Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-30388/v1

Abstract

Objective: To conduct a systematic review and meta-analysis on the comorbidities, symptoms, clinical characteristics and treatment of COVID-19 patients.

Method: Epidemiological studies published in 2020 (from January-March) on the clinical presentation, laboratory findings and treatments of COVID-19 patients were identified from PubMed/MEDLINE and Embase databases. Studies published in English by 27th March, 2020 with original data were included. A random-effects model was used to aggregate estimates across eligible studies and produce meta-analytic estimates. Primary outcomes included comorbidities of COVID-19 patients, their symptoms presented on hospital admission, laboratory results and radiological outcomes, and pharmacological and in-patient treatments.

Results: 77 studies were included in this meta-analysis, accounting for a total of 11,028 COVID- 19 patients in multiple countries. The most common comorbidities were hypertension (18.1%, 95%CI: 15.4-20.8%). The most frequently identified symptoms were fever (72.4%, 95%CI: 67.2-77.7%) and cough (55.5%, 95%CI: 50.7-60.3%). For pharmacological treatment, 63.9% (95%CI: 52.5-75.3%), 62.4% (95%CI: 47.9-76.8%) and 29.7% (95%CI: 21.8-37.6%) of patients were given antibiotics, antiviral, and corticosteroid, respectively. Notably, 62.6% (95%CI: 39.9- 85.4%) and 20.2% (95%CI: 14.6-25.9%) of in-patients received oxygen therapy and non- invasive mechanical ventilation, respectively.

Conclusions: This meta-analysis informed healthcare providers about the timely status of characteristics and treatments of COVID-19 patients across different countries.

PROSPERO Registration Number: CRD42020176589

Introduction

Following the possible patient zero of coronavirus infection identified in early December 2019 (1), the Coronavirus Disease 2019 (COVID-19) has been recognized as a pandemic in mid- March 2020 (2), after the increasing global attention to the exponential growth of confirmed cases (3). As on 29 March, 2020, around 690 thousand persons were confirmed infected, affecting 199 countries and territories around the world, in addition to 2 international conveyances: the Diamond Princess cruise ship harbored in Yokohama, Japan, and the Holland America's MS Zaandam cruise ship. Overall, more than 32 thousand died and about 146 thousand have recovered (4).

A novel bat-origin virus, 2019 novel coronavirus, was identified by means of deep sequencing analysis. SARS-CoV-2 was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%) (5), both of which were respectively responsible for two zoonotic human coronavirus epidemics in the early 21st century. Following a few initial human infections (6), the disease could easily be transmitted to a substantial number of individuals with increased social gathering (7) and population mobility during holidays in December and January (8). An early report has described its high infectivity (9) even before the infected becomes symptomatic (10). These natural and social factors have potentially influenced the general progression and trajectory of the COVID-19 epidemiology.

By the end of March 2020, there have been approximately 3,000 reports about COVID-19 (11). The number of COVID-19-related reports keeps growing everyday, yet it is still far from a clear picture on the spectrum of clinical conditions, transmissibility and mortality, alongside the limitation of medical reports associated with reporting in real time the evolution of an emerging pathogen in its early phase. Previous reports covered mostly the COVID-19 patients in China. With the spread of the virus to other continents, there is an imminent need to review the current knowledge on the clinical features and outcomes of the early patients, so that further research and measures on epidemic control could be developed in this epoch of the pandemic.

methods

Search strategy and selection criteria

The systematic review was conducted according to the protocol registered in the PROSPERO database (CRD42020176589). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline throughout this review, data were identified by searches of MEDLINE, Embase and references from relevant articles using the search terms "COVID", “SARS-CoV-2”, and "novel coronavirus" (Appendix 1). Articles published in English up to 27th March, 2020 were included. Studies with original data including original articles, short and brief communication, letters, correspondences were included. Editorials, viewpoints, infographics, commentaries, reviews, or studies without original data were excluded. Studies were also excluded if they were animal studies, modelling studies, or did not measure symptoms presentation, laboratory findings, treatment and therapeutics during hospitalization. 

After the removal of duplicate records, two reviewers (CW and CHA) independently screened the eligibility criteria of study titles, abstracts and full-texts, and reference lists of the studies retrieved by the literature search. Disagreements regarding the procedures of database search, study selection and eligibility were resolved by discussion. The second and the last authors (JW and AW) verified the eligibility of included studies.

Outcomes definitions

Signs and symptoms were defined as the presentation of fever, cough, sore throat, headache, dyspnea, muscle pain, diarrhea, and rhinorrhea at the hospital admission.

Laboratory findings included a complete blood count (white blood count, neutrophil, lymphocyte, platelet count), procalcitonin, prothrombin time, urea, and serum biochemical measurements (including electrolytes, renal-function and liver-function values, creatine kinase, lactate dehydrogenase, C-reactive protein, Erythrocyte sedimentation rate), and treatment measures (i.e. antiviral therapy, antibiotics, corticosteroid therapy, mechanical ventilation, intubation, respiratory support, and renal replacement therapy). Radiological outcomes included bilateral involvement identified and pneumonia identified by chest radiograph.

Comorbidities of patients evaluated in this study were hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular disease, chronic kidney disease, liver disease and cancer.

In-patient treatment included intensive care unit admission, oxygen therapy, non-invasive ventilation, mechanical ventilation, Extracorporeal membrane oxygenation (ECMO), renal replacement therapy, and pharmacological treatment. Use of antiviral drugs (Lopinavir/ritonavirm, Ribavirin, Interferon-alpha, or Interferon-beta), antibiotic drugs, corticosteroid, and inotropes (Nor-adrenaline, Adrenaline, Vasopressin, Phenylephrine, Dopamine, or Dobutamine) were considered.

Data analysis

Three authors (CW, EHMT and CHA) extracted data using a standardized spreadsheet to record the article type, country of original, surname of first author, year of publications, sample size, demographics, comorbidities, symptoms, laboratory and radiology results, pharmacological and non-pharmacological treatments. 

We aggregated estimates across 90 eligible studies to produce meta-analytic estimates using a random-effects model. For dichotomous outcomes, we estimated the proportion and its respective 95% confidence interval. For laboratory parameters as continuous outcomes, we estimated the mean and standard deviation from the median and interquartile range if the mean and standard deviation were not available from the study (12), and calculated the mean and its respective 95% confidence intervals. Random-effect models on DerSimonian and Laird method were adopted due to the significant heterogeneity, checked by the I2 statistics and the p-values. I2 statistic of <25%, 25-75% and ≥75% is considered as low, moderate, high likelihood of heterogeneity. Pooled estimates were calculated and presented by using forest plots. Publication bias was estimated by Egger’s regression test. Funnel plots of outcomes were also presented to assess publication bias.

All statistical analyses were conducted using the STATA Version 13.0 (Statacorp, College Station, TX). The random effects model was generated by the Stata packages ‘Metaprop’ for proportions (13) and ‘Metan’ for continuous variables (14). 

Ethical approval

This study was approved by the Institutional Review Board of the University of Hong Kong/ Hospital Authority Hong Long West Cluster (Reference Number: UW 20-112).

Role of the funding source

There was no funding source for this study.

Results

The selection and screen process are presented in eFigure 1 in the Supplement. A total of 241 studies were found by our searching strategy (71 in PubMed and 170 in Embase). 46 records were excluded due to duplication. After screening the abstracts and titles, 100 English studies were with original data and included in full-text screening. By further excluding 10 studies with not reporting symptoms presentation, laboratory findings, treatment and therapeutics, 90 studies (15-104) and 77 studies (15-29, 32-38, 40-43, 47-52, 55-62, 65-77, 79-94, 96, 98-103) were included in the current systematic review and meta-analysis respectively. 73.3% (66) studies were conducted in China. The summary of the included study is shown in Table 1.

Of those 90 eligible studies, 11,028 COVID-19 patients were identified and included in the systematic review. More than half of patients (6,336, 57.5%) were from mainland China. The pooled mean age was 45.8 (95% CI: 38.6-52.5) years and 49.3% (pooled 95% CI: 45.6-53.0%) of them were male.

For specific comorbidity status, the most prevalent comorbidity was hypertension (18.1%, 95% CI: 15.4-20.8%), followed by cardiovascular disease (11.8%, 95% CI: 9.4-14.2%) and diabetes (10.4%, 95% CI: 8.7-12.1%). The pooled prevalence (95% CI) of COPD, chronic kidney disease, liver disease and cancer were 2.0% (1.3-2.7%), 5.2% (1.7-8.8%), 2.5% (1.7-3.4%) and 2.1% (1.3%-2.8%) respectively. Moderate to substantial heterogeneity between reviewed studies were found, with I2 statistics ranging from 39.4% to 95.9% (p-values between <0.001-0.041), except for liver disease (I2 statistics: 1.7%, p=0.433). Detailed results for comorbidity status are displayed in Figure 1.

Regarding the symptoms presented at hospital admission, the most frequent symptoms were fever (pooled prevalence: 72.4%, 95% CI: 67.2-77.7%) and cough (pooled prevalence: 55.5%, 95% CI: 50.7-60.3%). Sore throat (pooled prevalence: 16.2%, 95% CI: 12.7-19.7%), dyspnoea (pooled prevalence: 18.8%, 95% CI: 14.7-22.8%) and muscle pain (pooled prevalence: 22.1%, 95% CI: 18.6-25.5%) were also common symptoms found in COVID-19 patients, but headache (pooled prevalence: 10.5%, 95% CI: 8.7-12.4%), diarrhoea (pooled prevalence: 7.9%, 95% CI: 6.3-9.6%), rhinorrhoea (pooled prevalence: 9.2%, 95% CI: 5.6-12.8%) were less common. The I2 statistics varied from 68.5% to 97.1% (all p-values<0.001), indicating a high heterogeneity exists across studies. Figure 2 shows the pooled proportion of symptoms of patients presented at hospital.

For laboratory parameters, white blood cell (pooled mean: 5.31 ×109/L, 95% CI: 5.03- 5.58×109/L), neutrophil (pooled mean: 3.60×109/L, 95% CI: 3.31-3.89×109/L), lymphocyte (pooled mean: 1.11 ×109/L, 95% CI: 1.04-1.17×109/L), platelet count (pooled mean: 179.5 U/L, 95% CI: 172.6-186.3 U/L), aspartate aminotransferase (pooled mean: 30.3 U/L, 95% CI: 27.9-32.7 U/L), alanine aminotransferase (pooled mean: 27.0 U/L, 95% CI: 24.4-29.6 U/L) and C- reactive protein (CRP) (pooled mean: 22.0 mg/L, 95% CI: 18.3-25.8 mg/L) and D-dimer (0.93 mg/L, 95% CI: 0.68-1.18 mg/L) were the common laboratory test taken for COVID-19 patients. Above results and other clinical factors are depicted in Figure 3. Same with the comorbidity status and symptoms, high likelihood of heterogeneity was detected by I2 statistics for a majority of clinical parameters.

Figure 4 presents the distribution of the pharmacological treatments received for COVID-19 patients. 10.6% of patients admitted to intensive care units (pooled 95% CI: 8.1-13.2%). For drug treatment, 63.9% (pooled 95% CI: 52.5-75.3%), 62.4% (pooled 95% CI: 47.9-76.8%) and 29.7% (pooled 95% CI: 21.8-37.6%) patients used antibiotics, antiviral, and corticosteroid, respectively. 41.3% (pooled 95% CI: 14.3-68.3%) and 50.7% (pooled 95% CI: 9.2-92.3%) reported using Lopinavir/Ritonavir and interferon-alpha as antiviral drug treatment, respectively. No reviewed studies reported the proportion of patients receiving Ribavirin, Interferon-beta, or inotropes.

The prevalence of radiological outcomes and non-pharmacological treatments were presented in Figure 5. Radiology findings detected chest x-ray abnormalities, with 74.4% (95% CI: 67.6- 81.1%) of patients with bilateral involvement and 74.9% (95% CI: 68.0-81.8%) of patients with viral pneumonia. 62.6% (pooled 95% CI: 39.9-85.4%), 20.2% (pooled 95% CI: 14.6-25.9%), 15.3% (pooled 95% CI: 11.0-19.7%), 1.1% (pooled 95% CI: 0.4 -1.8%) and 4.7% (pooled 95% CI: 2.1-7.4%) took oxygen therapy, non-invasive ventilation, mechanical ventilation, ECMO and dialysis respectively. 

The funnel plots and results Egger’s test of comorbidity status, symptoms presented, laboratory test and treatment were presented in eFigure 2-6 in the Supplement.

Discussion

This meta-analysis reveals the condition of global medical community responding to COVID-19 in the early phase. During the past four months, a new major epidemic focus of COVID-19, some without traceable origin, has been identified. Following its first identification in Wuhan, China, the virus has been rapidly spreading to Europe, North America, Asia, and the Middle East, in addition to African and Latin American countries. Three months since Wuhan CDC admitted that there was a cluster of unknown pneumonia cases related to Huanan Seafood Market and a new coronavirus was identified as the cause of the pneumonia (105), as on 1 April, 2020, there have been 858,371 persons confirmed infected with COVID-19, affecting 202 countries and territories around the world. Although this rapid review is limited by the domination of reports from patients in China, and the patient population is of relative male dominance reflecting the gender imbalance of the Chinese population (106), it provides essential information and practical guidance for clinicians and policy makers.

In this review, the pooled mean age was 45.8 years. Similar to the MERS-CoV pandemic (107), middle-aged adults were the at-risk group for COVID-19 infections in the initial phase, which was different from the H1N1 influenza pandemic where children and adolescents were more frequently affected (108). Biological differences may affect the clinical presentations of infections; however, in this review, studies examining the asymptomatic COVID-19 infections or reporting any previous infections were not included. It is suggested that another systematic review should be conducted to compare the age-specific incidence rates between the pre- pandemic and post-pandemic periods, so as to understand the pattern and spread of the disease, and tailor specific strategies in infection control.

Both sexes exhibited clinical presentations similar in symptomatology and frequency to those noted in other severe acute respiratory infections, namely influenza A H1N1 (109) and SARS (110, 111). These generally included fever, new onset or exacerbation of cough, breathing difficulty, sore throat and muscle pain. Among critically ill patients usually presented with dyspnoea and chest tightness (20, 37, 69, 70), 141 (4.6%) of them with persistent or progressive hypoxia resultsed in the requirement of intubation and mechanical ventilation (112), while 194 (6.4%) of them required non-invasive ventilation, yielding a total of 11% of patients requiring ventilatory support, which was similar to SARS (113).

The major comorbidities identified in this review included hypertension, cardiovascular diseases and diabetes mellitus. Meanwhile, the percentages of patients with chronic renal diseases and cancer were relatively low. These chronic conditions influencing the severity of COVID-19 had also been noted to have similar effects in other respiratory illnesses such as SARS, MERS-CoV and influenza (114, 115). Higher mortality had been observed among older patients and those with comorbidities.

Early diagnosis of COVID-19 was based on recognition of epidemiological linkages; the presence of typical clinical, laboratory, and radiographic features; and the exclusion of other respiratory pathogens. The case definition had initially been narrow, but was gradually broadened to allow for the detection of more cases, as milder cases and those without epidemiological links to Wuhan or other known cases had been identified (116, 117). Laboratory investigations among COVID-19 patients did not reveal specific characteristics - lymphopenia and elevated inflammatory markers such as CRP are some of the most common haematological and biochemical abnormalities, which had also been noticed in SARS (118). None of these features were specific to COVID-19. Therefore, diagnosis should be confirmed by SARS-CoV–2 specific microbiological and serological studies, although initial management will continue to be based on a clinical and epidemiological assessment of the likelihood of a COVID-19 infection.

Radiology imaging often plays an important role in evaluating patients with acute respiratory distress; however, in this review, radiological findings of SARS-CoV-2 pneumonia were non- specific. Despite chest radiograph usually revealed bilateral involvement and Computed Tomography usually showed bilateral multiple ground-glass opacities or consolidation, there were also patients with normal chest radiograph, implying that chest radiograph might not have high specificity to rule out pneumonia in COVID-19.

Limited clinical data were available for asymptomatic COVID-19 infected persons. Nevertheless, asymptomatic infection could be unknowingly contagious (119). From some of the official figures, 6.4% of 150 non-travel-related COVID-19 infections in Singapore (120), 39.9% of cases from the Diamond Princess cruise ship in Japan (121), and up to 78% of cases in China as extracted on April 1st, 2020, were found to be asymptomatic (119). Asymptomatic infection intensifies the challenges of isolation measures. More global reports are crucially needed to give a better picture of the spectrum of presentations among all COVID-19 infected persons. Also, public health policies including social and physical distancing, monitoring and surveillance, as well as contact tracing, are necessary to reduce the spread of COVID-19.

Concerning potential treatment regime, 62.4% of patients received antivirals (including oseltamivir, lopinavir-ritonavir, interferon alfa), while 63.9% received antibiotics (such as moxifloxacin, and ceftriaxone). In this review, around one-third of patients were given steroid, suggestive as an adjunct to IFN, or sepsis management. Antiviral agents such as ribavirin, IFN-α, and lopinavir-ritonavir were used during SARS, and the initial uncontrolled reports then noted resolution of fever and improvement in oxygenation and radiographic appearance (110, 122, 123), without further evidence on its effectiveness. At the time of manuscript preparation, there has been no clear evidence guiding the use of antivirals (124). Further research is needed to inform clinicians of the appropriate use of antivirals for specific groups of infected patients.

Limitations of this meta-analysis should be considered. First, a high statistical heterogeneity was found, which could be related to the highly varied sample sizes (9 to 4,226 patients) and study designs. Second, variations of follow-up period may miss the event leading to heterogeneity. In fact, some patients were still hospitalized in the included studies. Third, since only a few studies had compared the comorbidities of severe and non-severe patients, sensitivity analysis and subgroup analysis were not conducted. Lastly, this meta-analysis reviewed only a limited number of reports, with a predominant patient population from China. This review is expected to inform clinicians of the epidemiology of COVID-19 at this early stage. A recent report estimated the number of confirmed cases in China could reach as high as 232,000 (95% CI: 161,000, 359,000) with the case definition adopted in 5th Edition. In this connection, further evidence on the epidemiology is in imminent need.

Declarations

Biographical Sketch

Dr Carlos KH Wong is an Assistant Professor (Research) at the University of Hong Kong, Hong Kong SAR, China, and is a statistician and methodologist.

Contributors

CW, JW and AW contributed equally to all aspects of study design, conduct, data interpretation, and the writing of the manuscript. CW, ET and CHA contributed to eligibility screening, data extraction from eligible studies, and data analysis and interpretation.

Declaration of interests

Authors have nothing to disclose.

Acknowledgements

None

References

  1. Oliveira N. Shrimp vendor identified as possible coronavirus 'patient zero,' leaked document says. 27 March 2020. New York Daily News.
  2. World Health Organization. Basic protective measures against the new 2020 [cited 16 April 2020]; Available from: https://www.who.int/emergencies/diseases/novel- coronavirus-2019/advice-for-public
  3. Google Trend. when will coronavirus end. 2020 [cited 29 March 2020 29 March 2020]; Available from:            https://trends.google.com/trends/explore?date=today%203- m&q=when%20will%20coronavirus%20end,%2Fm%2F01cpyy
  4. COVID-19 Coronavirus Pandemic. 2020 [cited 29 March 2020]; Available from: https://www.worldometers.info/coronavirus/
  5. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395(10224):565-74.
  6. Ralph R, Lew J, Zeng T, Francis M, Xue B, Roux M, et al. 2019-nCoV (Wuhan virus), a novel Coronavirus: human-to-human transmission, travel-related cases, and vaccine readiness. The Journal of Infection in Developing Countries. 2020 01/31;14(01).
  7. Sun Z, Thilakavathy K, Kumar SS, He G, Liu SV. Potential Factors Influencing Repeated SARS Outbreaks in China. Int J Environ Res Public Health. 2020;17(5):1633.
  8. Zhao S, Zhuang Z, Ran J, Lin J, Yang G, Yang L, et al. The association between domestic train transportation and novel coronavirus (2019-nCoV) outbreak in China from 2019 to 2020: A data-driven correlational report. Travel Medicine and Infectious Disease. 2020 2020/01/01/;33:101568.
  9. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia. New England Journal of Medicine. 2020;382(13):1199-207.
  10. Chen J. Pathogenicity and transmissibility of 2019-nCoV—A quick overview and comparison with other emerging viruses. Microbes and Infection. 2020 2020/03/01/;22(2):69-71.
  11. Organization WH. Database of publications on coronavirus disease (COVID-19). 2020 [cited 30 March 2020 30 March 2020]; Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel- coronavirus-2019-ncov
  1. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology. 2014 2014/12/19;14(1):135.
  2. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Archives of Public Health. 2014 2014/11/10;72(1):39.
  3. Harris RJ, Deeks JJ, Altman DG, Bradburn MJ, Harbord RM, Sterne JAC. Metan: Fixed- and Random-Effects Meta-Analysis. The Stata Journal. 2008 2008/04/01;8(1):3-28.
  4. Xu X, Yu C, Qu J, Zhang L, Jiang S, Huang D, et al. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging. 2020 May;47(5):1275-80.
  5. Cao J, Hu X, Cheng W, Yu L, Tu WJ, Liu Q. Clinical features and short-term outcomes of 18 patients with corona virus disease 2019 in intensive care unit. Intensive Care Med. 2020 Mar
  6. Xiong Y, Sun D, Liu Y, Fan Y, Zhao L, Li X, et al. Clinical and High-Resolution CT Features of the COVID-19 Infection: Comparison of the Initial and Follow-up Changes. Invest Radiol. 2020 Mar
  7. Arentz M, Yim E, Klaff L, Lokhandwala S, Riedo FX, Chong M, et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020 Mar
  8. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.
  9. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb
  10. Zhao D, Yao F, Wang L, Zheng L, Gao Y, Ye J, et al. A comparative study on the clinical features of COVID-19 pneumonia to other pneumonias. Clin Infect Dis. 2020 Mar
  11. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020 Feb 19;368:m606.
  1. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020 Feb 15;395(10223):514-23.
  2. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-13.
  3. Pung R, Chiew CJ, Young BE, Chin S, Chen MI, Clapham HE, et al. Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures. Lancet. 2020 Mar 28;395(10229):1039-46.
  4. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Feb
  5. Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020 Mar
  6. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020 Mar 7;395(10226):809-15.
  7. Huang WH, Teng LC, Yeh TK, Chen YJ, Lo WJ, Wu MJ, et al. 2019 novel coronavirus disease (COVID-19) in Taiwan: Reports of two cases from Wuhan, China. J Microbiol Immunol Infect. 2020 Feb
  8. Cheng SC, Chang YC, Fan Chiang YL, Chien YC, Cheng M, Yang CH, et al. First case of Coronavirus Disease 2019 (COVID-19) pneumonia in Taiwan. J Formos Med Assoc. 2020 Mar;119(3):747-51.
  9. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020 Mar 5;382(10):929-36.
  10. Wei M, Yuan J, Liu Y, Fu T, Yu X, Zhang ZJ. Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. JAMA. 2020 Feb
  11. Bernard Stoecklin S, Rolland P, Silue Y, Mailles A, Campese C, Simondon A, et al. First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures, January 2020. Euro Surveill. 2020 Feb;25(6).
  1. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020 Apr;20(4):425-34.
  2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-33.
  3. Ghinai I, McPherson TD, Hunter JC, Kirking HL, Christiansen D, Joshi K, et al. First known person-to-person transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the USA. Lancet. 2020 Apr 4;395(10230):1137-44.
  4. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62.
  5. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 Feb
  6. Kim JY, Choe PG, Oh Y, Oh KJ, Kim J, Park SJ, et al. The First Case of 2019 Novel Coronavirus Pneumonia Imported into Korea from Wuhan, China: Implication for Infection Prevention and Control Measures. J Korean Med Sci. 2020 Feb 10;35(5):e61.
  7. Okada P, Buathong R, Phuygun S, Thanadachakul T, Parnmen S, Wongboot W, et al. Early transmission patterns of coronavirus disease 2019 (COVID-19) in travellers from Wuhan to Thailand, January 2020. Euro Surveill. 2020 Feb;25(8).
  8. Arashiro T, Furukawa K, Nakamura A. COVID-19 in 2 Persons with Mild Upper Respiratory Symptoms on a Cruise Ship, Japan. Emerg Infect Dis. 2020 Jun 17;26(6).
  9. Lillie PJ, Samson A, Li A, Adams K, Capstick R, Barlow GD, et al. Novel coronavirus disease (Covid-19): The first two patients in the UK with person to person transmission. J Infect. 2020 Feb
  10. Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer. J Thorac Oncol. 2020 Feb
  11. Haveri A, Smura T, Kuivanen S, Osterlund P, Hepojoki J, Ikonen N, et al. Serological and molecular findings during SARS-CoV-2 infection: the first case study in Finland, January to February 2020. Euro Surveill. 2020 Mar;25(11).
  1. Nicastri E, D'Abramo A, Faggioni G, De Santis R, Mariano A, Lepore L, et al. Coronavirus disease (COVID-19) in a paucisymptomatic patient: epidemiological and clinical challenge in settings with limited community transmission, Italy, February 2020. Euro Surveill. 2020 Mar;25(11).
  2. Van Cuong L, Giang HTN, Linh LK, Shah J, Van Sy L, Hung TH, et al. The first Vietnamese case of COVID-19 acquired from China. Lancet Infect Dis. 2020 Apr;20(4):408-9.
  3. Spiteri G, Fielding J, Diercke M, Campese C, Enouf V, Gaymard A, et al. First cases of coronavirus disease 2019 (COVID-19) in the WHO European Region, 24 January to 21 February 2020. Euro Surveill. 2020 Mar;25(9).
  4. Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med. 2020 Mar 5;382(10):970-1.
  5. Tong ZD, Tang A, Li KF, Li P, Wang HL, Yi JP, et al. Potential Presymptomatic Transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis. 2020 May 17;26(5).
  6. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020 Feb
  7. Yu P, Zhu J, Zhang Z, Han Y, Huang A familial cluster of infection associated with the 2019 novel coronavirus indicating potential person-to-person transmission during the incubation period. J Infect Dis. 2020 Feb 18.
  8. Li P, Fu JB, Li KF, Chen Y, Wang HL, Liu LJ, et al. Transmission of COVID-19 in the terminal stage of incubation period: a familial cluster. Int J Infect Dis. 2020 Mar
  9. Tang A, Tong ZD, Wang HL, Dai YX, Li KF, Liu JN, et al. Detection of Novel Coronavirus by RT-PCR in Stool Specimen from Asymptomatic Child, China. Emerg Infect Dis. 2020 Jun 17;26(6).
  10. Kam KQ, Yung CF, Cui L, Lin Tzer Pin R, Mak TM, Maiwald M, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020 Feb
  11. Zhou S, Wang Y, Zhu T, Xia L. CT Features of Coronavirus Disease 2019 (COVID-19) Pneumonia in 62 Patients in Wuhan, China. AJR Am J Roentgenol. 2020 Mar 5:1-8.
  1. Zhao W, Zhong Z, Xie X, Yu Q, Liu J. Relation Between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19) Pneumonia: A Multicenter Study. AJR Am J Roentgenol. 2020 Mar 3:1-6.
  2. Cheng Z, Lu Y, Cao Q, Qin L, Pan Z, Yan F, et al. Clinical Features and Chest CT Manifestations of Coronavirus Disease 2019 (COVID-19) in a Single-Center Study in Shanghai, China. AJR Am J Roentgenol. 2020 Mar 14:1-6.
  3. Chung M, Bernheim A, Mei X, Zhang N, Huang M, Zeng X, et al. CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV). Radiology. 2020 Apr;295(1):202-7.
  4. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020 Feb
  5. Chang, Lin M, Wei L, Xie L, Zhu G, Dela Cruz CS, et al. Epidemiologic and Clinical Characteristics of Novel Coronavirus Infections Involving 13 Patients Outside Wuhan, China. JAMA. 2020 Feb
  6. COVID-19 National Incident Room Surveillance Team. COVID-19, Australia: Epidemiology Report 7 (Reporting week ending 19:00 AEDT 14 March 2020). Commun Dis Intell (2018). 2020 Mar 19;44.
  7. Pan F, Ye T, Sun P, Gui S, Liang B, Li L, et al. Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia. Radiology. 2020 Feb 13:200370.
  8. Wang S, Guo L, Chen L, Liu W, Cao Y, Zhang J, et al. A case report of neonatal COVID-19 infection in China. Clin Infect Dis. 2020 Mar
  9. Bastola A, Sah R, Rodriguez-Morales AJ, Lal BK, Jha R, Ojha HC, et al. The first 2019 novel coronavirus case in Nepal. Lancet Infect Dis. 2020 Mar;20(3):279-80.
  10. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis. 2020 Mar
  11. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Feb
  12. Ye G, Pan Z, Pan Y, Deng Q, Chen L, Li J, et al. Clinical characteristics of severe acute respiratory syndrome coronavirus 2 reactivation. J Infect. 2020 Mar
  1. Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020 Mar;63(3):364-74.
  2. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020 Mar 26;368:m1091.
  3. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis. Eur Respir J. 2020 Mar 26:2000547.
  4. Wong HYF, Lam HYS, Fong AH, Leung ST, Chin TW, Lo CSY, et al. Frequency and Distribution of Chest Radiographic Findings in COVID-19 Positive Patients. Radiology. 2019 Mar 27:201160.
  5. Xu T, Chen C, Zhu Z, Cui M, Chen C, Dai H, et al. Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19. Int J Infect Dis. 2020 Mar
  6. Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 Mar
  7. Kimball A, Hatfield KM, Arons M, James A, Taylor J, Spicer K, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility - King County, Washington, March 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 3;69(13):377-81.
  8. CDC COVID-Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-6.
  9. Wu J, Liu J, Zhao X, Liu C, Wang W, Wang D, et al. Clinical Characteristics of Imported Cases of COVID-19 in Jiangsu Province: A Multicenter Descriptive Study. Clin Infect Dis. 2020 Feb
  10. Yang W, Cao Q, Qin L, Wang X, Cheng Z, Pan A, et al. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China. J Infect. 2020 Apr;80(4):388-93.
  1. Zhu L, Xu X, Ma K, Yang J, Guan H, Chen S, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant. 2020 Mar
  2. Zhu W, Xie K, Lu H, Xu L, Zhou S, Fang S. Initial clinical features of suspected coronavirus disease 2019 in two emergency departments outside of Hubei, China. J Med Virol. 2020 Mar
  3. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Mar 13.
  4. Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends. 2020 Mar 16;14(1):64-8.
  5. Wang Y, Liu Y, Liu L, Wang X, Luo N, Ling L. Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-Coronavirus-2 in Shenzhen, China. J Infect Dis. 2020 Mar
  6. Wan S, Xiang Y, Fang W, Zheng Y, Li B, Hu Y, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol. 2020 Mar
  7. Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. J Infect. 2020 Apr;80(4):401-6.
  8. Sun D, Li H, Lu XX, Xiao H, Ren J, Zhang FR, et al. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study. World J Pediatr. 2020 Mar
  9. Song F, Shi N, Shan F, Zhang Z, Shen J, Lu H, et al. Emerging 2019 Novel Coronavirus (2019-nCoV) Pneumonia. Radiology. 2020 Apr;295(1):210-7.
  10. Hu Z, Song C, Xu C, Jin G, Chen Y, Xu X, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci. 2020 Mar
  11. Qu R, Ling Y, Zhang YH, Wei LY, Chen X, Li XM, et al. Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19. J Med Virol. 2020 Mar
  1. Qian GQ, Yang NB, Ding F, Ma AHY, Wang ZY, Shen YF, et al. Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang, China: A retrospective, multi-centre case series. QJM. 2020 Mar
  2. Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis. 2020 Mar
  3. Liu W, Tao ZW, Lei W, Ming-Li Y, Kui L, Ling Z, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J (Engl). 2020 Feb
  4. Liu K, Chen Y, Lin R, Han K. Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J Infect. 2020 Mar
  5. Liu F, Xu A, Zhang Y, Xuan W, Yan T, Pan K, et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis. 2020 Mar 12.
  6. Liu D, Li L, Wu X, Zheng D, Wang J, Yang L, et al. Pregnancy and Perinatal Outcomes of Women With Coronavirus Disease (COVID-19) Pneumonia: A Preliminary Analysis. AJR Am J Roentgenol. 2020 Mar 18:1-6.
  7. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A, et al. Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant. 2020 Mar
  8. Dong X, Cao YY, Lu XX, Zhang JJ, Du H, Yan YQ, et al. Eleven faces of coronavirus disease 2019. Allergy. 2020 Mar
  9. Fan C, Lei D, Fang C, Li C, Wang M, Liu Y, et al. Perinatal Transmission of COVID-19 Associated SARS-CoV-2: Should We Worry? Clin Infect Dis. 2020 Mar
  10. Chen R, Zhang Y, Huang L, Cheng BH, Xia ZY, Meng QT. Safety and efficacy of different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a case series of 17 patients. Can J Anaesth. 2020 Mar
  11. Chen L, Liu W, Zhang Q, Xu K, Ye G, Wu W, et al. RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak. Emerg Microbes Infect. 2020;9(1):313-9.
  12. Chen J, Qi T, Liu L, Ling Y, Qian Z, Li T, et al. Clinical progression of patients with COVID-19 in Shanghai, China. J Infect. 2020 Mar
  1. Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and influenza virus in Wuhan, China. J Med Virol. 2020 Mar
  2. Covid-19 National Emergency Response Center E, Case Management Team KCfDC, Prevention. Early Epidemiological and Clinical Characteristics of 28 Cases of Coronavirus Disease in South Korea. Osong Public Health Res Perspect. 2020 Feb;11(1):8-14.
  3. Li Y, Guo F, Cao Y, Li L, Guo Y. Insight into COVID-2019 for pediatricians. Pediatr Pulmonol. 2020 Mar
  4. Ai JW, Zhang Y, Zhang HC, Xu T, Zhang WH. Era of molecular diagnosis for pathogen identification of unexplained pneumonia, lessons to be learned. Emerg Microbes Infect. 2020;9(1):597-600.
  5. Khan N. New Virus Discovered by Chinese Scientists Investigating Pneumonia Outbreak. Wall Street Journal.
  6. 国家统计局 (National Bureau of Statistics). 2019 年国民经济运行总体平稳 发展主要预期目标较好实现 (In 2019, the overall stable development of the national economic operation is expected to achieve the main goals). 2020 [cited; Available from: http://www.stats.gov.cn/tjsj/zxfb/202001/t20200117_1723383.html
  1. Park JE, Jung S, Kim A, Park JE. MERS transmission and risk factors: a systematic review. BMC Public Health. 2018 May 2;18(1):574.
  2. Van Kerkhove MD, Vandemaele KA, Shinde V, Jaramillo-Gutierrez G, Koukounari A, Donnelly CA, et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLoS Med. 2011 Jul;8(7):e1001053.
  3. Wang C, Yu E, Xu B, Wang W, Li L, Zhang W, et al. Epidemiological and clinical characteristics of the outbreak of 2009 pandemic influenza A (H1N1) at a middle school in Luoyang, China. Public Health. 2012 2012/04/01/;126(4):289-94.
  4. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 May 15;348(20):1986-94.
  5. Booth CM, Matukas LM, Tomlinson GA, Rachlis AR, Rose DB, Dwosh HA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003 Jun 4;289(21):2801-9.
  1. Fowler RA, Lapinsky SE, Hallett D, Detsky AS, Sibbald WJ, Slutsky AS, et al. Critically ill patients with severe acute respiratory syndrome. JAMA. 2003 Jul 16;290(3):367-73.
  2. Christian MD, Poutanen SM, Loutfy MR, Muller MP, Low DE. Severe acute respiratory syndrome. Clin Infect Dis. 2004 May 15;38(10):1420-7.
  3. Mertz D, Kim TH, Johnstone J, Lam PP, Science M, Kuster SP, et al. Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis. Bmj-Brit Med J. 2013 Aug 23;347:f5061.
  4. Badawi A, Ryoo SG. Prevalence of comorbidities in the Middle East respiratory syndrome coronavirus (MERS-CoV): a systematic review and meta-analysis. Int J Infect Dis. 2016 Aug;49:129-33.
  5. Tsang TK, Wu P, Lin Y, Lau EHY, Leung GM, Cowling BJ. Impact of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China. medRxiv. 2020.
  6. 国家卫生健康委办公厅(Office of National Health Comission). 新型冠状病毒肺炎诊疗方案( 试行第七版)(Clinical Guideline for  Novel Coronavirus Pneumonia -  Interim 7th Edition). 2020.
  1. File TM, Jr., Tsang KW. Severe acute respiratory syndrome: pertinent clinical characteristics and therapy. Treat Respir Med. 2005;4(2):95-106.
  2. Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ. 2020 Apr 2;369:m1375.
  3. Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. Morbidity and Mortality Weekly Report.
  4. Mizumoto K, Kagaya K, Zarebski A, Chowell G. Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board the Diamond Princess cruise ship, Yokohama, Japan, 2020. Euro Surveill. 2020 Mar;25(10):2000180.
  5. Poutanen SM, Low DE, Henry B, Finkelstein S, Rose D, Green K, et al. Identification of severe acute respiratory syndrome in Canada. N Engl J Med. 2003 May 15;348(20):1995-2005.
  1. Tsang KW, Ho PL, Ooi GC, Yee WK, Wang T, Chan-Yeung M, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003 May 15;348(20):1977- 85.
  2. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 Mar

Tables

Due to technical limitations, Table 1 is only available as a download in the supplemental files section