CT measurement of airway remodeling and emphysema in advanced COPD: correlation to pulmonary hypertension

Transcription

1 SUPPLEMENTAL APPENDIX CT measurement of airway remodeling and emphysema in advanced COPD: correlation to pulmonary hypertension Authors Gaël Dournes MD 1,2,3, François Laurent MD 1,2,3, Florence Coste PhD-St 1,2, Claire Dromer MD 3, Elodie Blanchard 3, François Picard MD 3, Fabien Baldacci PhD 4, Michel Montaudon MD-PhD 1,2,3, Pierre-Olivier Girodet MD-PhD 1,2,3, Roger Marthan MD-PhD 1,2,3, Patrick Berger MD-PhD 1,2,3 Affiliations : 1 Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, F-3300 Bordeaux, France 2 Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, F-3300 Bordeaux, France 3 CHU de Bordeaux, Service d Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service de Cardiologie, Service des Explorations Fonctionnelles Respiratoires, F Pessac, France 4 Univ. Bordeaux, LaBRI, Talence, France

2 Supplemental Methods Pulmonary function test Standardized measurements of lung function were performed by spirometry and static lung volumes were assessed by using body plethysmography (Medisoft; BodyBox, Sorinnes, Belgium). The forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and residual volume (RV) were recorded in litres and expressed as percentages of predicted values. The carbon monoxide diffusion capacity (TLCO) was assessed by using HypAir Compact (Medisoft) and expressed as percentage of predicted value. References values were those of the American Thoracic Society and European Respiratory Society guidelines (1, 2). Arterial blood (room air) was drawn for measuring arterial blood gases including PaO 2, PaCO 2 and expressed in mmhg. The 6 minute walk test (6MWT) was performed in a standardized manner following ATS recommendation, and the walking distance was expressed in meters. CT protocol CT of the chest was acquired on a Somatom Definition 64 (Siemens, Erlangen, Germany) by using the following parameters: 110-kV tube voltage, 50-mAs tube current, 75-msec rotation time and 0.75-mm collimation, no contrast injection. Data were acquired in the supine position at full inspiration (TLC). CT datasets were reconstructed with both high-spatialfrequency and standard algorithm, with a 1-mm reconstruction section thickness, 1-mm reconstruction interval, 320x320-mm field-of-view, and 512x512 matrix, pixel size 0.625mm 2. CT scans were anonymized before further full automatic quantitative analysis, in a blinded fashion from other patients data. E1

3 Quantitative CT analysis of bronchial wall thickness and emphysema Automatic quantitative analysis of bronchial dimensions was performed on CT datasets of images reconstructed with high spatial frequency algorithm and displayed with parenchymal windowing. These images were analyzed in three dimensions using validated and reproducible software (3) using the Laplacian-of-Gaussian algorithm (4) to segment wall area (WA) and lumen area (LA) on cross-section orthogonal to the bronchus main axis. An arbitrary set of four bronchial paths were analyzed from the third to the fifth generation, starting from RB1 (right upper lobe), RB10 (right lower lobe), LB1 (left upper lobe) and LB10 (left lower lobe). The wall thickness of a standardized bronchus with an internal perimeter of 10 mm (WT-Pi10) was used to assess airway wall remodeling (5). WT-Pi10 was obtained by synthetizing the whole WA and LA measurements into a single value, by calculating the regression line between the square root of wall areas and the internal perimeters of lumen. WT-Pi10 corresponds to the wall thickness of associated with an internal perimeter of 10mm. Additional assessment of spatially-matched airways was performed to get spatial information on airway remodeling distribution (6, 7), as previous authors reported that small-sized airways are more likely to correlate with pulmonary functional impairment in COPD. For these latter analyses, the plain wall thickness value was measured using standard calculation from WA and LA (8) as follows: - WT= [ (WA+LA)/π] - (LA/π) For each bronchi analyzed, two measurements were performed into the middle third of bronchi length and averaged to get a single mean value. At each generation, the whole WT measurements made over the four bronchial paths were averaged to get a single mean value. Though a single bronchial measurement has been reported to be representative of the whole bronchial tree alteration in COPD (8), this averaging method was used to reduce possible E2

4 intra-subject variability (from upper to lower lung regions, and from right and left lung), and reduce intra-observer variability in measurements, as compared to a single measurement. Automatic quantification of emphysema was performed on CT images reconstructed with standard algorithm by using dedicated software for whole-lung densitometry (Myrian software, Montpellier, France). Percentage of low lung attenuation areas (LAA%) was derived from the voxel frequency distribution histogram and represented voxels less than a threshold of -950 HU. LAA% represents emphysema extent on CT scans (9). Right heart catheterization Right heart catheterization (RHC) was performed under local anaesthesia by using a flowdirected balloon-tipped 7F Swan-Ganz catheter (131HF7; Baxter Healthcare Cop., Irvine, USA) which was inserted via the jugular vein (10). The following hemodynamic parameters were obtained by averaging three measurements at end-expiration: systolic, mean and diastolic pulmonary artery pressure (PAP s, - m, - d ), pulmonary capillary wedge pressure (PCWP). During the procedure, oxygen was administered to maintain oxygen saturation superior to 92 mmhg. The gradient was calculated as the difference between PAP d and PCWP. Cardiac output (CO) was determined by the direct Fick method. E3

5 Supplemental Statistics: Stepwise regression analysis To determine the best model in order to predict PH, we used a forward/backward stepwise regression analysis (11), using PAP m as the dependent outcome. Variables were candidates to enter the model whether they were normally distributed, showed to correlate to PAP m in literature or demonstrated to correlate to PAP m at univariate analysis in the present study. The level of significance of the p-value of regression coefficients to enter or to exit the model was set to The independent predictor most associated with PAP m was allowed to enter the model whether the p-value of the regression coefficient was inferior to 0.20 at univariate analysis. Regression analysis was then performed to assess whether the p-value of the regression coefficient was inferior to Other variables associated with PAP m where thus tested step by step following the same procedure to enter or exit the model. The process was stopped when all variables, enable to both enter and stay into the model, were included. Conservative assessment of multicollinearity was performed to remove redundant information from the best model. Multicollinearity was detected whether the pair-wise coefficient of correlation between two variables was significantly superior to 0.5 (12) and/or their variance inflation factor inferior to 5 (13). Variables significantly cross-correlated were not entered into same models in order to determine the best model predictive of PAP m elevation. E4

6 Supplemental references 1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, Force AET. Standardisation of spirometry. The European respiratory journal 2005; 26: Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson D, Macintyre N, McKay R, Miller MR, Navajas D, Pellegrino R, Viegi G. Standardisation of the measurement of lung volumes. The European respiratory journal 2005; 26: Montaudon M, Berger P, de Dietrich G, Braquelaire A, Marthan R, Tunon-de-Lara JM, Laurent F. Assessment of airways with three-dimensional quantitative thin-section CT: in vitro and in vivo validation. Radiology 2007; 242: Berger P, Perot V, Desbarats P, Tunon-de-Lara JM, Marthan R, Laurent F. Airway wall thickness in cigarette smokers: quantitative thin-section CT assessment. Radiology 2005; 235: Johannessen A, Skorge TD, Bottai M, Grydeland TB, Nilsen RM, Coxson H, Dirksen A, Omenaas E, Gulsvik A, Bakke P. Mortality by level of emphysema and airway wall thickness. American journal of respiratory and critical care medicine 2013; 187: Hasegawa M, Nasuhara Y, Onodera Y, Makita H, Nagai K, Fuke S, Ito Y, Betsuyaku T, Nishimura M. Airflow limitation and airway dimensions in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 2006; 173: Smith BM, Hoffman EA, Rennard S, Barr RG. Location, location, location: studying anatomically comparable airways is highly relevant to understanding COPD. Thorax Nakano Y, Muro S, Sakai H, Hirai T, Chin K, Tsukino M, Nishimura K, Itoh H, Pare PD, Hogg JC, Mishima M. Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. American journal of respiratory and critical care medicine 2000; 162: Matsuoka S, Yamashiro T, Washko GR, Kurihara Y, Nakajima Y, Hatabu H. Quantitative CT assessment of chronic obstructive pulmonary disease. Radiographics : a review publication of the Radiological Society of North America, Inc 2010; 30: Dumas de La Roque E, Savineau JP, Metivier AC, Billes MA, Kraemer JP, Doutreleau S, Jougon J, Marthan R, Moore N, Fayon M, Baulieu EE, Dromer C. Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): a pilot study. Annales d'endocrinologie 2012; 73: Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis New York: Springer-Verlag; Hair JF, Anderson RE, Tatham RL, Black WC. Multivariate data analysis (4th ed.): with readings. New Jersey: Prentice Hall; Grewald R, Cote JA, Baumgartner H. Multicollinearity and Measurement Error in Structural Equation Models: Implications for Theory Testing. Marketing Science 2004: 23:24, E5

7 Supplemental Table 1. Spatially-matched comparisons of wall thickness assessed per bronchial generation in COPD with and without PH. COPD patients COPD patients without PH with PH n=26 n=34 p-value Mean WT (mm) Bronchial generation 3 rd 1.30 ± ± th 1.13 ± ± * 5 th 0.98 ± ± * * indicates a p-value inferior to Legend: WT=wall thickness E6

8 Supplemental Table 2. Spatially-matched correlations between CT measurements of wall thickness and PAP m in four bronchial paths. Bronchial paths RB1 RB10 LB1 LB10 ρ p-value ρ p-value ρ p-value ρ p-value Mean WT (mm) Bronchial generation 3rd * < th * < * th 0.50* < * < * < * 0.02 Data are rho coefficient correlation of Spearman. * indicates a p-value inferior to Legend: WT=wall thickness; RB1=apical bronchus of right upper lobe; RB10=postero-basal bronchus of right lower lobe; LB1=apical bronchus of left upper lobe; LB10=postero-basal bronchus of left lower lobe. E7

9 Supplemental Table 3. Correlation matrix of PAP m, respiratory function and CT parameters in 34 COPD patients with PAP m 25mmHg PAP m FEV1% TLCO% PaO 2 AP/AO LAA% FEV1% (0.11) TLCO% -0.66* (<0.001) 0.16 (0.38) PaO (0.12) (0.63) 0.22 (0.25) AP/AO 0.24 (0.16) 0.16 (0.38) (0.64) (0.12) LAA% (0.42) (0.14) ) 0.32 (0.06) (0.59) WT-Pi * (<0.001) (0.32) -0.38* (0.03) (0.42) 0.22 (0.20) (0.85) Data are rho correlation coefficient of Spearman and data between parentheses are associated p-values. * indicates a p-value inferior to Legend: PAPm=mean Pulmonary Arterial Pressure; FEV1= Forced Expiratory Volume in 1 second; TLCO=transfer lung capacity of carbon monoxide; PaO 2 =Arterial Pressure of dioxygen; AP=Pulmonary Artery troncus; AO=Aorta; LAA%=Low lung Attenuation Area percentage; WT- Pi10=square root wall area of standardized bronchus with an internal perimeter of 10mm. E8

10 Supplemental Table 4. Correlation matrix of PAP m, respiratory function, and CT parameters in 26 COPD patients with PAP m < 25mmHg PAP m FEV1% TLCO% PaO 2 AP/AO LAA% FEV1% 0.02 (0.89) TLCO% (0.12) 0.44* (0.03) PaO (0.40) 0.12 (0.53) 0.13 (0.50) AP/AO (0.83) -0.54* (0.005) (0.40) (0.19) LAA% 0.28 (0.16) -0.57* (0.002) -0.56* (0.003) (0.80) 0.22 (0.27) WT-Pi * (0.001) (0.053) -0.41* (0.04) (0.57) 0.22 (0.27) 0.59* (0.001) Data are rho correlation coefficient of Spearman and data between parentheses are associated p-values. * indicates a p-value inferior to Legends: PAPm=mean Pulmonary Arterial Pressure; FEV1= Forced Expiratory Volume in 1 second; TLCO=transfer lung capacity of carbon monoxide; PaO 2 =Arterial Pressure of dioxygen; AP=Pulmonary Artery troncus; AO=Aorta; LAA%=Low lung Attenuation Area percentage; WT- Pi10=square root wall area of standardized bronchus with an internal perimeter of 10mm. E9