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Quantifying Heterogeneity in Emphysema from High-Resolution Computed Tomography

Posted Jan 31, 2013 Updated Apr 10, 2023
By Cuneyt Yilmaz PhD , Dan M. Dane MSc , Nova C. Patel MD , Connie C.W. Hsia MD
16 min read

Rationale and Objectives

To quantify spatial distribution of emphysema using high-resolution computed tomography (HRCT), we applied semiautomated analysis with internal attenuation calibration to measure regional air volume, tissue volume, and fractional tissue volume (FTV = tissue/[air + tissue] volume) in well-characterized patients studied by the Lung Tissue Research Consortium (LTRC).

Methods

HRCT was obtained at supine end-inspiration and end-expiration, and prone end-inspiration from 31 patients with mild, moderate, severe, or very severe emphysema (stages II–V, forced expiratory volume at 1 second >75%, 51%–75%, 21%–50% and ≤20% predicted, respectively). Control data were from 20 healthy non-smokers (stage I). Each lobe was analyzed separately. Heterogeneity of FTV was assessed from coefficients of variation (CV) within and among lobes, and the kurtosis and skewness of FTV histograms.

Results

In emphysema, lobar air volume increased up to 177% above normal except in the right middle lobe. Lobar tissue volume increased up to 107% in mild-moderate stages then normalized in advanced stages. Normally, FTV was up to 82% higher in lower than upper lobes. In mild-moderate emphysema, lobar FTV increased by up to 74% above normal at supine inspiration. In severe emphysema, FTV declined below normal in all lobes and positions in correlation with pulmonary function ( P < .05). Markers of FTV heterogeneity increased steadily with disease stage in correlation with pulmonary function ( P < .05); the pattern is distinct from that seen in interstitial lung disease (ILD).

Conclusion

CT-derived biomarkers differentiate the spatial patterns of emphysema distribution and heterogeneity from that in ILD. Early emphysema is associated with elevated tissue volume and FTV, consistent with hyperemia, inflammation or atelectasis.

Introduction

Chest computed tomography (CT) is extensively used in the diagnosis and management of chronic lung disease. Clinical evaluation by CT is usually qualitative or semiquantitative, resulting in unavoidable spatial, temporal, interobserver and interscanner variability, particularly in the presence of volume change or local architectural distortion, making it difficult to match the same anatomical regions on successive scans. Currently, the large digital dataset generated by each CT study is routinely underused. Given the widespread use of CT, its expense and the small but real risk of harm due to cumulative radiation exposure , there is a corresponding need for standardized imaging biomarkers to objectively characterize anatomical disease severity and distribution, monitor pathological progression and assess response to therapy. By maximally exploiting the information content of CT datasets, quantitative image analysis has the potential to improve the precision and accuracy of patient stratification, cross-sectional comparisons and longitudinal follow-up.

Both attenuation-based and texture-based image analysis algorithms have been used to quantify pulmonary emphysema. Attenuation-based methods commonly employ an arbitrary threshold value (eg, −910 Hounsfield units [HU]) , to separate normal from emphysematous parenchyma ; these methods are relatively easy to use but highly sensitive to lung inflation. A range of threshold values has been reported , and most studies do not take into account intra- or interlobar heterogeneity, a key feature in emphysema evolution. Texture-based methods rely on analysis of detailed morphologic patterns on high-resolution CT (HRCT) (eg, shape, skewness, kurtosis, gradient, contrast, correlation, circularity, aspect ratio, area, number of clusters). Although offering more information, texture-based analysis involves greater computational complexity and higher cost.

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Materials and methods

Subjects

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HRCT

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Image Analysis

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Lobar Reconstruction

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HRCT-derived Indices

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Figure 1, Representative reconstruction of the right upper lobe from a normal subject ( upper panels ) and a patient with severe emphysema ( lower panels ) illustrates the analysis of intralobar gradients along standard x, y, z coordinate axes. Each lobe was divided into six regions along the span (0%–10%, 10%–30%, 30%–50%, 50%–70%, 70%–90%, and 90%–100%) of a given axis. The results were expressed with respect to the average positions of a region (5%, 20%, 40%, 60%, 80%, and 95%) along the span of a given axis.

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Analyzing Images with and without Gaps

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Statistical Analysis

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Results

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Table 1

Demographic Data and Lung Function

Stage I II III IV V Emphysema severity Normal Mild Moderate Severe More Severe Number of subjects 20 3 7 10 10 Male/female 11/9 3/0 5/2 6/4 6/4 Age, y 51 ± 12 67 ± 8 ∗ 62 ± 9 ∗ 61 ± 12 ∗ 59 ± 6 ∗ Height, cm 171 ± 12 173 ± 11 171 ± 13 170 ± 13 168 ± 7 Weight, kg 79 ± 23 92 ± 30 78 ± 19 76 ± 21 75 ± 12 BMI, kg·m −2 28.8 ± 11.7 30.5 ± 7.3 25.7 ± 4.0 25.8 ± 4.5 26.3 ± 2.5 Hemoglobin, g·dL −1 13.7 ± 1.4 13.3 ± 1.2 14.1 ± 2.6 13.6 ± 0.8 13.3 ± 1.1 FEV 1 , L 3.33 ± 0.90 2.57 ± 0.06 2.21 ± 0.47 ∗ 1.11 ± 0.46 ∗,§,† 0.61 ± 0.25 ∗,§,†,‡ FEV 1 , % predicted 105 ± 14 85 ± 9 ∗ 65 ± 8 ∗,§ 31 ± 4 ∗,§,† 17 ± 5 ∗,§,†,‡ FVC, L 4.28 ± 1.10 4.47 ± 0.35 3.77 ± 0.62 2.91 ± 0.74 ∗,§ 2.02 ± 0.76 ∗,§,†,‡ FVC, % predicted 111 ± 15 108 ± 15 86 ± 7 ∗ 67 ± 11 ∗,§,† 54 ± 18 ∗,§,† FEV 1 /FVC 0.78 ± 0.04 0.58 ± 0.05 ∗ 0.59 ± 0.05 ∗ 0.37 ± 0.10 ∗,§,† 0.31 ± 0.09 ∗,§,†,‡ FEV 1 /FVC, % predicted 95 ± 5 79 ± 7 ∗ 76 ± 10 ∗ 47 ± 10 ∗,§,† 34 ± 8 ∗,§,†,‡ DL CO , mL·(min·mmHg) −1 23.3 ± 5.9 14.0 ± 6.1 ∗ 14.5 ± 7.5 ∗ 10.5 ± 7.7 ∗ 6.5 ± 1.3 ∗ DL CO , % predicted 88 ± 17 53 ± 11 ∗ 62 ± 22 ∗ 44 ± 22 ∗,† 30 ± 8 ∗,† TLC, L 5.77 ± 1.28 6.70 ± 0.26 6.42 ± 1.08 7.19 ± 1.35 ∗ 7.20 ± 1.28 ∗ RV, L 1.48 ± 0.52 2.07 ± 0.40 2.57 ± 0.33 ∗ 3.86 ± 0.72 ∗,§,† 4.40 ± 0.88 ∗,§,† RV/TLC 0.26 ± 0.08 0.31 ± 0.05 0.41 ± 0.06 ∗ 0.54 ± 0.07 ∗,§,† 0.61 ± 0.09 ∗,§,†,‡

BMI, body mass index; DL CO , lung diffusing capacity for carbon monoxide; FEV 1 , forced expiratory volume at 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.

Mean ± SD.

P < .05

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Table 2

Whole Lung Attenuation Values and Histogram of FTV

Stage Emphysema severity I

Normal II

Mild III

Moderate IV

Severe V

More severe II-V

All Emphysema Attenuation (HU) Tracheal air −969 ± 9 −974 ± 19 −975 ± 13 −985 ± 8 ∗ −989 ± 2 ∗,§,† −983 ± 13 ∗ Liver 64 ± 9 60 ± 3 57 ± 10 57 ± 11 59 ± 6 58 ± 9 ∗ Histogram of FTV Prone end-inspiration Mean lung FTV 0.106 ± 0.029 0.138 ± 0.011 0.130 ± 0.042 0.101 ± 0.022 0.077 ± 0.013 ∗,§,†,‡ 0.104 ± 0.033 Kurtosis −0.558 1.513 −1.112 0.756 −0.025 0.620 Skewness 0.368 1.303 0.247 0.666 −0.376 0.727 Supine end-inspiration Mean lung FTV 0.106 ± 0.030 0.154 ± 0.015 ∗ 0.126 ± 0.047 0.096 ± 0.017 §,† 0.078 ± 0.017 ∗,§,† 0.102 ± 0.035 Kurtosis 0.304 −0.708 2.526 −0.765 −0.692 2.590 # Skewness 0.671 0.817 1.528 0.431 −0.342 1.283 # Supine end-expiration Mean lung FTV 0.201 ± 0.046 0.191 ± 0.020 0.210 ± 0.066 0.120 ± 0.033 ∗,§,† 0.096 ± 0.021 ∗,§,† 0.140 ± 0.060 ∗ Kurtosis −0.604 −1.603 0.156 −0.897 −0.488 1.601 Skewness 0.467 0.462 0.849 0.207 −0.078 1.071 # Critical values ( P < .05, two-sided) Kurtosis (range of normality) −1.27 to 2.56 −3.64 to 4.36 −2.79 to 4.10 −1.81 to 3.58 −1.71 to 3.44 −1.12 to 2.22 Skewness 1.03 1.83 1.68 1.44 1.37 0.894

FTV, fractional tissue volume calculated using tissue attenuation of the liver; HU, Hounsfield units.

Mean±SD.

P < .05

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Figure 2, Representative axial high-resolution computed tomography images and the corresponding color maps of fractional tissue volume (FTV) from comparable regions of the upper (first and second rows) and lower (third and fourth rows) lobes, with three-dimensional surface color maps of FTV (fifth row) from one subject in each severity category: normal, mild, moderate, severe and more severe emphysema (stages I–V, respectively) shown at supine end-inspiration.

Figure 3, Lobar air and tissue volumes and fractional tissue volume (FTV) are shown at prone end-inspiration, supine end-inspiration and supine end-expiration in each emphysema stage: normal, mild, moderate, severe and more severe (stages I–V, respectively). Mean +SD or −SD. In the left upper panel all the lobes are indicated for identification. In other panels the lobes are indicated only to show significant differences. P < .05 *versus I (normal); §versus II (mild), †versus III (moderate); ‡versus IV (severe) by factorial analysis of variance; (a) versus right middle lobe (RML); (b) versus right lower lobe (RLL); (c) versus LUL; and (d) versus left lower lobe (LLL), by repeated measures analysis of variance. Air volume increased with disease stage in all lobes except the small RML. FTV was higher in both lower lobes than upper lobes in supine but not prone position; the difference is exaggerated in mild-moderate emphysema due to a higher FTV at supine inspiration. In all lobes, FTV does not decline below normal until stages IV and V.

Figure 4, Whole lung air volume, tissue volume, and average fractional tissue volume (FTV) are shown at prone end-inspiration, supine end-inspiration, and supine end-expiration for each emphysema stage: normal, mild, moderate, severe, and more severe (stages I–V, respectively). Solid lines : average; dashed lines : 95% confidence interval. P < .05 *versus I (normal); §versus II (mild), †versus III (moderate); ‡versus IV (severe) by factorial analysis of variance.

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Figure 5, Intralobar distribution of air volume at supine end-expiration is shown with respect to the position (% of the total span) along a given axis in each lobe and emphysema stage: normal, mild, moderate, severe and more severe (stages I–V, respectively). Mean +SD or −SD. P <.05 *versus I (normal); §versus II (mild), †versus III (moderate); ‡versus IV (severe) by factorial analysis of variance. With increasing emphysema severity, air volume increased asymmetrically in different regions within the left and right upper lobes (RUL and LUL) and lower (RLL and LLL) lobes. In contrast, regional air volume increased minimally in the right middle lobe (RML).

Figure 6, Intralobar distribution of fractional tissue volume (FTV) at supine end-expiration is shown with respect to the position (% of the total span) along a given axis in each lobe and emphysema stage: normal, mild, moderate, severe, and more severe (stages I–V, respectively). Mean +SD or −SD. P < .05 *versus I (normal); §versus II (mild), †versus III (moderate); ‡versus IV (severe) by factorial analysis of variance. In stages II and III, regional FTV was unchanged or mildly elevated above normal. In stages IV and V, regional FTV declined below normal in the central regions of all lobes.

Table 3

Pearson Correlation Coefficients and 95% Confidence Interval (CI) for the Correlations of Whole Lung FTV, the Coefficients of Variation (CV) of FTV within and among Lobes, and the Kurtosis and Skewness of FTV, with Respect to Pulmonary Function

FTV

Supine End-expiration CV of FTV within Lobes

Supine End-inspiration CV of FTV among Lobes

Prone End-inspiration Kurtosis †

Supine End-expiration Skewness †

Supine End-expiration_r_ 95% CI_r_ 95% CI_r_ 95% CI_r_ 95% CI_r_ 95% CI FEV 1 , % pred 0.67 ∗ 0.47 to 0.80 −0.88 ∗ −0.93 to −0.79 −0.59 ∗ −0.75 to −0.37 −0.66 ∗ −0.79 to −0.46 −0.63 ∗ −0.77 to −0.41 FVC, % pred 0.55 ∗ 0.31 to 0.72 −0.75 ∗ −0.85 to −0.59 −0.56 ∗ −0.72 to −0.33 −0.58 ∗ −0.75 to −0.36 −0.55 ∗ −0.72 to −0.31 DL CO , % pred 0.52 ∗ 0.28 to 0.70 −0.79 ∗ −0.88 to −0.65 −0.46 ∗ −0.66 to −0.20 −0.59 ∗ −0.75 to −0.37 −0.63 ∗ −0.77 to −0.41 FEV 1 /FVC, % pred 0.73 ∗ 0.57 to 0.84 −0.88 ∗ −0.93 to −0.79 −0.59 ∗ −0.75 to −0.37 −0.65 ∗ −0.79 to −0.44 −0.64 ∗ −0.78 to −0.44 RV, L −0.75 ∗ −0.85 to −0.59 0.79 ∗ 0.64 to 0.88 0.64 ∗ 0.43 to 0.58 0.52 ∗ 0.27 to 0.71 0.45 ∗ 0.18 to 0.66 TLC, L −0.42 ∗ −0.63 to −0.15 0.37 ∗ 0.09 to 0.60 0.46 ∗ 0.20 to 0.66 0.25 −0.05 to 0.51 0.04 −0.26 to 0.33 RV/TLC −0.74 ∗ −0.85 to −0.57 0.81 ∗ 0.68 to 0.89 0.55 ∗ 0.31 to 0.73 0.54 ∗ 0.29 to 0.72 0.54 ∗ 0.29 to 0.72

DL CO , lung diffusing capacity for carbon monoxide; FEV 1 , forced expiratory volume at 1 second; FVC, forced vital capacity; RV, residual volume. TLC, total lung capacity.

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Figure 7, Coefficients of variation (CVs) of fractional tissue volume (FTV) among lobes ( left panels ) and within lobes ( right panels ) at prone end-inspiration ( upper ), supine end-inspiration ( middle ), and supine end-expiration ( lower ) are shown with respect to emphysema severity: normal, mild, moderate, severe, and more severe (stages I–V, respectively). Mean +SD or −SD. P < .05 *versus I (normal); §versus II (mild), †versus III (moderate); ‡versus IV (severe) by factorial ANOVA.

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Figure 8, Kurtosis ( upper panels ) and skewness ( lower panels ) of whole-lung fractional tissue volume (FTV) distribution along each axis (x, medial to lateral: left panels ; y, posterior to anterior: middle panels ; and z, cephalad to caudal: right panels ) are shown at supine end-expiration with respect to emphysema severity: normal, mild, moderate, severe, and more severe (stages I–V, respectively). Mean +SD or −SD. * P < .05 ( a P = .065) versus I (normal); §versus II (mild), †versus III (moderate) by factorial analysis of variance.

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Discussion

Summary of Results

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Significance of the Findings

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Critique of Methods

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HRCT in Emphysema

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Comparison to ILD

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Figure 9, Side-by-side comparison of selected imaging biomarkers during progression of interstitial lung disease (ILD) and emphysema. Whole lung air volume, tissue volume, fractional tissue volume (FTV), and coefficients of variation (CV) of FTV among and within lobes are shown at prone end-inspiration. Mean ± 95% confidence interval. Published ILD data are from a separate Lung Tissue Research Consortium study (19) that used the same imaging and analytical methods and the results compared to the same control subjects (stage I) as in the present study. ILD severity was categorized by FVC (% predicted): mild (stage II, ≥80%), moderate (stage III, 50–80%), severe (stage IV, 30–50%), more severe (stage V, <30%). P < .05 *versus I (normal); § P < .05 and # P = .06 versus II (mild); P < .05 †versus III (moderate) and ‡versus IV (severe) by factorial analysis of variance.

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Physiological Correlates

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Research and Clinical Applications

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Academic Radiology, Volume 20, Issue 2
Journals General Radiology
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