Michael B. Rubens

Idiopathic pulmonary fibrosis-a composite physiologic index derived from disease extent observed by computed tomography

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests

BACKGROUND An obstructive defect is usual in bronchiectasis, but the pathophysiological basis of airflow obstruction remains uncertain. High resolution computed tomographic (CT) scanning now allows quantitation of static morphological abnormalities, as well as dynamic changes shown on expiratory CT scans. The aim of this study was to determine which static and dynamic structural abnormalities on the CT scan are associated with airflow obstruction in bronchiectasis. METHODS The inspiratory and expiratory features on the CT scan of 100 patients with bronchiectasis undergoing concurrent lung function tests were scored semi-quantitatively by three observers. RESULTS On univariate analysis the extent and severity of bronchiectasis, the severity of bronchial wall thickening, and the extent of decreased attenuation on the expiratory CT scan correlated strongly with the severity of airflow obstruction; the closest relationship was seen between decreased forced expiratory volume in one second (FEV1) and the extent of decreased attenuation on the expiratory CT scan (R s = –0.55, p<0.00005). On multivariate analysis bronchial wall thickness and decreased attenuation were consistently the strongest independent determinants of airflow obstruction. The extent of decreased attenuation was positively associated with the severity of bronchial wall thickness, but was not independently linked to gas transfer levels. Endobronchial secretions seen on CT scanning had no functional significance; the severity of bronchial dilatation was negatively associated with airflow obstruction after adjustment for other morphological features. CONCLUSIONS These findings indicate that airflow obstruction in bronchiectasis is primarily linked to evidence of intrinsic disease of small and medium airways on CT scanning and not to bronchiectatic abnormalities in large airways, emphysema, or retained endobronchial secretions.

Multimodality Imaging in Transcatheter Aortic Valve Implantation and Post-Procedural Aortic Regurgitation : Comparison Among Cardiovascular Magnetic Resonance, Cardiac Computed Tomography, and Echocardiography

OBJECTIVES The purpose of this study was to determine imaging predictors of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) and the agreement and reproducibility of cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT), and transthoracic echocardiography (TTE) in aortic root assessment. BACKGROUND The optimal imaging strategy for planning TAVI is unclear with a paucity of comparative multimodality imaging data. The association between aortic root morphology and outcomes after TAVI also remains incompletely understood. METHODS A total of 202 consecutive patients assessed by CMR, CCT, and TTE for TAVI were studied. Agreement and variability among and within imaging modalities was assessed by Bland-Altman analysis. Postoperative AR was assessed by TTE. RESULTS Of the 202 patients undergoing TAVI assessment with both CMR and TTE, 133 also underwent CCT. Close agreement was observed between CMR and CCT in dimensions of the aortic annulus (bias, -0.4 mm; 95% limits of agreement: -5.7 to 5.0 mm), and similarly for sinus of Valsalva, sinotubular junction, and ascending aortic measures. Agreement between TTE-derived measures and either CMR or CCT was less precise. Intraobserver and interobserver variability were lowest with CMR. The presence and severity of AR after TAVI were associated with larger aortic valve annulus measurements by both CMR (p = 0.03) and CCT (p = 0.04) but not TTE-derived measures (p = 0.10). Neither CCT nor CMR measures of annulus eccentricity, however, predicted AR after TAVI (p = 0.33 and p = 0.78, respectively). CONCLUSIONS In patients undergoing imaging assessment for TAVI, the presence and severity of AR after TAVI were associated with larger aortic annulus measurements by both CMR and CCT, but not TTE. Both CMR and CCT provide highly reproducible information in the assessment of patients undergoing TAVI.

Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study

AIMS The PREDICT Study is a prospective cohort study designed to evaluate coronary artery calcification score (CACS) as a predictor of cardiovascular events in type 2 diabetes (T2DM). METHODS AND RESULTS A total of 589 patients with no history of cardiovascular disease and with established T2DM had CACS measured, as well as risk factors, including plasma lipoprotein, apolipoprotein, homocysteine and C-reactive protein concentrations, homeostasis model assessment insulin resistance (HOMA-IR), and urine albumin creatinine ratio. Participants were followed for a median of 4 years and first coronary heart disease (CHD) and stroke events were identified as primary endpoints. There were 66 first cardiovascular events (including 10 strokes). CACS was a highly significant, independent predictor of events (P < 0.001), with a doubling in CACS being associated with a 32% increase in risk of events (29% after adjustment). Hazard ratios relative to CACS in the range 0-10 Agatston units (AU) were: CACS 11-100 AU, 5.4 (P = 0.02); 101-400 AU 10.5 (P = 0.001); 401-1000 AU, 11.9 (P = 0.001), and >1000 AU, 19.8 (P < 0.001). Only HOMA-IR predicted primary endpoints independently of CACS (P = 0.01). The areas under the receiver operator characteristic curve for United Kingdom Prospective Diabetes Study (UKPDS) risk engine primary endpoint risk and for UKPDS risk plus CACS were 0.63 and 0.73, respectively (P = 0.03). CONCLUSION Measurement of CACS is a powerful predictor of cardiovascular events in asymptomatic patients with T2DM and can further enhance prediction provided by established risk models.

Fibrosing alveolitis in systemic sclerosis : indices of lung function in relation to extent of disease on computed tomography

OBJECTIVE Thin-section computed tomography (CT) provides a sensitive and reproducible method of quantifying the morphologic extent of disease in the clinical management of fibrosing alveolitis associated with systemic sclerosis (FASSc). The aim of this study was to determine which indices of lung function best reflect the extent of disease on CT in FASSc, and to determine the independent influences of smoking history, extent of fibrosing alveolitis, demographic features, and concurrent treatment upon functional impairment in FASSc. METHODS Sixty-four patients with FASSc were studied using CT and static and exercise lung function testing. Statistical relationships were determined by multiple regression analyses. RESULTS Five patients with overt pulmonary hypertension were characterized by severe impairment in 3 indices of lung function: diffusing capacity for carbon monoxide (DLCO), DLCO adjusted for alveolar volume (KCO), and arterial partial pressure of oxygen. On multiple regression analysis, the major determinant of functional impairment was the extent of fibrosing alveolitis on CT. A history of smoking was independently associated with preservation of total lung capacity and depression of KCO, but did not otherwise influence functional-morphologic correlations. The percent predicted DLCO correlated better with extent of disease on CT (r = -0.70) than did oxygen desaturation on exercise (r = 0.55), the physiologic component of the clinical-radiographic-physiologic score (CRP index) (r = 0.52), or other indices of lung function. Lung volume measures correlated poorly with disease extent on CT. CONCLUSION The percent predicted DLCO best reflects the extent of fibrosing alveolitis in FASSc, and therefore should be measured in routine evaluations. Exercise testing may also have a useful role in staging the severity of pulmonary fibrosis, but the CRP index offers no additional advantage over the DLCO and exercise testing.

The Effect of Type 1 Diabetes Mellitus on the Gender Difference in Coronary Artery Calcification

OBJECTIVES To examine whether the gender difference in coronary artery calcification, a measure of atherosclerotic plaque burden, is lost in type 1 diabetic patients, and whether abnormalities in established coronary heart disease risk factors explain this. BACKGROUND Type 1 diabetes abolishes the gender difference in coronary heart disease mortality because it is associated with a greater elevation of coronary disease risk in women than men. The pathophysiological basis of this is not understood. METHODS Coronary artery calcification and coronary risk factors were compared in 199 type 1 diabetic patients and 201 nondiabetic participants of similar age (30 to 55 years) and gender (50% female) distribution. Only one subject had a history of coronary disease. Calcification was measured with electron beam computed tomography. RESULTS In nondiabetic participants there was a large gender difference in calcification prevalence (men 54%, women 21%, odds ratio 4.5, p < 0.001), half of which was explained by established risk factors (odds ratio after adjustment = 2.2). Diabetes was associated with a greatly increased prevalence of calcification in women (47%), but not men (52%), so that the gender difference in calcification was lost (p = 0.002 for the greater effect of diabetes on calcification in women than men). On adjustment for risk factors, diabetes remained associated with a threefold higher odds ratio of calcification in women than men (p = 0.02). CONCLUSIONS In type 1 diabetes coronary artery calcification is greatly increased in women and the gender difference in calcification is lost. Little of this is explained by known coronary risk factors.

Chronic inflammation and coronary microvascular dysfunction in patients without risk factors for coronary artery disease

AIMS To demonstrate that exposure to chronic inflammation results in coronary microvascular dysfunction (CMD). METHODS AND RESULTS Using positron emission tomography, resting and hyperaemic (adenosine, 140 microg/kg/min) myocardial blood flow (MBF) was measured in 25 patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Coronary flow reserve (CFR) was calculated as adenosine/resting MBF. Patients had normal or minimally diseased (i.e. <or=20% luminal diameter) coronary arteries at angiography and no cardiovascular risk factors. Twenty five age- and gender-matched healthy volunteers served as controls. Resting MBF was similar in patients and controls (1.25 +/- 0.27 vs. 1.15 +/- 0.24 mL/min/g; P = 0.15) while patients had lower hyperaemic MBF (2.94 +/- 0.83 vs. 4.11 +/- 0.84 mL/min/g; P < 0.001) and CFR (2.44 +/- 0.78 vs. 3.81 +/- 1.07; P < 0.001). CFR was inversely related to disease duration (r = -0.65; P < 0.001) and SLE disease activity (r = -0.69; P = 0.01). Seven patients showed ischaemic electrocardiographic changes during adenosine. They had longer disease duration (21 +/- 7 vs. 14 +/- 5 years; P = 0.03) and lower CFR (1.76 +/- 0.81 vs. 2.49 +/- 0.54; P = 0.006) when compared with patients without changes. CONCLUSION A reduced CFR in the absence of significant coronary disease is suggestive of CMD. We speculate that this is the consequence of prolonged systemic inflammation, which may precede and contribute to premature coronary artery disease in these patients.

Accuracy of the typical computed tomographic appearances of fibrosing alveolitis.

BACKGROUND--Open lung biopsy is often performed to confirm the diagnosis in patients with suspected fibrosing alveolitis. The superior sensitivity and specificity of high resolution computed tomography (CT) over chest radiography in various diffuse lung diseases suggest that the characteristic appearance of fibrosing alveolitis on high resolution CT might render biopsy confirmation unnecessary. METHODS--The chest radiographs and high resolution CT scans of 86 patients (41 with fibrosing alveolitis and 45 with various other diffuse lung diseases) were examined individually and independently by two observers. No clinical information was given and the observers gave a level of confidence when the diagnosis was thought to be fibrosing alveolitis. RESULTS--The observers correctly and confidently discriminated between fibrosing alveolitis and other diffuse lung diseases on high resolution CT with an accuracy of 88% and on chest radiography with an accuracy of 76%. The false negative rate for fibrosing alveolitis diminished from 29% on chest radiography to 11% on high resolution CT. The false positive rate on chest radiography was 19% and on high resolution CT 13%; the false positive diagnoses on CT were the result of a few conditions (extrinsic allergic alveolitis, sarcoidosis, cryptogenic organising pneumonia, and pulmonary eosinophilia) which mimicked some of the CT features of fibrosing alveolitis. The superficial similarity of the CT patterns of these conditions are discussed. CONCLUSIONS--High resolution CT is superior to chest radiography in establishing the diagnosis of fibrosing alveolitis and the typical CT appearances are virtually pathognomonic. The diagnostic advantages of CT over chest radiography should further reduce the need for open lung biopsy in this condition.

Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial

BACKGROUND Lung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis. METHODS We did a single-centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score ≥3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to-treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234. FINDINGS 50 patients (62% male, FEV1 [% predicted] mean 31·7% [SD 10·2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8·77% (IQR 2·27-35·85) versus 2·88% (0-8·51) in the control group (Mann-Whitney p=0·0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax. INTERPRETATION Unilateral lobar occlusion with endobronchial valves in patients with heterogeneous emphysema and intact interlobar fissures produces significant improvements in lung function. There is a risk of significant complications and further trials are needed that compare valve placement with lung volume reduction surgery. FUNDING Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Observer variation in pattern type and extent of disease in fibrosing alveolitis on thin section computed tomography and chest radiography

In fibrosing alveolitis the pattern type on thin section computed tomography (CT) predicts histological appearances at open lung biopsy and the likelihood of response to treatment. To test the level of inter- and intra-observer variability on CT and chest radiography (CXR), the pattern type and extent of disease were assessed by four observers (two experienced, two inexperienced). A total of 126 CT examinations and 108 concurrent postero-anterior chest radiographs were scored on two occasions, at least 8 weeks apart. A confidence rating was assigned to each observation. Three out of four observers agreed on pattern type in 81% of cases on CT compared with 54% on CXR (kappa coefficient 0.48 and 0.16 for CT and CXR, respectively). Inter-observer variability in categorizing pattern type on CT was lowest in patients with the highest confidence scores (kappa = 0.63). Confident observations were associated with extensive or moderately extensive disease (P < 0.001), and with a predominantly reticular pattern (P < 0.0001). Intra-observer variability for pattern type on CT was less for the experienced observers (kappa = 0.78 and 0.70) than for the inexperienced group (kappa = 0.50 and 0.37). Inter-observer variability for extent of disease was significantly less on CT than on CXR (standard deviations 7.8% and 9.2% respectively, P < 0.001). This study shows that observer variability using a clinical grading system is lower with CT than with chest radiography in fibrosing alveolitis.