Evolution of CT Findings in Patients with COVID-19 Pneumonia

Objectives To delineate the evolution of CT findings in patients with mild COVID-19 pneumonia outside of Wuhan. Methods CT images and medical records of 88 patients with confirmed mild COVID-19 pneumonia outside of Wuhan, a baseline and at least one follow-up CT were retrospectively reviewed. CT features including lobar distribution and presence of ground glass opacities (GGO), consolidation, and linear opacities, were analyzed on per patient basis during each of five time intervals spanning the three weeks after disease onset. Total severity scores were calculated. Results 85.2 % of patients had travel history to Wuhan or known contact with infected individuals. The most common symptoms were fever (84.1%) and cough (56.8%). The baseline CT was obtained on average 5 days from symptom onset. Four patients (4.5%) had negative initial CT. Significant differences were found among the time intervals in the proportion of pulmonary lesions that are 1) pure GGO, 2) mixed attenuation, 3) mixed attenuation with linear opacities, 4) consolidation with linear opacities, and 5) pure consolidation. The majority of patients had involvement of ≥ 3 lobes. Bilateral involvement was more prevalent than unilateral involvement. The proportions of patients observed to have pure GGO or GGO and consolidation decreased over time while proportion of patients with GGO and linear opacities increased. Total severity score showed an increasing trend in the first two weeks. Conclusions While bilateral GGO are predominant features, CT findings changed during different time intervals in the three weeks after symptom onset in patients with COVID-19.

Common presenting symptoms for patients with confirmed infection include fever, cough, and myalgia and fatigue [1][2][3]. Typical laboratory findings on admission include normal leucocytes in majority of patients and decreased lymphocytes in 35% of patients [2].
According to published reports, common CT findings consist of bilateral patchy ground glass opacities with peripheral predominance [5,6]. As the disease progresses, consolidation becomes more common [6]. Acute respiratory distress syndromes (ARDS) develop in up to 30% of patients [1]. Intrathoracic lymphadenopathy and pleural effusions are uncommon findings [2,5]. Chest radiographic (CXR) findings include bilateral patchy opacities [3,7] though CXRs are considered unreliable in detecting early phase of the pneumonia [8]. Negative chest CTs have been reported in 14 % of patients in one study [5]. Only a small number of cases with follow-up imaging have been reported thus far [6,9]. Therefore, we evaluated serial CT pneumonia in patients with mild COVID-19 outside of Wuhan to elucidate the evolution of CT features with correlation to clinical findings.

Materials And Methods:
A retrospective review of patient data and imaging studies was approved by the institutional review board. No patient consent was required for this HIPAA-compliant study.
Between January 22, and February 8, 2020, 88 patients with COVID-19 were identified from six hospitals in Shannxi provinces in China, which is approximately 800 km northwest of Wuhan. The inclusion criteria were as follows: (1)  Healthcare; Somatom Spirit, Siemens Healthcare; GE Optima 680, GE Healthcare). The CT parameters were as follows: 120 kVp, current intelligent control (auto mA) of 30-300 mA, and slice thickness reconstructions of 0.6-3.0 mm. All CT examinations were performed without intravenous contrast material.

Data collection and evaluation
The medical records of patients were reviewed to determine the demographic data, CT images were reviewed independently by two radiologists each with 10 years of experience. Differences were resolved by discussion to reach consensus. Similar to a previously published report [6], CT findings including the presence and distribution of ground glass opacities (GGO), consolidation, linear opacities, discrete pulmonary nodules, pleural effusion, lymphadenopathy, and cavitation were evaluated. Degree of lobar involvement and overall lung "total severity score" were recorded. Each of the five lung lobes was assessed for degree or area of involvement and assigned a score of 0 for 0 % lobe involvement, 1 for 1 -25% lobe involvement, 2 for 26 -50% lobe involvement, 3 for 51 -75% lobe involvement, or 4 for 76 -100% lobe involvement ( Figure.4). An overall lung "total severity score" was reached by summing the five lobe scores (range of possible scores, 0 -20) [5].

Statistical Analysis
Continuous variables were represented as means and standard deviations, while categorical variables were expressed as counts and percentages. Differences of CT characteristics, lobar involvement and overall total severity score among different time intervals were statistically compared by the Chi-square test or Analysis of Variance (ANOVA). Linear regression analysis was further used to characterize the linear evolution trends of the variables that were significant at the above analysis.
Statistical analysis was performed by using R software (version 3.6.0; http://www.Rproject.org). The packages in R that were used in this study are "gmodels" packages. All P values were considered statistically significant at P < 0.05.

Patient demographics
Of 88 patients in the study cohort, 51 (58.0%) were male and 37 (42.0%) were female; mean age was 42.7 years (range, 4-82 years). 53 (60.2%) patients had 2 CTs, 24 (27.2%) had 3 CTs, and 11 (12.5%) had 4 or more CTs. The mean time interval between symptom onset and baseline CT was 5.5±3.5 days (range 1-15d ). 5 (5.7%) patients in the study cohort were known to have been discharged from the hospital. All of the patients had mild pneumonia based on the WHO definition [10].
The demographics of the study cohort are detailed in Table 1. Patients with exposure history (recent travel to Wuhan or contact with infected patient) accounted for 85.2% of study cohort. Fever (84.1%) and cough (56.8%) were the most common presenting symptoms. Low lymphocyte and white cell counts were observed in 26.4% and 25.0% of patients, while high C-reactive protein was observed in 55.0% of patients.

Evolution of CT findings in patients with COVID-19
Evolution of CT characteristics of pulmonary lesions

Evolution of lobar distribution in patients with COVID-19
No statistically significant difference was found in the lobar distribution of pulmonary findings over different time intervals from symptom onset but some trends were observed.
For example, the proportion of patients with fewer than 3 lobes affected decreased in the first 10 days (Figure 2A). The proportion of patients with three or more affected lobes was higher in all of the time intervals analyzed. Bilateral involvement was more prevalent than unilateral involvement with a trend toward increase in proportion of patients with bilateral CT abnormalities in the first two weeks after disease onset ( Figure 2B). Lower lobes have higher rates of involvement than the others but the differences are not statistically significant ( Figure 2C).

Evolution of CT findings in patients with COVID-19
The initial CTs of 4 out of 88 (4.5%) patients were negative. Two of these four patients  pneumonia.

Discussion
Patient demographics in terms of age and gender distributions are similar to other published studies [5,6]. Clinical symptoms and laboratory findings also match those of other initial reports with smaller cohorts [5,6] with fever and cough in the majority of the patients. The majority patients had normal white blood cell count and lymphocyte counts at presentation though 26.4% lymphocyte counts below normal range. 85.2% of patients in this study had travelled from Wuhan or known contacts with infected individuals. Notably, 14.8% of patients in this study based in Shannxi did not have known or identifiable exposures. While currently, the small numbers of COVID-19 patients outside of China all seem to have recent travel history to Asia or contacts with infected individuals, the source of infection may become increasingly difficult to identify if the disease becomes more widespread.
Depending on the severity of clinical symptoms, patients do not always present within the first few days of symptom onset. In our study cohort, the interval between symptom onset and first chest CT ranged from 1-15 days. Hence, familiarity with evolution of CT findings is useful to radiologists. Ground glass opacities are the most common CT findings within 0-3 days of symptom onsets as described in other published reports focused on initial presentations [11] . Over time, GGO remains a common finding and consolidation occurs with higher frequencies than in the early phase of disease, which means the disease is progressing rapidly. It is different from what happened with SARS [12]. Frequency of consolidation decreases two weeks after symptom onset. Reticulations and linear opacities, signs of interstitial involvement and fibrosis become increasing prevalent later is the disease course. The total severity score shows slight decrease in the third week.
Cavitations were present in a small percentage of patients and likely present pre-existing conditions as none of the patients in the study cohort were observed to develop cavitation during the course of COVID-19. Lymphadenopathy and pleural effusions were absent on all the CTs analyzed, even on scans obtained 15-21 days after symptom onset. These findings are also similar to other reports [5]. Also similar to other published studies [13], we have observed a lower lobe predominance of pulmonary involvement. Bilateral involvement is found in majority of patients though a significant number of patients do have unilateral involvement. Awareness of a significant minority of patients with only unilateral findings on CT at various time intervals is important so that radiologists do not exclude the possibility of COVID-19 simply because the findings were unilateral. Finally, in some patients, the CT findings can be minimal or even negative.
In areas outside of China, influenza remains the significantly more prevalent at the current time. Common imaging findings of influenza virus associated pneumonia include GGO, consolidation, and a combination of both. Pleural effusion, if present, is usually minimal and lymphadenopathy is rare [14,15]. Organizing pneumonia has also been reported [16]. These findings are nearly identical to the CT findings of in our study cohort and other reports of COVID-19 patients [5,6,17]. Laboratory testing for the novel coronavirus is time-consuming, and there are reports of shortage of test kits in some locations [18]. As we learned increasingly, initial laboratory tests for coronavirus can be falsely negative [18]. Therefore, presence of suspicious CT findings in patients, correlated with number of days after symptom onset, should prompt repeat laboratory testing and consideration of respiratory isolation.in patients with appropriate travel and exposure history.
Limitations of our study include retrospective nature of the study where all patients in the cohort presented to healthcare setting for evaluation. It is possible that there are infected individuals within the population with subclinical or mild clinical symptoms who did not present for care and the findings reported here are skewed toward those who were more symptomatic. Additionally, many of the more critically ill patients were transferred to other hospital which is not included in this study. Our data were collected from six sites with variable CT scanning parameters though the data heterogeneity reflects the different     54-year-old woman with exposure to infected patient, presented with fever, cough and low back pain for 2 days and remains hospitalized. a~c, CT shows left lower lobe GGO (thin arrow) on Day 2. The total severity score is 1. d~f, CT on Day 7 20 shows significant increase in GGO in both lungs. The severity score of the left lower lobe is 2 (thick arrow). The total severity score is 5. h~j, CT on day 9 shows bilateral GGO and subpleural consolidation (thick arrows). The severity score of the left lower lobe is 3. The total severity score is 9. k~m, CT on day 11 shows interlobular septal thickening (thick arrow) and linear opacities. The severity score of the left lower lobe is 4. The total severity score is 12. Figure 4 24-year-old man with exposure to infected patient, presented with fever and