Quantitative Assessment and Comparative Analysis of Longitudinal Lung CT Scans of Chest-Irradiated Nonhuman Primates

Abstract

Computed tomography (CT) imaging has been used to diagnose radiation-induced lung injury for decades. However, histogram-based quantitative tools have rarely been applied to assess lung abnormality due to radiation-induced lung injury (RILI). Here, we used first-order summary statistics to derive and assess threshold measures extracted from whole lung histograms of CT radiodensity in rhesus macaques. For the present study, CT scans of animals exposed to 10 Gy of whole thorax irradiation were utilized from a previous study spanning 2-9 months postirradiation. These animals were grouped into survivors and non-survivors based on their clinical and experimental endpoints. We quantified the change in lung attenuation after irradiation relative to baseline using three density parameters; average lung density (ALD), percent change in hyper-dense lung volume (PCHV), hyperdense volume as a percent of total volume (PCHV/TV) at 2-month intervals and compared each parameter between the two irradiated groups (non-survivors and survivors). We also correlated our results with histological findings. All the three indices (ALD, PCHV, PCHV/TV) obtained from density histograms showed a significant increase in lung injury in non-survivors relative to survivors, with PCHV relatively more sensitive to detect early RILI changes. We observed a significant positive correlation between histologic pneumonitis scores and each of the three CT measurements, indicating that CT density is useful as a surrogate for histologic disease severity in RILI. CT-based three density parameters, ALD, PCHV, PCHV/TV, may serve as surrogates for likely histopathology patterns in future studies of RILI disease progression.

FIG. 1.

Histogram of entire segmented lung over time (0–8 months postirradiation). Panel A: Computed tomographic images (axial and coronal view) of a representative non-survivor at baseline and 2 months postirradiation. Panel B: Histograms of the same non-survivor show the percentage of total voxels within the segmented lung at a particular voxel density (Hounsfield Units). Panel C: Example of manual lung segmentation; representative coronal images of baseline, a non-survivor and a survivor; the entire lung (left and right) was segmented excluding major airways and blood vessels. Panel D: Computed tomographic images (axial and coronal view) of a representative survivor over time. Panel E: Histograms of the same survivor show the percentage of total voxels in the segmented lung across a continuum of voxel density (HU).

FIG. 2.

Average lung density (ALD) of postirradiation lung injury in non-survivors and survivors. Panel A: ALD of survivors and non-survivors at baseline (BL) and postirradiation timepoints. Each dot represents average radiodensity of the entire segmented lung of one animal. Panel B: ALD of non-survivors at baseline (BL, n=7), at 2 months (n=7), and at 4 months (n=3). Panel C: ALD of survivors over time (n=8). Panels D–F are representative gross images of a healthy normal lung, a postirradiation non-survivor lung and a survivor lung at necropsy; red discolored regions (black arrows) represent radiation pneumonitis. Results are expressed as the mean ± SD; statistical significance was determined by unpaired t test. *P < 0.05; **P < 0.01; ***P < 0.001 for all data.

FIG. 3.

Histograms changes above 5 percent cutoff value. Panel A: Overlapping histograms of a non-survivor at baseline and 2 months postirradiation (same animal as used in Fig. 1) with projected histogram changes above 5% cutoff value determined at baseline (−720 HU). Panel B: Overlapping histograms of a survivor at baseline, at 2, 4, 6 and 8 months postirradiation (same animal as used in Fig. 1) with projected histogram changes above 5% cutoff value determined at baseline (−650 HU).

FIG. 4.

Quantitative measurement of hyper dense lung volume. Panel A: Postirradiation percent change in hyperdense lung volume (PCHV) of survivors and non-survivors from baseline (PCHV = [(V_n–V_b)/V_b] × 100). Results are expressed as the mean ± SD, statistical significance was determined by unpaired t test. Panel B: Percent change in hyperdense lung volume of non-survivors from baseline (BL, n=7) at 2 months (n=7) and at 4 months (n=3); each dot represents an animal. Panel C: Percent change in hyperdense lung volume of survivors over time (n=8); each dot represents an animal. Results are expressed as the median, and the Wilcoxon signed rank test was used for statistical significance. Panel D: Hyperdense lung volume as a percent of entire segmented lung volume (PCHV/TV) of survivors and non-survivors Panel E: PCHV/TV of non-survivors at baseline (BL, n=7), at 2 months (n=7) and at 4 months (n=3); each dot represents an animal. Results are expressed as the mean ± SD, statistical significance was determined by unpaired t test. Panel F: PCHV/TV of survivors at baseline, 2, 4, 6 and 8months (n=8); each dot represents one animal. Results are expressed as the mean ± SD, statistical significance was determined by paired t test. *P < 0.05; **P < 0.01; ***P < 0.001 for all data.

FIG. 5.

Correlation between histologic pneumonitis score, and ALD, PCHV, PCHV/TV in irradiated subjects at their corresponding lung CT scans (last scans). Panel A: Pearson correlation analysis of pneumonitis scores and average lung density (ALD) of entire segmented lung (n=15). Panel B: Pearson correlation analysis of pneumonitis scores and PCHV (n=15). Panel C: Pearson correlation analysis of histologic pneumonitis score and PCHV/TV (n=15). Panel D: Pearson correlation analysis of baseline ALD and final ALD scans (n=15). *P < 0.05; **P < 0.005; ***P < 0.0005, ****P < 0.0001 for all data.