key: cord-0955028-hqech99b
authors: Zhu, Jieyun; Zhong, Zhimei; Ji, Pan; Li, Hongyuan; Li, Bocheng; Pang, Jielong; Zhang, Jianfeng; Zhao, Chunling
title: Clinicopathological characteristics of 8697 patients with COVID-19 in China: a meta-analysis
date: 2020-05-05
journal: Fam Med Community Health
DOI: 10.1136/fmch-2020-000406
sha: 234186cc46f365c308f0ef5b0aca4c270be12041
doc_id: 955028
cord_uid: hqech99b

OBJECTIVE: Our study aims to present a summary of the clinicopathological characteristics of patients affected by the coronavirus disease 2019 (COVID-19) that can be used as a reference for further research and clinical decisions. DESIGN: Studies were included in the meta-analysis if they had cohort, case–control or case series designs and provided sufficient details on clinical symptoms, laboratory outcomes and asymptomatic patients. SETTING: PubMed, Embase, Chinese Biomedical Literature Database, Wanfang, China Science and Technology Journal Database and China National Knowledge Infrastructure databases were electronically searched to identify related studies published between 1 January 2020 and 16 March 2020. Three reviewers independently examined the literature, extracted relevant data and assessed the risk of publication bias before including the studies in the meta-analysis. PARTICIPANTS: The confirmed cases of COVID-19. RESULTS: A total of 55 unique retrospective studies involving 8697 patients with COVID-19 were identified. Meta-analysis showed that a higher proportion of infected patients were male (53.3%), and the two major symptoms observed were fever (78.4%) and cough (58.3%). Other common symptoms included fatigue (34%), myalgia (21.9%), expectoration (23.7%), anorexia (22.9%), chest tightness (22.9%) and dyspnoea (20.6%). Minor symptoms included nausea and vomiting (6.6%), diarrhoea (8.2%), headache (11.3%), pharyngalgia (11.6%), shivering (15.2%) and rhinorrhea (7.3%). About 5.4% of the patients were asymptomatic. Most patients showed normal leucocyte counts (64.7%) and elevated C reactive protein levels (65.9%). Lymphopaenia was observed in about 47.6% of the infected patients, along with abnormal levels of myocardial enzymes (49.4%) and liver function (26.4%). Other findings included leucopenia (23.5%), elevated D-dimer (20.4%), elevated erythrocyte sedimentation rate (20.4%), leucocytosis (9.9%), elevated procalcitonin (16.7%) and abnormal renal function (10.9%). CONCLUSIONS: The most commonly experienced symptoms of patients with COVID-19 were fever and cough. Myalgia, anorexia, chest tightness and dyspnoea were found in some patients. A relatively small percentage of patients were asymptomatic and could act as carriers of the disease. Most patients showed normal leucocyte counts, elevated levels of C reactive protein and lymphopaenia, confirming the viral origin of the disease.

Objective Our study aims to present a summary of the clinicopathological characteristics of patients affected by the coronavirus disease 2019 (COVID-19) that can be used as a reference for further research and clinical decisions. Design Studies were included in the meta-analysis if they had cohort, case-control or case series designs and provided sufficient details on clinical symptoms, laboratory outcomes and asymptomatic patients. setting PubMed, Embase, Chinese Biomedical Literature Database, Wanfang, China Science and Technology Journal Database and China National Knowledge Infrastructure databases were electronically searched to identify related studies published between 1 January 2020 and 16 March 2020. Three reviewers independently examined the literature, extracted relevant data and assessed the risk of publication bias before including the studies in the metaanalysis. Participants The confirmed cases of COVID- 19 . results A total of 55 unique retrospective studies involving 8697 patients with COVID-19 were identified. Meta-analysis showed that a higher proportion of infected patients were male (53.3%), and the two major symptoms observed were fever (78.4%) and cough (58.3%). Other common symptoms included fatigue (34%), myalgia (21.9%), expectoration (23.7%), anorexia (22.9%), chest tightness (22.9%) and dyspnoea (20.6%). Minor symptoms included nausea and vomiting (6.6%), diarrhoea (8.2%), headache (11.3%), pharyngalgia (11.6%), shivering (15.2%) and rhinorrhea (7.3%). About 5.4% of the patients were asymptomatic. Most patients showed normal leucocyte counts (64.7%) and elevated C reactive protein levels (65.9%). Lymphopaenia was observed in about 47.6% of the infected patients, along with abnormal levels of myocardial enzymes (49.4%) and liver function (26.4%). Other findings included leucopenia (23.5%), elevated D-dimer (20.4%), elevated erythrocyte sedimentation rate (20.4%), leucocytosis (9.9%), elevated procalcitonin (16.7%) and abnormal renal function (10.9%). Conclusions The most commonly experienced symptoms of patients with COVID-19 were fever and cough. Myalgia, anorexia, chest tightness and dyspnoea were found in some patients. A relatively small percentage of patients were asymptomatic and could act as carriers of the disease. Most patients showed normal leucocyte counts, elevated levels of C reactive protein and lymphopaenia, confirming the viral origin of the disease.

In the spring of 2020, the coronavirus disease 2019 (COVID-19) pandemic has spread to more than 200 countries around the world. 1 2 As of 27 March 2020, the total number of confirmed cases has exceeded 500 000. 3 This pandemic has become a serious threat to global health and continues to challenge healthcare systems worldwide. It was determined to be caused by a novel coronavirus, the severe acute respiratory syndrome coronavirus 2. 4 Therefore, it is critical to understand and identify the key clinical and laboratory characteristics of patients with COVID-19 in order to help in early detection and isolation of infected individuals, as well as minimise the spread of the disease. 5 Although a number of studies have attempted to explore this subject, most of them were single-centre studies that were conducted in a specific hospital or region. Due to differences in study design and small samples, the clinical symptoms, laboratory findings and other key outcomes of these studies are complicated and unclear. [6] [7] [8] For example, two recent systematic reviews 9 10 of studies of patients with COVID-19 indicated a high incidence of fever (>88%) and cough (>68%), but only one 10 reported symptoms of myalgia or fatigue (35.8%). Both reviews meta-analysed small samples pooled from 10 studies.

Therefore, the present meta-analysis was performed to provide the most extensive, up-to-date description so far of clinicopathological characteristics of patients with COVID-19 and to provide a reference for clinical decisions and future research.

This meta-analysis was carried out based on the guidelines of the Preferred Reporting Items for Meta-Analyses of Observational Studies in Epidemiology Statement. 11 We systematically examined the studies on clinicopathological characteristics of patients with COVID-19 indexed in the PubMed, Embase, Chinese Biomedical Literature, Wanfang, China Science and Technology Journal Database and China National Knowledge Infrastructure databases between 1 January 2020 and 16 March 2020. All references cited in these studies were also analysed manually to ensure that eligible papers were not overlooked. If multiple studies analysed the same patient population, we included only the one with more detailed information or the one published more recently. No language restrictions were incorporated during the literature search, and only literature published online was included. The following keywords were used, both separately and in combination, as part of the search strategy in each database: 'Corona virus', 'Coronavirus', '2019-nCoV', 'COVID-19' or 'SARS-CoV-2' (box 1).

Studies were included in the meta-analysis if they had cohort, case-control or case series designs and provided sufficient details on clinical symptoms, laboratory outcomes and asymptomatic patients. Only studies of more than 40 patients were included.

Data extraction and quality assessment The literature selected was independently assessed by three reviewers based on the eligibility criteria, and relevant data were extracted. Disagreements were resolved by consensus. The titles and abstracts were first screened to identify the eligible articles, followed by a full-text review to obtain detailed information. When required, the authors were contacted directly to obtain further information and clarifications regarding their study. The following data were extracted from each included study: surname of first author; date of publication; study design; number, age and sex of patients; clinical and laboratory outcomes; and data relevant for assessing publication bias. The quality of observational case series was independently evaluated by the three reviewers based on the British National Institute for Clinical Excellence 12 guidelines. This evaluation was conducted based on a set of eight criteria, and studies with a score greater than 4 were considered to be of high quality (total score=8).

All statistical analyses were performed using STATA V.12. Original incidence rates r were transformed by the double arcsine method to ensure a normal distribution, and the resulting transformed rate tr was used in single-arm metaanalysis. The heterogeneity between studies was analysed using a χ 2 test (p<0.10) and quantified using the I 2 statistic. When no statistical heterogeneity was observed, a fixed-effects model was used. Otherwise, potential sources of clinical heterogeneity were identified using subgroup and sensitivity analyses; these sources were eliminated, and the meta-analysis was repeated using a random-effects model. Pooled incidence rates R were back-calculated from transformed rates tr using the R=[sin (tr / 2)]. 2 A two-tailed p<0.05 was considered statistically significant. Publication bias was evaluated using a funnel plot along with Egger's regression test and Begg's test.

results literature screening and assessment A total of 5576 records were identified from the various databases examined. After a detailed assessment based on the inclusion criteria, 55 unique studies 6-8 13-64 involving 8697 patients with COVID-19 were included in the metaanalysis (figure 1).

All studies included in the meta-analysis were conducted in China and published between 6 February 2020 and 16 March 2020. These retrospective studies examined Chinese patients distributed across 31 provinces. A large proportion of these studies (n=40) were based on data collected from a single centre, with no clear explanation regarding eligibility criteria. Follow-up data were reported for most patients. All studies received quality scores of 5-8, indicating high quality (table 1) . 

Relevant data regarding the clinicopathological characteristics of 8697 patients with COVID-19 was collected. 6-8 13-64 Significant heterogeneity was observed across all included studies (I 2 =93.7%), therefore, a random-effects model was used in the meta-analysis. We found that 53.3% (95%CI 50.3 to 56.4) of the patients were male.

Two major symptoms, including fever (78.4%) and cough (58.3%), were highly prevalent among patients. Fatigue (34%), myalgia (21.9%), expectoration (23.7%), anorexia (22.9%), chest tightness (22.9%) and dyspnoea (20.6%) also occurred frequently. Less frequent symptoms were nausea and vomiting (6.6%), diarrhoea (8.2%), headache (11.3%), pharyngalgia (11.6%), shivering (15.2%) and rhinorrhea (7.3%). Only 5.4% of patients with COVID-19 were found to be asymptomatic (table 2) .

A large proportion of patients had normal leucocyte counts (64.7%) and high levels of C reactive protein (65.9%) (figures 2 and 3). Lymphopaenia was observed Open access 

Patients were stratified into two groups based on the date of initial diagnosis: group 1 included all patients and group 2 included those diagnosed between December 2019 and 31 January 2020 (table 4). We found that all patients diagnosed before 31 January had higher incidence rates of fever and cough. No significant difference was observed in the heterogeneity between the subgroups and the overall heterogeneity, indicating that the date of initial diagnosis was not the main source of heterogeneity.

A sensitivity analysis was carried out by excluding one study at a time and reanalysing the entire dataset. We found that the pooled incidence rates did not change substantially, indicating the reliability and stability of our meta-analysis (eg, figure 4) .

The p values derived using the Egger's and the Begg's test for all the clinicopathological characteristics showed no obvious publication bias ( 5 ). These results confirm that there is no publication bias.

In this meta-analysis, we examined 55 independent studies 6-8 13-64 reporting clinicopathological data on 8697 patients with COVID-19 distributed across 31 provinces in China. The studies included in this analysis comprise the latest research available on COVID-19 through 16 March 2020. Our results indicate that there is a slightly higher proportion of male patients (53.3%) and that the main symptoms of this disease are fever (78.4%), cough (58.3%) and fatigue (34%). Compared with previous results, 9 10 our findings reveal lower incidence rates of the two major symptoms of this disease, which we found to depend to some extent on whether diagnosis was made before or after 31 January 2020, reflecting with the progress of the epidemic, the number of atypical manifestations has growed gradually. For example, some patients developed gastrointestinal symptoms, such as diarrhoea, nausea and vomiting. These results highlight the importance of also taking into account non-respiratory symptoms of the disease. Most patients with COVID-19 showed normal leucocyte counts and lymphopqenia. Few patients had leucocytosis and elevated procalcitonin levels, confirming that this disease is transmitted by a virus. Therefore, it is essential for clinicians to use such pathological findings to rule out the presence of bacterial infections. In this study, 49.4% of the patients presented with myocardial enzyme spectrum abnormalities, which manifested as an increase in lactate dehydrogenase levels. Studies have shown that elevated levels of lactate dehydrogenase can be a risk factor for rapid progression from mild to critical COVID-19. 65 Therefore, monitoring the function of important organs during treatment is critical, and treatment should be adjusted as needed to preserve and maintain organ function.

Infected people who are asymptomatic can act as a source of infection, 66 especially since the estimated median incubation period is 5-6 days (range 0-14 days). An analysis by the Chinese Center for Disease Control and Prevention conducted through 17 February 2020 suggested that the proportion of asymptomatic patients was only around 1%, 67 but our results suggest that the proportion is closer to 5%. This increase may reflect the growing experience of hospitals with this novel disease and increasing screening of suspected COVID-19 cases for viral infection, allowing the correct diagnosis of greater proportions of patients showing no or less typical manifestations. Therefore, to control the spread of this disease, general practitioners should carefully monitor individuals with histories of contact in areas where outbreaks have occurred or who had contact with suspected or confirmed cases of COVID-19 within 14 days before onset of symptoms. 68 Epidemiological history of patients should be investigated in detail, and asymptomatic infected people in the community should be identified as quickly as possible to control spread of the disease.

A recent study suggests that, considering different scenarios, highly effective contact tracing and case isolation are sufficient to control a new outbreak of COVID-19 within 3 months. 69 Therefore, isolation, quarantine, social distancing, and community containment measures should be rapidly implemented in high-risk countries or regions. 70 In China, community engagement has been the first line of defence in the battle against the COVID-19 pandemic. General practitioners act as both gatekeepers and health promoters by educating the public and guiding the community in the fight against this disease. 71 Monitoring people at designated checkpoints, intercepting transmission routes in a timely manner and preventing local outbreaks are critical to prevent repeat epidemics. 72 Although this study rigorously analysed clinical and laboratory data collected from a large sample of patients with COVID-19, we were unable to eliminate the significant heterogeneity observed between studies. For example, the course and the severity of the disease varied across studies. Given that most of the studies included in our meta-analysis were single-centre, retrospective studies, it was difficult for us to control for the effects of several confounding factors, including bias in patient admission and selection, as well as differences in disease severity and course. Further research is required to verify and extend our results for China. Continued surveillance across multiple countries, along with transparent and accurate reporting of patient characteristics and testing policies, will help us gain a better understanding of this global pandemic. 73 COnClusIOn In summary, Current evidence showed that the most commonly experienced symptoms of patients with COVID-19 were fever and cough. Myalgia, anorexia, Open access chest tightness and dyspnoea were found in some patients. A relatively small percentage of patients were asymptomatic and could act as carriers of the disease. Most patients showed normal leucocyte counts, elevated levels of C reactive protein and lymphopenia, confirming the viral origin of the disease. Due to limited quality and quantity of the included studies, more highquality prospective studies are required to verify above conclusions.

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A preliminary study on TCM syndrome characteristics of 88 patients with COVID-19 in Tianjin

Analysis of traditional Chinese medicine syndromes of 46 cases of COVID-19

Analysis on Chinese medical clinical characteristics of 50 patients with 2019-nCoV-infected pneumonia

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Chest CT performance and clinical characteristics of coronavirus disease 2019 (COVID-19)

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Epidemiological and clinical characteristics of 57 casesof new coronavirus pneumonia in nonepidemic areas

Analysis of clinical characteristics of 49 patientswith novel coronavirus pneumonia in Jiangxi Province

Manifestations of the initial chest CT and its association with laboratory tests in 75 COVID-19 patients

Analysis on TCM clinical characteristics of66 COVID-19 cases in the recover period

The clinical characteristics and medication analysis of corona virus disease 2019

Study of TCM syndrome in 209 novel coronavirus pneumonia cases of Chongqing in 2020

Clinical characteristics of 223 novel coronavirus pneumonia cases in Chongqing

Clinical observation on 49 cases of non-critical coronavirus disease 2019 in Shanghai treated by integrated traditional Chinese and Western medicine

Clinical characteristics, treatment, and prognosis in89 cases of COVID-2019

Retrospective study on the epidemiological characteristics of 139 patients with novel coronavirus pneumonia on the effects of severity

Retrospective analysis on 308 cases of COVID-19 and clinical application program of Kang Yi Qiang Shen Gong exercise prescription

Clinical characteristics and treatment effect of 537 cases of novel coronavirus pneumonia in Shandong Province

Clinical characteristics and TCM syndrome distribution in 524 cases of novel coronavirus pneumonia in Henan

Analysis on TCM syndrome rules of 60 Casesof novel coronavirus pneumonia in Gansu area

Clinical characteristics of 463 patients with common and severe type coronavirus disease 2019

Clinical features and CT imaging analysis of 76patiens with corona virus disease 2019

Clinical characteristics of 120 patients infected with SARS-CoV-2

Clinical features of 62 cases of coronavirus disease 2019complicated with acute renal injury

The clinical and chest CT features associated with severe and critical COVID-19 pneumonia

Clinical characteristics of imported cases of COVID-19 in Jiangsu Province: a multicenter descriptive study

Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2

Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2

Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

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Clinical characteristics of 2019 novel coronavirus infection in China

Chest CT findings in coronavirus Disease-19 (COVID-19): relationship to duration of infection

Chest CT findings in patients with coronavirus disease 2019 and its relationship with clinical features

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

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Ct features of coronavirus disease 2019 (COVID-19) pneumonia in 62 patients in Wuhan, China

Clinical efficacy analysis of 50 cases of corona virus disease 2019 in traditional Chinese medicine

Clinical characteristics and treatment analysis of 79 cases of COVID-19

Analysis of the relationship between clinical features and tongue manifestations of 40 cases with novel coronavirus pneumonia

A preliminary study on the clinical characteristicsandchinese medical syndrome of 42 cases of COVID-19 in Nanjing

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