Chest CT and Clinical Features of COVID-19 Patients in the Early Stage of the Epidemic: An Observational Study from China

Background: COVID-19 had caused more than 2.8 million deaths globally, and the epidemic will persist for an extended period of time. We analyzed clinical features of patients in the early stage of the epidemic, so as to deepen the understanding of the disease. Methods: In this retrospective study, we included 84 conrmed cases of COVID-19 during February 1, 2020 and March 31, 2020. Baseline data were used to classify patients as moderate (57%) or severe/critical based on Chinese protocol. We focused on analyzing the differences in chest computed tomography (CT) between the two groups. Results: Of the 84 cases, 50 were male and the median age was 69 years. 55 (65%) patients had comorbidities at admission, more in the severe/critical group (P=0.040). 94% patients had bilateral lesions on CT, up to 68% had lesions involving all lobes. Ground glass opacication (GGO) (96%), consolidation (44%), Linear opacities (50%) and Air bronchogram (23%) were the mainly lesions. The lesion was gradually absorbed over time, but imaging abnormalities can persist for a long time. Compared with moderate cases, the severe/critical group had more pulmonary consolidation changes (P=0.044) and signicantly higher CT severity Score (CTSS) (P=0.040). Lymphocyte counts were signicantly lower (P=0.011) and NLR were higher (P=0.029) in severe/critical cases. Conclusions: Chest CT showed bilateral and multiple GGO and consolidation mainly. After treatment, pulmonary lesions were gradually absorbed over time, and imaging abnormalities can be persistent for a long time. Lung consolidation, CTSS, comorbidity, lymphocyte counts, and NLR may be predictors of severe COVID-19.


Introduction
Coronavirus disease 2019 (COVID-19) has spread rapidly around the world [1,2]. By March 2020, WHO has o cially declared COVID-19 to be a Worldwide Pandemic. Globally, as of 9 April 2021, there have been 133,552,774 con rmed cases of COVID-19, including 2,894,295 deaths(https://covid19.who.int/). More seriously, the global epidemic continues to spread and is likely to persist for a long time. The number of deaths due to infection with COVID-19 will continue to increase. So far, our understanding of the disease is limited, COVID-19 is caused by SARS-CoV-2 (previously known as2019-nCoV) [3], which belongs to the beta genus of coronaviruses. SARS-CoV-2 is highly homologous to SARS-COV, and has 40 different strains. RT-PCR detection has greatly improved the diagnostic e ciency of the disease [4], but it is still limited by the sensitivity and accessibility [5]. More important, PCR detection does not re ect the condition of pulmonary lesions, while pneumonia is often an important cause of poor prognosis and death in COVID- 19. Chest CT plays a pivotal role in the diagnosis and evaluation of pulmonary diseases [6]. Since the early stage of the epidemic, Chest CT has been used as an adjunct for screening patients suspected of COVID-19 and monitoring treatment responses based on dynamic changes in imaging. So, although Chest CT is somewhat de cient in speci city, we still unremittingly analyze the images.

Study design and participants
In this retrospective,single-center, observational study, we enrolled 100 consecutive patients con rmed COVID-19, who were treated by the medical team of Shandong University Qilu Hospital in the RENMIN HOSPITAL OF WUHAN UNIVERSITY (East Branch). All patients had positive nucleic acid test results of SARS-CoV-2 [7], and had a non-contrast chest CT on admission. The study design was approved by the institutional ethics board and written informed consent was waived.
We excluded 16 cases that did not meet the inclusion criteria, including: age younger than 18 years old (n = 1); data missing(n = 10); negative CT test n = 5 . Finally,84 cases were included in the study. According to Diagnosis and Treatment Protocol for COVID-19 Patients (Tentative 8th Edition) 48 patients 57% were moderate and 36 were severe/critical Severe cases: 31 Critical cases 5 (Table 1).
In this study, 89.3% of patients had undergone at least two Chest CT examinations during hospitalization, and the longest observation was 65 days after the onset of symptoms. Repeat Chest CT was obtained at approximately one-week intervals. Through the comparative analysis of chest CT at different time points, we found that: in the second week after the onset of symptoms, the pulmonary lesions in CT were the most serious, mainly bilateral and multiple ground-glass opacities and consolidation, mostly involving multiple lobes. A few have unilateral or bilateral pleural effusion. With continuous treatment, 94.7% of the patients showed reduced lesion scope and gradual absorption of lesions on CT (Fig. 2). However, we also found that pulmonary lesions may be manifested on CT for a long time. In one patient included in this study, reexamination of chest CT 65 days after the onset of symptoms still showed signi cant multiple ground-glass opacities in both lungs.
Comparison between moderate and severe/critical patients The clinical and CT characteristics of moderate patients and severe/critical patients are presented in Table 3. There was no signi cant difference in age, gender composition, smoking history and other demographic information between the two groups, but more patients with comorbidities were found in the severe/critical group than in the moderate group (P = 0.040). The main symptoms and signs were generally similar between the two groups, but sputum production appeared to be more common in the moderate cases (P = 0.048) and headache slightly more frequent in the severe/critical group (P = 0.079). Compared with the moderate patients, severe/critical patients had signi cantly lower lymphocyte count (P = 0.011), higher NLR (P = 0.029), and slightly more patients with elevated C-reactive protein (P = 0.076).
There were no signi cant differences between the two groups in white blood cell count, neutrophil count, PCT, platelet count, HGB, ALT, AST, total bilirubin, creatinine, creatine kinase, lactate dehydrogenase, etc.   Subsequently, we analyzed the chest CT features of patients in both groups, and the imaging features were relatively consistent. In ammatory lesions mostly involved multiple lobes in both lungs and were widely distributed, mainly including ground glass opacities, consolidation, linear opacities and air bronchogram (Fig. 3). However, pulmonary consolidation was more common (P = 0.044) and CT severity score (CTSS) was signi cantly higher (P = 0.040) in the severe/critical group than in the moderate group ( Table 3). The total CTSS was the sum of the individual lobar scores (score 1-5 for each lobe, range 0-25) [8,9]. Discussion COVID-19 is an acute respiratory infectious disease caused by SARS-CoV-2. It is mainly transmitted through respiratory droplets and close contact and has developed into a worldwide pandemic [10,11].
Infected with SARS-CoV-2, most patients had mild symptoms and good prognosis, and some patients rapidly progressed to severe or critical pneumonia (14% and 5% of laboratory-con rmed patients, respectively [12]), with a signi cantly increased mortality rate. The clinical manifestations of COVID-19 are diverse [13,14], and existing studies suggest that older age and male gender may be associated with higher disease severity [15][16][17][18]. Fever [15,19], shortness of breath/dyspnea [19,20] and gastrointestinal symptoms seems to be important risk factors for severity of COVID-19 [21]. What's more, some comorbidities, such as Hypertension, Diabetes, obesity, Metabolic Syndrome, COPD and so on, may increase severe outcome [22][23][24][25][26][27][28][29][30][31]. The Charlson Comorbidity index (CCI) score has been identi ed in studies as a prognostic factor for COVID-19-related death [32]. Patient age and disease burden (number and severity of conditions) are directly and signi cantly associated with an increased risk of unfavorable clinical outcomes [33]. In this study, we did not nd signi cant differences in age, gender and other demographic indicators between patients with severe/critical pneumonia and those with moderate pneumonia. Statistics of the clinical symptoms of COVID-19 revealed that sputum production was more common in patients with moderate pneumonia, while headache appeared to be more pronounced in severe/critical patients. Some studies suggest that SARS-CoV-2 virus is not only con ned to the respiratory tract, but may also invade the central nervous system [34][35][36][37], and further studies are needed to clarify whether central nervous system infections are more pronounced in critically ill patients [38]. In addition, we similarly found that, the prevalence of comorbidities is found to be signi cantly different according to disease severity: higher in the severe/critical group.
We conducted simple statistics on the laboratory indicators, and the results showed that lymphocyte count, NLR and severity of COVID-19 were related. Lymphocyte count of the severe/critical pneumonia group were signi cantly lower, and NLR was signi cantly higher. This is consistent with some previous studies. A number of studies have shown that, compared with mild cases, the absolute number of lymphocytes in severe patients is signi cantly reduced [39,40], and the continuous decrease of peripheral blood lymphocyte count may be an early indicator for severe/critical patients with COVID-19. A metaanalysis showed that high NLR levels on admission were associated with severe COVID-19 and mortality [41]. In addition, factors associated with low lymphocyte count and high lactate dehydrogenase levels are important and independent risk factors for adverse clinical outcomes [42,43]. Han et al. found that serum LDH and CRP were signi cantly correlated with the severity of COVID-19. And Smilowitz NR et al. also came to the conclusion that CRP was strongly associated with critical illness and mortality in COVID-19 [44]. In our study, CRP elevation appeared to be higher in the severe/critical group than in the moderate group (P = 0.076). However, due to the limitation of detection methods, the CRP value below 0.5 cannot be measured and accurate numerical analysis cannot be carried out.
Chest CT is a routine examination for COVID-19. At the beginning of the epidemic, clinicians selected chest CT as an important assessment tool for COVID-19 based on their experience in managing similar diseases. It has also been proved that chest CT plays an irreplaceable role in the diagnosis, differential diagnosis, clinical classi cation, prognosis and therapeutic effect evaluation of COVID-19 [9,45]. In particular, CTSS has important reference value for the assessment of disease severity and the prediction of mortality [46,47]. In addition, several studies have described the temporal changes of chest CT, and it is believed that chest CT lesions are most obvious and CT severity score highest about 9-12 days after symptom onset [47,48]. We also found that about 2 weeks after the onset of symptoms, the lesions on chest CT were gradually absorbed over time with reduced density. Moreover, pulmonary consolidation was evident in severe/critical patients, with higher CT severity scores. These conclusions corroborate with previous studies to some extent. It should be noted, however, that imaging abnormalities in patients may persist for long periods of time. In the chest CT reexamined 50 days after the onset of symptoms, obvious ground-glass opacities and other lesions can still be seen, and the extent of the lesions is mostly smaller than before, with signi cantly reduced density. At this time, the patient's condition must be assessed in combination with the patient's clinical manifestations. In addition, we also observed that in a few cases, during the absorption and dissipation of the lesion, there was a signi cant deterioration (expansion of the extent of the lesion, appearance of new consolidation, etc.) This also reminds us that our understanding of COVID-19 is still very limited and cannot be taken lightly prematurely, especially in severe /critical patients.

Conclusions
At the early stage of the outbreak, in order to ensured that all those in need have been tested, isolated, hospitalized or treated, China launched the "mobile cabin hospitals", concentrated on the treatment of patients with COVID-19. A large number of mild or asymptomatic con rmed patients were admitted to "mobile cabin hospitals" for isolation and treatment. During this period, various designated hospitals for COVID-19 in Wuhan mainly admitted symptomatic or critically ill patients. Therefore, among the patients included in this study, the proportion of severe/critical patients was high, and most of them were admitted after one week of onset. Based on the above premise, we observed that after the patient developed symptoms for more than one week, chest CT was dominated by bilateral, multiple groundglass opacities and consolidation. After treatment, the lung lesions were gradually absorbed over time, showing a reduction in the extent and density of the lesions. In some patients, imaging abnormalities persisted for a long time, and multiple ground-glass opacities were still observed until 65 days after the onset of symptoms in this study. The presence of pulmonary consolidation and higher CT severity scores may be associated with severe disease. In addition, the presence of headache symptoms, comorbidity, reduced lymphocyte counts and elevated NLR may be predictors of COVID-19. Availability of data and materials

Abbreviations
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.  CT features between moderate and severe/critical cases.