Pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as coronavirus disease 2019 (COVID-19), has become a pandemic.1 2 3 By 1 March 2020, a total of 87 137 cases were confirmed globally, including 79 968 in China and 7169 distributed across 58 countries outside China. On 23 January 2020, the Chinese Central Government imposed a lockdown in Wuhan and other cities in Hubei Province to isolate the epicentre of the outbreak; to the best of our knowledge, the ‘Wuhan lockdown’ represents the first lockdown of a major city in modern history.4 Subsequently, compulsory policies have been established, such as suspension of public gatherings and the requirement to wear masks.5 In addition to non-medical interventions, the scientific community is responding to this challenge by working to understand and control the disease.6 7 8 9 10 11 However, there have been limited studies regarding the clinical and radiological features of patients with COVID-19, based on multicentre, multiprovincial cohorts at the peak of the epidemic.

In this context, we retrospectively analysed 189 patients with laboratory-confirmed COVID-19, using data collected from seven hospitals in four provinces from 18 January 2020 to 3 February 2020. We compared clinical features, laboratory tests, and chest computed tomography (CT) image findings of these patients with respect to time (ie, before and after Wuhan lockdown) and space (ie, in and outside of Wuhan epidemic area); we investigated potential associations between CT findings and laboratory data. Our findings may help further understand the epidemiological characteristics of COVID-19 and improve the public health response to the epidemic; they can be used as a reference for implementing control measures in other regions or countries with increasing numbers of patients with COVID-19.

Data regarding 189 patients were obtained from the following seven hospitals: Taihe Hospital (n=59), Xiangya Hospital of Central South University (n=21), The Second Xiangya Hospital of Central South University (n=9), Wenzhou Hospital (n=76), Jinling Hospital (n=1), Nanjing Drum Tower Hospital (n=12), and Wuhan Hospital (n=11). Wenzhou is the prefecture-level city with the most confirmed cases outside Hubei Province. Symptom onset time was recorded from 31 December 2019 to 2 February 2020; patients were hospitalised from 18 January 2020 to 3 February 2020, with final follow-up for this report on 4 February 2020. Patients with suspected COVID-19 were admitted and quarantined, then diagnosed with COVID-19 in accordance with the ‘Novel Coronavirus Pneumonia Prevention and Control Program’ (sixth edition)—a patient was confirmed to have COVID-19 based on high throughput sequencing or real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assays of nasal and pharyngeal swab specimens.12 Two target genes—open reading frame 1ab (ORF1ab) and nucleocapsid protein (N)—were simultaneously amplified and tested in real-time RT-PCR assays. Target 1 (ORF1ab) comprised forward primer 5’-CCCTGTGGGTTTTACACTTAA-3’, reverse primer 5’-ACGATTGTGCATCAGCTGA-3’, and the probe 5’-VIC-CCGTCTGCGGTATGTGGAAAGGTTATGG-BHQ1-3’. Target 2 (N) comprised forward primer 5’-GGGGAACTTCTCCTGCTAGAAT-3’, reverse primer 5’-CAGACATTTTGCTCTCAAGCTG-3’, and the probe 5’-FAMTTGCTGCTGCTTGACAGATT-TAMRA-3’. Real-time RT-PCR assays were conducted using a SARS-CoV-2 nucleic acid detection kit, in accordance with the manufacturer’s protocol (Shanghai BioGerm Medical Technology Company, Shanghai, China).

Epidemiological, clinical, laboratory, and radiological characteristics were obtained from electronic medical records by using data collection forms. Date of disease onset was defined as the day when symptoms were noticed. The number of days between symptom onset and date of the first positive test was recorded. Fever was defined as an axillary temperature of ≥37.5°C. Hypoxaemia was defined as 94% oxygen saturation, in accordance with respiratory department criteria. Major CT features were described using standard international nomenclature, defined by the Fleischner Society glossary and peer-reviewed literature regarding viral pneumonia. Degree of COVID-19 severity at the time of admission was defined as mild, moderate, severe, or critical, using preliminary diagnostic guidance from the National Health Commission of the People’s Republic of China. Disease was further separated into non-severe (ie, mild and moderate) and severe (ie, severe and critical) classifications for simplicity. Direct exposure history was defined as patient confirmation of a direct visit to Wuhan, China, during a particular period; close exposure history was defined as close patient contact with an individual who had confirmed or suspected COVID-19. To analyse spatiotemporal differences, patients were divided into different categories according to the start date for the Wuhan lockdown (ie, 23 January 2020) for temporal analysis or heavy epidemic province classification (eg, Hubei and Zhejiang provinces13) for spatial analysis.

Continuous variables were described as the mean (±standard deviation); categorical variables were expressed as frequency (%). All statistical analyses were conducted with R (version 3.6.2; https://www.r-project.org/), using Fisher’s exact test for categorical data and a two-sample Mann-Whitney test or Student’s t test for continuous data (as appropriate). Correlations were measured by Pearson’s correlation coefficient (ρ). Co-morbidities, signs, and symptoms that appeared in more than 10% of the patients were regarded as common co-existing medical conditions. For unadjusted comparisons, two-sided P values <0.05 were considered statistically significant. The analyses were not adjusted for multiple comparisons; thus, given the potential for type I error, the findings should be interpreted as exploratory and descriptive.

The present study included 189 patients with confirmed COVID-19 from four provinces in China, including 70 (37.0%) from Hubei (11 [5.8%] from Wuhan), 30 (15.9%) from Hunan, 76 (40.2%) from Zhejiang, and 13 (6.9%) from Jiangsu. Dates of confirmed infection by RT-PCR ranged from 18 January 2020 to 3 February 2020. The mean date of disease onset was 21 January 2020; the mean date of confirmed infection by RT-PCR was 28 January 2020. The mean duration between symptomology onset and first positive test was 6±5 days. Patients in severely affected areas (eg, Hubei and Zhejiang provinces) showed symptoms earlier than patients in other areas (Fig 1).

The overall characteristics of included patients are summarised in Table 1. The mean age was 44±14 years (range, 17-92 years); 100 patients (52.9%) were men. Of the 189 patients, 181 (95.8%) exhibited positive findings for COVID-19 in the initial RT-PCR assay; 186 patients (98.4%) had ≥1 co-existing medical condition. Fever (161 [86.1%]; two missing records), cough (113 [59.8%]), fatigue (68 [36.0%]), myalgia (35 [18.5%]), diarrhoea (25 [13.2%]), and headache (19 [10.1%]) were the most common symptoms at onset; hypertension (34 [18.0%]) was the most common co-morbidity. Less common co-morbidities included chronic obstructive pulmonary disease, chronic kidney disease, and malignancy (one patient each). Most patients (180 [95.2%]) had non-severe disease; patients with severe disease tended to be older (P=0.067) and had significantly greater breathing frequency (P=0.009) than patients with non-severe disease (online supplementary Appendix 1). Notably, fever was the primary symptom indicative of COVID-19 in patients with suspected disease during the epidemic; however, in our cohort, fever was independent of other imaging findings (data not shown).

On admission, 10 patients (5.3%) presented with hypoxaemia at the time of initial diagnosis; leukopenia was present in 31.2% of the patients, lymphocytopenia was present in 20.6%, and neutropenia was present in 13.2%. Patients with critical disease had more laboratory abnormalities than those with severe disease, including lymphocytopenia (44.4% vs 19.6%; P=0.09) and hypoxaemia (55.6% vs 2.8%; P<0.001). Approximately 91.0% of lesions exhibited subpleural distribution; 17.5% of lesions were diffusely distributed. The most common patterns on chest CT were mixed ground-glass opacity with consolidation (mGGO-C, 84.7%); 59.8% of patients had grid-like shadows and 27.5% of patients exhibited radiological manifestations of typical paving stones (Fig 2). Patients with severe disease showed more frequent involvement of multiple lobes (all P<0.05) and more frequent diffuse distribution (P=0.008), compared with patients who exhibited non-severe disease (online supplementary Appendix 1).

To evaluate the severity of respiratory damage caused by COVID-19, 26 patients (13.8%) who presented with subjective dyspnoea or objective hypoxia were selected for detailed analysis (Table 2). These 26 patients were generally older (50±16 years; P=0.013) and showed more diverse clinical symptoms (eg, cough [80.8%; P=0.033], fatigue [53.8%; P=0.068], nausea [30.8%; P<0.001], diarrhoea [34.6%; P=0.002], and abdominal pain [11.5%; P=0.017]), co-morbidities (eg, hypertension [38.5%; P=0.008]), and haematological abnormalities (eg, lymphocytopenia [38.5%; P=0.051]), compared with patients who did not exhibit dyspnoea or hypoxia. The radiological manifestations in these patients were not optimistic because all patients demonstrated multiple lesions (100%; P=0.123) and mGGO-C (100%; P=0.361); many patients had diffusely distributed lesions (42.3%; P=0.001) and grid-like shadows (80.8%; P=0.033) [Table 3]. Among nine patients with severe disease, seven (77.8%) had varying degrees of hypoxia and dyspnoea. Additionally, patients with haematological abnormalities (especially leukopenia or lymphocytopenia) showed more severe lobe involvement and tended to show diffusely distributed pulmonary lesions (online supplementary Appendix 2). Specifically, the white blood cell count was significantly negatively correlated with the numbers of lesions in left upper (ρ=-0.18, P=0.012), left lower (ρ=-0.23, P=0.002), and right lower lobes (ρ=-0.19, P=0.009).

Although there is no evidence that patients with hypertension are more susceptible to COVID-19, 18.0% of patients with confirmed disease exhibited hypertension, which was the most common clinical co-morbidity in our cohort. These patients were likely to exhibit hypoxaemia (14.7%; P=0.022); furthermore, their lung lobes were severely involved (all P<0.05) and lesions were significantly diffusely distributed (35.3%; P=0.006). Therefore, these patients require close clinical monitoring (Table 4).

In this cohort, all patients with severe disease showed mGGO-C. Paving stones, a sign of the inflammatory absorption period, and grid-like shadows, a sign of interstitial lung lesions, were significantly associated with the presence of mGGO-C (both P<0.05); thus, these radiological findings might serve as comprehensive indicators of disease severity in patients with COVID-19 (online supplementary Appendix 3). Additionally, these patients also showed unfavourable imaging findings, including multiple lesions and severe lung lobe involvement (all P≤0.001).

To further investigate the spatiotemporal differences among patients with COVID-19, we compared clinical, laboratory, and radiological characteristics of patients with respect to the start date of the Wuhan lockdown, as well as heavy epidemic province classification status (online supplementary Appendices 4 and 5). We found that patients in severely affected areas (eg, Hubei and Zhejiang provinces) demonstrated slightly higher body temperature (mean: 37.9℃ vs 37.6℃; P=0.070), more frequent fatigue (39.7% vs 23.3%, P=0.072), and more frequent dyspnoea (11.6% vs 0, P=0.041), compared with patients in other areas. Imaging findings showed more manifestations of multiple lesions (92.9% vs 78.0%, P=0.031), more severe lobe involvement, and more frequent radiological manifestations of mGGO-C (87.7% vs 74.4%, P=0.060). Additionally, after implementation of the ‘Wuhan lockdown’ policy, the symptoms of cough (51.0% vs 70.1%, P=0.012), nausea (3.9% vs 16.1%, P=0.010), and dyspnoea (2.0% vs 17.2%, P=0.001) were significantly alleviated in patients with newly confirmed COVID-19; lung lobe involvement was also dramatically improved, compared with patients who had been diagnosed prior to the start date of the lockdown.

This study assessed the epidemiological, clinical, laboratory, and imaging characteristics of 189 patients with confirmed COVID-19 from multiple hospitals and provinces; it also included spatiotemporal analysis of disease in these patients. As expected, there were more male patients than female patients in our cohort; fever, cough, and dyspnoea were the main symptoms at the time of initial diagnosis, accompanied by lymphocytopenia, hypoxaemia, and other haematological abnormalities. Furthermore, patients with severe disease showed significantly more severe lobe involvement and diffuse distribution of pulmonary lesions, consistent with the findings in previous studies.6 11 12 13 14 Reductions in the numbers of white blood cells or lymphocytes are closely associated with lobe involvement and diffuse distribution, such that a large number of inflammatory cells is consumed at pulmonary lesions in a short period; this finding is consistent with past pathological findings in patients with COVID-1915—interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, have been observed in both lungs; multinucleated syncytial cells with atypical enlarged pneumocytes (characterised by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli) were identified in intra-alveolar spaces, which constituted a viral cytopathy-like change. Additionally, lymphopenia is a common laboratory finding in patients with COVID-19. A serological study16 and a pathological result15 demonstrated that patients’ interleukin-6 levels increased during the course of the disease, whereas the levels of CD4+ T cells, CD8+ T cells, and natural killer cells decreased. These findings imply that, as the disease progresses, patients begin to develop immunosuppression; lymphopenia may therefore be a key factor related to disease severity and mortality in patients with COVID-19.

Another important finding in this study was that patients with hypertension were likely to exhibit hypoxaemia, accompanied by unfavourable radiological manifestations; this was presumably because the patients included in this study were mostly middle-aged or elderly people. The reported prevalence of hypertension in China was 23.2% in adults,17 which was slightly higher than the prevalence in our cohort. In general, older people are more susceptible to COVID-19 and more likely to experience severe disease, compared with people younger than 50 years of age, because older people exhibit greater numbers of health conditions and co-morbidities. Notably, the zinc metallopeptidase angiotensin-converting enzyme 2 (ACE2)18 19—a negative regulator of the angiotensin system which affects heart function, hypertension, and diabetes—has been identified as a key receptor for SARS-CoV-2 in humans. Angiotensin-converting enzyme 2 protects against acute lung injury in several animal models of acute respiratory distress syndrome, which indicates that the renin-angiotensin system may play a critical role in the pathogenesis of acute lung injury. Thus, enhancement of ACE2 activity might be a novel approach for the treatment of acute lung failure in several diseases. Angiotensin-converting enzyme 2 receptors are widely expressed in nasal mucosa, bronchus, lung, heart, oesophagus, kidney, stomach, bladder, and ileum; importantly, the entrance of SARS-CoV-2 into cells mainly occurs through binding to ACE2. Thus, unlike other β-coronaviruses, SARS-CoV-2 replication is not limited to the upper respiratory mucosa epithelium (eg, nasal cavity and pharynx); it also occurs in the digestive tract and other organs, which partially explains the non-respiratory symptoms (eg, diarrhoea, liver damage, and kidney damage).20 Multiple affected organs cause diverse clinical manifestations and large individual differences, which lead to complex conditions. Accordingly, patients with a history of hypertension should receive closer monitoring.

Respiratory system infections end in respiratory failure or multiple organ failure.21 Similar to previous reports of patients with severe acute respiratory syndrome (SARS), some patients in the present study experienced dyspnoea and hypoxaemia during the course of COVID-19 (online supplementary Appendix 6). Notably, our patients showed greater numbers of clinical symptoms and unfavourable imaging findings. Pathologically, SARS mainly causes the formation of hyaline membranes, which result in large numbers of inflammatory exudates into the alveolar cavity, as well as patchy haemorrhage and focal necrosis; these changes lead to respiratory failure and extremely high mortality. In contrast, our patients with COVID-19 generally exhibited mGGO-C as the main imaging feature, which causes airway obstruction without obvious hyaline membrane formation; thus, ventilator support can be used to improve patient prognosis. We presume that the presence of early imaging findings indicates that proactive interventions (eg, positive pressure ventilation) are needed to enhance blood oxygen concentration.

Fever, the most common symptom at the first visit and the most commonly used indicator for COVID-19, showed no significant relationship with radiological findings in the present study, which implies that patients may show no abnormalities (eg, changes in body temperature) when obvious lesions form in the lungs. Furthermore, a recent study22 demonstrated that the sensitivity of RT-PCR for confirmation of COVID-19 is lower than the sensitivity of chest imaging scans, which also suggests that radiological examinations should be used as the primary screening method in this epidemic because of their efficiency, instead of the current approach of body temperature checks and RT-PCR assays.

Overall, the spatial distribution of the epidemic demonstrated here is consistent with the official statistics.23 The distribution of disease incidence had a clear relationship with population mobility. In particular, cities surrounding Wuhan (throughout Hubei Province) reported the vast majority of cases, followed by Wenzhou (Zhejiang Province), which has a large floating population from Wuhan. Wan et al24 and Wrapp et al25 showed that SARS-CoV-2 is more infectious than SARS-CoV. Imported cases were most common in the early period of the epidemic; symptoms then began to appear among individuals who had been in contact with the first group of infected individuals, which contributed to a rapid increase in the number of infections. The symptoms of fatigue and dyspnoea were alleviated outside severely affected areas, which implied reduction of virus potency during intergenerational transmission and early admission to hospitals. In the present study, we used the date of disease onset for analysis of affected patients. Patients in Hubei and Zhejiang provinces showed symptoms earlier and were confirmed to have COVID-19 an average of 6 days later, compared with patients in other areas; these findings coincide with the reported 14-day incubation period.26 Gradually, clinical symptoms and chest CT findings were alleviated in patients with newly confirmed COVID-19 after the beginning of the Wuhan lockdown; these changes also implied reduction of virus potency during intergenerational transmission.

In general, the radiological manifestations of COVID-19 are similar to those of SARS and Middle East respiratory syndrome (MERS), but pleural effusion is rare in patients with COVID-19 (online supplementary Appendix 6). In two previous studies,27 28 the proportions of patients with SARS and MERS who had pleural effusions were 25% (4/16) and 14.5% (8/55), whereas only one patient with COVID-19 (0.5%) had pleural effusions in our cohort. Current studies indicate that the binding forces between the SARS-CoV-2 S protein and human ACE2 are similar to (or stronger than) those between the SARS-CoV S protein and its receptor.25 Given the state of the epidemic, SARS-CoV-2 is highly infectious; its basic reproduction number (R0) is considerably greater than that of either SARS or MERS.29 The World Health Organization reported that the R0 of SARS-CoV-2 ranged from 1.4 to 2.5, whereas a study in China indicated an R0 of 3.3 to 5.530 and a study in the United States estimated an R0 of 3.77 (95% confidence interval, 3.51-4.05).31 The findings of our multicentre retrospective study demonstrate that current measures have affected the early epidemiological pattern (ie, rapid increase) because R0 is decreasing each day in China; however, considering the complexity of influencing factors, further evaluations and predictions are needed. The majority of patients with COVID-19 exhibit non-severe disease, which is an essential source of infection and a ‘blind spot’ for public health efforts; therefore, CT findings such as infiltration, nodules, and consolidation should be identified during early diagnosis. Notably, flu season is approaching rapidly; there is a need for attention to epidemiological history and condition monitoring, as well as efforts to block routes of transmission as quickly as possible.

We acknowledge some limitations in this study. First, the cohort size was relatively small, and data were not collected equally from each included province, which may have led to bias in the conclusions. Second, documentation was incomplete for some patients, given the variations in electronic database structures among participating sites and the urgent timeline for data extraction. Missing data included contact history, heart rate, respiratory rate, and body temperature. Because of the small numbers of patients for whom these data were missing, the main conclusions of this study were presumably unaffected. Third, the sizes and densities of mGGO-C were not compared among patients; thus, analysis of relationships between these characteristics and COVID-19 progression warrants investigation.

Clinical and imaging features were compared among patients with COVID-19 at the peak of epidemic in China. The findings suggest that mGGO-C, paving stones, and grid-like shadows might serve as comprehensive indicators of disease severity in these patients. Furthermore, radiological examinations may be useful as the primary screening method in this epidemic because of their efficiency, in contrast to the current approach of body temperature checks and RT-PCR assays.

Overall spatiotemporal trends were also evaluated retrospectively in this study. Patients in severely affected areas demonstrated slightly higher body temperature, more frequent fatigue, and more frequent dyspnoea. After implementation of the ‘Wuhan lockdown’ policy, cough, nausea, and dyspnoea were significantly alleviated in patients with newly confirmed COVID-19. These data indicate that the preventive measures adopted by China’s Central Government may be appropriate for planning efforts in other regions or countries with increasing numbers of infected patients.

Concept or design: Y Wang, F Yan, B Zhang, DY Zhang, and ZY Sun.
Acquisition of data: ZQ Wen, W Chen, W Chen, WH Liao, J Liu, Y Yang, JC Shi, SD Liu, F Xia, and ZH Yan.
Analysis or interpretation of data: X Lu, T Chen, and Y Wang.
Drafting of the manuscript: Y Wang, S Luo, CS Zhou, X Lu, and T Chen.
Critical revision of the manuscript for important intellectual content: Y Wang, B Zhang, DY Zhang, and Z Sun.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors declare no competing interests.

We thank Prof Guangming Lu (Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China) for his coordination during the cross-centre data collection process. We also thank all hospital staff for their efforts in collecting the information used in this study; all patients who consented to inclusion of their data in the analysis; and all medical staff involved in patient care.

This work was supported by the National Natural Science Foundation of China (81720108022, 91649116, 81571040, 81973145), the Social Development Project of Science and Technology in Jiangsu Province (BE2016605, BE201707), the National Key R&D Program of China (2017YFC0112801), the Key Medical Talents of Jiangsu Province, the ‘13th Five-Year’ Health Promotion Project of Jiangsu Province (B.Z.2016-2020), the Jiangsu Provincial Key Medical Discipline (Laboratory) (ZDXKA2016020), the Project of the Sixth Peak of Talented People (WSN-138, BZ), the China Postdoctoral Science Foundation (2019M651805), the “Double First-Class” University project (CPU2018GY09), and Nanjing Health and Family Planning Commission (YKK17089). The funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

This study adhered to the tenets of the Declaration of Helsinki and was approved by the ethics committees of the seven hospitals (Taihe Hospital, Xiangya Hospital of Central South University, The Second Xiangya Hospital of Central South University, Wenzhou Hospital, Jinling Hospital, Nanjing Drum Tower Hospital, and Wuhan Hospital) with a unified approval number [M202003050028] led by Nanjing Drum Tower Hospital; a waiver of informed consent was granted because the study involved patients with emerging infectious diseases.

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