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Athol U Wells

Publications and source records attributed to Athol U Wells.

At least 19 recordsLinked to original sources
PubMed2006

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.

AIMS AND METHODS: A review was undertaken of 19 patients diagnosed with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) between 1992 and 2006. RESULTS: Most patients were women (n = 15) and non-smokers (n = 16). Clinical presentation was either with symptomatic pulmonary disease (group 1; n = 9) or as an incidental finding during investigation for another disorder, most frequently malignant disease (group 2; n = 10). In group 1, cough and dyspnoea were the most frequent symptoms, with an average duration of 8.6 years before diagnosis. Both groups showed mainly stable disease without treatment, although one patient progressed to severe airflow obstruction and one was diagnosed at single lung transplantation. Mosaicism with nodule(s) was the typical pattern of DIPNECH on high-resolution computed tomography, but one case had normal imaging despite airflow obstruction. Lung function tests showed obstructive (n = 8), mixed (n = 3) or normal (n = 5, all group 2) physiology. Two patients underwent a bronchoalveolar lavage and showed a lymphocytosis (30%) with mild chronic bronchiolitis being seen in all biopsies. Tumourlets and associated typical carcinoids (n = 9) showed weak positivity for thyroid transcription factor-1. Three patients had atypical carcinoids, one with multiple endocrine neoplasia type 1 syndrome. CONCLUSIONS: DIPNECH is being increasingly recognised, probably because of an increase in the usage and accuracy of investigative imaging and increased awareness of the entity. Most cases remain stable over many years independent of the mode of presentation, although a few patients progress to severe airflow obstruction.

Adult↗
PubMed2006

Asbestos-induced and smoking-related disease: apportioning pulmonary function deficit by using thin-section CT.

PURPOSE: To retrospectively correlate the extent of individual diseases seen at thin-section computed tomography (CT) with pulmonary function in an initial group of patients with asbestos-related parenchymal disease (asbestosis) and to test these findings in a subsequent group of patients whose CT scans were retrospectively identified. MATERIALS AND METHODS: This retrospective study had Institutional Review Board approval; informed consent was not required. The study included 133 individuals who had been exposed to asbestos. In the initial study group (81 patients; 79 men, two women; median age, 67 years), two observers used a CT scoring system to quantify the extent of pulmonary fibrosis, diffuse pleural thickening, small-airways disease, and emphysema. Multivariate equations were formulated by using independent CT variables to predict changes in total lung capacity (TLC) and carbon monoxide diffusing capacity (Dlco). The validity of these equations was then tested in a subsequent group of patients (52 patients; all men; median age, 60 years). RESULTS: At thin-section CT, the extent of asbestos-induced pleuropulmonary disease and emphysema correlated significantly with physiologic impairment (P<.001). Combined CT variables predicted 58% and 57% of the variability in TLC and Dlco, respectively, despite considerable variation in the proportion of coexisting pathologic conditions. When predictive equations with CT variables derived from the initial study group were applied to the subsequent study group, predicted TLC (rho=0.75, P<.001) and Dlco (rho=0.64, P<.001) correlated strongly with measured values. CONCLUSION: The proposed CT system provides a semiquantitative method for assessing the relative contribution of asbestos-induced pleuropulmonary disease and smoking-related emphysema to functional impairment.

Aged↗
PubMed2006

Quantification of emphysema: a composite physiologic index derived from CT estimation of disease extent.

The combination of functional indices best reflecting the extent of emphysema is not known. High-resolution computed tomography (HRCT) studies of 106 patients with emphysema [men=71; median age=61 (range=26-86 years)] were reviewed and the extent of emphysema was quantified: (a) visually (emphysema(vis)) and (b) by automated estimation (emphysema(auto)). Functional-morphologic relationships were compared for the two scoring systems, and a composite physiologic index (CPI) (providing the best fit of functional indices against emphysema extent) was derived. Emphysema(vis) and emphysema(auto) were strongly correlated (r=0.90; p<0.0005), but the extent of emphysema(vis) was consistently greater (p<0.00005). Emphysema(vis) correlated most strongly with indices of gas transfer [percent predicted single-breath carbon monoxide diffusing capacity (Dl(co)) and alveolar volume (K(co)); r=-0.70, both p<0.0005]. The combination of physiologic indices most representative of emphysema extent on CT (using visual or automated methods) consisted of K(co) and forced expiratory volume in 1 s (FEV(1)) levels. The equation explanatory power was higher for visual scoring [emphysema(vis)=96.8-(0.67 x % predicted K(co))-(0.41 x % predicted FEV(1)); equation r(2)=0.57] than automated estimation (equation r(2)=0.48). Weighted combinations of K(co) and FEV(1) levels provide a CPI best reflecting morphologic emphysema extent. CPI has the potential to refine the stratification of patients in epidemiological and therapeutic studies.

Adult↗
PubMed2006

A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

Administration, Oral↗
PubMed2006

Pulmonary capillaritis and its relationship to development of emphysema in hypocomplementaemic urticarial vasculitis syndrome.

Hypocomplementaemic urticarial vasculitis syndrome (HUVS) is a rare disorder characterised by complement activation and the presence of C1q precipitins together with a syndrome of urticarial vasculitis, angioedema, arthralgia, ocular inflammation, glomerulonephritis and obstructive lung disease. The pathophysiology of the obstructive airways disease is poorly understood. We report a 46 year-old woman with HUVS who developed progressive obstructive airways disease. Lung biopsy early in the course of her disease revealed pulmonary capillaritis. The disease progressed despite treatment with steroids and cyclosporin and the patient eventually underwent successful double lung transplantation. The explanted lung showed the coexistence of a patchy active vasculitis with severe panacinar emphysema. This is the first description of the histopathological process of HUVS in an explanted lung. Through analysis of serial histopathological specimens and clinical data we show the evolution of pulmonary capillaritis to emphysema, and demonstrate that active vasculitis can coexist with emphysema in patients with HUVS and obstructive airways disease. We suggest that there is a role for ongoing immunosuppressive therapy in these patients.

Biopsy↗
PubMed2005

Interstitial lung disease: effects of thin-section CT on clinical decision making.

PURPOSE: To retrospectively quantify the change in the diagnosis and management of suspected interstitial lung disease when thin-section computed tomography (CT) is added to pretest probabilities. MATERIALS AND METHODS: The institutional review board does not require approval or patient informed consent for retrospective study of case records and CT studies. Six pulmonologists reviewed data sheets containing clinical information and results of pulmonary function tests and chest radiographs of 168 consecutive patients (86 women and 82 men; mean age, 59.8 years; age range, 22-86 years) suspected of having interstitial lung disease. Differential diagnoses and responses to specific questions regarding patient care were recorded before and after assimilation of thin-section CT findings. Both unweighted and weighted kappa analyses were used to determine agreement between pulmonologists before and after CT. RESULTS: First-choice diagnosis changed in 520 (51%) of 1008 cases, and agreement on first-choice diagnosis increased from 0.47 to 0.72 after thin-section CT. In addition, confidence in the first-choice diagnosis increased, and there was a reduction in the number of differential diagnoses offered by all pulmonologists (P < .005 and P < .001, respectively). Agreement on diagnostic probabilities for individual disorders increased substantially, particularly for diagnoses of idiopathic pulmonary fibrosis (weighted kappa = 0.58-0.89). With CT findings, pulmonologists changed their pre-CT responses regarding the use of bronchoalveolar lavage, transbronchial biopsy, and thoracoscopic biopsy in 242 (24.0%), 282 (28.0%), and 292 (29.0%) of 1008 cases, respectively. However, agreement for the use of these investigations was low both before and after CT. The request rate for thoracoscopic biopsy in patients in whom idiopathic fibrosis was diagnosed decreased from 48 of 179 (26.8%) to 26 of 233 (11.2%) after CT. CONCLUSION: Thin-section CT resulted in a change in first-choice diagnosis in half the cases. Diagnostic confidence improved, and CT findings increased agreement between pulmonologists on diagnostic probabilities across a range of interstitial lung diseases.

Adult↗
PubMed2005

Interlobular septal thickening in idiopathic bronchiectasis: a thin-section CT study of 94 patients.

PURPOSE: To retrospectively establish the prevalence of interlobular septal thickening at thin-section computed tomography (CT) in patients with bronchiectasis and to retrospectively examine the relationship between septal thickening and various CT features of bronchiectasis and functional parameters. MATERIALS AND METHODS: Institutional review board approval or informed consent are not required for such a retrospective study. Thin-section CT scans of 94 patients (29 men, 65 women; age range, 18-82 years) with idiopathic bronchiectasis confirmed at thin-section CT and without any history or condition that causes bronchiectasis were assessed independently by two observers. The presence and signs of bronchiectasis, extent and distribution of septal thickening at global and lobar levels, and presence of emphysema were recorded. Univariate and multiple regression analyses were used to identify relationships between individual parameters of bronchiectasis, the extent of septal thickening, and functional indices. RESULTS: Interlobular septal thickening was present in 56 (60%) of 94 patients with idiopathic bronchiectasis, excluding those with trivial septal thickening (34 of 94, 36%). At a lobar level, 69% (514 of 748) of lobes with bronchiectasis had septal thickening. There was strong correlation between the extent of septal thickening and the extent (r = 0.61, P < .001) and severity (r = 0.54, P < .001) of bronchiectasis. Stepwise regression analysis showed a relationship between the extent of septal thickening and the extent of bronchiectasis (P < .001). Septal thickening was not linked to functional indices of obstruction or restriction. CONCLUSION: At thin-section CT, interlobular septal thickening is a frequent finding in patients with idiopathic bronchiectasis.

Adolescent↗
PubMed2005

C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis.

RATIONALE: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. OBJECTIVES: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. METHODS: In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. MEASUREMENTS AND MAIN RESULTS: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage >or= II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96-13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5-17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5-18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8-16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5-23.1; corrected p = 0.0009). CONCLUSIONS: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.

Case-Control Studies↗
PubMed2005

No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients.

GOALS OF WORK: The aims of this study were (1) to prospectively evaluate the clinical benefits of switching from morphine to an alternative opioid, using oxycodone as first-line alternative opioid, in patients with cancer, (2) to evaluate the consistency of the clinical decision for the need to switch by comparing two hospital sites, and (3) to evaluate whether there were objective predictors that would help identify morphine non-responders who require switching to an alternative opioid and from this to construct a clinical model to predict the need to switch. PATIENTS AND METHODS: One hundred eighty-six palliative care patients were prospectively recruited from two hospital sites. Responders were patients treated with morphine for more than 4 weeks with good analgesia and minimal side effects. Non-responders (switchers) were patients who had either uncontrolled pain or unacceptable side effects on morphine and therefore required an alternative opioid. The differentiation between responders and switchers was made clinically and later confirmed by objective parameters. RESULTS: In this prospective study 74% (138/186) had a good response to morphine (responders). One patient was lost to follow up. Twenty-five percent (47/186) did not respond to morphine. These non-responders were switched to alternative opioids (switchers). Furthermore, of 186 patients, 37 achieved a successful outcome when switched to oxycodone and an additional 4 were well controlled when switched to more than one alternative opioid. Overall successful pain control with minimal side effects was achieved in 96% (179/186) of patients. There were no significant differences in the need to switch between the two hospital sites. CONCLUSIONS: This study has shown that proactive clinical identification and management of patients that require opioid switching is reproducible in different clinical settings and significantly improves pain control. Further studies are required to develop and test the predictive model.

Adult↗
PubMed2005

Six-minute walk, maximal exercise tests: reproducibility in fibrotic interstitial pneumonia.

Resting pulmonary function and exercise variables are widely used to stage and monitor idiopathic interstitial pneumonia (IIP). However, the variability of exercise data (maximal exercise and the 6-minute walk test) has not been evaluated definitively. We have prospectively quantified the reproducibility of resting and exercise functional data in fibrotic IIP (idiopathic pulmonary fibrosis, fibrotic nonspecific interstitial pneumonia) and have evaluated interrelationships between variables. Thirty consecutive patients with fibrotic IIP underwent serial resting pulmonary function tests, 6-minute walk (n = 29), and maximal exercise (n = 24) at an interval of 1 week, with all testing performed in accordance with American Thoracic Society standards. Within-subject reproducibility was excellent for 6-minute walk distance (SD/mean = 4.2%) and clinically acceptable for resting pulmonary function indices and VO(2)max on maximal exercise testing. However, the amplitude of oxygen desaturation at the end of exercise was poorly reproducible in both 6-minute walk and maximal exercise testing (SD/mean > 25%). There was a highly significant relationship between VO2max on maximal exercise testing and 6-minute walk distance (r(s) = 0.78, p < 0.0001). In fibrotic IIP, the excellent reproducibility of the 6-minute walk distance is a major advantage in routine staging and monitoring, whereas maximal exercise variables are poorly reproducible.

Aged↗
PubMed2005

Functional impairment in emphysema: contribution of airway abnormalities and distribution of parenchymal disease.

OBJECTIVE: The aim of this study was to identify ancillary morphologic features on high-resolution CT that modify airflow obstruction and gas transfer levels in individuals with emphysema. MATERIALS AND METHODS: The extent of emphysema on high-resolution CT was quantified by density masking in 101 patients. CT scans were evaluated for airway abnormalities (bronchial wall thickness, extent of bronchiectasis, bronchial dilatation, and evidence of small airways disease) and disease heterogeneity (uniformity, core-rind distribution, craniocaudal distribution, and lung texture). Stepwise regression analysis was used to determine CT features that influenced forced expiratory volume in 1 sec (FEV1) and the single-breath diffusing capacity for carbon monoxide (Dlco) for a given extent of emphysema. RESULTS: The extent of emphysema using automated estimation was 28.4% +/- 12.3% (mean +/- SD). On univariate analysis the extent of emphysema correlated strongly with FEV1 (R = -0.63, p < 0.0005) and Dlco (R = -0.63, p < 0.0005) levels. Stepwise regression analysis revealed that bronchial wall thickness and the extent of emphysema were the strongest independent determinants of FEV1 (model R2 = 0.49; p = 0.002 and < 0.001, respectively); the extent of bronchiectasis and degree of bronchial dilation did not separately influence FEV1 levels. The only morphologic features linked to Dlco levels on multivariate analysis were increasingly extensive emphysema and a higher proportion of emphysema in the core region (model R2 = 0.45; p < 0.001 and 0.002, respectively). CONCLUSION: The important additional CT abnormalities in individuals with emphysema that influence FEV1 and Dlco levels irrespective of disease extent are bronchial wall thickness and core-rind heterogeneity, respectively. These observations have implications for the accurate functional assessment of patients considered for lung volume reduction surgery.

Adult↗
PubMed2004

Gene expression profiling reveals novel TGFbeta targets in adult lung fibroblasts.

BACKGROUND: Transforming growth factor beta (TGFbeta), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFbeta on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown. METHODS: We used Affymetrix oligonucleotide microarrays U95v2, containing approximately 12,000 human genes, to study the transcriptional profile in response to a four hour treatment with TGFbeta in control lung fibroblasts and in fibroblasts from patients with idiopathic and scleroderma-associated pulmonary fibrosis. A combination of the Affymetrix change algorithm (Microarray Suite 5) and of analysis of variance models was used to identify TGFbeta-regulated genes. Additional criteria were an average up- or down- regulation of at least two fold. RESULTS: Exposure of fibroblasts to TGFbeta had a profound impact on gene expression, resulting in regulation of 129 transcripts. We focused on genes not previously found to be regulated by TGFbeta in lung fibroblasts or other cell types, including nuclear co-repressor 2, SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), bone morphogenetic protein 4, and angiotensin II receptor type 1 (AGTR1), and confirmed the microarray results by real time-PCR. Western Blotting confirmed induction at the protein level of AGTR1, the most highly induced gene in both control and fibrotic lung fibroblasts among genes encoding for signal transduction molecules. Upregulation of AGTR1 occurred through the MKK1/MKK2 signalling pathway. Immunohistochemical staining showed AGTR1 expression by lung fibroblasts in fibroblastic foci within biopsies of idiopathic pulmonary fibrosis. CONCLUSIONS: This study identifies several novel TGFbeta targets in lung fibroblasts, and confirms with independent methods the induction of angiotensin II receptor type 1, underlining a potential role for angiotensin II receptor 1 antagonism in the treatment of lung fibrosis.

Cells, Cultured↗
PubMed2004

Organizing pneumonia: perilobular pattern at thin-section CT.

PURPOSE: To describe the appearance and frequency of a perilobular pattern at thin-section computed tomography (CT) in patients with organizing pneumonia. MATERIALS AND METHODS: Thin-section CT scans of 21 consecutive patients with cryptogenic organizing pneumonia were retrospectively reviewed. Two thoracic radiologists in consensus recorded the presence and distribution of the CT abnormalities (consolidation, ground-glass opacification, nodules, bandlike opacities, interlobular septal thickening, and findings of fibrosis), with a particular focus on the presence and predominant location of the perilobular pattern, that is, a poorly defined arcadelike or polygonal appearance. RESULTS: The perilobular pattern was present in 12 (57%) of 21 patients, 10 of whom had five or more perilobular opacities. Other CT features were consolidation (20 patients, 95%), which was predominantly a subpleural and/or peribronchial distribution in 17 patients, and ground-glass opacification (18 patients, 86%). Bandlike opacities and interlobular septal thickening were observed in four patients and one patient, respectively. The perilobular pattern abutted the pleural surface in 10 of 12 patients and was surrounded by aerated lung parenchyma in 11 of 12 patients. There was no obvious relationship between perilobular opacities and CT findings indicative of established fibrosis. CONCLUSION: A perilobular pattern was present in more than half of the patients, along with the expected thin-section CT features of organizing pneumonia.

Adult↗
PubMed2004

The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma.

OBJECTIVE: Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), antitopoisomerase antibody, and anti-RNA polymerase antibody. The purpose of this study was to investigate tumor necrosis factor (TNF) polymorphisms in scleroderma, with the specific aim of determining whether TNF polymorphisms would prove to be stronger markers for ACA than class II major histocompatibility complex (MHC). METHODS: We studied 214 UK white scleroderma patients and 354 healthy controls. All subjects were investigated for 5 TNF promoter region polymorphisms by sequence-specific polymerase chain reaction. RESULTS: We showed that an NF-kappaB binding site polymorphism (known to be functionally relevant) in the TNF promoter region was present in 51.8% of patients with ACA and 16.3% of patients without ACA (chi(2) = 25.1, P = 0.000004 [corrected P = 0.00002]). Using haplotype mapping, we showed that this was a primary TNF association that could explain the previous weak links between ACA production and class II MHC alleles. In marked contrast to our ACA results, HLA class II (especially DRB1*11) appeared to be primary in that it could explain the weaker TNF association with antitopoisomerase production. Further, we observed a separate TNF haplotype to be associated with scleroderma per se, although the level of significance was much lower (chi(2) = 8.7, P = 0.003 [corrected P = 0.02]). CONCLUSION: We believe these findings may have importance both for the directional pathogenesis of scleroderma progression and for the treatment of scleroderma with anti-TNF agents.

Alleles↗
PubMed2004

Respiratory bronchiolitis associated with interstitial lung disease and desquamative interstitial pneumonia.

This article explores issues of the diagnosis and management of respiratory bronchiolitis, respiratory bronchiolitis-associated interstitial lung disease, and desquamative interstitial pneumonia. These three diseases have common and overlapping features and sometimes are viewed as a continuum of smoking-induced disease, rather than as distinct and separate entities.

Bronchiolitis↗