Performance of Infection Region Segmentation
By segmenting the 300 validating CT images, the average Dice is 91.6%±10.0%, and for the same dataset the inter-rater variability analysis between two radiologists indicates that the average Dice coefficient is 96.1%±3.5%. By comparing with a V-Net segmentation (with average Dice 87.3%±10.1%) the segmentation performance of VB-Net has been improved significantly (p < 0.001). For annotating the training images, we performed three round of training and correcting of the training samples, and the average annotating time was reduced to around 4.7 minutes per case from 211 minutes per case, showing a significant time reduction when drawing the masks for infection regions. Notice that to have a fair comparison, the annotation of the validating dataset was performed by two independent radiologists and did not refer to any automatic segmentation results.
Comparison between Distribution Maps of COVID-19 and CAP
The distribution maps for the spatial distribution of infections of 1) 2954 CT images of 2760 COVID-19 patients (first row, left of Fig. 2) and 2) 1343 images of 1089 CAP patients (first row, right of Fig. 2) were calculated. The COVID-19 infections have the occurring frequency up to 35.1%, and mostly distributed on peripheral, posterior, and middle-lower pulmonary lobes. On the contrary, the highest infection frequency count was much lower (8.9%) as reflected by the CAP map. In general, the CAP induced infections were smaller in overall size or number. Also, the CAP infections tended to be peripheral and close to the diaphragm.
Figure 2 also shows GGO (second row) and consolidation (third row) infection distributions of COVID-19 and CAP. For COVID-19, GGO infections held a large percentage of infected regions and spread more widely than consolidation infections. In COVID-19, the maximum probabilities of GGO and consolidation components were 26.1% and 10.7%, respectively. In CAP, these two types of infections were relatively mild, with the maximum probability of 7.9% in GGO and 5.1% in consolidation.
The p-value map between infection frequencies of COVID-19 and CAP was calculated using X^2 test and shown on the bottom (right) of Fig. 2. This p-value map highlights the locations where two maps and their underlining patient cohorts have significant difference. The locations with p < 0.05 accounted for 48.0% of the total lung field volume, indicating that the locations and sizes of COVID-19 infections were prevalently and significantly different from CAP in the lung. We further computed the ratios of the volumes of significantly different voxels in the right and left lungs, as well as five lobes over the entire lung volume, and reported them in Table 1. The most different region is the right lung, especially the right-lower lobe. The left-upper lobe is another affected region with p-value < 0.05, with the volume of voxels being 12.8% of the entire lung.
Table 1
Ratio between the volume of statistically different regions (with p < 0.05) and the total volume of lung/lung lobe, compared between COVID-19 and CAP in Fig. 2 and between severe and critical COVID-19 in Fig. 3, respectively.
Region
|
Lung
|
Lobe
|
Lung
|
Lung-R
|
Lung-L
|
Upper-R
|
Middle-R
|
Lower-R
|
Upper-L
|
Lower-L
|
COVID-19 vs. CAP
|
48.0%
|
28.3%
|
19.7%
|
10.2%
|
6.1%
|
12.0%
|
12.8%
|
6.9%
|
Severe vs. Critical
|
0.1%
|
0.1%
|
0%
|
0%
|
0%
|
0.1%
|
0%
|
0%
|
To further analyze the HU distributions, we calculated the histograms of HU values within the infection regions of all the samples of the two groups (bottom left of Fig. 2). For statistical analysis, K-S statistics was employed to compare the histograms of two groups. It turns out that, by splitting the histograms using HU threshold − 300 (as shown by the vertical dotted-dashed line), the p-value of the GGO part (HU<-300) was 0.42, and the p-value of the consolidation part (HU≥-300) between COVID-19 and CAP was 0.0005. Thus, comparing with CAP, COVID-19 had significantly less consolidation components.
Comparison between Onset Stages of Severe and Critical COVID-19 Cases
The severe COVID-19 cases were those undergoing inpatient treatments without going to ICU, and the critical COVID-19 cases were those admitted to ICUs (as described in the data collection subsection). All selected cases finally recovered after hospitalization. The above patient cohort allows us to observe the difference of infection patterns between severe cases and critical cases. Because it is highly interesting to see whether these patients’ CT images are different from the initial stage of the illness, we hereby chose to use the first images captured when the patients were diagnosed and prior to ICU admission if any, for comparison.
Figure 3 shows the lesion distributions for severe (top) and critical (middle) cases at their first scan, and the p-value maps calculated using K-S test are shown on the bottom. Each group had 45 images from different subjects. The two distribution maps were quite similar, and the region with significant difference was also small (i.e., counting for 0.1% of the lung volume). This might partially explain why it is difficult to predict severity with onset images, although it is invaluable for exploring such a prediction. Table 1 gives the ratios between the volume of significantly different region to the total lung volume. The right lung, especially the right-lower lobe, had relative difference (0.1%).
Time Course of Critical COVID-19 Patients
To assess the images of critical patients during the disease course, the spatial-temporal infection distributions were calculated and shown in Fig. 4. For each patient, all images were temporally sorted based on Day 0, which was defined as the date admitting the patient into ICU. Nine groups along the time course were identified for a total of 457 images (83 patients): Day − 10~-6, n = 33; Day − 5~-2, n = 54; Day − 1 ~ 1, n = 79; Day 2 ~ 5, n = 82; Day 6 ~ 9, n = 59; Day 10 ~ 13, n = 39; Day 14 ~ 17, n = 35; Day 18 ~ 24, n = 34; and Day > 25, n = 42. Figure 4 shows that the infections rapidly grew and reached the peak at 2 ~ 5 days after being admitted to ICU (Day 0). The infections started to absorb in Day 6 ~ 13, yet enlarged again in Day 14 ~ 17. After 18 days, the infections were slowly absorbed. The above findings further confirm that COVID-19 progresses rapidly and recovers slowly for severe cases.
Similarly, we also grouped the time course images of severe patients into nine stages and computed their infection distributions accordingly. The volume curves of the regions with high infection probability in both critical and severe patient groups are calculated using a threshold (35%) and plotted on the bottom of Fig. 4. It can be clearly seen that the distribution maps have demonstrated the progression (Day − 10 ~ 5), absorption (Day 6 ~ 13), enlargement (Day 14 ~ 17), and further absorption (Day > 17) stages for critical patients, while the curve of severe patients shows gradual increase in first 10 days and then decrease thereafter. And meanwhile, the volume of high infection probability in severe patients is smaller (peak volume less than 25 cc) than critical patients (up to 400 cc).
Figure 5 (top) shows the HU distributions of the nine time-course groups of severe (right) and critical (left) patients. We used black solid curve to represent the earliest HU distribution, and four dashed curves and four dotted curves of critical patients (left, top) shows the progression and recovery stages, respectively. It can be seen that GGO and consolidation changes are clearly associated with the disease time course. Similarly, the top-right part of Fig. 5 is the HU distributions of severe patients. The black solid curve is the average histogram at the first time-point. The consolidation in severe patients also tends to increase initially and then gradually decrease. The overall variation of severe patient is smaller compared to critical patients.
Figure 5 (middle) plots both the ratios of consolidation lesions (i.e., the areas under the curves for HU greater than − 300) and the HU values of the GGO peaks. The time course of the ratios of consolidation in critical patients (the middle-left plot) is consistent with the aforementioned progression, absorption, enlargement, and further absorption stages; and the HU values of GGO peaks consistently shift after reaching the peak (severe) stage. The ratios of consolidation in severe patients (the middle-right plot) first increase and then gradually decrease, and the GGO peak HU values are smaller than those of critical patients and show a trend of overall gradual decrease across with time. The videos showing time course of COVID-19 (severe stage) are in the supplementary material.
After grouping the critical cases into the progression stage (dashed curves in Fig. 5) and the recovery stage (dotted curves in the bottom left of Fig. 5) and calculating their average histograms, the p-values of K-S tests among the three distributions were 0.0004 between progression and recovery stages, 0.008 between onset and progression stages, and 0.36 between onset and recovery stages, respectively. After splitting the GGO and consolidation parts, the p-values of GGO lesions were 0.0005 between progression and recovery stages, 0.0003 between onset and progression stages, and 0.26 between onset and recovery stages, respectively. For the consolidation parts, all the K-S tests showed significant difference (p-value < 0.05) for all combinations. These results supported the possibility of identifying respective image features of these stages and correlating them with clinical measures. Similar grouping of severe patients is shown in the bottom right picture of Fig. 5.