Dynamic changes of Chest CT follow-up in Coronavirus Disease-19 (COVID-19) pneumonia: relationship to clinical typing

Background To investigate the CT changes of different clinical types of COVID-19 pneumonia. Methods This retrospective study included 50 patients with COVID-19 from 16 January 2020 to 25 February 2020. We analyzed the clinical characteristics, CT characteristics and the pneumonia involvement of the patients between the moderate group and the severe and critical group, and the dynamic changes of severity with the CT follow-up time. Results There were differences in the CT severity score of the right lung in the initial CT, and total CT severity score in the initial and follow-up CT between the moderate group and the severe and critical group (all p < 0.05). There was a quadratic relationship between total CT severity score and CT follow-up time in the severe and critical group (r2 = 0.137, p = 0.008), the total CT severity score peaked at the second follow-up CT. There was no correlation between total CT severity score and CT follow-up time in the moderate group (p > 0.05). There were no differences in the occurrence rate of CT characteristics in the initial CT between the two groups (all p > 0.05). There were differences in the occurrence rate of ground-glass opacity and crazy-paving pattern in the second follow-up CT, and pleural thickening or adhesion in the third follow-up CT between the two groups (all p < 0.05). Conclusions The CT changes of COVID-19 pneumonia with different severity were different, and the extent of pneumonia involvement by CT can help to assess the severity of COVID-19 pneumonia rather than the initial CT characteristics.

diagnosis and treatment. In the present, the National Health Commission of the People's Republic of China [16] has taken the CT manifestations of pneumonia absorption as one of the discharge criteria. Chest CT follow-up is of great value in the evaluation of the condition assessment and therapeutic effect of COVID-19 pneumonia [17][18][19]. However, it is not clear whether there are differences in chest CT findings of COVID-19 pneumonia with different severity. CT imaging is helpful to judge the evolution and prognosis of COVID-19 pneumonia, but whether COVID-19 with different severity has characteristic CT findings is still unclear. Therefore, it is still a question worth discussing whether CT imaging can help to evaluate the clinical type of COVID- 19. To answer that question, we retrospectively characterize the initial CT and follow-up CT findings in COVID-19 pneumonia with different clinical types, and the dynamic changes of different clinical types with the CT follow-up time from initial diagnosis until patient recovery. To our knowledge, this is a relatively comprehensive study of the characteristics and dynamic changes of CT between the moderate type and severe or critical type patients with COVID-19 pneumonia. This will help to clarify the value of CT in assessing the severity of COVID-19, and it also help clinicians and radiologists to improve the understanding of CT changes with the evolution of COVID-19 pneumonia of different severity.

Methods
Our institutional review board approved this retrospective study and written informed consent from all patients was waived.

Patients and CT image data acquisition
Fifty-three patients with confirmed COVID-19 from seven hospitals in Sichuan province in China were enrolled in our study. They underwent chest CT examination and reexamination from 16 January 2020 to 25 February 2020. Patient selection was consecutive, and the exclusion criteria were COVID-19 patients without abnormal manifestations on CT. Finally, three patients were excluded because of no abnormal manifestations on CT, and fifty patients were included. The clinical history, laboratory, epidemic characteristics, and chest CT images were collected. The date of both the initial chest CT examination and the first positive RT-PCR test was recorded for each participant. All patients underwent CT scanning and laboratory tests when the initial mouth swab test was performed. All patients were followed up with chest CT during the study period without intravenous contrast agents. All patients were imaged with 0.6 mm to 1. 25

Clinical evaluation
All patients were at least two positive results by realtime RT-PCR assay for COVID-19 at laboratory testing of respiratory secretions obtained from the nasopharyngeal swab, oropharyngeal swab, endotracheal aspirate, or bronchoalveolar lavage [3]. According to the guideline of COVID-19 (Trial Version 6) [16], the patients were typed into two groups. The moderate group was defined as: the patient had a fever, respiratory symptoms, and abnormal imaging findings of pneumonia. The severe and critical group was defined as meeting any of the following [20]: Severe respiratory distress (respiratory rate > 30 breaths/min); Oxygen saturation (SpO2) ≤ 93% at rest; Partial arterial oxygen pressure (PaO2)/ Fraction of inspired oxygen (FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa); Respiratory failure and requirement for mechanical ventilation; Shock; and Combined with multi-organ failure and requirement for intensive care unit (ICU).
The patients with diagnosed COVID-19 pneumonia were isolated and hospitalized for treatment. Discharge standards [3,16] are as follows: 1. The temperature returned to normal for more than 3 days; 2. Respiratory symptoms were significantly improved; 3. Pulmonary imaging showed obvious signs of absorption in acute exudation inflammation of the lungs; and 4. Respiratory nucleic acid was negative for two consecutive times (at least one-day sampling time interval). The patient who meets the four conditions simultaneously can be released from isolation.

Chest CT evaluation
The initial and follow-up chest CT images were assessed as the following ten characteristics according to the Fleischner Society Glossary [21,22] and peer-reviewed literature on viral pneumonia [13,17], such as ground-glass opacity (GGO), crazy-paving pattern, consolidation, pleural thickening or adhesion, fibrosis, discrete nodules, cavitation, lymph node enlargement, pleural effusion, and bronchiectasis. A semi-quantitative scoring system was used to quantitatively estimate the extent of pulmonary involvement [13]. The area of abnormal pulmonary involvement was scored for each of the five lung lobes as follow: zero scores (no abnormal involvement), one score (1-25% abnormal involvement), two scores (26-49% abnormal involvement), three scores (50-75% abnormal involvement), and four scores (76-100% abnormal involvement). Finally, the total CT severity score was a sum of 5 lobe scores ranging from 0 to 20. The interval time between initial CT and the first follow-up CT scan was defined as Interval-1, and the interval between initial CT and the second follow-up CT was defined as Interval-2, and so on. Image analysis was performed by two radiologists with more than 8 years of experience (N.L. and XH.H.) by using a DICOM Viewer software (Medixant. RadiAnt DICOM Viewer [Software]. URL: https://www.radiantviewer.com). Images were reviewed independently, and final scores were reached by consensus.

Statistical analysis
All statistical analyses were conducted using SPSS software (version 22.0, U.S.A.). Quantitative variables were expressed as mean ± standard deviation (minimum-maximum) and the categorical variables were expressed as the percentage of the total. Demographic variables (e.g., age and gender), clinical characteristics (i.e., the hospitalized period and mean number of scans), and the occurrence rate of CT characteristics were compared by independent sample t test, chi-square test, or Fisher's exact test. The Shapiro-Wilk test was used for the normal distribution. The CT severity scores were compared by the Mann-Whitney U test. SPSS curve estimation module was used to quantitatively evaluate the total CT severity score of pulmonary as a function of CT follow-up time. The statistical significance level was set at p = 0.05 with two-tailed.

Demographic and clinical characteristics
The demographic and clinical characteristics of patients are listed in Table 1. There were 34 cases of the moderate group (mean age, 44 ± 12 years; age range, 21-69 years) and 16 cases of the severe and critical group (mean age, 50 ± 14 years; age range, 33-74 years). There was no significant difference in age, gender, and symptoms with fever and cough between the severe and critical group and the moderate group (all p > 0.05). There was a significant difference in exposure history between the severe and critical group and the moderate group (16/34 vs. 16/16, p < 0.001). The hospitalized period and numbers of scan in the severe and critical group were higher than that in the moderate group (28 ± 7 vs. 20 ± 8, p = 0.002; 6 ± 1 vs. 4 ± 1, p < 0.001, respectively). There was no significant difference in the consistency of PCR and CT results at the initial presentation between the two groups.

The findings of CT severity scores with CT follow-up time in the two groups
In the initial CT, the CT severity scores of right upper, middle and lower lobe in the severe and critical group was higher than that in the moderate group (1.7 ± 1.4 vs. 0.7 ± 0.5, 1.3 ± 1.3 vs. 0.4 ± 0.5, 1.9 ± 1.2 vs. 1.2 ± 0.7; all p < 0.05, Table 2). There were no significant differences in the CT scores of left upper and lower lobe between the two groups (all p > 0.05, Table 2). There were no significant differences in the number of involved lobes between the two groups (all p > 0.05). The total CT severity score of the severe and critical group in the initial CT and follow-up CT was significantly higher than that of the moderate group (all p < 0.05, Table 3). There were no significant differences in the interval time of The interval between the adjacent scans (d) 5 ± 3 (2-10) 5 ± 2 (2-13) 5 ± 2 (1-10) NA Note: Quantitative data were presented as mean ± standard deviation (minimum-maximum), while the counting data were presented as count (percentage of the total) NA not applicable; ** p < 0.01; *** p < 0.001  Note: Quantitative data were presented as mean ± standard deviation (minimum-maximum), while the counting data were presented as count (percentage of the total). * p < 0.05; ** p < 0.01   Note: Quantitative data were presented as mean ± standard deviation (minimum-maximum), Interval-1, the interval between initial CT and first follow-up CT; Interval-2, the interval between initial CT and second follow-up CT, and so on. NA, not applicable; d, day ** p < 0.01; *** p < 0.001 Interval-1, Interval-2, Interval-3, and Interval-4 between the two groups (all p > 0.05, Table 3). There was a quadratic curve between the total CT severity score and CT follow-up times in the severe and critical group by the SPSS curve estimation module (r 2 = 0.137, p = 0.008, Fig. 1). The total CT severity score in the severe and critical group peaked at the second follow-up CT (12.1 ± 5.5, range 7 to 20) with a mean interval of 8 ± 3 days after the initial CT scan, and then gradually decreased. In the moderate group, there was no correlation between the total CT severity score and CT follow-up times by the SPSS curve estimation module (p > 0.05, Fig. 1).

The findings of CT characteristics in the two groups
Among 50 patients, the occurrence rate of CT characteristics were GGO (88%), pleural thickening or adhesion (52%), crazy-paving pattern (50%), consolidation (48%), fibrosis (32%), discrete nodules (8%), bronchiectasis (6%), thoracic lymphadenopathy (4%), pleural effusion (4%), and cavitation (2%) ( Table 2). There was no significant difference in the occurrence rate of all ten CT characteristics in the initial CT between the two groups (all p > 0.05). However, there were differences in the occurrence rate of ground-glass opacity (50% vs. 82%, p = 0.040) and crazy-paving pattern (75% vs. 39%, p = 0.031) in the second follow-up CT, and pleural thickening or adhesion (100% vs. 65%, p = 0.019) in the third follow-up CT between the severe and critical group and the moderate group (Table 4). There were no differences in the occurrence rate of consolidation and fibrosis in every followup CT between the two groups (all p > 0.05, Table 4).
In the severe and critical group, the GGO, fibrosis, and pleural thickening or adhesion could be found in every follow-up CT and were the main signs in the last two CT follow-up (Fig. 2). The proportions of patients with the crazy-paving pattern (75%) and consolidation (81%) reached a peak with the decrease in the proportion of GGO (50%) at the second follow-up CT. The occurrence rate of pleural thickening or adhesion (100 and 100%) peaked at the second and the third follow-up CT.
In the moderate group, the proportions of patients with GGO and the crazy-paving pattern gradually decreased from the initial CT. The proportions of patients with the consolidation (79%) and pleural thickening or adhesion (79%) reached the peak with the decrease in the proportion of crazy-paving pattern (39%) at the second follow-up CT. Both in the third and fourth followup CT, the GGO and pleural thickening or adhesion the main demonstration with the obvious absorption of Fig. 1 The dynamic changes of total CT severity score with CT follow-up times. In the severe and critical type, peak total CT severity scores occurred at the second follow-up CT (curve fitting equation: y = −0.477*x 2 + 3.167*x + 6.887, in which x = number of CT examination, y = total CT severity scores; r 2 = 0.137, p = 0.008). In the moderate type, there was no correlation between the total CT severity score and CT follow-up times by the SPSS curve estimation module (p = 0.426)

Discussion
In our study, we analyzed the different characteristics and involvement severity of CT in the two clinical groups at initial diagnosis and follow-ups. Our study found that the lesion's involvement of the severe and critical group in the area of the right lung and whole lung was more extensive than those of the moderate group. The dynamic changes of severity as CT follow-up time were different between the two groups. There were no differences in the occurrence rate of CT characteristics in the initial CT between the two groups, which indicates that the initial CT characteristics had no certain specificity and regularity in distinguishing the severity of COVID-19 pneumonia. However, the extent of pneumonia involvement by CT findings can help clinicians to assess the severity of COVID-19 in the early stage, so as to achieve the purpose of early and accurate treatment.
The study found that the severe and critical group showed more extensive and severer involvement than those in the moderate group, mainly involving the right lung in the initial CT and the whole lung in the initial and follow-up CT. This finding is similar to previous studies [20,23], which also reported the initial CT score of the whole lung in the severe and critical patients was higher than that in the moderate patients. Furthermore, we found that the patients with severe and critical type progressed rapidly with the greatest severity at the second follow-up CT, and then gradually recovered. The moderate type is relatively stable, though the total CT severity scores also peaked at the second follow-up CT. These findings indicated that the extent of pneumonia involvement by CT could help in the evaluation of the severity and extent of COVID-19 pneumonia. It is also helpful for clinicians to identify and prevent the condition of severe and critical patients from getting worse in the early stage.
In our study, the most common initial CT characteristics of COVID-19 pneumonia of the two groups are ground-glass opacity, crazy-paving pattern, consolidation, pleural thickening or adhesion, and mainly distributed in a subpleural area. These findings were consistent with previous studies [13,14,[24][25][26]. Besides, we did not find differences in the incidence of above CT characteristics between the two groups in the initial CT, which was consistent with the previous study [27]. However, the occurrence rate of the crazy-paving pattern in the severe and critical group was higher than that in the moderate group in the second follow-up CT with a mean interval of 8 ± 3 days after the initial CT scan, while the occurrence rate of ground-glass opacity was the opposite. These findings indicated that the progression of the crazy-paving pattern might represent further infiltration of the lung parenchyma and lung interstitium [24,28]. The previous studies [26,29,30] have reported that in the progression or peak period of pneumonia (1-3 weeks), the progression of crazy-paving pattern, septal thickening and consolidation can be observed. However, COVID-19 pneumonia has different CT manifestations at different stages, which are mainly related to pathogenesis. Therefore, the dynamic changes of different clinical types can be demonstrated by CT characteristics, but it is still difficult to distinguish the clinical types by initial CT characteristics.
This study has several limitations. Firstly, the sample size was relatively small, especially in the severe and critical group. Further studies with more patients are warranted to obtain a definitive answer. Secondly, the number and interval of CT follow-up per patient were different, though the interval time of each follow-up chest CT was of no difference between the two groups. These factors need to be considered when interpreting our findings. Finally, the quantitative and semiquantitative measurements of the pulmonary lesions may have certain subjectivity, and can only partly reflect the severity. Accurate quantitative analyses should be made to identify the changes in clinical and imaging characteristics in future studies.

Conclusions
In conclusion, the results of this study confirmed the great significance of chest CT for the differentiation of moderate type and severe or critical type, and the dynamic changes of chest follow-up CT in different severity of COVID-19 pneumonia. COVID-19 pneumonia with severe and critical type progressed rapidly with the greatest severity at the second follow-up CT, and the moderate type is stable. There were no differences in the incidence of ten CT characteristics between the two groups in the initial CT. Therefore, the CT changes of COVID-19 pneumonia with different severity were different, and the extent of pneumonia involvement by CT finding can help to evaluate the severity of COVID-19 pneumonia rather than the initial CT characteristics.