Diagnosis of occupational asthma from serial measurements of forced expiratory volume in 1 s (FEV1) using the Area Between Curves (ABC) score from the Oasys plotter.

OBJECTIVES: To identify the changes in serial 2-hourly forced expiratory volume in 1 s (FEV1) measurements required to identify occupational asthma (OA) using the Oasys Area Between Curves (ABC) score. METHODS: The ABC score from 2-hourly measurements of FEV1 was compared between workers with confirmed OA and asthmatics without occupational exposure to identify the optimum separation using receiver operator characteristic (ROC) analysis. Separate analyses were made for plots using clock time and time from waking to allow for use in shift workers. Minimum record criteria were ≥6 readings per day, >4 day shifts and >4 rest days (or >9 days for controls). RESULTS: A retrospective analysis identified 22 workers with OA and 30 control asthmatics whose records reached the quality standards. Median FEV1 diurnal variation was 20.3% (IQR 16.1-32.6) for OA and 19.5% (IQR 14.5-26.1) for asthmatic controls. ROC curve analysis identified that a difference of 0.056 L/hour gave a ROC score of 0.821 for clock time and 0.768 for time from waking with a sensitivity of 73% and a specificity of 93% for the diagnosis of OA. CONCLUSIONS: The diagnosis of OA requires objective confirmation. Unsupervised serial FEV1 measurements are more difficult to obtain reliably than measurements of peak expiratory flow, which are likely to remain the standard for general use. A FEV1 ABC score >0.056 L/hour provides a valid cut-off for those who wish to use FEV1 rather than peak expiratory flow.

Correction to: Aortic dilatation in children with mild to moderate chronic kidney disease.

The original version of this article unfortunately contained a mistake.

Identification of late asthmatic reactions following specific inhalation challenge.

Specific inhalation challenge (SIC) is the reference standard for the diagnosis of occupational asthma. Current guidelines for identifying late asthmatic reactions are not evidence based. OBJECTIVES: To identify the fall in forced expiratory volume in 1 s (FEV1) required following SIC to exceed the 95% CI for control days, factors which influence this and to show how this can be applied in routine practice using a statistical method based on the pooled SD for FEV1 from three control days. METHODS: Fifty consecutive workers being investigated for occupational asthma were asked to self-record FEV1 hourly for 2 days before admission for SIC. These 2 days were added to the in-hospital control day to calculate the pooled SD and 95% CI. RESULTS: 45/50 kept adequate measurements. The pooled 95% CI was 385 mL (SD 126), or 14.2% (SD 6.2) of the baseline FEV1, but was unrelated to the baseline FEV1 (r=0.06, p=0.68), or gender, atopy, smoking, non-specific reactivity or treatment before or during SIC. Thirteen workers had a late asthmatic reaction with ≥2 consecutive FEV1 measurements below the 95% CI for pooled control days, 4/13 had <15% and 9/13 >15% late fall from baseline. The four workers with ≥2 values below the 95% CI all had independent evidence of occupational asthma. CONCLUSION: The pooled SD method for defining late asthmatic reactions has scientific validity, accounts for interpatient spirometric variability and diurnal variation and can identify clinically relevant late asthmatic reactions from smaller exposures. For baseline FEV1 <2.5 L, a 15% fall is within the 95% CI.

The Impact of a Dementia-Friendly Exercise Class on People Living with Dementia: A Mixed-Methods Study.

Exercise has multiple benefits for people living with dementia. A programme of group exercise classes for people with dementia and their family carers has been established in a University sports centre. This study aims to explore the impact of this programme on participants with dementia and their carers. A mixed-methods design including a prospective, repeated measures cohort study followed by focus groups was employed. Physiological and cognitive outcome measures were repeated at baseline and three months in a cohort of people with dementia attending a group exercise class. Focus groups on the participants' experiences and their perceptions of the impact of the exercise class on their lives were then conducted. The results were analysed and mapped on a model, to illustrate the components that most likely promote participation. Sixteen participants (n = 8 with dementia, and n = 8 carers) were recruited, and completed both baseline and follow up assessments. Positive mean differences were found in physical activity (4.44), loneliness (1.75), mood (1.33) and cognition (1.13). Ten participants were included in the focus groups, which found that accessibility of the exercise venue, opportunities for socialisation and staff who were experienced working with people living with dementia were key to participants reporting benefits. The four key themes from the focus group data were synthesised to produce a model outlining the components that might generate a positive impact of the exercise classes and promote participation. Exercise classes for people with dementia can be delivered with success in novel environments such as University sports centres. There is some indication of improvement over a short period of time. The model derived from this study will inform strategies to promote attendance at dementia-friendly exercise classes.

Aortic dilatation in children with mild to moderate chronic kidney disease.

BACKGROUND: Children with mild to moderate chronic kidney disease are at an increased risk for cardiovascular sequelae, the leading cause of death in children with end-stage renal disease. We aimed to establish the prevalence of aortic dilatation, a newly recognized cardiovascular sequelae of renal disease, within a cohort of pediatric patients with mild to moderate kidney disease. METHODS: A total of 501 children enrolled in the Chronic Kidney Disease in Children study contributed imaging data between April 2011 and February 2015. Aortic dilatation was defined as a dimension exceeding a z-score of 2 at any of three locations: aortic root, sinotubular junction, or the ascending aorta. RESULTS: At baseline echocardiographic evaluation, 30 (6%) children were identified to have aortic dilatation in at least one of the three locations. Multivariate analysis demonstrated an increased odds ratio for the presence of aortic dilatation associated with the following variables: high diastolic blood pressure z-scores, low weight z-score, and low body mass index z-score. Presense of protein energy wasting (modified definition, OR 2.41, 95%CI 1.23, 4.70) was the strongest independent predictor of aortic dilatation. CONCLUSION: In conclusion, aortic dilatation does occur early in the course of chronic kidney disease and associates with markers of poor nutrition. Future studies should continue to evaluate these risk factors longitudinally as the kidney disease progresses.

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.

Characteristics of hypersensitivity pneumonitis diagnosed by interstitial and occupational lung disease multi-disciplinary team consensus.

INTRODUCTION: The causes of hypersensitivity pneumonitis (HP) in the UK are changing as working practices evolve, and metalworking fluid (MWF) is now a frequently reported causative exposure. We aimed to review and describe all cases of HP from our UK regional service, with respect to the causative exposure and diagnostic characteristics. METHODS: In a retrospective, cross-sectional study, we collected patient data for all 206 cases of HP diagnosed within our UK-based regional NHS interstitial and occupational lung disease service, 2002-17. This included demographics, environmental and occupational exposures, clinical features, and diagnostic tests (CT imaging, bronchiolo-alveolar cell count, lung function, histology). We grouped the data by cause (occupational, non-occupational and unknown) and by presence or absence of fibrosis on CT, in order to undertake hypothesis testing. RESULTS: Cases were occupational (n = 50), non-occupational (n = 56) or cryptogenic (n = 100) in aetiology. The commonest causes were birds = 37 (18%) and MWF = 36 (17%). Other occupational causes included humidifiers and household or commercial waste, but only one case of farmers' lung. Cryptogenic cases were associated with significantly older age, female gender, lower lung function parameters, fewer alveolar lymphocyte counts >20%, and fibrosis on CT; exposure information was missing in 22-33% of cryptogenic cases. CONCLUSION: MWF is the commonest occupational cause of HP, where workers usually present with more acute/subacute features and less fibrosis on CT; refuse work is an emerging cause. Cryptogenic HP has a fibrotic phenotype, and a full occupational history should be taken, as historical workplace exposures may be relevant.

Occupational asthma; the limited role of air-fed respiratory protective equipment.

BACKGROUND: Evidence-based reviews have found that evidence for the efficacy of respiratory protective equipment (RPE) in the management of occupational asthma (OA) is lacking. AIMS: To quantify the effectiveness of air-fed RPE in workers with sensitizer-induced OA exposed to metal-working fluid aerosols in a car engine and transmission manufacturing facility. METHODS: All workers from an outbreak of metal-working fluid-induced OA who had continuing peak expiratory flow (PEF) evidence of sensitizer-induced OA after steam cleaning and replacement of all metal-working fluid were included. Workers kept 2-hourly PEF measurements at home and work, before and after a strictly enforced programme of RPE with air-fed respirators with charcoal filters. The area-between-curve (ABC) score from the Oasys plotter was used to assess the effectiveness of the RPE. RESULTS: Twenty workers met the inclusion criteria. Records were kept for a mean of 24.6 day shifts and rest days before and 24.7 after the institution of RPE. The ABC score improved from 26.6 (SD 16.2) to 17.7 (SD 25.4) l/min/h (P > 0.05) post-RPE; however, work-related decline was <15 l/min/h in only 12 of 20 workers, despite increased asthma treatment in 5 workers. CONCLUSIONS: Serial PEF measurements assessed with the ABC score from the Oasys system allowed quantification of the effect of RPE in sensitized workers. The RPE reduced falls in PEF associated with work exposure, but this was rarely complete. This study suggests that RPE use cannot be relied on to replace source control in workers with OA, and that monitoring post-RPE introduction is needed.

Hospital Attendances and Acute Admissions Preceding a Diagnosis of Occupational Asthma.

PURPOSE: Occupational exposures are a common cause of adult-onset asthma; rapid removal from exposure to the causative agent offers the best chance of a good outcome. Despite this, occupational asthma (OA) is widely underdiagnosed. We aimed to see whether chances of diagnosis were missed during acute hospital attendances in the period between symptom onset and the diagnosis of OA. METHODS: Patients diagnosed with OA at the regional occupational lung disease service in Birmingham between 2007 and 2018 whose home address had a Birmingham postcode were included. Emergency department (ED) attendances and acute admission data were retrieved from acute hospitals in the Birmingham conurbation for the period between symptom onset and diagnosis. RESULTS: OA was diagnosed in 406 patients, 147 having a Birmingham postcode. Thirty-four percent (50/147) had acute hospital attendances to a Birmingham conurbation hospital preceding their diagnosis of OA, including 35 (24%) with respiratory illnesses, which resulted in referral for investigation of possible OA in 2/35. The median delay between symptom onset and diagnosis of OA was 30 months (IQR = 13-60) and between first hospital attendance with respiratory illness and diagnosis 12 months (IQR = 12-48, range 3-96 months) CONCLUSIONS: The chance to reduce the delay in the diagnosis of OA was missed in 33/35 patients admitted or seen in ED with respiratory symptoms in the period between symptom onset and diagnosis of OA. The diagnosis of OA was delayed by a median of 12 months by failure to ask about employment and work relationship of symptoms.

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.

A randomised controlled trial of an exercise intervention promoting activity, independence and stability in older adults with mild cognitive impairment and early dementia (PrAISED) - A Protocol.

BACKGROUND: People with dementia progressively lose cognitive and functional abilities. Interventions promoting exercise and activity may slow decline. We developed a novel intervention to promote activity and independence and prevent falls in people with mild cognitive impairment (MCI) or early dementia. We successfully undertook a feasibility randomised controlled trial (RCT) to refine the intervention and research delivery. We are now delivering a multi-centred RCT to evaluate its clinical and cost-effectiveness. METHODS: We will recruit 368 people with MCI or early dementia (Montreal Cognitive Assessment score 13-25) and a family member or carer from memory assessment clinics, other community health or social care venues or an online register (the National Institute for Health Research Join Dementia Research). Participants will be randomised to an individually tailored activity and exercise programme delivered using motivational theory to promote adherence and continued engagement, with up to 50 supervised sessions over one year, or a brief falls prevention assessment (control). The intervention will be delivered in participants' homes by trained physiotherapists, occupational therapists and therapy assistants. We will measure disabilities in activities of daily living, physical activity, balance, cognition, mood, quality of life, falls, carer strain and healthcare and social care use. We will use a mixed methods approach to conduct a process evaluation to assess staff training and delivery of the intervention, and to identify individual- and context-level mechanisms affecting intervention engagement and activity maintenance. We will undertake a health economic evaluation to determine if the intervention is cost-effective. DISCUSSION: We describe the protocol for a multi-centre RCT that will evaluate the clinical and cost-effectiveness of a therapy programme designed to promote activity and independence amongst people living with dementia. TRIAL REGISTRATION: ISRCTN, ISRCTN15320670. Registered on 4 September 2018.

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.

Do laboratory challenge tests for occupational asthma represent what happens in the workplace?

Specific inhalation challenge (SIC) is the diagnostic reference standard for occupational asthma; however, a positive test cannot be considered truly significant unless it can be reproduced by usual work exposures. We have compared the timing and responses during SIC in hospital to Oasys analysis of serial peak expiratory flow (PEF) during usual work exposures.All workers with a positive SIC to occupational agents between 2006 and 2015 were asked to measure PEF every 2 h from waking to sleeping for 4 weeks during usual occupational exposures. Responses were compared between the laboratory challenge and the real-world exposures at work.All 53 workers with positive SIC were included. 49 out of 53 had records suitable for Oasys analysis, 14 required more than one attempt and all confirmed occupational work-related changes in PEF. Immediate SIC reactors and deterioration within the first 2 h of starting work were significantly correlated with early recovery, and late SIC reactors and a delayed start to workplace deterioration were significantly correlated with delayed recovery. Dual SIC reactions had features of immediate or late SIC reactions at work rather than dual reactions.The concordance of timings of reactions during SIC and at work provides further validation for the clinical significance of each test.

The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice.

Aim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles as transcription factors in the regulation of carbohydrate, lipid, and protein metabolism. We hypothesized that the activation of PPAR signaling with PPAR agonist bezafibrate (BF) may ameliorate impaired cardiac and skeletal muscle function in TazKD mice. This study examined the effects of BF on cardiac function, exercise capacity, and metabolic status in the heart of TazKD mice. Additionally, we elucidated the impact of PPAR activation on molecular pathways in TazKD hearts. Methods: BF (0.05% w/w) was given to TazKD mice with rodent chow. Cardiac function in wild type-, TazKD-, and BF-treated TazKD mice was evaluated by echocardiography. Exercise capacity was evaluated by exercising mice on the treadmill until exhaustion. The impact of BF on metabolic pathways was evaluated by analyzing the total transcriptome of the heart by RNA sequencing. Results: The uptake of BF during a 4-month period at a clinically relevant dose effectively protected the cardiac left ventricular systolic function in TazKD mice. BF alone did not improve the exercise capacity however, in combination with everyday voluntary running on the running wheel BF significantly ameliorated the impaired exercise capacity in TazKD mice. Analysis of cardiac transcriptome revealed that BF upregulated PPAR downstream target genes involved in a wide spectrum of metabolic (energy and protein) pathways as well as chromatin modification and RNA processing. In addition, the Ostn gene, which encodes the metabolic hormone musclin, is highly induced in TazKD myocardium and human failing hearts, likely as a compensatory response to diminished bioenergetic homeostasis in cardiomyocytes. Conclusion: The PPAR agonist BF at a clinically relevant dose has the therapeutic potential to attenuate cardiac dysfunction, and possibly exercise intolerance in BTHS. The role of musclin in the failing heart should be further investigated.

A development study and randomised feasibility trial of a tailored intervention to improve activity and reduce falls in older adults with mild cognitive impairment and mild dementia.

BACKGROUND: People with dementia progressively lose abilities and are prone to falling. Exercise- and activity-based interventions hold the prospect of increasing abilities, reducing falls, and slowing decline in cognition. Current falls prevention approaches are poorly suited to people with dementia, however, and are of uncertain effectiveness. We used multiple sources, and a co-production approach, to develop a new intervention, which we will evaluate in a feasibility randomised controlled trial (RCT), with embedded adherence, process and economic analyses. METHODS: We will recruit people with mild cognitive impairment or mild dementia from memory assessment clinics, and a family member or carer. We will randomise participants between a therapy programme with high intensity supervision over 12 months, a therapy programme with moderate intensity supervision over 3 months, and brief falls assessment and advice as a control intervention. The therapy programmes will be delivered at home by mental health specialist therapists and therapy assistants. We will measure activities of daily living, falls and a battery of intermediate and distal health status outcomes, including activity, balance, cognition, mood and quality of life. The main aim is to test recruitment and retention, intervention delivery, data collection and other trial processes in advance of a planned definitive RCT. We will also study motivation and adherence, and conduct a process evaluation to help understand why results occurred using mixed methods, including a qualitative interview study and scales measuring psychological, motivation and communication variables. We will undertake an economic study, including modelling of future impact and cost to end-of-life, and a social return on investment analysis. DISCUSSION: In this study, we aim to better understand the practicalities of both intervention and research delivery, and to generate substantial new knowledge on motivation, adherence and the approach to economic analysis. This will enable us to refine a novel intervention to promote activity and safety after a diagnosis of dementia, which will be evaluated in a definitive randomised controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02874300; ISRCTN 10550694.