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Biomedical subjects

R A Stockley

Publications and source records attributed to R A Stockley.

At least 19 recordsLinked to original sources
PubMed2006

Validation of computed tomographic lung densitometry for monitoring emphysema in alpha1-antitrypsin deficiency.

BACKGROUND: Lung densitometry derived from computed tomographic images offers an opportunity to quantify emphysema non-invasively, but a pathological standard cannot be applied to validate its use in longitudinal monitoring studies. Consequently, forced expiratory volume in 1 second (FEV1) remains the standard against which new methods must be judged. We related progression of densitometry (15th percentile point and voxel index, threshold -950 Hounsfield units) to disease stage and FEV1 decline in two studies of subjects with alpha1-antitrypsin deficiency (PiZ). METHODS: Consistency of progression, measured using densitometry and FEV1, was assessed in relation to disease stage in a 2 year study of 74 subjects grouped according to the FEV1 criteria employed in the GOLD guidelines. In the second study of a subgroup of subjects with extended data (n=34), summary statistics were applied to measurements performed annually over 3 years and the rate of progression of densitometry was related to FEV1 decline. RESULTS: The progression of percentile point was consistent across a wide spectrum of disease severity, but voxel index progression varied in association with disease stage (p=0.004). In the second study, FEV1 decline correlated with progression of lung densitometry (percentile point: rS=0.527, p=0.001; voxel index: rS=-0.398, p=0.012). CONCLUSIONS: 15th percentile point is a more consistent measure of lung density loss across a wide range of physiological impairment than voxel index. However, both methods are valid for use in longitudinal and interventional studies in which emphysema is the major outcome target.

Absorptiometry, Photon↗
PubMed2006

Addition of salmeterol to existing treatment in patients with COPD: a 12 month study.

BACKGROUND: This study investigated the addition of salmeterol to existing treatment for exacerbations in patients with poorly reversible chronic obstructive pulmonary disease (COPD). METHODS: 634 patients aged >40 years with a history of COPD exacerbations (including at least two in the previous year) and poor reversibility of airflow obstruction (< or =10% predicted forced expiratory volume in 1 second) received either salmeterol 50 mug or placebo twice daily from a Diskus inhaler for 12 months. The primary outcome was the number of moderate and severe exacerbations. RESULTS: The median rate of moderate or severe exacerbations in the intent-to-treat (ITT) population was lower in the salmeterol group (0.00, range 0.0-9.8, n = 316) than in the placebo group (0.93, range 0.0-13.0, n = 318), but the difference was not statistically significant (p = 0.27). The median rate of exacerbations in the per protocol population (>90% compliance) was also found to be lower in the salmeterol group (0.00, range 0.0-5.0, n = 206) than in the placebo group (0.93, range 0.0-5.6, n = 195) and did reach statistical significance (p = 0.007). For secondary end points, patients receiving salmeterol had significant improvement in lung hyperinflation measured by inspiratory capacity which was evident at 4 weeks and maintained over 12 months (p = 0.035), and a significant improvement in health status measured by the St George's Respiratory Questionnaire at 12 months (p = 0.002). CONCLUSION: Salmeterol has a positive effect on symptoms and health status of patients with COPD when added to usual treatment. Exacerbations are only reduced in patients who comply with treatment.

Albuterol↗
PubMed2006

COPD exacerbations . 2: aetiology.

Exacerbations of COPD are thought to be caused by complex interactions between the host, bacteria, viruses, and environmental pollution. These factors increase the inflammatory burden in the lower airways, overwhelming the protective anti-inflammatory defences leading to tissue damage. Frequent exacerbations are associated with increased morbidity and mortality, a faster decline in lung function, and poorer health status, so prevention or optimal treatment of exacerbations is a global priority. In order to evolve new treatment strategies there has been great interest in the aetiology and pathophysiology of exacerbations, but progress has been hindered by the heterogeneous nature of these episodes, vague definitions of an exacerbation, and poor stratification of known confounding factors when interpreting results. We review how an exacerbation should be defined, its inflammatory basis, and the importance of exacerbations on disease progression. Important aetiologies, with their potential underlying mechanisms, are discussed and the significance of each aetiology is considered.

Bacterial Infections↗
PubMed2005

Exercise training and inspiratory muscle training in patients with bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic suppurative lung disease often characterised by airflow obstruction and hyperinflation, and leading to decreased exercise tolerance and reduced health status. The role of pulmonary rehabilitation (PR) and inspiratory muscle training (IMT) has not been investigated in this group of patients. METHODS: Thirty two patients with idiopathic bronchiectasis were randomly allocated to one of three groups: PR plus sham IMT (PR-SHAM), PR plus targeted IMT (PR-IMT), or control. All patients (except the control group) underwent an 8 week training programme of either PR or PR plus targeted IMT. Exercise training during PR was performed three times weekly at 80% of the peak heart rate. IMT was performed at home for 15 minutes twice daily over the 8 week period. RESULTS: PR-SHAM and PR-IMT resulted in significant increases in the incremental shuttle walking test of 96.7 metres (95% confidence interval (CI) 59.6 to 133.7) and 124.5 metres (95% CI 63.2 to 185.9), respectively, and in endurance exercise capacity of 174.9% (95% CI 34.7 to 426.1) and 205.7% (95% CI 31.6 to 310.6). There were no statistically significant differences in the improvements in exercise between the two groups. Significant improvements in inspiratory muscle strength were also observed both in the PR-IMT group (21.4 cm H2O increase, 95% CI 9.3 to 33.4; p = 0.008) and the PR-SHAM group (12.0 cm H2O increase, 95% CI 1.1 to 22.9; p = 0.04), the magnitude of which were also similar (p = 0.220). Improvements in exercise capacity were maintained in the PR-IMT group 3 months after training, but not in the PR-SHAM group. CONCLUSION: PR is effective in improving exercise tolerance in bronchiectasis but there is no additional advantage of simultaneous IMT. IMT may, however, be important in the longevity of the training effects.

Breathing Exercises↗
PubMed2005

Exacerbations in {alpha}1-antitrypsin deficiency.

This study aimed to investigate the nature and effect of exacerbations in patients with alpha(1)-antitrypsin deficiency and to assess the impact of exacerbations on health status. Furthermore, the relationship of exacerbations to changes in lung function and health status was investigated. In total, 265 patients with severe deficiency (PiZ phenotype) were assessed over 12 months and a subgroup of 87 patients was studied for 3 yrs. Exacerbations were recorded and patients underwent full lung function testing and health status measurement. Exacerbations occurred in 142 patients (54%) over 12 months, with a median duration of 14 days (interquartile range 7-21). Health status was significantly worse in patients with exacerbations, especially those with frequent exacerbations. Neither the presence nor the frequency of exacerbations showed a relationship to decline in forced expiratory volume in one second, but the number of exacerbations was weakly associated with decline in gas transfer of the lung for carbon monoxide. Despite lung function decline, health status did not change significantly over 3 yrs. In conclusion, exacerbations occur commonly in patients with alpha(1)-antitrypsin deficiency and are associated with worse health status. Exacerbations were associated with a decline in the gas transfer of the lung for carbon monoxide over time, but show no relationship to changes in forced expiratory volume in one second. Despite lung function decline, patients do not show a progressive loss in health status.

Administration, Inhalation↗
PubMed2005

Endothelial interactions of neutrophils under flow in chronic obstructive pulmonary disease.

It is generally accepted that the neutrophil is central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Enhanced endothelial interactions of this cell may contribute to the susceptibility of smokers who develop the disease; however, these interactions have not previously been studied in COPD. The aim of the current study was to determine whether enhanced endothelial interactions of neutrophils from smokers are a predisposing factor for the development of COPD. Endothelial interactions under flow and adhesion molecule expression of peripheral blood neutrophils were compared between seven never-smokers (NS), seven healthy smokers (HS), 11 COPD patients with severe alpha1-antitrypsin deficiency (PiZ) and neutrophils from 11 COPD patients without the deficiency (PiM). Total adhesive and migratory responses (per mm2 endothelium per 10(6) neutrophils) were significantly greater in the PiM group (mean+/-se 704.2+/-57.9 versus 509.3+/-48.8 in the PiZ group, 499.3+/-40.1 in the HS and 491.2+/-33.7 in the NS). This corresponded with increased macrophage antigen-1 (CD11b) expression on stimulated neutrophils in the PiM group compared with the PiZ group (mean+/-se relative fluorescence intensity 1.4+/-0.1 versus 1.1+/-0.1). In conclusion, the enhanced endothelial interaction of neutrophils from smokers who have developed chronic obstructive pulmonary disease in the presence of normal levels of alpha1-antitrypsin deficiency, but not in those with severe alpha(1)-antitrypsin deficiency, suggests that this is a predisposing factor for the development of the disease, and upregulation of macrophage antigen-1 may be responsible.

Aged↗
PubMed2005

COPD: current therapeutic interventions and future approaches.

Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-alpha. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B(4) antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.

Administration, Inhalation↗
PubMed2003

Panniculitis secondary to extravasation of clarithromycin in a patient with alpha 1-antitrypsin deficiency (phenotype PiZ).

alpha 1-Antitrypsin deficiency (AATD) is known to be associated with panniculitis. Although reports of this association are rare, the true incidence may be unappreciated because of underdiagnosis of AATD. We report a case of panniculitis occurring in a 34-year-old woman with severe AATD following the extravasation of clarithromycin infused intravenously for treatment of community-acquired pneumonia. Resolution occurred with conservative management. The histopathology and management of this unusual condition are discussed, with a review of the literature.

Adult↗
PubMed2003

Chronic obstructive pulmonary disease . 6: The aetiology of exacerbations of chronic obstructive pulmonary disease.

Exacerbations of COPD are thought to be caused by interactions between host factors, bacteria, viruses, and changes in air quality to produce increased inflammation in the lower airway. The evidence for this and the potential mechanisms by which they result in the characteristic symptoms of exacerbations is reviewed. A better understanding of the causes and processes is needed for the appropriate use of existing treatments and the development of new ones. Future studies need to define populations clearly, stratify for known confounding factors, and should aim to identify clinical correlates so that clinical practice can be modified appropriately.

Air Pollution↗
PubMed2003

Predictors of mortality in alpha1-antitrypsin deficiency.

BACKGROUND: Lung density measurements by computed tomography have previously been found to be a more sensitive indicator of disease progression in emphysema of alpha(1)-antitrypsin deficiency than lung function measurements. The aim of this study was to investigate the predictive potential of several parameters, including CT scanning, for mortality in patients with severe alpha(1)-antitrypsin deficiency. METHODS: Over a 5 year period, 256 patients with alpha(1)-antitrypsin deficiency (PiZ phenotype) were assessed, of whom 254 underwent lung function testing and 197 had thoracic CT scans. Lung function, CT scans, health status (St George's Respiratory Questionnaire, SGRQ), and other clinical data of survivors and non-survivors were compared and these parameters were applied to survival analyses. RESULTS: There were 22 deaths in this patient cohort, 10 of which were classified as "respiratory" deaths. Baseline lung function parameters (forced expiratory volume in 1 second (FEV(1)), carbon monoxide transfer coefficient (KCO)), and CT scores were significantly lower in the non-survivors than in the survivors. 170 of the 256 patients had complete data for entry into multiple regression analyses (Cox proportional hazards model). In the univariate analysis, upper zone expiratory scan had the best association with all cause (p = 0.001) and respiratory mortality (p<0.001), whereas FEV(1) (p = 0.158 all cause, 0.015 respiratory) and KCO (p = 0.002 all cause, 0.012 respiratory) had poorer associations with mortality. Only age gave further independent predictive information regarding all cause or respiratory mortality when the CT scan was entered into the survival analyses. CONCLUSIONS: CT scanning predicts respiratory and all cause mortality in alpha(1)-antitrypsin deficiency and appears to be superior to lung function parameters, especially FEV(1).

Disease Progression↗
PubMed2003

Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis.

BACKGROUND: Recent studies of the role of bacteria in chronic bronchitis have shown that bacterial colonisation is associated with enhanced inflammation and that purulent acute exacerbations of chronic bronchitis (AECB) are associated with bacteria and characterised by increased inflammation. Changes in bronchial inflammation in response to the success or failure of bacterial eradication following AECB were therefore studied. METHODS: Bacterial quantitative culture and sputum markers of inflammation (myeloperoxidase (MPO), neutrophil elastase, leukotriene B4 (LTB4), sol:serum albumin ratio, and secretory leukoprotease inhibitor) were measured in patients presenting with culture positive purulent AECB and repeated 10 days and 2 months later. 41 patients provided sputum sufficient for both bacteriology and assessment of inflammation at baseline and day 10, and 46 provided sufficient sample for bacteriology, 40 of which could also be analysed for inflammation at 2 months (when clinically stable). RESULTS: At day 10, 17 of the 41 patient samples had a positive bacterial culture. In the stable state, 18 of the 46 samples had a positive culture, but with a significantly lower bacterial load than at presentation. Although there was no difference between the groups at presentation, the concentration of MPO was lower (p<0.05) in those in whom bacteria were eradicated by day 10 than in those with persisting bacteria. The LTB4 concentration was similarly lower (p<0.001) in those in whom bacteria were eradicated than in those with persistent bacteria. In the stable clinical state the concentrations of both MPO and LTB4 were lower in those in whom bacteria were eradicated than in patients with persisting bacteria. CONCLUSION: Resolution of bronchial inflammation following AECB is related to bacterial eradication. Those in whom bacteria continue to be cultured in their sputum have partial resolution of inflammation which may reflect continued stimulation by the reduced bacterial load.

Adult↗
PubMed2002

The incremental shuttle walking test in elderly people with chronic airflow limitation.

BACKGROUND: There is a concern that comorbidity or frailty in older people could limit the usefulness of currently available exercise tests for chronic lung disease. This study evaluated the feasibility and reproducibility of the incremental shuttle walking test (SWT) in people aged 70 years or over, compared exercise tolerance with other disability markers, and assessed whether the SWT is responsive to change after bronchodilators. METHODS: Fifty elderly patients with chronic airflow limitation (CAL) and 32 controls without airflow limitation attempted the SWT before and after combined nebulised salbutamol/ipratropium bromide. Subjects also completed the Nottingham Extended Activities of Daily Living index (NEADL) and the London Handicap score (LHS). RESULTS: Forty four subjects with CAL (88%) and 29 controls (84%) completed the SWT, including many with co-morbidities. Two week repeatability was good and the SWT was strongly associated with EADL (r=0.51, p<0.001) and LHS (r=0.43, p<0.004), but only weakly with forced expiratory volume in 1 second (FEV1) (r=0.31, p=0.05). Subjects with CAL walked a mean distance of 177.7 m compared with 243.3 m in controls (p<0.001); following bronchodilator therapy the distance walked increased in the CAL group by 13.2% (p=0.009). CONCLUSION: The SWT is a feasible and reproducible measure of exercise tolerance in elderly people with and without airflow obstruction and correlates with other markers of disability. It is sensitive to change following bronchodilation in subjects with CAL, although the change correlates less well with improvements in FEV1. Overall, these results suggest that the SWT might be an appropriate measure to assess interventions in elderly people.

Administration, Inhalation↗
PubMed2002

Effect of sputum processing with dithiothreitol on the detection of inflammatory mediators in chronic bronchitis and bronchiectasis.

BACKGROUND: Sputum analysis is used increasingly to assess airway inflammation in patients with chronic obstructive pulmonary disease, including those with chronic bronchitis and bronchiectasis. However, it is not known whether dithiothreitol (DTT), a reducing mucolytic agent regularly used to homogenise sputum, affects the detection of inflammatory mediators in the sputum soluble phase from such patients. METHODS: Thirty two spontaneous sputum samples were collected from 13 patients with chronic bronchitis and 17 with bronchiectasis. An aliquot from each sample was treated with either freshly prepared 0.1% DTT plus normal saline (NaCl) or NaCl alone, then ultracentrifuged to obtain the sputum sol phase. Interleukin (IL)-1beta, IL-6, IL-8, leukotriene B(4) (LTB(4)), secretory leukoprotease inhibitor (SLPI), alpha-1-antitrypsin (alpha(1)-AT), and tumour necrosis factor alpha (TNFalpha) were measured by ELISA, and neutrophil elastase (NE) and myeloperoxidase (MPO) by chromogenic substrate assay. The effect of DTT on the detection of assay standards was also determined. RESULTS: Median levels of IL-1beta, IL-6, IL-8, SLPI, and NE were similar in the DTT and NaCl treated samples. There was a significant reduction in median (IQR) levels of detectable TNFalpha (0.07 (0.00-0.47) pM v 0.90 (0.06-6.98) pM, p<0.001), LTB(4) (1.67 (1.31-2.64) nM v 2.29 (0.95-4.22) nM, p<0.05) and MPO (0.00 (0.00-0.00) mg/l v 4.48 (0.00-33.66) mg/l, p<0.001) and a small increase in the median alpha(1)-AT concentration (0.05 (0.03-0.08) nM v 0.03 (0.02-0.08) nM, p<0.01) in the DTT treated samples. DTT had no effect on the assay standards for IL-1beta, IL-8 or TNFalpha, but at higher concentrations it did affect IL-6, SLPI, NE, and LTB(4) standards (43%, 70%, 76% and 643% of control value for top standard, respectively) and at all concentrations DTT completely abolished MPO activity. CONCLUSIONS: Sputum processing with DTT significantly reduces the detectable concentration of TNFalpha, LTB(4) and MPO, and produces a small but significant increase in median alpha(1)-AT levels. To avoid this problem we recommend that an untreated aliquot of sputum be retained for cytokine analysis, unless the assay has been specifically validated.

Bronchiectasis↗