key: cord-1003728-7pkbd3kg
authors: Han, Xiaoyu; Cao, Yukun; Jiang, Nanchuan; Chen, Yan; Alwalid, Osamah; Zhang, Xin; Gu, Jin; Dai, Meng; Liu, Jie; Zhu, Wanyue; Zheng, Chuansheng; Shi, Heshui
title: Novel Coronavirus Pneumonia (COVID-19) Progression Course in 17 Discharged Patients: Comparison of Clinical and Thin-Section CT Features During Recovery
date: 2020-03-30
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa271
sha: d00a0e49339e14493cb55796ee8eb47bebcb4273
doc_id: 1003728
cord_uid: 7pkbd3kg

BACKGROUND: To retrospectively analyze the evolution of clinical features and thin-section CT imaging of novel coronavirus pneumonia (COVID-19) in 17 discharged patients. METHODS: Serial thin-section CT scans of 17 discharged patients with COVID-19 were obtained during recovery. Longitudinal changes of clinical parameters and CT pattern were documented in all patients during 4 weeks since admission. CT score was used to evaluate the extent of the disease. RESULTS: There was a marked improvement of fever, lymphocytes count, C-reactive protein and erythrocyte sedimentation rate within the first two weeks since admission. However, the mean CT score rapidly increased from the 1(st) to 3(rd) week, with a top score of 8.2 obtained in the 2(nd) week. During the 1(st) week, the main CT pattern was ground-glass opacities (GGO,76.5%). The frequency of GGO (52.9%) decreased in the 2(nd) week. Consolidation and mixed patterns (47.0%) were noted in the 2(nd) week. Thereafter, consolidations generally dissipated into GGO and the frequency of GGO increased in the 3(rd) week (76.5%) and 4(th) week (71.4%). Opacities were mainly located in the peripheral (76.5%), subpleural (47.1%) zones of the lungs, and presented as focal (35.3%) or multifocal (29.4%) in the 1(st) week and became more diffuse in the 2(nd) (47.1%) and 3(rd )week (58.8%), then showed reduced extent in 4(th )week (50%). CONCLUSIONS: The progression course of CT pattern was later than the clinical parameters within the first two weeks since admission; however, there was a synchronized improvement in both clinical and radiologic features in the 4(th) week.

In late December 2019, a new pneumonia of unknown cause broke out in Wuhan city, China [1, 2] , and the infection has spread rapidly in China and worldwide [3] [4] [5] [6] . On 7 th of January 2020, a novel coronavirus (SARS-COV-2) was identified as the cause via deep sequencing analysis of the respiratory tract samples [2, 4] . SARS-COV-2 possess a strong ability to infect humans, with the capability of human-to-human transmission [7, 8] . The number of patients is increasing rapidly. By March 7, 2020, more than 8,0000 cases of pneumonia were reported in China, including 3073 cases of death (the mortality rate is round 3.8 %).

The epidemiological and clinical characteristics of the initial novel coronavirus pneumonia population in Wuhan have been recently published [9] [10] [11] [12] .

The common presentation of these patients was as a rapidly progressing lower respiratory tract illness with fever and cough. The diagnosis of COVID-19 mainly depends on the results of viral nucleic acid, which possesses a high specificity but a poor sensitivity. According to a recent publication, half of the patients were diagnosed as COVID-19 without fever in the early stage [12] , and even with negative nucleic acid tests at first few times [13] . Therefore, combining imaging features with clinical and laboratory findings can help make an early diagnosis of COVID-19. At present, a limited number of reports have focused on chest imaging findings of COVID-19 [13] [14] [15] [16] .

The common CT findings of patients with COVID-19 in those reports include bilateral ground-glass opacities or areas of consolidation of the peripheral lung, which bear some resemblance to SARS-CoV [17] [18] [19] and MERS-CoV [20, 21] . In a recent report of 81 patients, CT findings across different timepoints throughout the disease course has been described [16] .However, the longitudinal progression of thin-section CT imaging changes in 5 patients with COVID-19 and its correlation with changes in clinical parameters remains unclear.

Hence, this study aimed to analyze the serial thin-section CT changes of 17 discharged patients with COVID-19, and to compare the progression trend of imaging pattern and clinical parameters.

This retrospective study was approved by the Institutional Review Board. The requirement for informed patient consent was waived by the Ethics Committee for the emerging infectious disease.

Between December 20 th , 2019 and February 2 nd , 2020, 17 patients with confirmed COVID-19 who underwent at least three serial chest CT scans were retrospectively included. Throat swab samples were collected for confirmation of COVID-19 by the RT-PCR as previously described [9] [10] . All the patients showed improvement both clinically and on thin-section CT imaging on discharge.

The standard for survive and discharge of patients was according to the guideline of Diagnosis and Treatment of Pneumonia Caused by SARS-COV-2 (trial sixth version) published by the China Ministry of Health [22] , which include: temperature returning to normal for more than 3 days, both the clinical and chest imaging showing significant improvement, and two consecutive respiratory pathogen nucleic acid tests turning negative (the interval at least 24 hours). Three readers (X.H.,Y.C., M.D.) recorded the clinical parameters of the patients during treatment.

CT was performed using the following CT scanners: SOMATOM Definition AS+, Siemens

Healthineers, Germany. CT scan parameters were as described in our previous study [16] . All follow-up scans were obtained by using the same scanner used to obtain the initial scans. Of 17 6 cases, four scans were available in 14 cases, and three scans in 3 cases.

The initial images and follow-up chest CT scans obtained from 17 patients were reviewed by three experienced radiologists (H.S., N.J., Y.C.). All Digital Imaging and Communications in Medicine (DICOM) images were analyzed from the CT studies without access to clinical findings of the patients. After separate evaluations, disagreements wherever found were solved by discussion and consensus. On each CT scan, lung segment involved, the location of lesion categorized as central, peripheral or both; and the distribution of opacities classified as being predominantly subpleural, peribronchovascular or random were recorded. The extent of lesion involvement was categorized as focal, multifocal, diffuse. The predominant pattern was categorized as ground glass opacities, consolidation, reticular and mixed pattern. In addition, the margin definition, interlobular/septal thickening , crazy paving (thickened interlobular septa and intralobular lines superimposed on a background of ground-glass opacity) [23] , air bronchogram, bronchiolectasis, cavitation, calcifications, thickening of the adjacent pleura , evidence of pulmonary fibrosis , tree-in-bud, pleural effusion and lymphadenopathy were also documented.

The extent of pulmonary abnormalities on thin-slice CT was also evaluated. A semi-quantitative CT scoring system was used to quantitatively estimate the pulmonary involvement of all these abnormalities on the basis of the area involved, as previously reported by Ooi et al [24] . After evaluation, the scans were classified according to the time from the admission to 1, 2, 3, and 4 weeks. 

The analyses were performed using SAS (SAS, version 9.4, SAS Institute, Cary, NC, USA).

Distribution normality was assessed using the Kolmogorov-Smirnov test. Normally, non-normally distributed data and categorical variables were expressed as the mean ± standard deviation, median (interquartile range) and frequency (percentage), respectively. Differences between weeks were analyzed by generalized linear mixed models (for categorical data) or linear mixed models (for continuous data without/with square root transformation). A P value <0.05 (two-tailed) was considered to be statistically significant.

Clinical characteristics and laboratory findings in all patients on admission are summarized in 

The mean time of treatment was 22 days (range, 18-31 days). Patients were treated by anti-viral drug (ganciclovir, abidol hydrochloride, oseltamivir, or interferon) and empirical antibacterial drug (moxifloxacin hydrochloride, amoxicillin, meropenem or linezolid). Abidol hydrochloride is approved in China and Russia as an antivirals drug for influenza treatment. The hexadecadrol (5mg) was given to three patients (P6, P14 and P17), and the methylprednisolone(40mg) and auxiliary ventilation were used in Patient 1 and 2. There was a marked resolution of fever within the first two week since admission (Figure1a, p＜0.0001) and improvement in oxygen saturation and heart rate ( Figure 1b ) within the first two weeks ( Table 2) .

There was also a trend of improvement in lymphocyte (Figure 1d ), CRP and ESR (Figure1e) within the first week (Table 2 ). There was an initial increase of ALT level in 3 rd week followed by improvement, and a slow continuous increase in AST level from 2 nd week ( Figure 1f , Table 2 ).

As Table 3 and 4 illustrate, the initial chest CT in first week was abnormal in all patients (100%).

The mean CT score was 4.3 per/ patient (ranged from 1 to 11). The predominant CT feature was poor-defined (88.2%) ground-glass opacities (GGO, 76.5%) with enlarged pulmonary vessels 

As Figure 3 showed, there was a marked increase of mean CT score of all patients from 1 st week to 3 rd week (4.3, 8.2 and 7.2 per/ patients in 1 st , 2 nd and 3 rd week, respectively). After that, a decrease to a mean CT score of 4.2 occurred in the 4 th week(p=0.0190). When analyzing the evolution of CT findings, the present study had identified three patterns of radiographic progression ( Figure 3 ). Type 1 evolution pattern was the most common observed in 12 patients (70.6%), with initial radiographic deteriorations in the 2 nd week followed by radiographic improvement in the 3 rd and 4 th week ( Figure 4 ). Four patients (23.5%) had type 3 evolution pattern (static radiographic change, Figure 5 ). One patient (Patient 15, 5.9%) had type 2 pattern (progressive radiographic improvement, Figure 6 ).

The predominant abnormality of CT changes through 4 weeks are shown in table 4 and Figure 7 . Crazy paving appearance had the highest frequency in 2 nd week (76.5%), but disappeared in the 4 th week(p＜0.0001). Pleural effusion appeared from 2 nd week (11.8%) and peaked at 3 rd week(23.5%). In the 4 th week, bronchiectasis was identified in 2 patients (15.4%) and evidence of pulmonary fibrosis was seen in 3 patients (23.7%, p=0.0012). Presence of subpleural nodule was 10 found in one scan(P7) at 3 rd week, which was dissipated on follow-up CT scans. The other findings such as air bronchogram, enlarged pulmonary vessels, thickening of the adjacent pleura and interlobe fissure displacement were observed over 4 weeks.

In our study, the age of patients was 40±6 years old, younger than previously reported [9] [10] [11] [12] .

Besides, five patients (29.4%) had underlying diseases, similar to previous studies [9, 10] . There was a female gender predilection (male: female, 6:11). On the contrary, COVID-19 patients were mostly men (73%) in a previous study [9] . Such a discrepancy may be due to the different study [19, 20] . There was a marked resolution of fever within the first week, and improvement in oxygen saturation and heart rate within the first two weeks. There was also a trend towards improvement in lymphocyte, CRP and ESR within the first week. However, there was an initial increase of ALT level in the 3 rd week followed by improvement, and a slow continuous increase of AST level from 2 nd weeks in those patients. The preliminary results indicate that patients with COVID-19 may develop liver damage during hospitalization. This may due to the viral infection of liver cells [25] , therapeutic medications [25, 26] or immune-mediated inflammation [25] causing damage to liver tissue.

Initial chest CTs were abnormal in all patients (100% infections, which was linked to variable histopathologic changes, such as diffuse alveolar damage or interstitial (intrapulmonary or airway) inflammatory cell infiltration [27, 28] . Moreover, the enlarged pulmonary vessels also indicated an inflammatory cell infiltration of the vessels. The peripheral, subpleural lung involvement bare some resemblance to SARS-CoV [17] [18] [19] and MERS-CoV [20, 21] . However, in contrast, SARS-CoV infection usually presents with unifocal opacification [24] . The focal or multifocal of lesion involvement were common CT findings in our case series of COVID-19 in early stage, consistent with the report by Chuang et al. [15] . Other common CT findings included thickening of the adjacent pleura (41.2%), crazy paving (35.3%), air bronchogram (29.4%) and interlobar fissural displacement (23.5%).

A marked increase of mean CT score was noted during the 1 st to 2 nd week (from 4.3 to 8.2).

Then, there was a slow decline in CT score (7.2) at 3 rd week in 58.8% (10 of 17) of patients.

Thereafter, the extent of changes rapidly decreased to a mean CT score of 4.2 in 4 th week indicating resolution. When analyzing the evolution of CT finding of all patients by time, the 12 present study found that most patients recovering from COVID-19 showed an initial radiographic deterioration to a peak (mean time, 2 nd week) followed by radiographic improvement in the 3 rd and 4 th week. Nevertheless, there was remarkable resolution of fever and improvement in oxygen saturation and heart rate, lymphocyte, CRP and ESR within the first two weeks. Accordingly, we may conclude that the progression course of CT pattern was later than the clinical parameters within the first two weeks. This may result from inflammatory reaction occurring earlier than the morphological changes of lung. Thereafter, the radiologic findings and clinical parameter showed a synchronization of improvement at 4 th week. Although, the four patients had a static radiographic course, the CT score remained low (＜4) in those cases. Therefore, evolution course type 1, 2 or 3 with a consistent low CT score may be associated with a favorable outcome. present study. The crazy paving reached the highest frequency in the 2 nd week (76.5%), but was not seen in the 4 th week. This phenomenon suggests that the presence of crazy paving may be associated with an early period of disease. Pleural effusion appeared from the 2 nd week (11.8%) and peaked at the 3 rd week (23.5%). This feature is different from SARS-CoV [17] [18] [19] and other recent publications on COVID-19 [13] [14] [15] , which barely present with pleural effusion. Previous studies showed that the presence of pleural effusion in patients infected with MERS-CoV or Avian flu (H5N1) was a poor prognostic factor [20, 29] . Nevertheless, in three patients, pleural effusion was totally absorbed on follow-up CT scans.

In the 4 th week, bronchiectasis in 2 patients (15.4%) and evidence of pulmonary fibrosis in 3 patients (23.7%) were identified. As Antonio et al [30] described, pulmonary fibrosis included parenchymal bands, traction bronchiectasis, and irregular interfaces. They found 15 (62%) of SARS patients to have evidence of fibrosis on CT after discharge. Since the natural history of COVID-19 has not been fully studied, it may be premature to define these pulmonary changes as irreversible and longer-term follow-up is needed. Lymphadenopathy, tree-in-bud, masses, cavitation and calcifications were not observed in our case series, which is in line with the previous studies on COVID-19 [15] and SARS-CoV [17] [18] [19] .

Our study had several limitations. First, this study was performed at a single center with a small sample size. Second, the subjects included in our study were all discharged patients, cases of death or other outcomes were not included. Hence, natural selection bias may have occurred Thirdly, only patients with serial chest CT thin-section CT images available were included, which make the findings non-generalizable to people with milder disease who did not undergo serial CT or those with asymptomatic disease. Finally, due to the short time of follow up, the CT findings 14 after discharge were not documented.

In conclusion, most patients with COVID-19 showed an initial radiographic deterioration to a peak at the 2 nd week since admission followed by radiographic improvement in the 3 rd and 4 th

week. The progression course of CT pattern was later than the clinical parameters within the first two weeks, but showed synchronization of improvement in both clinical and radiologic features in the 4 th week. Longer-term follow-up is required to determine whether the findings (bronchiectasis and pulmonary fibrosis) in the 4 th week represent irreversible fibrosis.

We would like to thank all colleagues for helping us during the current study. We highly appreciate Drs. Xiaoming Yang, MD, PhD, FSIR (Radiology, University of Washington) and

Hanping Potential conflicts of interest. The authors declare no competing non-financial/financial interest. T, temperature; CRP, C-reactive protein, ESR, erythrocyte sedimentation rate; AST, Aspartate aminotransferase. ALT, Alanine aminotransferase, COPD, chronic obstructive pulmonary disease. Data are presented as the n (n/N %), where N is the total number of CT scans with available data. # 14 CT scans were available at 4 th week. *P<0.05 between over 4 weeks since admission determined from serial chest CT scans. Type 1 stands for an initial radiographic deterioration to a peak level followed by radiographic improvement, with maximum difference in overall mean lung involvement greater than 25%; Type 2 is progressive radiographic improvement. Type 3 represents a static radiographic change with no discernible radiographic peak or change in overall mean lung involvement of less than 25% for more than 2 weeks. 

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