest of the patients and, therefore, possibly hyperreactive to unspecific respiratory triggers at work. Rhinologic diseases caused our patients a marked burden with high work absenteeism.

Occupational buckwheat allergy as a cause of allergic rhinitis, asthma, contact urticaria and anaphylaxis-An emerging problem in food-handling occupations?

Buckwheat is a known, though uncommon, allergen in occupational settings. It has recently gained popularity as healthy food and as an ingredient in gluten-free diets. We describe a series of six patient cases with occupational immediate allergy to buckwheat. Three cooks, two bakers, and a worker in a grocery store were occupationally exposed to buckwheat flour and developed immediate allergy to buckwheat, which was confirmed by skin prick testing and measurement of specific immunoglobulin E antibodies. Four of the patients were diagnosed with occupational asthma, four with occupational rhinitis, and two with occupational contact urticaria caused by buckwheat. Three of the six patients suffered anaphylaxis as consequence of their occupational buckwheat allergy after ingestion of food that contained buckwheat. The high rate of life-threatening reactions, together with a short exposure time to buckwheat before sensitization occurred in these cases, highlights the importance of a detailed occupational history and a high index of suspicion for occupational food allergens.

Occupational rhinitis, asthma, and contact urticaria from IgE-mediated allergy to pork.

We describe four cases of slaughterhouse workers with occupational immediate allergy to raw pork allergens, confirmed by positive skin prick testing and specific immunoglobulin E (IgE) antibodies. Our first patient was diagnosed with occupational asthma from raw pork allergens. Two patients were diagnosed with occupational rhinitis caused by raw pork allergens, which was confirmed by a nasal provocation test. One of these also had occupational contact urticaria caused by raw pork meat. We were unable to diagnose an occupational respiratory or skin disease in the fourth patient, despite signs of immediate sensitization to raw pork meat from occupational exposure. Based on proper diagnoses, measures to prevent allergen exposure were taken, which led to the improvement of symptoms in these four patients. The present patient cases highlight the importance of recognition of early signs of occupational allergy and identification of causative allergens in order to allow avoidance of allergens, with the aim of preventing persistence and worsening of symptoms.

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.

Paprika rhinoconjunctivitis case reveals new occupational Capsicum allergens.

No allergens related to paprika or cayenne respiratory allergy have been identified thus far. We describe a previously healthy 28-year woman who developed work-related rhinoconjunctivitis after four years of kebab-restaurant work. The allergy was studied using skin prick tests, serum specific IgE and nasal provocation tests. Specific IgE protein reactions were studied by Western blot analysis. Paprika, cayenne and curry allergens were identified from the strongest immunoblot bands using tandem mass spectrometry. A positive skin prick test, high specific IgE and positive nasal provocation test confirmed occupational rhinoconjunctivitis from Capsicum spices. Defensin J1 and Vicilin were identified as major paprika and cayenne allergens in this case. Vicilin was detected also from the curry ingredients. Two new occupational respiratory allergens from the Capsicum species were identified. These differ from previously reported bell pepper allergens. We emphasize that substantial spice handling at work poses an allergy risk.

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.

[Clinical assessment of work-related rhinitis]. / Työperäinen nuha.

In the examinations of recurrent or chronic rhinitis, important aspect is whether the rhinitis symptoms and work are related. Dusts, fumes, smoke, vapours and smells at work can all cause nasal irritation or rhinitis. Occupational rhinitis (OR) means that rhinitis is mainly caused by work. OR is usually IgE-mediated allergic rhinitis, and rarely caused by other mechanisms. The crucial tasks in the examination of work-related rhinitis are description of the job, its allergens and irritants, and performing relevant allergy testing and nasal examinations to exclude other causes of rhinitis. The main focus in management of OR is to avoid further exposure.

Use of nasal provocation test in the diagnostics of occupational rhinitis.

OBJECTIVES: The purpose of the study was to evaluate the usefulness and clinical value of the nasal provocation test (NPT) with various allergens and non-IgE-mediated irritants in the diagnostics assessing occupational rhinitis. METHODS: A large number nasal provocation data from patients with suspected occupational rhinitis was evaluated retrospectively. The results of nasal provocation tests with different agents, as well as the correlation of nasal scoring to weighed mucus secretion, were analyzed. RESULTS: Altogether 507 NPTs were done in three years in 165 persons. In total, 39% of the allergen provocations (125/318) were positive. The most common positive reactions were against flours, animal epithelia, storage mites and various plants. Wood dusts, mainly through non-IgE-mediated reactions, gave 50% positive results. Positive NPTs to moulds were observed mainly in sensitized patients. Altogether, 10% of the control provocations were positive. The weighting of mucus secretion added sensitivity of NPT. CONCLUSIONS: The NPT is an essential standard tool in the diagnostics of allergic occupational rhinitis; however it needs to be evaluated in the context of the medical and work history and knowledge of sensitization. Although expensive and laborious, NPT is safe and easy for the patient. We still need reliable diagnostic tools for non-allergic work-related rhinitis.

Detecting inaudible vocal organ changes through glottal inverse filtering.

The aim of this study was to investigate if there were objective quantities extracted from the speech pressure waveforms that underlay inaudible changes in the symptoms of the vocal organ. This was done through analyzing 180 voice samples obtained from nine subjects (five females and four males) before and after exposure to a placebo substance (lactose) and an organic dust substance. Acoustical analysis of the voice samples was achieved by using glottal inverse filtering. Results showed that the values of primary open quotient and primary speed quotient changed significantly (P<0.05) as did the amplitude quotient (P<0.01). Exposure to lactose resulted in significant changes of secondary open quotient (P<0.05) but opposite to effects found for exposure to organic dust. Modeling of the vocal tract into cross-sectional planes revealed that the immediate plane above the vocal folds correlates inversely with the feeling that voice is tense, or feeling the need to make an effort when speaking in addition having a feeling of shortness of breath or the need to gasp for air. Such results may point to acoustically detected subclinical changes in the vocal organ that the subject him/herself feels while they remain perceptually undetected by others.

Thaumatin-like protein and baker's respiratory allergy.

BACKGROUND: Baker's asthma and rhinitis are among the most common occupational diseases. Inhaled cereal flours, such as wheat, especially cause this disease. OBJECTIVE: To identify and test in vivo clinically important wheat allergens in baker's respiratory allergy in a Finnish population. METHODS: Potential wheat allergens were purified using chromatographic methods from salt-soluble protein extracts of wheat flour and were used in skin prick tests with serial 10-fold dilutions (0.5-0.005 mg/mL). Twenty patients with baker's rhinitis, asthma, or both participated in this study. All the patients had positive skin prick test reactions and specific IgE antibodies to wheat flour. The control group consisted of 10 healthy individuals. Molecular identities of purified wheat allergens were characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and tandem mass spectrometry. RESULTS: Allergen concentrations of 0.3-0.5 mg/mL revealed that 12 patients reacted to a-amylase inhibitor (alpha-AI), 9 to peroxidase I (PI), 9 to thaumatin-like protein (TLP), and 6 to lipid transfer protein 2G (LTP2G). Conversely, with allergen concentrations of 0.05 mg/mL, 5 patients responded to alpha-AI, 3 to PI, 4 to LTP2G, and 6 to TLP. Of these, TLP and LTP2G are now observed to be new allergens associated with baker's asthma. CONCLUSIONS: In addition to the earlier-described alpha-AI and PI, TLP and LTP2G are important in vivo wheat allergens in baker's allergies in Finland. Further studies are needed to elucidate the role of these novel wheat allergens in respiratory disorders.

Pilot study on acute voice and throat symptoms related to exposure to organic dust: preliminary findings from a provocation test.

The aim of this pilot research was to investigate acute voice and throat symptoms related to organic dust exposure among nine subjects with suspected occupational rhinitis or asthma. Subjective voice and throat symptoms were recorded before and after an occupational exposure test. In addition, the study included perceptual assessment of subjects' voice samples recorded before and after the exposure tests. The results showed a number of (statistically) significant voice and throat changes in symptoms based on subjects' own assessments. These symptoms included a hoarse, husky, or tense voice, requiring an extra effort when speaking and difficulty in starting phonation (P < 0.05). Other significant symptoms included feeling of shortness of breath or the need to gasp for air and feeling that the voice is weak or that it does not resonate (P < 0.01). Such changes were not, however, detected by voice clinicians in the listening test of subjects' voice samples recorded before and after the exposure. These results suggest that the larynx reacts to organic dust with symptoms that are felt by the patient rather than heard by the voice clinician. The voice disorder in such cases is a diagnosis based on symptoms expressed by subjects.

Long-term exposure and health-related quality of life among patients with occupational rhinitis.

OBJECTIVE: This article evaluates health-related quality of life (HRQoL) among patients with occupational rhinitis (OR), with an average of 10 years after diagnosis. METHODS: A cross-sectional questionnaire with general (RAND-36) and disease-specific (Rhinasthma) HRQoL questions was completed by 119 OR patients and 173 controls of the same age and locality. In addition, the patients compared their estimation of current occupational exposure level with that at the time of OR diagnosis. RESULTS: HRQoL was impaired among patients with continuing occupational allergen exposure in all Rhinasthma and several RAND-36 scores. The HRQoL among patients no longer exposed was mainly similar to that of the healthy controls. CONCLUSIONS: Among OR patients, continuous occupational exposure decreases QoL years after the diagnosis. To restore the well being of patients with OR, medication only is not sufficient; reduction or cessation of exposure is necessary.

Inhalation challenge test in the diagnosis of occupational rhinitis.

BACKGROUND: Evaluations of rhinitis reactions in inhalation challenges (ICs) are sparse compared with research on nasal challenges. This study evaluates the outcome of IC tests in assessing occupational rhinitis (OR). It presents the largest rhinologic IC data in the literature, analyzing the exposure method of various agents causing OR and their relation to asthma. METHODS: Challenge tests performed on 829 individuals with suspected cases of OR were reviewed. Results from both exposures with occupational agents (n = 1229) and placebo (n = 838) were evaluated. RESULTS: A total of 10% of the occupational ICs (n = 123) were positive, suggesting OR, and 13% (n = 161) showed asthmatic reaction in the same challenge. In control challenges 2% showed rhinitis and 6% showed asthma symptoms. The most common agents tested were molds (160 tests), flours, and animal fodders (115 tests) and formaldehyde (122 tests). Obeche wood dust and latex produced positive nasal reactions the most frequently, followed by acid anhydrides. CONCLUSION: Although IC is a resource-intensive methodology, the evaluation of nasal symptoms and signs together with bronchial reactions saves time and expense compared with the organization of multiple individual challenges. We encourage the simultaneous evaluation of both nasal and bronchial reactions in IC tests.