Biomedical subjects
A U Wells
Publications and source records attributed to A U Wells.
The effect of Pseudomonas aeruginosa on pulmonary function in patients with bronchiectasis.
Bronchiectasis patients are susceptible to infection with Pseudomonas aeruginosa. Isolation is associated with increased severity of disease, greater airflow obstruction and poorer quality of life. It is not known whether infection by P. aeruginosa is a marker of disease severity or contributes to disease progression. Consecutive non-cystic fibrosis adult bronchiectasis outpatients (n = 163) with multiple sputum cultures and follow-up pulmonary function tests were designated, according to isolation of P. aeruginosa, as "never infected" (group 1; n = 67), "intermittently isolated" (group 2; n = 82) and "chronically infected" (group 3; n = 14). Based upon change in forced expiratory volume in one second (FEV(1)) % predicted levels at >or=2 yrs after presentation, longitudinal behaviour was characterised as "improvement" (>or=10% rise), "decline" (>or=10% fall) or "stability". Baseline pulmonary-function tests and longitudinal behaviour were examined in relation to pseudomonas status. There was no difference between the groups in age, sex, smoking habit or length of follow-up. Baseline FEV(1) levels were highest in group 1 (mean+/-sd: 77.4+/-24.3) and higher in group 2 (67.3+/-25.7) than in group 3 (55.2+/-18.5). The same significant trends were seen for baseline FEV(1)/forced vital capacity ratios and diffusing capacity of the lung for carbon monoxide levels. Subsequent longitudinal behaviour was linked to baseline FEV(1) levels, which were lowest in patients with improvement and lower in association with decline than with stability. However, longitudinal behaviour did not differ between groups 1, 2 and 3, either before or after adjustment for baseline FEV(1) levels. Infection by Pseudomonas aeruginosa occurs in bronchiectasis patients with more severe impairment of pulmonary function but does not influence rate of decline in pulmonary function either before or after adjustment for baseline disease severity. Thus, Pseudomonas aeruginosa is a marker of bronchiectasis severity but is not linked to an accelerated decline in pulmonary function.
Submaximal exercise testing in the assessment of interstitial lung disease secondary to systemic sclerosis: reproducibility and correlations of the 6-min walk test.
BACKGROUND: The 6-min walk test (6MWT) is increasingly used as an outcome measure in interstitial lung disease (ILD). AIM: To evaluate the usefulness of the 6MWT in a cohort of patients with ILD secondary to systemic sclerosis (SSc) and to correlate with established physiological parameters. METHODS: 163 patients with SSc-ILD were recruited for a multicentre, randomised, double-blind clinical trial. Available data at protocol screening included repeated 6MWTs, pulmonary function testing with diffusing capacity, Doppler echocardiography and high-resolution computed tomography of the thorax. Borg Dyspnoea Index was evaluated before and after 6MWT. RESULTS: Mean (standard deviation (SD)) distance walked during walk test 1 was 396.6 (84.55) m compared with 399.5 (86.28) m at walk test 2. The within-subject, intertest correlation as determined by Pearson's correlation coefficient testing was 0.95 (p<0.001). However, only weak correlations of 6MWT with percentage forced vital capacity and the Borg Dyspnoea Index were observed, and no correlation was observed with percentage diffusing capacity. CONCLUSION: These data confirm the high reproducibility of the 6MWT in patients with SSc-ILD and therefore the validity of the test in this cohort. The lack of correlation of 6MWT with standard physiological parameters of ILD suggests a multifactorial basis for limited exercise capacity in patients with SSc and calls into question the utility of the 6MWT as a measure of outcome in future studies on SSc-ILD.
Thin-section CT of the lungs: eye-tracking analysis of the visual approach to reading tiled and stacked display formats.
OBJECTIVE: To use eye-tracking analysis to identify the differences in approach to and efficiency of reading thin-section CT of the lungs presented tiled and stacked soft-copy displays. MATERIALS AND METHODS: Four chest radiologists read 16 thin-section CT examinations displayed in either a tiled (four images at once) or stacked (full screen cine) format. Eye-movements were recorded and analysed in terms of movement type; saccade distance (classified by the calculated range of useful peripheral vision), number of fixations, duration and direction of gaze-comparison of the areas of the images viewed. RESULTS: Cases presented in stacked format were read quicker than when presented in tiled format with a greater fixation frequency (5 fixations versus 4.5 fixations points per 100 data points; p<0.001) and a greater proportion of short saccades (97% versus 94%; p<0.005). The consistency with which the observers viewed equivalent areas of the scan images in different cases was greater when viewing in stacked format (mean kappa 0.45 versus 0.36; p<0.05) suggesting a more systematic approach to reading. CONCLUSION: Eye-tracking data demonstrates why thin-section CT examinations of the lungs are read more efficiently when displayed in a stack as opposed to a tiled format.
Computed tomography and pulmonary function abnormalities in sickle cell disease.
The aim of this study was to determine whether patients with sickle cell disease (SCD) in steady state had pulmonary abnormalities seen on high-resolution computed tomography (HRCT) and whether any abnormalities correlated with contemporaneously diagnosed lung function abnormalities. A subsidiary question was whether the results of a noninvasive measure of haemolysis (end-tidal carbon monoxide (ETCO) levels) correlated with pulmonary function abnormalities. Thirty three patients with SCD, median (range) age 36 yrs (17-67 yrs) were examined. The degree of lobar volume loss and ground-glass opacification and prominence of central vessels on HRCT were quantitatively assessed. Pulmonary function was assessed by measurements of lung volumes, spirometry, gas transfer and oxygen saturation. ETCO levels were measured using an end-tidal CO monitor. Forced expiratory volume in one second (FEV1), forced vital capacity and total lung capacity significantly correlated with HRCT findings, particularly lobar volume loss. ETCO levels significantly negatively correlated with FEV1, vital capacity measured using a plethysmograph, specific airway conductance and arterial oxygen saturation measured by pulse oxymetry. In conclusion, the present results suggest that high-resolution computed tomography noninvasive assessment of haemolysis might be useful to identify sickle cell disease patients with respiratory function impairment.
Pulmonary involvement by Niemann-Pick disease. A report of six cases.
AIMS: Although pulmonary involvement is a known cause of morbidity in Niemann-Pick disease, histological features in the lung are not well characterized. The purpose of this study is to document the histological features seen in pulmonary involvement by types B and C Niemann-Pick disease and to correlate them with clinical and imaging data. METHODS AND RESULTS: Surgical lung biopsies from six patients (four with type B and two with type C disease) were reviewed and all showed diffuse endogenous lipid pneumonia, with lesser involvement of the interstitium by fibrosis and foamy macrophage accumulation. In type B disease only, there was also fine cytoplasmic vacuolation within the cytoplasm of ciliated epithelial cells. Neither disease showed foamy changes within pneumocytes. One patient had a bronchial cast removed on whole lung lavage. Electron microscopy showed abnormal lamellar inclusions within lysosomes of affected cells in type B disease. In patients with type C disease, biopsies were undertaken as part of investigations into acute respiratory failure in the context of multiorgan systemic presentation. Three patients with type B disease had clinical disease limited to the lung, all adults (mean age of 40 years) with unexplained diffuse parenchymal lung disease and mainly ground-glass shadowing on high-resolution computed tomography. CONCLUSIONS: Niemann-Pick disease should be considered for any patient with unexplained diffuse endogenous lipid pneumonia, even when disease is limited to the lungs and presentation is during adulthood.
A polymorphism in the promoter region of the CD86 (B7.2) gene is associated with systemic sclerosis.
Systemic sclerosis (SSc) is a connective tissue disease of unknown aetiology characterized by fibrosis of the skin and internal organs, vascular abnormalities and humoral autoimmunity. Strong T-cell-dependent autoantibody and HLA associations are found in SSc subsets. The co-stimulatory molecule, CD86, expressed by antigen-presenting cells, plays a crucial role in priming naïve lymphocytes. We hypothesized that SSc, or one of the disease subsets, could be associated with single-nucleotide polymorphisms of the CD86 gene. Using sequence specific primer-polymerase chain reaction (SSP-PCR) methodology, we assessed four CD86 polymorphisms in 221 patients with SSc and 227 healthy control subjects from the UK. Haplotypes were constructed by inference and confirmed using PHASE algorithm. We found a strong association between SSc and a specific haplotype (haplotype 5), which was more prevalent in patients than in controls (29% vs 15%, OR = 2.3, chi(2) = 12, P = 0.0005). This association could be attributed to the novel -3479 promoter polymorphism; a significant difference was observed in the distribution of the CD86 -3479 G allele in patients with SSc compared to controls (43.7% vs. 32.4%, OR = 1.7, chi(2) = 12.1, P = 0.0005). TRANSFAC analyses suggest that the CD86-3479T allele contains putative GATA and TBP sites, whereas G allele does not. We assessed the relative DNA protein-binding activity of the -3479 polymorphism in vitro using electromobility gel shift assays (EMSA), which showed that the -3479G allele has less binding affinity compared to the T allele for nuclear proteins. These findings highlight the importance of co-stimulatory pathways in SSc pathogenesis.
Antioxidant therapy in idiopathic pulmonary fibrosis: hope is kindled.
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Exhaled nitric oxide in sarcoidosis.
BACKGROUND: Increased production of nitric oxide (NO) by the lower respiratory tract is viewed as a marker of airway inflammation in asthma and bronchiectasis. NO is a potentially important immune modulator, inhibiting the release of several key pro-inflammatory cytokines. As sarcoidosis is characterised by granulomatous airway inflammation, we hypothesised that exhaled NO levels might be raised in sarcoidosis and correlate with the morphological extent and functional severity of disease. METHODS: Fifty two patients with sarcoidosis (29 men) of mean age 42 years underwent thin section computed tomography (CT), pulmonary function tests, and measurement of exhaled NO. RESULTS: Exhaled NO levels (median 6.8 ppb, range 2.4-21.8) did not differ significantly from values in 44 control subjects, and were not related to the extent of individual CT abnormalities or the level of pulmonary function impairment. CONCLUSION: Exhaled NO levels are not increased in pulmonary sarcoidosis.
Prostacyclin for pulmonary hypertension in adults.
BACKGROUND: Primary pulmonary hypertension (PPH) is progressive, resulting in right ventricular failure. Pulmonary hypertension can be idiopathic or associated with other conditions. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation, and can be given orally, subcutaneously, intravenously or inhaled via a nebuliser. OBJECTIVES: To determine the efficacy of prostacyclin or one of its analogues in idiopathic primary pulmonary hypertension. SEARCH STRATEGY: Electronic searches were carried out with pre-specified terms. Searches were current as of July 2004. SELECTION CRITERIA: Two reviewers selected randomised controlled trials (RCTs) involving adults with pulmonary hypertension for inclusion. DATA COLLECTION AND ANALYSIS: Study quality was assessed and data extracted independently by two reviewers. Outcomes were analysed as continuous and dichotomous outcomes. We sub-grouped data where possible by aetiology of PH (PPH, PH secondary to connective tissue disorder or mixed populations). MAIN RESULTS: Nine RCTs of mixed duration (3 days-52 weeks), recruiting 1175 participants were included (NYHA functional classes II-IV). Intravenous prostacyclin versus usual care (four studies): There were significant improvements in exercise capacity of around 90 metres, cardiopulmonary haemodynamics and NYHA functional class over 3 days-12 weeks. Effects were consistent in primary and secondary pulmonary hypertension. Oral prostacyclin versus placebo (two studies): Short-term data (3-6 months) indicated that there was a significant improvement in exercise capacity, but data from one study of 52 weeks reported no significant difference at 12 months. No significant differences were observed for any other outcome. Subcutaneous treprostinil versus placebo (two studies, 8-12 weeks):One large study reported a significant median improvement in exercise capacity of around 16 metres. Cardiopulmonary haemodynamics and symptom scores favoured treprostinil. Infusion site pain and withdrawals due to adverse events were more frequent with treprostinil. Inhaled prostacyclin versus placebo (one study, 12 weeks):There was a significant increase in exercise capacity of approximately 36 metres. Treatment led to better symptom scores and functional class status than with placebo. Subgroup analyses reported by individual studies showed a better exercise capacity in participants with PPH, than those participants with PH secondary to other diseases. Side effects and adverse events were common in the studies. AUTHORS' CONCLUSIONS: There is evidence that intravenous prostacyclin in addition to conventional therapy at tolerable doses optimised by titration, can confer some short-term benefits (up to 12 weeks of treatment) in exercise capacity, NYHA functional class and cardiopulmonary haemodynamics. There is also some evidence that patients with more severe disease based upon NYHA functional class showed a greater response to treatment.
Clinical response to morphine in cancer patients and genetic variation in candidate genes.
Morphine is the analgesic of choice for moderate to severe cancer pain; however, 10-30% of patients do not tolerate morphine. This study evaluated genetic variation in the mu-opioid receptor, betaarrestin2, stat6 and uridine diphosphate-glucuronysltransferase 2B7 (UGT2B7) genes, in patients who responded to morphine vs those who were switched to alternative opioids. We prospectively recruited and genotyped 162 Caucasian patients (117 controls, 39 switchers). Switchers, were more likely to carry the common allele at 1182 G/A, 5864 G/A, 8622T/C and 11143 G/A in the betaarrestin2 gene (P = 0.021, 0.043, 0.013, 0.043, respectively). Switchers had increased carriage of the T allele (-1714 C/T) and a significant difference in the allelic frequency at 9065 C/T (chi(2) = 3.86, P = 0.049) in the stat6 gene. No differences were seen in genotype or allele frequencies of SNPs in the mu-opioid receptor gene or UGT2B7 gene. This study presents novel data suggesting that variation in genes involved in mu-opioid receptor signalling influence clinical response to morphine.
Lung function estimates in idiopathic pulmonary fibrosis: the potential for a simple classification.
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Single-nucleotide polymorphisms in the SPARC gene are not associated with susceptibility to scleroderma.
OBJECTIVE: SPARC (secreted protein, acidic and rich in cysteine) is a matricellular protein that modulates cell-cell and cell-extracellular matrix interactions. SPARC expression is restricted mainly to sites of tissue remodelling and wound repair, and is prominent in fibrotic disorders. Single-nucleotide polymorphisms (SNPs) in the SPARC gene are reportedly linked to scleroderma in four ethnic groups: Choctaw Indians, Caucasians, African Americans and Mexican Americans. We set out to reproduce and to positionally clone these disease associations in a set of UK Caucasian scleroderma patients and ethnically matched controls. METHODS: One hundred and twenty-one scleroderma subjects and 200 controls were genotyped by polymerase chain reaction with sequence-specific primers differing only in the 3' nucleotide corresponding to each allele of the biallelic SNPs. Scleroderma patients were analysed against controls and on the basis of their fibrosing alveolitis status as judged by high-resolution computed tomography evaluation and the extent of cutaneous involvement. RESULTS: Eight biallelic SNPs were genotyped: three from the last untranslated exon, which had been described previously, and an additional five novel SNPs: two in the promoter region, one in exon three and two in the 3' untranslated region. Six major haplotypes were constructed across all eight SNP positions. No significant differences in genotype, allele or haplotype frequency were observed between scleroderma and controls or within scleroderma subgroups. CONCLUSIONS: SNPs in the SPARC gene are not associated with susceptibility to scleroderma. This research adds to the genetic knowledge of the SPARC gene by identifying five novel SNPs spanning the whole gene and inserting these within the context of clearly defined haplotypes.
Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis.
OBJECTIVE: A prospective study to evaluate echocardiography and gas transfer (DLCO) by comparison with cardiac catheterization in discriminating between patients with and without systemic sclerosis-associated pulmonary arterial hypertension (SScPAH). METHOD: A total of 137 (52 with and 85 without pulmonary fibrosis) had echocardiography and lung function tests within 3 months of their definitive invasive study. RESULTS: At cardiac catheterization 99 of these patients were found to have PAH, while PAH was excluded in 38. Echocardiographically estimated tricuspid gradient (TG) showed a moderate positive correlation (r(2) = 0.44, P<0.005) with both mean pulmonary pressure and invasively determined tricuspid gradient. DLCO showed a weak correlation (r(2 )= 0.09, P = 0.006), when compared with mean pulmonary arterial pressure. In total, 97% of patients with an echocardiographically determined TG of > 45 mmHg were found to have pulmonary hypertension at catheterization. However, no threshold could be defined with either screening test that safely excluded PAH. CONCLUSIONS: The positive predictive accuracy of currently used non-invasive tests are adequate for the diagnosis of advanced PAH provided sufficiently high thresholds (TG > 45 mmHg or DLCO < 55% predicted) are used. These tests cannot be relied upon to exclude pulmonary hypertension where pre-test probability is high.
Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis.
AIMS AND METHODS: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non-specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjögren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. RESULTS AND CONCLUSIONS: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjögren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.
Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking.
AIMS: Respiratory bronchiolitis (RB) and desquamative interstitial pneumonia (DIP) are closely associated histological patterns of interstitial pneumonia, although there are no studies on the extent of individual histological parameters. Furthermore, the term smoking related-interstitial lung disease (SR-ILD) has been proposed as a term to encompass patients with both these histological patterns who give a history of smoking, though it is not well defined how this term relates to historical cases of DIP. The aim of this study was to compare histological parameters in cases of DIP and RB and then to review in detail clinical, imaging and histological data for DIP in relation to a history of smoking. METHODS AND RESULTS: Forty-nine cases were reviewed, 24 with RB and 25 with DIP; five cases of DIP were re-classified as RB on review due to bronchocentricity of the infiltrate. There was a significantly greater extent of interstitial fibrosis (P = 0.02), lymphoid follicles (P < 0.001) and eosinophilic infiltration (P < 0.0001) in patients with DIP compared with RB. In addition, the extents of these three parameters were significantly interrelated. Patients with DIP had a lower incidence of smoking (60%) when compared with patients with RB-ILD (93%) (P < 0.005). Further analysis of smokers versus never-smokers with DIP showed no difference in histological parameters, extent of haemosiderin deposition or the number of CD1a+ macrophages between the two groups, nor were there any differences in clinical data to suggest other aetiologies. Follow-up high-resolution computed tomography data from patients with DIP suggested that a pattern of fibrotic non-specific interstitial pneumonia (NSIP) may develop in the long term in both smokers and never-smokers. CONCLUSION: There are significant differences in the extent of interstitial fibrosis, lymphoid follicles and eosinophilic infiltration between DIP and RB, as well as a much lower incidence of smoking in patients with DIP. Whether the lower reported incidence of smoking in DIP reflects referral bias or conservatism in giving a history of smoking remains uncertain, as neither histological parameters nor clinical data indicate a difference between smokers and never-smokers with DIP. Nevertheless, some cases of DIP are likely to remain idiopathic and unrelated to RB, though still have a good prognosis. Furthermore, they may evolve into a pattern resembling fibrotic NSIP. Therefore, whilst SR-ILD is appropriate in the correct clinical setting, the distinction between the histological patterns of RB and DIP remains appropriate.
Mapping of the immunodominant T cell epitopes of the protein topoisomerase I.
OBJECTIVES: To identify the immunodominant T cell epitopes of the topoisomerase I protein in patients with systemic sclerosis (SSc) and control subjects, using computational analysis software (TEPITOPE) and T cell proliferation assays. METHODS: Six oligopeptides, predicted by TEPITOPE software as potential topoisomerase protein epitopes, were used to perform T cell proliferation assays in 21 patients with SSc and 15 healthy controls. RESULTS: A positive response to at least one of the peptides was seen in 10/21 patients and 7/15 healthy controls. Among responders, the proliferative response was limited to a single peptide in 6/7 healthy controls, whereas 5/10 patients responded to more than one peptide. In responding patients a significant correlation was found between disease duration and number of peptides inducing a response (p = 0.007). CONCLUSIONS: Several T cell epitopes of the topoisomerase I protein have been identified and evidence has been found to suggest epitope spreading in patients with SSc.
Inter-observer variation between pathologists in diffuse parenchymal lung disease.
BACKGROUND: There have been few inter-observer studies of diffuse parenchymal lung disease (DPLD), but the recent ATS/ERS consensus classification provides a basis for such a study. METHODS: A method for categorising numerically the percentage likelihood of these differential diagnoses was developed, and the diagnostic confidence of pathologists using this classification and the reproducibility of their diagnoses were assessed. RESULTS: The overall kappa coefficient of agreement for the first choice diagnosis was 0.38 (n = 133 biopsies), increasing to 0.43 for patients (n = 83) with multiple biopsies. Weighted kappa coefficients of agreement, quantifying the level of probability of individual diagnoses, were moderate to good (mean 0.58, range 0.40-0.75). However, in 18% of biopsy specimens the diagnosis was given with low confidence. Over 50% of inter-observer variation related to the diagnosis of non-specific interstitial pneumonia and, in particular, its distinction from usual interstitial pneumonia. CONCLUSION: These results show that the ATS/ERS classification can be applied reproducibly by pathologists who evaluate DPLD routinely, and support the practice of taking multiple biopsy specimens.