Death and work: recognition of occupational association and coroner's investigation.

BACKGROUND: The degree of recognition of occupation as a contributory factor at the time of death certification is not known and there are few data describing the frequency with which a link to work is confirmed by the coroner. The medical examiner (ME) in England and Wales has a remit to scrutinize the circumstances of death and ensure accurate certificate completion with a requirement to pay specific attention to occupational factors. AIMS: To examine work assessment in the death certification process. METHODS: Deaths between March 2011 and December 2012 scrutinized by the Sheffield ME were assessed to identify the number of cases in which occupation was recorded and considered, the proportion of deaths referred to the coroner on the grounds of occupational history and the subsequent action taken by the coroner. RESULTS: A total of 5018 deaths were included in the study. Occupation was recorded in medical documentation used to complete the medical certificate of cause of death (MCCD) in 32% (1581) of cases. Of 1775 cases referred to the coroner by the ME, 8% (142) were on the grounds of occupation with 102 of these requiring autopsy, inquest or both. A total of 50 deaths were confirmed by the coroner as due to industrial disease. CONCLUSIONS: Our study describes an important step towards improving the validity of data on occupational mortality, using trained independent review prior to medical certification. Wider implementation of the ME scheme can improve the accuracy of MCCD completion and improve judgement of the contribution of occupation to an individual's death.

Increased augmentation index in patients with cystic fibrosis.

Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. We determined large artery parameters in adults with cystic fibrosis (CF). 50 clinically stable adult patients with CF (mean+/-sd age 28.0+/-8.2 yrs) and 26 controls matched for age, sex and body mass index were studied. Central aortic blood pressure, augmentation index (AIx) and aortic pulse wave velocity (PWV) were determined using applanation tonometry. Lung function, diabetic status and C-reactive protein (CRP) were also determined. Mean+/-sd AIx was greater in patients than controls, 8.5+/-11.1% and -1.8+/-13.1%, respectively (p<0.001), while PWV was similar. Although AIx was greatest in the sub-group with CF-related diabetes (CFRD), it was also increased in the non-CFRD sub-group when compared with controls. In patients, AIx was related to log(10) CRP (r = 0.33) and forced vital capacity (r = -0.34; both p<0.05), and CRP remained predictive in multiple regression. AIx is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status. These findings have implications for management and require further exploration so that cardiovascular health can be maintained.

Circulating matrix metalloproteinase-9 and osteoporosis in patients with chronic obstructive pulmonary disease.

Matrix metalloproteinase-9 (MMP-9) has been implicated in airways injury in chronic obstructive pulmonary disease (COPD). Osteoporosis is common in patients with COPD, and MMP-9 is an indicator of activated osteoclasts. We hypothesized that circulating MMP-9 would be related to bone mineral density (BMD) in COPD. We explored the relationship between MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1 and -2, and BMD status in patients with COPD. A total of 70 clinically stable patients with confirmed COPD and 39 control subjects underwent spirometry, dual-energy x-ray absorptiometry to determine BMD, and venous sampling for measurement of cytokines and MMP-9 and TIMP-1 and -2. In patients, circulating MMP-9 was increased: mean (SD) 38.5 (2.2) compared with control subjects 20.1 (2.0) ng/mL, P < 0.001, whereas TIMP-1 and -2 were not different. In the patients, MMP-9 was greater in those with osteoporosis, compared with those with osteopenia, no bone disease or control subjects, and patients with osteopenia had greater MMP-9 than control subjects. The adjusted receiver operating characteristics curve area for MMP-9 detecting osteoporosis was 0.86. Patients had elevated systemic inflammatory mediators compared with control subjects, but these were unrelated to bone status. Increased circulating MMP-9 in patients with COPD was related to the presence of osteoporosis and not to lung function. MMP-9 may be a biomarker of increased bone resorption.

What community measurements can be used to predict bone disease in patients with COPD?

BACKGROUND: Osteoporosis is common in patients with COPD. Previously we have reported that loss of fat-free mass (FFM), measured by dual X-ray absorptiometry (DXA) is associated with loss of bone mineral density (BMD). In addition, in patients with a low body mass index (BMI) and a low FFM, all had evidence of bone thinning, 50% having osteopenia and 50% osteoporosis. We explored the utility of different anthropometric measures in detecting osteoporosis in a community-based COPD population. METHODS: Patients with confirmed COPD and not on long-term oral corticosteroids (n=58) performed spirometry. They underwent nutritional assessment by skinfold anthropometry, midarm circumference, calculation of both % ideal body weight (IBW) and BMI. All had DXA assessment of BMD. RESULTS: A total of 58 COPD patients had anthropometric measurements taken, with a mean age of 66.8 (SD 8.7) years, 31 (58%) were male, with a forced expiratory volume in 1s (FEV(1)) of 54.17 (20.18)% predicted. Osteoporosis was present at either the hip or lumbar region in 14 patients (24%). The useful anthropometric measurements identifying those with osteoporosis were both % IBW and BMI. The adjusted odds ratio for %IBW was 0.93 (95% confidence interval (CI) 0.87, 0.99), p=0.016 and for BMI: 0.79 (0.64-0.98), p=0.03. The receiver operating characteristics (ROC) score for both was 0.88, indicating a good fit. CONCLUSION: Osteoporosis is common, even in patients with mild airways obstruction. Nutritional assessment, incorporating a calculation of their BMI or %IBW may confer an additional benefit in detecting those at risk of osteoporosis and guide referral for BMD measurement.

Insulin resistance and inflammation - A further systemic complication of COPD.

Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p=0.032. Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r=0.276, p=0.039, and tumour necrosis factor alpha soluble receptor I, r=0.351, p=0.008. Both IL-6 and BMI were predictive variables of insulin resistance r(2)=0.288, p<0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD.

Attaining a correct diagnosis of COPD in general practice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is common. Diagnosis should include objective evidence of airways obstruction and spirometry is recommended in guidelines and the general medical services contract in the UK. We assessed the impact of spirometry in general practice. METHOD: We determined by questionnaire the availability, staff training, use and the interpretation results of spirometry in 72% of general practices in Wales. We reviewed the diagnosis of COPD previously made in two general practices without spirometry. RESULTS: Most practices had a spirometer (82.4%) and used it (85.6%). Confidence in use and interpretation of results varied widely: 58.1% were confident in use and 33.8% confident in interpretation. Spirometry was performed more often if confident in use and interpretation (both P<0.001) and was related to greater training periods (P<0.001). Spirometric confirmation of COPD varied widely (0-100%, median 37%). Of the 125 patients previously diagnosed with COPD 61 had spirometric confirmation, while 25 had reversible obstruction (range 210-800 mls), 34 had normal and 5 had restrictive spirometry. CONCLUSION: Despite incentives to perform spirometry in general practice, lack of adequate training in use and interpretation suggests use is confounded and the diagnosis of COPD is likely to be made on imprecise clinical grounds.

A short-term comparison of two methods of sputum expectoration in cystic fibrosis.

The aim of this study was to determine whether repeated maximum inspiratory vital capacity manoeuvres against a fixed resistance increased effective short-term sputum clearance in adults with cystic fibrosis (CF). Twenty adults with CF were randomised to receive, on alternate days, either standardised physiotherapy (SP) for 30 min, comprising postural drainage and the active cycle of breathing technique, or a series of resistive inspiratory manoeuvres (RIM) at 80% of their maximum sustained inspiratory pressure developed between residual volume and total lung capacity during the first 4 days of the treatment of an exacerbation of respiratory symptoms. Expectorated sputum was collected during and for 30 min after each treatment and weighed. Total protein, immunoreactive interleukin (IL)-8 and human neutrophil elastase (HNE) concentrations, and the amount of each component expectorated, were determined. Compared with SP, RIM increased sputum weight two-fold, independent of treatment order or day. The concentrations of protein, IL-8 and HNE in sputum were similar for both treatments, while the quantity expectorated was greater with RIM treatment. In conclusion, short-term resistive inspiratory manoeuvres treatment was more effective at clearing sputum and inflammatory mediators than standardised physiotherapy.

Altered tissue distribution in adults with cystic fibrosis.

BACKGROUND: Regional body composition was determined in adults with cystic fibrosis (CF). Our hypothesis was that dual energy x ray absorptiometry (DXA) scanning could assess the fat free mass, bone mineral content, and fat mass and determine the distribution of the changes. METHOD: Height squared indices were derived for fat mass (FMI), fat free mass (FFMI), and bone mineral content (BMCI) of the arm, leg, and trunk by DXA in 51 patients and 18 age/sex matched healthy subjects. RESULTS: The arm and leg FFMI in patients were less than in healthy controls (p<0.05); the deficit was leg>arm>trunk (-18.19%, -14.86%, +0.09%, p<0.02) and was related to severity of lung disease. Patients with a normal BMI and low total FFM (hidden loss) had a lower arm, leg and trunk FFMI than those with a normal BMI and total FFM (p<0.05). The BMCI for all body segments was lower in patients than in controls (p<0.001). The BMCI was lower in the leg and trunk (p<0.01) in patients with severe disease than in those with mild lung disease. In those with hidden FFM loss the BMCI was lower (p<0.05 in leg and trunk). There was no difference in the BMCI deficit between body segments. Fat mass in patients was not reduced. CONCLUSION: Preferential loss of FFM is related to severity of lung disease and occurs in patients with a normal BMI. A similar loss of BMC occurs while FM is preserved. A hierarchical pattern of FFM loss of legs>arms>trunk was shown; BMC loss was evenly distributed.

Inflammatory response and body composition in chronic obstructive pulmonary disease.

Weight loss in chronic obstructive airways disease (COPD) is associated with an increased energy cost of breathing. To determine an association between body composition and the inflammatory response we studied 80 clinically stable patients. Body composition was determined anthropometrically and skeletal muscle mass was determined as the creatinine-height index (CHI). Forty patients had their nitrogen balance determined. Circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and their soluble receptors were determined for 68 patients. Body mass index (BMI) was normal (> 20 kg/m(2)) in 55 patients, of whom 17 (31%) had a low CHI (< 80% predicted). A reduced CHI was associated with increased circulating levels of IL-6 (p = 0.001), TNF-alpha (p = 0.032) and their soluble receptors IL-6sr (p = 0.002), TNF-alpha sr1 (p = 0.03), and TNF-alpha sr2 (p = 0.001). Patients with a normal BMI and low CHI had inflammatory mediator levels similar to patients with a low BMI and CHI; both were significantly greater than in those with a normal BMI and CHI. Nitrogen balance was similar between normal and low CHI groups, although nitrogen excretion was significantly increased in the low CHI group. Skeletal muscle loss in COPD is probably multifactorial in origin, but our data suggest a link with systemic inflammation, even when weight loss is inapparent.

Subclinical right ventricular dysfunction in cystic fibrosis. A study using tissue Doppler echocardiography.

Patients with severe cystic fibrosis can develop cor pulmonale, but little is known about the function of the right ventricle (RV) early in the disease. We hypothesized that such patients might have subclinical RV dysfunction, detectable by tissue Doppler echocardiography, and related to the severity of lung disease. We studied 21 clinically stable patients (Group 1), five patients with severe lung disease (Group 2), and 23 age-matched healthy subjects. Patients had impaired RV systolic function. The mean (SD) systolic velocities of the RV free wall were 8.9 (1.7) cm/s in Group 1, 7.7 (1.0) in Group 2, and 10.8 (1.9) in healthy subjects (p < 0.001). The velocities of the tricuspid annulus were less in patients (p < 0.0001). Patients had a greater isovolumic relaxation time (p < 0.001), indicating RV diastolic dysfunction. RV wall thickness was greater in patients (0.4 [0.1] versus 0.3 [0.1] cm/m(2), p < 0.01). RV systolic function was related to C-reactive protein (r = - 0.66, p < 0.001) and FEV(1) (r = 0.62, p = 0.003) and diastolic function to interleukin-6 (r = 0.64, p < 0.005). Patients with cystic fibrosis have subclinical RV dysfunction, which correlates with the severity of lung disease. Tissue Doppler echocardiography provides a quantifiable indicator useful for detection and monitoring of disease progression.

Bone density, body composition, and inflammatory status in cystic fibrosis.

Low body weight and loss of bone mass are major problems in adults with cystic fibrosis (CF) and chronic pulmonary infection. Although these complications probably have a multifactorial origin, we hypothesized that the continuous acute-phase inflammatory and catabolic state may contribute. We determined body composition, bone turnover, physical activity, and circulating interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and their soluble receptors in 22 adults with CF and 22 age- and sex-matched healthy subjects. Comparisons were also made within patients before and after treatment of an exacerbation of respiratory symptoms. The patients had a lower mean (95% confidence interval [CI]) fat-free mass (FFM) 39.9 (36.3, 43.6) kg than healthy subjects, 49.4 (45.1, 53.7) kg, p < 0.05. The patients were in negative nitrogen balance and 20 had bone mineral density (BMD) Z scores

Antibody response to Burkholderia cepacia in patients with cystic fibrosis colonized with Burkholderia cepacia and Pseudomonas aeruginosa.

INTRODUCTION: This study was designed to determine the relationship between formation of serum antibodies to lipopolysaccharide (LPS) core antigen of Burkholderia cepacia and pulmonary colonization with B. cepacia and Pseudomonas aeruginosa in patients with cystic fibrosis (CF), and to define if an enhanced host humoral immune response to B. cepacia was related to a poor clinical outcome. METHODS: Serum IgG to B. cepacia LPS core antigen was measured in adult cystic fibrosis patients colonized with B. cepacia and P. aeruginosa, and serial titres were measured in 13 B. cepacia and 41 P. aeruginosa colonized patients followed prospectively over 18 months. RESULTS: The median B. cepacia antibody titre was significantly greater in the patients colonized with B. cepacia compared to those colonized with P. aeruginosa, a group which grew B. cepacia intermittently from their sputum. and nine healthy controls. The median antibody titre at recruitment into the study was significantly greater in patients who later went into exacerbations compared with those who remained clinically stable. but there was no difference between B. cepacia antibody titres in patients who died and those who survived the study duration. DISCUSSION: The degree of overlap of serum IgG levels to B. cepacia LPS core antigen in cystic fibrosis patients colonized with B. cepacia and P. aeruginosa does not allow this antibody to be used in a clinical context to define infection status. The magnitude of the humoral response to B. cepacia may influence occurrence of pulmonary exacerbations, but a more exuberant humoral immune response to B. cepacia core LPS is not the mechanism by which pulmonary deterioration occurs.

Metabolic and inflammatory responses to pulmonary exacerbation in adults with cystic fibrosis.

BACKGROUND: We hypothesized that increased resting energy expenditure in adults with cystic fibrosis was related to chronic inflammation secondary to pulmonary infection and could be modified by treatment of the underlying infection. METHOD: To determine the relationship between resting energy expenditure and the inflammatory and metabolic responses, we studied 22 adults with cystic fibrosis and chronic Pseudomonas aeruginosa infection before and after treatment of a respiratory exacerbation. Resting energy expenditure was measured by indirect calorimetry. Spirometry and circulating concentrations of C-reactive protein, neutrophil elastase alpha1-antiproteinase complex, catecholamines, non-esterified fatty acids and glycerol were determined. RESULTS: The mean (95% confidence interval)% predicted FEV1 was 28.5% (20.6, 36.4) and mean body weight 50.7 kg (47.4, 54.1). Following treatment, 1-s forced expiratory volume (FEV1) and weight increased, while C-reactive protein (P<0.0001) and neutrophil elastase alpha1-antiproteinase complex concentrations (P<0.0001) were reduced. Resting energy expenditure decreased from 6.8 (6.3, 7.2) to 6.25 (5.9, 6.6) MJ day-1 by day 15 (P<0.001). Changes in resting energy expenditure and C-reactive protein were related (r = 0.66, P< 0.0001). Weight gain was inversely related to resting energy expenditure (r = 0.43, P = 0.02) and unrelated to energy intake (r = 0.02, P = 0.47). Post-treatment reduction in norepinephrine was related to changes in heart rate (r = 0.57, P<0.01), resting energy expenditure (r = 0.51, P = 0.001) and non-esterified fatty acids (r = 0.42, P< 0.05). CONCLUSIONS: A parallel reduction in the host inflammatory and catabolic responses followed treatment of a respiratory exacerbation and may have contributed to weight gain.

Elective versus symptomatic antibiotic treatment in cystic fibrosis patients with chronic Pseudomonas infection of the lungs.

BACKGROUND: A previous retrospective study suggested that a policy of regular anti-pseudomonal antibiotic treatment improved pulmonary function and increased survival in patients with cystic fibrosis chronically infected with Pseudomonas species. The results of a prospective multicentre study to compare the effects on pulmonary function and mortality of three monthly elective anti-pseudomonal antibiotic treatment with conventional symptomatic treatment are reported. METHODS: Sixty patients with cystic fibrosis, chronically infected with P aeruginosa, were randomised to the two treatment arms (elective or symptomatic) and followed clinically at yearly reviews. The major end points were changes in forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC). Survival was a secondary end point. RESULTS: Patients in the symptomatic group received a mean of three antibiotic treatments each year and those in the elective group received four antibiotic treatments during each year of the study. No significant differences in FEV(1) and FVC were found between the two groups after three years. There was a statistically non-significant higher rate of deaths in the elective group (n = 4), three of which were associated with B cepacia infection, compared with the symptomatic group (n = 0). CONCLUSIONS: This study did not demonstrate an advantage of a policy of elective antibiotic treatment over symptomatic treatment in patients with cystic fibrosis chronically infected with Pseudomonas species.

Pulmonary function, serum markers of inflammation, and IgG antibodies to core lipopolysaccharide of Burkholderia cepacia in adults with cystic fibrosis, following colonization with Burkholderia cepacia.

Eight patients with cystic fibrosis [CF] colonized with Pseudomonas aeruginosa (P. aeruginosa) had serial lung function, peripheral blood inflammatory markers, and serum IgG antibodies to Burkholderia cepacia (B. cepacia) lipopolysaccharide measured in the months preceding and following colonisation with B. cepacia. One patient experienced a fall in FEV(1) from 33% to 19% of predicted values, coinciding with the first sputum isolation of B. cepacia, and he died 12 weeks later. He had a rise in inflammatory markers preterminally, and this change was refractory to antibiotic therapy. There was no significant fall in FEV(1) % of predicted values in the remaining seven patients, and no significant changes in their serum markers of inflammation following colonization with B. cepacia over a median (range) period of 10.9 (7.3-12.0) months.

Cystic fibrosis: inflammatory response to infection with Burkholderia cepacia and Pseudomonas aeruginosa.

Pulmonary colonization by Burkholderia cepacia in cystic fibrosis (CF) may be associated with enhanced deterioration of pulmonary function. This may be due to a more florid host inflammatory response than in colonization by Pseudomonas aeruginosa, leading to greater lung injury. Circulating markers of inflammation were determined during infective exacerbations and periods of clinical stability in an 18 month prospective study in adults with CF colonized by P. aeruginosa (n=41). B. cepacia (n=13) and in adults who intermittently grew B. cepacia (n=6). There were no differences between the levels of the inflammation markers measured in the three groups (P. aeruginosa, B. cepacia, B. cepacia intermittent) at any of the assessment points. When clinically stable, levels of inflammatory markers in all groups were elevated compared to a matched non-CF population, indicating, continuous inflammation and the potential for lung damage between infective exacerbations. This study does not support the hypothesis that pulmonary colonization with Burkholderia cepacia is associated with a heightened inflammatory response compared with Pseudomonas aeruginosa colonization.

IL-8 and neutrophil elastase levels in the respiratory tract of infants with RSV bronchiolitis.

The aim of this study was to determine whether interleukin (IL)-8 is released within the upper respiratory tract of infants during respiratory syncytial virus (RSV) bronchiolitis and whether the large number of polymorphonuclear neutrophils (PMNs) present in the respiratory tract of these infants are contributing to the inflammation through release of inflammatory mediators. Twenty-seven infants with acute bronchiolitis were recruited during one winter epidemic and 20 infant control subjects were recruited from a cohort participating in a community-based vaccine study. Samples of airways fluid were obtained using nasal lavage. The lavage fluid was spun to remove the cells, and the supernatant was stored at -70 degrees C. The supernatants were subsequently assayed for the presence of IL-8, total human neutrophil elastase (HNE) and neutrophil elastase activity. In the children with bronchiolitis compared with control infants, elevated levels of IL-8 (median (range) 1.53 (0-153) versus 0 (0-5.6) ng x mL(-1)) HNE (136 (32-694) versus 14 (0-516) ng x mL(-1)) and elastase activity (4 (1-220) versus 1 (0-339) mU x mL(-1)) were found. These results indicate that interleukin-8 is released in the upper respiratory tract in response to respiratory syncytial virus infection and suggest that polymorphonuclear neutrophil products are playing an important role in the inflammatory response to respiratory syncytial virus infection in infants with acute bronchiolitis. This contrasts with the predominantly eosinophilic response evident in atopic upper and lower respiratory tract disease.

Repeatability and methodology of resting energy expenditure in patients with cystic fibrosis.

In this study, intra-individual variation of resting energy expenditure (REE) in adults with cystic fibrosis (CF) and the effect of measurement duration were determined. Twelve adults with CF and chronic Pseudomonas aeruginosa (Ps. aeruginosa) infection and 12 healthy volunteers, matched for age and sex were studied whilst clinically stable on days 1.2, and 15. Respiratory gas exchange was monitored by continuous measurement of oxygen uptake (VO2) and carbon dioxide production (VCO2) using a ventilated hood indirect calorimeter. Coefficients of variation (CVs) were 4.3% in patients and 2.4% in controls comparing days 1 and 2. The CV for patients was 5.0% and for controls 2.9% comparing days 1 and 15. The effect of measurement duration on REE was assessed in eight of the CF patients. REE remained stable for 40 min but tended to rise by 80 min. Plasma catecholamine concentrations were stable between study days in patients but fell with time in controls suggesting some adaptation to experimental procedure. The greater variability of REE in patients was related to change in serum CRP over 2 weeks. REE is a repeatable measurement in clinically stable patients with CF, though variability was greater in patients than healthy subjects. This has implications for the design and interpretation of longitudinal studies of REE in patients with chronic lung disease.