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Thorax 03/2013; · 6.84 Impact Factor
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Angelo De Lauretis,
Piersante Sestini,
Panagiotis Pantelidis,
Rachel Hoyles,
David M Hansell,
Nicole S L Goh,
Christopher J Zappala,
Dina Visca,
Toby M Maher,
Christopher P Denton,
Voon H Ong,
David J Abraham,
Peter Kelleher,
Laureen Hector, Athol U Wells,
Elisabetta A Renzoni
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ABSTRACT: OBJECTIVE: Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). METHODS: A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. RESULTS: In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4-7.2, p = 0.007), but not in those with severe ILD. CONCLUSION: In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.
The Journal of Rheumatology 02/2013; · 3.69 Impact Factor
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Carmel J Stock,
Hiroe Sato,
Carmen Fonseca,
Winston A S Banya,
Philip L Molyneaux,
Huzaifa Adamali,
Anne-Marie Russell,
Christopher P Denton,
David J Abraham,
David M Hansell,
Andrew G Nicholson,
Toby M Maher, Athol U Wells,
Gisela E Lindahl,
Elisabetta A Renzoni
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ABSTRACT: BACKGROUND: A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. METHODS: Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. RESULTS: A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04×10(-17); OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. CONCLUSIONS: We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.
Thorax 01/2013; · 6.84 Impact Factor
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ABSTRACT: Introduction: Novel compounds targeting various aspects of fibrogenesis have been developed consequent to the increasing knowledge of the pathogenetic mechanisms of the interstitial lung diseases (ILDs). The authors review the evolution of treatment approaches in the ILDs, informed by recent placebo-controlled trials, and discuss current clinical trials in which emerging pathogenetic mechanisms are targeted as novel therapeutic agents. Areas covered: In idiopathic pulmonary fibrosis (IPF), recent randomised, placebo-controlled trials have tested the efficacy of new therapies, and although primary end points have not been met in most, treatment effects have been observed. The demonstration of harmful effects from widely used IPF therapies has been equally important. Pirfenidone and nintedanib are emerging agents that exert pleiotropic effects, reflective of the multiple mechanistic pathways of IPF. Treatment may necessitate a similarly multifaceted approach using combination regimens of antifibrotic and antioxidant agents in order to be effective. In other ILDs, including systemic sclerosis, other connective tissue diseases and pulmonary sarcoidosis, the inflammatory/fibrotic model remains appropriate. Studies in systemic sclerosis have provided 'proof of concept' data for immunosuppressive therapy in the prevention of disease progression but there is a continuing need for controlled clinical trials in the more prevalent ILDs. Expert opinion: In IPF, significant treatment effects have been reported with pirfenidone, nintedanib and N-acetylcysteine. Combinations of these pleiotropic agents, along with future monotherapies, in 'oncological regimens' may hold the key to more effective IPF treatment. In disorders other than IPF, there is an ongoing need for the controlled evaluation of traditional anti-inflammatory and immunosuppressive therapies. 'Cohort enrichment' (the selective recruitment of patients most likely to progress) holds the key to the identification of worthwhile treatment benefits.
Expert Opinion on Pharmacotherapy 01/2013; 14(1):79-89. · 3.20 Impact Factor
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ABSTRACT: RATIONALE: Health status is impaired in patients with sarcoidosis. There is a paucity of tools that assess health status in sarcoidosis. The objective of this study was to develop and validate the King's Sarcoidosis Questionnaire (KSQ), a new modular health status measure. METHODS: Patients with sarcoidosis were recruited from outpatient clinics. The development of the questionnaire consisted of three phases: item generation; item reduction, Rasch analysis to create unidimensional scales and validation; repeatability testing. RESULTS: 207 patients with sarcoidosis (organ involvement: 184 lung, 54 skin, 45 eye disease) completed a 65-item preliminary questionnaire. 36 items were removed due to redundancy or poor fit to the Rasch model. The final version of the KSQ consisted of five modules (General health status, Lung, Skin, Eye, Medications). Internal consistency assessed with Cronbach's α coefficient was 0.70-0.93 for KSQ modules. Concurrent validity of the Lung module was high compared with St George's Respiratory Questionnaire (r=-0.83) and moderate when compared to forced vital capacity (r=0.49). Concurrent validity with skin-specific and eye-specific measures ranged from r=-0.4 to 0.8. The KSQ was repeatable over 2 weeks (n=39), intraclass correlation coefficients for modules were 0.90-0.96. CONCLUSIONS: The KSQ is a brief, valid, self-completed health status measure for sarcoidosis. It can be used in the clinic to assess sarcoidosis from the patients' perspective.
Thorax 10/2012; · 6.84 Impact Factor
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Athol U Wells,
Juergen Behr,
Ulrich Costabel,
Vincent Cottin,
Venerino Poletti,
Luca Richeldi,
Albera C,
Ancochea J,
Antoniou KM,
Bonella F, [......],
Saltini C,
Skold M,
Spagnolo P,
Thomeer M,
Tomasseti S,
Valeyre D,
Vancheri C,
Wallaert B,
Wuyts W,
Xaubet A
Thorax 10/2012; 67(11):938-40. · 6.84 Impact Factor
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The Lancet 08/2012; 380(9842):627-9. · 38.28 Impact Factor
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Amit S Patel,
Richard J Siegert,
Katherine Brignall,
Patrick Gordon,
Sophia Steer,
Sujal R Desai,
Toby M Maher,
Elisabetta A Renzoni, Athol U Wells,
Irene J Higginson,
Surinder S Birring
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ABSTRACT: Health status is impaired in patients with interstitial lung disease (ILD). There is a paucity of tools that assess health status in ILD. The objective of this study was to develop and validate the King's Brief Interstitial Lung Disease questionnaire (K-BILD), a new health status measure for patients with ILD.
Patients with ILD were recruited from outpatient clinics. The development of the questionnaire consisted of three phases: item generation; item reduction, allocation to domains by factor analysis, Rasch analysis to create unidimensional scales and validation; and repeatability testing.
173 patients with ILD (49 with idiopathic pulmonary fibrosis) completed a preliminary 71-item questionnaire. 56 items were removed due to redundancy, low factor loadings or poor fit to the Rasch model. The final version of the K-BILD questionnaire consisted of 15 items and three domains (breathlessness and activities, chest symptoms and psychological). Internal consistency assessed with Cronbach's α coefficient was 0.94 for the K-BILD total score. Concurrent validity of the K-BILD questionnaire was high compared with St George's Respiratory Questionnaire (r=0.90) and moderate with lung function (vital capacity, r=0.50). The K-BILD questionnaire was repeatable over 2 weeks (n=44), with intraclass correlation coefficients for domains and total score 0.86-0.94. The K-BILD construct validity for patients with idiopathic pulmonary fibrosis was similar to that of other ILDs.
The K-BILD questionnaire is a brief, valid, self-completed health status measure for ILD. It could be used in the clinic to assess ILD from the patients' perspective.
Thorax 05/2012; 67(9):804-10. · 6.84 Impact Factor
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Thorax 04/2012; · 6.84 Impact Factor
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ABSTRACT: : To test the hypothesis that there is a difference between the lung computed tomography (CT) microstructure of asymptomatic older individuals and that of young individuals as evaluated by objective indices of complexity and density.
: Two study groups of nonsmoking urban-dwelling individuals over 75 years and under 55 years were prospectively identified. Thirty-three consecutive volunteers (21 older than 75 y and 12 less than 55 y) were included, and CTs were performed with concurrent pulmonary function testing. Pulmonary regions of interest (ROIs) were evaluated with fractal dimension (FD) analysis (an index of complexity), mean lung density (MLD), and percentage of pixels with lung density (LD) less than thresholds of -910 HU and -950 HU. The Student t test and the Mann-Whitney test were used to evaluate for differences in mean values between groups. The Pearson correlation coefficient was used to correlate mean FD value and LD data with pulmonary function.
: Significant correlations of ROI MLD, LD -910 HU, and LD -950 HU with age and sex were shown (P=0.029-0.003). The ROI mean FD value was greater in younger individuals compared with older individuals (76.5±1.7 vs. 70.3±1.2; P=0.004). There was a correlation between Kco (gas-diffusing capacity adjusted for alveolar volume) and mean FD value (P=0.006) and MLD (P=0.015).
: The lung parenchyma of nonsmoking older urban-dwelling asymptomatic individuals has significantly different CT density and complexity compared with younger individuals.
Journal of thoracic imaging 04/2012; 27(6):366-71. · 1.42 Impact Factor
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ABSTRACT: To investigate high resolution computed tomography (HRCT) and pulmonary function indices (PFTs) for determining prognosis in patients with chronic fibrotic hypersensitivity pneumonitis (CHP).
Case records, PFTs (FEV(1), FVC and DLco) and HRCTs of ninety-two patients with chronic hypersensitivity pneumonitis were evaluated. HRCT studies were scored by two observers for total disease extent, ground-glass opacification, fine and coarse reticulation, microcystic and macrocystic honeycombing, centrilobular emphysema and consolidation. Traction bronchiectasis within each pattern was graded. Using Cox proportional hazards regression models the prognostic strength of individual HRCT patterns and pulmonary function test variables were determined.
There were forty two deaths during the study period. Increasing severity of traction bronchiectasis was the strongest predictor of mortality (HR 1.10, P < 0.001, 95%CI 1.04-1.16). Increasing global interstitial disease extent (HR 1.02, P = 0.02, 95%CI 1.00-1.03), microcystic honeycombing (HR 1.09, P = 0.019, 95%CI 1.01-1.17) and macrocystic honeycombing (HR 1.06, P < 0.01, 95%CI 1.01-1.10) were also independent predictors of mortality. In contrast, no individual PFT variable was predictive of mortality once HRCT patterns were accounted for.
HRCT patterns, in particular, severity of traction bronchiectasis and extent of honeycombing are superior to pulmonary function tests for predicting mortality in patients with CHP.
• HRCT is increasingly used to assess chronic fibrotic hypersensitivity pneumonitis. • HRCT patterns are superior to pulmonary function tests for predicting mortality. • Extensive traction bronchiectasis strongly predicts poor survival in chronic hypersensitivity pneumonitis.
European Radiology 04/2012; 22(8):1672-9. · 3.22 Impact Factor
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ABSTRACT: In spite of their presumed relevance in maintaining interalveolar septal fluid homeostasis, the knowledge of the anatomy of human lung lymphatics is still incomplete. The recent discovery of reliable markers specific for lymphatic endothelium has led to the observation that, contrary to previous assumptions, human lymphatic vessels extend deep inside the pulmonary lobule in association with bronchioles, intralobular arterioles or small pulmonary veins. The aim of this study was to provide a morphometric characterization of lymphatic vessels in the periphery of the human lung. Human lung sections were immunolabelled with the lymphatic marker D2-40, followed by blood vessel staining with von Willebrand Factor. Lymphatic vessels were classified into: intralobular (including those associated with bronchovascular bundles, perivascular, peribronchiolar and interalveolar), pleural (in the connective tissue of the visceral pleura), and interlobular (in interlobular septa). The percentage area occupied by the lymphatic lumen was much greater in the interlobular septa and in the subpleural space than in the lobule. Most of the intralobular lymphatic vessels were in close contact with a blood vessel, either alone or within a bronchovascular bundle, whereas 7% were associated with a bronchiole and < 1% were not connected to blood vessels or bronchioles (interalveolar). Intralobular lymphatic size progressively decreased from bronchovascular through to peribronchiolar, perivascular and interalveolar lymphatics. Lymphatics associated with bronchovascular bundles had similar morphometric characteristics to pleural and interlobular lymphatics. Shape factors were similar across lymphatic populations, except that peribronchiolar lymphatics had a marginally increased roundness and circularity, suggesting a more regular shape due to increased filling, and interlobular lymphatics had greater elongation, due to a greater proportion of conducting lymphatics cut longitudinally. Unsupervised cluster analysis confirmed a marked heterogeneity of lymphatic vessels both within and between groups, with a cluster of smaller vessels specifically represented in perivascular and interalveolar lymphatics within the alveolar interstitium. Our data indicate that intralobular lymphatics are a heterogeneous population, including vessels surrounding the bronchovascular bundle analogous to the conducting vessels present in the pleural and interlobular septa, many small perivascular lymphatics responsible for maintaining fluid balance in the alveolar interstitium, and a minority of intermediate lymphatics draining the peripheral airways. These lymphatic populations could be differentially involved in the pathogenesis of diseases preferentially involving distinct lung compartments.
Journal of Anatomy 01/2012; 220(4):396-404. · 2.37 Impact Factor
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Tamera J Corte,
Stephen J Wort,
Peter S MacDonald,
Anthony Edey,
David M Hansell,
Elisabetta Renzoni,
Toby M Maher,
Andrew G Nicholson,
Steven Bandula,
Paul Bresser, Athol U Wells
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ABSTRACT: Pulmonary hypertension (PH) is associated with increased mortality in fibrotic idiopathic interstitial pneumonia (IIP). We hypothesize that baseline K(CO) (diffusing capacity of carbon monoxide/alveolar volume) and 6-month decline in K(CO) reflect PH, thus predicting mortality in IIP.
All IIP referrals (2004-2007) were identified (n = 269). 192 had pulmonary function at 6 months. Fifty-two (27%) died during follow-up (median 22.5 months). Outcome was evaluated for early (1 year from 6-month pulmonary function) and overall mortality. A vascular index best predicting mortality was identified (using baseline and 6-month decline in K(CO) ) and evaluated against PH at echocardiography.
Baseline and 6-month decline in K(CO) were associated with early and overall mortality. A positive vascular index (baseline K(CO) % ≤ 50% and/or ≥15% decline in K(CO) at 6 months; n = 40) was strongly predictive of early and overall mortality. Neither a diagnosis of idiopathic pulmonary fibrosis nor PH predicted early death when incorporated into this model. In patients without baseline PH, with follow-up echocardiography (n = 60), a positive vascular index was associated with PH at follow-up.
A vascular index comprised of baseline and 6-month decline in K(CO) strongly predicted increased mortality and development of PH on echocardiography. In, K(CO) may be an important marker for pulmonary vascular disease and its associated mortality.
Respirology 12/2011; 17(4):674-80. · 2.42 Impact Factor
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Camilla Rowan,
David M Hansell,
Elisabetta Renzoni,
Toby M Maher, Athol U Wells,
Michael I Polkey,
Pauline K Rehal,
Wanis H Ibrahim,
Georges Ng Man Kwong,
Thomas V Colby,
Massimo Pistolesi,
Francesca Bigazzi,
Camilla E Comin,
Andrew G Nicholson
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ABSTRACT: Diffuse "true" cystic lung disease is rare, and the specificity of high-resolution computed tomography (HRCT) has reduced the need for biopsy. We present 5 patients with similar clinical and HRCT features of cystic lung disease that were sufficiently atypical to warrant surgical lung biopsies that showed coexistent small airway diseases (SAD). There were 4 female patients and 1 male patient with a mean age of 43 years. All were never smokers. Four had symptoms such as dyspnea (1), cough (2), or both (1). HRCTs showed variably sized thin-walled cystic airspaces without zonal distribution, some with prominent vessels in their walls. One case was unilateral. Surgical lung biopsy showed cystic change comprising localized loss of alveolar density with coexistent SADs [chronic bronchiolitis (n=2), eosinophilic bronchiolitis, probable asthma (n=1), and diffuse idiopathic neuroendocrine cell hyperplasia (n=2)]. Two patients who were tested for Birt-Hogg-Dube-related gene mutations proved negative, and all lacked other features of Birt-Hogg-Dube. We hypothesize that chronic damage to small airways may lead to cystic degeneration in a minority of patients. Precedents in relation to Sjogren syndrome and hypersensitivity pneumonitis raise the possibility of a causal association between pathologies in these 2 anatomic compartments, although HRCT data in relation to common SADs indicate that this would be a rare phenomenon. The driving factor remains unknown.
The American journal of surgical pathology 11/2011; 36(2):228-34. · 4.06 Impact Factor
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Roland M du Bois,
Derek Weycker,
Carlo Albera,
Williamson Z Bradford,
Ulrich Costabel,
Alex Kartashov,
Talmadge E King,
Lisa Lancaster,
Paul W Noble,
Steven A Sahn,
Michiel Thomeer,
Dominique Valeyre, Athol U Wells
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ABSTRACT: Forced vital capacity (FVC) is an established measure of pulmonary function in idiopathic pulmonary fibrosis (IPF). Evidence regarding its measurement properties and minimal clinically important difference (MCID) in this population is limited.
To assess the reliability, validity, and responsiveness of FVC and estimate the MCID in patients with IPF.
The study population included all 1,156 randomized patients in two clinical trials of IFN-γ1b. FVC and other measures of functional status were measured at screening or baseline and 24-week intervals thereafter. Reliability was assessed based on two proximal measures of FVC, validity was assessed based on correlations between FVC and other measures of functional status, and responsiveness was assessed based on the relationship between 24-week changes in FVC and other measures of functional status. Distribution-based and anchor-based methods were used to estimate the MCID.
Correlation of percent-predicted FVC between measurements (mean interval, 18 d) was high (r = 0.93; P < 0.001). Correlations between FVC and other parameters were generally weak, with the strongest observed correlation between FVC and carbon monoxide diffusing capacity (r = 0.38; P < 0.001). Correlations between change in FVC and changes in other parameters were slightly stronger (range, r = 0.16-0.37; P < 0.001). Importantly, 1-year risk of death was more than twofold higher (P < 0.001) in patients with a 24-week decline in FVC between 5% and 10%. The estimated MCID was 2-6%.
FVC is a reliable, valid, and responsive measure of clinical status in patients with IPF, and a decline of 2-6%, although small, represents a clinically important difference.
American Journal of Respiratory and Critical Care Medicine 09/2011; 184(12):1382-9. · 11.08 Impact Factor
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ABSTRACT: To investigate the effect of diffuse interstitial lung disease (DILD) on the image quality of computed tomographic pulmonary angiography (CTPA).
The study group comprised 130 patients with DILD who underwent CTPA between April 2005 and April 2009. One hundred and thirty patients without significant parenchymal lung disease were used as a control group. Contrast enhancement of pulmonary arteries in the left upper lobe and right lower lobe was evaluated to the sub-subsegmental level both subjectively and objectively. The global and lobar extents of interstitial lung disease were also estimated in the study group. Subjective assessment was performed by 2 observers, initially independently and subsequently by consensus in cases of discordance.
At the sub-subsegmental level, the number of patients with adequately opacified arteries was significantly lower in the DILD group (29.2% left upper lobe, 36.2% right lower lobe) compared with the control group (78.5% left upper lobe, 89.2% right lower lobe) (P<0.001). Subjective image quality scores of the sub-subsegmental arteries were strongly correlated with mean vascular attenuation values at this level (P<0.001) but not to the global or lobar extent of lung parenchymal disease. There was no clinically significant difference in image quality (either subjectively or objectively) between the DILD and control groups in the subsegmental and more proximal arterial branches.
In the majority of patients with DILD, CTPA image quality is sufficient only to the subsegmental level. Emboli at the sub-subsegmental level, which may have greater clinical significance in patients with DILD than in those without, are unlikely to be excluded using CTPA.
Journal of thoracic imaging 09/2011; 27(3):156-63. · 1.42 Impact Factor
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American Journal of Respiratory and Critical Care Medicine 08/2011; 184(4):395-7. · 11.08 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate the association between pulmonary hypertension estimated with CT and outcome among patients with bronchiectasis.
The cases of 91 patients with bronchiectasis were studied. CT signs of pulmonary hypertension examined were main pulmonary artery diameter, right and left main pulmonary artery diameters, and the ratio between the diameters of the main pulmonary artery and the ascending aorta. CT scans were scored for extent of bronchiectasis and presence of bronchial dilatation, bronchial wall thickening, mucous plugging, mosaicism, and emphysema. Univariate, bivariate, and multivariate Cox proportional hazards models were used to test the influence of CT signs on mortality.
Average right and left main pulmonary artery diameter was the best predictor of mortality (hazard ratio, 1.24; 95% CI, 1.13-1.35; p < 0.0001) and was associated with outcome independent of CT signs of bronchiectasis.
Pulmonary hypertension, reflected by pulmonary arterial enlargement on CT scans, is a highly significant prognostic indicator in the evaluation of patients with bronchiectasis.
American Journal of Roentgenology 06/2011; 196(6):1300-4. · 2.78 Impact Factor
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Thorax 03/2011; 66(3):183-84. · 6.84 Impact Factor
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ABSTRACT: The study aims were to identify CT features that predict outcome of fibrotic idiopathic interstitial pneumonia (IIP) when information from lung biopsy data is unavailable.
HRCTs of 146 consecutive patients presenting with fibrotic IIP were studied. Visual estimates were made of the extent of abnormal lung and proportional contribution of fine and coarse reticulation, microcystic (cysts ≤4 mm) and macrocystic honeycombing. A score for severity of traction bronchiectasis was also assigned. Using death as our primary outcome measure, variables were analysed using the Cox proportional hazards model.
CT features predictive of a worse outcome were coarse reticulation, microcystic and macrocystic honeycombing, as well as overall extent of lung abnormality (p < 0.001). Importantly, increased severity of traction bronchiectasis, corrected for extent of parenchymal abnormality, was predictive of poor prognosis regardless of the background pattern of abnormal lung (HR = 1.04, CI = 1.03-1.06, p < 0.001). On bivariate Cox analysis microcystic honeycombing was a more powerful determinant of a poor prognosis than macrocystic honeycombing.
In fibrotic IIPs we have shown that increasingly severe traction bronchiectasis is indicative of higher mortality irrespective of the HRCT pattern and extent of disease. Extent of microcystic honeycombing is a more powerful determinant of outcome than macrocystic honeycombing.
European Radiology 03/2011; 21(8):1586-93. · 3.22 Impact Factor
